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Research Letter

Increased Cough Receptor Sensitivity to Capsaicin Predicts a Positive Bronchial Thermoplasty Response

A Single-center Retrospective Study

Yamamura, Kenta MD*; Hara, Johsuke MD, PhD; Ohkura, Noriyuki MD, PhD; Abo, Miki MD, PhD; Sone, Takashi MD, PhD; Kimura, Hideharu MD, PhD*; Kasahara, Kazuo MD, PhD*

Author Information
Journal of Bronchology & Interventional Pulmonology: April 2019 - Volume 26 - Issue 2 - p 137-141
doi: 10.1097/LBR.0000000000000577
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Abstract

Bronchial thermoplasty (BT) is a novel bronchoscopic therapy for severe uncontrolled asthma unresponsive to standard pharmacological treatment including high-dose inhaled corticosteroids and long-acting beta-2 agonists. Although several studies have shown that BT improves asthma-specific quality of life (QOL) and reduces severe asthma exacerbations,1,2 optimal predictors of BT response are still unknown. We reviewed clinical outcomes of patients treated with BT in our hospital to identify factors that might predict which patients will benefit from BT.

PATIENTS AND METHODS

The medical records of 10 consecutive patients who were treated with BT at Kanazawa University Hospital between January 2016 and March 2018 were retrospectively reviewed. The study was carried out in accordance with the Declaration of Helsinki and was approved by the ethical review board of Kanazawa University hospital (approval date: March 14, 2017; approved number: 2380).

BT was performed under general anesthesia using a standard procedure that consisted of 3 sessions at least 3 weeks apart using The Alair Bronchial Thermoplasty System (Boston Scientific Corporation). Before and every 3 months after the last BT session, all patients were assessed for asthma-related symptoms, number of severe asthma exacerbations requiring systemic corticosteroids, asthma control using the Asthma Control Questionnaire-6 (ACQ-6), asthma-specific health-related QOL using the Asthma Quality of Life Questionnaire (AQLQ), and pulmonary function including reversibility to beta-2 agonists, fractional exhaled nitric oxide, and cough receptor sensitivity to capsaicin, as well as adverse events related to BT.

RESULTS

The clinical characteristics and baseline pulmonary functions of the patients are shown in Table 1. All patients satisfied the 2017 Japanese guidelines for adult asthma. All patients had the most severe persistent asthma and were uncontrolled despite treatment including high-dose inhaled corticosteroids and long-acting beta-2 agonists. Of the 10 patients, 3 had severely impaired pulmonary function [prebronchodilator forced expiratory volume in 1 second (FEV1)<60% of predicted] and 1 patient showed reversibility to beta-2 agonist. Two patients showed bronchial hyperresponsiveness to methacholine and 4 patients showed increased cough receptor sensitivity to capsaicin. The mean values of ACQ-6 and AQLQ were 2.4±1.3 and 4.2±1.2, respectively. Eight patients showed ACQ>1.5, which indicated poor control.

TABLE 1
TABLE 1:
Patient Characteristics and Pulmonary Function at Baseline

The effects of BT on ACQ-6, AQLQ, and pulmonary function are shown in Table 2. Six patients showed a significant improvement in ACQ-6, asthma-related symptoms, and asthma exacerbations requiring systemic corticosteroids. Eight patients showed a significant improvement in AQLQ. One patient (case 2) had a reduced maintenance oral corticosteroids dose (data not shown). Only 1 patient who was severely impaired before BT showed an improvement in prebronchodilator FEV1. There was no association between clinical efficacy and the change in respiratory function. In all patients, the post-BT fractional exhaled nitric oxide, reversibility to beta-2 agonists and cough receptor sensitivity to capsaicin did not change from the pre-BT values.

TABLE 2
TABLE 2:
The Effects of BT on Asthma Control, Asthma-specific Health-related Quality of Life, and Pulmonary Function

In summary, 6 of 10 patients showed an improvement of asthma-related symptoms, number of asthma exacerbations requiring systemic corticosteroids, asthma control, and asthma-specific health-related QOL. Interestingly, all patients with increased cough receptor sensitivity to capsaicin (cases 2, 5, 6, and 9) responded to BT. No other factors were associated with a positive BT response. In 3 patients (cases 2, 5, and 7), BT was complicated by transient asthma exacerbation, but no other severe adverse events were observed.

DISCUSSION

BT was approved by the US Food and Drug Administration in 2010 and has become a widespread and useful treatment option for patients with severe uncontrolled asthma. In the Asthma Research Intervention-2 (AIR-2) trial, 79% of severe asthma patients could benefit an improvement of asthma-specific QOL after BT.1 However, some patients did not benefit from BT. To date, predictors of BT response have not been clarified. In the present study, we found that increased cough receptor sensitivity to capsaicin was associated with a positive response to BT.

BT reduces airway smooth muscle (ASM) mass, and thus diminishes bronchial constriction, by delivering controlled thermal energy to the airway walls.3,4 Recently, Pretolani et al5 reported that BT reduced not only ASM but also neuroendocrine epithelial cells, submucosal nerves, and ASM-associated nerves. Furthermore, the extent of histopathologic change correlated with the clinical efficacy of BT, suggesting that airway nerves may be an important BT target.

The transient receptor potential vanilloid 1 (TRPV1), which is one of the TRP families, is expressed on airway sensory nerves and terminals; it is activated by various stimuli including capsaicin.6 Activation of TRPV1 is associated with bronchoconstriction, chemotaxis, mucus hypersecretion, vasodilation, a sensation of dyspnea, airway irritation, and the urge to cough. The capsaicin inhalation challenge is an established tool for assessing cough receptor sensitivity and thus airway nerve function.7 Previous studies have suggested that cough receptor sensitivity does not differ between mild asthmatic patients and healthy subjects.8 In contrast, more severe asthmatic patients had increased cough receptor sensitivity to capsaicin.9 TRPV1 expression increases with increased severity of bronchial asthma.10 However, the extent of TRPV1 expression varies among patients with severe asthma. In our study, 4 of 10 patients showed increased cough receptor sensitivity to capsaicin and all 4 patients had a positive response to BT. Considering the effect of BT on airway nerves, BT may be most effective in severe asthmatic patients with high TRPV1 expression. Thus, increased cough receptor sensitivity to capsaicin might predict positive BT response.

Our study has several limitations. First, it was a single-center retrospective study and included only 10 patients. Second, the study did not include a sham control group and thus did not control for possible BT placebo effects. Third, the follow-up period was only 2 year at the longest. Finally, some patients had a good therapeutic response to BT despite having a high cough threshold to capsaicin, suggesting that other predictors of BT response may exist. To confirm our findings, larger studies are needed. However, considering the novel mechanism of BT on airway nerves, we believe that increased cough receptor sensitivity to capsaicin is one of the possible predictors of BT response.

CONCLUSIONS

Our data suggest that increased cough receptor sensitivity to capsaicin is one of the predictors of BT response. Larger, long-term, multicenter studies are required to confirm our findings.

REFERENCES

1. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181:116–124.
2. Chupp G, Laviolette M, Cohn L, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multicentre studies. Eur Respir J. 2017;50:1700017.
3. Pretolani M, Dombret MC, Thabut G, et al. Reduction of airway smooth muscle mass by bronchial thermoplasty in patients with severe asthma. Am J Respir Crit Care Med. 2014;190:1452–1454.
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8. Fujimura M, Sakamoto S, Kamio Y, et al. Cough threshold to inhaled tartaric acid and bronchial responsiveness to methacholine in patients with asthma and sino-bronchial syndrome. Intern Med. 1992;31:17–21.
9. Doherty MJ, Mister R, Pearson MG, et al. Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease. Thorax. 2000;55:643–649.
10. McGarvey LP, Butler CA, Stokesberry S, et al. Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with severe asthma. J Allergy Clin Immunol. 2014;133:704.e4–712.e4.
Keywords:

bronchial thermoplasty; bronchial asthma; cough receptor sensitivity; transient receptor potential vanilloid 1

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