Research on the Effectiveness and Safety of Bronchial Thermoplasty in Patients with Chronic Obstructive Pulmonary Disease

doi:10.21203/rs.3.rs-2122788/v1

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Research Article

Research on the Effectiveness and Safety of Bronchial Thermoplasty in Patients with Chronic Obstructive Pulmonary Disease

https://doi.org/10.21203/rs.3.rs-2122788/v1

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Journal Publication

published 09 Sep, 2023

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Objective

To investigate the clinical efficacy and safety of bronchial thermoplasty (BT) in treating chronic obstructive pulmonary disease (COPD) patients.

Methods

Clinical data of 57 COPD patients were randomized into control (n = 29, conventional inhalation drug) or observation group (n = 28, convention inhalation drug plus BT). Primary outcomes were differences in clinical symptom changes, pulmonary function-related indicators, 6-min walk test (6MWT), COPD assessment test (CAT) score, Modified Medical Research Council (mMRC) and acute exacerbation incidence from baseline to average of 3 and 12 months. Safety was assessed by adverse events.

Results

FVC, FEV1 and FEV1% predicted value in both groups improved to varying degrees post-treatment compared with those pre-treatment (P < 0.05), except for FEV1/FVC. Observation group showed greater increase amplitudes of FEV1 (Ftime × between groups = 21.713, P < 0.001) and FEV1% predicted value (Ftime × between groups = 31.216, P < 0.001) than control groups, with no significant difference in FVC variation trend (Ftime × between groups = 1.705, P = 0.193). mMRC, 6MWT and CAT scores of both groups post-treatment improved to varying degrees (Ps < 0.05), but the improving amplitudes of mMRC (Ftime × between groups=3.947, P = 0.025), 6MWT (Ftime × between groups༝16.988, P < 0.001) and CAT score (Ftime × between groups༝16.741, P < 0.001) in observation group were greater than control groups. According to COPD acute exacerbation risk assessment, the proportion of high-risk COPD patients with acute exacerbation in control and observation groups at 1 year post-treatment (100% vs 65%, 100% vs 28.6%), inpatient proportion (100% vs 62.1%; 100% vs 28.6%), COPD acute exacerbation number [3.0 (2.50, 5.0) vs 1.0 (1.0, 2.50); 3.0(3.0, 4.0) vs 0 (0, 1.0)] and hospitalization number [2.0 (2.0, 3.0) vs 1.0 (0, 2.0); 2.0 (2.0, 3.0) vs 0 (0, 1.0)] were significantly lower than those pre-treatment (P < 0.05). Besides, data of observation group were significantly lower than control group (P < 0.05).

Conclusion

Combined BT treatment better improves lung function and life quality of COPD patients than conventional medical treatment, and reduce the COPD exacerbation risk without serious adverse events.

COPD

Bronchial thermoplasty

Effectiveness

Safety

Chronic obstructive pulmonary disease (COPD) is a common lung disease worldwide [1]. Based on latest epidemiological data, COPD is the third leading cause of disease-related death [2].Nearly 25% of COPD patients have a history of asthma [3], and about 50% of asthma patients have COPD overlap syndrome. ACO (asthma‑COPD overlap) patients must rely on long-term drugs to suppress their exacerbation and acute attacks [4, 5]. Bronchial thermoplasty (BT) uses radiofrequency catheter to release radiofrequency energy in the airway wall at a specified location, converts it into heat energy and acts on bronchial smooth muscle cells to ablate the thickened airway smooth muscle layer and reduce airway responsiveness [4]. Numerous studies have confirmed the effectiveness and safety of BT therapy for refractory severe asthma [6–8]. Some individual cases report that BT has a good therapeutic effect on ACO patients. Clinically-used drugs for COPD are limited by poor efficacy and adverse reactions [9], which will increase physical, psychological and economic burden on patients, and induce irregular drug use and poor treatment compliance. Currently, BT has not been applied in COPD treatment. COPD and asthma share similarities like airway remodeling [10] during disease development. Some COPD patients develop pathological airway smooth muscle hyperplasia change [11, 12]. Recent studies find the role of BT in airway smooth muscle and airway epithelium, which can reverse airway remodeling [13]. Thus, the effectiveness of BT treatment for COPD patients deserves further exploration. This study compared and observed COPD symptom changes including lung function, hormone dosage, wheezing, shortness of breath after exercise in COPD patients pre- and post-BT treatment, to provide more evidence for related treatment.

Research objects

Moderate-to-severe COPD inpatients between January 2019 and March 2021 were selected by purposeful sampling.

1) Inclusion criteria:

Following diagnostic criteria of COPD in 2019 Global Initiative for COPD (GOLD Guidelines): FEV₁/FVC < 0.70 after bronchodilator use, 2-3GOLD level, poor conventional medical treatment effect, and repeated acute aggravated. Other diseases presenting with incomplete airflow limitation were excluded [2].
Following definition of COPD stable stage in 2019 Global Initiative for COPD (GOLD Guidelines): stable disease, no cough, sputum, shortness of breath or other aggravating symptoms, no need to change treatment plan [2].
Regular inhalant use, following recommendations for COPD patients in Group D in 2019 Global Initiative for COPD (GOLD Guidelines) [2].
COPD patients were diagnosed as stable group D. The airflow limitation severity ranges from level II (moderate) to level IV (very severe).
Aged 40–75 yearsd.
SpO₂ ≥ 89% on room air during screening.
CAT score ≥ 10 during screening.
Documented history of ≥ 2 moderate COPD exacerbations or ≥ 1 severe COPD exacerbation causing hospitalization within 12 months before consent.
Documented history of taking at least Long-Acting Muscarinic Antagonist (LAMA) and a Long-Acting Beta₂ -Agonist (LABA) as regular respiratory maintenance medication for ≥ 12 months at the time of consent.
Candidate for bronchoscopy decided by the physician or per hospital guidelines. Suitability of bronchoscopy candidates includes but is not limited to: cardiovascular fitness, ability for intubation, ability for oxygenation, no previously diagnosed high-grade tracheal obstruction, no uncorrectable coagulopathy (i.e. participant cannot stop taking blood thinning medication, except aspirin, 7 days before and not restart until 7 days after study).

2) Exclusion criteria:

Implanted cardiac pacemakers;
Acute myocardial infarction within 6 weeks;
Severe cardiopulmonary disease preventing bronchoscopy;
Allergy to anesthetics and unsuitability for bronchoscopy;
Acute COPD exacerbation within 2 weeks;
Inability to stop taking anticoagulant or antiplatelet drugs or uncorrectable coagulation disorders;
ALT and AST ≥ 1.5-fold of upper limit of normal (ULN), and Cr > ULN.
Neurological and psychiatric diseases;
Pregnant or breastfeeding women or those planning to become pregnant in the near future;
Serious primary diseases of heart, liver, kidney, hematopoietic system and other important organs and systems;
Infections (including respiratory and extra-respiratory) within 2 weeks.
Pulmonary nodule suspected of malignancy.
Malignancy treated with radiation or chemotherapy within 2 years of consent.
Daily use of > 10 mg prednisone or its equivalent at the time of consent.
Any disease or condition possibly interfering with study or procedure completion (e.g., severe pulmonary hypertension, emphysema, bullae, bronchial asthma, cystic fibrosis, bronchiectasis, mechanical upper airway obstruction, structural esophageal disorder, life expectancy < 3 years).
Known contraindication or allergy to medications required for bronchoscopy or general anesthesia uncontrollable medically.

3) Exit criteria:

Patients asking to withdraw after enrollment, having poor compliance, or not completing corresponding examinations as required;
Those not completing 3 BT procedures for various reasons;
Those without follow-up for half a year;
Those not evaluating the BT efficacy due to incomplete clinical data;
Those using other treatments or drugs prohibited from concomitant use and affected judgment of effectiveness and safety.

This study was approved by the Research Review Ethics Committee of Shenzhen Hospital, University of Chinese Academy of Sciences (GKDSY-LL-XJS-2018003).

BT operation procedure

Preoperative assessment: Preoperative baseline data of all patients were collected, including age, gender, disease course, smoking history, allergy history, height, weight, Body Mass Index (BMI), and preoperative basal pulmonary function (preoperative FEV₁% in predicted value, FEV₁, and FVC), blood eosinophil percentage, Fractional excretion of exhaled nitrogen (FeNO), and baseline Asthma Control Questionnaire (ACQ) score.
Three BT procedures were performed by the same experienced respiratory interventional physician at intervals of ≥ 3 weeks. The first session was bronchus of right lower lung lobe + right main bronchus BT. The second session was bronchus of left lower lung lobe + left main bronchus BT. The third session was bilateral upper lobe BT. BT was mainly completed by the Alair bronchial thermoforming system (Boston Scientific Corporation, USA Model: M005ATS25010). The BF260 bronchoscope was purchased from Olympus Company (Japan). Under direct view of the bronchoscope, the ablation probe was inserted into the airways one by one from small airways ≥ 3 mm up to the lobar bronchial opening from distal to proximal. Each radiofrequency ablation lasted for 10s. The heating catheter was moved proximally about 5 mm for the next ablation. The ablation was completed until all bronchi 3-10-mm in diameter within the selected lung lobe were visible under the microscope. The whole process was continuous, orderly and not repetitive. Prednisone (30 mg) was administered orally once daily for 3 days preoperatively, on the operation day, and 1 day postoperatively. Meanwhile, patients took antibiotics to prevent infection. The original maintenance medication remained unchanged [14].

Research proposal

Patients were randomized into observation (conventional inhaled triple-combination drug plus BT) and control (conventional inhaled triple-combination drug (flutimervir)) groups.

Indicator collection

(1) Efficacy observation indicators

Initially, patients were required to conduct lung function tests and every 3 months thereafter. Changes in patient clinical symptoms were observed and recorded pre-treatment and at 4 and 12 weeks post-treatment. British Medical Research Council (mMRC) scores and CAT scores were queried. Pulmonary function-related indices (FVC, FEV₁, FEV₁% in predicted value, and FEV₁/FVC), 6-min walk test (6MWT), and exacerbation incidence were examined. The CAT scoring questionnaire included cough, chest tightness, expectoration, sleep, mental, daily living limitations, dyspnea with increased activity, and confidence in outdoor activities. Each aspect was scored on the 0–5 scale based on severity. The total score was 40 points, and the higher score indicated more severe patient condition [6].

The mMRC scoring standards included [7]:

① 0 point: no breathlessness except on strenuous exercise;

② 1 point: shortness of breath when hurrying on the level or walking up a slight hill;

③ 2 points: slower walking than people of same age on the level because of breathlessness or necessity to stop to catch breath when walking at their own pace on the level;

④ 3 points: necessity to stop for breath after walking ~ 100 m or after few minutes on the level;

⑤ 4 points: too breathless to leave the house, or breathless when dressing or undressing.

(2) Safety observation indicators

All patients conducted electrocardiogram, blood routine, urine routine, blood biochemistry, liver function, renal function and other tests before and after the study. Adverse events were recorded.

(3) Chest imaging examination: Patients underwent routine chest X-ray 1 day postoperatively, and repeat chest CT scan 12 months postoperatively.

(4) Patient diary

The patient treatment, concomitant medications, regular follow-up visits, (non-)compliance behavior, and medication use (inhaled medication, daily frequency of medication, and triple-combination medication) were recorded.

(5) Medication compliance analysis

Drug use must be understood. In each visit, the remaining medication number was recorded and compared with the patient’s own records. Concerning compliance, a ratio > 80% between the use number calculated by the remaining dose and that recorded in the patient’s diary was defined as good compliance, and vice versa for poor compliance.

Statistical analysis

SPSS26.0 was employed for data recording and analysis. Normally-distributed continuous data conforming to homogeneity of variance were compared by parametric test (independent samples t-test), and expressed as mean ± standard deviation (± s). Abnormally-distributed data were compared by Mann-Whitney U test and expressed as median and quartile [M (QR)]. Categorical and enumeration data were presented as frequency (rate) and compared by Chi-square test or Fisher test. Through repeated measures ANOVA, indicators pre-treatment, 3 months and 1 year post-treatment were compared and analyzed. Shapiro-Wilk test was used for normal distribution. Mauchly’s spherical hypothesis test was also adopted for analysis. Greenhouse & Geisser was utilized to correct the non-equal variable covariance matrices. A separate effect test was applied for significant interaction, otherwise, a main effects test was performed. Bonferroni correction was conducted to compare time points within groups. p < 0.05 (two-sided) represented statistical significance.

Patient general information

Totally 57 patients were randomly divided into control group and observation group. The patients in the control group (n=29) were treated with conventional medical treatment in the stable COPD period, while those in the observation group (n=28) were treated with conventional medical treatment combined with BT ablation in the normalized stable COPD period ( Figure 1). All patients had received high doses of ICS in the past year and were using LABAs and LAMAs. The study found that there was no significant difference between the two groups in age, gender, course of disease, FeNO, height, weight, BMI, etc. (P>0.05). There were no significant differences in baseline conditions for general data（Table 1）.

BT activation times

For the combined BT treatment group, the effective radiofrequency activation of right, left lower lobe, bilateral upper lung lobes, and total effective radiofrequency activation were (61.47 ± 12.59), (65.53 ± 13.91), [79.50 ( 63.75, 92.50)], and (207.03 ± 33.34) times, separately.

Comparison of lung function pre- and post-treatment between two groups

Through repeated measures ANOVA, changes in FVC, FEV₁, FEV₁/FVC and FEV₁% in predicted value (%) of different groups were judged (Table 2 and Figure 2). There was no interaction between group and time for FVC (F=1.705, P=0.193). Therefore, intervention and time factors were tested for main effects. Consequently, the main effect on FVC was not statistically significant among different groups (F=0.259, P=0.613), while that of time factor on FVC was statistically significant (F=29.280, P<0.001). FVC was significantly different at different time points (pre-treatment, 3 months and 1 year post-treatment) (P<0.001). Therefore, FVC of two groups post-treatment was improved compared with that before treatment (Table 2 and Figure 2A).

There was an interaction between group and time in FEV₁ (F=21.713, P<0.001). Changes in different groups exerted different effects on FEV₁, with inconsistent trends in FEV₁ elevation. Comparatively, FEV₁ increased faster in observation group than control group. Intervention and time factors were tested for separate effects. Thus, difference was not significant between control and observation groups pre-treatment (F=0.525, P=0.475). At each time point post-treatment (3 months and 1 year post-treatment), FEV₁ of observation group increased relative to control group, but with no statistical significance (F=0.039, P=0.845; F=0.825, P=0.372). In intra-group comparison, differences were significant between two groups at each time point (pre-treatment, 3 months and 1 year post-treatment) (Table 2 and Figure 2B) (control group: F=24.590, P<0.001; observation group: F= 108.528, P<0.001).

For FEV₁/FVC, the interaction between group and time was not significant (F=2.797, P=0.070), suggesting no significant difference in FEV₁/FVC variation trend between two groups. Intervention and time factors were tested for main effects. Therefore, the main effect of different groups on FEV₁/FVC (F=0.016, P=0.899) and that of time factor on FEV₁/FVC were not statistically significant (F=2.797, P=0.070) (Table 2 and Figure 2C).

The FEV₁% in predicted value showed a group-time interaction (F=31.216, P<0.001). Different groups had different effects on FEV₁%predicted, with inconsistent change magnitude between two groups. Through inter-group comparison, control group had higher FEV₁%predicted than observation group at each time point (pre-treatment, 3 months and 1 year post-treatment) without statistical significance (F=1.141, P=0.295; F=0.136, P=0.715; F=1.692, P=0.204). According to intra-group comparison, control (F=13.794, P<0.001) and observation (F=112.178, P<0.001) groups showed statistical significance between pre-treatment, 3 months and 1 year post-treatment (Table 2 and Figure 2D).

Life quality and exercise tolerance (scoring system) comparison

Effects of different groups on mMRC, 6MWT and CAT were judged by repeated measures ANOVA (Table 3). There was a group-time interaction for mMRC (F=3.947, P=0.025). Changes in different groups had significantly different effects on mMRC. Between-group factors and time were tested for separate effects. In between-group comparison, difference between control and observation groups was not significant pre-treatment (F=0.015, P=0.523), but that was significant at 3 months (F=5.642, P=0.025) and 1 year post-treatment (F=10.446, P=0.003). Upon intra-group comparison, control (F=9.646, P=0.001) and observation (F=45.098, P<0.001) groups had statistical significance pre-treatment, 3 months and 1 year post-treatment (Table 3 and Figure 3A).

There was a group-time interaction for 6MWT (F=16.988, P<0.001). Specifically, 6MWT of different groups had different trends over time, with differences in change magnitude. Between-group factors and time were tested for separate effects. In between-group comparison, observation group was higher than control group pre-treatment, 3 months and 1 year post-treatment. Noteworthily, difference was not significant pre-treatment (F=0.306, P=0.585) and 3 months post-treatment (F=2.441, P=0.130), but significant 1 year post-treatment (F=9.205, P=0.005). In intra-group comparison, control (F=112.042, P<0.001) and observation (F=84.121, P<0.001) groups showed significant changes pre-treatment, 3 months and 1 year post-treatment (Table 3 and Figure 3B).

There was a group-time interaction for CAT (F=16.741, P<0.001). CAT of different groups had different trends over time, with different change magnitudes. Between-group factors and time were tested for separate effects. In between-group comparison, observation group was lower than control group pre-treatment, 3 months and 1 year post-treatment. Difference between two groups pre-treatment was not significant (F=0.013, P=0.911), but that was significant 3 months (F=5.880, P=0.022) and 1 year post-treatment (F=21.104 , P<0.001). Through intra-group comparison, control (F=57.986, P<0.001) and observation (F=84.636, P<0.001) groups had significant changes pre-treatment, 3 months and 1 year post-treatment. CAT gradually decreased with time (Table 3 and Figure 3C).

Acute exacerbation risk of two groups of patients before and after treatment

Assessment of COPD acute exacerbation risk: Based on the number of acute exacerbations in the previous year, it is assessed as a high-risk group for exacerbations if there are 2 or more moderate/severe exacerbations in a year, or one or more hospitalizations for an exacerbation.

In the comparison of the proportion of high-risk patients with COPD acute exacerbation, the within-group comparison showed that the proportion of high-risk patients after treatment in that control group decreased to 65.5%, and that in the observation group reduced to 28.6%. Using paired Chi-square test, the proportion of high-risk patients with acute exacerbation in the control group and observation group was statistically significant before and after treatment. The comparison between groups showed that the proportion of high-risk patients with acute exacerbation in the observation group after treatment was significantly lower than that in the control group (X²=7.800, P=0.005), as shown in Table 4.

In the comparison of cumulative number of patients with COPD acute exacerbation, within-group comparison shows that the cumulative number of cases with acute exacerbation in that control group and observation group were significantly lower after treatment (P<0.001). According to the comparison between groups, the cumulative number of cases with acute exacerbation in the observation group was significantly lower than that in the control group after treatment (Z=-3.624, P<0.001), as shown in Table 4.

In the comparative analysis of the proportion of hospitalized patients in the two groups of COPD acute exacerbation patients, the intra-group comparison results showed that the proportion of hospitalized patients after treatment in the control group decreased to 62.1%, while the proportion of patients treated in the observation group decreased to 28.6%. With the paired Chi-square test, the difference in the proportion of hospitalized patients between the control group and the observation group was statistically significant before and after treatment. The comparison between groups showed that the proportion of hospitalized patients in the observation group after treatment was significantly lower than that in the control group (X²=6.443, P=0.011), as shown in Table 4.

In the comparison of the cumulative number of inpatients with COPD acute exacerbation between the two groups, the intra-group comparison results showed that the cumulative number of cases with acute exacerbation in the control group and observation group were significantly decreased after treatment (P<0.001). According to the comparison between groups, the cumulative number of cases with acute exacerbation in the observation group was significantly lower than that in the control group after treatment (Z=-3.050, P=0.002), as shown in Table 4.

Safety analysis and comparison of respiratory adverse events in two groups of patients within 4 weeks after treatment

In the combined BT treatment group, the main adverse events in patients with COPD within 3 weeks after treatment were cough, phlegm, and short-lived wheezing. Specifically, there were cough (39 cases), increased expectoration (32 cases), short-term wheezing (32 cases), blood in sputum (8 cases), chest tightness and pain (4 cases), pneumonia (3 cases) cases), focal atelectasis (13 cases), hypoxemia (1 case), and hypercapnia (2 cases). Most adverse events resolved spontaneously one week after operation or disappeared after symptomatic treatment such as sputum suction under bronchoscopy and non-invasive ventilator-assisted ventilation. In addition, no structural changes such as bronchial stenosis or tracheal dilatation or segmental atelectasis occurred during postoperative chest computed tomography (CT) follow-up. There were no patients in each group who terminated the study early due to adverse reactions or experienced serious adverse reactions within 3 weeks.

COPD is a chronic airway inflammatory disease characterized by incompletely reversible airflow limitation, whose symptoms include small airway mucus formation, airway wall fibrosis, and emphysema [15]. Like asthma, airway remodeling is also a major pathogenesis of COPD [16,17]. COPD induces airway remodeling changes like airway wall thickening and airway smooth muscle hyperplasia. COPD-induced airway smooth muscle proliferation mainly occurs in small airways [18,19]. The increased ASM mass caused by hyperplasia and hypertrophy significantly affects overall airway remodeling in COPD patients, which is closely related to disease severity [20, 21]. The lungs have numerous vagal parasympathetic nerves interacting with cholinergic receptors in the bronchial tree by releasing acetylcholine. Therefore, smooth muscle contraction, airway mucus secretion, and local inflammatory responses occur [22]. In COPD patients, enhanced pulmonary vagal parasympathetic nerve activity is an important contributor to the reversible distal airway obstruction [23]. These pathological changes are closely related to declined lung function and life quality in COPD patients [24-27]

Bronchodilator agents are the cornerstone of COPD treatment, but they cannot completely reverse airway remodeling. As a new interventional technique, BT is effective on improving airway remodeling and lung function and relieving COPD [28-31]. The AIR, AIR2, and RISA [32-34] trials are conducted on moderate-to-severe, severe and refractory severe asthma patients, confirming that BT improves life quality and clinical symptoms of moderate-to-severe and above asthma patients. Asthma and COPD are chronic airway inflammatory diseases characterized by airflow limitation, which share multiple similarities, including ① common molecular targets and inflammatory mediators, ② interchanged inflammatory features during acute exacerbations and infections, and ③ changes in airway smooth muscle hyperplasia and airway remodeling [35]. However, the BT mechanisms remain largely unclear, which may have other mechanisms besides airway smooth muscle ablation [36]. BT has different effects on various airway cellular components (inflammatory cells and epithelial cells) and the complex airway wall structure to exert therapeutic effects. Since 2015, targeted lung denervation (TLD) has safely achieved long-term targeted, minimally-invasive regulation of lung vagal sympathetic nerve, which has gradually developed into an emerging technology for treating COPD. BT reduces nerves in small airways and denervate the lungs, showing a therapeutic effect on COPD [37]. In individual reports, BT successfully improves lung function and clinical symptoms in childhood asthmatic COPD patients [38]. Our previous results showed that BT significantly improves lung function and life quality in ACO patients. Therefore, BT treatment combined with conventional medical treatment may better treat COPD.

This study compared efficacy difference between combined BT treatment and conventional medical treatment. Both treatments improved FVC, FEV₁ and FEV₁%predicted in a time-dependent manner, with better effect being achieved in a longer time. Therefore, both treatment modalities have effects on improving lung function. In further intergroup comparison, observation group after combined BT treatment had higher FVC at 3 months and 1 year postoperatively than control group, but with no significant difference. FVC is a measure of lung volume. Existing inhaled drugs primarily work by relaxing bronchial smooth muscle, dilating bronchi, and relieving airflow limitation. Combined BT treatment mainly works by ablating bronchial smooth muscle, which has only a slow and limited effect on improving lung volume in emphysema patients. FVC showed a clear upward trend. Therefore, the insignificant difference between observation and control groups at 3 months and 1 year postoperatively is related to the short observation time. Based on relevant foreign studies, BT treatment has long-term effectiveness [39, 40, 41]. Thus, prolonging the observation time further reveals BT’s therapeutic efficacy, and combined BT treatment may achieve significantly better effect than conventional medical treatment.

Moreover, FEV₁ and FEV₁%predicted showed group-time interactions. The trend and magnitude of FEV₁ improvement over time were different between two group. Combined BT treatment improved more FEV₁ and FEV₁%predicted in COPD patients. In inter-group comparison, observation group had significantly higher FEV₁ at 3 months and 1 year post-treatment than control group, indicating that combined BT treatment had a better effect on improving FEV₁, possibly because that BT primarily ablated airway smooth muscle. Airflow restriction is improved by further airway opening. As an indicator of reaction gas flow rate, BT more significantly improved FEV₁ than conventional medical treatment, which was evident 3 months and 1 year post-treatment. However, difference in FEV₁%predicted was not significant between two groups at 3 months and 1 year post-treatment, possibly because thatFEV₁%predicted was affected by patient's lung volume. There was no group-time interaction between FEV₁/FVC, or statistical significance between-group main effect and time main effect, probably because of insignificant improvements in FVC and FEV₁, causing the insignificant improvement in ratio.

Lung functional changes do not accurately reflect patient life quality. Poor lung function does not necessarily influence on patient life quality. Conversely, some patients with good lung function develop severe clinical symptoms that significantly affect their life quality. Assessing patient life quality and exercise tolerance is important to determine the effectiveness of combined BT treatment for COPD.

The 6-min walk test is closely related to lung function parameters in COPD patients, with longer 6-min walking distance indicating better pulmonary ventilation function [42]. Observation group had significantly higher 6-min walking distance at 3 months and 1 year post-treatment than control group. Combined BT treatment led to greater improvements. Therefore, combined BT treatment better improves exercise tolerance in COPD patients, possibly by improving lung function.

mMRC assesses dyspnea level based on the shortness of breath symptom at the corresponding exercise intensity. Combined BT treatment significantly reduced mMRC and improved dyspnea. Considering the relatively one-sided assessment of mMRC, CAT assessment was conducted. CAT is a questionnaire based on SGRQ, reflecting life quality in COPD patients. Compared with assessing COPD life quality based on FEV₁ alone, CAT accurately represents the current true level, which is no less than other complex health questionnaires. Similar results to mMRC were obtained. Compared with control group, combined BT treatment further reduced CAT score in COPD patients, suggesting its effect on better improving patient life quality. Furthermore, this effect was markedly effective 3 months and 1 year post-treatment

COPD acute exacerbation indicates an acute exacerbation of a patient’s respiratory symptoms and the need for additional treatment. After an exacerbation, about 20% of COPD patients do not return to their previous state. Declined lung function induces persistently severe COPD and reduced life quality [43]. Moreover, COPD acute exacerbations lead to airway inflammation deterioration and hematological immune responses, significantly increasing the death risk in patients [44]. Thus, exacerbations play an important role in managing COPD disease. In this study, combined BT treatment remarkably reduced COPD acute exacerbations, the resultant hospitalizations. Thereby, numbers of high-risk patients and hospitalized patients decrease, suggesting that combined BT treatment partially reduces acute exacerbations in COPD patients. The lung function in COPD patients is a factor affecting their acute exacerbations. FEV₁ is often used to predict COPD severity, acute exacerbation risk and mortality. Combined BT treatment better improved FEV₁, reducing the COPD acute exacerbation risk.

Using long-acting anticholinergic drugs (LAMAs) is found to effectively improve lung function and reduce acute exacerbations in asthma and COPD patients [45,46]. TLD treatment significantly reduces the exacerbation-induced hospitalizations in moderate-to-severe COPD patients [47]. BT treatment can achieve denervation, reducing the COPD acute exacerbation risk.

COPD is a chronic respiratory tract inflammatory disease. Studies find that persistent and low-grade systemic inflammation is a factor for frequency-sensitive exacerbations [48-50]. BT acts on airway smooth muscle and airway epithelium cells [51], while the former cells secrete pro-inflammatory factors and cytokines [52]. Therefore, BT may affect airway inflammation by ablating airway smooth muscle. BT treatment reduces airway TGF-beta, and blood eosinophil levels [53]. Consequently, BT’s effect on reducing COPD acute exacerbations may associate with its effect on airway inflammation.

For safety, respiratory adverse events in both groups mostly included cough, phlegm, and short-term wheezing, which were effectively controlled in a short time. No serious adverse events like malignant arrhythmia or death were observed in both groups within 1 year post-treatment. Therefore, BT treatment is safe and feasible for COPD patients.

Combined BT treatment better improve lung function in COPD patients than conventional medical treatment, significantly improve life quality and reduce COPD acute exacerbation. BT-related adverse reactions are controllable in the short term, without serious adverse events.

Combined BT treatment can better improve lung function in COPD patients, definitely improve the patient life quality, and greatly prevent COPD acute exacerbation. Therefore, BT is a new interventional therapy for COPD patients with repeated acute exacerbations or failure in conventional medical treatment.

BT: bronchial thermoplasty (BT); COPD: chronic obstructive pulmonary disease; FVC: forced vital capacity; FEV₁: forced expiratory volume in the first second; FEV1/FVC: Ratio of FEV1/FVC; CAT: COPD assessment test; mMRC: Modified Medical Research Council; ACO: asthma-COPD overlap; BMI: Body Mass Index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Cr: creatinine; ULN: upper limit of normal; 6MWT: 6-min walk test; LAMA: Long-Acting Muscarinic Antagonist; LABA: Long-Acting Beta2 -Agonist; CT: computed tomography; TLD: targeted lung denervation.

Acknowledgments

Not applicable

Funding

This study was funded by Special fund for economic development of GuangMing District (2020R01004).

Availability of data and materials

Please contact the primary author for data requests.

Authors’ contributions

FL and SML had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. PF, TW, SH, QW, ZH, LL, WH, FH, PF, JG, HD and GY contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript.

Ethics Approval and Consent to Participate

The study was performed in compliance with the guidelines for human studies and conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Written informed consent was given by the participants and the study was approved by the Scientific Research Review Ethics Committee of the Shenzhen Hospital of the Chinese Academy of Sciences(approval number: LL-KT-2020185).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Table 1

Comparison of the basic clinical data of the two groups of patients
	Control group (n = 29)	Observation group (n = 28)	t/z/χ²	P value
Characteristic
Age (year, x̄±s)	66.48 ± 9.89	68.18 ± 6.99	-0.745	0.459
Gender (%)			-	0.352
Male	25 (86.2%)	27(96.4%)
Female	4 (13.8%)	1 (3.6%)
Course of disease [year, M(Q₁, Q₃)]	10.0 (7.0, 20.0)	10.0 (6.0, 10.0)	-0.900	0.368
Course of smoking [year, x̄±s]	29.0 ± 18.70	37.04 ± 13.38	-1.860	0.068
Height (cm, x̄±s)	163.72 ± 8.45	164.21 ± 8.80	-0.215	0.831
Weight (Kg, x̄±s)	59.43 ± 11.11	60.82 ± 16.67	-0.372	0.711
BMI (kg/m², x̄±s)	22.08 ± 3.08	22.33 ± 4.48	-0.242	0.810
Percentage of blood eosinophils (%, M(Q₁, Q₃)	2.90 (1.50, 4.80)	1.90 (0.40, 4.35)	-1.286	0.199
FeNO (ppb, x̄±s)	34.38 ± 12.54	29.46 ± 12.30	1.493	0.141
Medication
LABA/LAMA/ICS, % (n)	100%(29/29)	100%(28/28)
Notes: Control group (n = 29) received conventional medical treatment with normalized stable COPD, and observation group (n = 28) received conventional medical treatment plus BT ablation during the normalized stable COPD period. Data were expressed as mean ± SD or number, percentage, median [interquartile range (IQR)], with significance level at P < 0.05.
Abbreviations: BMI, body mass index; FeNO, fractional excretion of exhaled nitrogen; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist.

Table 2

Comparison of lung function before and after treatment in two groups of patients
Time	Group	FVC	FEV₁	FEV₁/FVC	FEV₁%predicted(%)
Before treatment	Control group	1.85 ± 0.59	0.93 ± 0.47	49.61 ± 15.68	37.52 ± 13.9
Before treatment	Observation group	1.87 ± 0.51	0.88 ± 0.34	46.77 ± 10.54	34.6 ± 10.54
3 months after BT	Control group	2.07 ± 0.7	1.03 ± 0.46	49.64 ± 10.89	40.81 ± 13.61
3 months after BT	Observation group	2.11 ± 0.55	1.07 ± 0.35	50.93 ± 10.40	42.25 ± 11.08
1 year after BT	Control group	2.06 ± 0.69	1.05 ± 0.48	49.89 ± 11.53	41.29 ± 13.78
1 year after BT	Observation group	2.22 ± 0.50	1.17 ± 0.35	52.51 ± 9.25	46.22 ± 11.21
	F_{time × between groups}/P value	1.705/0.193	21.713/<0.001	2.237/0.117	31.216/<0.001
	F_{main effect between groups}/P value	0.259/0.613	-	0.016/0.899	-
	F_{time main effect}/P value	29.280/<0.001	-	2.797/0.070	-
Notes: F_{time × between groups}: interaction effect of group and time; F_{between groups}: main effect between groups; F_{time: time} main effect. Data were expressed as mean ± standard deviation, with significance level at P-value < 0.05.
Abbreviations: FVC, Forced vital capacity, FEV₁, forced expiratory volume in the first second.

Table 3

Comparison of mMRC, 6MWT and CAT scores between the two groups of patients
Time	Group	mMRC	6min walk test (m)	CAT
Before treatment	Control group	3.03 ± 0.73	243.10 ± 75.29	27.93 ± 3.35
Before treatment	Observation group	2.89 ± 0.63	254.29 ± 49.18	27.68 ± 4.51
3 months after BT	Control group	2.62 ± 0.62	267.93 ± 73.62	25.17 ± 3.08
3 months after BT	Observation group	2.21 ± 0.57	297.07 ± 50.4	22.75 ± 3.86
1 year after BT	Control group	2.52 ± 0.74	274.62 ± 83.33	24.41 ± 3.72
1 year after BT	Observation group	1.89 ± 0.57	332.36 ± 48.81	20.32 ± 2.97
	F_{time × between groups}/P value	3.947/0.025	16.988/<0.001	16.741/<0.001
Notes: F_{time × between groups}: interaction effect of group and time. Data were expressed as mean ± standard deviation, with significance level at P-value < 0.05.
Abbreviations: FVC, Forced vital capacity; FEV₁, forced expiratory volume in the first second.

Table 4

Comparison of quality of life before and after treatment between the two groups of patients
Project	Group	Time		Z/ X²	P
Project	Group	1 year before treatment	1 year after treatment	Z/ X²	P
Proportion of high-risk patients with acute exacerbation of COPD (%)	Control group	29(100%)	19(65.5%)	8.100	0.002
	Observation group	28(100%)	8(28.6%)	18.050	< 0.001
	X²	-	7.800
	P	-	0.005
Cumulative number of patients with acute exacerbation of COPD	Control group	3.0(2.50, 5.0)	1.0(1.0, 2.50)	--4.795	< 0.001
	Observation group	3.0(3.0, 4.0)	0(0, 1.0)	-4.697	< 0.001
	Z	-0.363	-3.624
	P	0.717	< 0.001
Number of inpatients with acute exacerbation of COPD (%)	Control group	29(100%)	18(62.1%)	9.091	0.001
	Observation group	28(100%)	8(28.6%)	18.050	< 0.001
	X²	-	6.443
	P	-	0.011
Cumulative number of inpatients with acute exacerbation of COPD	Control group	2.0(2.0, 3.0)	1.0(0, 2.0)	-4.381	< 0.001
	Observation group	2.0(2.0, 3.0)	0(0, 1.0)	-4.960	< 0.001
	Z	0.009	-3.050
	P	0.993	0.002
Notes: Data were expressed as percentage or median [interquartile range (IQR)], with significance level at P-value < 0.05.

No competing interests reported.

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