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Abstract

Aim: Acupuncture has traditionally been used in Japan in the treatment of bronchial asthma and is being increasingly applied. Although there are many published studies on acupuncture and asthma, few meet the scientific criteria necessary to prove the effectiveness of acupuncture. This study, therefore, presents the clinical results of acupuncture treatment for adult bronchial asthma.
Design: Single-subject research design (N-of-1 method).
Setting: Department of Internal Medicine, Acupuncture and Moxibustion Center, Meiji University of Oriental Medicine, Japan.
Participants: Six patients of both genders (mean age, 49.0 years) with moderate to severe persistent bronchial asthma.
Intervention: Six patients received 10 sessions of acupuncture treatment (one time per week for 10 weeks). The basic combination of meridian points for the treatment of the patients were LU1 (Zhongfu), LU5 (Chize), LU9 (Taiyan), CV4 (Guanyuan), CV12 (Zhongwan), BL13 (Feishu), BL20 (Pishu), and BL23 (Shenshu).
Measurements: Primary outcome was the symptom of asthma at the end of the 10 treatment periods. Secondary outcomes were Visual Analogue Scale of dyspnea (DVAS), respiratory function, Peak Expiratory Flow Rate (PEFR), blood, the use of asthma drugs. The effect of the intervention on eosinophils in blood was assessed.
Main results: Late effects of asthma patients showed significantly better results, compared with base line on outcome measures after the 10 weeks. In this study, symptoms of asthma and dyspnea VAS in patients with asthma were significantly improved by acupuncture.
Conclusion: This study indicated that acupuncture was effective for asthma symptoms and respiratory function.

Key words: Bronchial asthma, Acupuncture, Lung function, Steroid, Single case study

I. INTRODUCTION

Bronchial asthma is a condition characterized by increasing airway hypersensitivity and reversible obstruction of bronchial airways due to various stimulations. Its main symptoms are episodic wheezing or dyspnea. In patients with severe symptoms of asthma, their daily lives and social lives are disturbed. Airway obstruction is induced by inflammation of airways such as spasms in bronchial smooth muscle, airway edema, or increases in airway secretion and it is thought to be a chronic inflammatory disorder of airways1. For the treatment of asthma, inhaled and oral corticosteroids are administered, which are generally accepted to be the most effective therapeutic drugs for bronchial asthma. There are, however, some patients with bronchial asthma who do not respond to corticosteroids2.
Acupuncture is a traditional medicine that has been applied to respiratory diseases for a long time and has recently been used for chronic bronchitis and emphysema as well as bronchial asthma3. In particular, some cases of acupuncture treatment for bronchial asthma have been reported, and Fung et al.4 reported that acupuncture treatment was effective in preventing exercise-induced asthma. In a systematic review performed by Martin et al.5, however, no obvious evidence was shown because there were differences in the methods of acupuncture treatment between each report. There is no consistent observation on the effect of acupuncture treatment for bronchial asthma.
We, therefore, provided acupuncture treatment in conjunction with medication for patients with bronchial asthma who could not fully control it by inhaled or oral corticosteroids and evaluated the effect of acupuncture treatment for symptoms of asthma and respiratory functions using a single-subject research design (N-of 1, single case study).

II. SUBJECTS AND METHODS

f Period A. When remarkable exacerbations of asthma were observed in a patient and he/she wished to receive acupuncture treatment during Period B, the next Period A was started at that point.

2) Choice of meridian points and methods of treatment
Meridian points for the treatment of patients in the present study were those shown to be effective for patients with bronchial asthma and those that were shown to be effective in various reports5, 8, 9. The basic combination of meridian points for the treatment were Taiyan (LU 9), Chize (LU 5), Zhonghu (LU 1), Zhongwan (CV 12), Guanyuan (CV 4), Feishu (BL 13), Pishu (BL 20) and Shenshu (BL 23). Depth of insertion was about 10 mm to 30 mm at all meridian points, which depended on body habitus of the patients. At Taiyan, from the peripheral cite to the central cite, transverse insertion was performed, and at other meridian points, perpendicular insertion was performed. For acupuncture stimulation, manual twisting after insertion was performed for about ten seconds and the needles retained for ten minutes after patients recognized needle sensation (de qi). When patients suffered from anorexia, insomnia, generalized fatigue or lumbago, those were treated as well. For those treatments, disposable stainless needles (Seirin Corp.), 40 mm in length and 0.16 to 0.20 mm in diameter, were used.

III. EVALUATION METHODS

1. Symptoms of asthma
Patients recorded their asthma symptoms everyday in an asthma diary10 developed by the Bronchial Asthma Severity Criteria Review Committee and their symptoms for a week were scored (asthma score).

2. Dyspnea
Severity of dyspnea was evaluated by a 100　mm Visual Analogue Scale (VAS) of which the right end (100 mm) indicates the　worst dyspnea imaginable, while the left end(0mm) indicates no dyspnea, both at the beginning and at the end of the period A.

3. Respiratory functions
Vital capacity was measured with a spirograph before Period A1 began and when Period A2 ended. Forced expiratory vital capacity, flow volume for a second and V25 were measured by Flow Volume.
PEFR was also measured by peak flow meters (Vitalograph Ltd., Ireland). PEFR was measured at rise time and bedtime everyday. It was measured three times at each rise time and bedtime, and the highest value was recorded in the asthma diary.

4. Administration doses of corticosteroids
Changes of administration doses of oral and inhaled corticosteroids were evaluated four times before the beginning and at the end of each Period A.

5. Statistical analysis
Data on asthma attack scores and VAS are expressed as means ± standard errors, while PEFR was expressed as mean ± standard deviation. Changes in the asthma attack scores, VAS and PEFR were analyzed with one factor ANOVA, which was followed by Fisher’s PLSD multiple comparisons if necessary. Differences were considered statistically significant when the value was less than 0.05.

IV. RESULTS

There were no withdrawals due to remarkable adverse events or no interruption according to a doctor’s judgment.
1. Changes in asthma attacks (Fig.1)
Asthma scores before the start of Period A1 were 30.0 ± 8.1 and those at the end of the period were significantly improved to 4.7 ± 3.1 (p < 0.01). The values before the start of Period A2, however, significantly increased to 21.6 ± 6.5 (p < 0.05). Asthma scores at the end of Period A2 significantly improved to 1.5 ± 0.8 (p < 0.05). Conditions of asthma attacks significantly improved from 30.0 ± 8.1 before the start of Period A1 to 1.5 ± 0.8 at the end of Period A2 (p < 0.01).

2. Effect of acupuncture on dyspnea (Fig. 2)
Severity of dyspnea measured with VAS before the start of Period A1 was　55.7 ± 20.4　mm, which significantly improved to 19.7 ± 21.0　mm at the end of period A1 (p < 0.01). VAS values significantly improved from 57.8 ± 25.7　mm before the start of Period A2 to 15.5 ± 11.5　mm at the end of Period A2 (p < 0.01). The values before the start of Period A1 and at the end of period A2 significantly improved from 55.7 ± 20.4 to 15.5 ± 11.5　mm (p < 0.01).

3. Changes in PEFR on rising before and after the period of acupuncture treatment (Fig. 3-1)
Mean value of PEFR on rising significantly increased from 235.0 ± 62.2 L/min before the start of Period A1 to 325.8 ± 83.1 L/min at the end of Period A1 (p < 0.05). The mean value at the end of Period A1 was 325.8 ± 83.1 L/min and decreased to 244.2 ± 45.4 L/min before the start of Period A2 (p = 0.053). The mean value before the start of Period A2 increased from 244.2 ± 45.4 to 323.3 ± 77.6 L/min at the end of Period A2 (p = 0.059). The mean value before the start of Period A1 significantly increased from 235.0 ± 62.2 L/min to 323.3 ± 77.6 L/min at the end of Period A2 (p < 0.05).

4. Changes in PEFR at bedtime before and after the period of acupuncture treatment (Fig. 3-2)
Mean value of PEFR at bedtime increased from 263.3 ± 62.5 L/min before the start of Period A1 to 331.7 ± 88.4 L/min at the end of period A1. The mean value at the end of Period A1 was 331.7 ± 88.4 L/min and decreased to 273.3 ± 78.1 L/min before the start of Period A2. The mean value before the start of Period A2 increased from 273.3 ± 78.1 L/min to 326.7 ± 85.0 L/min at the end of period A2. The mean value before the start of Period A1 increased from 263.3 ± 62.5 L/min to 326.7 ± 85.0 L/min at the end of Period A2.

5. Respiratory function tests (Table 4-1)
In four cases (#2, #4, #5, and #6) out of six, respiratory function tests were performed before and after acupuncture treatment. Before the start of Period A1 and at the end of Period A2, cases in which improvement of more than 20% was seen in each respiratory function test were one case out of four for VC, two cases out of four for FVC, three cases out of four for FEV1 and three cases out of four for V25.

6. Changes in eosinophil counts in the peripheral blood (Table 4-2)
Hematological examinations were performed in five out of six patients before and after the period of acupuncture. There were three patients (#3, #5, and #6) who showed more than a standard value of eosinophils (below 5%) before the start of Period A. However, at the end of Period A, cases 3, 5 and 6 showed decreases in the eosinophil counts from 6.6% to 1.1%, 9.8% to 4.5%, and 18.9% to 10.4%, respectively. In addition, for case 1, there was a decrease from 0.8% to 0.3%, although the change was observed within the normal limits.

7. Changes in administration doses of inhaled and oral corticosteroids (Table 5)
Before the start and at the end of the Period A, the doses of oral corticosteroids were reduced in three (#1, #2, #3) out of four patients as were the doses of inhaled corticosteroids in two (#2, #5) out of five patients.
Due to the deterioration of asthma attacks during Period B, doses of oral and inhaled corticosteroids needed to be increased in three out of four cases (#1, #2, and #3) and two (#2, #5) out of five patients, respectively.
Before the start of and at the end of the Period A, the doses of oral corticosteroids were reduced in three (#1, #2, and #4) out of four patients and the doses of inhaled corticosteroids were reduced in three out of five patients (#1, #2, and #3)

8. Changes in severity of asthma (Table 5)
At the end of Period A, the severity of asthma symptoms were improved in six patients compared with that before the start of Period A, as asthma attacks were ameliorated. However, due to deterioration of asthma attacks in five patients during Period B, exacerbations of asthma were observed before the start of Period A2 in three out of five patients. At the end of Period A2, severity was improved in five patients compared with that before the start of Period A2. When compared with the state before the start of Period A1, improvement in the severity was observed in six patients at the end of Period A2.

V. DISCUSSION

1. Study design and clinical effect
To evaluate the effect of acupuncture treatment from the viewpoint of Evidence Based Medicine (EBM), it is desirable to prove the effect of acupuncture treatment in a setting of a randomized controlled trial (RCT). There are, however, difficulties in performing an RCT study with control groups in practical and clinical settings, since most patients want acupuncture treatment in actual clinical acupuncture scenes. Accordingly, in the proof of the effect of acupuncture treatment, this study utilized a single-subject research design (N-of-1), in which the clinical effect could be assessed without a control group. In the single case study used here, it was thought that the clinical effect could be assessed by obtaining reproducible data from a single patient who repeated two periods alternately, Periods A and B.
With this single case study of six patients in an improved state of asthma during Period A, five patients who showed exacerbations of asthma when entering into Period B showed improvement in asthma symptoms when entering Period A2 again. Moreover, all cases with the administration of corticosteroids in the total observation period showed improvement in asthma symptoms when treated with acupuncture, indicating that this improvement was obtained due to the effect of acupuncture treatment, and not to either the drug effects or a self-remitting natural course. We considered, by using the single-subject research design (N-of-1) in a single case study, that it could evaluate the effect of acupuncture treatment for asthma.

2. Clinical effects of acupuncture treatment
The patients with bronchial asthma studied here improved their asthma symptoms and VAS during Period A (acupuncture treatment period). Moreover, there were improvements in the airway obstruction in the assessment of FEV1 and PEFR, and improvements in bronchial asthma were observed not only from the subjective symptoms but also from the findings of objective examinations.
As in the past, due to obstructive ventilation impairment caused by the constriction of bronchial smooth muscle, bronchial asthma is characterized by decreases in respiratory function tests, such as FEV1, PEFR and V25. Particularly, FEV1 reflects the airflow of the central airway of the respiratory tract, while V25 reflects the airflow of the peripheral airway. From the data in this study, improvements in the obstructive ventilation impairment was observed by acupuncture treatment in three (#2, #5, #6) out of four patients in the assessable respiratory function test who showed increases in FEV1 and V25 at the end of Period A. Alternatively, in case #4 who had a common cold since one day before the last examination day and showed a slightly positive C-reactive protein (CRP: < 0.5), respiratory function was decreased due to upper respiratory inflammation.
Additionally, PEFR at rise time and bedtime in all cases was improved at the end of Period A. Because PEFR indicates the maximal expiratory flow volume in reflection of airflow of the central airway, the value is significantly lowered in patients with asthma symptoms. Furthermore, PEFR values on rising being lower than that at bedtime suggest a possible asthma attack from night to morning time. All cases examined in this study had an asthma attack at night and five of six cases showed lower PEFR on rising compared with that at bedtime (Table 1). However, with the continuous performance of acupuncture, the difference of the average values of PEFR at rise time and bedtime was decreased at every endpoint of Period A. The frequency of asthma attacks at night was decreased in many cases. Moreover, the patients commented that the absence of nighttime attacks led to sound sleep and physical relaxation. These findings in respiration function, in which an asthma attack was improved during Period A, indicated the effect of acupuncture. Alternatively, in Period B (period without acupuncture), five of six cases showed deterioration of asthma attacks. Of five with deterioration, three (#1, #2, and #3) needed extra-outpatient visits other than regular visits. In addition, more use of short-acting inhalation β2-agonists (bronchial dilatation drugs) was commented by all of these five patients. These results, in which a combined usage of this type of acupuncture (choice of meridian points, time of treatment) improved asthma attacks but the 10 week course of acupuncture allowing deterioration of asthma attacks, suggested that acupuncture has an immediate, but little lasting, effect on asthma attacks. In the guideline at present11, bronchial asthma is regarded as a disease that is not cured, but controlled symptomatically over long periods of time. As the guideline focuses mainly on drug therapy such as inhaled corticosteroids, it may be desirable that acupuncture combined with drug therapy should be continued for a certain period of time even after achieving improvement or disappearance of asthma attacks. Further study is, however, needed on how long acupuncture should be continued.
The therapeutic mechanism of acupuncture to bronchial asthma has been speculated as a bronchial dilatation action through the autonomic nerve afferent pathway from a somatic visceral reflex stimulated by acupuncture, as well as relaxation of bronchial smooth muscle through the autonomic nervous system12. Sugiura et al. 13 reported that bronchial asthma patients treated with acupuncture showed sedation and relaxation of constricted bronchial smooth muscle for one hour after acupuncture, which accompanied an improvement in respiratory resistance. Similarly, this study, in which relief of dyspnea as well as improvements in FEV1 and V25 were experienced in patients, suggested a possibility that acupuncture induced sedation and relaxation of the bronchial smooth muscle constriction state.
Bronchial asthma has been recognized as a chronic inflammatory disorder as research of the pathophysiology of bronchial asthma advances. Particularly, it has been proved that cytokine networks involving eosinophils at the center induces release of cytotoxic eosinophil-specific granules to the airway that generate inflammation in the airway, leading to edema at the bronchial mucosa or submucosa, increased production of mucus, constriction of bronchial smooth muscle, and airway obstruction. Therefore, airway inflammation through the eosinophil-centered cytokine network plays an important role in causing the attack of bronchial asthma.
In this study, two courses of acupuncture treatment (during Period A and Period B) showed improvement in asthma attacks in patients and decreased eosinophil counts in blood in four out of five cases, which could be measured (#1, #3, #5, and #6). We15 also provided acupuncture treatment for patients who have both bronchial asthma (severe persistent asthma) and chronic obstructive pulmonary disease (COPD), once a week for ten weeks and observed that the acupuncture treatment improved asthma attacks and decreased eosinophil counts in blood and Eosinophil Cationic Protein (ECP), a cytotoxic protein induced by eoshinophils, as a result. These findings indicate a possibility that one of therapeutic mechanisms of acupuncture treatment for patients with bronchial asthma may be involved in improving eosinophilic inflammation. However, until this point, among clinical reports3, 16 on acupuncture treatment for bronchial asthma, there are no reports that acupuncture treatment decreased eoshinophils specifically. Because there is no definitive evidence of the possibility that acupuncture treatment may improve eosinophilic inflammation of airways even though the possibility has been suggested, we consider that we will need to review the effect of acupuncture treatment on this point,

3. Doses of corticosteroids
At present, according to NIHLBI Guidelines for the Diagnosis and Management of Asthma17, corticosteroids for bronchial asthma are described to be the most effective anti-asthma drugs, and are extensively used as an improvement drug for acute symptoms or long-term prevention drug. Inhaled corticosteroids are considered to be most effective for patients with persistent asthma, from moderate persistent (step 2) to severe persistent (step 4). Oral corticosteroids are recommended when patients do not respond to inhaled corticosteroids. There are, however, some patients with asthma who are controlled poorly with these steroids2. For such patients, the dose of corticosteroids is increased in accordance with a clinical guideline and the side effects of these drugs may cause problems. Inhaled corticosteroids have relatively few side effects compared with oral steroids because they are inhaled to airways directly, but there are still some side effects10. In this study, subjects were patients with asthma whose symptoms were controlled poorly even after they were administered persistent inhaled and oral steroids or bronchodilators. Acupuncture treatment for these patients who did not fully responded to certain doses of steroids, improved their asthma symptoms in all cases in this study, which suggested that one course of (ten sessions) acupuncture treatment has efficient effects on improvement of asthma symptoms. Mitchell et al. 19 also performed a clinical examination on 31 patients with mild to moderate asthma, in which an　acupuncture treatment group and fake group were randomly assigned. It was reported that after eight acupuncture treatments for 12 weeks, asthma attacks and PEFR were improved significantly and doses of inhaled steroids could be decreased. This result was similar to our findings in the present study.
According to medication therapy response to severity in the Asthma Prevention and Management Guideline6, when symptoms are not controlled by ongoing treatment, another more strict treatment should be provided. In Japan, we take a step-up approach in the treatment with corticosteroids in which doses of steroids are increased when defined doses of corticosteroids according to grades of severity offer little effect. As for the cases in this study, patients had been administered normal doses of corticosteroids without improvement in asthma attacks and doses had to be increased. We provided acupuncture treatment on these patients in combination with medication and observed the disappearance of asthma attacks in two out of six cases and improvement in four out of six cases at the end of the second course of acupuncture treatment. This made it possible for doses of steroids to be reduced or cut (Table 5). It was suggested that patients who have difficulties in controlling asthma symptoms with only medication can be controlled by acupuncture treatment in combination with medication.

VI. CONCLUSION

1. Acupuncture treatment was provided for six patients with bronchial asthma who were controlled poorly even with standard medication including corticosteroids.
2. In all cases, improvement or disappearance of asthma symptoms was observed in accordance with length of the acupuncture treatment
3. At the end of the acupuncture treatment, improvement of respiratory function and decrease in eosinophil counts were observed along with improvement of asthma symptoms. In four out of six cases, doses of corticosteroids could be reduced.
4. As a result of acupuncture treatment provided for patients with bronchial asthma, who were controlled poorly with medication, acupuncture treatment was considered to be effective in improving asthma attacks, subjective symptoms, and respiratory function of the patients.

Acknowledgements

We are thankful to Dr. Naoto Ishizaki who made a great contribution to this paper.

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