Effect of point application therapy for bronchial asthma: a multicenter randomized controlled trial

Abstract

OBJECTIVE:

To assess the efficacy of point application therapy (PAT) in alleviating the exacerbation of chronic respiratory diseases represented by bronchial asthma.

METHODS:

In this multicenter randomized placebo-controlled trial, eligible bronchial asthma patients received placebo PAT on the dog days of the first summer to establish a baseline, and then patients who continued to participate in the trial and repassed the eligibility review were randomized to receive regular or placebo PAT in the next two consecutive summers. The primary outcome was the change from baseline in the number of asthma exacerbations at 24 months. Secondary outcomes included severity of asthma exacerbation, asthma control test (ACT) score, percentage of forced expiratory volume in 1 s (FEV₁) to the predicated value (FEV₁%pred), peak expiratory flow (PEF), ratio of FEV₁ to forced vital capacity (FEV₁/FVC), and use of palliative drugs during bronchial asthma exacerbations at 12 and 24 months. The adverse events (AEs) were also assessed.

RESULTS:

A total of 835 patients with bronchial asthma were randomized in this trial. Compared with the placebo control, the PAT significantly decreased the mean number of asthma exacerbations (1.42; 95% confidence interval, 0.69 to 2.14; P < 0.001), and increased the FEV₁%pred at 24 months (P = 0.039) and FEV₁/FVC at 12 months (P = 0.01) and 24 months (P = 0.01). There were no significant differences between the groups in PEF or ACT score at 12 and 24 months, or in FEV₁%pred at 12 months. Treatment-related AEs were mild and more common in the PAT group than in the placebo PAT group. No serious AEs were reported.

CONCLUSION:

PAT conducted on dog days could reduce asthma exacerbations in patients with bronchial asthma.

1. INTRODUCTION

Bronchial asthma is a common chronic respiratory disease. Its clinical manifestations include recurrent wheezing, shortness of breath, with or without chest tightness or cough, as well as airway hyperre-sponsiveness and variable airflow restriction.¹ With approximately 300 million people affected worldwide,² the prevalence of asthma in Asian adults varies from 0.7% to 11.9%.³ According to the World Health Organization, nearly 250 000 patients die of asthma every year. Although the importance of asthma control has been emphasized since 2004,⁴ asthma exacerbation remains a major reason for health care utilization and a significant financial burden to patients and society.

Frequent asthma exacerbations can usually be controlled by adequate inhaled corticosteroids (ICSs) or by a combination of ICSs and long-acting β-agonists (LABAs),⁵ whereas the number of asthma exacerbations does not change significantly in patients with severe asthma or persistent symptoms.⁶ For patients with severe asthma, targeted drugs such as anti-immunoglobulin E (IgE) and anti-interleukin-5 (IL-5) can be used as add-on treatments, but the evidence is limited.⁵ The management of asthma exacerbation remains unsatisfactory.

Point application therapy (PAT) is an external treatment of Traditional Chinese Medicine (TCM). Chinese herb complex plaster is applied to selected acupoints at specific times (mostly on dog days in the summer) to achieve the comprehensive effects of Chinese herbs, acupoints and treatment timing. PAT has been extensively applied for asthma treatment in TCM medical institutions in almost every province and city since the 1950s in China. In Beijing, there are more than 700 medical institutions providing PAT for asthma patients, with approximately 11 million patches used annually, and serving more than 1.5 million patients in the past decade.⁷ Previous studies have indicated that PAT can reduce acute exacerbation in patients with bronchial asthma and improve their quality of life and lung function.^8,9 A benign adjustment to the disordered neuro-endocrino-immune network is considered one of the mechanisms of PAT in the treatment of asthma, presenting with a significant increase in the serum levels of immunoglobulin A (IgA), IgG, vasoactive intestinal peptide and interferon-γ (IFN-γ) and a decrease in the serum levels of IgE, IL-4 and plasma substances.¹⁰ Unfortunately, in contrast to its vigorous application, there are few clinical studies on PAT. The effect of PAT on bronchial asthma remains uncertain due to the small sample size, poor design and high risk of bias in previous studies. The efficacy of PAT requires high-quality evidence. This multicenter, randomized, placebo-controlled trial aimed to evaluate the efficacy and safety of PAT in patients with bronchial asthma.

2. MATERIALS AND METHODS

2.1. Study design

In this multicenter, randomized, placebo-controlled trial, we recruited participants with bronchial asthma from 9 tertiary hospitals in China. The trial was approved by the ethics committees of all centers and registered with the Chinese clinical trial registry (identifier: ChiCTR-IOR-15006794). All the participants provided written informed consent.

2.2. Participants, recruitment, randomization, and blinding

Participants with bronchial asthma were recruited from hospitals and communities via poster and WeChat advertisements. The diagnosis of bronchial asthma was confirmed by respiratory physicians according to the Global Initiative for Asthma (GINA), with recurrent episodes of wheezing, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitations.¹ The participants included in the study were aged between 18 and 75 years, had uncontrolled or partly controlled asthma assessed by both symptoms and adverse outcomes,¹¹ had experienced at least two asthma exacerbations in the past year, and had not received PAT treatment for asthma in the past two years. Participants were excluded from the study if they met any of the following criteria: (a) were pregnant, were breastfeeding or planning to become pregnant; (b) were allergic to Chinese herbs or excipients used in the PAT or had wounds, ulcers or infections on the skin of the application site, or had a cicatricial constitution; (c) had fever, thick yellow sputum, hemoptysis, bronchiectasis, or pulmonary interstitial fibrosis; (d) had uncontrolled diabetes, severe diseases of the heart, brain, liver, kidney or hematopoietic system, malignant tumors, mental diseases or cognitive impairment; or (e) were unable to receive PAT on 3 consecutive summers or were reluctant to undergo long-term follow-up.

Eligible participants were randomly assigned to receive regular or placebo PAT via a central randomization system at a 1∶1 ratio. Randomization was stratified by centers with a block size of 6. The randomization scheme was produced by a statistician via the statistical analysis software SAS 9.3 (Institute Inc, Cary, NC, USA with the “proc plan” program and was maintained by another staff member who took no part in this trial.

In this study, participants, outcome assessors and statisticians were blinded to the treatment allocation. Patient blinding was achieved via a placebo plaster, which had the same specification, color and smell as the regular plaster. A center was randomly selected for blinding assessment by asking patients to guess whether they received regular PAT within 10 min after the last treatment.

2.3. Intervention

2.3.1. Regular PAT

Plaster: in the PAT group, Chinese herb complex plasters were made of raw and ripe Baijiezi (Semen Sinapis), Xixin (Herba Asari Mandshurici), Yanhusuo (Rhizoma Corydalis Yanhusuo), and Gansui (Radix Kansui). Chinese herbs were processed into powder, passed through an 80-mesh sieve, mixed with 100% fresh ginger juice, and then made into circular plaster with a diameter of 10 mm and thickness of 3 mm. Each plaster contained 3 g of Chinese herb powder. The regular plasters were prepared in the TCM preparation room of Xi'an Hospital of Encephalopathy.

Acupoints: acupoints Feishu (BL13), Xinshu (BL15) and Geshu (BL17) were used in PAT. Feishu (BL13), Xinshu (BL15) and Geshu (BL17) are located bilaterally on the midline between the inner margin of the scapula and the posterior midline and horizontally below the spinous process of the 3rd, 5th and 7th thoracic vertebra, respectively.

2.3.2. Placebo PAT

Placebo plaster: placebo Chinese herb complex plasters were made of Chinese herb powder (with a very small amount), corn cob, starch and brown pigments, mixed with 100% fresh ginger juice, and made into plasters with the same specifications and color as the regular plasters. Each placebo plaster contained only 0.2 g of Chinese herb powder. The placebo plaster could cause mild irritation when applied to the skin due to the fresh ginger juice, which was helpful for implementing blinding. The placebo plasters were also prepared in the TCM preparation room of Xi'an hospital of encephalopathy.

The plecebo acupoints: Placebo points used in this trial were bilaterally located on the parallel line 4.5 cun (1.5 times the distance between the inner margin of the shoulder blade and the median posterior line) from the posterior median line, horizontally below the spinous process of the 3rd, 5th and 7th thoracic vertebra, respectively.

2.3.3. Procedure of regular and placebo PAT

Procedure of PAT mainly included the following steps. (a) Participant took a sitting position and exposed the upper back. (b) The doctor sterilized the acupoints, removed the antisticking layer of the plaster, applied the adhesive surface to the acupoints, and pressed the plaster gently to make it stick firmly. (c) Participant kept the plaster for 2 to 6 h. (d) Participants removed the plasters and washed the application sites with warm water.

During the application process, participants might feel different degrees (no to severe) of hot sensation, pain or itching at the application site, which are normal reactions. In the case of unbearable reactions during the application process, participants could remove the plaster immediately, regardless of the application time. Common skin reactions of PAT include slight redness, a hot sensation, itching, small blisters, large blisters, etc. Large blisters can be punctured with sterile needles to remove exudate. Other skin reactions usually resolve without treatment.

2.3.4. Time of regular or placebo PAT

PAT was conducted on dog days in the summer of 3 consecutive years (2015-2017), with 4 sessions per year (once every 10 d) as follows: (a) Baseline (2015): All participants received placebo PAT, scheduled on July 13-15, July 23-25, August 2-4, and August 12-14; (b) First intervention year (2016): Participants were randomized to regular PAT or placebo PAT, scheduled on July 17-19, July 27-29, August 6-8, and August 16-18; (c) Second intervention year (2017): The grouping and intervention protocol remained unchanged from 2016, scheduled on July 12-14, July 22-24, August 1-3, and August 11-13.

2.4. Outcome measures

The primary outcome was the change from baseline in the number of asthma exacerbations after 24 months.

In this study, asthma exacerbation refers to the sudden onset or exacerbation of symptoms of wheezing, shortness of breath, chest tightness, and coughing, accompanied by decreased expiratory airflow, often caused by exposure to irritants such as allergens or inappropriate treatment.^1,12 Throughout the trial, participants were asked to record each asthma exacerbation in the asthma diary, including the date, duration, main symptoms, treatment, medication used, dosage, etc. The asthma diary were collected and issued every 13 weeks from the first day of the dog days. The severity of asthma was judged by respiratory physicians. The number of asthma exacerbations in this study was calculated as the total number of asthma exacerbations in the 12 months (between the first day of this dog day and the day before the next dog day) divided by the number of patients with asthma exacerbation. The number of asthma exacerbations between July 13, 2015, and July 16, 2016, was used as the baseline, whereas the data for the periods from July 17 2016, July 11, 2017, and July 12, 2017 to July 16, 2018, were described as the number of asthma exacerbations at 12 and 24 months, respectively.

The secondary outcomes included the change from baseline in the number of asthma exacerbations at 12 months, severity of asthma exacerbation, asthma control test (ACT) score, percentage of forced expiratory volume in 1 s (FEV₁) to the predicated value (FEV₁%pred), peak expiratory flow (PEF), ratio of FEV₁ to forced vital capacity (FEV₁/FVC), and use of palliative drugs for bronchial asthma exacerbations at 12 and 24 months. Adverse events (AEs) and the success rate of participant blinding were also assessed.

The severity of asthma exacerbation was classified into three categories: mild, moderate and severe.¹² During severe asthma exacerbation, emergency measures are needed to prevent patients from being hospitalized or dying from asthma. It includes any one of the following two conditions: (a) patients need systemic hormone therapy or increase the hormone dosage in addition to the previous maintenance dose for at least 3 d; (b) patients require emergency treatment or hospitalization, and systemic hormone therapy is required for treatment. Notably, only a severe asthma attack occurring one week or more apart can be considered an independent severe asthma exacerbation. Moderate asthma exacerbation is defined as less severe asthma symptoms that do not warrant systemic hormone use or hospitalization, including worsened asthma symptoms, decreased lung function or increased emergency bronchodilator use for at least 2 d. Patients with moderate asthma exacerbation need to temporarily change their treatment regimen to prevent a transition to severe asthma exacerbation. Mild asthma exacerbations are those in which asthma symptoms are mild and less severe than moderate asthma attacks.

The FEV₁%pred, PEF and FEV₁/FVC were measured by spirometry in the first two weeks before the dog days annually from 2015 to 2018. The mean values of these indicators in 2015 and 2016 were used as baselines, and those values in 2017 and 2018 were considered the corresponding data for 12 and 24 months, respectively.

The ACT provides a numerical score to assess the control of asthma.¹³ The ACT assesses five items related to asthma control, including the frequency of shortness of breath, night-time/early awakening, rescue medication use, overall asthma control, and loss of productivity. Each item is answered on a 5-point scale, with a total score ranging from 5 to 25, and higher scores indicate better asthma control. Scores of 20-25 are classified as ‘well-controlled’; 16-19 as ‘not well-controlled’; and 5-15 as very poorly controlled asthma. The ACT score was assessed at weeks 13, 26, 39 and 52 from the first day of the dog days of each year, and the mean value of these four weeks was used as the score of that year.

2.5. Sample size and statistical analyses

2.5.1. Sample size calculation

The primary outcome was the change from baseline in the number of asthma exacerbations at 24 months. There are currently no clinical trials with a follow-up period of up to 3 years to assess the effect of PAT for asthma. According to the results of our pilot study with a 12-month follow-up (unpublished), we assumed that the decreases in the number of asthma exacerbations were (2.90 ± 2.00) and (1.00 ± 1.16) for regular and placebo PAT at 24 months, respectively. A total of 528 participants would be needed to provide 80% power to detect a between-group difference of 1.5 at a two-sided significance level of 0.05. Assuming 20% loss to follow-up, 660 participants would be enrolled. Compared with routine randomized controlled trials (RCTs), this study included fewer treatments but a longer follow-up. In addition, all participants were treated with placebo PAT in the first year, and randomization was conducted in the second year after reconfirmation of participant eligibility. The sample size of this study was therefore expanded to 1000 for reliable results.

2.5.2. Statistical analyses

The primary outcome was analyzed according to the intention-to-treat principle. Missing data on the primary outcome were imputed via the multiple imputation method by chained equations (MICE) method, which can handle a mixture of continuous, binary, and categorical data. Five imputed datasets were generated using the MICE algorithm and subsequently pooled into a single dataset for further analysis. The change from baseline in the number of asthma exacerbations at 24 months was analyzed via a mixed-effect model, with baseline used as a covariate, treatment used as a fixed effect, and site and patient identity used as random effects accounting for center and individual differences. The same approach was used for the change from baseline in the number of asthma exacerbations at 12 months. Continuous data were expressed as mean ± standard deviation ($\overline{x}\pm s$) or median (interquartile range, IQR) based on normality; categorical data were presented as counts and percentages [n (%)]. For other continuous data, comparisons between groups were assessed via the t test or Wilcoxon rank-sum test, whereas categorical data were analyzed via the χ² test or Wilcoxon rank-sum test, as appropriate. A paired t test or Wilcoxon rank-sum test was used to compare the differences within groups. All the statistical analyses were performed via SPSS version 27 (IBM Corp., Armonk, NY, USA), with a 2-sided P value of less than 0.05 considered significant.

3. RESULTS

In the first year of this trial, a total of 1651 patients with bronchial asthma were screened for eligibility, of whom 1299 patients were eligible and received placebo PAT between July 13 and August 14, 2015, to establish a baseline. Those of the 1299 patients who wished to remain in the study were reassessed for their eligibility before the dog days of 2016, among which 835 patients repassed the review and were randomized to receive either PAT (n = 418) or placebo PAT (n = 417) on the dog days of 2016 and 2017, respectively. The study flow diagram is shown in Figure 1. Approximately 61% of the patients were women, the age was (52.6 ± 12.5) years, and the duration of bronchial asthma was (10.3 ± 6.1) years. Among the randomized participants, 644 (77.1%) completed the study. The baseline characteristics were comparable between the groups (Table 1).

Figure 1. Flow of participants.

PAT: point application therapy; ITT: intention-to-treat.

Table 1.

Baseline characteristics of the participants

Characteristic	PAT (n = 418)	Placebo PAT (n = 417)
Female Sex [n (%)]	257 (61.48)	253 (64.99)
Age ($\overline{x}\pm s$, years)	52.5±12.5	52.7±12.6
Smoker [n (%)]	63 (15.07)	77 (18.47)
Duration of disease ($\overline{x}\pm s$, years)	10.4±6.1	10.1±6.0
Patients with comorbidities [n (%)]	46 (11.08)	45 (10.87)
Number of asthma exacerbation [median (Q1, Q3)]	4.00 (2.00, 7.00)	4.00 (2.00, 8.00)
Severity of asthma exacerbation [n (%)]a
Mild	1718 (77.04)	1654 (75.42)
Moderate	436 (19.55)	451 (20.57)
Severe	76 (3.41)	88 (4.01)
Lung function
FEV1%pred ($\overline{x}\pm s$, %)	74.4±23.4	73.1±23.4
FEV1/FVC ($\overline{x}\pm s$)	70.4±15.5	68.3±15.4
PEF ($\overline{x}\pm s$, L/s)	4.1±2.8	3.8±2.5
ACT score ($\overline{x}\pm s$)	20.5±3.0	20.6±2.9
Patients using reliever medications [n (%)]	355 (84.93)	334 (80.10)
Use of reliever [n (%)]
Corticosteroids	235 (56.22)	242 (58.03)
β2 receptor agonist	224 (53.59)	228 (54.68)
Others	69 (16.51)	75 (17.99)
AEs [n (%)]	20 (4.78)	20 (4.80)

Notes: PAT group: regular PAT during dog days; 3 g Chinese herb complex powder [raw/ripe Baijiezi (Semen Sinapis), Xixin (Herba Asari Mandshurici), Yanhusuo (Rhizoma Corydalis Yanhusuo), and Gansui (Radix Kansui)] mixed with 100% fresh ginger juice, applied to Feishu (BL13), Xinshu (BL15) and Geshu (BL17) for 2-6 h per session, 4 sessions/summer (once/10 d). Placebo PAT group: Placebo PAT during dog days; 0.2 g trace Chinese herb powder + corn cob, starch, brown pigments mixed with 100% fresh ginger juice, applied to non-acupoints, with the same duration and frequency as PAT group. PAT: point application therapy; FEV₁: forced expiratory volume in 1 second; FEV₁%pred: percentage of forced expiratory volume in 1 second to the predicated value; FEV₁/FVC: ratio of FEV₁ to forced vital capacity; PEF: peak expiratory flow; ACT: asthma control test; AE: adverse event. Continuous data were expressed as mean ± standard deviation ($\overline{x}\pm s$) or median (interquartile range) based on normality; categorical data were presented as counts and percentages [n (%)]. ^aRefers to the number of patients with asthma exacerbations, excluding those without asthma exacerbation and those who withdrew from the trial (PAT group: n = 365, Placebo PAT group: n = 220).

3.1. The number of asthma exacerbations

The median number of asthma exacerbations was 4.00 (2.00, 7.00) at baseline and 1.00 (0, 3.00) at 24 months in the PAT group and 4.00 (2.00, 8.00) at baseline and 2.00 (0, 4.00) at 24 months in the placebo group, with a statistically significant difference between the two groups at 24 months (P = 0.005). The decrease in the number of asthma exacerbations was greater in the PAT group (mean, －4.08) than in the placebo group (mean, －2.66), with a difference of 1.42 (95% CI, 0.69 to 2.14; P < 0.001) at 24 months. Similar results were observed at 12 months, the median number of asthma exacerbations was 2.00 (0, 4.50) in the PAT group and 3.00 (0, 6.00) in the placebo group, with no statistically significant difference between the two groups (P = 0.093); in terms of the decrease from baseline, the mean change was －2.33 in the PAT group and －1.52 in the placebo group, with a difference of －0.81 (95% CI, －1.57 to －0.06; P < 0.001).

In this study, mild asthma exacerbations were the most common at each time point in both groups, accounting for approximately 75% to 85% of the total number of exacerbations. This was followed by moderate asthma exacerbations, accounting for approximately 12% to 23% of the total. Severe asthma exacerbations were rare, occurring in only approximately 1% to 4% of the total. There were no differences between the groups in terms of the severity of asthma exacerbations at 12 months. The proportion of mild asthma exacerbations was significantly higher in the PAT group than in the placebo PAT group at 24 months (P < 0.001) (Table 2).

Table 2.

Severity of asthma exacerbations [n (%)]

Variable	PAT	Placebo PAT	P value
12 months			0.062
Mild	630 (79.85)	(75.51)
Moderate	148 (18.76)	217 (22.14)
Severe	11 (1.39)	23 (2.35)
24 months			< 0.001
Mild	473 (85.53)	(74.56)
Moderate	68 (12.30)	171 (23.01)
Severe	12 (2.17)	18 (2.42)

Notes: PAT group: regular PAT during dog days; 3 g Chinese herb complex powder [raw/ripe Baijiezi (Semen Sinapis), Xixin (Herba Asari Mandshurici), Yanhusuo (Rhizoma Corydalis Yanhusuo), and Gansui (Radix Kansui)] mixed with 100% fresh ginger juice, applied to Feishu (BL13), Xinshu (BL15) and Geshu (BL17) for 2-6 h per session, 4 sessions/summer (once/10 d). Placebo PAT group: Placebo PAT during dog days; 0.2 g trace Chinese herb powder + corn cob, starch, brown pigments mixed with 100% fresh ginger juice, applied to non-acupoints, with the same duration and frequency as PAT group. PAT group (12 months): n = 205; PAT group (24 months): n = 220; Placebo PAT group (12 months): n = 141; Placebo PAT group (24 months): n = 158. PAT: point application therapy. Values are reported as n (%). Inter-group comparisons were performed using the χ² test.

3.2. Secondary outcomes

For the lung function parameters, compared with the placebo PAT, the PAT significantly increased the FEV₁/FVC (P < 0.001) at 12 months but improved both the FEV₁%pred and the FEV₁/FVC (both P < 0.001) at 24 months. There were no significant differences in the PEF between the groups at 12 and 24 months (Table 4).

Table 4.

Treatment-related AEs [n (%)]

AEsa	PAT (n = 418)	Placebo PAT (n = 417)
Totalb	81 (19.4)	21 (5)
SAEs	0	0
Blister	3 (0.7)	4 (1.0)
Asthma aggravation	3 (0.7)	1 (0.2)
Cough	1 (0.2)	2 (0.5)
Skin allergyb	74 (17.7)	14 (3.4)

Notes: PAT group: regular PAT during dog days; 3 g Chinese herb complex powder [raw/ripe Baijiezi (Semen Sinapis), Xixin (Herba Asari Mandshurici), Yanhusuo (Rhizoma Corydalis Yanhusuo), and Gansui (Radix Kansui)] mixed with 100% fresh ginger juice, applied to Feishu (BL13), Xinshu (BL15) and Geshu (BL17) for 2-6 h per session, 4 sessions/summer (once/10 d). Placebo PAT group: Placebo PAT during dog days; 0.2 g trace Chinese herb powder + corn cob, starch, brown pigments mixed with 100% fresh ginger juice, applied to non-acupoints, with the same duration and frequency as PAT group. PAT: point application therapy; AE: adverse event; SAEs: no severe AEs. Categorical data expressed as n (%), inter-group comparison by χ ² test. ^aAEs were counted by type rather than frequency in the same participant. Multiple occurrences of the same AE in a participant were recorded as one AE, while AEs with different types occurring in one participant were recorded as independent AEs. ^bWith a significant difference between groups.

ACT scores were comparable between PAT and placebo PAT from baseline to 24 months, though a statistical difference (without clinical significance) was observed at 24 months (Table 3). The proportion of asthma reliever use was comparable between the groups at 12 months and was significantly lower in the PAT group than in the placebo PAT group at 24 months (Table 3).

Table 3.

Other secondary outcomes

Variable	PAT (n = 418)	Placebo PAT (n = 417)	Difference (95% CI)	P value
FEV1%pred ($\overline{x}\pm s$, %)
12 months	76.5±20.4	73.3±23.9	2.92 (－0.79, 6.23)	0.120
24 months	76.4±18.7	73.4±23.0	3.05 (－0.35, 6.45)	0.039
FEV1/FVC ($\overline{x}\pm s$, %)
12 months	71.6±15.8	67.8±15.6	4.11 (1.76, 6.47)	0.001
24 months	77.2±16.7	72.2±18.1	4.61 (1.72, 7.51)	0.001
PEF ($\overline{x}\pm s$, L/s)
12 months	4.2±2.8	4.2±2.7	－0.03 (－0.37, 0.30)	0.755
24 months	4.2±2.7	4.07±2.6	0.25 (－0.09, 0.58)	0.645
ACT score ($\overline{x}\pm s$)
12 months	21.7±2.4	21.5±2.3	0.26 (－0.05, 0.58)	0.269
24 months	22.1±2.2	21.5±2.5	0.60 (0.33, 0.87)	0.005
Patients using reliever medications [n (%)]
12 months	186 (44.50)	218 (52.28)		0.024
24 months	159 (38.04)	175 (41.97)		0.037
Use of relievera [n (%)]
12 months
Corticosteroid	109 (26.08)	129 (30.94)		0.050
β2 receptor agonist	109 (26.08)	137 (32.85)
Others	56 (13.40)	75 (17.99)
24 months
Corticosteroid	91 (21.78)	105 (25.18)		0.039
β2 receptor agonist	91 (21.78)	109 (26.14)
Others	38 (9.10)	41 (9.83)
Blindness assessmentb [n (%)]
Yes	28 (75.67)	25 (67.56)		0.688
No	3 (8.11)	5 (13.51)
Unknown	6 (16.22)	7 (18.92)

Notes: PAT group: regular PAT during dog days; 3 g Chinese herb complex powder [raw/ripe Baijiezi (Semen Sinapis), Xixin (Herba Asari Mandshurici), Yanhusuo (Rhizoma Corydalis Yanhusuo), and Gansui (Radix Kansui)] mixed with 100% fresh ginger juice, applied to Feishu (BL13), Xinshu (BL15) and Geshu (BL17) for 2-6 h per session, 4 sessions/summer (once/10 d). Placebo PAT group: Placebo PAT during dog days; 0.2 g trace Chinese herb powder + corn cob, starch, brown pigments mixed with 100% fresh ginger juice, applied to non-acupoints, with the same duration and frequency as PAT group. PAT: point application therapy; FEV₁: forced expiratory volume in 1 second; FEV₁%pred: percentage of forced expiratory volume in 1 second to the predicated value; FEV₁/FVC: ratio of FEV₁ to forced vital capacity; PEF: peak expiratory flow; ACT: asthma control test. Measurement data were expressed as mean ± standard deviation, inter-group comparison by t-test; categorical data as n (%), compared by χ ² test. a: Use of reliever measures the number of patients using different types of drugs, not the number of times the drug is used. Different types of drugs used by a single participant were counted as independent events. Multiple uses of the same drug were recorded as one event. b: Blindness assessment was conducted in a randomly selected center with 37 patients in each group.

We assessed the credibility of participant blinding. Patients in a randomly selected center were asked to guess whether they received regular PAT within 10 min after the last treatment. The choices were categorized into three types: yes, no or unknown. No difference between the groups was found (P = 0.688) (Table 3).

3.3. AEs

Treatment-related AEs included hot sensations, pain or itching at the application site, skin allergies (erythema and edema), blistering, asthma aggravation, cough, etc. These adverse events were mild and transient and more common in the PAT than in the placebo PAT. The most frequent AE was skin allergy. The incidence of skin allergies was 17.7% in the PAT group, which was significantly higher than the 3.4% reported in the placebo PAT group. Nontreatment-related AEs occurred infrequently and comparably between the groups. No severe AEs (SAEs) were observed in either group (Table 4).

4. DISCUSSION

Compared with the placebo PAT, the PAT conducted on the dog days of two consecutive summers resulted in a greater reduction in the number of asthma exacerbations. Patients receiving PAT also showed improvements in the severity of asthma exacerbation and lung function at 24 months. PAT-related cutaneous adverse reactions were not rare but were mild, as expected.

In this trial, the number of asthma exacerbations was used to evaluate asthma control and the effect of PAT.¹ Previous systematic reviews indicated that the frequency of acute asthma attacks was reduced by a mean of 0.11 to 2.19 sessions per patient-year in PAT patients compared with controls.^14-17 In this trial, the decrease in the number of asthma exacerbations in the PAT group was 1.42 sessions (95% CI, 0.69 to 2.14) lower than that in the placebo PAT group per patient-year, which was consistent with the above studies. In drug studies, moderate and severe exacerbations were reported to be reduced by 0.17 to 1.02 sessions per patient-year after ICS/LABA inhaler administration for those with mild to moderate asthma.^18,19 In this study, the majority of asthma exacerbations were mild, and a significant increase in the proportion of mild asthma exacerbations was observed in the PAT at 24 months. Because we did not focus on changes in the severity of asthma attacks in the same patients, our results cannot be compared with those from drug studies.

PAT also showed better results than placebo PAT in terms of FEV₁%pred and FEV₁/FVC at 24 months, indicating an improvement in airflow limitation. The between-group difference in the FEV₁%pred at 24 months was 3.05%, which was consistent with other randomized studies of PAT.^14,16 However, the observed improvement in FEV₁%pred fails to achieve clinical relevance.²⁰ The results of FEV₁/FVC varied in different studies. No difference was observed between PAT and sham PAT,²¹ whereas better results were reported in PAT plus conventional therapy than in conventional therapy.^14,22 In this study, compared with the placebo PAT, the PAT significantly improved the FEV₁/FVC.

The ACT score is a patient-based tool for identifying patients with poorly controlled asthma.¹³ It assesses the recent symptom control over the previous 1 to 4 weeks. There are no validated tools for assessing asthma symptom control over a longer period (e.g.,12 months),²³ and patients with good symptom control can still be at risk of future severe exacerbations. In this study, the baseline ACT scores were high in both groups, suggesting good recent asthma control. Though a statistically significant improvement of 0.6 points was observed in the PAT group compared with the placebo group at 24 months, the improvement of ACT lacked clinical significance because the minimal clinically important difference is 3 points in the adult population.²⁴ The comparable results between the two groups may be related to the fact that ACT only reflects recent asthma control over the previous 4 weeks, and the fact that baseline ACT values were already high in both groups.

A remarkably high rate of skin allergy was observed in patients receiving PAT. This kind of skin reaction is due to transdermal absorption of the drug, which is an inherent characteristic of PAT. It is mild and considered to be closely related to its effects.²⁵ Similar scenarios have been observed in other PAT studies.^26,27

Notably, PAT was used during a specific period known as the dog days of summer, referred to as “Sanfu” in China. The "Sanfu" period, known as the hottest and most humid phase in the traditional Chinese calendar, is characterized by extreme heat and high humidity. It encompasses three to four 10-day intervals predicted to be the hottest in a year, typically occurring from middle July to mid-August in China. According to TCM theory, human life activities are closely intertwined with natural phenomena. Sanfu marks the time of year when the yang-qi of nature has reached its zenith; correspondingly, it signifies the most vigorous period of human Yang-Qi. Consequently, Sanfu is the best time of the year to strengthen Yang-Qi of the human body via the help of Yang-Qi of nature. This period is particularly advantageous for addressing diseases that are prone to onset or exacerbation during colder seasons, with bronchial asthma being a notable example of such conditions. According to TCM theory, bronchial asthma is primarily attributed to the accumulation of phlegm that has been retained in the lungs over an extended period. When triggered by factors such as external evil invasion, improper diet, emotional disturbances, and fatigue, this accumulated phlegm can obstruct the airways. This obstruction may result in airway constriction, hinder the descending function of pulmonary Qi, and result in an adverse upward movement of pulmonary Qi, ultimately contributing to the onset of asthma. In this study, PAT is used to treat bronchial asthma through the synergistic effects of drugs, acupoints and treatment timing. Drugs used in this study were characterized as pungent and warm, which enhanced transdermal absorption. Their active components were demonstrated to alleviate asthma.²⁸ The acupoints selected for this study represent the most frequently used in PAT.^29,30 They are situated near the lung and along the foot Taiyang meridian on the upper back-regions identified in TCM theory as having a rich supply of Yang-Qi.

In contemporary medicine, the pathogenesis of bronchial asthma is intricate and not yet fully understood. It is generally accepted that factors such as airway inflammation, airway hyperresponsiveness, airway remodeling, immune response, and neuromodulation are closely associated with the development of bronchial asthma.^31,32 Within the immune-inflammatory mechanisms affecting the airways, Th2 dominance resulting from an imbalance between Th1 and Th2 cells plays a critical role in the pathogenesis of asthma. PAT could increase the expression of Th1-related cytokines IL-2 and IFN-γ while reducing levels of Th2-related cytokines IL-4, IL-5 and IL-13.^33,34 Additionally, it could effectively modulate the expression of upstream transcription factors T-box transcription factor expressed in T cells and GATA-binding protein 3 messenger mRNA in lung tissue of rats.³⁵ Pulmonary pathological assessments showed that PAT significantly alleviated inflammatory infiltration and glandular hyperplasia.³⁴ Moreover, PAT improved airway remodeling by down-regulating the expression of transforming growth factor-β1 (TGF-β1)/Smad family member 3 in chronic asthmatic mice.³⁶ It also inhibited phosphorylation processes involving TGF-β along with its downstream effectors extracellular signal-regulated kinase 1/2 and P38 mitogen-activated protein kinase to reduce the expression and activity of matrix protease, thereby reducing airway hypersensitivity.³⁷ Following PAT intervention, patients showed increased plasm levels of vasoactive intestinal peptide alongside decreased substance peptide content, indicating that PAT may regulate the airway non-adrenergic non-cholinergic nervous system to alleviate asthma symptoms.³⁸

To improve participants’ blinding, a placebo PAT marked by a minimal dose of Chinese herb powder and non-acupoints was used as a control in this study. Given the short treatment cycle and extended follow-up of PAT, previous studies on PATs conducted on dog days typically relied on retrospective data for baseline comparisons. To mitigate potential biases stemming from such retrospective data and to establish a reliable baseline, we implemented a placebo PAT for all eligible participants during the first summer. Prior to randomization, we conducted a reassessment of eligibility for those participants who expressed willingness to continue in the trial during the second summer, which distinguishes our approach from conventional RCTs.

This study has several limitations. First, the drop-out rate of 22.9% was slightly high. In this study, patients received only four separate PAT treatments in one month and were followed up by telephone and outpatient visits every 13 weeks for 3 years. The short treatment period and long follow-up with less efficient methods were probably the reasons for high drop-out rate of this study. In future studies, some advanced technologies that can help patients easily enter information, such as voice input and automatic picture recognition, as well as convenient doctor-patient communication tools, such as Wechat, can improve patient compliance and reduce the drop-out rate. Second, placebo PAT is not guaranteed to be completely ineffective because it contains an extremely low dose of Chinese herb powder. Third, despite our regular follow-up, the use of palliative drugs was largely dependent on patients’ records, and omission might have occurred. Fourth, for the use of palliative asthma drugs, we counted only the number of drugs used and the number of patients and did not record the dosage of drugs used, which led to incomplete information on drug use. In addition, the application of the results of this study to other populations and settings needs to be cautious.

In conclusion, among patients with bronchial asthma, compared with placebo PAT, PAT conducted on the dog days of two consecutive summers resulted in fewer asthma exacerbations. Further research is needed to understand the difference in efficacy between acupuncture and asthma control medication.

5. ACKNOWLEDGMENTS

The authors would like to thank all the participants in this trial.

Funding Statement

Supported by “12th Five-year” National Science and Technology Pillar Program by the Ministry of Science and Technology of the People’s Republic of China: Clinical Evaluation and Technical Operation Specification Research on Preventing Bronchial Asthma Attacks by Acupoint Application in Winter Disease Summer Treatment (No. 2015BAI04B11)