Bronchial thermoplasty for severe asthmatics: a real-world clinical study from Malaysia

INTRODUCTION

Over the past century, the emergence of different phenotypes and endotypes of asthma has resulted in the development of new specific pathway-targeted therapies such as anti-IL-5, anti-IgE and anti-IL-4/IL-13. The hallmark of asthma involves airway hyperreactivity, chronic airway inflammation and reversible airflow obstruction.[1] Interest in the remodelling process and increased airway smooth muscle mass in asthmatic patients has shifted the treatment paradigm towards bronchial thermoplasty (BT). Bronchial thermoplasty is an endoscopic procedure that utilises controlled thermal energy delivered in three separate sessions via a basket catheter to achieve a reduction in airway smooth muscle mass, thus antagonising airway remodelling and reducing the amount of bronchoconstriction.[2,3] An activation is recorded when the thermal basket catheter is activated to deliver a 65°C thermal therapy lasting 10 s.[4,5] It is listed in the Global Initiative for Asthma step 5 treatment options.[6]

METHODS

We retrospectively reviewed the medical records of patients with severe asthma, as defined by the European Respiratory Society/American Thoracic Society (ERS/ATS),[7] who underwent BT between 2012 and 2018. We recorded the patient demographics, baseline postbronchodilator forced expiratory volume in 1 sec (FEV₁) (ERS/ATS standards),[8] medications, exacerbation frequency and severity, Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) scores[9,10,11] and total activations pre- and post-BT and at 12 months (at the respective centres). Bronchial thermoplasty was performed according to published protocols by a trained interventional pulmonologist using Alair^™ Bronchial Thermoplasty System (Boston Scientific, Marlborough, MA, USA) and Olympus BF Q190 flexible bronchoscopy (Olympus Medical, Tokyo, Japan) under general anaesthesia.

Statistical analysis was done using IBM SPSS Statistics version 23.0 for Macintosh (IBM Corp, Armonk, NY, USA). Normally distributed and non-normally distributed data were presented as mean ± standard deviation and median (interquartile [IQR] range), respectively. The results were compared using the Wilcoxon signed-rank test and paired t-test. P-values were two sided, and a P value < 0.05 was considered statistically significant.

RESULTS

Twenty patients with severe asthma underwent BT. Three patients were excluded from the analysis due to loss to follow-up. A retrospective analysis was done on the remaining 17 patients. Table 1 shows the demographics of the patients. Of the patients, 14 (82%) were female. Median age was 48 (IQR 33–55) years. All patients were on high dose of inhaled corticosteroids (budesonide equivalent mean 1,106 ± 571 mcg) and long-acting β2-agonist. Twelve (71%) patients were on long-acting anti-muscarinic, and three (18%) were on bronchodilator with ultra-fine properties. Other maintenance medications included montelukast sodium (n=17, 100%), theophylline (n=13, 76%) and oral corticosteroid (OCS) (n=13, 76%), and the median daily OCS (prednisolone) dosage was 10 (IQR 0–13.75) mg. Three (18%) patients had undergone treatment with omalizumab. Mean total number of BT activations was 126 ± 27.6.

Table 1.

Characteristics of patients with severe persistent asthma who underwent BT and completed 12 months follow-up (N=17).

Characteristic	n (%)
Agea (yr)	48 (33–55)
Gender
Male	3 (18)
Female	14 (82)
Heightb (cm)	157±5.4
Body mass indexa (kg/m2)	24.8 (19.7–34.0)
Race
Malay	6 (35)
Chinese	6 (35)
Indian	4 (24)
Others	1 (6)
Medications
ICS and LABA	4 (24)
ICS, LABA and LAMA	10 (59)
ICS and LABA (UF particles)	1 (6)
ICS, LABA (UF particles) and LAMA	2 (11)
Montelukast sodium	17 (100)
Oral theophylline	13 (76)
Oral prednisolone	13 (76)
Omalizumab	3 (18)
Frequency of nebulisation
More than once daily	5 (25)
Once daily	6 (30)
Two to three weekly	6 (30)
Once weekly	3 (15)
History of intubation (≥2 years before BT)	9 (45)

^aData presented as median (interquartile range). ^bData presented as mean±standard deviation. BT: bronchial thermoplasty, ICS: inhaled corticosteroids, LABA: long-acting β-agonists, LAMA: long-acting muscarinic antagonists, UF: ultrafine

The ACQ score improved from 3.7 ± 0.5 to 2.6 ± 0.8 at 12 months (mean difference of 1.1, P < 0.001) [Figure 1a]. Of the 17 patients, 15 (88%) demonstrated a minimal clinically significant difference of 0.5 unit. The baseline AQLQ median score of 3.4 (IQR 2.5–3.6) showed a significant improvement of 0.9 to 4.3 (IQR 3.9–4.6) (P < 0.001) post-BT [Figure 1b]. There was a reduction in mild to moderate exacerbations (per patient) from 4 (IQR 2.50–8.50) pre-BT to 1 (IQR 0–2.00) post-BT, with a reduction rate of three exacerbations (P < 0.005). Severe exacerbations (per patient) were 2 (IQR 1–2) and 0 (IQR 0–1) for pre- and post-procedure respectively, which is an improvement of two exacerbations (P = 0.02) [Figure 1c].

Figure 1.

Boxplots show the comparisons of (a) Asthma Control Questionnaire (ACQ) score, (b) Asthma Quality of Life Questionnaire (AQLQ) score, and (c) exacerbation rates pre-bronchial thermoplasty (BT) and at 12 months post-BT.

The mean pre-procedure FEV₁ was 59.2 ± 15.7%. At 12 months, the mean FEV₁ was 62.8% ± 14.7%. Improvement in mean FEV₁ was 3.6% (P = 0.23). Thirteen (76%) patients were dependent on OCS with a median dosage of 10 (IQR 0–13.75) mg. Post-BT, 10 (59%) patients were OCS free. The median dose of OCS reduction was 10 mg (P < 0.005). One (6%) patient remained on the baseline dosage. No correlation was established between the number of activations and changes in ACQ score, AQLQ score or exacerbation rates. A summary of the results is shown in Table 2.

Table 2.

Evaluation for asthma control, quality of life, lung function, exacerbation rates and usage of corticosteroid before and at 12 months after BT.

Outcome	Median (IQR)		P
	Baseline	12 months
ACQa	3.7±0.5	2.6±0.8	<0.001
AQLQ	3.4 (1.1)	4.3 (0.7)	<0.001
FEV1a (predicted %)	59.2±15.7	62.8±14.7	0.23
Mild to moderate exacerbation	4 (6)	1 (2)	<0.005
Severe exacerbation	2 (1)	0 (1)	0.02
OCS dose (mg/day)	10 (15)	0 (0)	<0.005

^aData presented as mean±standard deviation. ACQ: Asthma Control Questionnaire, AQLQ: Asthma Quality of Life Questionnaire, BT: bronchial thermoplasty, FEV₁: forced expiratory volume in 1 s prebronchodilator, OCS: oral corticosteroid

Exacerbation was defined according to the AST/ERS statement.[12] Overall, 12 (71%) patients recorded mild to moderate exacerbation; two (12%) had isolated incidence of severe exacerbation requiring intubation (one patient developed severe anaphylactic reaction with bronchospasm secondary to naloxone). There were no deaths. Of a total of 50 bronchoscopies, 15 (30%) had exacerbation requiring an extended duration of OCS (7 days). Other isolated complications included one incident of hospital-acquired pneumonia and transient middle lobe atelectasis secondary to mucous plugging.

DISCUSSION

Precision medicine in the management of severe persistent asthma coincides with improvement in phenotyping of the condition.[7,13] Targeted therapies are explored specifically for T2-high subtype of patients. Macrolide antibiotics can be considered in T2-low non-eosinophilic patients. Bronchial thermoplasty may have a role when there is an unsatisfactory response to the targeted therapies mentioned. Our patients had debilitated symptoms despite being on third-line treatment and were evaluated for targeted therapies. Due to the exorbitant cost of targeted therapies, BT became a reasonable alternative.

Our patients’ demographics were somewhat similar to that reported in previous randomised controlled trials.[14,15] However, the degree of asthma (baseline FEV₁, AQLQ scores and exacerbation rates) was more severe compared to that of the cohorts in AIR2 and PAS2 trials.[15,16] The AIR2 trial recruited patients with prebronchodilator FEV₁ ≥60% predicted and excluded patients who had more than three hospitalisations for asthma in the previous year. This was echoed in the data from the postmarket arm in PAS2. Both demonstrated mean AQLQ scores of >4. Our patients had a mean postbronchodilator FEV₁ value of 59.2% and a median baseline AQLQ of 3.4 and experienced a median of four exacerbations requiring hospital admission in the previous year. Our practice (to apply BT) still adhered to the strict recommendations to exclude patients with life-threatening exacerbations requiring intubation or intensive care unit admissions 2 years before the procedure.

Bronchial thermoplasty was carried out by a single trained bronchoscopist. This reduces potential proceduralist-influenced bias in results. Generally, 40–70 and 50–100 activations are required for both lower and upper lobes, respectively.[4] Data from Asia demonstrated 1.28 times higher number of activations compared to 151 activations reported in AIR2.[17] Another study reported that a minimum of 140 activations are required for significant improvement in ACQ score, and the overall response to treatment can be determined by the number of activations provided.[5] Interestingly, the mean total number of activations in our patients was only 126±27.6. We are unable to establish a correlation between the number of activations and improvement in AQLQ scores or exacerbation rates.

The main reason for a low total number of activations is attributed to low total mean activations recorded for both upper lobes (47 ± 12.8). The subsegments of the upper lobes were ‘short’ and were able to accommodate either one or at the most two activations only. This was most evident involving the subapical segments. Although evidence in ethnicity differences in human lung segments are lacking, we postulated that the length and size of these subsegments could be influenced by smaller body habitus and height of the Asian population. A further study to analyse activation numbers corresponding to bronchial length measured on chest computed tomography would reinforce this hypothesis.

Despite lower total mean activation, our patients demonstrated significant improvement in ACQ and AQLQ scores and reduction in exacerbation rates at 12 months. Bronchial thermoplasty also helped to liberate patients from prolonged OCS usage. Usage of other maintenance medications remained similar.

One patient declined the third BT session due to an increase in exacerbation rates, despite being provided with a reasonable explanation and informed of a potential reduction in treatment efficacy. This patient was a non-responder to BT at 12 months review. Despite a 30% exacerbation rate in the first week postprocedure (15 incidents out of 50 bronchoscopies), the incidence of intubation was isolated. More severe patients in our cohort could have resulted in the higher incidence of exacerbation post-BT compared to the AIR2 trial.[15] Long-term follow-up studies demonstrated no side effects and a sustained treatment response of up to 5 years duration.[18,19,20] In addition, it is believed that BT may be cost-effective once a lower cost of procedure is established.[21]

Some limitations of this study include the small number of subjects studied and the involvement of only a single centre. In addition, missing data from three patients could have an impact on the measured outcomes. The utilisation of monoclonal antibodies as the preferred treatment option for severe allergic asthma may have played a role in influencing a small cohort in our study.

In conclusion, BT is effective in preventing exacerbation in problematic asthma patients from an Asian population. It is well tolerated and has proven safety profile. Future large-scale prospective cohort studies will be invaluable in providing more robust data to improve our understanding of BT in the Asian population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.