B ro n c h i a l
Thermo plasty
Gerard Cox, MB, FRCP(C), FRCP(I)
KEYWORDS
 Asthma  Thermoplasty  Broncoconstriction  Allergy
Airway narrowing is a central event in asthma.1
Contraction of airway muscles, or bronchocon-
striction, is a dynamic process that contributes to
airway narrowing in asthma and has long been
the target of treatment with drugs that cause
muscle relaxation.1,2 Since inflammatory events
underlie asthma, therapy typically includes antiin-
flammatory agents.3,4 The current standard-of-
care has been defined by a variety of expert
groups and evidence-based guidelines for the
treatment of asthma have been published.5 As
asthma is most often mild or moderate, it can
be appropriately managed provided there is
adequate compliance with prescribed measures;
typically included in these are bronchodilating
and antiinflammatory medications.5
Asthma, by definition is a variable disease.
When there is greater than normal natural variation
in airflow, the illness can be provoked by a wide
range of stimuli that include infectious, allergic,
and environmental agents.6 Bronchoconstriction
determines much of the short-term variability in
airflow that characterizes asthma.1,6 Development
of bronchoconstriction is facilitated because the
airways in asthma are hyperresponsive in that
they can constrict to a greater degree and are
more sensitive than normal.7
In chronic asthma, certain characteristic struc-
tural abnormalities are found in the airway walls.8
These changes are collectively termed remodel-
ing. Excessive accumulation of smooth muscle is
typical of airway remodeling and has been found
in the airways of patients with a range of severity
of asthma.8,9 Such remodeling of the airway wall,
with increased smooth muscle along with height-
ened connective tissue elements and mucus
glands may contribute further to the airway nar-
rowing that is fixed and largely resistant to
Firestone Institute for Respiratory Health, St Joseph’s Healthcare Hamilton, 50 Charlton Avenue E, Hamilton,
ON L8N 4A6, Canada
E-mail address: coxp@mcmaster.ca
Clin Chest Med 31 (2010) 135–140
doi:10.1016/j.ccm.2009.09.003
0272-5231/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
conventional asthma treatment.1,3,6,8 It is not
surprising that airflow obstruction as a result of
tissue changes in the airway does not improve
with bronchodilators; antiinflammatory therapy
that controls cellular changes including eosino-
philia has also not been found to reverse remodeling
of the airway walls.8
Thus, there is evident need for new approaches
that target airway smooth muscle. Ideally, such
a treatment should address both mechanisms of
airway narrowing, that is, preventing bronchocon-
striction and reducing the amount of muscle in the
remodeled airway. Such an intervention should
have a prolonged effect.
DEVELOPMENT OF THE ALAIR SYSTEM
FOR BRONCHIAL THERMOPLASTY
Thermoplasty refers to the use of heat to induce
structural changes. Bronchial thermoplasty (BT)
is performed during bronchoscopy using the Alair
system, which comprises a specially designed
treatment catheter and a radiofrequency (RF)
controller.10 The energy delivered at each treat-
ment site is about 18 W. This is substantially lower
than the energy used in other procedures that use
RF for cautery or tissue ablation. For example, the
Prosiva system for treating benign prostatic hyper-
trophy delivers 30 W for 2 to 3 minutes and the
COBRA surgical probe delivers up to 150 W.
When passed through the working channel of an
(adult) bronchoscope, the electrode array at the
end of the catheter is expanded to touch the
airway wall under direct vision. Once contact is
achieved, a 10-second pulse of RF energy is deliv-
chestmed.theclinics.com
ered, and the array is collapsed and moved 5 mm
proximally to the next treatment site.
136 Cox

Fig. 1. Histology of canine airway 3 years after treatment, stained with Masson’s trichrome. Control airway in the
left panel was untreated and shows normal airway wall elements including bundles of smooth muscle. The panel
on the right shows a treatment site, which contains reduced amounts of smooth muscle. In addition, the area
previously occupied by muscle now contains connective tissue elements with no evidence of excessive collagen
deposition or scarring.

The Alair system was developed over a series of echoes the histology findings, which showed no
preclinical studies and was first applied in the evidence of scar formation over 3 years following
canine airway.11 The treatment effect was depen- BT (see Fig. 1).
dent on the temperature reached in the airway
wall. During preclinical studies parameters for HUMAN STUDIES OF BT
energy delivery, duration of treatment, and temper-
BT was first applied in the human airway in
ature were examined. The optimal parameters that
led to stable partial reduction in muscle mass patients who were scheduled for surgery for
without excessive tissue injury were identified.
Histologic examination of treated sites revealed
that smooth muscle was replaced with connective
tissue elements.11 Long-term studies of 3 years
showed no evidence of scarring and the effect on
reducing muscle mass was stable (Fig. 1). Func-
tionally, airways treated with BT contracted less
following methacholine instillation than untreated
sites and this effect was related to the degree to
which muscle was reduced (Fig. 2).11,12
High-resolution computed tomography (HRCT)
has been used to examine structural and func-
tional changes in airways over time.13 After BT,
canine airways were significantly less sensitive to
challenge with aerosolized methacholine. Bron-
choconstriction of treated airways continues to
some degree indicating that BT reduces, but Fig. 2. Relationship between the potential for stimu-
does not completely ablate, the mass of airway lated bronchoconstriction and the amount of smooth
smooth muscle.11 Furthermore, there was muscle present in the airway wall, expressed as how
a detectable increase in the baseline diameter of much of the circumference of the airway contained
treated airways consistent with lower tone as recognizable muscle bundles. Untreated airways had
a result of the reduced amount of muscle present. almost complete circumferential muscle layer and nar-
That the maximal postbronchodilator diameter rowed by 80%. Treatment at increasing temperatures
caused dose-dependent reduction in the amount of
was similar in treated and control airways shows
muscle, which correlated with diminished broncho-
that relaxation is not impaired. Treated airways constriction following local instillation of methacho-
were more distensible suggesting that when line. (From Danek C, Lombard CM, Dungworth DL,
muscle is replaced by connective tissue elements et al. Reduction in airway hyperresponsiveness to
the stiffness or elasticity of the airway is not methacholine by the application of RF energy in
adversely affected.14 This functional outcome dogs. J Appl Physiol 2004;97:1949; with permission.)

suspected lung cancer.15 At the time of bronchos-
copy, which was performed 1 to 3 weeks before
surgery, BT was performed in normal-appearing
airways in the areas to be removed. Following
resection, histologic comparison of treated and
untreated sites showed less smooth muscle in
airways treated with BT. The extent and nature of
the treatment effects in the human airway closely
resembled those documented in the canine
airway.11,15 Over an interval of 1 to 3 weeks, there
was evidence of resolution of the acute changes
that follow treatment. The epithelium, which can
be injured mechanically by the catheter and by
heat, was largely reconstituted between the
second and third weeks. As had been seen in the
canine airway, the tissue changes were tempera-
ture dependent.
Mayse and colleagues16 provided a description
of how to use the Alair system for performing BT in
patients with asthma. Although general anesthetic
was used for the very first procedure, local anes-
thetic and moderate or conscious sedation are
now standard.16,17 This is an outpatient proce-
dure, performed in endoscopy or bronchoscopy
units. Typically, it takes 3 separate procedures,
usually 3 weeks apart, to treat the entire bronchial
tree (except the right middle lobe because of
concerns about causing the right middle lobe
syndrome). All airways that can be accessed are
targeted for treatment. The catheter is deployed
only under direct vision; airways outside the bron-
choscopic field of view are not treated. Thus, any
treated airway can be inspected later in case there
are any concerns. The Alair catheter must be
partially expanded before it can be activated.
Hence, it can treat airways with a diameter
between 3 and 10 mm. The treatment begins as
distally as possible. The RF energy is delivered at
5-mm intervals, providing continuous treatment
to the airway (as the exposed section of the elec-
trode is 5-mm long). In practice, each procedure
lasts between 45 and 60 minutes; the duration is
determined mainly by the number of treatment
activations delivered. Since the endobronchial
anatomy and caliber can vary considerably among
patients, the number of activations per procedure
is quite variable but is expected to average
between 40 and 60. At the time of treatment, there
is little if any evidence of heat effect. The most
common observations are blanching of the airway
when there is contact with electrode arms. A
buildup of mucus on the electrode array may occur
and may need to be removed to prevent the field of
view being obscured. As a mechanical device is
being deployed, superficial trauma to the airway
is inevitable. Minor immediate bleeding, or more
often oozing, is observed occasionally, but is
Bronchial Thermoplasty 137
minimal and self-limited. Since the energy deliv-
ered is modest and the temperature in the tissues
reaches 65 C, there is no evidence of tissues
burning or of sparking.
TREATING ASTHMA WITH THE ALAIR
SYSTEM FOR BT
BT for asthma was first studied in 16 patients with
a range of asthma severity.17 This study showed
that it was feasible to perform BT safely in patients
with asthma. In addition, certain asthma parameters
(numbers of symptom-free days and peak expira-
tory flows) showed improvements at 3 months.
Bronchial hyperresponsiveness was reduced and
this effect persisted beyond 12 months. Treatment
was well tolerated and adverse events that
occurred following bronchoscopy were managed
with the same measures used to treat usual exacer-
bations of asthma symptoms.
The impact of BT in 109 patients with moderate
to severe asthma was examined in the Asthma
Intervention Research (AIR) trial.18 Asthma severity
was indicated by medication, all subjects were
using at least 200 mg/d of inhaled corticosteroids
(ICS) for maintenance treatment (Table 1). All
subjects also required treatment with long-acting
b-agonists (LABA) shown by deterioration in
asthma control on withholding LABA for 2 weeks.
The group that underwent treatment with the
Alair system showed statistically significant reduc-
tion in their rates of mild exacerbations. They also
enjoyed improvements in a number of other
parameters including asthma quality of life,
asthma control, use of rescue medication and
numbers of symptom-free days (Table 2). Per-
forming BT causes temporary worsening of
asthma symptoms that usually begins on the day
of the procedure. Subjects in the AIR trial had
severe asthma to begin with; on occasion, their
symptoms were severe enough to require hospital
admission soon after treatment, which did not
occur in the previous trial (Table 3). There were 6
hospitalizations among 55 subjects who had
undergone 161 treatment procedures compared
with 2 admissions for asthma deterioration in 54
control subjects. Reassuringly, these adverse
events following BT are familiar problems that
respond typically within 1 week to usual measures
for care of asthma exacerbations.
A population with even more severe asthma was
enrolled in the Research in Severe Asthma (RISA)
trial.19 The 32 subjects had higher requirements
for maintenance medications that included oral
corticosteroids (OCS), and had other evidence of
more severe asthma than the subjects in either of
the 2 previous trials (see Table 1). At 22 weeks
138 Cox

Table 1
Comparison of inclusion criteria for clinical trials of BT for asthma

Feasibility AIR RISA AIR2

Age (y) 18–65 18–65 18–65 18–65
ICS dose (mg/d) %1800 R200 >1500 >1000
(beclomethasone
or equivalent)
LABA dose (mg/d) 0–100 R100 R100 R100
(salmeterol)
OCS dose (mg/d) 0 0 %30 %10
Pre-BD FEV1 >65 (post-BD) 60–85 R50 R60
(% predicted)
Symptoms Not required Worse with LABA Symptoms on R10/ R2/28 d
withdrawal 14 d, or rescue
med use on R8/14 d

after treatment, subjects followed an algorithm to
taper their steroid dose providing control of their
asthma did not deteriorate. This is the only time
that reductions in antiinflammatory therapy were
advocated in subjects undergoing BT. Because
the therapeutic rationale for BT is that it reduces
the amount of smooth muscle in the airway, it is
expected that following successful treatment
patients would still need to take their antiinflamma-
tory medications.10 The difference in severe
asthma is that patients may be taking excessive
doses of steroids and that reduction in the dosage
may be possible if asthma control is improved by
some other means.
According to various parameters, the group
treated with the Alair system showed improvement
in the control of their asthma.19 There were signif-
icantly greater improvements in asthma quality of
life, asthma control questionnaire score, and use
of rescue medications (see Table 2). Doses of
steroids for maintenance treatment were reduced
in both groups and the difference between them
was not statistically different (the trial had insuffi-
cient power to detect this difference as only half
of the subjects were taking oral steroids at entry).
There was an increase in the severity of adverse
events encountered in the actively treated group
compared with previous trials probably related to
the severity of asthma of the subjects (see Table 3).
There were 5 hospital admissions within 1 week of
45 procedures in the BT-treated group.
Even though multiple studies reported benefits
following treatment with BT, it should be recog-
nized that there is substantial potential for placebo
effect, especially with a novel procedure.20 Thus,
the Asthma Intervention Research 2 (AIR2) trial
was designed with a control group that underwent
3 bronchoscopies and sham treatment with the
Alair system.21 This comprised placement of the
treatment catheter in targeted airways, expansion
of the electrode array but no delivery of RF energy
when the controller was activated. The selection of
subjects was designed to enroll subjects with
asthma of sufficient severity to have large potential
for benefit, but not so severe as to be at high risk of
requiring hospitalization should asthma symptoms
worsen post procedure.18,19 A total of 297
subjects with severe asthma and persistent symp-
toms were randomized 2:1 to active and sham
control groups. The primary outcome was a

Table 2
Comparison among studies of outcomes indicating benefit from BT

Feasibility AIR RISA AIR2

Well tolerated Exacerbations AQLQ AQLQ
PEF AQLQ ACQ Severe exacerbations
Symptom-free days Symptom-free days Rescue medications ER visits
Hyperresponsiveness Rescue medications [Reduced oral Time lost from work/
steroids P 5 .12] school

Table 3
Comparison among studies of rates of hospitalization in the period following treatment bronchoscopy
AIR
Alair Control
(n 5 55) (n 5 54)
No. 6 (4) 2 (2)
hospitalizations
(no. of subjects)
No of 161 — 45
bronchoscopies
Events/bronch (%) 3.7 — 15.6
change in the asthma quality of life questionnaire
(AQLQ) score. This improved in both groups, but
to a statistically significant greater extent in the
BT group compared with the sham group.22
Secondary outcomes showed trends for benefit
from BT that were not statistically significant.
Safety was reported by rates of hospitalization
and other health care use at 2 time intervals:
around the time of treatment and from then to
the end of 1 year (see Table 2). The selection
criteria were successful in excluding subjects at
risk of severe asthma exacerbation following the
procedure, and this was confirmed by the rate of
hospitalization, which approximated that found in
the AIR trial and was substantially less than in
the RISA trial (see Table 3). Use of health care
resources, such as unscheduled office or emer-
gency department visits, and admissions were
lower in the BT-treated group than the sham
control group during the second interval of
follow-up (see Table 2).22
LONG-TERM CLINICAL FOLLOW-UP
There has been speculation from the very outset
regarding the possibility of certain adverse
outcomes developing late after BT. One specific
concern relates to the potential for long-term
damage to treated airways because of scar forma-
tion or to loss of integrity of the airway wall. It is
now possible to begin to address such concerns
with data from long-term follow-up of treated
patients. HRCT examinations have been per-
formed annually for 5 years in the subjects who
participated in the feasibility trial. Treated airways
appear normal, without evidence of either airway
stenosis or dilation (bronchiectasis). There was
also no evidence of damage to the parenchyma
adjacent to treated airways indicating the treat-
ment effect is limited to the airways.
Longer term follow-up of subjects who were
treated in the Feasibility, AIR, AIR2 and RISA trials
Bronchial Thermoplasty 139
RISA AIR2
Alair Control Alair Sham
(n 5 15) (n 5 17) (n 5 190) (n 5 98)
7 (4) 0 (0) 19 (16) 2 (2)
— 558 292
— 3.4 0.7
now exceeds 500 patient-years. The majority of
subjects report either stable or improved control
of their asthma. Pre- and postbronchodilator
FEV1 has remained stable over 3 or more years
in subjects who completed the first 3 studies.
This experience suggests there are no late devel-
oping adverse consequences of treating asthmatic
airways with BT.
SUMMARY
Despite major progress in developing medical
treatments for asthma, a substantial proportion
of patients continue to suffer from inadequate
control of their disease.23 In others, although their
disease can be controlled this requires such high
doses of medications that side effects are trouble-
some.24,25 Current treatments do not redress the
excess smooth muscle mass that is present in
the remodeled airway in chronic asthma. Thus, it
is intriguing to consider the potential contribution
of BT (a procedure that involves controlled heat
treatment to reduce the mass of the airway
smooth muscle) as an effective therapy for poorly
controlled asthma. If effective, BT would reverse
the excess accumulation of muscle in the airway
and reduce the potential for bronchoconstriction.
Although the short-term increase in asthma symp-
toms (requiring hospitalization at times) is evident,
these should be weighed against the benefits that
are present for a prolonged time (>1 year in all trials
to date). Even though the results of 4 clinical trials
show benefits following BT in patients with asthma
ranging from mild to severe, it is most likely that
this treatment will be indicated for patients with
severe asthma that is not well controlled by combi-
nations of currently available therapies. These are
the patients who most need an additional effective
asthma therapy and, based on the results of trials
published to date, have the greatest potential to
benefit from BT.
140 Cox
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