The Effectiveness of Traditional Chinese Medicine (TCM) as an Adjunct Treatment on Stable COPD Patients: A Systematic Review and Meta-Analysis

Background Traditional Chinese medicine (TCM), including Chinese herbal medicine (CHM) and acupuncture, exhibits beneficial effects on stable chronic obstructive pulmonary disease (COPD) such as improving lung function and reducing exacerbation. Previous research studies have examined either CHM or acupuncture alone, which are not the usual practice in TCM clinic setting. We conduct a systematic review for evaluating the clinical effectiveness and safety of TCM by combining CHM and acupuncture. Methods Databases are searched from inception to November 2019. Randomized controlled trials examining either acupuncture or CHM on stable COPD are included. Primary outcomes include lung functions, exacerbations, and COPD assessment test. Secondary outcomes include quality of life, TCM syndrome score and effective rate, and 6-minute walk distance. Two independent reviewers extract data and assess the quality of evidence and generate meta-analysis and risk of bias by STATA. This protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. Results 100 randomized controlled trials (8291 participants) were included to compare add-on Chinese medicine treatment with conventional treatment (CT). Combining CHM with CT improves FEV1 (MD: 0.18, 95% CI: 0.08, 0.28), exacerbation rate (MD: −0.29, 95% CI: −0.61, 0.03), COPD assessment test (MD: −2.16, 95% CI: −3.44, -0.88), TCM syndrome score (MD: −3.96, 95% CI: −5.41, −2.51) and effective rate (RR: 0.89, 95% CI: 0.80, 0.93), and 6-minute walk test (MD: 37.81, 95% CI: 20.90, 54.73). No serious adverse events were reported. Risk of bias: low to unclear. Conclusions This review identifies sufficient moderate-to-low-quality evidence to suggest TCM as an adjunct treatment for stable COPD patients. Though heterogeneity was low among studies, the results were limited and the quality of evidence was low or very low based on small sample sizes and risk of bias. Future studies with larger sample sizes are warranted. The trial is registered with CRD42019161324.


Introduction
Chronic obstructive pulmonary disease (COPD) is a common, treatable, and preventable disease, which is characterized by chronic respiratory symptoms and airflow limitation owing to airway and/or alveolar abnormalities caused by persistent exposure to noxious gases or molecules. e major known pathogenesis of COPD is a complex mixture of small airway disease, parenchymal destruction, and chronic airway and/or systemic inflammation.
COPD is an important cause of chronic morbidity and mortality in the world, which ranks the fourth in the leading cause of death and is projected to be the third by 2020 [1,2]. It is a common, preventable, and treatable disease but poses an economic burden on the society. COPD patients are usually characterized by persistent respiratory symptoms and airflow limitation. Occasionally, they may have acute exacerbation induced by respiratory infection and increase the hospitalization and readmission rate.
Current COPD prevalence data show significant differences among countries, probably because of different diagnostic criteria, survey techniques, and analytical methods [3].
e Burden of Obstructive Lung Diseases (BOLD) program has reported the prevalence and risk factors for COPD in people aged ≥40 in more than 29 countries and found that COPD is more common in men than women [4,5]. Up to now, there are around three million deaths per year [6]. e prevalence of COPD is predicted to rise in the coming 30 years, and by 2030, there might be over 4.5 million deaths per year from COPD and comorbidities [7,8].
Diagnosis of COPD is primarily by spirometry which measures the patient's airflow limitation. It is the most widely accepted, easily available, and reproducible test of lung function. A ratio of postbronchodilator forced expiratory volume in first second (FEV 1 )/forced vital capacity (FVC) <0. 70 confirms the presence of persistent airflow limitation [9]. Main symptoms include dyspnea, chronic cough, chronic sputum production, wheezing, and chest tightness. But the severity of airflow limitation is weakly correlated with symptoms in clinical context [10], and spirometry itself has a relatively low specificity [11]. So other symptom assessments are required to categorize COPD patients, which commonly include the Modified British Medical Research Council (mMRC) Questionnaire [12] and COPD Assessment Test (CAT TM ) [13][14][15].
ere are three classifications of exacerbations: mild (short-acting bronchodilators (SABDs) only), moderate (SABDs plus antibiotics and/or oral corticosteroids), and severe (hospitalization or visiting emergency room). e best indicator of frequent exacerbations (defined as two or more exacerbations per annum) is a history of earlier treated events [20]. Apart from these tests, physical exercise measurements, such as paced shuttle walk test and the unpaced 6-minute walk test, are also suggested for monitoring patient health status and predicting prognosis [21][22][23].
For stable COPD, the goals of pharmacological therapy are to reduce symptoms, reduce the frequency and severity of exacerbations, and improve health status and exercise tolerance. Apart from smoking cessation and vaccinations, there are two major classes of medications: bronchodilators and anti-inflammatory drugs. Bronchodilators can increase FEV 1 and/or modify other spirometric values and are usually prescribed regularly to prevent or reduce symptoms. Commonly used bronchodilators include short-acting and long-acting beta 2 -agonists (SABA and LABA, respectively) and short-acting and long-acting anticholinergics (SAMA and LAMA, respectively) [24][25][26][27].
Traditional Chinese medicine (TCM) has been using to treat symptoms similar to those in COPD, for instance, cough, sputum, or shortness of breath and has shown beneficial effects for over hundreds of decades. However, there is no such a disease term as COPD in TCM. Instead, COPD patients are classified as having "Fei Zhang" with reference to TCM theory [28]. In a normal TCM clinical setting, either Chinese herbal medicine, acupuncture, or the combination of both is used to relieve COPD symptoms and improve lung functions and/or exercise tolerance [29][30][31][32].
TCM is very different from contemporary medicine in both diagnosis and treatment methods. Commonly used TCM treatments include herbal medicinal formula, acupuncture, moxibustion, Tuina, or the combination of them. In a daily TCM healthcare setting, patients with COPD symptoms are often given a set of treatments such as acupuncture/moxibustion, or acupuncture/medicinal formula. Most RCTs for TCM treatments were conducted only on several acupoints, or a single herb or formulae, which is not similar to the usual TCM practice. is study aims to examine the effectiveness and adverse effects of adding TCM treatments on western medicine in stable COPD, to synthesize the best available data towards recommendations of optimal treatment. e primary objective of this study is to measure the effectiveness of TCM as an adjunct treatment on stable COPD patients in any setting and the adverse events associated with its use in clinical trials measured by lung function and exacerbation rate. e secondary objective of this study is to compare the efficacy of either herbal medicine, acupuncture, or the combination of both on treating stable COPD patients reflected by TCM syndrome score and health status. requested, and unpublished clinical trials with online results available were included.

Types of Excluded Studies.
Abstracts alone, nonrandomized trials, case reports, cohort studies, case-control studies, cross-sectional studies, retrospective surveys or chart reviews, editorials, commentaries, and clinical observations were excluded from this systematic review. Other systematic reviews were not included, but the reference lists of similar were searched.

Types of Included Participants.
Our search was designed to include (1) patients who were 18 years old or above, regardless of sex, education, race, and socioeconomic status, and (2) patients who were diagnosed with stable COPD according to the diagnostic criteria from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [6]. Stable COPD patients were defined as patients having mild cough, expectoration, and dyspnea.

Types of Excluded Participants.
We excluded patients with other diseases such as asthma, tuberculosis, bronchiolitis, congestive heart failure, or other severe complications because we only wanted to examine the efficacy of TCM on stable COPD.

Types of Interventions.
We included any herbal drugs, extracted active ingredients, or formula administered orally, which could be either in a form of TCM granules or boiled soup, and compared to no treatment, placebo, or any active comparator plus conventional medicine. We also included any acupuncture treatment, or dry needling, using any acupoint combinations, and compared to no treatment, placebo, or any active comparator plus conventional medicine. Studies in any healthcare and any global setting were included. Interventions either alone or in combination with each other were included.

Types of Outcome Measures
Primary Outcomes. We included the following items as primary outcomes: (1) lung functions by measuring the change in FEV 1 [35]; (2) exacerbations defined as time-tofirst exacerbation or exacerbation rate [6]; (3) COPD assessment test [36]; and (4) adverse events of any cause.
Secondary Outcomes. As an assessment of COPD patients' quality of life, we included quality of life such as sleep patterns, mood, and mental health and physical exercise regime on a validated scale; (2) TCM syndrome score and effective rate [37]; and (3) 6-minute walk distance [38]  e risk of bias was assessed at the individual study level and the risk of bias was also considered when assessing Grading of Recommendations, Assessment, Development, and Evaluation system (GRADE) [40]. ese seven domains were assessed for each included study as outlined by the Cochrane Handbook for Systematic Reviews of Interventions [32]: (1) Random sequence generation (examine potential selection bias): studies were assessed for the methods used to generate the allocation sequence (2) Allocation concealment (examine potential selection bias): studies were assessed for the methods used to conceal allocation to interventions before the study starts (3) Blinding of participants and personnel (examine potential performance bias): studies were assessed for methods used to blind the participants and personnel from knowing which intervention a participant would receive (4) Blinding of outcome assessment (examine potential detection bias): studies were assessed for methods used to blind the outcome assessors from knowing which intervention a participant would receive (5) Incomplete outcome data (examine potential attrition bias): studies were assessed for the nature, number, and handling of incomplete outcome data (6) Selective reporting (examine potential reporting bias): studies were assessed whether all planned outcomes were reported in the results (7) Other bias: studies were assessed for any additional sources of bias as low, unclear, or high and provided rationale

Assessment of Heterogeneity.
To evaluate clinical heterogeneity, only studies with similar conditions and treatments were compared to get a clinically useful result [32]. Statistical heterogeneity was assessed visually [41] with the I 2 statistic and p value. If I 2 was larger than 50%, possible reasons were discussed [32].

Data Synthesis.
e meta-analysis was conducted on extracted data using STATA (version 16) using a randomeffects model. Binary data were expressed as risk ratio with 95% confidence intervals (CIs) and were analyzed by Mantel-Haenszel method. For continuous variables, mean difference (MD) with 95% CIs are calculated. Heterogeneity was examined by I 2 tests.
Quality of Evidence. GRADE was used to assess the quality of evidence related to each outcome measure and to provide recommendations for clinical practice [32,40]. A GRADE rating was assigned for each primary and secondary outcome using the four key levels: high, moderate, low, or very low quality, with reasons provided to upgrade or downgrade [40]. Under certain circumstances, the overall GRADE rating might require adjustment. For instance, a study reported very small sample sizes and results were at risk of being down to play of chance [42]. On the other hand, if no data were reported for an outcome, the term "no evidence" or "lack of evidence" could imply there were data and that the results might show no evidence of effect.

Subgroup Analysis.
Subgroup analyses were performed to assess factors such as different TCM dosage, forms, duration of treatment, acupoints used, and measurements of results to see whether they have any impact on the effect estimate. Sensitivity analysis was conducted to examine heterogeneity. e effect of methodological quality, sample size, or missing data was also considered. Analysis was repeated after removing methodologically low-quality studies. If more than ten studies were selected, the Egger regression test was used to assess any possible publication bias [43].

Ethical Considerations.
ere were no ethical issues or approvals needed for this type of study as it used aggregate data already anonymized.

Study Identification.
e PRISMA study flowchart of search results is shown in Figure 1.
Updated on 1 March 2020, a total of 7124 records are identified from databases and 0 records are found from other sources. After removing duplicates, 6792 titles and abstracts are screened and 323 full-text articles are obtained. Among them, 100 articles are included and 223 are excluded with reasons provided in Appendix 7. No studies are ongoing or under assessment. Table 2 summarizes the basic characteristics of 100 included studies. We report sample sizes, ages, course of the disease, and gender for control and intervention groups. Types of Chinese medicine, treatment duration, baseline difference, and quality control are also listed.

Design.
All studies are randomized, double-blind, and controlled clinical trials and report primary and secondary outcomes.

Participants.
All studies recruit participants according to the GOLD guidelines [6], and all participants are in stable phase with stages between II and IV. e course of disease (in years) ranges from 3.03 ± 0.38 (mean ± SE) [58] to 33.57 ± 10.97 in the control group [28] and from 3.05 ± 0.37 [58] to 33.26 ± 9.41 [28] in the intervention group. irty studies do not report the course of years shown in Table 2.

Setting and Location.
All studies are single-centered trials and based in hospital settings. e location of studies scatters across different provinces in China.

Interventions
Comparison Arms. ere is no acupuncture plus conventional medicine versus conventional treatment (CT) identified. Ninety-nine studies compare one Chinese herbal medicine (CHM) formulae plus CT with conventional medicine. One study has three arms: conventional medicine, CHM decoction plus CT, and CHM powder plus CT [48].
Types of Chinese Medicine. One hundred different CHM formulae are used and detailed compositions and dosages of each formula are shown in Appendix 6. Conventional medicine is prescribed with reference to GOLD guidelines.

Duration of Treatment.
e duration of treatment differs across studies, which ranges from 1 week [59] to 42 weeks [60]. e mean duration of treatment is 14 weeks. Two studies do not report the duration of treatment [61,62]. Table 3 summarizes the availability of outcome measures reported. Forty studies report a change in FEV 1 (mean ± SE). irteen studies report exacerbation rate (mean ± SE) as a continuous outcome at the study endpoint. Twenty studies report COPD assessment test (mean ± SE). Twenty-five studies report 6-minute walk test (mean ± SE).

Outcomes.
irty-five studies report TCM syndrome score (mean ± SE) and sixty-two studies report TCM effective rate as dichotomous outcome. For quality of life, seventeen studies report in different QoL scales (mean ± SE), including SGRQ and COPD quality of life. Only one study reports all withdrawals [63]. Eight studies report adverse events of any cause with reason provided. One study reports withdrawals due to lack of efficacy [56]. irteen studies report none of the primary and secondary outcomes.

Language.
One full text is written in English. e remaining 99 full texts are written in Chinese and are translated by KH (myself ).

Description of Excluded Studies.
Two hundred and twenty-three studies are excluded after reading the full-text articles. Detailed exclusion reasons for each study are shown in Appendix 7.
Sixty-four studies (29%) are excluded because the participants are not stable COPD patients, or there is no evidence to indicate the disease phase.
Ninety-seven studies (43%) are excluded due to interventions. Reasons include that (1) CHM is not administered in the form of decoction or granules, (2) intervention group does not combine with conventional treatment, (3) intervention is not CHM or acupuncture, and (4) there is more than one CHM treatment.
Nine studies (4%) are excluded in the absence of control group or conventional treatment. Twelve studies (6%) do not report the wanted primary and secondary outcomes or do not use "intention-to-treat" analysis.
Forty-one studies (18%) are not included in the light of study designs, with reasons being not randomized or no such evidence.

Risk of Bias Summary of Included Studies.
e risk of bias summary diagram shows the risk of bias for all included studies from low to unclear (Table 4). No study shows a low Evidence-Based Complementary and Alternative Medicine risk of bias in all six domains. Two studies (2%) show a high risk of bias in one domain [51,56]. Ninety-nine studies (99%) display unclear risk of bias in four domains and one study (1%) shows unclear risk in two domains [63].

Random Sequence Generation (Selection Bias).
All studies describe their randomization methods which are mostly random number generation by 1 : 1 ratio (low risk).

Allocation Concealment (Selection Bias).
All studies do not report information about the concealment method of what types of treatment are given to participants (unclear risk).

Blinding of Participants and Personnel (Performance Bias).
Ninety-nine studies (99%) provide no information on how participants and research personnel are blinded (unclear risk). One study reports adequately the blinding procedures of both participants and personnel (low risk) [63].

Blinding of Outcome Assessors (Detection Bias).
Ninety-nine studies (99%) provide no information how participants and research personnel are blinded (unclear risk). One study reports adequately the blinding procedures of both participants and personnel (low risk) [63].

Outcome Measures.
One hundred studies are included with a total of 8,318. Forty studies report change in FEV 1 .
irteen studies report exacerbation rate at the study endpoint. Twenty studies report COPD assessment test.   Evidence-Based Complementary and Alternative Medicine    irty-five studies report TCM syndrome score and sixty-two studies report TCM effective rate as dichotomous outcome. Seventeen studies report various QoL scales. Eleven studies report all withdrawals. Eight studies report adverse events of any cause with reason provided. One study reports withdrawals due to lack of efficacy. irteen studies report none of the primary and secondary outcomes. 1 . Forty studies report the mean and standard error (SE) of FEV 1 (in liters) at baseline and endpoint of the study. Data are converted to standard deviation (SD) and meta-analyzed in Figure 2.

Primary Outcome: Change in FEV
e results are presented as mean change in FEV 1 and SD. e effect estimate is 0.18 (95% CI: 0.08, 0.28; p ≤ 0.001) with I 2 � 0.0% (p � 1.000), which means intervention significantly increases FEV 1 by 0.18 liter with zero heterogeneity.
GRADE: the overall quality of this evidence is judged to be moderate, downgraded once for risk of bias and once for imprecision.

Primary Outcome: Exacerbation Rate.
irteen studies reported the mean exacerbation rate and standard error at the endpoint of the study. Data are converted to standard deviation (SD) and meta-analyzed in Figure 3. e effect estimate was −0.29 (95% CI: −0.61, 0.03; p � 0.075733) with I 2 � 0.0% (p � 0.455).
GRADE: the overall quality of this evidence is judged to be very low, downgraded once for risk of bias, once for imprecision, and once for too few data from included studies. Evidence-Based Complementary and Alternative Medicine

Primary Outcome: COPD Assessment Test.
Twenty studies report COPD assessment test (CAT) with mean and standard error. Data are converted to standard deviation (SD) and meta-analyzed in Figure 4. e effect estimate is −2.16 (95% CI: −3.44, −0.88; p ≤ 0.001) with I 2 � 0.0% (p � 0.982). Adding on CHM with conventional medicine significantly reduces the score of CAT. GRADE: the overall quality of this evidence is judged to be low, downgraded once for risk of bias and once for imprecision.

Primary Outcome: Adverse Events of Any Cause.
Eight studies report adverse events of any cause and data are summarized in Table 5. Of these, four studies have no adverse events throughout the study period [28,[66][67][68]. Wang reports 2 cases of nausea, Liu reports 1 case of mouth dryness, and Huang reports 3 cases of acute exacerbation with hospitalization. Hong reports 2 epigastric discomfort and 1 diarrhea in the control group and 1 pale yellow phlegm in the intervention group.
GRADE: the overall quality of this evidence is judged to be low, downgraded once for risk of bias and once for imprecision.
GRADE: the overall quality of this evidence is judged to be very low, downgraded once for risk of bias, once for inconsistency, and once for imprecision.

Secondary Outcome: TCM Syndrome Score and Effective Rate.
irty-five studies reported total TCM syndrome score in mean plus standard error and sixty-two studies reported TCM effective rate as a number of events in each group. Data were converted to mean plus standard error and risk ratio. Meta-analysis results are presented in Figures 6 and 7, respectively. e total TCM syndrome score was reduced after adding CHM (effect estimate: MD: −3.96, 95% CI: −5.41, −2.51, p < 0.00001) with I 2 � 0.0% (p � 0.915). e effect estimate for TCM effective rate was 0.89 (95% CI: 0.86, 0.93, p < 0.00001) with heterogeneity � 0.0% (p � 1.000).
GRADE: the overall quality of this evidence is judged to be moderate, downgraded once for risk of bias and once for imprecision.

Secondary Outcome: 6-Minute Walk Test.
Twenty-five studies reported 6-minute walk test and data were reported as mean distance (in meters) and standard   GRADE: the overall quality of this evidence is judged to be low, downgraded once for risk of bias and once for imprecision.

Publication Bias. Publication bias was examined using
Egger's test in TCM effective rate from 62 studies. e p value is 0.011 (Figure 9), which means there was a small study effect and might influence the interpretation of the summary estimate.

Summary of Evidence.
is systematic review evaluates the available evidence in English and Chinese of combining Traditional Chinese medicine (including Chinese herbal medicine and acupuncture) with conventional medicine on treating stable chronic obstructive pulmonary disease patients. Although there is no high-quality evidence identified, we have low-to-moderate quality randomized controlled trials with 8291 participants to suggest that it might be beneficial to incorporate TCM into conventional treatment.
is review included 100 double-blinded, randomized controlled trials (8291 participants), with one comparison arm: Chinese herbal medicine plus conventional medicine versus conventional medicine only. e overall risks of bias for these studies are low to unclear. Reasons include (1) unclear reporting of allocation concealment, (2) no detailed information on blinding of participants, personnel, and outcome assessors, and (3) lack of methods reporting how to deal with missing data.
For primary outcomes, there are 40 studies showing the addition of TCM improved the force expiratory volume in 1 s (mean change: 0.18 (L), 95% CI: 0.08, 0.28, I 2 : 0.0%). But there are few reports about exacerbation rate, only 13 studies were meta-analyzed and the summary effect showed no reduction in acute exacerbation (mean change: −0.29, 95%  Only eight studies reported a total of 10 adverse events, including gastrointestinal symptoms such as nausea, mouth dryness, epigastric discomfort, diarrhea, and respiratory symptoms such as pale yellow phlegm and acute exacerbation with hospitalization. Ten studies were excluded from this review because they did not perform "intention-to-treat" analysis when facing withdrawals. Only one study reported 2 withdrawals in the TCM + CT group and 3 in the CT group, which were mostly lost during treatment. No studies reported adverse effects of either Chinese herbal medicine or acupuncture.   16 Evidence-Based Complementary and Alternative Medicine GRADE: the outcomes change in FEV1, TCM syndrome score, and effective rate were rated as moderate. is implies there is some confidence in the effect estimate, and the true effect is likely to be close to the estimate of effect, but there is a chance that it is substantially different. Future research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate [40]. e outcomes COPD assessment test, adverse events of any cause, all withdrawals of study participants, and 6-minute walk test were judged to be low-quality evidence. is   Evidence-Based Complementary and Alternative Medicine implies there is limited confidence in the effect estimate and the true effect may be substantially different from the estimate of effect. Future research is very likely to change the estimate of effect or impact the confidence in the estimate of effect [40]. e outcomes exacerbation rate, withdrawals due to a lack of efficacy, and quality of life were rated as very lowquality evidence. is implies there is very little confidence in the effect estimate between types of treatments and the true effect is likely to be substantially different from the estimate of effect. e results of these outcomes are very uncertain and the effect estimate is not accurate enough to recommend any use of Chinese herbal medicine [40]. In summary, the body of evidence suggests that adding Chinese herbal medicine to conventional treatment may be beneficial in stable COPD patients.

Strengths of is Review.
A major strength of this review is we strictly included level 1 evidence of double-blinded RCTs only. is review does not include studies where participants have both acute exacerbated and stable chronic obstructive pulmonary disease and any complicated diseases. Previous systematic reviews report either one single herb extract or formulae, or one specific TCM syndrome-related treatment method [32,67,[84][85][86][87][88][89][90][91]. However, this is not the usual practice of traditional Chinese medicine. In both outpatient and inpatient settings, TCM uses various formula or acupoints combination according to syndrome differentiation even in the same stable COPD population.
is review identifies the add-on effect of any formation of Chinese herbal medicine with different TCM syndromes in comparison with conventional medicine only. is fills the gaps between the normal use of TCM and contemporary research in treating stable COPD patients.
is review identifies the need for high-quality doubleblinded randomized controlled trials with more participants in each arm and more detailed reporting of research methods (randomization and blinding of participants and accessors).

Limitations of is Review.
e key methodological limitation to this review was the language restriction, and only Chinese and English literature studies were searched. We believed there were studies written in other languages such as Korean and Japanese, where Chinese herbal medicine and acupuncture were often used. A more comprehensive review might be needed to include all languages. A second limitation to this review was the broad inclusion criteria of herbal formulae or drugs and treatment duration. is would limit the specificity analysis of a certain herb or formulae, as we generally analyzed CHM as an adjunct treatment to conventional medicine. is might also limit the usage of CHM in clinical situation because we would need a registered Chinese medicine practitioner to diagnose with syndrome differentiation. Subgroup analyses were planned but could not be done in this review as there were too many combinations of herbal drugs and treatment durations. It was unable to investigate whether any of these variables affected treatment efficacy.
A third limitation of this review was lacking studies with sample sizes larger than or equal to 200 participants per arm.

Implications for Clinical Practice.
Traditional Chinese medicine has been used to treat COPD-related symptoms over decades, yet its effectiveness and safety remain uncertain. Previous clinical studies reported either one single Chinese herbal formulae or one specific Chinese medicine treatment method. Considering there are numerous formulae or combinations of herbs that might be beneficial to stable COPD patients, it is difficult to use current evidence to guide the use of TCM in addition to conventional medicine.
Although we saw some statistical significance in several outcome parameters, it did not mean that there are real treatment effects clinically. Our data suggested that TCM combined with conventional treatment was beneficial in FEV 1 , COPD assessment test, 6-minute walk distance, and TCM syndrome statistically. Clinicians may consider incorporating TCM into the mainstream medical system with reference to their own clinical experience.

Implications for Research.
High-quality randomized controlled clinical trials or pragmatic trials are needed. In order to provide real information for Chinese medicine practitioners, TCM theories and diagnoses must be taken into account when designing clinical research protocols and conducting trials.
More advanced analyses, like individual participant data and network meta-analysis, can be applied to provide more information on different combinations of herbal drugs and/ or acupuncture and generate personalized evidence with reference to TCM theories. Intention-to-treat LABA:

Abbreviations
Long-acting beta 2 -agonist LAMA: Long-acting anticholinergic MD: Mean difference MeSH: Medical subject headings mMRC: Modified British Medical Research Council mRCT: metaRegister of controlled trials PRISMA-P: Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols PROSPERO: Prospective register of systematic review QoL: Quality of life RCT: Randomized controlled trial SABA: Short-acting beta 2 -agonist SABD: Short-acting bronchodilator SAMA: Short-acting anticholinergic SD: Standard deviation SE: Standard error SGRQ: St. George's Respiratory Questionnaire SMD: Standardized mean difference TCM: Traditional Chinese medicine VIP: Chinese Scientific and Technological Periodical Database WHO: World Health Organization.

Data Availability
e clinical data used to support the findings of this study are included within the supplementary information files.

Disclosure
is study is part of the MSc dissertation of the first author (K. H. Chan). K. H. Chan is the lead investigator of this project.

Conflicts of Interest
e authors declare that there are no conflicts of interest.

Authors' Contributions
K. H. designed the research protocol, screened databases, extracted data, performed meta-analysis, and wrote the dissertation. Y. Y. S. acted as a second reviewer to screen titles and abstracts for eligibility and extracted data from included studies.