Gao Zhen, Jing Jing, Xu Dan, Li Zheng, Li Fengsen, and Sun Qi. Correspondence should be addressed to Li Fengsen;

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1 Hindawi Evidence-ased Complementary and Alternative Medicine Volume 7, Article ID 98, pages Research Article A Randomized Controlled Study of the Yi Qi Gu iao Pill in the Treatment of Frequent Exacerbator Phenotype in Chronic Obstructive Pulmonary Disease (Lung and Spleen Qi Deficiency Syndrome) Gao Zhen, Jing Jing, Xu Dan, Li Zheng, Li Fengsen, and Sun Qi National Clinical Research ase of Traditional Chinese Medicine, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi 8, China Correspondence should be addressed to Li Fengsen; fengsen6@6.com Received July 7; Revised 7 October 7; Accepted 9 October 7; Published December 7 Academic Editor: Albert S. Yeung Copyright 7 Gao Zhen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To evaluate the efficacy and safety of Yi Qi Gu iao (YQG) pill in treating frequent exacerbator phenotype in chronic obstructive pulmonary disease (lung and spleen qi deficiency syndrome) (FEPCOPD). Methods. This prospective, randomized, double-blind, controlled study assessed cases (6 included) of FEPCOPD treated at the outpatient department in our hospital in January August 6. The patients were randomly divided into YQG and placebo (Pb) and treated for three. Lung function,,, and symptom scores (s) were observed. Results. Compared with Pb, YQG showed decreased wheezing symptom scores (WSs) and s at one and decreased and s at three. From one to three,, cough, sputum, WSs, and s in YQG were lower than pre values. ut in Pb, was lower than pre values after one ;, sputum, and s were lower than pre values after two ;, cough, sputum, WSs, and s were lower than pre values after three. Conclusion. Yi Qi Gu iao pill can improve wheezing, health status, and s in FEPCOPD and also can shorten the durations of cough, sputum, and wheezing. This trial is registered in the Clinical Trials Registry of China: ChiCTR-IOR-7 (on 8 December ).. Introduction The clinical phenotype refers to disease characteristics associated with clinical manifestations such as symptoms, acute exacerbation, response, disease progression, and death that can reflect the differences among COPD patients [] and has constituted a hot research topic for chronic obstructive pulmonary disease (COPD) in recent years. Phenotypic identification not only helps understand the differences between COPD types, but also more importantly has potential diagnostic and therapeutic significance; in addition, it can better reflect the heterogeneity of COPD, prompting a more comprehensive and in-depth research in COPD. According to the relationship between the clinical course of COPD and prognosis, as well as the different responses of currently available methods, three phenotypes can be distinguished, including frequent exacerbator phenotype, COPD-asthma overlap, and emphysema-airway hyperresponsiveness []. The frequent exacerbator phenotype is the most frequently encountered in COPD patients; it occurs notonlyintheseverephaseofcopd,butalsoin% of patients with GOLD grade disease []. The frequent exacerbator phenotype in COPD refers to patients with more than two yearly disease episodes, with oral administration of glucocorticoids and/or antibiotics needed each time, or those requiring hospitalization []. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in the bacterial colonization lower airways, and a possible increased susceptibility to viral infections. Patients with the frequent exacerbator phenotype are also at increased risk of comorbid extrapulmonary diseases, including cardiovascular disease, gastroesophageal

2 Evidence-ased Complementary and Alternative Medicine reflux, depression, osteoporosis, and cognitive impairment. Overall, these patients have poorer health status, accelerated loss of forced expiratory volume over s (FEV), worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype []. Therefore, the frequent exacerbator phenotype in COPD is well worthy of special attention from clinicians and scientists. A previous research demonstrated that [] Yi Qi Gu iao pill can prolong the interval of acute exacerbation in COPD patients by days, while reducing the number of acute exacerbations by./6. Moreover, its therapeutic effects are consistent with the main purpose for the frequent exacerbator phenotype in COPD, that is, reduction of the number of acute exacerbations. Therefore, this randomized controlled study assessed the efficacyandsafetyofyiqiguiaopillintreatingthe frequent exacerbator phenotype in COPD (lung and spleen qi deficiency syndrome) [6].. Materials and Methods.. Diagnostic Criteria. The diagnostic criteria of COPD were based on the Global Strategy for Diagnosis, Treatment, and Prevention of Chronic Obstructive Pulmonary Diseases (Revised Edition in ) [7]. The diagnostic criteria for the frequent exacerbator phenotype in COPD were [, ] more than two yearly disease onset events, requiring oral administration of glucocorticoids and/or antibiotics and requirement for hospitalization during. years were used as a prospective endpoint... Diagnosis and Criteria of Syndrome Differential Classification. Diagnostic criteria for lung and spleen qi deficiency syndrome were based on the diagnostic criteria of syndromes for chronic obstructive pulmonary disease ( revision) proposed by the Committee of Chinese Medicine Association of Internal Medicine ranch of the Pulmonary Disease [8]... Inclusion Criteria. The following inclusion criteria were adopted: () diagnostic criteria for chronic obstructive pulmonary disease at a stable stage; () diagnostic criteria of syndrome of qi deficiency of lung and spleen; () age between and 7 years; () survival period greater than three ; () good compliance, agreement to cooperate in this study, and signed informed consent... Exclusion Criteria. Patients were excluded due to the following: () comorbidity with diseases such as bronchial asthma, tuberculosis, bronchiectasis, pulmonary cystic fibrosis, lung cancer, lung abscess, and congestive heart failure; () combined primary diseases such as severe cardiovascular and cerebrovascular diseases, liver and kidney ailments, and hematopoietic system diseases; () pregnant or lactating women; () mental diseases; () disability such as blindness, deafness, mental retardation, and physical impairment; (6) allergy or contraindications to the experimental drugs; (7) combined with tumors; (8) congenital or acquired immunodeficiency; and (9) implication in other clinical experiments within the past... Withdrawal Criteria. The following were considered: () patient change of medical prescription half-way or supplementation of a combination of nonprescribed drugs, especially those that have large impact on the experimental drugs, affecting judgment of effectiveness and safety; () development of allergic reactions or serious adverse events; () other complications and special physiological changes disqualifying from further testing; and () voluntary withdrawal..6. Administration Method []. The YQG group was treated with the drug during stable stage as recommended by the Global Strategy for the Diagnosis, Treatment, and Prevention of Chronic Obstructive Pulmonary Disease ( revision). Meanwhile, oral administration of the Yi Qi Gu iao pill ( pills/time and.9 g/pill) was performed three times every day with a total course of weeks. The Pb group was treated based on the the Global Strategy for the Diagnosis, Treatment, and Prevention of Chronic Obstructive Pulmonary Disease (the revision). Meanwhile, oral administration of the placebo ( pills/time and.9 g/pill) was performed three times every day with a total course of weeks..7. Observation Outcomes and Methods.7.. Pulmonary Function Test. The pulmonary function of patients was tested on a HI- pulmonary function instrument manufactured by CHEST Co., Ltd., Japan. efore the test, the investigators first explained the specific operational procedures and requirements to the subjects to ensure accurate and reliable results. All operations were completed by the same technician, and the following pulmonary function indicators were detected: forced expiratory volume in one second (FEV) and FEV percentage in the predicted value (FEV% pred), forced vital capacity (FVC) and FVC percentage in the predicted value (FVC% pred), and FEV/FVC..7.. Assessment Methods and Standards of COPD Assessment Test (). The Chinese version of the scoring questionnaire was used [9]. The questionnaire comprises a total of eight questions, including cough, sputum, chest tightness, the feeling of climbing or climbing a staircase, housework, degree of confidence away from home, sleep, and energy. The score for each question from mild to severe diseasewas ;thetotalscorewascalculatedafter scoring each question by the patients, and scores ranged between and. Upon definite diagnosis, the same researcher explained the questionnaire contents and the scoring method to the patients. The patients filled the questionnaire independently without reminder. Finally, two investigators evaluated the scores..7.. Classification Criteria of Modified Medical ritish Research Council () []. The disease was graded

3 Evidence-ased Complementary and Alternative Medicine as follows:, dyspnea occurring only during exercise;, shortnessofbreathonlyafterfastwalkingonaflatsurfaceor walking up a small slope;, due to shortness of breath, slower walking on a flat surface than the peers or need to stop for rest;, stop breathing after walking for about meters on aflatsurfaceorafewminutes;,inabilitytoleavehomedue to severe dyspnea, or dyspnea occurring during dressing and undressing..7.. Syndrome. The was based on the quantitative criteria of chronic bronchitis symptom standards in Guidelines for Clinical Research of Chinese Drugs, including the eight syndromes of cough, sputum, wheezing, weight loss, fatigue, poor appetite, abdominal distension, and loose stool..8. Statistical Methods. Group-wise comparison between the YQG and Pb groups was performed by independent samples t-test; comparison before and after the foreachgroupwasassessedbypairedt-test. Chi-square test was used for categorical variables. For the, the minimally important difference is generally accepted as a - point change, so chi-square test was used for categorical data and<.ap value of <. was deemed statistically significant. All data were analyzed with SPSS version 7. (IM Corp., Armonk, NY, USA).. Results.. General Data. The subjects were follow-up visit patients at the National Clinical Research ase of Traditional Chinese Medicine of the Affiliated Hospital of Xinjiang Medical University, between January 6 and August 6. A randomized, double-bind, single-, and parallel controlled experimental design was used. The patients were divided into the YQG and Pb groups, with each group involving 6 patients. After exclusion, there were patients in the YQG group and in the Pb group. There were no statistically significant differences in gender, height, weight, age, MI, pulmonary function,,, and (Table ) between the two groups of patients... Group-Wise Comparison... Pulmonary Functions between YQG and Pb Groups. There were no statistical significant differences in pulmonary functions between the YQG and Pb groups, within the three of (Figure )....,, and Syndrome s. etween the YQG and Pb groups, the YQG group showed a reduced score of wheezing symptom at one compared with the Pb group (P <.); was reduced as well (P <.). The YQG group showed decreased (P <.) andsyndrome(p <.) scoresatthree compared with the Pb group (Figure, Table ). Table : Characteristics of the study groups. YQG Pb Demographic data n = n = Age (years) 68.7 ± ±. Gender (male/female) 6/7 / MI. ±.86. ±. Height 6.8 ± ± 7.68 Weight 6. ± ±.8 Smoking habit n = n = Smoking 9 Non smoking Course of disease n = n = Course of disease (years) 6.8 ±. 7.6±.9 Scale score n = n = 6. ± ± 9.. ±.79. ±.6.8 ±.66. ±.7.8 ±..97 ±.6.7 ±.. ±.69 symptoms.97 ±.8.8 ± 6.6 Spirometry n = n =8 FEV/FVC.7 ±.7.87 ±.9 FEV.76 ± ±.7 Table:ThechangeofbetweentheYQGandPbgroups. The change of after one (n) < The change of after two (n) < The change of after three (n) < YQG 7 Pb 8 6 X P Pulmonary Functions before and after the Treatment between the YQG and Pb Groups. There were no statistical significant differences in these parameters at different time compared to pre values in both YQG group and Pb group (Figures 8)....,, Main Symptom, and Syndrome s before and after the Treatment between the YQG and Pb Groups. After one, in the YQG group scores were lower than pre values (P <.); cough, sputum, and wheezing symptom scores were also lower (P <.), as well as s (P <.). In the Pb group, was lower than pre values (P <.) (Figures 9 and ). After two, in the YQG group, scores were lower than pre values (P <.), as well as cough, sputum, and wheezing symptom scores (P <., P <., and P <.), and s (P <.). In the

4 Evidence-ased Complementary and Alternative Medicine efore FEV/FVC 6 6 efore FEV efore FVC efore FEV% pre 8 6 efore FVC% pre YQG Pb Figure : Pulmonary functions in the two groups in three of. Pb group, only and sputum symptom scores were lower than pre values (P <., P <.)(Figuresand ). After three, in the YQG group, scores were lower than pre values (P <.), as well as cough, sputum, and wheezing symptom scores (P <.) and s (P <.). In the Pb group, scores were lower than pre values (P <.), as well as cough, sputum, and wheezing symptom scores (P <.) and s (P <.) (Figures and )... Adverse Reactions. There were no abnormal changes of clinical significance in laboratory indicators such as blood and urine routine tests, renal function, and ECG. Moreover, there were no adverse reactions such as nausea, abdominal pain, and diarrhea.. Discussion COPD prevalence is 8.% in the subpopulation above years old in the seven provinces in China [] and.% in Korea []. COPD is an important cause of disability and

5 Evidence-ased Complementary and Alternative Medicine efore efore..... efore efore efore efore of symptoms YQG Pb YQG Pb Figure :,, and s in the two groups in three of. P <., P <.. death worldwide, imposing huge and growing economic and social burden to mankind []. Therefore, how to effectively control COPD has become a major public health problem that needs urgent solution. COPD is a disorder of progressive airflow limitation caused by chronic inflammation of the airways and lung parenchyma; it is associated with symptoms such as cough, sputum production, and dyspnea []. However, the risk of acute exacerbation in COPD patients with symptoms of chronic cough and sputum is increased by. times, with the risk of hospitalization due to acute exacerbation increasing by.8 times []. Meanwhile, increasing symptom burden is associated with higher health care resource utilization with a detrimental impact on work productivity [6]. Therefore, symptomatic has a great clinical appeal for COPD patients. However, according to syndrome difference based on the four diagnostic principles of diagnosis through observation, diagnosis through auscultation and olfaction, diagnosis through inquiry, and diagnosis through pulse feeling is the characteristic and one of the advantages of traditional Chinese medicine. The Yi Qi Gu iao pill, a compound preparation including Chinese herbs (Salvia miltiorrhiza unge, lighted wheat, Atractylodes macrocephala Koidz, Pinellia ternate, Citrus reticulata lanco, Perilla frutescens (L.) ritt., Poria cocos (Schw.) Wolf, Saposhnikovia divaricata (Trucz.) Schischk.,

6 6 Evidence-ased Complementary and Alternative Medicine FEV/FVC FEV FVC FEV% pre FVC% pre FEV/FVC FEV FVC FEV% pre FVC% pre efore the After one Figure : Pulmonary functions in the YQG group after one and before. efore the After three Figure : Pulmonary functions in the YQG group after three and before the FEV/FVC FEV FVC FEV% pre FVC% pre FEV/FVC FEV FVC FEV% pre FVC% pre efore the After two Figure : Pulmonary functions in the YQG group after two and before the. efore the After one Figure 6: Pulmonary functions in the Pb group after one and before the. Coix lacryma-jobi L. war.ma-yuen (Roman.) Stapf, Tussilago farfara L., Scutellaria baicalensis Georgi, Fritillaria cirrhosa D. Don, and Eriobotrya japonica (Thunb.) Lindl.) is used to treat COPD at a stable stage. We found that the Yi Qi Gu iao pill improves the quality of life of COPD patients at a stable stage, reducing the number of annual acute exacerbation events []. COPD is a publicly recognized heterogeneous disease, with therapeutic responses greatly differing even for patients with thesamesymptomsanddrugs[7].asedonapreviousstudy, to evaluate the efficacy and safety of the Yi Qi Gu iao pill for treating the frequent exacerbator phenotype in COPD (lung and spleen qi deficiency syndrome), we conducted a randomized, double-blind, placebo-controlled superiority trial. This study only included the exacerbator phenotype in COPD (lung and spleen qi deficiency syndrome), as subjects to obtain a small sample size in order to standardize the group homogeneity of syndrome differentiation and further clarify the effectiveness or ineffectiveness of the Yi Qi Gu iao pill. The Yi Qi Gu iao pill had little impact on pulmonary function in patients with the exacerbator phenotype in COPD (lung and spleen qi deficiency syndrome), with equivalent efficacy with the Pb during the of. However, FVC values after two and three of with Yi Qi Gu iao pill were increased compared with pre counterparts. Changes of pulmonary function parameters before and after the were not significant. There were no statistically significant differences in the changes of pulmonary function parameters between the two groups after with Yi Qi Gu iao pill.

7 Evidence-ased Complementary and Alternative Medicine FEV/FVC FEV FVC FEV% pre FVC% pre efore the After two Figure 7: Pulmonary functions in the Pb group after two and before the. 9 efore the After one Figure 9: and scores in the YQG group after one and before the. P <., P <., and P < FEV/FVC FEV FVC FEV% pre FVC% pre 7 efore the After three Figure 8: Pulmonary functions in the Pb group after three and before the. Research showed that wheezing correlated with a higher possibility of acute exacerbation. Even among those who were treated according to the GOLD guidelines, patients with wheezing still had worse symptom scores and more exacerbations. Our study showed that wheezing symptom scores one after with Yi Qi Gu iao pill were improved compared with those of the Pb group. Meanwhile, cough, sputum, and wheezing scores after one of with the Yi Qi Gu iao pill were improved compared to pre values. However, in the Pb group the cough, sputum, and wheezing scores did not improve until the third suggesting that Yi Qi Gu iao pill can cooperate with Western medicine to shorten the duration of cough, sputum, and wheezing symptoms in frequent exacerbator phenotype in COPD. efore the After one Figure : and in the Pb group after one and before the. P <.. COPD assessment test () is a new health-related scale evaluating the health status of COPD patients [8], mainly for COPD patients at a stable stage [9]. After three of with the Yi Qi Gu iao pill, scores were reduced compared with the Pb group, indicating that prolonged and sustained administration of the drug is required for its effects of improving s and

8 8 Evidence-ased Complementary and Alternative Medicine efore the After two Figure : and in the YQG group after two and before the. P <., P <.. efore the After three Figure : and in the YQG group after three and before the. P < efore the After two Figure : and in the Pb group after two and before the. P <., P <.. efore the After three Figure:andinthePbgroupafterthreeand before the. P <., P <.. the health status of patients ( ). Interestingly, Yi Qi Gu iao pill could improve scores after one, as demonstrated by comparing pre values with those after. However, the degree of improvement varied, as reflected in differences between the two groups before and after the ; this means three of with the Yi Qi Gu iao pill results in a higher degree of improvement of scores compared with Pb administration. Improvement of syndrome in the patients was better than Pb group at and after with the Yi Qi Gu iao pill. Interestingly, s were improved compared with pre values, after one ofwiththeyiqiguiaopill.however,

9 Evidence-ased Complementary and Alternative Medicine 9 such difference occurred in the Pb group only after two of. Substantial placebo effect sizes have been documented for at least years for various psychiatric symptoms []. Previous systematic reviews and meta-analyses have found placebo effect sizes that were inconsistent between studies and that have increased over time []. Findings [] indicate that interactions between personality type and environmental cues may contribute to placebo responding. So, placebo effects, including patient s cognition, expectation, attention, preference, and communication with doctor as well as doctor s suggestion, expectation, and indirect regulation of diagnosis and environment on patient s psychology, were essential factors for therapy efficacy. So, in this study, it showed improvements within the placebo groups.. Conclusion The Yi Qi Gu iao pill can improve wheezing, health status, and syndrome in patients with frequent exacerbator phenotype in COPD (lung and spleen qi deficiency syndrome) and also can shorten the durations of cough, sputum, and wheezing. Ethical Approval This study was approved by the Ethics Committee of Traditional Chinese Medicine of Xinjiang Uygur Autonomous Region (Ethics Committee Document no. XE). Conflicts of Interest The authors declare that they have no conflicts of interest. Acknowledgments ThisworkissupportedbyNationalNaturalScienceFoundation of China (no. 8678): Research of Plasma Proteomics in Patients with Frequent Exacerbator Phenotype in Chronic ObstructivePulmonaryDisease(LungandSpleenQiDeficiency Syndrome) Treated with Yi Qi Gu iao Pill. References [] M. K. Han, A. Agusti, P. M. Calverley et al., Chronic obstructive pulmonary disease phenotypes: the future of COPD, American JournalofRespiratoryandCriticalCareMedicine,vol.8,no., pp. 98 6,. [] M. 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