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Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Collaborative Innovation Centre for Biotherapy, Chengdu 610041, China
Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Collaborative Innovation Centre for Biotherapy, Chengdu 610041, China
Corresponding author. Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Collaborative Innovation Centre for Biotherapy, Chengdu 610041, ChinaDepartment of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
Despite advances in asthma management, exacerbations constitute a significant health economic burden.
Objective
To observe the efficacy and safety of Chinese herbal medicine formula entitled PingchuanYiqi (PCYQ) granule, on acute asthma and to explore its possible mechanism.
Materials and methods
This proof-of-concept study consisted of a randomized, double-blind, placebo-controlled trial in patients with acute asthma (n = 300). Participants with acute mild-to-moderate asthma recruited from seven centers in China were randomly assigned to receive PCYQ or placebo. The primary outcomes were PEF (L/min) and total asthma symptom scores. Furthermore, a panel of cytokines including serum IL-4, IL-5, IL-6, IL-8, IL-1β, IL-17A, IFN-α, IFN-β, IFN-γ, CRP, CCL-5, IP-10, and PGD2 levels was detected using ELISA.
Results
The PCYQ (n = 139) significantly improved the morning PEF on day 4 (349.73 ± 93.92 vs. 313.56 ± 92.91 L/min, P = 0.004) and day 7 (360.42 ± 94.39 vs. 329.52 ± 95.97 L/min, P = 0.023), and the evening PEF on day 4 (352.65 ± 95.47 vs. 320.58 ± 95.30 L/min, P = 0.012) and day 7 (360.42 ± 94.39 vs. 336.86 ± 95.59 L/min, P = 0.029) in comparison with the placebo (n = 143). The PCYQ also improved the clinical symptoms scores and reduced the puffs of short-acting β2-agonist (all P < 0.05). Furthermore, the PCYQ statistically reduced IL-5, IL-8, IL-1β and PGD2 in serum.
Conclusion
The PCYQ as the Chinese herbal medicine formula significantly improves lung function and symptoms of acute asthma, and reduces SABA dosage possibly via decrease of inflammatory biomarkers such as IL-5, IL-8, IL-1β and PGD2.
Asthma is one of the most common chronic diseases worldwide affecting 1–18% of the population in different countries. The long-term goals of asthma management are to achieve asthma control and to minimize future risk of exacerbations. Poor asthma control and exacerbations have significant implications for individuals and health care providers, and constitute a significant health economic burden [
]. Exacerbations of asthma are episodes which are characterized by a progressive increase in symptoms of breathlessness, cough, wheezing or chest tightness and progressive decrease in lung function, and represent a change from the patient's usual status that is sufficient to require a change in treatment [
An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.
]. Potent anti-inflammatory corticosteroids and β2-agonists can improve asthma symptoms and are recommended by Global Initiative for Asthma management (GINA) [
] and other guidelines. Systemic corticosteroids have broad immuno-suppressive effect and potential serious side-effects, and may further promote viral-induced acute exacerbations [
], although these adverse effects with inhaled corticosteroids are very low. Chronic use of these drugs can also cause disturbance of adrenal function, particularly long-term growth in children [
]. Traditional Chinese medicine (TCM) has been increasingly shown to be one of the complementary and alternative remedies in the treatment of asthma exacerbations.
Asthma has long been treated using herbs in multiple traditional medicine systems in Europe, the Middle East and China [
Effects of Traditional Chinese Medicine herbs for tonifying Qi and kidney, and replenishing spleen on intermittent asthma in children aged 2 to 5 years old.
] that TCM is effective in chronic persistent asthma, despite a lack of recommendations by the international guidelines. For example, A randomized, double-blind, placebo-controlled, and crossover study by Urata et al. [
] showed that TJ-96 as herbal medicine improved the inhaled methacholine-induced PC20, eosinophils and symptoms after 4-week treatment in chronic asthma. Chang et al. conducted a 6-month randomized, double-blind, placebo-controlled trial to explore effects of the TCM formula STA-1 in chronic mild-to-moderate asthma [
]. As a result, STA-1 has a statistically significant reduction of symptoms scores, systemic steroid dose, IgE levels, and improvement of FEV1. Chan et al. found the Ding Chuan Tang as a Chinese herb decoction improved airway hyper-responsiveness, and symptom and medication scores in a 12-week randomized, double-blind, placebo-controlled trial [
]. A double-blind, randomized trial by Wen and his colleagues found anti-asthma herbal medicine entitled ASHMI that consisted of Ganodermalucidum, Sophoraflavescens and Glycyrrhizauralensis, appeared to be a safe and effective alternative remedy for treating persistent moderate-severe asthma with no adverse effect on adrenal function [
] including 29 randomized controlled trials indicated herbal medicines could improve lung function, use of rescue medication and asthma control, although it was of the low or moderate quality of the evidence assessed by GRADE approach.
Chinese herbal medicine formulas have also been shown to have antiviral and immunomodulatory effects [
Effects of Astragalus membranaceus in promoting T-helper cell type 1 polarization and interferon-gamma production by up-regulating T-bet expression in patients with asthma.
], which would have potential implications for treatment of asthma exacerbations. The Chinese herbal medicine formula named Pingchuan Yiqi (PCYQ) in treatment of acute asthma has been widely and empirically used in Chinese population, although it indicated that PCYQ, composed of nine herbs including many chemical compounds, has multiple effects such as anti-allergic reaction, anti-inflammation, antitussive, and bronchial relaxation in vitro studies and animal models (supplementary materials). However, there are few well-controlled studies that support the efficacy of herbal remedies in the treatment and clinical improvement of patients with asthma exacerbations. In this study we conducted the multi-center, randomized, double-blind, placebo-controlled, proof-of-concept trial to observe the efficacy and safety of Chinese herbal medicine formula named PCYQ in asthma exacerbations, and to explore its possible mechanism of action.
2. Methods
2.1 Study design
This proof-of-concept study consisted of a multi-center, randomized, double-blind, placebo-controlled trial from July 2011 to December 2012 at seven sites in China. The study was in conformance with Good Clinical Practice standards and was approved by Institutional Review Board at West China Hospital, Sichuan University (Chengdu, China), with the ethics approval number No. 201004. All participants with acute asthma signed written informed consent forms before enrollments. This study was registered with No. ISRCTN61674768 at https://doi.org/10.1186/ISRCTN61674768 [
], which would improve the reporting quality of this randomized controlled trial for Chinese herbal medicine formula in treatment of acute asthma (Table E1).
2.2 Subjects
Subjects aged 15–75 years who presented within 72 h after onset of mild to moderate asthma exacerbations were enrolled. Asthma was diagnosed according to GINA [
] based on current (within the past 12 months) episodic symptoms, physician diagnosis, and confirmed evidence of airway hyperresponsiveness or a 12% or greater improvement inforced expiratory volume in 1 s (FEV1) after bronchodilator. The severity of asthma exacerbations was defined by an official ATS/ERS statement [
An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.
] and GINA 2006 (Table E2). The controller therapies for at least one month before this study need unchanged for eligible subjects during this acute asthma episode. If the subjects received any more additional maintenance therapies such as theophylline, corticosteroids, or leukotriene modifiers during this acute asthma episode before entry, they were excluded. Further, they also were excluded if were pregnant or breastfeeding, had uncontrolled co-morbidities, or if they have ever experienced invasive mechanical ventilation or ICU stay for asthma. Equal allocation randomization into either Chinese herbal medicine formula or placebo interventions, stratified by centers, was performed using computerized by PROCPLAN of the analysis system of SAS (Version 6.12 for Windows) and stratified by the seven centers. Allocation sequence was placed in a sealed envelope and study investigators and patients were blinded to treatment allocation.
2.3 Interventions
The formula of PCYQ granule (Lot number: YBZ09112005; Validity: 2 years) form used in this study was composed of nine herbs including Mahuang, Hongshen, Chuanshanlong, Kuxingren, Houpo, Suye, Chaihu, Chenpi, Gancao (Table 1), which was supplied by Hangzhou East China Pharmaceutical Company (Hangzhou, China) [
Two new fatty acids esters were detected in ginseng stems by the application of azoxystrobin and the increasing of antioxidant enzyme activity and ginsenosides content.
The cytotoxicity of methyl protoneogracillin (NSC-698793) and gracillin (NSC-698787), two steroidal saponins from the rhizomes of Dioscorea collettii var. hypoglauca, against human cancer cells in vitro.
The flavonoid hesperidin exerts anti-photoaging effect by downregulating matrix metalloproteinase (MMP)-9 expression via mitogen activated protein kinase (MAPK)-dependent signaling pathways.
Protective effects of hesperidin (citrus flavonone) on high glucose induced oxidative stress and apoptosis in a cellular model for diabetic retinopathy.
Constituents of the anti-asthma herbal formula ASHMI(TM) synergistically inhibit IL-4 and IL-5 secretion by murine Th2 memory cells, and eotaxin by human lung fibroblasts in vitro.
] and approved by China Food and Drug Administration (CFDA) (No.Z20050258). PCYQ was standardized to 3.0 g per bag and the color appearance, dissolved color, taste and smell for the placebo were almost similar to the PCYQ granule as the intervention. The participants with acute asthma received 6.0 g of PCYQ or placebo 3 times daily via oral administration for 7 days. During this study period, all participants were asked to maintain their controller medications and receive inhaled short-acting β2-agonist (SABA) (100 μg/puff, Ventolin, GSK, Spain) as needed in self-management. If the symptoms deteriorated after entry, the subjects were required to contact with investigators or physicians at any time for initiating further management according to GINA and China Asthma guideline.
Table 1Standard formula of Chinese herbal medicine formula entitled PingchuanYiqi granule.
Chinese name
Pharmaceutical name
Source
Place of production
Weights (%)
The possible compounds
Possible mechanism of action
Mahuang
Ephdrasinicastapf
Stems, leaves
Gansu province
12.19
Ephedrine, pseudoephedrine, methylephedrine, ephedra et al.
Inhibit the release of allergic neurotransmitters; reduce hemolysin, anti-complement effect, antiasthmatic effect [
], anti-allergic reaction, anti-inflammation, improve immune function, inhibit allergic reactions to food by preventing reductions in the ratio of IFN-γ to IL-4 and in IL-12 production induced by dietary antigens in spleen cells [
Two new fatty acids esters were detected in ginseng stems by the application of azoxystrobin and the increasing of antioxidant enzyme activity and ginsenosides content.
The cytotoxicity of methyl protoneogracillin (NSC-698793) and gracillin (NSC-698787), two steroidal saponins from the rhizomes of Dioscorea collettii var. hypoglauca, against human cancer cells in vitro.
], honokiol have promise as a novel class of anti-inflammatory agents in the treatment of chronic asthma which symptoms and pathology of asthma can be alleviated even in the presence of increased Th2 cytokines [
The flavonoid hesperidin exerts anti-photoaging effect by downregulating matrix metalloproteinase (MMP)-9 expression via mitogen activated protein kinase (MAPK)-dependent signaling pathways.
Protective effects of hesperidin (citrus flavonone) on high glucose induced oxidative stress and apoptosis in a cellular model for diabetic retinopathy.
Constituents of the anti-asthma herbal formula ASHMI(TM) synergistically inhibit IL-4 and IL-5 secretion by murine Th2 memory cells, and eotaxin by human lung fibroblasts in vitro.
The predetermined primary outcome measures were peak expiratory flow rate (PEF) and asthma symptom scores. When the participants were enrolled, the investigators trained them how to test PEF until they were qualified. Then, all patients had a measure of PEF using a PEF meter (Keka®, Shanghai, China) on admission. Participants conducted PEF monitoring at morning and evening by themselves throughout the study period, and recorded the PEF data before as-needed inhalation of SABA in the daily asthma diary. All measurements of PEF were determined according to European Respiratory Society (ERS) [
]. Asthma symptom scores were assessed using symptoms-based scale by investigators at entry and on days 4 and 8. Assessment of shortness of breath, and wheeze ranged on a scale from 0, 3, 6, and 9 scores for no, mild, moderate, severe symptoms, respectively, while measurements of chest tightness and cough ranged on a scale from 0, 1, 2, 3 for no, mild, moderate and severe symptoms. The secondary outcomes included dosage of SABA as needed during the study period, absolute and percentage of eosinophils in peripheral venous blood, the number of patients requiring systemic glucocorticoids or hospitalizations.
2.5 Cytokine assays
To explore the possible mechanisms if PCYQ improved clinical features of acute asthma, inflammatory mediators in serum were detected at entry and after treatment. Serum samples were collected from the participants (n = 60) at West China Hospital, Sichuan University (Chengdu, China), which were obtained from peripheral venous blood by centrifugation at 3000 rpm, 4 °C for 10 min (H2050R, cence®, Changsha, China), and then were frozen immediately at −80 °C for further detection. A panel of cytokines including interleukin (IL) −4, IL-5, IL-6, IL-8, IL-1β, IL-17A, interferon (IFN)-α, IFN-β, IFN-γ, chemokine ligand (CCL)-5, IFN-γ-induced protein (IP)-10, PGD2 was determined using commercially available enzyme-linked immunosorbent assays (ELISAs) (VeriKine ELISA Kit, Pestka Biomedical Laboratories, Inc., USA) following the manufacturer's instructions. The sensitivities of IL-1β, IL-4, IL-5, IL-6, IL-8, IP-10 and PGD2 were <1.0 pg/mL, <5.0 pg/mL for IL-17A, 1.0 pg/mL for IFN-α and IFN-γ, 0.1 ng/mL for IFN-β, 1.0 ng/mL for CCL-5. All of the cytokines do not cross-react with other soluble structural analogues.
2.6 Safety
All participants were required to record any unexpected signs and symptoms during the study period. Safety evaluations included adverse event reporting, physical examinations, electrocardiograms and clinical laboratory testing.
2.7 Statistical analysis
The targeted sample size of 296 randomized subjects would need to be enrolled, to allow for 20% withdrawals, in order to provide 80% power to detect a difference of 40 L/min in PEF at a one-sided 0.05 level, according to our previous study [
], thus we intended to finally recruit 300 participants. The primary and secondary efficacy measures were evaluated by using the intention-to-treat (ITT) population analysis. Safety analyses were performed on those populations who received at least one dose of medication and who had at least one follow-up for safety, whether or not they were withdrawn prematurely. Means (SDs) or medians (Q1, Q3) were calculated to summarize continuous variables if no indications were provided. For categorical variables, the proportion of patients in each category was calculated. Measurement data showing a non-normalized distribution were described as median and analyzed by the Wilcoxon rank-sum test. Frequency data were analyzed using the chi-squared (χ2) or Fisher's tests. Multi-center continuous data were analyzed using CMH method. P ≤ 0.05 for one-tailed tests was considered to be significant. All analyses were conducted using STATA 11.0 (College Station, Texas, USA).
3. Results
3.1 Participant characteristics
Of the 367 subjects who were enrolled, 67 were excluded. Thus, 300 patients underwent randomization at seven sites, of whom 282 provided sufficient data in the asthma diaries and entered into the analysis of the ITT population (Fig. 1). The rate of adherence to study medication was 98.56% for Chinese herbal medicine formula and 99.31% for placebo. The mean age was 45.5 years (SD, 14.0), and 41.8% of participants were male. All of included patients were of mild or moderate severity of acute asthma. Table 2 presents baseline demographic and clinical characteristics between the two groups. Subjects in both groups were comparable with respect to baseline demographic, asthma characteristics, baseline PEF and co-morbid diseases.
Table 2Demographic and clinical characteristics of patients at baseline.
Variables
Chinese herbal medicine formula (n = 139)
Placebo (n = 143)
P value
Demographic details
Men, n (%)
56 (40.29)
62 (43.36)
0.601
Ages(years)
45.3 ± 14.4
45.7 ± 13.6
0.808
BMI (kg/m2)
23.28 ± 2.90
22.92 ± 2.67
0.354
Current smoker, n (%)
11(7.91)
12(8.39)
0.581
Asthma features
Asthma duration (years)
3.00 (1.50–5.00)
3.00 (1.98–6.00)
0.205
Duration of asthma exacerbations (hours)
24.00 (15.50–40.00)
24.00 (12.00–36.00)
0.130
Spirometry
PEF (L/min)
308.6 ± 101.9
302.6 ± 101.8
0.625
PEF(% predicted)
72.80 ± 22.66
71.24 ± 24.38
0.582
Maintenance treatment
Use of maintenance therapy, n (%)
37(26.62)
35(24.48)
0.680
Theophylline, n (%)
5(3.60)
7(4.90)
0.568
Leukotriene modifiers, n (%)
8(5.76)
4(2.80)
0.378
Long-acting β2- receptor agonists, n (%)
4(2.88)
3(2.10)
0.731
Anticholinergics, n (%)
0(0.00)
1(0.70)
0.310
ICs, n (%)
1(0.70)
0(0.00)
0.324
Rescue therapy drugs
SABA, n (%)
40(28.78)
41(28.67)
0.794
Co-morbid diseases
Allergic rhinitis, n (%)
22(15.83)
28(19.58)
0.295
Atopic dermatitis, n (%)
4(2.88)
1(0.70)
0.371
Other diseases, n (%)
2(1.44)
4(2.80)
0.442
Data are n, n/N (%) or mean ± standard deviation (SD) or median (Q1, Q3). BMI = body mass index. PEF= Peak expiratory flow rate. ICs = inhaled corticosteroids. SABA= Short-acting β2-receptor agonists.
The morning PEF in the PCYQ group statistically improved on day 4 (349.73 ± 93.92 vs.313.56 ± 92.91 L/min, (P = 0.004) and day 7 (360.42 ± 94.39 vs. 329.52 ± 95.97 L/min, P = 0.023) compared with the placebo group (Fig. 2A), and the corresponding evening PEF in the PCYQ group was much better than that in the placebo group on day 4 (352.65 ± 95.47 vs. 320.58 ± 95.30 L/min, P = 0.012) and day 7 (360.42 ± 94.39 vs. 336.86 ± 95.59 L/min, P = 0.029) (Fig. 2B). The largest mean difference was achieved between the two groups (35.3 ± 38.23 vs. 15.0 ± 66.91 L/min, P < 0.001) in evening on day 4.
Fig. 2The improvements of morning (A) and evening (B) PEF after Chinese herbal medicine formula and placebo intervention during the 7-day treatment period. mPEF, morning PEF; ePEF, evening PEF. Bar indicated as standard error. ∗P < 0.05; ∗∗P < 0.001.
The puffs of salbutamol in the PCYQ group were less than those in the placebo group (1.60 ± 1.52 vs. 2.01 ± 1.74 puffs, P = 0.058; 1.40 ± 1.29 vs. 1.78 ± 1.48 puffs, P = 0.031; 1.15 ± 1.22 vs. 1.62 ± 1.46 puffs, P = 0.010; 0.92 ± 1.19 vs. 1.37 ± 1.37 puffs, P = 0.005; 0.69 ± 1.01 vs. 1.21 ± 1.37 puffs, P = 0.001; and 0.62 ± 1.10 vs. 1.07 ± 1.34 puffs, P = 0.003) from days 1–6 (Fig. 3). The area of under cure (AUC) analysis for SABA showed no statistical differences for the total puffs of SABA within one week of the treatment between the two groups (10 (4, 16) vs. 8 (3, 12) puffs/week, P = 0.101). Accordingly, the difference of PEF between intervention and placebo was not attributed to the usage of SABA.
Fig. 3Dosage of as-needed salbutamol use (puffs/day) after Chinese herbal medicine formula and placebo intervention during 7-day treatment period. Bar indicated as standard error. ∗P < 0.05.
Chinese herbal medicine formula significantly improved the asthma symptoms (shortness of breath, wheeze, chest tightness, and cough) compared with placebo after 4-day (−3.93 ± 6.8 vs. −2.58 ± 2.82, P = 0.002) and 7-day treatment (−5.55 ± 3. 95 vs. −3.83 ± 3.24, P = 0.001). But there were no differences in numbers of eosinophils in blood (0.206 ± 0.153 vs. 0.195 ± 0.156 × 109/L, P = 0.2753) or percentage of eosinophils (3.09 ± 2.31 vs. 3.02 ± 2.35%, P = 0.4005) between the two groups at the end of the treatment. During the study period, no patients required systemic glucocorticoids or hospitalizations due to asthma deterioration, although the patients were asked to contact physicians if asthma symptoms worsened.
3.3 Cytokines
After 7-day oral administration of PCYQ, the levels of IL-5 (−10.50 [-31.25, 5.63] vs. 3 [-14.50, 30.75] pg/mL, P = 0.0487), IL-8 (17.50 [-37.50, 33.50] vs. 2.06 [-5.36, 6.07] pg/mL, P = 0.0483), IL-1β (−2.57 [-21.88, 10.03] vs. 25.00 [1.25, 52.25] pg/mL, P = 0.027), PGD2 (0.00 [-109.84, 27.09] vs. 1.50 [-12.04, 43.26] pg/mL, P = 0.022) were statistically reduced compared with those in the placebo group. These differences remained statistically adjusted for SABA dosage, baseline asthma symptom scores and cytokine levels. However, there was no difference in levels of IL-4 (−16.00 [-34.62, 19.00] vs. 0.00 [-20.25, 14.50] pg/mL, P = 0.842), IL-6 ((7.75 [-9.50, 21.50] vs. 13.00 [1.00, 21.75] pg/mL, P = 0.536), IFN-α (−0.50 [-3.88, 5.12] vs. 0.00 [-3.25, 6.25] pg/mL, P = 0.870), IFN-β (1.00 [-2.33, 3.38] vs. 0.00 [-3.25, 4.00] pg/mL, P = 0.555), IFN-γ (−21.25 [-104.75, 62.50] vs. −8.50 [-143.50, 164.50] pg/mL, P = 0.916), CCL-5 (−0.50 [-34.13, 51.88] vs. 22.00 [-21.50, 66.00] pg/mL, P = 0.443), IP-10 (9.75 [-19.88, 20.88] vs. 3.00 [-17.25, 32.25] pg/mL, P = 0.771), and IL-17A (0.25 [-4.13, 3.00] vs. 0.00 [-2.50, 5.50] pg/mL, P = 0.265) between the two groups.
3.4 Safety
During the treatment period, Chinese herbal medicine formula was generally well tolerated compared with placebo, with no increase in withdrawal rates because of adverse events. There were 22 adverse events, half of which were in the PCYQ group, but no serious adverse events were found. Manifestations of adverse events in patients who received Chinese herbal medicine formula were palpitations (n = 2), nausea (n = 4), dry mouth (n = 1), epigastric discomfort (n = 2), insomnia (n = 1) and rash (n = 1).
4. Discussion
To our knowledge, this is the first registered randomized, placebo-controlled trial to investigate the efficacy and safety of Chinese herbal medicine formula in treatment of acute asthma. We found that Chinese herbal medicine formula significantly improved lung function, decreased the dose of SABA, and improved the clinical symptoms (shortness of breath, wheezing, chest tightness, cough) potentially via reducing systemic inflammatory biomarkers such as IL-5, IL-8, IL-1β and PGD2, with no serious adverse events.
Asthma exacerbation is an exaggerated lower airway response to an environmental exposure. Airway inflammation is a key part of the lower airway response in asthma exacerbations, and occurs together with airflow obstruction and increases airway responsiveness. Respiratory virus infections, especially human rhinovirus, is the most common environmental exposure to cause an asthma exacerbation [
]. Chinese herbs (Herba Ephdra, Semen Armeniacae Amarum, Radix Glycyrrhizae) were effective in treatment of influenza virus and rhinovirus infection in adults [
According to a study by Santanello et al., the minimal important changes for asthma measures in a clinical trial are 18.79 L/min for PEF and −0.81 puffs/day for inhaled SABA use [
]. Our study found that the Chinese herbal medicine formula significantly improved the morning and evening PEF, with difference between the two groups reached the minimal important clinical changes that ranged from 23.6 to 35 L/min. This indicates that the patients with mild to moderate asthma exacerbation could obtain a minimal important clinical improvement of lung function in PEF after a 7-day treatment of PCYQ. Therefore, PCYQ granule could improve the lung function in acute asthma. Furthermore, although there was a significantly statistical difference in the puffs of salbutamol from days 1–6 between intervention and placebo, the reduced dosage of salbutamol after treatment of PCYQ did not reach the minimal important clinical changes. This is likely due to the included participants who were mild to moderate exacerbations and the heterogeneity of asthma. Reddel HK et al. [
An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.
] reported that minimal important differences have rarely been reported for symptom scores, with most papers merely reporting statistically significant changes in mean scores. Therefore, Chinese herbal medicine formula significantly improved lung function, decreased the dose of SABA, and improved the clinical symptoms, with no serious adverse events.
The mechanisms of Chinese herbal medicines in the treatment of acute asthma is complex. Jayaprakasam et al. discovered individual ganoderma lucidum, flavescens, licorice extracts and ASHMI (the combination of individual extracts) inhibited production of IL-4 and IL-5 by murine memory TH2 cells [
]. Yang et al. demonstrated that three flavonoids of Glycyrrhizauralensis inhibited memory TH2 cells proliferation in vitro and reduced production of IL-4 and IL-5 [
]. Shih et al. discovered hesperetin which is present in the TCM ‘Tangerine peel’ significantly suppressed elevations of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including IL-2, IL-4, IL-5, IFN-γ, and tumor necrosis factor (TNF)-α in bronchoalveolarlavage fluid (BALF) [
]. Wen et al. found anti-asthma herbal medicine intervention appears to be a safe and effective alternative medicine for treating asthma in humans. In contrast with prednisone, ASHMI had no adverse effect on adrenal function and had a beneficial effect on TH1 and TH2 balance [
]. In this study, PCYQ granule and its compounds were effective in treatment of asthma exacerbations possibly involving in the mechanism of actions including inhibiting the release of allergic neurotransmitters, anti-complement effect, anti-inflammatory, antitussive effect, antiviral, antibacterial effects, enhanced antioxidant enzyme activity, corticosteroid-like effects and inhibiting TNF-α-induced ICAM-1 expression in human lung epithelial cells [
IL-1β is a subtype of IL-1 which is mainly derived from monocytes and macrophages which is a potent pyrogenic cytokine that can further increase the production of pro-inflammatory cytokines. IL-1β increased the thickness of conducting airways, enhanced mucin production, and lymphocytic aggregates in the airways. IL-1β increases the production of the neutrophil attractant CXC chemokines KC (CXCL1) and MIP-2 (CXCL2), matrix metalloproteases (MMP-9) and −12 [
]. Our study demonstrated that PCYQ granule as Chinese herbal medicine formula, reduced the systemic IL-1β level, which indicated that this Chinese herbal medicine formula could improve the exacerbation-induced airway remodeling and reduce the production of the neutrophil attractant CXC chemokines, thereby reduce the production of pro-inflammatory cytokines. PGD2, a lipid mediator released by mast cells, is known to participate in asthma inflammation. Lipid peroxidation, assessed as isoprostane levels, is found to be markedly increased in acute asthma, and falls with resolution of the exacerbation [
]. Srivastava et al. found the anti-asthma herbal medicine ASHMI inhibited airway smooth muscle contraction via prostaglandin E2 activation of EP2/EP4 receptors [
Prostaglandin D2 reinforces Th2 type inflammatory responses of airways to low-dose antigen through bronchial expression of macrophage-derived chemokine.
] were shown to prevent mast cell-related immediate and delayed allergic diseases via inhibiting PGD2 release in mast cell dependent passive cutaneous anaphylaxis animal model. We speculated that PCYQ could reduce IL-5 release through inhibiting PGD2 production. One component of the PCYQ granule, licorice could inhibit production of IL-4 and IL-5 by murine memory TH2 cells and eotaxin-1 production [
]. More importantly, PCYQ did not affect the production of antiviral cytokines (IFN-α/-β), this indicates that PCYQ may provide a more precise inhibition of cytokines involved in inflammation and fibrosis, without affecting antiviral immunity that is observed in corticosteroids [
There are some strengths in our study. First, this is the first well-designed randomized controlled trial to explore the efficacy and safety of Chinese herbal medicine formula PCYQ in asthma exacerbations. Second, we explored the possible mechanism of PCYQ as a treatment in asthma exacerbations. However, our study also has some limitations. First, we did not measure FEV1% and FVC which are quite critical in assessing airway obstruction of asthma. We used PEF because it is convenient for participants and widely used in everyday life at home, and which can be easily accessible to the participants. PEF as an indicator in lung function, has also been applied as the primary outcome in many studies [
]. Second, the time of treatment with 7 days is relatively short, but for asthma exacerbations it is enough to determine the efficacy, and further we did not include follow-up after treatment. Third, almost all subjects included were on GINA steps 1 and 2 strategies in stable stage before entry, and about 20% of them were using diverse controller drugs. However, the diverse controller drugs are evenly distributed between Chinese herbal medicine formula and placebo groups, and the fixed-dose maintenance for controlled drugs could reduce their effects on the judgment of efficacy. Fourth, our study only restricted to patients with acute mild to moderate asthma that led to no patient required systemic glucocorticoids or hospitalizations due to asthma deterioration, because this is only a proof of concept study in design. Fifth, although the statistical difference in asthma symptoms scores between the intervention and the placebo was found, the asthma symptom scoring system had not been validated before.
In conclusion, Chinese herbal medicine formula entitled PCYQ, significantly improved lung function and the clinical symptoms of acute mild-to-moderate asthma, reduced the dose of SABA, and decreased systemic inflammatory biomarkers such as IL-5, IL-8, IL-1β, and PGD2 without affecting antiviral immune responses. Furthermore, PCYQ was generally well tolerated, and its safety profile was comparable to that of the placebo group. Chinese herbal medicine formula as an important supplementary alternative medicine, could improve the shared-decision treatment for asthma patients, but it needed to be validated in patients with acute moderate to severe asthma in further studies.
Declarations of interest
None.
Funding
This study was partly supported by the National Natural Science Foundation of China (81370122, 81570023 and 81670023), Sichuan University Young Teachers Research Foundation (2017SCU11024) and Sichuan Provincial Health Department foundation (17PJ043).
Acknowledgements
All authors thank all the participants who volunteered for this study, and Dr. Chun E Jia, Dr. Chao F Chen, Dr. Yan Chen and Dr. Bin She for their assistance with this study in recruiting participants. The authors also thank Professor A. Sonia Buist, MD, in the Department of Pulmonary and Critical Care Medicine at Oregon Health & Science University, Portland, OR, Dr. William Vollmer, PhD, at the Kaiser Permanente Center for Health Research in Portland, OR, Assistant Professor Christianne Lane, PhD, Keck School of Medicine, University of Southern California, Los Angeles, CA, Professor David Hsiang-Shan Au, MD, Division of Pulmonary and Critical Care Medicine, at the VA Puget Sound Health Care System, at the University of Washington, WA, Dr. Diana Buist, MPH, PhD, at the University of Washington School of Public Health, WA, for their beneficial comments on this study during the American Thoracic Society (ATS) Methods in Epidemiologic, Clinical, and Operations Research (MECOR) training course in Cesme, Turkey in 2015.
Appendix A. Supplementary data
The following are the supplementary data related to this article:
An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.
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Two new fatty acids esters were detected in ginseng stems by the application of azoxystrobin and the increasing of antioxidant enzyme activity and ginsenosides content.
The cytotoxicity of methyl protoneogracillin (NSC-698793) and gracillin (NSC-698787), two steroidal saponins from the rhizomes of Dioscorea collettii var. hypoglauca, against human cancer cells in vitro.
The flavonoid hesperidin exerts anti-photoaging effect by downregulating matrix metalloproteinase (MMP)-9 expression via mitogen activated protein kinase (MAPK)-dependent signaling pathways.
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Constituents of the anti-asthma herbal formula ASHMI(TM) synergistically inhibit IL-4 and IL-5 secretion by murine Th2 memory cells, and eotaxin by human lung fibroblasts in vitro.
Prostaglandin D2 reinforces Th2 type inflammatory responses of airways to low-dose antigen through bronchial expression of macrophage-derived chemokine.
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