Severe asthma treated by bronchial thermoplasty: A success not due to the small airways?

The currently recognized mechanisms sustaining severe asthma involve bronchial hyper-responsiveness, airway inflammation and structural changes of the airways. Eosinophils are key players in the majority of situations. Recently, it was reproducibly found that airway epithelial cells are the orchestrators of immune cell trafficking1 and airway smooth muscle (ASM) cell activation and proliferation from the proximal bronchi to the alveoli.2

The distal or small airways are known to be the main contributors to the overall increased airflow resistance characteristic of asthma. Non-invasive tools for their assessment include forced oscillations techniques and imaging techniques using expiratory computed tomography (CT) scan analysis or 3He magnetic resonance imaging (MRI). Roughly, 50–60% of asthmatic patients of various severities have measurable small airways disease.3 This involvement leads to heterogeneous ventilation, increased airway resistances and decreased lung elasticity, with an increase in lung distention impairing ventilation. These changes are thought to contribute to symptoms, notably shortness of breath on exercise.

Impulse oscillometry (IOS) applies oscillating pressure variations in the shape of random noise to the respiratory system to determine the mechanical properties of the lung. Distal airway contribution may be assessed by the difference between the two reactances and resistances, evaluated at different frequencies (R5–R20) and providing insight into the narrowing of the small airways. It is a sensitive but non-specific method that was able to discriminate asthmatic and non-asthmatic patients, whereas it was undoubtedly abnormal in severe asthma, even in the absence of proximal airway obstruction.4

Bronchial thermoplasty (BT) is a technique now available worldwide to treat asthma and is approved by several health agencies, including the European Medicines Agency (EMEA) and Food and Drug Administration (FDA). It is a treatment developed for severe asthma whose benefits in achieving long-term asthma control likely outweigh the short-term risk of deterioration and hospitalization in the days following the treatment reported both in clinical trials and in the real-life setting.5 It was found to decrease the ASM mass, decrease the deposition of collagen beneath the basement membrane and even impact the bronchial epithelium by decreasing the mucus released without an excess of bronchial inflammation.6 However, many questions remain regarding the mechanisms of action of this treatment. The challenge for ongoing studies is to find out the optimal responders to BT, the best tools and appropriate timing to assess effectiveness.

In a recent publication in Respirology, Langton et al. report that IOS was unaffected in 43 patients with severe asthma but was clinically successfully improved by BT in two distinct academic centres in Australia.7 They found that residual volume changed marginally 6 months after BT, but IOS parameters were unaffected. It is an important study, despite some limitations. It explores the way through which BT may affect asthma control and then may interfere with the natural history of the disease. These results are in line with a real-life pragmatic long-term investigation from northern America where the ‘classical’ pulmonary function tests were not modified, both after a short and a long period of time, following the procedure.8

The ASM layer is thickened in the airway walls of asthma patients, shaped as bundles spread from the proximal to the distal airways. Interestingly, it was hypothesized that BT could act all along the ASM bundles as the wick of a dynamite stick and thus reach the distal airways. The authors therefore investigated the contribution of small airways in an attempt to decipher the clinical benefit on asthma control. In a small subset of BT-treated patients, short-term CT investigations have shown that abnormalities extended across the treated zones and consisted of ground-glass attenuation areas and some segmental hyper-densities compatible with alveolar consolidation. These abnormalities were then affecting the distal part of the lung but, fortunately, spontaneously resolved.9 Whether these images fit with distal airway changes propagated by the ASM bundles remain largely unknown. In the early development of BT, an animal study and the first in-human study examined lung tissue for safety reasons. Some focal pulmonary oedema areas were reported in the dog study.10 The pathology of human lung, 3 weeks after BT, and the microscopical analysis of the lung tissue removed for planned lung cancer treatments displayed some peribronchial alveolar accumulation of lymphocytes, but no attention in this study was paid to the structure of the bronchioli.11 The sophisticated 3He technique allowed some authors to demonstrate changes in ventilation following BT.12 Recently, using optical coherence tomography, a team in the Netherlands found extension of lesions from proximal towards distal airways, consistent with CT imaging findings shortly after a BT session.13

The negative findings from the present study challenge the effect of BT on small airways and merit comments and questions. First, investigation of distal airways using a single approach may have impacted the results. Perhaps IOS is not a method sensitive enough to be influenced by BT treatments. N2 or multiple-breath washout slope techniques may represent alternatives addressing different potential contributors to small airway changes.14 Second, imaging the airways and combining several approaches including quantification of air trapping by expiratory CT or 3He MRI can also be evaluated as outcomes alone or in combination with functional techniques such as IOS. Finally, the number of patients enrolled in the present study was limited, and the ideal timing to assess small airway is not known. Indeed, small airways can be narrowed by multiple mechanisms and not all can definitely be controlled in such a study: infiltration of the airway wall by inflammatory cells, hypervascularity and oedema, mucus plugging, persistent smooth muscle tone, peribronchiolar fibrosis, external mechanical constraints (like the one seen in obesity) and loss of elastic recoil classically described in asthma under the term ‘pseudo-emphysma’.15 Even though the authors tried to control most variables (stable anti-inflammatory treatment, enough time away from an exacerbation and recorded at maximal bronchodilation), the level of evidence presently provided remains mainly descriptive. Moreover, trajectories of lung function identified that the theory of the small lung may also apply to asthma, and it is rather unclear at the moment if small airway function may change over time in patients.16

Does the present study close the debate about the effect of BT treatment on distal airways in severe asthma? Clearly, the answer is no, but it opens an important field to better understand the mechanisms sustaining the clinical response observed in real life and the need to standardize new methods to assess distal airway involvement in asthma. An objective biomarker is a potential add-on aspect of this clinical research. A biomarker can then be used to diagnose and to predict the involvement of distal airways involvement in severe asthma.17

Disclosure statement

P.C. has provided consultancy services to Boehringer Ingelheim, GlaxoSmithKline, ALK, AstraZeneca, Novartis, Teva, Chiesi, Sanofi and SNCF; has served on advisory boards of Boehringer Ingelheim, GlaxoSmithKline, Circadia, AstraZeneca, Novartis, Teva, Chiesi and Sanofi; has received lecture fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Novartis, Teva, Chiesi, Boston Scientific and ALK; and has received industry-sponsored grants from Roche, Boston Scientific, Boehringer Ingelheim, Centocor, GlaxoSmithKline, AstraZeneca, ALK, Novartis, Teva and Chiesi.