Asthma is a common respiratory condition, affecting 1–18% of the population in different countries. It is characterised by symptoms such as breathlessness, wheeze, cough and chest tightness. Typically, these symptoms vary over time, reflecting the variable expiratory airflow limitation that underpins its diagnosis. The variations in symptoms and airflow limitation can be caused by temporary (or persistent) exposure to trigger factors such as allergens or irritants, exercise, change in weather, or viral respiratory infections.1
The long-term goals of asthma management include symptom control, normal activity levels, as well as reducing the risk of exacerbations. This is achieved using both pharmacological and non-pharmacological treatments, in a step-wise manner. Severe asthma is defined as asthma that requires Step 4 or 5 treatment, which includes medium- or high-dose inhaled corticosteroid (ICS) in conjunction with long-acting beta-agonist (LABA). Severe asthma may also require additional medications such as leukotriene receptor antagonists (LTRA), theophylline, anti-immunoglobulin E (anti-IgE), anti-interleukin 5 (anti-IL5), low dose oral corticosteroids (OCS) and tiotropium.1
A novel treatment
Targeted lung denervation (TLD) is a novel bronchoscopic treatment that has been trialled in patients with moderate to severe chronic obstructive pulmonary disease (COPD), with early indications that it could be of benefit. In a randomised, double-blind, sham-controlled study, TLD demonstrated a significant reduction in respiratory adverse events and a tendency towards improved quality of life, dyspnoea and pulmonary function when compared with the sham arm.2 It uses a radiofrequency (RF) ablation catheter to disrupt the pulmonary connections of the vagus nerve with a minimally-invasive technique. As a result, acetylcholine release on airway smooth muscle and submucosal glands is curtailed, causing a reduction in the cholinergic effects of bronchoconstriction and mucous secretion respectively. All pulmonary parasympathetic innervation stems from the pulmonary trunks of the vagus nerves as they enter the lung at the hila.3 During TLD, nerve ablation occurs at the main bronchi and therefore it exerts its actions on airways downstream from this treatment site. At the time of ablation, the airway epithelium is prevented from the effects
of excessive heating by a coolant-filled balloon, which is situated adjacent to the ablation electrode.
The rational for TLD in COPD is the putative pathological increase in vagus nerve input to the smooth muscle cells and submucosal glands of the airways. It has been reported that enhanced parasympathetic activity is the dominant reversible component of airway obstruction in COPD.4 Treatment to address this component has already been developed and the current state of the art is tiotropium bromide, a muscarinic antagonist. While tiotropium improves airflow obstruction, only 50% of patients derive a clinically significant benefit.5 Furthermore, only 40% of patients persist with tiotropium after one year of starting treatment.6 Tiotropium does provide sustained bronchodilation over twenty-four hours, hence its use as one of the most common maintenance therapies in COPD. However, there are still significant changes in the FEV1 over the course of the day, with trough values being half those of peak values.7
Tiotropium, like all other inhalers, is affected by problems with drug deposition and duration of action. Tiotropium and TLD act by blocking the action of the vagus nerve on the airways, the former via a pharmacological mechanism, and the latter through a more direct physical approach. Pharmacological treatment is also dependent on patient compliance. The physical approach has the theoretical advantage of bronchodilating all airways distal to the main bronchus (including the smaller, peripheral airways), as well as having a constant effect over the course of the day and night. It has already been stated that tiotropium is a treatment option for asthma. Is there an argument, therefore, for TLD as a potential therapy in asthma?
Vagus nerve and asthma pathophysology
Before we can answer this question, we must first understand the role of the vagus nerve in the pathophysiology of asthma. One way to elucidate its contribution is to assess the effects of temporarily blocking its actions. This was carried in a small study that measured the effect of intravenous atropine on nocturnal airflow limitation in ten asthma patients with known diurnal variation in peak expiratory flow (PEF). Atropine is a naturally-occurring compound and a competitive antagonist of muscarinic cholinergic receptors. Intravenous atropine administration would therefore cause systemic disruption of parasympathetic pathways, including those supplied by the pulmonary trunks of the vagus nerve. Both nocturnal and daytime PEF significantly improved after atropine. Whilst the nocturnal fall in PEF was not completely abolished, it was certainly diminished. The proposed mechanism was speculative, but it was suggested that the normal circadian effects of the vagus nerve are exaggerated by hypersensitisation of airway muscarinic receptors by inflammatory mediators.8 Therefore blocking the actions of the nerve (pharmacologically or physically) could help to limit nocturnal airflow obstruction, a phenomenon which causes symptoms in many asthma patients.
History of vagal section
TLD is not the first procedure proposed for asthma that involves section of airway nerves.
In 1923, the German surgeon Professor Hermann Kümmell reported the first surgical intervention on the nerve supply to the lungs for asthma.9
He actually performed a unilateral cervical sympathectomy in the belief that some vagal fibres enter the lung via the sympathetic trunk.
It was subsequently postulated that the sympathetic trunk is the afferent part of a reflex arc, of which the efferent component is the bronchoconstriction-inducing parasympathetic vagal fibres.3 Kümmell’s report documented immediate relief of asthma after the surgery.
This led to the uptake of similar procedures in other centres. In 1929, Phillips and Scott published a review of cases of operations to the pulmonary nerves. They found over 300 cases had been performed since 1923, but only 29 had been reported in sufficient detail and had undergone at least 6 months follow-up. Of these, 8 (28%) were ‘cured,’ 5 (17%) were ‘improved,’ and 16 (55%) were ‘unimproved.’10 Most of these procedures involved intervention to the sympathetic trunk, with few vagotomy procedures.
Vagal section for asthma underwent something of a revival in the 1950s. Blades et al carried out procedures that involved destruction of the pulmonary plexus around the main bronchus, as well as division of the vagus nerve below the level of the recurrent laryngeal nerve. Of the 38 patients treated, 22 saw a resolution or improvement in their asthma, though 7 patients died.11 Dimitrov-Skokodi et al performed 19 cases of vagotomy and sympathectomy. They reported asthma attacks ceased altogether in ten patients and were reduced in seven. There were also improvements in mucosal oedema, sputum volume and eosinophilia, radiographic ‘emphysema,’ bronchographic bronchospasm and forced vital capacity.12 Rienhoff and Gay described bilateral pulmonary plexus resection in 11 patients. Results were very similar to Dimitrov-Skokodi’s results, with a reduction in the severity and frequency of asthma attacks, reduced sputum volume, and resolution of radiographic ‘emphysema.’13 Given the period these reports were published in, the assessment of outcomes are mostly subjective with little objective physiological data. It was also prior to the onset of randomised controlled trials, with the reports mostly published as case series and therefore prone to measurement bias. Nonetheless, it cannot be dismissed that a significant proportion of patients reported subjective improvement of their asthma, and that this was the experience across several different treating centres.
The literature on surgical intervention for asthma is more sparse after the 1950s, coinciding with improvements in pharmacological treatments during this period. Inhaled anti-vagal medications (that is, antimuscarinics) are introduced in asthma later in the century in the form of atropine14 and ipratropium bromide.15 The most established of the antimuscarinics in asthma is tiotropium bromide, which has also been used in COPD maintenance therapy for
a number of years. Tiotropium’s success has been attributed to its kinetic selectivity for the M1 and M3 muscarinic receptors. It dissociates from these receptors much slower (around 100-fold) than from the M2 receptor, a prejunctional autoinhibitory receptor that restricts acetylcholine (ACh) release when activated.
By allowing the M2 receptor to resume its action as the ‘handbrake’ of ACh-induced bronchoconstriction, whilst providing durable M3 receptor antagonism, tiotropium has an advantage over its non-selective antimuscarinic counterparts atropine and ipratropium bromide.16 Tiotropium has been shown to reduce exacerbations and improve lung function in asthma poorly controlled on an inhaled corticosteroid and long-acting beta-agonist. In a randomised placebo-controlled trial, tiotropium improved FEV1 by 154ml and reduced severe exacerbations by 21%.17 It has also been shown to improve symptoms and lung function in patients uncontrolled on inhaled corticosteroids alone.18
The reduction in exacerbations by both tiotropium and surgical denervation leads to the exciting possibility that anti-vagal therapies cause a reduction in airways inflammation. From animal models and in vitro studies, acetylcholine has been shown to have a role in allergen-induced airways inflammation and remodelling.19 Furthermore, a pilot study of TLD in COPD showed reductions in neutrophils as well as the chemokines CXCL8 and CCL4 at 30 days post-treatment. RNA profiling also highlighted reduced gene expression of TGF-β, IL-6 and MUC5AC.20
Conclusions
TLD is a treatment in its infancy. The evidence base for TLD is limited in COPD, and even more so in asthma. Here, we have attempted to make a case for a denervation procedure in asthma. Invasive interventions for obstructive airways diseases have not always, and perhaps still do not have the uptake that their respective evidence bases should afford them. Lung volume reduction in emphysema and bronchial thermoplasty in asthma are two examples of such procedures.
The anti-vagal therapies described above illustrate the benefits that this approach can potentially confer in severe asthma. In particular, while the surgical denervation data are not of the high scientific quality we expect in the current age of evidence-based medicine, it certainly does enough to stoke our interest and curiosity into the potential value of a denervation procedure of some form. A safety and feasibility trial of TLD
in severe asthma (NCT02872298) is currently recruiting across Europe and its results are eagerly awaited.
References
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