Original Article
Adjunctive Traditional Chinese Medicine Therapy for Patients with Chronic
Rhinosinusitis: A Population-based Study Authors
Hung-Rong Yen, MD, PhD 1,2,4,5, Mao-Feng Sun, MD, PhD 2,4,5, Cheng-Li Lin, MSc 3, Fung-Chang Sung, PhD, MPH 6, Chen-Chi Wang, MD 7,8, Kai-Li Liang, MD 7,8,9 Affiliations
1Research Center for Traditional Chinese Medicine, Department of Medical Research,
2Department of Chinese Medicine, 3 Health Data Management Office, China Medical
University Hospital, Taichung, Taiwan; 4 Chinese Medicine & Acupuncture Research Center, 5 School of Chinese Medicine, 6 Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; 7Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan; 8 Department of Medicine, National Yang-Ming Medical University, Taipei, Taiwan; 9 School of Medicine, Chung Shan Medical University, Taichung, Taiwan
Running title: Chinese medicine for chronic rhinosinusitis
Address for correspondence: Kai-Li Liang, M.D.
1650, Sect. 4, Taiwan Boulevard, Taichung 40705, Taiwan. Tel: +886-4-23592525 ext. 5405
Fax: +886-4-23596868
ABSTRACT
Background Chronic rhinosinusitis (CRS) is a chronic illness with a high prevalence
worldwide. The purpose of this study was to investigate the characteristics of adjunctive traditional Chinese medicine (TCM) use in patients with CRS.
Methods Data were retrieved from a dataset made available by the Taiwan National
Health Insurance Research Database containing the medical records of 1,000,000 randomly sampled beneficiaries insured in the year 2000. Patients newly diagnosed with CRS in the year 2000 were enrolled, and their medical records during the period 2000-2011 were collected and analyzed.
Results A total of 14,806 CRS subjects were enrolled in this study: 10,512 were
non-TCM users and 4.294 were non-TCM users. non-TCM group had a significantly higher proportion of females, were younger, and a greater proportion lived in urban areas compared with the non-TCM group (all p < 0.0001). Ninety-seven percent of the TCM users received herbal remedies. The most common Chinese herbal formula used was Xin-Yi-Qing-Fei-Tang and the most commonly used single herb was Baizhi. The hazard ratio for endoscopic sinus surgery (ESS) was 0.17 for TCM users (95% CI
=0.15 - 0.20) compared with non-TCM users after adjusting for age, sex, urbanization, and co-morbidities.
Conclusions Our investigation found that 29% of CRS patients used TCM in addition
to Western medical treatment. A lower proportion of patients in the TCM group underwent ESS compared with that in the non-TCM group. These findings may be of value in further studies evaluating the efficacy and safety of TCM use in CRS patients.
INTRODUCTION
Chronic rhinosinusitis (CRS) is a chronic illness with a prevalence of 10.9% in Europe and 13-17% in the United States, 1, 2 which places a tremendous burden on the patients and healthcare system.3 It is estimated that rhinosinusitis contributed to the majority of 257,000 sinus surgeries in 2006 and an average loss of 5.67 workdays per year (similar to that of acute asthma) in the United States.4, 5 Furthermore, it is often related to allergies and should be taken into account by healthcare providers treating allergic diseases due to its significant impact on lower airway diseases such as bronchiectasis and asthma.6, 7
Although a number of international studies on CRS have been conducted such as the GA²LEN study in Europe 8 and the National Health and Nutrition Examination Survey in the United States, 1 large-scale surveys on the use of complementary and alternative medicine (CAM) to treat CRS are lacking. CAM has grown in popularity in many countries. It is believed that use of CAM is particularly prevalent among patients with allergic disorders or rhinosinusitis particularly.9,10 Previous questionnaire surveys and telephone interviews revealed that 65% of Scottish patients in a rhinology clinic,11 42% of Californian adults with asthma or rhinosinusitis,12 15.6% of Canadian
patients with CRS,13 and 21% of Israeli patients with CRS14 have used CAM as a treatment modality.
Our previous study, which employed a questionnaire-based survey to evaluate CRS patients in a medical center, found that 34.4% patients with rhinitis/rhinosinusitis had used Traditional Chinese Medicine (TCM). 15 TCM is an important part of CAM as defined by the National Center for Complementary and Alternative Medicine (NCCAM, U.S.A.), and has been a mainstay of treatment modalities for many conditions and diseases in Asian countries for several millennia.16 We have previously established TCM use in adults and children in Taiwan based on nationwide population-based epidemiological data.17, 18 We also explored the characteristics of TCM usage in patients with allergic disorders such as asthma 19 and atopic dermatitis 20 in a large-scale study. However, the existing knowledge of TCM use among
patients with CRS is limited and thus comprehensive studies to investigate the issue are necessary. While current conventional medications and endoscopic sinus surgery (ESS) can alleviate most symptoms of CRS, 2, 21 there are 10 -20% of CRS cases are recalcitrant to current treatment.22
effect of TCM in the treatment of CRS, we investigated the pharmaco-epidemiological data of adjunctive TCM use in patients with CRS and determined whether this adjunction of TCM could minimize the need for surgery by analyzing a cohort of one million national health beneficiaries randomly sampled from the National Health Insurance Research Database (NHIRD) in Taiwan. This data set is a nationwide population-based claims database with long-term follow-up. The representative data from this claims database were also generalizable to the population as a whole, and thus the potential for sampling bias was reduced to a minimum.
MATERIALS AND METHODS
Data source
In this study, a dataset obtained from the National Health Insurance Research Database (NHIRD) in Taiwan was analyzed. Taiwan launched the National Health Insurance Program in March 1995. Western medical treatment as well as TCM therapies have been available on Taiwan's NHI system since 1996.18 Approximately 23 million enrollees, comprising 99.89% of the total Taiwan’s population, were covered by the program at the end of 2010.23 The NHIRD is a repository of health
insurance registration files and original claims data of all beneficiaries in the NHI program, and anonymized datasets are made available for scientific research. In this study, we investigated TCM use in patients with CRS in Taiwan using data from a cohort of 1,000,000 persons enrolled in 2000 who were randomly sampled from the NHIRD (Longitudinal Health Insurance Database 2000; LHID 2000). This study was approved by the Institutional Review Board of China Medical University and Hospital (CMU-REC-101-012). The data files were de-identified and further scrambled before being released to researchers in accordance with privacy protocols. Thus, it was not possible to query the data to identify individuals at any level using this database. Study Subjects
The medical records and reimbursement claims of the sampled enrollees were collected from January 2000 to December 2011. The data collection flowchart is shown in Figure 1. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) and Procedure Coding System (ICD-9-PCS) were used to establish patients’ diagnoses and treatment. We identified CRS cases (ICD-9-CM code: 473) from LHID 2000 who were newly diagnosed in the year 2000 and these patients served as the study cohort. Patients who had been diagnosed as CRS before
2000, had incomplete medical information, or were under 20 years old were excluded. All enrolled cases were required to have been diagnosed with CRS by a Western medicine doctors in the first instance, followed by outpatient visits to either Western medicine or TCM doctors for CRS treatment at least twice. Four allergic diseases, common co-morbidities of CRS (allergic rhinitis ICD-9: 477; asthma ICD-9: 493; atopic dermatitis ICD-9: 691; urticaria (ICD-9: 708), were also identified in the study cohort.
The demographic information and claims data of the study cohort were collected and analyzed. Those patients receiving TCM consultation, acupuncture, or herbal treatment for CRS were considered to be TCM users. Otherwise, they were identified as non-TCM users. Residence areas of the study cohort were divided into 4 levels of urbanization which were defined by various criteria, including population density (people/km2), the population ratio of different educational level, ratio of elderly people, ratio of people of agriculture workers, and the number of physicians per 100,000 people.24 Level 1 had the highest degree of urbanization and level 4 had the lowest. Urbanization levels 1 and 2 were defined as urban areas, while levels 3 and 4 were classified as rural areas.
Statistical Analysis
SAS software version 9.1 (SAS Institute, Inc., Cary, NC, USA) was used for statistical analyses. The independent t-test was utilized to examine differences in age between two groups. The Chi-square test was used to test for differences in sex, urbanization status, and comorbidities between TCM and non-TCM users. A Cox’s Proportional Hazards regression model was used to estimate the hazard ratio (HR) of subsequent ESS between TCM users and non-TCM users, after adjustment for age, sex, urbanization, and co-morbidities. A two-sided p of < 0.05 was considered statistically significant.
RESULTS
Characteristics of study subjects
A total of 14,806 subjects who were newly diagnosed with CRS in the year 2000 were included in the analysis (Table 1). Among them, 10,512 did not use TCM for treatment of CRS in the follow-up period, and 4,294 had used adjunctive TCM treatment for their CRS. TCM users were more likely to be female, younger, and resident in an urban area (all p < 0.0001). The prevalence of allergic co-morbidities was high in the study cohort. There were significantly more allergic rhinitis patients in
the TCM group and more asthmatic patients in the non-TCM group (both p < 0.0001). Traditional Chinese Medicine prescription patterns for CRS
Most of the TCM users received herbal treatment, whereas only a few of them underwent acupuncture. About 39% of the TCM users visited an outpatient department more than 3 times (Table 2). The herbal prescription patterns are listed in Table 3. The most commonly prescribed Chinese herbal formula was “Xin-Yi-Qing-Fei-Tang” (Magnolia Flower and Gypsum Combination), followed by “Xiao-Qing-Long-Tang” (Minor Blue-green Dragon Decoction), “Xin-Yi-San” (Magnolia Flower Powder), “Cang-Er-San” (Xanthium Powder) and “Ge-Gen-Tang” (Pueraria Combination). The frequently used single herbs prescribed for CRS were Baizhi (Radix Angelicae Dahuricae), Yuxingcao (Herba Houttuyniae), Jiegeng (Radix Platycodi), Cangerzi (Fructus Xanthii), and Huangqin (Radix Scutellariae).
Hazard ratio of subsequent endoscopic sinus surgery (ESS)
Among the 10,512 non-TCM users, 2,226 underwent ESS during the study period. However, only 176 TCM users underwent ESS for CRS treatment. A Cox’s regression model was used to analyze the risk factors for ESS. The hazard ratio for ESS was 0.17 for TCM users (95% CI =0.15 - 0.20) compared with the non-TCM users after adjusting for age, sex, urbanization, and co-morbidities (Table 4).
DISCUSSION
In this study, we analyzed a randomly sampled cohort of 1,000,000 persons enrolled in the National Health Insurance program in Taiwan and investigated the prevalence, demographic data, comorbidity of allergic disorders, prescription patterns, and subsequent ESS among TCM and non-TCM users with CRS. The high prevalence of CAM use in patients with CRS that was found in previous studies was determined by questionnaires and interviews.9, 11-14 Previously, the GA(2)LEN study revealed a strong association of CRS, asthma and allergic rhinitis.7, 8, 25 Ours and other’s previous nationwide population-based studies have also characterized TCM use in patients with allergic disorders such as asthma19 and allergic rhinitis.26 Herein, we extended the current knowledge to examine TCM use among patients with CRS. We identified that Xin-Yi-Qing-Fei-Tang (Magnolia Flower and Gypsum Combination) and Baizhi (Radix Angelicae Dahuricae) were the most commonly used TCM herbal formula and single herb, respectively. Those patients conjunctively used TCM had a decreased need for subsequent ESS. This investigation is the first comprehensive analysis of TCM use in patients with CRS.
Clinical diagnosis of CRS includes the presence of more than two of the following symptoms: nasal blockage/obstruction/congestion, nasal discharge, facial pain/pressure or reduction/loss of smell, plus either endoscopic signs or CT changes.2 Our investigation analyzed patients who were diagnosed with CRS by a Western medicine doctor and who visited an outpatient clinic for follow-up (more than three visits in total) in order to minimize selection bias and to ensure that similar disease entities existed in TCM and non-TCM users. In the nationwide population-based study cohort, nearly one-third of the patients had used TCM in conjunction with Western medicine for their CRS. This is in line with the prevalence rates reported in previous studies of CAM use among rhinosinusitis patients (range from 15.6% to 65%).11-14
In addition, we found that TCM users were significantly more likely to be female, younger, and to have better access to medical resources (i.e., resident in an urban area). Several studies have reported that females are more likely to use CAM.27, 28 This is also in accordance with a previous general population study indicating that female gender, high socioeconomic status, and higher education levels were associated with greater prevalence of TCM use.29
Although TCM has been used for millennia in the treatment of otorhinolaryngological conditions, 30 few randomized controlled studies on the use of
TCM herbs in rhinology have been published. Our recent randomized-controlled study demonstrated that Chinese herbal remedies (Tsang-Erh-San and Yuxingcao) had an efficacy similar to that of macrolides in the treatment of CRS without nasal polyps.31 However, selection of an optimal herbal formula and single herb for a clinical investigation is difficult due to the individualized nature of TCM treatment. In this study, we further comprehensively analyzed the most commonly prescribed TCM formulas and single herbs to establish a consensus of effective remedies for CRS. In the literature, the benefits of TCM herbal formulae have been demonstrated in a number of in vivo and animal experiments, as follows: “Xiao-Qing-Long-Tang” can inhibit Th2 cytokines production and suppress histamine signaling, therefore reducing allergic inflammation;32 “Ge-Gen-Tang” and “Long-Dan-Xie-Gan-Tang” have
anti-viral activities;33, 34 “Bu-Zhong-Yi-Qi-Tang” can reduce IgE production and has an
anti-allergic effect.35 Individual herbs including Cangerzi (Fructus Xanthii) and Xinyi
(Flos Magnoliae) have anti-allergic and anti-oxidative effects;36, 37 Baizhi (Radix Angelicae Dahuricae) exhibits anti-microbial and cyclooxygenase-2 inhibition.38, 39
We found that 5 out of the top 10 TCM formulae for CRS were also the most common TCM prescription for allergic rhinitis in Taiwan.26 The high prevalence of comorbid allergic rhinitis in TCM users in the study cohort could explain at least in part this commonality. Surprisingly, although Xin-Yi-Qing-Fei-Tang has been frequently used for allergic rhinitis 26 and CRS in our study, no high-quality randomized clinical trial has been conducted to date.
Multiple etiologies have been associated with the development of CRS, including impaired mucociliary function, allergy, anatomic abnormalities, infection, and environmental pollutants. The aforementioned factors contribute to chronic inflammation in the nose and paranasal sinuses.2 The therapeutic effects of
acupuncture for CRS possibly result from reduced mucosal congestion and improved mucociliary function.40 A randomized, double-blinded study with a small number of patients demonstrated that acupuncture reduced nasal obstruction and improved the results of rhinomanometry.41 A previous study conducted in California found that acupuncture appeared to show good efficacy in the treatment of patients with chronic sinus and nasal symptoms.42 Two studies compared the quality of life of CRS patients who received acupuncture, sham acupuncture, or conventional medical treatment
(saline irrigation, antibiotics, oral steroids, and nasal decongestants) and both demonstrated that there were no significant differences among the 3 groups.43, 44 The limited effect of acupuncture in the present study may reflect the very small percentage of patients who received acupuncture treatment and thus further investigations are warranted.
ESS is the current standard surgical management for adult rhinosinusitis that failed to respond to more conservative medical treatment.21 In this study, a significantly
lower proportion of patients who received adjunctive TCM treatment underwent ESS compared to those patients who received Western medicine alone. Although possible confounding factors (age, sex, urbanization and allergic co-morbidities) were adjusted, we understand the disease severity at baseline could not be evaluated in the NHIRD. However, patients who received combined treatment might be reasonably postulated to have had a lower rate of medical treatment failure. Our previous questionnaire-based survey revealed that rhinitis patients with worse disease-specific quality of life had higher utilization of combined TCM treatment.15 An earlier
questionnaire-based survey in 2002 conducted in Taiwan also indicated that patients with self-reported poor health status tended to be more likely to visit a TCM clinic.45
A nationwide study conducted in the U.S. revealed that most of the study subjects used alternative therapies in conjunction with conventional medicine; only a few of them relied primarily on alternative therapies. The use of alternative therapies was not a result of dissatisfaction with conventional medicine; rather, the CAM treatments were more congruent with their values and beliefs with respect to health. 46 The better
satisfaction in patients receiving combined Western and alternative therapies may tend to make them more likely to decline further surgical management. It is important to note that difficult-to-treat rhinosinusitis does exist and CRS is usually associated with allergic disorders.7, 25, 47, 48 As a recent pilot study demonstrated, an integrated
approach using Western and Eastern medicine may improve the symptoms and quality of life of patients with recalcitrant CRS.49 Given that adjunctive TCM
treatment appears to have the potential to reduce the risk of refractory CRS, further validation by high-quality clinical trials are warranted.
There were several potential limitations in our study. First, although the database provides complete claims data of the enrolled subjects, factors such as disease severity and smoking habit were not provided in the database. However, all patients were diagnosed by Western medical doctors and visited the outpatient department for
follow-up at least three times, which minimized the bias in diagnosis. Second, the allocation of TCM or non-TCM use was also based on the patients’ own request and preferences. As shown in our previous survey and in other studies, adjunctive TCM users might have worse disease severity or health status.15, 45 Studies have also suggested patients with allergies are motivated to use CAM as a result of dissatisfaction with conventional medication.10 Although our study suggested that adjunctive TCM use could reduce the risk of subsequent ESS, further randomized controlled clinical trials are necessary to confirm this finding.
CONCLUSION
Our investigation found that 29% of CRS patients used TCM in conjunction with Western medicine. Xin-Yi-Qing-Fei-Tang and Baizhi (Radix Angelicae Dahuricae) were the most commonly used TCM formula and single herb, respectively, for CRS. Adjunctive TCM use might reduce the need for ESS. These data suggest that adjunctive TCM treatment may provide an alternative choice of therapy to improve CRS symptoms. Further investigations to evaluate the efficacy and safety of adjunctive TCM treatment are warranted.
Abbreviations
CAM: complementary and alternative medicine; CRS: chronic rhinosinusitis; FESS: functional endoscopic sinus surgery; NHIRD: National Health Insurance Research Database TCM: Traditional Chinese Medicine; ICD-9-CM: the International Classification of Diseases, 9th Revision, Clinical Modification; ICD-9-PCS: the International Classification of Diseases, 9th Revision, Procedure Coding System.
Acknowledgments
This study was supported by China Medical University under the Aim for Top University Plan of Taiwan’s Ministry of Education. This study was also supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and the Research Center of Excellence (MOHW103-TDU-B-212-113002). Yen H-R. is supported by a physician scientist grant (DMR-103-123) from China Medical University Hospital and a career-developing grant (NHRI-EX101-10124SC, NHRI-EX102-10124SC and NHRI-EX103-10124SC) from the National Health Research Institutes, Taiwan. This study was based in part on data from the National Health Insurance Research Database provided by the National Health Insurance Administration, Ministry of Health and Welfare and managed by the National Health Research Institutes. The
interpretation and conclusions contained herein do not necessarily represent those of the National Health Insurance Administration, Ministry of Health and Welfare or the National Health Research Institutes.
Authors’ Contributions
HRY and KLL conceptualized the study. CLL and FCS performed the statistical analysis. HRY and KLL drafted the manuscript and finalized the manuscript. HRY and MFS contributed to the interpretation of TCM data. CCW and KLL interpreted the data of Western medicine and surgical procedures. All of the authors read and approved the final manuscript.
Conflicts of interest
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Figure legend
Figure 1. Flow recruitment chart of subjects from the one million random samples obtained from the National Health Insurance Research Database (NHIRD) in Taiwan. LHID 2000 = Longitudinal Health Insurance Database 2000
