HHE Respiratory 2019 - Page 7

RESPIRATORY Targeted lung denervation in severe asthma Introducing a novel minimally-invasive treatment for obstructive airways disease and the rationale for its application in patients with severe asthma Karthi Srikanthan MBBS MRCP National Heart and Lung Institute, Imperial College, UK Pallav L Shah MD MBBS FRCP National Heart and Lung Institute, Imperial College, UK Royal Brompton Hospital, London, UK Chelsea and Westminster Hospital, UK 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 7 HHE 2019 | hospitalhealthcare.com 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