Airway smooth muscle and long-term clinical efficacy following bronchial thermoplasty in severe asthma

Abstract

The mechanism of action of bronchial thermoplasty (BT) treatment for patients with severe asthma is incompletely understood. This study investigated the 2.5-year impact of BT on airway smooth muscle (ASM) mass and clinical parameters by paired data analysis in 22 patients. Our findings demonstrate the persistence of ASM mass reduction of >50% after 2.5 years. Furthermore, sustained improvement in asthma control, quality of life and exacerbation rates was found, which is in line with previous reports. An association was found between the remaining ASM and both the exacerbation rate (r=0.61, p=0.04 for desmin, r=0.85, p<0.01 for alpha smooth muscle actin (SMA)) and post-bronchodilator forced expiratory volume in 1 s predicted percentage (r=−0.69, p=0.03 for desmin, r=−0.58, p=0.08 for alpha SMA). This study provides new insight into the long-term impact of BT.

Introduction

Bronchial thermoplasty (BT) is a bronchoscopic treatment option for patients with severe asthma, showing clinical benefits with long-term outcomes reported up to 10 years.¹ Next to clinical improvements, several studies documented reduction in the airway smooth muscle (ASM) mass after BT.^2–6 Despite consistent reports demonstrating clinical improvements and ASM reduction associated with BT, a definitive relationship between BT response and histological changes has not been established.^{5 7 8} Only few reports with limited patient numbers have shown a correlation between the reduction in ASM mass and clinical parameters.^{3 9} Furthermore, long-term follow-up of ASM data over more than 2.5 years has been reported in two studies, however either performed in a small cohort⁴ or the ASM data were not measured in the same patients longitudinally.⁶

Methods

Recently, we published the TASMA randomised controlled trial (RCT)⁷ in which both clinical outcomes and reduction of >50% in ASM mass 0.5 year after BT were described. To investigate long-term effects, this extension study aimed to assess clinical outcomes, ASM mass and their relation 2.5 years after BT (ClinicalTrials.gov NCT02975284). In this study, participants from the Amsterdam cohort were invited to participate. Subjects were offered repeat bronchoscopy for airway histology and were monitored for clinical response at 1.5 and 2.5 years after BT. Clinical data, including annualised exacerbation rate, lung function, Asthma Control Questionnaire (ACQ) scores and Asthma Quality of Life Questionnaire (AQLQ) scores were collected. During bronchoscopy, four endobronchial biopsies were obtained, processed and stained for ASM-specific desmin and alpha smooth muscle actin (α-SMA) as previously described.⁷ ASM mass was expressed as percentage of positive stained area as compared with the total biopsy area.⁷

Endpoints of this study were to determine clinical response, including AQLQ, ACQ and annualised exacerbation rate yearly after BT aligned with ASM mass 2.5 years after BT as compared with baseline and 0.5 year after BT. Other endpoints were medication use and pulmonary function tests. Due to the COVID-19 pandemic period, some study visits had to be postponed. The first subsequent time point at which data were available was used for analyses (1.5-year study visit with a median of 1.7 years (IQR 1.6–1.8), and 2.5-study visit with a median of 2.9 years (IQR 2.7–3.3)).

Statistical analyses were performed in IBM SPSS Statistics V.28.0 and GraphPad Prism V.9.0 (GraphPad Software, San Diego, California, USA). To describe the study population, mean with SD or median with IQRs was provided. Data from the TASMA trial were used for 0.5-year analysis. The comparison between time points was calculated with paired t-tests or Wilcoxon signed-rank test depending on the distribution of variables. Spearman’s correlation was used to explore associations between clinical outcomes and histology. All tests were two sided, and the level of significance was set to 0.05.

Results

From the Amsterdam TASMA cohort, 22 patients (85%) were included. Reasons for exclusion were declining to participate (n=2), loss of follow-up (n=1) and start of biological treatment (n=1). Sustained improvements were observed in ACQ score (p<0.01), AQLQ score (p<0.01) and exacerbation rate (p=0.01) 2.5 years after BT as compared with baseline (table 1). The observed reduction in ASM area at 0.5 year persisted at 2.5-year follow-up. Desmin analysis showed 10.05% area of the total biopsy surface at baseline, 4.93% area 0.5 year after BT and 3.70% area 2.5 years post-BT. The α-SMA analysis showed a comparable reduction: 20.54% area at baseline, 13.16% area 0.5 year after BT and 10.21% area 2.5 years post-BT (table 1 and figure 1). Associations were explored between ASM content with clinical characteristics at baseline, 2.5 years post-BT and between the delta (defined as post-BT minus pre-BT values). ASM at baseline and ASM delta were not associated with clinical parameters, nor with changes in clinical parameters. A positive association was found at 2.5 years after BT between remaining ASM mass at 2.5 years after BT and the exacerbation rate (r=0.61, p=0.04 for desmin, r=0.85, p<0.01 for α-SMA). A negative association was found between post-bronchodilator forced expiratory volume in 1 s predicted percentage (FEV₁%predicted) and desmin-stained ASM (r=−0.69, p=0.03) and a trend with α-SMA-stained ASM (r=−0.58, p=0.08).

Table 1.

Clinical characteristics and ASM mass before and after bronchial thermoplasty (BT) (n=22)

Characteristics	Baseline		0.5 year after BT	1.5 years after BT	2.5 years after BT	P value linear mixed model
ACQ-6 score	2.67 (±0.61)		2.18 (±1.09)*	1.73 (±1.23)	1.87 (±1.17)*	<0.01† A,B,C
AQLQ score	4.18 (±0.98)		4.84 (±1.16)*	5.20 (±1.13)	5.18 (±1.20)*	<0.01† A,B,C
Exacerbation rate (annualised)	3 (1–10 IQR)		2 (0–2 IQR)	2 (0–3 IQR)	2.4 (0–3.5 IQR)	0.01† A,B,C
Dose of ICS (μg/day fluticasone equivalents)	1201 (±521)		1306 (±567)	1215 (±425)	1238 (±426)	0.25
No of patients on maintenance use oOCS	7		6	8	9	0.22
Dose OCS (mg/day)	3±5.5		4±9.6	3.9±7.0	4.5±7.1	0.63
Pre-short-acting bronchodilator FEV1 (% predicted)*	85 (±20)		90 (±22)*	88 (±17)*	86 (±18)‡	0.46
Post-short-acting bronchodilator FEV1 (% predicted)*	99 (±17)		98 (±15)	97 (±13)	95 (±14)‡	0.50
Reversibility FEV1 (%)*	11 (3.5–15.5 IQR)		4 (2–13.5 IQR)‡	5 (1.5–11.5 IQR)*	7 (1.0–14 IQR)‡	0.08
PC20 (mg/mL)§	0.35 (−0.03; 2.83 IQR) n=19		1.22 (0.04–4.0 IQR) n=19	0.84 (0.04–18.6 IQR) n=13	4.0 (0.6–5.75 IQR) n=7	0.34
ASM mass desmin (%)¶	10.05 (6.9–11.8 IQR)		4.93 (2.6–7.2 IQR)		3.7 (3.1–5.4 IQR)	<0.01† A,C
ASM mass α-SMA (%)¶	20.54 (16.99–26.26 IQR)		13.16 (9.74–13.88 IQR)		10.21 (8.03–12.96 IQR)	<0.01†A,C

Analyses to show the overall effect of time were analysed with a linear mixed model assuming an autoregression 1 covariance structure and time point as fixed effect. Analyses between time points were analysed by the paired t-test or Wilcoxon signed-rank test.

Data are presented as mean (±SD) or median (IQR).

*Data available in n=21.

†Significant difference with p<0.05. A=p<0.05 baseline vs 0.5 year, B=p<0.05 baseline vs 1.5 years, C=p<0.05 baseline vs 2.5 years.

‡Data available in n=19.

§Values were log-transformed for statistical analyses and not available in all patients because of the inability to withhold asthma medications for the methacholine challenge test.

¶Data available in n=12.

ACQ, asthma Control Questionnaire; AQLQ, asthma Quality of Life Questionnaire; ASM, airway smooth muscle; FEV₁, forced expiratory volume in 1 s; ICS, inhaled corticosteroids; OCS, oral corticosteroids; PC20, methacholine provocation test.; α-SMA, alpha smooth muscle actin.

Figure 1.

The graphs show (A) the ASM desmin% area and (B) alpha actin% area data expressed as medians (IQRs) of 12 patients with asthma. Examples of biopsies showing ASM mass stained by desmin and alpha actin at baseline, 0.5 year post-BT and 2.5 years post-BT. P values are given between baseline and 0.5 year post-BT and between baseline and 2.5 years post-BT and calculated with the Wilcoxon signed-rank test. ASM, airway smooth muscle; BT, bronchial thermoplasty.

Discussion

To the best of our knowledge, this study is the first study that investigated the 2.5-year impact of BT on clinical outcomes and ASM by paired data analysis. Our findings demonstrate persistent clinical efficacy coincided with a reduction in the ASM mass until 2.5 years after-BT as compared with baseline. At this time point, a reduction in response to a bronchoconstrictor was found, which is in line with a recent study of Henry et al.¹⁰ Next to this, 2.5 years after BT, remaining ASM mass associated positively with exacerbation rate and negatively with post-bronchodilator FEV₁%predicted. Together, these findings indicate that the clinical benefits of BT involve the reduction of ASM. The association between BT-induced reductions in ASM mass and exacerbation rate in patients with severe asthma has been previously reported at 1 year after BT.³

During the TASMA trial, anti-interleukin (IL)-5 treatment was not available as standard of care. Interestingly, only one patient switched to anti-IL-5 treatment, suggesting that BT is an effective treatment option in patients with severe asthma, which may prevent costly and lifelong biological treatment. Furthermore, this study highlights improvements in quality of life, asthma control and exacerbation rates, aligning with previous RCTs and reinforcing BT’s lasting efficacy and safety.¹

The strength of this study is that it provides the longest follow-up impact on ASM mass after BT by paired longitudinal analysis. Limitations are the small sample size and the fact that not all patients from the Amsterdam TASMA cohort were included in this extension study. Finally, the ASM was measured from carina biopsies and therefore provide focal information. However, studies have shown that carina measurements reflect the ASM content of the complete bronchial tree.¹¹

In conclusion, this study reveals a consistent and enduring clinical effectiveness aligned with a decrease in ASM mass up to 2.5 years after BT compared with baseline. We found an association between the remaining ASM mass and exacerbation rate, as well as the post-bronchodilator FEV1%predicted, which provides new insight into the long-term impact of BT.

Ethics statements

Patient consent for publication

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Ethics approval

This study involves human participants and ethical approval was provided by the Ethical Review Committee of Amsterdam University Medical Centers, location Academic Medical Center (NL53703.018.15. 2015_163). Participants gave informed consent to participate in the study before taking part.