What is the role of bronchial thermoplasty in the management of severe asthma?

Asthma is a common chronic inflammatory condition of the airways. Conventional therapy comprises inhaled corticosteroid and bronchodilators as well as trigger avoidance and management of comorbid conditions. A small group remain symptomatic despite these strategies and novel therapies have been developed. Bronchial thermoplasty is a nonpharmacological therapy which targets airway smooth muscle to improve asthma control. Clinical trials to date have shown the efficacy and safety of bronchial thermoplasty with a persistent effect on extended follow up. Questions remain regarding the exact mechanism of action of bronchial thermoplasty, the cost effectiveness of the procedure and the ideal criteria for patient selection.

Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice.

We previously found that mesenchymal stem cells (MSCs) derived from human-induced pluripotent stem cells (iPSCs) exerted immunomodulatory effects on Th2-mediated allergic rhinitis in vitro. However, their contribution to the asthma and allergic rhinitis in animal models remains unclear. In this study, we developed a mouse model of ovalbumin (OVA)-induced allergic inflammation in both the upper and lower airways and evaluated the effects of the systemic administration of human iPSC-MSCs and bone marrow-derived MSCs (BM-MSCs) on allergic inflammation. Our results showed that treatments with both the iPSC-MSCs and BM-MSCs before the challenge phase protected the animals from the majority of allergy-specific pathological changes. This protection included an inhibition of inflammatory cell infiltration and mucus production in the lung, a reduction in eosinophil infiltration in the nose, and a decrease in inflammatory cell infiltration in both the bronchoalveolar and nasal lavage fluids. In addition, treatment with iPSC-MSCs or BM-MSCs before the challenge phase resulted in reduced serum levels of Th2 immunoglobulins (e.g., IgE) and decreased levels of Th2 cytokines including interleukin (IL)-4, IL-5, or IL-13 in the bronchoalveolar and/or nasal lavage fluids. Similar therapeutic effects were observed when the animals were pretreated with human iPSC-MSCs before the sensitization phase. These data suggest that iPSC-MSCs may be used as an alternative strategy to adult MSCs in the treatment of asthma and allergic rhinitis.

Bronchial thermoplasty: a novel technique in the treatment of severe asthma.

New therapies are needed for patients with severe persistent asthma who cannot achieve control with current therapy of inhaled corticosteroids and long-acting beta(2)-agonists. Bronchial thermoplasty is a novel intervention for asthma that delivers controlled thermal energy to the airway wall during a series of bronchoscopies, resulting in a prolonged reduction in airway smooth muscle mass. We review the method of performing bronchial thermoplasty with the Alair System, how to appropriately select and manage patients undergoing bronchial thermoplasty, and the clinical experience to date with this treatment. Randomized, controlled clinical trials with bronchial thermoplasty in subjects with severe asthma have resulted in improvements in overall asthma control as demonstrated by significant improvement in quality of life, asthma symptoms, severe exacerbations requiring corticosteroids, days lost from work/school/other daily activities due to asthma, and healthcare utilization.

Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial.

RATIONALE: Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. OBJECTIVES: To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta(2)-agonists. METHODS: A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%). MEASUREMENTS AND MAIN RESULTS: The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 +/- 1.10; sham, 1.16 +/- 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively). CONCLUSIONS: BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).

Bronchial thermoplasty for asthma: a critical review of a new therapy.

Bronchial thermoplasty (BT) is a novel experimental procedure involving the application of controlled heat from a radiofrequency source to the airway wall as a means to reduce airway smooth muscle in the airway wall. After BT was shown to reduce airway smooth muscle in preclinical studies in dogs, clinical studies in humans revealed that BT resulted in a significant improvement in asthma outcomes including mild asthma exacerbations, asthma symptom-free days, asthma rescue medication use, and airway hyperresponsiveness as measured by methacholine PC(20). A second trial in humans revealed that BT was safe and effective in patients with severe asthma refractory to the current standard of care. While current trials are ongoing, BT holds promise as an exciting novel therapy in the management of patients with asthma.

Bronchial thermoplasty in asthma.

In this review we discuss the potential of a new procedure, termed Bronchial Thermoplasty to prevent serious consequences resulting from excessive airway narrowing. The most important factor in minimizing an asthmatic attack is limiting the degree of smooth muscle shortening. The premise that airway smooth muscle can be either inactivated or obliterated without any long-term alteration of other lung tissues, and that airway function will remain normal, albeit with reduced bronchoconstriction, has now been demonstrated in dogs, a subset of normal subjects, and mild asthmatics. Bronchial Thermoplasty may thus develop into a useful clinical procedure to effectively impair the ability for airway smooth muscle to reach the levels of pathologic narrowing that characterizes an asthma attack. It may also enable more successful treatment of asthma patients who are unresponsive to more conventional therapies. Whether this will remain stable for the lifetime of the patient still remains to be determined, but at the present time, there are no indications that the smooth muscle contractility will return. This successful preliminary experience showing that Bronchial Thermoplasty could be safely performed in patients with asthma has led to an ongoing clinical trial at a number of sites in Europe and North America designed to examine the effectiveness of this procedure in subjects with moderately severe asthma.

Bronchial thermoplasty for asthma.

RATIONALE: Bronchial thermoplasty (BT) reduces the potential for smooth muscle-mediated bronchoconstriction by reducing the mass of smooth muscle in the walls of conducting airways. OBJECTIVES: This study was conducted to examine the safety and impact on lung function and airway responsiveness of BT over 2 yr. METHODS: The safety of BT was studied in 16 subjects with mild to moderate asthma. Baseline and 12-wk post-treatment measurements included spirometry, methacholine challenge, daily diary recordings of peak flow, symptoms, and medication usage. Subjects completed follow-up evaluations at 12 wk, 1 yr, and 2 yr. MEASUREMENTS AND MAIN RESULTS: The procedure was well tolerated; side effects were transient and typical of what is commonly observed after bronchoscopy. All subjects demonstrated improvement in airway responsiveness. The mean PC(20) increased by 2.37 +/- 1.72 (p < 0.001), 2.77 +/- 1.53 (p = 0.007), and 2.64 +/- 1.52 doublings (p < 0.001), at 12 wk, 1 yr, and 2 yr post-procedure, respectively. Data from daily diaries collected for 12 wk indicated significant improvements over baseline in symptom-free days (p = 0.015), morning peak flow (p = 0.01), and evening peak flow (p < or = 0.007). Spirometry measurements remained stable throughout the study period. CONCLUSIONS: BT is well tolerated in patients with asthma and results in decreased airway hyperresponsiveness that persists for at least 2 yr.

Gastroesophageal reflux and bronchial responsiveness: correlation and the effect of fundoplication.

BACKGROUND: A causal relationship between gastroesophageal reflux (GER) and asthma has been suggested. Should this be the case, one could expect treatment of GER to diminish bronchial sensitivity. There has been a lack of trials evaluating the efficacy of antireflux surgery on airway reactivity. OBJECTIVES: To investigate the correlation between GER and bronchial responsiveness, and to determine the efficacy of Nissen fundoplication on bronchial responsiveness and pulmonary function. METHODS: A methacholine inhalation challenge was performed on 15 consecutive GER patients preoperatively and approximately 5 months after Nissen fundoplication. Airway responsiveness was quantified with a dose-response slope (DRS), calculated by dividing the decrease in FEV(1) (%) with the dose of methacholine administered (micromoles). RESULTS: A positive correlation between the severity of distal esophageal reflux and bronchial responsiveness was found (r = 0.83, p < 0.001). There was an improvement in FEV(1) after fundoplication (p = 0.03). All 3 asthmatic patients participating in the study presented with bronchial hyperresponsiveness (BHR) which improved clearly in all of these patients after fundoplication. This resulted in an apparent trend for DRS to improve when the entire study population was considered (p = 0.12). CONCLUSIONS: According to the current study there seems to be a positive correlation between the severity of distal esophageal reflux and bronchial responsiveness. These data suggest that operative treatment of GER may ameliorate BHR in asthmatic patients. Moreover, the results of the present study suggest that fundoplication may improve pulmonary function in patients with GER.

Laparoscopic Nissen fundoplication for reactive airway disease.

BACKGROUND: Surgical management for gastroesophageal reflux disease (GERD)-induced reactive airway disease in children has been shown to be superior to medical therapy. Laparoscopic Nissen fundoplication is a safe and effective procedure in children. METHODS: The authors performed a retrospective review of 24 patients who underwent a laparoscopic Nissen fundoplication for documented GERD and reactive airway disease. RESULTS: Persistent cough was the primary symptom in 22 of 24 patients, and all but one had lipid laden macrophages on bronchoscopy. The mean length of hospital stay was 2.7 days. There were no major postoperative complications. Eighteen of 24 patients are symptom free and off all medications an average of 17 months postoperatively. The average medication burden of the 6 remaining patients was reduced from 6.8 to 2.3 medications. CONCLUSIONS: Children with reactive airway disease who do not respond to medical therapy should undergo a workup for GERD. These preliminary results suggest that laparoscopic Nissen fundoplication is a potentially effective treatment for pulmonary manifestations of GERD.

Bronchial responsiveness to inhaled histamine in canine pulmonary congestion.

To elucidate the role of bronchial hyperresponsiveness (BHR) in pulmonary congestion, an inhaled histamine provocation test was performed in dogs with acute pulmonary congestion, and the role of vagal nerve activity and arachidonic acid metabolites on bronchial responsiveness was evaluated. We assessed BHR with the provocation concentration of histamine causing a 100% increase in pulmonary resistance (PC100) in an openchest anesthetized and tracheotomized canine model before and after left atrial balloon inflation. Twenty-two mongrel dogs (8-14 kg) were anesthetized with sodium thiopental (15-20 mg/kg) and mechanically ventilated with positive end-expiratory pressure at 3 cmH2O. A Foley catheter was inserted into the left atrium to cause pulmonary congestion, in which mean left atrial pressure was increased to 18 mmHg. In 6 dogs, histamine provocation was examined before and after pulmonary congestion was effected. Intravenous indomethacin (1 mg/kg) administration and vagotomy were performed in 5 dogs. In pulmonary congestion, PC100 was significantly decreased both before and after vagotomy and after indomethacin administration. We conclude that pulmonary congestion augments bronchial responsiveness to inhaled histamine and that neither vagotomy nor indomethacin administration prevents bronchial hyperresponsiveness in pulmonary congestion. These findings suggest that bronchial hyperresponsiveness in pulmonary congestion is related to another factor such as bronchial edema.