Herbal medicine (HM) as an adjunct therapy has been shown to be promising for the chronic obstructive pulmonary disease (COPD). However, the role of herbs in COPD remains largely unexplored. In this present study, we conducted the systematic review to evaluate the efficacy of herbs in COPD. 176 clinical studies with reporting pulmonary function were retrieved from English and Chinese database. Commonly used herbs for acute exacerbations stage (AECOPD) and stable COPD stage (SCOPD) were identified. A meta-analysis conducted from 15 high quality studies (18 publications) showed that HM as an adjunct therapy had no significant improvement in pulmonary function (FEV1, FEV%, FVC, and FEV1/FVC) compared to conventional medicine. The efficacy of the adjunct HM on improving the arterial blood gas (PaCO2 and PaO2) for AECOPD and SCOPD remains inconclusive due to the heterogeneity among the studies. However, HM as an adjunct therapy improved clinical symptoms and quality of life (total score, activity score, and impact score of St. George’s Respiratory Questionnaire). Studies with large-scale and double-blind randomized controlled trials are required to confirm the role of the adjunct HM in the management of COPD.
Chronic obstructive pulmonary disease (COPD) is a progressive and chronic lung disease. It is the fourth leading cause of death as reported by the World Health Organization. COPD is characterized by chronic cough, excess sputum production, chest tightness, and shortness of breath during physical activity [
Recently, several systematic reviews have been conducted, indicating the potential effectiveness of Chinese herbal medicine in COPD [
Search strategy used in this study was as follows: (Chinese medicine OR Traditional Chinese Medicine OR Chinese herbal medicine OR Chinese herbal drug OR traditional herbal medicine OR herbal medicine OR traditional Japanese medicine OR traditional medicine OR Ethnomedicine OR Folk Medicine OR Folk Remedies OR Home Remedies OR Indigenous Medicine OR Primitive Medicine OR Materia Medica OR Homeopathic Remedies OR Nosodes OR traditional East Asian medicine OR Traditional Far Eastern Medicine OR Far East Medicine OR Oriental medicine OR Korean medicine OR Tibetan medicine OR herb OR herbaceous agent OR medicinal plant OR medicinal herbs OR medicinal plant product OR plant extract OR plant preparation OR Herbal Preparation OR botanic OR botany OR Kampo OR Kampo medicine OR Kanpo OR Traditional Mongolian Medicine OR Mongolian Folk Medicine OR Mongolian Medicine OR phytotherapy OR Herb Therapy OR Herbal Therapy OR Ethnopharmacology OR Ethnobotany OR phytogenics OR alternative medicine OR Alternative Therapy OR complementary therapy OR Complementary Medicine OR TCM OR CHM OR Zhong Yi Xue) AND (Chronic obstructive pulmonary disease OR COPD OR chronic obstructive lung disease OR chronic obstructive airway disease OR chronic airflow limitation OR chronic obstructive respiratory disease OR chronic bronchitis OR chronic emphysema OR shortness of breath OR SOB OR dyspnea). The keywords search was conducted in March 2012 and updated in November 2013.
Search strategy followed the Cochrane Collaboration without restriction of the language for publications. The following databases were searched: (1) PubMed; (2) MEDLINE; (3) EMBASE; (4) Cochrane Central Register of Controlled Trials (CENTRAL); (5) Cochrane Database of Systematic Reviews; (6) AMED; (7) China Academic Journal Full Text Database; and (8) China Master and Doctor Theses Full-Text Database.
Inclusion criteria included all published studies reporting quasi or randomized controlled trials (RCTs) and comparing HM or its variants as monotherapy or adjuvant therapy, with at least one control group that used the conventional western practice or placebo. Participants were required to have had a diagnosis of COPD according to the investigators of the trials. There would be no restriction on the ethnicity, gender, age, or disease duration of the participants in the trials. The HM interventions could have been either (1) extract(s) from a single herb; (2) preparation(s) containing multiple herbs; or (3) proprietary herbal product(s). They should be used alone or coadministered with western medications. The control intervention has to be either a placebo or a western medication (WM). Trials of all durations are welcomed. Both parallel and crossover designs would be accepted. Clinical studies had to report the pulmonary function in the research.
Studies without baseline and endpoint of pulmonary function tests during clinical trials were excluded.
All analyses were performed with RevMan version 5.1 (The Nordic Cochrane Centre, The Cochrane Collaboration) to quantify and compare the efficacy of outcomes of the treatment versus the control groups. Standard mean difference was given for continuous outcome variable with 95% confidence interval (CI), while odds ratio (OR) was given for dichotomous outcome variable with 95% CI. The random-effect model was employed when the study of heterogeneity (
7286 publications and theses were screened by the abstracts and retrieved from databases by two individual reviewers (HC and CM). 6702 publications were excluded while 584 full articles were further assessed for eligibility. 408 publications were excluded due to the lack of data in pulmonary function and randomization in clinical trials. 176 of the studies that satisfied the criteria were included for further analysis. Risk bias of these studies was assessed by seven features including the sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other biases. Studies with four or more features judged to have low risk bias were regarded as high quality studies. Eighteen high quality publications were identified according to the risk bias assessment tool (Figure
Characteristics of the included studies.
Studies | Diagnosis | Intervention group | Control group | Outcomes | Duration |
---|---|---|---|---|---|
Chen 2005 [ |
SCOPD/I~II | Chinese herb decoction + WM | WM | Clinical symptom; pulmonary function; arterial blood gas; medical expense; kidney, liver, urine, and blood routine test; and safety examination | 6 months |
He 2010 [ |
SCOPD/II~III | Chinese herb decoction + WM | WM | Clinical symptom; pulmonary function; and SGRQ | 3 months |
Ke 2010 [ |
SCOPD/I~IV | Chinese herb decoction + WM | Placebo + WM | Clinical symptom; pulmonary function; SGRQ; 6MWD; BODE; kidney, liver, urine, and blood routine test; and safety examination | 2 months |
Li 2006 [ |
AECOPD/I~II | Chinese herb decoction + WM | WM | Clinical symptom; pulmonary function; arterial blood gas; kidney, liver, urine, and blood routine test; TNF- |
10 days |
Li 2008 [ |
SCOPD/I~II | Bufei-Yishen-Huayu decoction + WM | WM | Clinical symptom; pulmonary function; kidney, liver, urine, blood, and stool routine test; safety examination; TNF- |
2 weeks |
Li et al. 2012 [ |
SCOPD/I~III | Bu-Fei Yi-Shen granule + Shu-Fei Tie ointment + WM | Placebo + WM | Frequency and duration of acute exacerbation of COPD; pulmonary function; quality of life; 6MWD; clinical symptom; and safety examination | 4 months |
Liu 2010 [ |
NA/NA | Chinese herb decoction + WM | Placebo + WM | Clinical symptom; pulmonary function; SGRQ; and safety examination | 1 month |
Luo 2007 [ |
AECOPD/I~III | Qinjin-Huatan decoction + WM | WM | Clinical symptom; pulmonary function; kidney, liver, urine, blood, and stool routine test; arterial blood gas; and safety examination | 10 days |
Matthys et al. 2013 [ |
SCOPD/II~III | EPs 7630 (roots of |
Placebo + WM | Time to first exacerbation of COPD; number and duration of exacerbations; pulmonary function; SGRQ; Integrative Medicine Patient Satisfaction Scale; laboratory safety parameters; and sputum examination | 6 months |
Murali et al. 2006 [ |
SCOPD/II | Herb ( |
Placebo + WM | Clinical symptom; pulmonary function; arterial blood gas; and safety observation | 6 months |
Worth et al. 2009 [ |
AECOPD/II~III | Herb (Eucalyptole) extraction + WM | Placebo + WM | Frequency, duration, and severity of exacerbations; pulmonary function; clinical symptom; SGRQ; and safety examination | 6 months |
Xiao 2008 [ |
SCOPD/I~III | Chinese herb extraction + routine medication | Theophylline + routine medication | Clinical symptom; pulmonary function; and IL-10 and TNF- |
3 months |
Zeng 2010 [ |
SCOPD/I~II | Chinese herb decoction + WM | Placebo + WM | Frequency, duration, and severity of exacerbations; pulmonary function; clinical symptom; SGRQ; and safety examination | 4 weeks |
Zhang et al. 2006 [ |
AECOPD/NA | Chinese herb injection + WM | Placebo + WM | Clinical symptom; pulmonary function; arterial blood gas; and safety observation | 1 week |
Zhao 2010 [ |
SCOPD/II~IV | Chinese herb decoction + WM | WM | Clinical symptom; BODE index; 6MWD; sTNF and iNOs; and safety observation | 3 months |
BODE: BMI, obstruction, dyspnea, and exercise; SGRQ: St. George’s Respiratory Questionnaire; WM: western medicine; 6MWD: six-minute walk distance.
Risk of bias. Risk of bias for the included studies was assessed according to the information that comes from studies at low, unclear, or high risk of bias for each item in the risk of bias tool.
Flow diagram on the screening of study. Fifteen of the studies with high quality were meta-analyzed.
To identify the commonly used HMs in COPD, we counted the frequency of herb medicines utilized in the 176 clinical trials (Table S1; see Supplementary Material available online at
Commonly used herbal medicines from the frequency analysis. The eight Chinese medicines were overlapped in AECOPD and SCOPD, which were further confirmed in the mixed COPD studies.
Next, we conducted meta-analysis for the included 15 studies [
Pulmonary function tests. (a) FEV1. (b) FEV%. (c) FVC. (d) FEV/FVC. The pulmonary function test analysis showed that HM had no advantage on improving pulmonary function compared to WM.
Finally, analysis of FEV1/FVC in six high quality studies [
Five high quality studies [
Studies reported symptom improvement according to SFDA Guidelines on Clinical Research of TCM New Drugs [
Efficacy and quality of life evaluation. (a) Efficacy of symptom improvement. (b) Subgroup analysis of total score of SGRQ. (c) Activity score of SGRQ. (d) Impact score of SGRQ. Data analysis showed that HM improved the efficacy and quality of life compared to WM. SGRQ, St. George’s Respiratory Questionnaire.
Five studies reported the findings using St. George’s Respiratory Questionnaire (SGRQ), including 3 SCOPD studies [
We examined the outcome measures with subgroup analysis (AECOPD, SCOP, and Mixed COPD). All outcomes measured show no significant difference among the subgroups except for the SGRQ total score (
In the subgroup analysis with the HM administration route, only one study administrated HM in the route of injection [
We further conducted the subgroup analysis in placebo/nonplacebo groups. All outcomes measurements showed no significant difference except for the SGRQ symptom. Subgroup analysis of SGRQ symptom showed the boarding significant differences between placebo and nonplacebo group (Table S4). Further analysis showed that the subgroup difference may be one of the causes leading to the heterogeneity of studies in the meta-analysis of SGRQ symptoms. However, the subgroup analysis also indicated that the efficacy of the adjunct HM in SGRQ symptom score remains to be further determined. Therefore, subgroup analysis for all outcomes based on placebo and nonplacebo groups did not alter the results in the present study.
COPD is one of the leading causes of morbidity and mortality worldwide; its economic and social burdens are substantial and increasing [
Pulmonary function is the essential criteria for the diagnosis of COPD according to GOLD [
Quality of life has become an important outcome measure in COPD patients since COPD is a long term disease without cure. SGRQ was widely used for QoL assessment in COPD patients within 3 categories (activity, symptoms, and impact). Analysis of SGRQ from high quality studies showed that HM as an adjunct therapy had an advantage over WM on total score, activity score, and impact score. However, the efficacy of HM as an adjunct therapy in improving the symptoms remains unclear due to the presence of heterogeneity. Importantly, the efficacy assessment of clinical symptoms and Chinese medicine symptoms partly covers symptoms assessed in SGRQ. Therefore, HM as an adjunct therapy may have advantage on improving quality of life and symptom compared to WM.
In the study, eight HMs frequently used for COPD were identified from 176 studies. The HMs fully follow the principles of Chinese medicine prescription for treating AECOPD and SCOPD. Furthermore, we found that the identified Chinese medicines have functions of regulating qi to reduce phlegm (e.g., Pericarpium Citri Reticulatae (Chen Pi), Rhizoma Pinelliae (Ban Xia), Semen Armeniacae Amarum (Xin Ren), and Fructus Perillae (Zi Su Zi)) as well as tonifying qi and promoting blood circulation (Radix Astragali (Huang Qi), Radix Salviae Miltiorrhizae (Dan Shen)). Herba Ephedrae (Ma Huang), Semen Persicae (Tao Ren), and Radix Scutellariae (Huang Qin) have functions such as clearing heat, promoting blood circulation, and facilitating flow in the lung. Radix Ginseng (Ren Shen), Rhizoma Atractylodis Macrocephalae (Bai Zhu), and Fructus Schisandrae (Wu Wei Zi) have the functions of tonifying qi, strengthening spleen to reduce phlegm, and arresting persistent cough. The commonly used herbs for AECOPD and SCOPD in the study were also aligned with the common differentiated symptoms in Chinese medicine for COPD (phlegm-heat in AECOPD and spleen and kidney deficiency in SCOPD).
Moreover, the usage of these herbs was also in line with the biological actions of herbs discovered by modern science. COPD is characterized by a chronic inflammation in the pulmonary tissue [
Pericarpium Citri Reticulatae (Chen Pi), Rhizoma Pinelliae (Ban Xia), Poria (Fu Ling), and Radix Glycyrrhizae (Gan Cao) identified in the study are the components of a famous Chinese medicine formula, namely, Er-Chen decoction, which functions as the removing phlegm in the principle of Chinese medicine. In vitro study shows that the extract of Pericarpium Citri Reticulatae (Chen Pi) has antioxidant and antimicrobial activities [
Though the molecular mechanisms of how HM improves QoL and clinical symptoms of COPD patients remain largely unexplored, multiple effects on anti-inflammation, immunoregulation, sedation, and bronchodilation may be central roles of Chinese medicine prescriptions in the COPD treatment. In addition, the quality control of HMs was not clearly stated in the included studies. The reproducibility of these medications to COPD remains to be further explored.
Analysis of adverse events from the included studies showed that HM as an adjunct therapy has low incidence of adverse effects. But no serious adverse effects were caused by herbal medicines in COPD patients. The common adverse effects are abdominal (“stomach”) discomfort, nausea and vomiting, skin allergy, and pain. It should be pointed out that only one-third of the studies (64 studies/176 studies) had included adverse effect as outcomes. Moreover, studies have shown that herb-drug interaction is a potential risk factor for the adverse events [
The quality of clinical trials has to be improved in the future studies. In the present study, 15 studies (18 publications) were identified as high quality studies while others were quasi-RCTs and RCTs with high risk bias. Randomization is one of the major concerns in the clinical trials. Most of the studies only stated that there is “randomization” in them, even when there is a lack of the details about the randomization methods. Descriptions of the methods may minimize or avoid selection bias. Indeed, randomization in some studies we reviewed has not been properly performed; for instance, the patients have been allocated according to the date or the odd and even sequence of admission. Selection bias may also arise from inadequate allocation concealments. In the 176 studies that have been reviewed, only fifteen studies described concealments of allocation. Central allocation or sequentially numbered, opaque, and sealed envelopes are recommended in future studies.
Blinding is the critical method to minimize or avoid the bias, which is absent in studies even in those studies with high quality. Blinding to participants may avoid performance bias. Placebo with similar odor, color, and taste to the intervention should be applied in future studies. It is recommended that there should be an outcome assessment to measure detection bias when TCM practitioners are involved in diagnosing and prescribing for patients.
Data incompetence is also a concern in clinical trials; for instance, few studies reported the details on the dropout or the followup of the study. Side effects or adverse effects should be reported as the outcome of the trials. The clinical trials can follow the international guideline for good clinical practice that has been developed by the International Conference on Harmonization Global Cooperation Group (
Current evidence reveals that HM as an adjunct therapy is uncertain to improve the pulmonary function but may improve clinical symptoms and quality of life for COPD patients. Studies with large scale and double-blind randomized controlled trials are required to confirm the role of HM in the management of COPD.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Zhang-Jin Zhang initiated and supervised the project. Hai Yong Chen and Chun Ho Ma retrieved the databases and extracted and analyzed the data. Hai Yong Chen wrote the paper. Hai Yong Chen, Chun Ho Ma, Ke-Jian Cao, James Chung-Man Ho, Eric Ziea, Vivian Taam Wong, and Zhang-Jin Zhang were all involved in the conception, design, data interpretation, revision, and final approval of the paper.
This work was supported by the Hong Kong Hospital Authority fund (HKU Project Reference no. 20006344).