alexa Anti-Inflammatory Effects of Chinese Herbal Medicine on COPD: A Systematic Review
ISSN: 2472-1018
Journal of Lung Diseases & Treatment

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  • Review Article   
  • Lung Dis Treat, Vol 2(2)
  • DOI: 10.4172/2472-1018.1000107

Anti-Inflammatory Effects of Chinese Herbal Medicine on COPD: A Systematic Review

Miao Q1, Cong X1, Du Y2, Wang B1, Qiao CY3 and An X4*
1No 1 Caochang St, Haidian district, Beijing, 100091, China
2Midwestern University 555 31st Street Downers Grove, IL, 60515, USA
3School of Health Sciences and Business, Australia
4H and J CRO PTY. LTD, Australia
*Corresponding Author: An X, H and J CRO PTY. LTD, Australia, Tel: 0061401777369, Email: [email protected]

Received Date: Feb 25, 2016 / Accepted Date: May 10, 2016 / Published Date: May 16, 2016

Abstract

Background: Airway inflammation and inflammatory mediators play an imperative role in the pathogenesis of COPD. Currently, understanding of the anti-inflammatory effect of Chinese herbal medicine (CHM) on COPD is limited, and CHM’s mechanism of actions is unclear. This systematic review (SR) evaluates anti-inflammatory effects of CHM on the concentration of various inflammatory mediators, such as Tumor Necrosis Factor-alpha (TNF-α) and interleukin-8 (IL-8), in the sputum and serum of COPD patients.
Methods: The studies chosen for this SR were obtained from Chinese and English databases. The study selection criteria were based on randomized, controlled trials of stable COPD patients on adjunct oral CHM; and the changes in concentration of inflammatory mediators post-treatment were analyzed via meta-analysis.
Results: 2,268 patients in 29 studies were evaluated. 2 studies were assessed to be of low-risk in all domains. The results showed significant reduction in the serum level of IL-8 (mean: -1.27 and 95% confidence interval (CI) [-1.86, -0.68]) and TNF-α (Mean: -0.72 and 95% CI [-1.01, -0.43]) in patients treated with CHM plus bronchodilators, compared to bronchodilators alone.
Conclusion: This SR explains CHM’s mechanism of action, and demonstrates CHM’s anti-inflammatory effects on patients with stable COPD.

Keywords: Chinese herbal medicine; Chronic obstructive pulmonary disease; Tumor necrosis factor-α; Interleukin-8; Systematic review

Abbreviations

AE: Adverse Events; BALF: Bronchial Alveolar Lavage Fluid; CENTRA: Cochrane Central Register of Controlled Trials; CHM: Chinese herbal medicine; CI: Confidential Interval; CINAHL: Cumulative Index to Nursing and Allied Health Literature; CNKI: China National Knowledge Infrastructure; COPD: Chronic obstructive pulmonary disease; CONSORT: Consolidated Standards of Reporting Trials; CQVIP: Chongqing VIP; GRADE: Grading of Recommendations Assessment, Development and Evaluation; IL- 6: Interleukin-6; IL-8: Interleukin-8; MD: Mean Difference; MMP- 9: Matrix Metalloproteinase-9; MOA: Mechanism Of Action; QoL: Quality of Life; PRISMA: Systematic Reviews and Meta-Analyses; RCTs: Randomized Controlled Trials; SR: Systematic Review; Std. MD: Standardized Mean Difference; TGF-β1: Transforming Growth Factor-β1; TNF-α: Tumor Necrosis Factor-alpha

Introduction

Chronic obstructive pulmonary disease (COPD) is a complex disease with multiple pathogeneses [1]. Airway inflammation plays an imperative role in the pathogenesis of COPD. A wide range of inflammatory mediators are associated with COPD; interleukin-8 (IL-8), IL-6, Tumor Necrosis Factor-alpha (TNF-α), and matrix metalloproteinase (MMP-9) have been shown to induce neutrophil production, alveolar macrophages release, emphysema formation, and lung remodeling [2]. Compared to healthy subjects, patients with stable COPD had an increased expression of inflammatory mediators, particularly in sputum and serum [3,4]. In addition, these inflammatory mediators correlated with clinical outcomes of lung function, BODE index, frequency of COPD exacerbation, and severity and mortality of COPD [5-7].

The use of Chinese herbal medicine (CHM) as an adjunct therapy for COPD has been documented in more than one hundred clinical trials over the past decade. Previous systematic reviews (SR) have shown that oral CHM provided symptom relief, improved Quality of life (QoL) and lung function, and reduced frequency of COPD exacerbation [8,9]. However, understanding of CHM’s anti-inflammatory effects is limited and CHM’s mechanism of action (MOA) is not clear. This study aims to investigate the effects of CHM on inflammatory mediators in induced sputum and serum in patients with stable COPD, as well as its MOA.

Materials and Method

This SR was conducted by Standard for Systematic Review [10] and guided by Preferred Reporting Items for Systematic Reviews and Meta- Analyses statement (PRISMA) [11].

Search strategy included identifying search databases and search terms. Relevant studies were selected from both English and Chinese databases. English databases included PubMed, CINAHL, and CENTRAL (Cochrane Central Register of Controlled Trials); Chinese databases included CNKI, CQVIP and Wan fang. Appropriate search terms (per guideline of Cochrane Airways Group) were used to identify appropriate studies. Potential studies were chosen from their respective inceptions until August 2014, without language restrictions.

Search terms were identified through PubMed using medical subject headings (MeSH) relevant to COPD and from the Cochrane Airways Group Specialized Register of COPD trials. These terms were separated into those relevant to COPD, such as ‘Pulmonary disease, chronic obstructive’ etc.; relevant to randomized clinical trials such as ‘Clinical trials’, ‘Randomized controlled trials’, etc.; relevant to Chinese medicine such as ‘Traditional Chinese Medicine’ and ‘Herbal Medicine’.

Study selection criteria

The criteria for study inclusion were based on study type, patient population, treatment method, and resulting outcomes. Studies that qualified for all previously stated criteria included: randomized controlled trials (RCTs) with a parallel group design; patients with stable COPD without complication of asthma, bronchiectasis, corpulmonale, or pulmonary hypertension; interventions that used oral administration of CHM; outcomes that focused on testing biomarkers of IL-8, TNF-α, in serum and sputum, transforming growth factor-β1 (TGF-β1), and IL-6 in serum.

Assessment of methodological quality

The methodological quality of each study’s risk-of-bias was assessed by Cochrane Collaboration, which consists of six domains: Sequence Generation, Allocation Concealment, Blinding Method and Outcomes Assessment, Incomplete Data, Selective Reporting and Other Bias [12]. The risk-of-bias of each study was evaluated as low, high or unclear. Selective Reporting was assessed by each study’s reporting protocol. Other Bias was assessed by comparing baseline data and method of statistical analysis in each respective study.

The quality of grading of recommendation

Grading of Recommendations Assessment, Development and Evaluation (GRADE) and GRADEpro [13] were used; the quality rating of each study was evaluated as high, moderate, low, or very low. Assessment of quality-of-evidence was based on Risk-of-Bias, Inconsistency, Indirectness, Imprecision, and Publication Bias. The Large Effect, Plausible Confounding Variables, and Dose-Response Gradient were evaluated as strongly supportive, weakly supportive, strongly oppose, or weakly oppose.

Outcome measure

The outcomes were mainly focused on the level of IL-8 examined and TNF-α in serum and sputum, and also involved the level of transforming growth factor-β1 (TGF-β1), and IL-6 in serum.

Data extraction and collection

The relevance of title, abstract, and citations were assessed by two reviewers. Full articles were assessed by two reviewers. The Methodological Quality was assessed by two reviewers, audited by a third reviewer. The decision making process to include potential studies is outlined as a flow diagram based on the template provided by PRISMA [11]. Details of each study’s treatment regimen were reported as RCTs using Consolidated Standards of Reporting Trials (CONSORT) [14].

Data synthesis and analysis

Datasets were analyzed with RewMan 5.3. The continuous data was expressed as Mean Difference (MD), standardized MD (Std. MD), and 95% Confidential Interval (CI). The model of Random Effects was applied for heterogeneity. All data sets were imported from RewMan and assessed by GRADEpro.

Results

3,886 potential studies were initially identified. 3,143 remained after duplicates were eliminated. Further screening resulted in the exclusion of 2,921 studies for various reasons: 323 were not RCTs (case reports, surveys, retrospective studies, etc.), 333 did not relate to COPD or had additional complications of respiratory failure, heart failure, pulmonary hypertension or cor-pulmonale, 94 had inappropriate treatment regimen, 965 did not include biomarkers in its outcomes, 212 were non-human trials, 807 were review articles, and 187 used non-CHM adjunct therapy. Of the 222 remaining studies, 81 did not administer oral CHM, 66 did not include desired outcomes, and 3 had patients with non-stable COPD (such as COPD exacerbation or unidentified COPD courses) as well as 3 others. 29 studies met all required criteria, and were retrieved and analyzed in this SR (Figure 1).

lung-diseases-treatment

Figure 1: The process of selection of studies.

Demographic information

Of the twenty nine studies, 27 were conducted in China and 2 in Japan. All of them were designed as parallel RCTs. Participants in each study were diagnosed with stable COPD, in accordance with the GOLD guideline modified by the CSRD [15]. Six studies [16-21] were done in out-patient settings only; one study [22] was in in-patient setting only, and five studies included participants in both out-patient and inpatient settings. Average age of participates ranged from 54.3 ± 4.7 to 72 in all studies except three, which did not specify age range [23-25]. 2,268 subjects were randomly selected and 2,193 subjects completed the entirety of their respective assessments, 75 subjects withdrew. 1,359 male subjects and 709 female subjects were identified, with the exception of two studies that did not include the gender of the participants [24,26]. Five studies identified the severity of COPD of their subjects as mild, moderate, or severe based on the GOLD guideline [19,27-30]. Seventeen studies defined COPD’s Differentiation of Syndrome in Chinese Medicine (CM) to be: lung and spleen qi deficiency [19,20,31-33], lung and kidney qi deficiency [21,22,27-29,34,35], or qi deficiency and blood stasis [17,23,30,36,37]; while other studies did not clearly define its differentiation of syndromes. Duration of treatment varied from: six months in seven studies [18,24,26,29,33-35], three months in nine studies [17,19-21,23,27,28,30,37], two months in six studies [16,19,22,31,38,39], six weeks in one study [40], one month in five studies [25,36,41-43], and two weeks in one study [44] (Table 1).

First author, Reference No. Location Out /in patients No. subjects
(R/A)
No. M/F Age
Mean SD (years)
*Severity of COPD/No. subjects *CMSD COPD history (years)
Studies with sputum test
Cao[38] Xingtai,
Hebei
NS T: 40/40
C: 40/40
T: 23/17
C: 24/16
T: 56 ± 13
C: 55 ± 14
NS NS NS
Che et al. [40] Shenyang,
Liaoning
NS T: 25/23
C: 25/23
T: 18/7
C: 16/9
T: 65.6 ±NS
C: 64.5 ±NS
T: IIA: 11, IIB: 10, III: 4
C: IIA: 10, IIB: 12, III: 3
NS T: 14 ± 8
C:15 ± 7.6
Du et al. [16] Shiyan,
Hubei
Out T: 18/18
C: 18/18
T: 16/2
C: 15/3
T:58.61 ± 10.69
C: 58.44 ± 9.54
T: IIA: 7, IIB: 6, III: 2
C: IIA:6, IIB: 7, III: 1
NS NS
Huang[18] Fangcheng
gang,
Guangxi
Out T: 30/30
C: 30/30
T: 16/14
C: 17/13
T:67.38 ± 5.66
C:65.25 ± 6.13
T: IIA: 12, IIB: 14, III: 4
C: IIA:10, IIB: 14, III: 6
NS NS
Luet al. [20] Fuzhou,
Fujian
Out T: 30/30
C: 30/30
T: 25/5
C: 23/7
T:64.6 ± NS
C:63.8 ± NS
T: II 30
C: II 30
Deficiency of Spleen Qi T: 11.2 ± NS
C:10.6 ± NS
Wang et al. [31] Hefei,
Anhui
NS T: 20/20
C: 20/20
T: 18/2
C: 19/1
T:59.4 ± 7.5
C:60.9 ± 7.9
T: IIA: 8, IIB: 9, III: 3
C: IIA:9, IIB: 9, III: 2
Deficiency of Lung and Spleen Qi T: 11.2 ± 4.1
C:11.8 ± 4.5
Xiao et al.[39] Zhanjiang,
Guangdong
NS T: 60/60
C: 56/56
T: 38/22
C: 35/21
T:66.4 ± 8.8
C:61.2 ± 6.3
T: IIA: 23,
IIB: 25, III: 12
C: IIA:21,
IIB: 22, III: 13
NS T:17.3 ± 10.2
C:18.5 ± 9.3
Zhou et al. [25] Taiwu,
Shandong
Both T: 30/30
C: 30/30
T: 22/8
C: 21/9
T:NS
C:NS
T: IIA: 30
C: IIA:30
NS NS
Studies with serum test
Chen et al. [37] Wuhan,
Hubei
NS T: 36/36
C: 36/36
T: 24/12
C: 26/10
T:62.9 ± 7.3
C:62.2 ± 7.8
T:III:25, IV:11
C:III:26, IV:10
Deficiency of Lung and Kidney Qi and blood stasis T:5.9 ± 1.7
C:6.2 ± 1.8
Cheng et al. [41] Chongqing Both T: 40/40
C: 40/40
T:35/5
C: 33/7
T: 83.2 ± 7.8
C: 82.7 ± 5.6
NS NS NS
Fenget al.[30] Beijing NS T: 46/46
C: 30/30
T:25/21
C:14/16
T:63.37 ± 8.99
C:62.26 ± 8.72
T: IIA:24, IIB:22
C: IIA:16, IIB:14
Deficiency of Qi and sputum blood stasis NS
Fu et al. [42] Tianjin NS T: 39/39
C: 31/31
T:31/31
C:31/31
T:60.56 ± 8.60
C:60.21 ± 10.01
NS NS NS
Guo et al. [17] Tianjin Out T: 70/69
C: 70/61
T:41/28
C:39/22
T:60.81 ± 8.18
C:60.51 ± 11.03
NS Deficiency of Lung Spleen Kidney Qi and sputum blood stasis T: 14.56 ± 6.32
C:14.52 ± 5.96
Hu [22] Lanzhou,
Gansu
In T: 35/35
C: 32/32
T:20/15
C:14/18
T:64.7 ± 7.5
C:63.2 ± 5.4
NS Yin deficiency of Lung and Kidney NS
Jiang et al. [44] Hezhou,
Guangxi
NS T: 30/30
C: 30/30
T:20/10
C:20/10
T:52.3 ± 10.9
C:51.8 ± 11.1
NS NS T: 12.36 ± 6.2
C:12.74 ± 6.5
Li et al. [36] Guangzhou,
Guangdong
Both T: 50/49
C: 50/48
T:27/22
C:28/20
T:66.3 ± 10.1
C:65.9 ± 9.8
NS Sputum blood stasis in Lung T: 8.9 ± 5.0
C:9.1 ± 4.8
Li et al. [19] Haerbin,
Heilongjiang
Out T: 35/35
C: 35/35
T:23/12
C:24/11
T:63.7 ± 5.3
C:60.1 ± 5.3
T:I:6, IIA:19, IIB:10
C:I:5, IIA:20, IIB:10
Deficiency of Lung and Spleen Qi T: 15.4 ± 3.1
C:13.1 ± 4.1
Ou et al. [32] Guiyang,
Guizhou
Both T: 36/30
C: 34/30
T:23/13
C:22/12
NS NS Deficiency of Lung and Spleen Qi NS
Shinozuka et al. [26] Chiba,
Japan
NS T: 17/17
C: 18/18
NS NS NS NS NS
Su et al. [23] Beijing NS T: 35/35
C: 37/37
T:16/19
C:18/19
T:60.6 ± 8.9
C:56.6 ± 8.8
NS Deficiency of Qi and sputum blood stasis NS
Tatsumi et al. [24] Chiba,
Japan
NS T: 34/34
C: 37/37
NS NS NS NS NS
Wang et al. [29] Shanghai NS T1:109/82
T2:109/89
C:113/91
T1:64/18
T2:62/27
C:69/22
T1:62.43 ± 9.04
T2:61.51 ± 8.79
C:62.68 ± 8.10
T1:I:1, II:34, III:45, IV:2
T2:I:0, II:42, III:44, IV:3
C:I:2, II:34, III:50, IV:5
1.Deficiency of Qi 2.Deficiency of Kidney Qi 3.Deficiency of Kidney Yang T1:12.57 ± 8.39
T2:12.75 ± 8.95
C:12.43 ± 9.46
Wang et al. [28] Liuyang,
Hunan
Both T: 30/30
C: 30/30
T:16/14
C:18/12
T:65.22 ± 2.45
C:62.75 ± 3.66
T:I:5,T:II:19, T:III:6
C:I:5,C:II:20, C:III:5
Deficiency of Lung and Kidney NS
Xiao et al. [27] Guangzhou,
Guangdong
NS T: 34/34
C: 31/31
T:26/8
C:25/6
T:62.3 ± 7.11
C:64.6 ± 8.62
T:I:6, II:25, III:3
C:I:7, II:21, III:3
Yin deficiency of Lung and Kidney NS
Xiong et al. [34] Shenzhen Both T: 30/30
C: 30/30
T:20/10
C:21/9
T:72 ± NS
C:71 ± NS
NS Deficiency of Lung and Kidney NS
Zhang et al. [33] Zhengzhou,
Henan
NS T: 35/34
C: 35/34
T:NS
C:27/8
T:NS
C:61.77 ± 10.18
NS 1.Deficiency of Lung and Spleen Qi 2.Deficiency of Lung and Kidney Qi 3.Deficiency of Qi and Yin NS
Zhao et al. [35] Xinxiang,
Henan
NS T: 30/30
C: 30/30
T:16/14
C:18/12
T:72.68 ± 7.18
C:72.18 ± 7.36
NS Deficiency of Lung and Kidney Qi NS
Zheng [43] Tangshan,
Hebei
Both T: 45/45
C: 45/45
T:30/15
C:28/17
T:54.3 ± 4.7
C:55.2 ± 4.1
NS NS T:11.3 ± 4.3
C:10.9 ± 4.8
Zhong et al. [21] Shenzhen Out T: 35/35
C: 35/35
T:20/15
C:21/14
T:68.3 ± 9.8
C:68.2 ± 9.5
NS Deficiency of Lung and Kidney NS
R:Randomized; A:Analyzed; T:Treatment; C:Control; *Severity of COPD:I-Mild; II-Moderate; III-Severe;
CMSD: Chinese Medicine Syndrome Differentiation

Table 1: The characteristics of each study.

Intervention

Medication regimens were based on GOLD guideline for management of patient with stable COPD [45]. Bronchodilators such as inhaled beta-2-agonists (salbutamol and salmeterol), anticholinergics (Tiotropium bromide), or theophylline tablets with salmeterol/ fluticasone propionate were used as mainstay treatments. Experimental groups consisted of CHM formulae or extraction of a single Chinese herb plus one drug of any category of bronchodilators. Control groups consisted of one drug of any category of bronchodilators alone or with placebo.

Oral forms of CHM formulae include oral liquid, capsules, granules, powder, or decoctions; their respective dosages are shown in Table 2. In seven studies [19,27,29,33,35,41,43], the CHM formula were produced as granule or capsule by pharmaceutical companies certified with Good Manufacturing Practice with strict quality control. Each CHM formula is comprised of 1 to 16 herbs, from a total of 77 different kinds of herbs. The most commonly used herbs in all studies were Huang Qi (Astragalus membranaceus), Gan Cao (Glycyrrhiza uralensis), Chen Pi (Citrus reticulate), Dang Shen (Codonopsis pilosula), Di Huang (Rehmannia glutinosa) and Fu Ling (Poria cocos) (Table 2).

First author, date Intervention *TD outcomes
Formula name (form)
/Ingredients/quantitative
Dosage regimen Qualitative testing Plus
bronchodilators
Studies with sputum test
Cao [38] Xiaoqinglong Decoction
Baishao10g, Banxia10g, Gancao10g, Ganjiang10g, Guizhi10g, Mahuang10g, Wuweizi10g, Xixin10g
1 Dose,
BID
Hospital Salmeterol/fluticasone 2mths Lung function,*MMP-9
Cheet al. [40] ZhikeQingfei Oral liquid (10ml oral liquid contains)
Banlangen1.67g, Gancao1.67g, Huangqi1.67g, Huangqin1.67g, Jinyinhua1.67g, Jiegeng0.83g, Kuandonghua0.67g, Lianqiao0.83g, Mahuang0.5g,
Pipaye 0.83g, Yuxingcao 0.83g, Ziwan 0.67g
20ml,
TID
Hospital Bronchodilators 6wks Lung function
Duet al. [16] Yinxingye extract tablet:
Ginkgo biloba extract
2 Tablets, TID Hospital No 2mths Lung function
Huang [18] BufeiYiyangHuatangranules:
Bajitian, Chuanbeimu, Dangshen, Duzhong, Gouqizi, Huanghuadaoshuilian, Huangqi, Jupi, Maimendong, Pipaye, Sangbaipi, Wuweizi, Yipichou, Yuxingcao ,Ziwan
20g, BID Hospital Bronchodilators 6mths NS
Luet al. [20] Liu Junzi Decoction contains (150ml):
Baizhu 9g, Banxia 9g, Chenpi 6g, Dangshen 20g, Fuling 15g
150ml,
BID
Hospital Bronchodilators 3mths Sputum *HDACs
activity
Wanget al. [31] YifeiJianpi Fang: Decoction (1 dose contains):
Baizhu 15g, Banxia 15g, Chenpi 10g,Dangshen 15g,Dilong 8g, Fangfeng 10g, Fuling 15g, Gancao 10g,Huangqi 30g, Kuandonghua 10g
1 Dose,
BID
Hospital Bronchodilators 2mths Lung function
Xiaoet al. [39] ManzhiKechuanling: Oral liquid:
Baizhu,Banxia,Buguzhi,Chuanbeimu,Ejiao,Fuling,Gancao,Gejie,Hetaorou,Huangqi,Lujiaojia,Renshen,Shanyao,Taoren,Yimucao,Ziheche,Zisuzi
10ml,
BID
Hospital Bronchodilators 2mths MMP-9
Zhou et al. [25] FeisaitongHeji: Oral liquid (100ml contains):
Chantui 9g, Danshen 30g, Dilong 12g, Gancao 6g, Huangqi 30g, Jiegeng 9g, Jinyinhua 18g, Laifuzi 12g, Shashen 18g, Yiyiren 30g, Zisuye 9g
100ml,
TID
Hospital Bronchodilators 1mth Lung function,
Syndromes
Studies with serum test
Chenet al. [37] BufeiHuoxue Decoction (dose contains):
Banxia 10g, Chuanxiong 15g, Danggui 10g, Dihuang 20g, Dilong 10g, Fuling 15g, Gancao 6g, Honghua 6g, Huajuhong 15g, Huangjing 20g, Huangqi 30g, Laifuzi 15g, Taoren 10g, Wuweiz 6g, Xiyangshen 10g, Yinyanghuo 10g
1 Dose,
QD
Hospital No 3mths   Lung function
*6MWD, *CAT,
Chenget al. [41] SuhuangZhike Capsule:
Dilong, Mahuang, Niubangzi, Qianhu, Wuweizi, Zisuye
3 Capsules,
TID
Yangtze River Pharmaceutical Group No 1mth Lung function
Fenget al. [30] Qi-replenishing Blood-activating and Phlegm-removing Decoction:
Huangqi, Shuizhi, Banxia, Dilong
1 Dose,
QD
Hospital Bronchodilators 3mths Quality of life,
Fu et al. [42] Bufei granules:
Chenpi, Dangshen, Dihuang, Mahuang, Shanzhuyu, Ziwan
16g,
BID
Hospital No 1mth *TCM syndromes
Guo et al. [17] Bufei granules:
Banxia, Chenpi, Chishao, Danggui, Dangshen, Dihuang, Gancao, Huangqin, Mahuang, Shanzhuyu, Ziwan
16g,
BID
Hospital No 3mths NS
Hu [22] Jiajianbufei Decoction:
Baibu10g, Bajitian15g, Buguzhi15g, Chenpi 12g,
Dangshen 15g, Danshen, Huangqi 20g, Jiegeng 10g, Maidong10g, Sangbaipi10g, Tusizi10g, Xuanshen10g
1 Dose,
QD
Hospital Inhaled albuterol & Aminophylline Sustained release tablets 2mths Lung function
Jianget al. [44] BufeiNashen Decoction:
Every dose contains: Chenxiang10g, Dangshen20g, Dihuang20g, Fuling15g , Gancao6g, Gejie1 pair, Huangqi20g, Sangbaipi15g, Wuweizi15g, Ziwan15g
2 Doses,
QD
Hospital Salmeterol/
fluticasone
2wks Lung function
Liet al. [36] SanziYangqin Decoction &TaohongSiwu Decoction:
Baijiezi10g, Baishao15g, Chuanxiong15g, Danggui10g, Dihuang10g, Honghua10g, Laifuzi10g, Taoren15g, Zisuzi15g
150ml,
QD
Hospital Aminophylline Sustained release tablets 1mth Lung function
Li et al. [19] YiqiJianpiHuatanFangDecoction:
Baizhu, Banxia, Chenpi, Dangshen, Huangqi, Xingren
1 Dose,
QD
Jiangyin
Tianjiang Pharmaceutical Co
Bronchodilators 3mths SGRQ
Ou et al. [32] JiajianBufei Decoction:
Huangqi 20g, Danshen15g, Dangshen10g, Buguzhi15g, Baibu 10g, Sangbaipi10g
300ml,
QD
Hospital Bronchodilators 3mths Lung function, TCM syndromes
Shinozuka et al. [26] Hochuekkito extract (BuzhongYiqi Tang): 7.5g extract 2.5g,
TID
NS Bronchodilators 6mths Lung function
Su et al. [23] Feikang Granules:
Huangqi, Haigeqiao
10g,
TID
Hospital No 3mths Lung function
Tatsmi et al. [24] Hochuekkito extract(BuzhongYiqi Tang): 7.5g extract 2.5g,
TID
NS Bronchodilators 6mths Lung function,
*SGRQ
Wang et al. [29] BushenFangchuan tablet
BushenYiqi granule
5 tablets, TID &1 Bag, BID The 2nd TCM manufactory of Taiji Group &Tianjiang Pharmacy company Ltd Inhaled albuterol 6mths 6MWD,
lung function,
*AEF,
*BODE SGRQ
Wang et al. [28] FufangYishenDuqi Capsule (0.7g):
Dangshen15g , Wuweizi10g , Maidong10g , Baibu10g , Xingren10g, Duzhong10g , Mahuang6g, Yiyiren20g, Kuandonghua10g, Zisuzi10g, Chenxiang3g, Baijiezi15g, Baishao10g, Baihe,10g Houpo10g, Shanzhuyu15g
0.7g,
TID
Hospital Tiotropium Bromide Powder 3mths SGRQ ,
TCM syndromes
Xiao et al. [27] ZhenqiFuzheng granules:
Huangqi, Nvzhenzi
15g,
BID
Xiuzheng Pharmaceutical Group Bronchodilators 3mths Lung function, TCM syndromes
Xiong et al. [34] Shenge powder:
Gejie, Renshen
5g,
BID
Hospital Salmeterol/
fluticasone propionate
6mths Lung function
Zhang et al. [33] Fixed prescription of TCM therapy: Granules: 3 Bags,
TID
Jiangyin
Tianjiang Pharmaceutical Co.
No 6mths T-cell subset numbers
Zhao et al. [35] Bailing Capsule:
Fermentation of cordycepssinensis powder
1.0g,
TID
East China Pharmaceutical Group Limited Co Inhaled albuterol 6mths 6MWD,
lung function
Zheng [43] Jinshuibao Capsule:
Fermentation of cordycepssinensis powder
3 capsules (0.99g),
TID
Jiangxi Jiminkexin Group Co Bronchodilators 1mths NS
Zhong et al. [21] JiaweiJinshuiLiujunJian Decoction:
Dangshen15g, Huangqi 20g, Banxia 10g, Danggui 10g, Dihuang 20g, Fuling 10g, Chenpi 10g, Shengjiang 5g, Gancao 5g, Wuweizi 5g
100ml,
BID
Hospital Aminophylline Sustained release tablets 3mths Syndromes,
Amount of sputum
TD: Treatment Duration; MMP-9: MatrixMetalloprotein-9; HDACs: Histone Deacetylases; 6MWD: 6-Minute Walk Distance;
CAT: COPD Assessment Test; TCM: Traditional Chinese Medicine;AEF:Acute Exacerbation Frequency;
BODE index: The Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index.

Table 2: Intervention of included studies.

Assessment of methodological quality

Sequence Generation in thirteen studies [16-18,21,27,29-31,33,35- 37,42] were low risk. Allocation Concealment in three studies [27,31,40] were low risk. The Blinding Method in three studies [17,29,42] were low risk; one study [20] had high risk due to its inadequate description of its Blinding Method. The remaining twenty five studies did not clearly describe its methods. Outcome Assessments were low risk in every study. Incomplete Data was either high risk in three studies without using of intention to treat analysis [17,33,36] or unclear in three studies [21,24,26]. Two studies were unclear of their Selective Reporting method [24,26]. Other Bias was assessed as low risk in all studies based on baseline data comparison (Figure 2).

lung-diseases-treatment

Figure 2: The assessment of risk of bias of 29 studies.

Assessment of the quality of grading of recommendation

The quality of Grading of Recommendation for the serum concentration of IL-8, TNF-α, TGF-β1, IL-6, and the sputum concentration of IL-8 was assessed as moderate level. The sputum concentration of TNF-α was assessed as low level due to its small sample size (Table 3).

Quality assessment No of patients Effect Quality
No of studies Risk of bias Inconsistency Indirectness Imprecision Other considerations CHM Control Absolute
Serum IL-8 (Better indicated by lower values)
11 Serious1 Serious2 No serious indirectness No serious imprecision Reduced effect for RR>>1 or RR<<13 554 557 MD 1.27 lower
(1.86 to 0.68 lower)
MODERATE
Serum TNF-a (Better indicated by lower values)
8 Serious1 Serious2 No serious indirectness No serious imprecision Reduced effect for RR>>1 or RR<<13 331 317 MD 0.72 lower
(1.01 to 0.43 lower)
MODERATE
Serum IL-6 (Better indicated by lower values)
5 Serious1 Serious2 No serious indirectness No serious imprecision Reduced effect for RR>>1 or RR<<13 349 344 MD 1 lower
(1.87 to 0.14 lower)
MODERATE
Serum TGF-ß1 (Better indicated by lower values)
4 Serious1 Serious2 No serious indirectness No serious imprecision Reduced effect for RR>>1 or RR<<13 320 323 MD 278.66 lower
(460.57 to 96.75 lower)
MODERATE
Sputum IL-8 (Better indicated by lower values)
7 Serious1 Serious2 No serious indirectness No serious imprecision Reduced effect for RR>>1 or RR<<13 221 217 MD 0.88 lower
(1.45 to 0.31 lower)
MODERATE
Sputum TNF- a (Better indicated by lower values)
4 Serious1 Serious2 No serious indirectness Serious4 Reduced effect for RR>>1 or RR<<13 103 103 SMD 1.05 lower
(1.97 to 0.13 lower)
LOW
1Allocation concealment in majority of studies was unclear; ITT was not applied in some incomplete data analysis
2Heterogeneity was high
3Severity of COPD and duration of treatment
4The sample size was small

Table 3: The quality of grading of recommendation assessment by GRADE pro.

Outcomes

In twenty two studies with 1,755 participants, the serum level of IL- 8, TNF-α, TGF-β1, and IL-6 were analyzed. Sputum levels of IL-8 and TNF-α were tested and reported in eight studies with 498 participants. Sputum level of IL-10 and MMP-9 was tested in one study [38]. The original data of IL-8, IL-6, TNF-α, and TGF-β1 were not included in four studies, and therefore not included in the meta-analysis [23,24,26,30].

Due to the usage of both Enzyme-Linked Immunosorbent Assay and Radioimmunoassay, the different units were converted and consolidated based on the Wang study before the meta-analysis [29].

Results of serum level of IL-8, TNF-α, IL-6 and TGF-β1

The serum level of IL-8 was analyzed in ten studies with 1,020 participants. Wang 2014 [29] was a three-arm clinical trial that compared the control group with two CHM groups. The data from Wang 2014 was used twice. Figure 3 showed that the serum level of IL-8 was significantly reduced in eleven studies with 1,111 patients [17,21,28,29,32-37,41] (MD-1.27, 95% CI [-1.86, -0.68]) (p<0.0001).

lung-diseases-treatment

Figure 3: Meta-analysis of CHM plus bronchodilators versus bronchodilators with reduction of serum IL-8 at the end of treatment as the outcome.

In eight studies with 648 participants, the serum level of TNF-α was found to be significantly reduced [17,21,22,27,32,33,36,43] (MD -0.72, 95% CI [-1.01, -0.43]) (p<0.00001) (Figure 4).

lung-diseases-treatment

Figure 4: Meta-analysis of CHM plus bronchodilators versus bronchodilators with reduction of serum TNF-a at the end of treatment as the outcome.

In five studies with 602 participants, the serum level of IL-6 was found to be significantly reduced [17,29,41,42,44]. Figure 5 shows six studies with 693 patients. The data was used from Wang [29] twice (MD-0.75, 95% CI [-0.90, -0.60]) (p=0.02) (Figure 5).

lung-diseases-treatment

Figure 5: Meta-analysis of CHM plus bronchodilators versus bronchodilators with reduction of serum IL-6 at the end of treatment as the outcome.

In four studies with 552 participants, the serum level of TGF-β1 was found to be significant reduced [17,19,29,43]. Figure 3 shows six studies with 643 patients. The data was used from Wang [29] twice (MD -123.62, 95% CI [-134.33, -122.91]) (p=0.003) (Figure 6).

lung-diseases-treatment

Figure 6: Meta-analysis of CHM plus bronchodilators versus bronchodilators with reduction of serum TGF-ß1 at the end of treatment as the outcome.

Results of sputum level of IL-8 and TNF-α

In seven studies with 438 participants, the sputum level of IL-8 was found to be significantly reduced [16,18,20,31,38-40] (MD -0.88, 95% CI [-1.45, -0.31]) (p=0.002) ) (Figure 7).

lung-diseases-treatment

Figure 7: Meta-analysis of CHM plus bronchodilators versus bronchodilators with reduction of sputum IL-8 at the end of treatment as the outcome.

In four studies with 206 participants, the sputum level of TNF-α was found to be significantly reduced [20,25,31,40]. Due to the wide range of values of TNF-α among these studies, Std.MD was used in the analysis (Std.MD -1.05, 95% CI [-1.97, -0.13]) (p=0.02) (Figure 8).

lung-diseases-treatment

Figure 8: Meta-analysis of CHM plus bronchodilators versus bronchodilators with reduction of sputum TNF-a at the end of treatment as the outcome.

Adverse events

Minor adverse events (AEs), such as abdominal distension, were found in five patients in one study [40]; two studies reported no AEs [16,24]; Wang [29] reported similar percentage ratio of subjects that experienced AEs. The remaining studies did not mention occurrence of AEs.

Discussion

This SR included 29 RCTs, and focused on the change in concentration levels of inflammatory mediators in both serum and sputum in patients with stable COPD. The experimental group received oral CHM (in the form of pill, tablet, granule, capsule, or decoction) plus bronchodilators (per GOLD guideline). The control group received bronchodilators, either alone or with placebo. Six studies were found in English databases and twenty three in Chinese databases. Twenty seven studies were conducted in China and two in Japan.

The methodological quality was of low risk-of-bias for all domains in two studies. The quality of evidence was assessed as low by GRADEpro for the meta-analysis of TNF-α in induced sputum, and moderate for other inflammatory mediators.

The study findings indicated that certain CHM formulae appear to reduce systemic inflammatory response in patients with stable COPD. A significant reduction in the concentration of IL-8, IL-6, and TNF-α, and TGF-β1 in serum, and IL-8 and TNF-α in induced sputum were found in the experimental groups compared to control groups. In addition, a statistically significant higher heterogeneity rate was also found through meta-analysis, which maybe correlated to the duration of intervention, severity of COPD, various differentiation syndromes, usage of various bronchodilators, and subject population in each trial. Further sub-analysis was not conducted in this SR due to limitation of high amount of studies.

Three RCTs reported a change in the concentration level of IL-8, IL-6, MMP-9, and TNF-α in induced sputum for stable COPD patients treated with salmeterol/fluticasone, roflumilast, and nutritional supplementation [46-48]; improvement to lung function and quality of life were also observed in the same studies. Therefore, the reduced level of inflammatory mediators in either induced sputum or serum may have caused a decrease in airway inflammation, which presumably explains the MOA.

TNF-α, IL-8 in serum, and lung function were assessed in twelve studies [22-24,26,27,29,32,34-37,41]. The QoL was assessed by the St. George Respiratory Questionnaire in five studies [19,24,29,30,37]. TNF-α in sputum and lung function was assessed in three studies [25,31,40]. All results demonstrated that usage of adjunctive CHM had similar anti-inflammatory effect as salmeterol/fluticasone, roflumilast and nutritional supplementation, which further indicates CHM’s potential MOA.

The theory of Chinese Medicine (CM) defines COPD as lung distension, and its differentiation of syndromes (differential diagnosis) include phlegm retention and deficiency of organs, which mainly correlates to deficiencies in lung, spleen, and kidney function. The goal of CM is to replenish the lung, invigorate the spleen, and tonify the kidney. In the 29 studies, the two most commonly used formulae were Bu Fei Tang (replenish lung) and Bu Zhong Yi Qi Tang (invigorate spleen). The most commonly used herbs consisted of Huang Qi (Astragalus membranaceus), Bai Zhu (Atractylodes macrocephala), Dang Shen (Codonopsis pilosula), and Wu Wei Zi (Schisandra chinensis).

Previous studies (on animal models) have shown that Bu Fei Tang affected the expression of MMP-9 on airway remodeling, and significantly reduced the level of TNF-α and IL-8 in a COPD rat model in Bronchial Alveolar Lavage Fluid with lung Qi deficiency [49,50]. Bu Zhong Yi Qi Tang has been shown to increase the rat T-lymphocytes division and the amount of IL-2 produced in mice with spleen deficiency [51].

Ginseng is consisted of ginsenosides and ginseng polysaccharides. Its pharmacological actions have been investigated worldwide. In mice, the extract was found to decrease airway inflammation [52].

Astragalus was found to modify responses of lipopolysaccharidestimulated macrophages and reduce the production of TNF-α, IL-6 and IL-10 [53]. Dang Shen extract (Codonopsis pilosula) was found to suppress the release of TNF-α, also indicating anti-inflammatory effects [54].

One of the components of Wu Wei Zi (Schisandra chinensis) is Schisandrin B, which down-regulated the production of proinflammatory mediators, such as TNF-α and IL-6. Bai Zhu (Atractylodes macrocephala) extracts were found to have anti-inflammatory effects on TNF-α and nitric oxide production from peritoneal macrophages in mice [55] and in a rat lung cell membrane chromatography model [56].

Based on clinical studies and experiments, the MOA of CHM on COPD includes: 1. Decrease in cytokine levels and suppression of airway inflammation; 2. Improvement of overall immune functions; 3. Maintenance of oxidant-antioxidant balance; and 4. Regulation of proteases and anti-proteases levels [57].

However, due to inconsistent methods used to measure inflammatory mediators, the small number of studies, the small sample size, and poor quality of methodology of certain studies, the effect of CHMs on inflammatory mediators could not be completely confirmed. Moreover, AEs related to liver and kidney function should be investigated in future clinical trials. Further, RCTs on CHM therapy should be reported through CONSORT 2010 [14,58].

Conclusion

This SR explains CHM’s mechanism of action, demonstrates CHM’s anti-inflammatory effects, and shows that CHM is well tolerated by patients with stable COPD. Furthermore, using CHM adjunctively has shown to be beneficial in treating and slowing the progression of COPD.

Author’s Contribution

Dr. Xuedong An and Dr Qing Miao are the guarantor, and will take responsibility for the manuscript, including the data and analysis of data. They contributed to the concept and design of this systematic review. XC, CQ, and BW contributed to data research and extraction. Dr. Yifei Du, Xiaodong Cong and Carole Yujia Qiao had full access to all the data in the study and take responsibility for the integrity of the data, accuracy of data analysis, and interpretation of data. Xuedong An and Carole Yujia Qiao contributed to writing the first draft of this manuscript. Xiaodong Cong, Bing Wang, and Qing Miao contributed by reviewing the manuscript. Xuedong and Yifei Du contributed to the final revision of the manuscript.

Funding

This study was funded by Beijing Municipal Science and Technology Commission of China (NO.Z131107002213053). The sponsors were not involved in this manuscript.

Acknowledgement

We thank the Beijing Municipal Science and Technology Commission of China for supporting this study.

References

Citation: Miao Q, Cong X, Du Y, Wang B, Qiao CY, et al. (2016) Anti-Inflammatory Effects of Chinese Herbal Medicine on COPD: A Systematic Review. Lung Dis Treat 2: 107. Doi: 10.4172/2472-1018.1000107

Copyright: © 2016 Miao Q, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Review summary

  1. jennifer snoddy
    Posted on Dec 14 2016 at 6:59 am
    How can I explain this to the world that there is a man who can cure COPD, I was diagnosed for the past 9years I have being into COPD drug since then,so I decide to look for help in the internet then I found this woman post write about this great man Dr.Abumere, telling people about him that this man have cured to COPD I don’t believe that because all I have in mind is COPD had no cure,thank god for my life today am COPD negative through the power of Dr.Abumere, I contacted this man for help because who write about him drop an email of the man I pick the email and emailed him for the cure this man told me what to do about the cure well am from Philadelphia so i bought the medicine from him,he deliver it to me without wasting any time because he told me my health is so much important to him,so i receive the herbal remedies on the address given to him,so i go with the instruction given to me,truly i went for check up which the doctor told me that am fully cured he was also surprise because i told him about this great doctor tho he never believed him,I'm a great testimony of it so i assure you that once you use his herbal medicine you shall be one,you can simply email him and follow the instruction given to you. Email address :[email protected] thank you Dr i will never stop sharing you testimony

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