CORRESPONDENCE and Blood Institute Severe Asthma Research Program. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med 2010;181:1033–1041. 4. Takayama G, Arima K, Kanaji T, Toda S, Tanaka H, Shoji S, McKenzie AN, Nagai H, Hotokebuchi T, Izuhara K. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol 2006;118:98–104. 5. Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, Shikotra A, Carter R, Audusseau S, Hamid Q, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol 2012;130:647–654.e610. 6. Matsumoto H. Serum periostin: a novel biomarker for asthma management. Allergol Int 2014;63:153–160. 7. Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, Muller SJ, Fahy JV. Roles of epithelial cell–derived periostin in TGF-b activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci USA 2010;107:14170–14175. 8. Kanemitsu Y, Ito I, Niimi A, Izuhara K, Ohta S, Ono J, Iwata T, Matsumoto H, Mishima M. Osteopontin and periostin are associated with a 20-year decline of pulmonary function in patients with asthma. Am J Respir Crit Care Med 2014;190:472–474. 9. Shoda T, Futamura K, Kobayashi F, Saito H, Matsumoto K, Matsuda A. Cell type–dependent effects of corticosteroid on periostin production by primary human tissue cells. Allergy 2013;68:1467–1470. 10. Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA 2007;104:15858–15863. 11. Kanemitsu Y, Matsumoto H, Izuhara K, Tohda Y, Kita H, Horiguchi T, Kuwabara K, Tomii K, Otsuka K, Fujimura M, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol 2013;132:305–312.e303. 12. Nagasaki T, Matsumoto H, Kanemitsu Y, Izuhara K, Tohda Y, Kita H, Horiguchi T, Kuwabara K, Tomii K, Otsuka K, et al. Integrating longitudinal information on pulmonary function and inflammation using asthma phenotypes. J Allergy Clin Immunol 2014;133:1474–1477.e1472. 13. American Thoracic Society; European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005;171:912–930. 14. Nagasaki T, Matsumoto H, Nakaji H, Niimi A, Ito I, Oguma T, Muro S, Inoue H, Iwata T, Tajiri T, et al. Smoking attenuates the age-related decrease in IgE levels and maintains eosinophilic inflammation. Clin Exp Allergy 2013;43:608–615. 15. Global Initiative for Asthma (GINA). GINA report: global strategy for asthma management and prevention. Available from: http://www.ginasthma.org 16. McNicholl DM, Stevenson M, McGarvey LP, Heaney LG. The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. Am J Respir Crit Care Med 2012; 186:1102–1108.
Copyright © 2014 by the American Thoracic Society
Reduction of Airway Smooth Muscle Mass by Bronchial Thermoplasty in Patients with Severe Asthma To the Editor: Bronchial thermoplasty (BT) is a procedure that consists of the delivery of controlled radiofrequency-generated activations via a catheter inserted into the bronchial tree through a flexible Supported by Legs Poix, Inserm. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
1452
bronchoscope. This procedure aims to reduce airway smooth muscle (ASM) mass, with the goal of diminishing bronchial constriction and ameliorating asthma symptoms. Preclinical studies have shown that BT reduced ASM mass in a canine model, a phenomenon that was associated with a long-lasting reduction of airway responsiveness to methacholine (1). Reduction in ASM after BT has been also reported in patients without asthma who underwent lung resection for carcinoma (2). However, alterations of ASM mass by BT in patients with asthma have never been reported. The current study was aimed at determining the effect of BT on the reduction of ASM mass in uncontrolled patients with severe asthma. Ten participants (Table 1) with asthma who met the ATS workshop criteria for severe refractory asthma (3) were recruited at Bichat University Hospital (Paris, France). All were uncontrolled, as assessed by an Asthma Control Test score of 10 or less, despite high-dose inhaled corticosteroid (>1,000 mg fluticasone propionate per day) and long-acting b-2 agonist with oral prednisone (seven patients). All patients had three or more severe exacerbations within the last 12 months. Patients who met the criteria (seven patients) received omalizumab for 6 months without successful clinical outcome. All patients underwent three sessions of BT (ALAIR; Boston Scientific, Natick, MA), separated by 1-month intervals. No activation was delivered in the middle lobe. A bronchoscopy was performed under local anesthesia 15 days before the first BT procedure and 3 months after the last one. Ten bronchial biopsies, one in each upper lobe (right upper lobe, lingula), three in each lower lobe (right lower lobe, left lower lobe), and two in the middle lobe, were taken at the same location before and 3 months after the last BT session. All bronchial biopsies were fixed in formaldehyde (10%) and paraffin, serially sectioned, and analyzed at Inserm UMR1152. Approximately 40 serial sections of 5 mm each were obtained for each biopsy. Morphology was established every 10 sections after staining with hematoxylin and eosin. ASM was detected by labeling a-actin (mouse IgG2a, clone 1A4, 1:200 dilution; Sigma-Aldrich, St. Louis, MO) and the corresponding isotype (mouse IgG2a), used as a control. Antigen detection was assessed using the Avidin Biotin Complex from the Vectastain ABC-Alkaline Phosphatase kit (Dako, Glostrup, Denmark), and the immunostaining was visualized with the chromogen fast red, followed by light nuclear Mayer’s hematoxylin counterstaining. ASM area was assessed by morphometry on a-actin–stained sections, and final results were expressed as percentage ASM area over total biopsy area. ASM area was examined in two serial sections from the same biopsy and in sections from the 10 biopsies obtained before and after BT. Sections were analyzed in a blind fashion by two independent observers (D.K. and F.H.), and the final figure was the mean of all the measurements obtained for each patient. The coefficients of variation between biopsies from the same patient and between ASM areas of the same biopsy were of 7–12% and 5–8%, respectively. All patients had a computed tomography (CT) scan before the first BT session and a chest X-ray the day after each session.
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 | December 15 2014
CORRESPONDENCE Table 1. Patient Characteristics
Patient 1 2 3 4 5 6 7 8 9 10
Sex
Asthma Duration (yr)
Number of Exacerbations in the Previous Year
FEV1% Predicted
Oral Steroid (mg/d)
F F M M M F M M F M
13 28 24 12 6 6 5 50 23 50
9 10 6 12 5 10 12 3 12 3
63 76 48 56 56 64 42 67 68 43
20 0 20 40 15 40 10 0 40 0
Before and after BT, mean ASM area amounted to 20.25% (SD = 4.12; range = 15.88–30.20; interquartile range [IQR] = 18.46–21.83) and 7.28% (SD = 3.2; range = 1.32–12.16; IQR = 5.91–9.58), respectively. The absolute decrease in ASM area was 12.93% (95% confidence interval, 10.48–15.36; P , 0.0001). Reduction of ASM area after BT ranged between 48.7 and 78.5% and amounted to, respectively, 48.7% (middle lobe), 78.5% (right upper lobe), 58.1% (right lower lobe), 75.0%
Yes, failure Yes, failure No Yes, failure No Yes, failure Yes, failure No Yes, failure Yes, failure
(left upper lobe), and 70.0% (left lower lobe) (Figure 1A). By multivariate analysis, the effect of BT was not significantly different between lung areas (P = 0.23). The decrease did not differ significantly either between the right and left lung (P = 0.36) and was not related to the number of activations (50–102) performed during each procedure. Unexpectedly, ASM area in the middle lobe, which was not treated by BT, decreased by an average of 48.7% (Figure 1A). This
A
C 35
Before thermoplasty After thermoplasty
30 Smooth muscle area (%)
Omalizumab Treatment
* *
*
25
*
Upper lobe
*
20 15 10
Middle lobe
5 0 ML
B
RUL Patient nº
RLL 005
Lingula
LLL
Patient nº
007
CT scan after BT Patient nº
001
Patient nº
006
Before BT
After BT
Middle lobe
Middle lobe
Lower left lobe
Lower left lobe
Figure 1. (A) Smooth muscle area in the different lobes, expressed as percentage of airway smooth muscle area over the total biopsy area before (solid bars) and after (open bars) bronchial thermoplasty (BT). LLL = left lower lobe; ML = middle lobe; RLL = right lower lobe; RUL = right upper lobe. *P , 0.0001. (B) Biopsies before and after BT in the different lobes showing airway smooth muscle (a-actin–stained sections). Airway smooth muscle in the ML did not change after BT in patient 005 and decreased in patient 007. (C) Computed tomography scan the day after a BT session in the RUL and lingula, showing alveolar and ground glass opacities in the RUL and the lingula and ground glass in the ML (arrow) in which no activation was performed.
Correspondence
1453
CORRESPONDENCE was observed in 7 of the 10 patients, with ASM being unchanged after BT in three patients (Figure 1B). Because the third patient treated had an abnormal chest X-ray with alveolar opacities in the two upper lobes the day after the third BT session, a CT scan was performed. The latter showed consolidation and ground glass opacities in the two upper lobes treated, as well as ground glass in the untreated middle lobe (Figure 1C). After this observation, a CT scan was performed the day after each procedure in the next seven patients. Whatever the lobe treated, alveolar and ground glass opacities were observed in all patients, and in the middle lobe in five patients. These ground glass infiltrates are probably linked to an alveolar inflammation secondary to heat shock induced by BT. To our knowledge, this is the first study that evaluates the effect of BT on ASM mass in patients with severe uncontrolled asthma. These findings demonstrate that BT is very effective in reducing ASM mass, which is an important component of airway remodeling in these patients (4). In addition, we found an important reduction of ASM area in the middle lobe, which was not treated, in 70% of our patients. This may be explained by a diffusion of the heat generated during the BT procedure, as suggested by the CT scan abnormalities, in the entire lobe treated and in the adjacent middle lobe. Diffusion in the middle lobe might be the consequence of pulmonary interlobar incomplete fissures that are not uncommon and have been described by high-resolution CT scan in 18–73% of cases (5). This finding suggests that the expected effect of BT goes beyond the treated bronchial area, which could explain the clinical benefit. Other potential mechanisms include increased secretion of inflammatory mediators from airway smooth muscle cells (6) and/or alterations in airway epithelial, neural, or inflammatory cell function. However, other mechanisms not directly linked to BT cannot be excluded at this point. In summary, although the exploratory nature of this study calls for further research, our data suggest that BT could be an effective therapeutic option in patients with severe uncontrolled asthma. The extent of the effect in a larger area than the treated airways gives new insights in the mechanisms underlying the previously observed clinical benefits (7–9). A larger study is ongoing to evaluate the relationship between the decreased ASM after BT and the clinical outcome, including asthma control and exacerbations, in these patients with severe difficult-to-treat disease. n Author disclosures are available with the text of this letter at www.atsjournals.org. Marina Pretolani, Ph.D.* Inserm UMR 1152 Paris, France and Universite´ Paris Diderot Paris, France Marie-Christine Dombret, M.D.* Gabriel Thabut, M.B., Ph.D. Inserm UMR 1152 Paris, France Universite´ Paris Diderot Paris, France and Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard Paris, France
1454
Dominique Knap Fatima Hamidi Inserm UMR 1152 Paris, France and Universite´ Paris Diderot Paris, France Marie-Pierre Debray, M.D. Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard Paris, France Camille Taille, M.D. Inserm UMR 1152 Paris, France Universite´ Paris Diderot Paris, France and Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard Paris, France Pascal Chanez, M.D., Ph.D. Aix Marseille Universite´ Marseille, France Michel Aubier, M.D. Inserm UMR 1152 Paris, France Universite´ Paris Diderot Paris, France and Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard Paris, France *These authors have contributed equally to this work.
References 1. Danek CJ, Lombard CM, Dungworth DL, Cox PG, Miller JD, Biggs MJ, Keast TM, Loomas BE, Wizeman WJ, Hogg JC, et al. Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs. J Appl Physiol (1985) 2004;97: 1946–1953. 2. Miller JD, Cox G, Vincic L, Lombard CM, Loomas BE, Danek CJ. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest 2005;127:1999–2006. 3. American Thoracic Society. Proceedings of the ATS workshop on refractory asthma. Am J Respir Crit Care Med 2000;162: 2341–2351. 4. Benayoun L, Druilhe A, Dombret MC, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med 2003;167:1360–1368. 5. Aziz A, Ashizawa K, Nagaoki K, Hayashi K. High resolution CT anatomy of the pulmonary fissures. J Thorac Imaging 2004;19: 186–191. 6. Zuyderduyn S, Sukkar MB, Fust A, Dhaliwal S, Burgess JK. Treating asthma means treating airway smooth muscle cells. Eur Respir J 2008;32:265–274. 7. Cox G, Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC, Olivenstein R, Pavord ID, McCormack D, Chaudhuri R, et al.; AIR Trial Study Group. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007;356:1327–1337. 8. Pavord ID, Cox G, Thomson NC, Rubin AS, Corris PA, Niven RM, Chung KF, Laviolette M; RISA Trial Study Group. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med 2007;176:1185–1191. 9. Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, Fiss E, Olivenstein R, Thomson NC, Niven RM, et al.; AIR2 Trial Study Group. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, doubleblind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010; 181:116–124.
Copyright © 2014 by the American Thoracic Society
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 | December 15 2014
Copyright © 2014 by the American Thoracic Society
Reduction of Airway Smooth Muscle Mass by Bronchial Thermoplasty in Patients with Severe Asthma To the Editor: Bronchial thermoplasty (BT) is a procedure that consists of the delivery of controlled radiofrequency-generated activations via a catheter inserted into the bronchial tree through a flexible Supported by Legs Poix, Inserm. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
1452
bronchoscope. This procedure aims to reduce airway smooth muscle (ASM) mass, with the goal of diminishing bronchial constriction and ameliorating asthma symptoms. Preclinical studies have shown that BT reduced ASM mass in a canine model, a phenomenon that was associated with a long-lasting reduction of airway responsiveness to methacholine (1). Reduction in ASM after BT has been also reported in patients without asthma who underwent lung resection for carcinoma (2). However, alterations of ASM mass by BT in patients with asthma have never been reported. The current study was aimed at determining the effect of BT on the reduction of ASM mass in uncontrolled patients with severe asthma. Ten participants (Table 1) with asthma who met the ATS workshop criteria for severe refractory asthma (3) were recruited at Bichat University Hospital (Paris, France). All were uncontrolled, as assessed by an Asthma Control Test score of 10 or less, despite high-dose inhaled corticosteroid (>1,000 mg fluticasone propionate per day) and long-acting b-2 agonist with oral prednisone (seven patients). All patients had three or more severe exacerbations within the last 12 months. Patients who met the criteria (seven patients) received omalizumab for 6 months without successful clinical outcome. All patients underwent three sessions of BT (ALAIR; Boston Scientific, Natick, MA), separated by 1-month intervals. No activation was delivered in the middle lobe. A bronchoscopy was performed under local anesthesia 15 days before the first BT procedure and 3 months after the last one. Ten bronchial biopsies, one in each upper lobe (right upper lobe, lingula), three in each lower lobe (right lower lobe, left lower lobe), and two in the middle lobe, were taken at the same location before and 3 months after the last BT session. All bronchial biopsies were fixed in formaldehyde (10%) and paraffin, serially sectioned, and analyzed at Inserm UMR1152. Approximately 40 serial sections of 5 mm each were obtained for each biopsy. Morphology was established every 10 sections after staining with hematoxylin and eosin. ASM was detected by labeling a-actin (mouse IgG2a, clone 1A4, 1:200 dilution; Sigma-Aldrich, St. Louis, MO) and the corresponding isotype (mouse IgG2a), used as a control. Antigen detection was assessed using the Avidin Biotin Complex from the Vectastain ABC-Alkaline Phosphatase kit (Dako, Glostrup, Denmark), and the immunostaining was visualized with the chromogen fast red, followed by light nuclear Mayer’s hematoxylin counterstaining. ASM area was assessed by morphometry on a-actin–stained sections, and final results were expressed as percentage ASM area over total biopsy area. ASM area was examined in two serial sections from the same biopsy and in sections from the 10 biopsies obtained before and after BT. Sections were analyzed in a blind fashion by two independent observers (D.K. and F.H.), and the final figure was the mean of all the measurements obtained for each patient. The coefficients of variation between biopsies from the same patient and between ASM areas of the same biopsy were of 7–12% and 5–8%, respectively. All patients had a computed tomography (CT) scan before the first BT session and a chest X-ray the day after each session.
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 | December 15 2014
CORRESPONDENCE Table 1. Patient Characteristics
Patient 1 2 3 4 5 6 7 8 9 10
Sex
Asthma Duration (yr)
Number of Exacerbations in the Previous Year
FEV1% Predicted
Oral Steroid (mg/d)
F F M M M F M M F M
13 28 24 12 6 6 5 50 23 50
9 10 6 12 5 10 12 3 12 3
63 76 48 56 56 64 42 67 68 43
20 0 20 40 15 40 10 0 40 0
Before and after BT, mean ASM area amounted to 20.25% (SD = 4.12; range = 15.88–30.20; interquartile range [IQR] = 18.46–21.83) and 7.28% (SD = 3.2; range = 1.32–12.16; IQR = 5.91–9.58), respectively. The absolute decrease in ASM area was 12.93% (95% confidence interval, 10.48–15.36; P , 0.0001). Reduction of ASM area after BT ranged between 48.7 and 78.5% and amounted to, respectively, 48.7% (middle lobe), 78.5% (right upper lobe), 58.1% (right lower lobe), 75.0%
Yes, failure Yes, failure No Yes, failure No Yes, failure Yes, failure No Yes, failure Yes, failure
(left upper lobe), and 70.0% (left lower lobe) (Figure 1A). By multivariate analysis, the effect of BT was not significantly different between lung areas (P = 0.23). The decrease did not differ significantly either between the right and left lung (P = 0.36) and was not related to the number of activations (50–102) performed during each procedure. Unexpectedly, ASM area in the middle lobe, which was not treated by BT, decreased by an average of 48.7% (Figure 1A). This
A
C 35
Before thermoplasty After thermoplasty
30 Smooth muscle area (%)
Omalizumab Treatment
* *
*
25
*
Upper lobe
*
20 15 10
Middle lobe
5 0 ML
B
RUL Patient nº
RLL 005
Lingula
LLL
Patient nº
007
CT scan after BT Patient nº
001
Patient nº
006
Before BT
After BT
Middle lobe
Middle lobe
Lower left lobe
Lower left lobe
Figure 1. (A) Smooth muscle area in the different lobes, expressed as percentage of airway smooth muscle area over the total biopsy area before (solid bars) and after (open bars) bronchial thermoplasty (BT). LLL = left lower lobe; ML = middle lobe; RLL = right lower lobe; RUL = right upper lobe. *P , 0.0001. (B) Biopsies before and after BT in the different lobes showing airway smooth muscle (a-actin–stained sections). Airway smooth muscle in the ML did not change after BT in patient 005 and decreased in patient 007. (C) Computed tomography scan the day after a BT session in the RUL and lingula, showing alveolar and ground glass opacities in the RUL and the lingula and ground glass in the ML (arrow) in which no activation was performed.
Correspondence
1453
CORRESPONDENCE was observed in 7 of the 10 patients, with ASM being unchanged after BT in three patients (Figure 1B). Because the third patient treated had an abnormal chest X-ray with alveolar opacities in the two upper lobes the day after the third BT session, a CT scan was performed. The latter showed consolidation and ground glass opacities in the two upper lobes treated, as well as ground glass in the untreated middle lobe (Figure 1C). After this observation, a CT scan was performed the day after each procedure in the next seven patients. Whatever the lobe treated, alveolar and ground glass opacities were observed in all patients, and in the middle lobe in five patients. These ground glass infiltrates are probably linked to an alveolar inflammation secondary to heat shock induced by BT. To our knowledge, this is the first study that evaluates the effect of BT on ASM mass in patients with severe uncontrolled asthma. These findings demonstrate that BT is very effective in reducing ASM mass, which is an important component of airway remodeling in these patients (4). In addition, we found an important reduction of ASM area in the middle lobe, which was not treated, in 70% of our patients. This may be explained by a diffusion of the heat generated during the BT procedure, as suggested by the CT scan abnormalities, in the entire lobe treated and in the adjacent middle lobe. Diffusion in the middle lobe might be the consequence of pulmonary interlobar incomplete fissures that are not uncommon and have been described by high-resolution CT scan in 18–73% of cases (5). This finding suggests that the expected effect of BT goes beyond the treated bronchial area, which could explain the clinical benefit. Other potential mechanisms include increased secretion of inflammatory mediators from airway smooth muscle cells (6) and/or alterations in airway epithelial, neural, or inflammatory cell function. However, other mechanisms not directly linked to BT cannot be excluded at this point. In summary, although the exploratory nature of this study calls for further research, our data suggest that BT could be an effective therapeutic option in patients with severe uncontrolled asthma. The extent of the effect in a larger area than the treated airways gives new insights in the mechanisms underlying the previously observed clinical benefits (7–9). A larger study is ongoing to evaluate the relationship between the decreased ASM after BT and the clinical outcome, including asthma control and exacerbations, in these patients with severe difficult-to-treat disease. n Author disclosures are available with the text of this letter at www.atsjournals.org. Marina Pretolani, Ph.D.* Inserm UMR 1152 Paris, France and Universite´ Paris Diderot Paris, France Marie-Christine Dombret, M.D.* Gabriel Thabut, M.B., Ph.D. Inserm UMR 1152 Paris, France Universite´ Paris Diderot Paris, France and Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard Paris, France
1454
Dominique Knap Fatima Hamidi Inserm UMR 1152 Paris, France and Universite´ Paris Diderot Paris, France Marie-Pierre Debray, M.D. Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard Paris, France Camille Taille, M.D. Inserm UMR 1152 Paris, France Universite´ Paris Diderot Paris, France and Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard Paris, France Pascal Chanez, M.D., Ph.D. Aix Marseille Universite´ Marseille, France Michel Aubier, M.D. Inserm UMR 1152 Paris, France Universite´ Paris Diderot Paris, France and Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard Paris, France *These authors have contributed equally to this work.
References 1. Danek CJ, Lombard CM, Dungworth DL, Cox PG, Miller JD, Biggs MJ, Keast TM, Loomas BE, Wizeman WJ, Hogg JC, et al. Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs. J Appl Physiol (1985) 2004;97: 1946–1953. 2. Miller JD, Cox G, Vincic L, Lombard CM, Loomas BE, Danek CJ. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest 2005;127:1999–2006. 3. American Thoracic Society. Proceedings of the ATS workshop on refractory asthma. Am J Respir Crit Care Med 2000;162: 2341–2351. 4. Benayoun L, Druilhe A, Dombret MC, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med 2003;167:1360–1368. 5. Aziz A, Ashizawa K, Nagaoki K, Hayashi K. High resolution CT anatomy of the pulmonary fissures. J Thorac Imaging 2004;19: 186–191. 6. Zuyderduyn S, Sukkar MB, Fust A, Dhaliwal S, Burgess JK. Treating asthma means treating airway smooth muscle cells. Eur Respir J 2008;32:265–274. 7. Cox G, Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC, Olivenstein R, Pavord ID, McCormack D, Chaudhuri R, et al.; AIR Trial Study Group. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007;356:1327–1337. 8. Pavord ID, Cox G, Thomson NC, Rubin AS, Corris PA, Niven RM, Chung KF, Laviolette M; RISA Trial Study Group. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med 2007;176:1185–1191. 9. Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, Fiss E, Olivenstein R, Thomson NC, Niven RM, et al.; AIR2 Trial Study Group. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, doubleblind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010; 181:116–124.
Copyright © 2014 by the American Thoracic Society
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 | December 15 2014
