Correspondence
Bronchial Thermoplasty
N Engl J Med 2007; 356:2744-2745June 28, 2007
- Article
To the Editor:
The article by Cox et al. (March 29 issue)1 about bronchial thermoplasty as a treatment for asthma, as well as the accompanying editorial by Solway and Irvin,2 point up the crucial role played by airway smooth muscle in the pathophysiology of this disease. The common assumption is that airway inflammation, usually allergic in origin, is the primary event in asthma, and that smooth-muscle hyperplasia, increased contractility of airway smooth muscle, and intermittent airway obstruction are secondary findings. However, it is possible that recurrent episodes of airway smooth-muscle constriction could cause an inflammatory reaction leading to the release of smooth-muscle agonists in a feed-forward loop, with persistency of the airway inflammation.3 In this case, the activation of airway smooth muscle would be a primary cause of and would have a pathogenetic role in asthma. Coexistent atopy would reinforce this loop and lead to an eosinophilic inflammatory reaction, but such a reaction would be secondary to the bronchoconstriction, rather than vice versa. It would seem worthwhile to test this hypothesis.
3 ReferencesPeter T. Macklem, M.D.
McGill University, Montreal, QC H2X 2P2, Canada
peter.macklem@gmail. com 1
Cox G ,Thomson NC ,Rubin AS , et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007;356:1327-1337
Full Text | Web of Science | Medline2
Solway J ,Irvin CG . Airway smooth muscle as a target for asthma therapy. N Engl J Med 2007;356:1367-1369
Full Text | Web of Science | Medline3
Tschumperlin DJ ,Dai G ,Maly IV , et al. Mechanotransduction through growth-factor shedding into the extracellular space. Nature 2004;429:83-86
CrossRef | Web of Science | Medline
To the Editor:
Perhaps the main long-term concern regarding bronchial thermoplasty is the potential for chronic progressive injury and fibrosis. Studies in animals have shown no evidence of such a problem over a period of 3 years,1,2 and indeed, evidence suggests that histologic resolution of the initial inflammation occurs by 12 weeks after bronchial thermoplasty. The current study adds to the data in humans, which have been reassuring up to a period of 12 months.2 One nonrandomized study in humans showed no deterioration in forced expiratory volume in 1 second (FEV1) over a period of 2 years.3 Are there any longer-term safety studies that give further reassurance, or are such studies ongoing?
3 ReferencesAndrew R.L. Medford, M.R.C.P.
Derriford Hospital, Plymouth PL6 8DH, United Kingdom1
Lombard CM ,Vincic L ,Cox G , et al. Histological effects of bronchial thermoplasty of canine and human airways. Am J Respir Crit Care Med 2002;165:A779-A7792
Cox PG ,Miller J ,Mitzner W ,Leff AR . Radiofrequency ablation of airway smooth muscle for sustained treatment of asthma: preliminary investigations. Eur Respir J 2004;24:659-663
CrossRef | Web of Science | Medline3
Cox G ,Miller JD ,McWilliams A ,Fitzgerald JM ,Lam S . Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006;173:965-969
CrossRef | Web of Science | Medline
To the Editor:
Cox and colleagues report that bronchoscopic thermoplasty improves the peak expiratory flow rate but not the FEV1 in patients with asthma. This finding may be related to the site of airflow limitation underlying forced exhalation. The wave-speed theory of expiratory flow states that in an airway segment, flow becomes maximal when its velocity reaches the speed of a pressure wave propagating through that airway.1 In the governing equation for wave speed, increased airway compliance will reduce the maximal expiratory flow, whereas increased airway area increases the maximal expiratory flow. Thus, permanent ablation of airway smooth muscle can become a two-edged sword, depending on the effects of ablation on airway compliance as compared with its effects on area.2 Because the site of flow limitation moves from central to peripheral airways as lung volume is progressively decreased,2,3 thermoplasty of bronchi 3 mm or larger in diameter may improve the maximal expiratory flow only when the site of flow limitation is in the central airway, such as when the peak expiratory flow rate4 is measured, but not necessarily over the large fraction of the vital capacity exhaled during an FEV1 maneuver.
4 ReferencesAnurag Agrawal, M.D., Ph.D.
Institute of Genomic and Integrative Biology, Delhi 110007, India
a.agrawal@igib. res. in 1
Dawson SV ,Elliott EA . Wave-speed limitation on expiratory flow -- a unifying concept. J Appl Physiol 1977;43:498-515
Web of Science | Medline2
Drazen JM . Asthma and the Human Genome Project: summary of the 45th annual Thomas L. Petty Aspen Lung Conference. Chest 2003;123:447S-449S
CrossRef | Web of Science | Medline3
Lambert RK ,Wilson TA ,Hyatt RE ,Rodarte JR . A computational model for expiratory flow. J Appl Physiol 1982;52:44-56
Web of Science | Medline4
Pedersen OF ,Brackel HJ ,Bogaard JM ,Kerrebijn KF . Wave-speed-determined flow limitation at peak flow in normal and asthmatic subjects. J Appl Physiol 1997;83:1721-1732
Web of Science | Medline
Author/Editor Response
Macklem posits that repeated contraction of airway smooth muscle contributes to the accumulation of smooth muscle. This hypothesis would be difficult to test in humans, because our measures of airway-wall constituents are probably not sufficiently sensitive.
We have shared Medford's concern about possible long-term adverse outcomes after bronchial thermoplasty. However, we have not identified any evidence of long-term injury, and there is no plausible mechanism for such injury to result from bronchial thermoplasty. The histologic data from studies in animals at 3 years after bronchial thermoplasty show no evidence of fibrosis, and to date, computed tomographic evaluation of human airways at 3 years after bronchial thermoplasty has shown no evidence of airway narrowing or structural change. We plan to follow our treated subjects annually for a period of 5 years.
Agrawal reminds us of the wave-speed theory of airflow limitation and offers a possible explanation for the observed improvement in airflow shown by peak flow, but not by FEV1. In a recent trial of bronchial thermoplasty involving patients with severe asthma and worse airflow obstruction than that of patients in the Asthma Intervention Research trial, we did see improvements in FEV1.1 It is interesting to speculate on the site of airflow obstruction in asthma, but until we have access to robust methods to examine this possibility, we will not be certain.
1 ReferencesGerard Cox, M.B.
McMaster University, Hamilton, ON L8N 4A6, Canada
coxp@mcmaster.ca Neil C. Thomson, M.D.
University of Glasgow, Glasgow G12 0YN, United KingdomMichel Laviolette, M.D.
Laval University, Sainte-Foy, QC G1V 4G5, Canada1
Niven R ,Pavord I ,Laviolette M , et al. Bronchial thermoplasty in refractory asthma: interim results in a severe asthma population. J Allergy Clin Immunol 2007;119:S1-S1
CrossRef | Web of Science | Medline
