Bronchial thermoplasty in severe asthma: a real-world study on efficacy and gene profiling

Abstract

Background: Bronchial thermoplasty (BT) is an effective treatment in severe asthma. How to select patients who more likely benefit from BT is an unmet clinical need. Moreover, mechanisms of BT efficacy are still largely unknown. We sought to determine BT efficacy and to identify potential mechanisms of response.

Methods: This retrospective cohort study evaluated clinical outcomes in 27 patients with severe asthma: 13 with T2-high and 14 with T2-low endotype. Expression levels of 20 genes were compared by real-time PCR in bronchial biopsies performed at the third BT session versus baseline. Clinical response was measured based on Asthma Control Questionnaire (ACQ) score < 1.5, asthma exacerbations < 2, oral corticosteroids reduction of at least 50% at 12 months post-BT. Patients were classified as responders when they had at least 2 of 3 outcome measures.

Results: 81% of patients were defined as responders. BT induced a reduction in alpha smooth muscle actin (ACTA2) and an increase in CD68, fibroblast activation protein-alpha (FAP), alpha-1 and alpha-2 type I collagen (COL1A1, COL1A2) gene expression in the majority of patients. A higher reduction in ubiquitin carboxy-terminal-hydrolase L1 (PGP9.5) mRNA correlated with a better response based on Asthma Quality of Life Questionnaire (AQLQ). Lower changes in CD68 and FAP mRNAs correlated with a better response based on ACQ. Lower levels of occludin (OCLN), CD68, connective tissue growth factor (CTGF), higher levels of secretory leukocyte protease inhibitor (SLPI) and lower changes in CD68 and CTGF mRNAs were observed in patients who had less than 2 exacerbations post-BT. Lower levels of COL1A2 at baseline were observed in patients who had ACQ < 1.5 at 12 months post-BT.

Conclusions: BT is effective irrespective of the asthma endotypes and seems associated with airway remodelling. Quantification of OCLN, CD68, CTGF, SLPI, COL1A2 mRNAs could be useful to identify patients with better results.

Trial registration: The study protocol was approved by the Local Ethics Committee (Azienda USL-IRCCS of Reggio Emilia-Comitato Etico Area Vasta Nord of Emilia Romagna; protocol number: 2019/0014076) and all the patients provided written informed consent before participating in the study.

Keywords: Bronchial biopsies; Bronchial thermoplasty; Gene expression; Real-time PCR; Severe asthma; Smooth muscle.

Fig. 1

Changes in gene expression following BT treatment. Gene expression levels in bronchial biopsies from each patient (n = 27) at baseline (T0) and at the third BT session (T2) were determined by real-time PCR. Gene expressions were calculated by the 2^{− ΔCt} method using the GAPDH as housekeeper gene. Data were analyzed by Wilcoxon test. Y axis is in logarithmic scale

Fig. 2

Changes in gene expression correlated with patients reported outcomes during BT treatment. Dot plot visualization of correlations between fold changes in gene expression and differences in ACQ (A) and AQLQ (B) scores between T2 and T0. Fold changes in gene expression were determined by real-time PCR relative to gene expression at T0 through the 2^−ΔΔCt method. Data were analyzed by Spearman's correlation test (n = 27). r = correlation coefficient; 95% CI = 95% confidence interval. Only genes which showed statistically significant correlations are depicted

Fig. 3

Gene expressions at T0 and T2 associated with the numbers of exacerbations post-BT. Gene expressions in bronchial biopsies at T0 and T2 were calculated by the 2^{− ΔCt} method using the GAPDH as housekeeper gene, classifying patients according to the number of exacerbations during the 12 months of follow up post BT (n = 27). Horizontal lines show the median ± interquartile range (IQR). Data were analyzed by Mann–Whitney U test. Only genes which showed statistically significant associations (p < 0.05) are depicted

Fig. 4

Changes in gene expression at T2 versus T0 associated with the numbers of exacerbations post-BT. Genes whose fold changes in expression in bronchial biopsies at T2 versus T0 were different grouping patients according to the numbers of exacerbations experienced during the 12 months of follow up post-BT (n = 27). Horizontal lines show the median ± interquartile range (IQR). Data were analyzed by Mann–Whitney U test. Only genes which showed statistically significant differences (p < 0.05) are depicted