Revista Societatii de Medicina Interna

Articolul face parte din revista :
  Nr.4 din luna septembrie 2015

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Autor

Ionela Iovan, Dorin Vancea, Voicu Tudorache, Ruxandra Ulmeanu

Titlu articol

Termoplastia bronsica in astmul sever necontrolatŞ indicatii, avantaje si limitari

Cuvinte cheie

bronchial thermoplasty, quality of life, severe uncontrolled asthma.

Articol

ABSTRACT
Bronchial thermoplasty (BT) is a new non‐drug, minimally invasive bronchoscopic procedure for selected severe asthma patients who remain poorly controlled despite maximal inhaled therapy with corticosteroids (ICS) and long-acting β2-agonists (LABA). The procedure consists in the reduction of airway smooth muscle (ASM) layer via delivering controlled thermal energy (radiofrequency ablation) to the airway wall. It takes place during a series of three bronchoscopies, with the goal of diminishing the ability of the smooth muscle to bronchoconstrict. In order to obtain relevant data, we performed an electronic Medline search of the articles related to BT, published up to December 2014. Short-term complications are respiratory infection and increased hospitalizations. Randomised controlled clinical trials in moderate-severe asthma patients have shown, after 1 year, a modest improvement in asthma quality of life and asthma control scores, a significant reduction of severe exacerbations, but no improvement in the lung function. On long-term basis (over a 5 years of follow-up period), the available evidence demonstrated, for treated patients, clinical and functional stability, with no structural alterations in the airways on high-resolution computed tomography (HRCT) scans. BT fits perfectly with the movement to expand personalised medicine in the field of chronic airway disorders. Further studies are necessary to identify the mechanism of action, the type of patients that benefit the most from this treatment and to establish the durability of the effect.
Keywords: bronchial thermoplasty, quality of life, severe uncontrolled asthma.




METHODS OF SELECTING, EXTRACTING AND SYNTHESIZING DATA
The systematic literature investigation comprised a computerised search of Medline Database up to December 2014, using the following terms: “bronchial thermoplasty”, “quality of life”, “asthma control scores”, “severe exacerbations” and “severe uncontrolled asthma”. We looked for articles of randomised controlled trials (RCTs) that evaluated the safety and efficacy of BT in patients with uncontrolled severe asthma. The final choosing of eligible studies was made on the basis of their full text, applying the selection criteria. We included 3 RCTs, a number of recent original and review articles related to BT and several medical guidelines. Two overview authors independently extracted data using a data extraction form. We resolved disagreements through discussion and consensus. The synthesizing data demonstrate that BT treatment was beneficial on the basis of clinical improvement in severe exacerbations, visits to the emergency department, days lost at work or school and hospitalizations.

INTRODUCTION
Asthma is a chronic inflammatory disease of the airways characterized by intermittent respiratory symptoms due to airway obstruction. The obstruction is reversible to a variable degree, either spontaneously or with the aid of bronchodilator medications. Bronchial hyperresponsiveness is the consequence of the underlying airways inflammation. It is estimated that, within the next 10-20 years, the prevalence of asthma will exceed 400-450 million worldwide. The severe uncontrolled asthma is more and more frequently diagnosed and associated with the highest medical burden. This disease subset is currently considered
to be a distinct heterogeneous phenotype which includes 5% of adults with asthma, and uses up to 50% of the overall healthcare costs attributed to asthma.(1)
According to the existing Global Initiative for Asthma (GINA) 2014 guideline, severe asthma patients requires Step 4 or 5 GINA treatment, but frequently remain suboptimally controlled.(2) Uncontrolled severe asthma definition may differ according to sources, but generally, incorporates patients who remain symptomatic despite maximal inhaled therapy after ruling out  non-asthma related causes, avoidable aggravating factors, poor medication compliance and bad inhalation technique. Maximal inhaled therapy consists in corticotherapy (ICS), budesonide 1600 or fluticasone 1000 μg/day or equivalent plus long-acting β2-agonists (LABA), at least salmeterol 50 or eformoterol 12 μg bid or equivalent.(3) Consequently, treating such patients is a continuous challenge and also a major source of frustration for the patients as well as for the clinicians.(4)
In asthma, airways smooth muscle (ASM) layer is significantly thickened due to hypertrophy (increased cell size) and hyperplasia (increased cell number) in all bronchi and bronchioles, as a result of chronic airways inflammation. These histopathological changes lead to increase in the thickness of the bronchial wall, airway hyperresponsiveness (AHR) and result in augmentation of bronchoconstriction (BC), which can be induced by a wide variety of physiological and pathological stimuli. Another important consequence of these changes is the reduction of the intraluminal diameter and consequently of the airflow rate. A very compelling message of Poiseuille’s Law is the dramatic effect of the bronchial lumen narrowing on fluid flow: a reduction in vessel diameter of only 10% can result in a decrease in flow of 36%, while a narrowing of 20% leads to a 59% reduction in flow.(5)
The increase in ASM mass can be determined by the assessment of high-resolution computed tomography (HRCT) scans. In a study conducted by Sumit Gupta(6) in all 4 subphenotypes of severe uncontrolled asthma investigated (determined by cluster analysis, smokers versus non-smokers, with and without persistent airflow obstruction), the bronchial wall area was increased and luminal area percentage was decreased compared with controls. The degree of airway remodelling was associated with airflow limitation, AHR and air trapping on expiratory CT scans and was significantly greater in patients with persistent airflow obstruction than in those without. The study confirmed that airway wall thickening (ASM hypertrophy and hyperplasia) and reduced luminal patency are features of severe uncontrolled asthma and play a central role in bronchial obstruction in these patients. The increased ASM mass is expected to lead to increased BC, wall remodelling and airway inflammation (by synthesis of proinflammatory mediators) which could explain the poor control of the disease even with maximal therapy.(6)
GINA 2014 recommends add-on therapy with long-acting beta agonists (LABA), leukotriene modifiers, theophylline, low‐dose oral corticosteroids (OCS) and omalizumab in patients with severe asthma who take inhaled corticosteroids (ICS).(2) Many of these add-on medications are expensive, have substantial side effects and require adherence to daily medications or monthly or biweekly injections. These therapies reduce inflammation or decrease airway narrowing by relaxing ASM, but do not prevent the chronic structural changes that occur in the ASM in individuals with asthma. Therefore, an alternative therapy is needed in this population. Bronchial thermoplasty, which is reducing the amount of excess ASM in the central and peripheral airways, could be such a therapy. With reduced muscle tissue, the airways constrict less, breathing is easier and there is less likelihood of an asthma exacerbation.(1)


CURRENT STATUS OF KNOWLEDGE
1. Bronchial Thermoplasty: rationale of the approach
BT can impair the ability of airways to constrict in response to methacholine chloride (Mch). According to studies in dogs, BT reduces the ASM mass and the AHR associated with asthma. BT does not eliminate all of the ASM around the airway, it also does not eliminate the ability of airway to close. Airways treated with BT had significantly increased luminal area at any dose of inhaled Mch when compared to untreated airways on HRCT scans. In one experimental animal study, the dogs received cumulative local challenges of Mch in concentrations of 0.03, 0.3, 3 and 30 mg/ml. At the 0.3 mg/ml dose, 100% treated airways were open, while 86% untreated airways remained open (p = 0.21). At the 3 mg/ml dose, 75% treated airways were open, while only 29% to be untreated airways remained open (p = 0.03). However, at maximum challenge with 30 mg/ml dose, about the same percent of treated and untreated airways remained open (6% versus 7%, p = 0.79). Treated airways are larger at any given dose of Mch, but if they are challenged sufficiently, they can be made to close.(7)
2. Bronchial Thermoplasty: potential mechanisms of action
There are a number of possible mechanisms of action that, alone or in combination, might explain the beneficial effects of BT. The most well documented mechanism is a marked reduction in ASM mass (observed experimentally in a canine model and in nonasthmatic human lobectomy specimens examined between 1 and 3 weeks after BT). A second mechanism is a direct effect of the application of temperatures exceeding 55°C on the contractile properties of the ASM (with the loss of ability on the part of the ASM to generate BC but with unaffected relaxation mediated by LABA). Other potential mechanisms include decreased secretion of inflammatory mediators by ASM cells and changes to the airways epithelium, to the nerve endings or to the function of the inflammatory cells that infiltrate the bronchial mucosa.(8) Currently, the mechanisms of action for BT are not established and poorly understood and require further extensive studies.(4)
3. The rationale of applying Bronchial Thermoplasty in clinical practice
It has been suggested that BT works by reducing ASM, thereby reducing the ability of the smooth muscle to bronchoconstrict. This treatment could then reduce asthma symptoms and exacerbations, resulting in improved asthma control and quality of life.(9)
3.1. Procedure in practice
Performing BT requires bronchoscopic rigour, dexterity and a thorough knowledge of the airway anatomy. BT is performed with the Alair Bronchial Thermoplasty System (Boston Scientific, Natick, Massachusetts), which applies controlled heat via radiofrequency waves during the bronchoscopy. The system consists of a radiofrequency generator and a single use catheter with a basket carrying four expandable electrodes. The thermoplasty catheter is inserted via the working channel of a flexible bronchoscope. The basket at the end of the catheter is then expanded with the manually operated handle, so that all four electrodes are in contact with the mucosa. The energy is subsequently released via a foot pedal.(8)
3.2. Interventional therapy steps
BT is done under local or general anaesthesia. Three bronchoscopic procedures are performed at 3-6 weeks interval. The sequence of treatments involves the right lower lobe (first session), then left lower lobe (second session), followed by both upper lobes (third session). The middle lobe is omitted due to a theoretical possible risk of middle lobe syndrome. Bronchi of 3-10 mm are reached (from distal to proximal) along their entire visible length. Each application lasts for 10 seconds for a local temperature of 65°C. The distance between 2 applications is 5 mm. A full procedure treatment consists of ≈40-100 activations per lobe. Each bronchoscopy takes 30-60 minutes. The heat leads to subsequent apoptosis, autophagy and necrotic cell death of ASM. The overall reduction of ASM is about 50%, which is replaced by connective tissue. The superficial tissues are acutely destroyed, but regenerate in time.(8,10)
4. Who is candidate for Bronchial Thermoplasty?
When selecting patients for this procedure, caution is advised as efficacy and safety information is available only for patients who satisfied the inclusion criteria for the pivotal clinical trials of the procedure (see Table 1).(11,12)
As per to the United States of America (USA) Food and Drug Administration (FDA), the exclusion criteria are according to the non-eligibility criteria for BT (see Table 2).(13)
5. Patient management before, during and after the procedure
BT, although simple in principle, should be performed only by an experienced bronchoscopist with the ability to address any potential post-intervention complications, in a healthcare setting with appropriate clinical monitoring. The appropriate assessment and monitoring of the patient before, during and after the procedure are described in Table 3. All studies showed a short-term clinical deterioration up to 6 weeks after BT.
Immediately after intervention, there was an increase of mild asthma exacerbations with respiratory symptoms (cough, wheeze, expectoration, dyspnoea, nocturnal awakening) or infections, some of these requiring hospitalization (8.4% in BT group; 2% in Sham control group). These adverse events were more common in the BT group and occurred between the first and seventh day post intervention. The increased frequency in respiratory complications for the BT group was equivalent to the control group after 6 weeks.(10,11)


6. Bronchial Thermoplasty: effectiveness and safety
After an initial study exploring the safety and clinical effects of BT in patients with mild to moderate asthma,(14) three RCTs were carried out in patients with moderate to severe asthma: the Asthma Intervention Research (AIR) Trial,(15) the Research in Severe Asthma (RISA) Trial(16) (both without Sham control arms) and the Asthma Intervention Research 2 (AIR2) Trial(17). The largest study, AIR2, was the only double-blinded, randomised, Sham-controlled study that enrolled patients who had severe uncontrolled asthma despite high-dose ICS and LABA. 190 patients were treated with BT (ICS+LABA+BT) and 98 received Sham thermoplasty (ICS+LABA+Sham) in a 2:1 randomization. The Sham thermoplasty treatment reproduced all the audio and visual signals of the technique, but the catheter did not deliver any radiofrequency energy. Eligible patients criteria used are specified in Table 1. The primary outcome measure was the change in Asthma Quality of Life Questionnaire (AQLQ) score from baseline to 12 months. The length of follow-up was 1 year for all patients and 5 years safety follow-up only for BT subjects in the Extension Study.(8)
6.1. Short-term results after BT - at year one in AIR2 Study
Patients were evaluated at 3, 6, 9, 12 months to assess the safety and the effectiveness of this treatment option.
6.1.1. Effects on primary endpoint (quality of life)
A total of 79% of patients (positive responders) in the BT group and 64% of patients in the Sham group demonstrated superior AQLQ scores (BT=1.35 ± 1.1, Sham 1.16 ± 1.23) compared with baseline. An AQLQ increase of range 0.75-1.50 indicates moderate improvement. But interestingly, there was also a significant improvement in the Sham group. The AQLQ difference in the primary endpoint between the 2 groups was only 0.19, below the clinically relevant difference in AQLQ of ≥0.5 points.(17)
6.1.2. Effects on secondary endpoints
The BT group demonstrated a significant reduction in severe exacerbations (reduction of 32%), visits to the emergency department (reduction of 84%), days lost at work or school (reduction of 66%), hospitalizations (reduction of 73%), with the absence of major events: pneumothorax, intubation, mechanical ventilation, airway stenosis or focal narrowing, cardiac arrhythmias, death.(17)
6.2. Long-term results after BT - at 5 years in AIR2 Study
Of the 190 subjects who underwent BT treatment in the AIR2 trial, 162 (85.3%) completed the 5-years follow-up to assess the long-term safety and effectiveness of BT in the Extension Study (in which no patient from Sham group was included, resulting in the absence of any Sham group comparison at 5 years).
Primary endpoint was the percentage of patients experiencing severe exacerbations during subsequent 1-5 years compared with the first year after BT. Secondary endpoints were emergency department visits, hospitalizations and pre-and post-bronchodilator FEV1.
The follow-up data of the above-mentioned studies show a clinical, functional and radiological stability over a period of 5 years after BT. There was no increase in severe asthma exacerbations or in the incidence of respiratory events. There was no increased incidence of hospitalizations or emergency room visits. There was no deterioration in lung function (FEV1) or asthma quality of life. There were no structural changes such as bronchiectasis, bronchial wall thickening, bronchial dilatation, parenchymal damage, development of emphysema or bronchiolitis obliterans in the airways (HRCT review). The absence of clinical complications, as well as the stability in lung function testing over a period of 5 years, makes BT a safe procedure.(18)

7. Histological findings after Bronchial Thermoplasty
In a 2013 study conducted by Gordon et al, on endobronchial biopsy in patients with BT, in three patients with severe persistent asthma, bronchoscopic endobronchial biopsies were taken before and after BT. The biopsies were examined for inflammation and structural (submucosal and epithelial) changes, such as the presence or absence of epithelial changes, intraepithelial inflammation, basement membrane thickening, prominent smooth muscle, irregularity of elastic fibres and submucosal mucous glands. In comparison to the control group, patients with severe asthma had more intraepithelial eosinophils (67% versus 17%, p < 0.001), more submucosal eosinophilic airway inflammation (79% versus 54%, p < 0.05) and lymphocytes (61% versus 27%, p = 0.005), more prominent smooth muscle (88% versus 29%, p < 0.001) and goblet cell hyperplasia (47% versus 22%, p = 0.004). No significant difference in the structure of the epithelial and basal membrane layer was shown. Following BT, ASM was reduced and was partially replaced by fibrosis.(10)
8. Bronchial Thermoplasty approval and guidelines recommendations
BT was approved in USA by FDA, in April 2010, for the treatment of severe persistent asthma in patients aged ≥18 years, whose asthma is not well controlled with ICS/LABA.
The Alair BT system has a "Conformité Européenne" mark and is available in European Union since September 2011, for the treatment of severe asthma in patients aged ≥18 years.(19)
The British Thoracic Society guideline for therapeutic flexible bronchoscopy in adults recommends BT as a possible modestly effective treatment option for selected patients with severe asthma already on maximal therapy, although its place in management remains to be established (Evidence A).(20)
According to GINA 2014 guideline, BT may be considered as add-on therapy in Step 5 GINA treatment, for some adult patients with severe asthma (Evidence B). The evidence is limited and only in selected patients. The long term effects are not known.(2)
According to International European Respiratory Society/American Thoracic Society (ERS/ATS) Guidelines on Definition, Evaluation and Treatment of Severe Asthma 2014, BT is performed in adults with severe asthma only in the context of an Institutional Review Board approved independent systematic registry or a clinical study.(21)
The American College of Chest Physicians (ACCP/CHEST) 2014 position statement for Coverage and Payment for Bronchial Thermoplasty recommended the procedure “for those adult patients with severe persistent, poorly controlled asthma who continue to experience asthma exacerbations, emergency department visits and hospitalizations despite maximal medical treatment”.(22) ACCP/CHEST “believe that, given the extensive body of evidence demonstrating safety, effectiveness, and durability, BT is not experimental and should not be withheld from patients pending additional clinical trials”.(22) The ACCP/CHEST has issued this statement because many of the currently published treatment guidelines were finalised prior to the publication of five years follow‐up data from the AIR2 study, the pivotal randomised controlled trial of BT.(23)
9. Bronchial Thermoplasty: challenges and limitations
The Cochrane Database of Systematic Reviews 2014 included three clinical trials (429 participants) in which BT was performed versus any active control in adults with moderate or severe persistent asthma. The primary outcomes were quality of life, asthma exacerbations and adverse events. The review provides a modest clinical benefit in quality of life and lower rates of asthma exacerbation, but no significant difference in asthma control scores. The overall quality of evidence regarding this procedure is moderate.(9)
In the AIR2 trial, the improvement in AQLQ (compared with baseline) between the BT group and the Sham group was only 0.19 (1.35 versus 1.16 points), which did not reach statistical significance (P=0.2). There was a large placebo effect in the Sham procedure arm, with the AQLQ improving by 1.16 points, or “moderate improvement”, with the absence of any information regarding 5-years post-BT outcomes in the Sham group.(19)
Current marketing of BT highlights its use for patients with severe asthma, which is interpreted by most clinicians as meaning oral corticosteroid dependence, frequent exacerbations, or a significantly reduced FEV1 with a poor quality of life. These types of patients were specifically excluded from potential candidates for BT and as a results, the data referring to BT cannot be generalized.(19)
BT is an invasive procedure which poses potential risks for the patients. Treatment must be performed by experienced interventional bronchoscopists. The very long-term clinical benefit and complications (past 5 years) are unknown. Repeated treatment with BT is currently not licensed. The high cost of the procedure needs to be considered (radiofrequency generator=30,000$, single use catheter=1,500$). A cost-benefit analysis must be performed. The favourable clinical response is not uniform among all the patients.(10)
Despite the large body of clinical work, many unanswered questions remain: How long does it last (over the 5-years)? Which are the mechanisms of action: on smooth muscle cells? on nerves? other cells? Are there effects on airway inflammation? Are there immunomodulatory effects? What are the causes of therapeutic failure? Why the positive response cannot be predicted? How do we adjust ICS and LABA after BT? How can we achieve a better patient selection?

10. Bronchial Thermoplasty: ongoing and future studies
Bronchial Thermoplasty in Severe Persistent Asthma (PAS2 Study) (NCT01350336)(24): This study is being conducted as part of the conditions of the premarket approval for the Alair system. Asthmatx Inc., the study sponsor, is required by FDA to evaluate the long-term safety and efficacy of the system in the intended use population in the USA. The study is being conducted at 3 USA sites and is including adults with asthma who are taking regular maintenance medication with pre-bronchodilator FEV1 at least 60% of predicted. The estimated study completion date is December 2019.
A Prospective Observational Study of Biopredictors of Bronchial Thermoplasty Response in Patients With Severe Refractory Asthma (BTR Study) (NCT01185275)(25): This is a prospective observational study of adults with asthma who have been taking regular maintenance medication for the past 12 months. Additional eligibility criteria include pre-bronchodilator FEV1 at least 50% of predicted and asthma symptoms on at least 2 days or 1 night per week over the past 2 weeks. The study will assess the relationship between baseline clinical, physiological, biological and imaging markers and response to BT to identify the factors that predict a beneficial clinical response. The expected study completion date is August 2017.
Future research are needed to confirm the mechanism(s) of action of BT(26,27) and to identify  new treatment procedures(28,29).




CONCLUSION
Bronchial thermoplasty is a modestly effective treatment option for selected patients with poorly controlled severe asthma.(20)
BT cannot be a substitute for the established five-step treatment plan of conservative therapy of asthma described in GINA 2014.(1) BT potentially represents an effective alternative, but not an add‐on therapy to omalizumab in uncontrolled severe allergic asthma.(23)
Procedure should be undertaken in centres that have expertise in uncontrolled asthma and in fibreoptic bronchoscopic procedures.(10)
The follow-up data of the above-mentioned studies suggest the long-term effectiveness and safety of the procedure out to 5 years, which outweigh the short-term risks, thus proving BT a safe procedure. But we must remember that the worldwide number of BT treated patients is less than 300.(29)
Because of restrictive inclusion criteria, a large majority of severe asthma patients (ex. with oral corticosteroid dependence, frequent exacerbations, or significantly reduced FEV1) are excluded as candidates for BT.(19)
Unfortunately, the clinical efficacy of BT in the treatment of severe asthma is unpredictable (only 79% of selected patients are positive responders)(16). Further studies should provide the factors that predict a beneficial clinical response, as well as BT effect in different asthma phenotypes or in patients with poor lung function.(30)



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9. Torrego A, Sola I, Munoz AM, Roque I Figuls M, Yepes-Nunez JJ, Alonso-Coello P, et al. Bronchial thermoplasty for moderate or severe persistent asthma in adults. Cochrane Database Syst Rev [Internet]. 2014 Mar 3. DOI: http://dx.doi.org/10.1002/14651858.CD009910.pub2
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11. Bicknell S, Chaudhuri R, Thomson NC. How to: Bronchial thermoplasty in asthma. Breathe [Internet]. 2014 Mar 1;10(1):48-59. DOI: http://dx.doi.org/10.1183/20734735.007813
12. Boston Scientific Corporation. Bronchial Thermoplasty [Internet]. Marlborough (MA): Boston Scientific Corporation; [created 2010 Feb 25] [cited 2015 Jan 14]. Available from: www.btforasthma.com
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14. Cox G, Miller JD, McWilliams A, FitzGerald JM, Lam S. Bronchial Thermoplasty for Asthma. Am J Respir Crit Care Med [Internet]. 2006;173(9):965-969. DOI: http://dx.doi.org/10.1164/rccm.200507-1162OC
15. Cox G, Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC, et al. Asthma Control during the Year after Bronchial Thermoplasty. N Engl J Med [Internet]. 2007;356:1327-1337. DOI: http://dx.doi.org/10.1056/NEJMoa064707
16. Pavord ID, Cox G, Thomson NC, Rubin AS, Corris PA, Niven RM, et al. Safety and Efficacy of Bronchial Thermoplasty in Symptomatic, Severe Asthma. Am J Respir Crit Care Med [Internet]. 2007;176(12):1185-1191. DOI: http://dx.doi.org/10.1164/rccm.200704-571OC
17. Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, 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 [Internet]. 2010;181(2):116-124. DOI: http://dx.doi.org/10.1164/rccm.200903-0354OC
18. Wechsler ME, Laviolette M, Rubin AS, Fiterman J, Lapa e Silva JR, Shah PL, et al. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol [Internet]. 2013;132(6):1295-1302.e3. DOI: http://dx.doi.org/10.1016/j.jaci.2013.08.009
19. Iyer VN, Lim KG. Bronchial Thermoplasty: Reappraising the Evidence (or Lack Thereof). Chest [Internet]. 2014;146(1):17-21. DOI: http://dx.doi.org/10.1378/chest.14-0536
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21. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J [Internet]. 2014 Feb 1;43(2):343-373. DOI: http://dx.doi.org/10.1183/09031936.00202013
22. American College Of Chest Physicians (CHEST). Position Statement for Coverage and Payment for Bronchial Thermoplasty. Chest [Internet]. 2014 May 12 [cited 2015 Jan 17]. Available from: http://www.chestnet.org/News/CHEST-News/2014/05/Position-Statement-for-Coverage-and-Payment-for-Bronchial-Thermoplasty
23. Medical Services Advisory Committee. Final Protocol for Bronchial Thermoplasty for the Treatment of Uncontrolled Severe Asthma, Medical Services Advisory Committee-Application 1384, For Consideration by the Protocol Advisory Sub ‐ Committee (PASC) October 2014 [Internet]. Canberra (ACT): Medical Services Advisory Committee; 2014 [cited 2015 Jan 18]. Available from: http://www.msac.gov.au/internet/msac/publishing.nsf/Content/0A85E8CA52DE4FDFCA257D07001C9BD7/$File/1384-Bronchial%20Thermoplasty-Final_Protocol-accessible.pdf
24. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- . Identifier NCT01350336, Bronchial Thermoplasty in Severe Persistent Asthma (PAS2); 2011 Apr 15 [updated 2014 May 15; cited 2015 Jan 19]; [about 7 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT01350336
25. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- . Identifier NCT01185275, A Prospective Observational Study of Biopredictors of Bronchial Thermoplasty Response in Patients With Severe Refractory Asthma (BTR Study); 2010 Jun 21 [updated 2014 Dec 20; cited 2015 Jan 19]; [about 9 screens]. Available from: https://clinicaltrials.gov/show/NCT01185275
26. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- . Identifier NCT01777360, Evaluating Bronchial THERMOPLASTY in a Patient Presenting Severe Uncontrolled Asthma (ASMATHERM); 2013 Jan 17 [updated 2014 Aug 25; cited 2015 Jan 19]; [about 6 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT01777360
27. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- . Identifier NCT01839591, Bronchial Thermoplasty: Effect on Neuronal and Chemosensitive Component of the Bronchial Mucosa (BT-ASMN); 2013 Apr 2 [updated 2014 Mar 31; cited 2015 Jan 19]; [about 7 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT01839591
28. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- . Identifier NCT01832363, Bronchial Thermoplasty for Severe Asthmatics Guided by HXe MRI (HXe-BT); 2013 Mar 28 [updated 2014 May 30; cited 2015 Jan 19]; [about 9 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT01832363
29. Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC, Olivenstein R, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med [Internet]. 2011 Feb 11;11:8. DOI: http://dx.doi.org/10.1186/1471-2466-11-8
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ACKNOWLEDGEMENTS
All authors have read and approved the final manuscript.

CONFLICT OF INTEREST
The author declares that there is no conflict of interests regarding the publication of this paper.

TABLES
Table 1. Patients potential candidates for Bronchial Thermoplasty. Modified.
Eligibility criteria for BT used in pivotal clinical trials AIR and AIR2.(12)
•     Adult aged 18–65 years
•     Asthma requiring regular high-dose ICS and LABA (ICS/LABA);
•    OCS at a dosage ≤10 mg per day
•     AQLQ score of 6.25 or less (stable >6 weeks)
•     AHR
•     Non-smoker for ≥1 year or greater (if ex-smoker, <10 pack-years total smoking history)
•     Pre-bronchodilator FEV1≥60%.
•     Patient considered suitable for bronchoscopy
AIR: Asthma Intervention Research; AIR2: Asthma Intervention Research 2; ICS: Inhaled corticosteroid; LABA: Long-Acting-β2-Agonist; OCS: Oral Corticosteroids; AQLQ: Asthma Quality of Life Questionnaire; AHR: Airway hyperresponsiveness; FEV1: Forced Expiratory Volume in 1 second

Table 2. Patients who are not candidates for Bronchial Thermoplasty. Modified.
Non-eligibility criteria for BT according to the USA FDA.(13)
• Excessively use of short-acting bronchodilator (>12 puffs/day within 48h of bronchoscopy)
• In the past 12 months: ≥4 lower respiratory tract infections; ≥4 OCS pulses for asthma exacerbation; ≥3 hospitalisations for respiratory symptoms
• Intubation for asthma or ICU admission for asthma within the prior 24 months
• Other respiratory diseases: emphysema, vocal cord dysfunction, mechanical upper airway
obstruction, bronchiectasis, cystic fibrosis or uncontrolled obstructive sleep apnoea
• Conditions associated with increased risk for adverse events associated with bronchoscopy or anaesthesia - pregnancy, insulin dependent diabetes, epilepsy or other significant comorbidities (uncontrolled coronary artery disease/hypertension, acute or chronic renal   failure)
• Presence of a pacemaker, internal defibrillator or other implantable electronic device
• Known sensitivity to medications required to perform bronchoscopy, including lignocaine, atropine and benzodiazepines
•  Patients previously treated with BT.
BT: Bronchial Thermoplasty; USA: United States of America; FDA: Food and Drug Administration; OCS: Oral Corticosteroids; ICU: Intensive Care Unit


Table 3. Patient management before, during and after the procedure.(11) Modified
Pre-procedure:
•    Prednisone 50 mg/day for 5 days starting 3 days before the procedure.
•    Bronchodilators: short acting beta agonists, long acting muscarinic agonists.
•    Stop anticoagulants.
•    Sedation (propophol + fentanyl) + orotracheal intubation.
•    Needs 2-3 bronchoscopists and 1 anesthesiologist.
During procedure-stop it in case of:
•    Unusual airway edema or inflammation.
•    Extensive or prolonged BC
•    Site of previous treatment does not seem to be sufficiently healed.
•    Difficulty to access airways (secretions, coughing, tortuous anatomy).
•    Other clinical instability.
Post-procedure:
•    4 hours monitoring (vital signs, spirometry - FEV1 ≈ 80% ).
•    Prednisone + intensify bronchodilatation + respiratory physiotherapy (to eliminate secretions).
•    Phone contact, weekly visit, long follow-up protocol.
BC: Bronchoconstriction; FEV1: Forced Expiratory Volume in 1 second