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
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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