WHAT'S NEW IN ASTHMA AND COPD

Published with
Volume 31:8 2003

Whats new in ...

Asthma and COPD

Medicine

P M A Calverley and Paul Walker

Airways disease remains important in the workload of hospital

respiratory physicians, and the respiratory workload of family doctors.
Much research on asthma and chronic obstructive pulmonary disease
(COPD) involves basic pathophysiology, including genetics, but this
article deals with advances of importance to non-specialists, both now
and in the future.
Asthma
Guidelines and delivery of care many
patients with asthma experience frequent
symptoms with consequent limitation of
activity. Individuals with persistent symptoms often believe that their asthma is well
controlled and do not discuss these symptoms or the restrictions with health-care
professionals. Potential consequences of
poor control include fixed airway obstruction and high numbers of exacerbations and
hospital admissions. The Global Initiative
for Asthma guidelines, though not evidencebased, attempt to highlight what the aims
of asthma management should be; these
include minimal chronic symptoms, no
limitation of activity and minimal use of
rescue medication.1 The British Thoracic
Society/Scottish Intercollegiate Guidelines
Network asthma guidelines are evidencebased, and it is hoped that they will help to
address current shortcomings in management and delivery of care.2 An established
principle in these guidelines is that asthma
in adolescents ( 12 years) should be managed as in adults.
Provision of written self-management
plans after hospital admission can have
a beneficial effect on symptoms (day and
night) and reduce re-admission rates over
the next year. A fivefold reduction in readmission was seen in patients who were
given such plans on their first admission.3
Proactive structured review in primary

care is associated with up to a threefold

reduction in days on which normal activity is limited by the symptoms of asthma.4
The latest UK asthma guidelines based on
a systematic review of data recommend
that a nurse trained in asthma management
should regularly review patients managed
in primary care, and that self-management
education, including written action plans,
should be provided to all patients.
Pharmacological therapy significant
advances have been made in the treatment
of asthma, largely involving improvements
in existing therapies such as corticosteroids
and -agonists.
When to commence inhaled corticosteroids has been debated for many years.
The START study assessed this in 7241
patients with mild persistent asthma of
less than 2 years duration who had not
previously undergone regular inhaled
corticosteroid treatment.5 Compared with
placebo, budesonide, 400 g once daily for
3 years, reduced the incidence of severe
asthma exacerbations by 44%, and led to
a decrease in both the number of courses
of oral corticosteroids required and the
symptoms. The results indicate that lowdose inhaled corticosteroids should be
commenced even in patients with mild
asthma of recent onset.
In patients with poorly controlled
asthma who are taking low-dose inhaled
corticosteroids and rescue short-acting
-agonists, the next step should be the

P M A Calverley FRCP FRCP(Ed) is Professor of Medicine at the University of Liverpool, UK.

Paul Walker MRCP is Specialist Registrar in Respiratory Medicine at University Hospital Aintree,
Liverpool, UK.

MEDICINE

addition of a long-acting -agonist, regardless of the severity of the asthma. This was
established several years ago in patients
with moderate-to-severe asthma, and more
recently in those with mild asthma in the
OPTIMA study.6 In this study, 1272 patients
with mild asthma who were taking only a
low dose of inhaled corticosteroid were
randomized to either 100 g or 200 g of
budesonide twice per day and either 4.5 g
of formoterol twice per day or placebo.
Those on the higher dose of budesonide
alone gained only minor benefit, whereas
asthma control was significantly improved
in those taking formoterol with either dose
of budesonide. Addition of formoterol reduced the risk of a first asthma exacerbation by 43%, the number of poorly controlled asthma days by 30%, and the incidence of severe exacerbations by 52%.
Addition of a long-acting -agonist and
an increase in the inhaled corticosteroid
dose are both superior to other therapies
(e.g. leukotriene receptor antagonists,
theophylline), which can be considered
if control remains poor. Current evidence
supports the fact that combinations of
inhaled corticosteroids and long-acting
-agonists are at least as effective as their
individual components and may help
adherence to therapy.
New therapies inhaled corticosteroids
with a more favourable efficacy:toxicity
ratio and hence fewer systemic side-effects
have been developed. Ciclesonide has the
advantage of once-daily dosing. Mometasone is an inhaled corticosteroid that has
recently been launched in the UK for mildto-moderate asthma and can also be used
once per day for maintenance therapy.
Phosphodiesterase-4 inhibitors have a
broad anti-inflammatory effect and roflumilast is currently being assessed in clinical
trials, though data published in abstract
form have been disappointing.
Omalizumab is a blocking antibody
to IgE that has been investigated in 546

2003 The Medicine Publishing Company Ltd

WHAT'S NEW IN ASTHMA AND COPD

moderate-to-severe allergic asthmatics. A

reduction of more than 50% in asthma
exacerbations was achieved, despite a
reduction in the dose of inhaled corticosteroids.7 The drug also has positive effects
on lung function, asthma symptoms and
quality of life, and its benefits continue for
up to 1 year.8 However, because of its action
on IgE it is likely to be useful only in atopic
asthma, and its cost and subcutaneous
administration mean that it will probably
be given only to carefully selected patients
with moderate-to-severe asthma.
Corticosteroid side-effects corticosteroids remain the primary diseasemodifying therapy in asthma, and sideeffects are an important issue. Currently
available inhaled corticosteroids undergo
significant systemic absorption, and this
is associated with reduced bone mineral
density. Recent work has shown a small
but significant increase in the incidence
of hip fracture in recent users of inhaled
corticosteroids; this association appears to
be dose related and is reduced only slightly
by adjustment for oral corticosteroid use.9
There is also an association between oral
corticosteroid dose and vertebral fracture
in patients with chronic lung disease.10 It
is important to reduce the dose of inhaled
corticosteroid to the minimum possible,
and patients taking high-dose inhaled or
regular oral corticosteroids should be considered for prophylactic therapy to prevent
reduction of bone mineral density.
Acute exacerbations management
of acute exacerbations has remained unchanged for many years, based on highflow oxygen, nebulized and intravenous
bronchodilators and oral or intravenous
corticosteroids. Magnesium has long been
recognized as a bronchodilator, however,
and has now been shown to be an effective
adjunct to conventional therapy in both
adults and children with acute severe
asthma exacerbations.11 Currently, a single
intravenous dose is usually prescribed.
Debate remains about the role of increased inhaled corticosteroid dose during
exacerbations. Clear evidence on which to
make recommendations is lacking.
Disease monitoring asthma therapy
is assessed by symptoms, exacerbations
and measures of lung function. These
are important, but are distant surrogates
for processes in the airways. Research
on different means of guiding treatment
has shown positive benefits on outcome
measures.

MEDICINE

Bronchial challenge testing is a measure

of airway smooth muscle reactivity that has
been used for many years as a diagnostic
test for asthma. Use of 3-monthly bronchial challenge tests to guide therapy in
75 patients with mild-to-moderate asthma
led to a near halving of mild exacerbations
over 2 years.12 At the end of 2 years, bronchial biopsy showed histological improvement that correlated with the eosinophil
count in the biopsies. Alternatively, the
eosinophil count in induced sputum can
be used to guide treatment. This has been
compared with standard management in
74 moderate-to-severe asthmatics.13 In the
sputum management group, there was
a threefold reduction in severe asthma
exacerbations and fewer hospitalizations
despite no significant difference in oral or
inhaled corticosteroid dose. A large reduction in sputum eosinophil count was also
seen in the sputum management group.
Neither of these strategies is currently
applicable to general respiratory practice,
but they may be increasingly used in trials
of new therapies and may be helpful in
selected individuals.

COPD
Guidelines many national and international bodies produce guidelines for
the management of COPD. The Global
Initiative for Chronic Obstructive Lung
Disease (www.goldcopd.com) guidelines
are a recent addition.14 These are the first
evidence-based guidelines and are updated
every July. The aim is that they will remain
up to date and promote international consensus on management.
Smoking cessation following diagnosis of COPD, the foundation of treatment
is encouraging smoking cessation in those
who have yet to stop. Long-term studies
have shown that decline in lung function is
accelerated in individuals who continue to
smoke. Furthermore, in the general population, self-reported smoking cessation is
associated with an approximately 40%
reduction in the rate of hospitalization for
exacerbation of COPD later in life. There
was no reduction in those who smoked less
but did not quit.15
Physiological tests abnormal spirometry is a cardinal diagnostic feature of
COPD, but remains a poor predictor of
exercise performance and response to
therapy. The reason for this has now been
shown by the observation that, in COPD,

end-expiratory lung volume increases

during exercise (dynamic hyperinflation),
rather than decreasing as in normal subjects. This explains the intensity of dyspnoea, at least in more severe disease, and
is associated with limitation of expiratory
airflow during tidal breathing, which can
be measured by applying negative pressure
during expiration (NEP). Although NEP is
little affected by bronchodilators at rest,16
the decrease in dynamic hyperinflation
after administration of a bronchodilator
is a better predictor of change in exercise
performance than is the change in forced
expiratory volume in 1 second (FEV1).17
Pulmonary rehabilitation out-patient
pulmonary rehabilitation is important in
the management of COPD. There is clear
evidence that it leads to improvements in
breathlessness, physical functioning, quality of life and hospitalizations. The benefits
last for at least 1 year, but then appear to
decline. Results of studies of maintenance
programmes have been disappointing.
A 1-year study of 85 COPD patients
involving the addition of monthly rehabilitation follow-up sessions to periodic
encouragement showed no benefit from
additional sessions, and less than onehalf of the subjects remained in the active
treatment arm by the end of the study.18
Another, larger study involved 172 patients
randomized to either weekly telephone
follow-up plus monthly rehabilitation sessions for 12 months, or standard care. In
the intervention group, improvements in
exercise capacity and health status were
better maintained over the first year, but
there was no difference in symptoms or
quality of life. After 2 years, there were
no differences between the groups and
patients had returned to levels close to
those before rehabilitation.19
Major barriers to continuing exercise
appear to be frequent exacerbations, and
problems with exercising during exacerbations or restarting exercise afterwards.
Whether rehabilitation can be enhanced by
nutritional supplementation or pharmacological intervention (e.g. growth hormone,
anabolic steroids) is unclear. Despite the
benefits, many UK hospitals UK do not provide a pulmonary rehabilitation service.
Lung volume reduction surgery there
has been much interest in lung volume
reduction surgery in COPD; however,
surgery is appropriate only in selected
patients. The National Emphysema Treatment Trial was established to determine

2003 The Medicine Publishing Company Ltd

WHAT'S NEW IN ASTHMA AND COPD

those likely to benefit. An early analysis

showed unacceptably high mortality in
patients with FEV1 less than 20% predicted and either a homogenous pattern
of emphysema on CT (no clearly severely
affected area to remove) or DLCO less
than 20% predicted.20 Full results were
published recently; patients lacking predominant upper lobe emphysema and with
good exercise capacity after pulmonary
rehabilitation exhibited excess mortality
with little long-term functional or quality
of life improvement. The patients most
likely to benefit are those with upper lobe
disease and poor exercise capacity after
rehabilitation.21
A promising new area of research is
bronchoscopic lung volume reduction surgery, which may be suitable for those who
are unsuitable for or refuse the operative
procedure.22 An early report of the insertion
of endobronchial valves in eight patients
has suggested that the procedure is safe
in the short term and can improve lung
function. However, much work is required
before the procedure can be deemed safe
or useful for a wider patient group.
Pharmacological therapy recent
evidence supports the use of combination
long-acting -agonist/inhaled corticosteroid inhalers. The TRISTAN study recruited
1465 patients with widely ranging severities
of COPD and random-ized them to a fluticasone/salmeterol combination (Seretide),
the individual components or placebo.23
The combin-ation therapy produced superior improvements in lung function and
a clinically significant improvement in
health status, with the greatest improvement in daily symptoms. Another study
of 812 subjects with moderate-to-severe
COPD compared a budesonide/formoterol
combination (Symbicort) with its components and placebo.24 The combination
treatment reduced the mean number of
severe exacerbations and improved lung
function compared with other treatment
arms, and produced the greatest decrease
in symptom scores.
The phosphodiesterase inhibitors
cilomilast and roflumilast are antiinflammatory agents with modest benefits
in clinical trials.25 They are currently not
licensed in the UK.
Exacerbations exacerbations are more
common in patients with worse baseline
lung function, and recovery takes longer
and is less likely to be complete. Quality
of life is worse and decline in lung func-

MEDICINE

tion more rapid in individuals who suffer

frequent exacerbations.26 Patients with
COPD not uncommonly harbour colonizing bacteria in their airways, and these
individuals suffer more frequent exacerbations, more airway inflammation and more
rapid disease progression.27 Colonization
with Haemophilus influenzae appears to be
particularly important.28 Timely treatment
of infective exacerbations is appropriate,
but there is currently no evidence to support a more aggressive policy of eradication
of bacteria. Small areas of bronchiectesis
are often seen on high-resolution CT in
patients with COPD, but the importance
of these is unclear.u

13

14

15

16

17

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2003 The Medicine Publishing Company Ltd