Review

Pharmacological management of mild or moderate

persistent asthma
Paul M O’Byrne, Krishnan Parameswaran

Lancet 2006; 368: 794–803 Patients with mild persistent asthma rarely see their doctor with symptoms of the disease. Partly as a result of this
Firestone Institute for situation, mild asthma is generally undertreated. Findings of several large randomised clinical trials have shown
Respiratory Health, St Joseph’s benefits for this population of regular treatment with low doses of inhaled corticosteroids. Additional drugs are rarely
Healthcare and Department of
needed, and although leukotriene modifiers are effective, they are less so than inhaled corticosteroids. People with
Medicine, McMaster
University, Hamilton, Ontario, moderate persistent asthma are not well controlled on low doses of inhaled corticosteroids. A combination of this
Canada (P M O’Byrne MB, drug and long-acting inhaled β2 agonists provides improved control compared with doubling of the maintenance
K Parameswaran MD) dose of inhaled corticosteroids. The combination of budesonide and formoterol has been assessed as both maintenance
Correspondence to: and reliever treatment. This approach further reduces the risk for severe exacerbations. With these strategies, most
Dr Paul M O’Byrne, McMaster
individuals can achieve good control of their asthma. For patients who do not achieve asthma control despite taking
University Medical Center,
1200 Main Street West, drugs, measurement of the inflammatory response in the airway in induced sputum could provide further information
Hamilton, Ontario L9G 4R7, to guide treatment.
Canada
obyrnep@mcmaster.ca
Consensus guidelines for asthma treatment have, in start receiving treatment; by contrast, someone with
general, characterised patients as intermittent (very mild) fairly mild symptoms—such as persistent cough—might
asthma, and mild, moderate, and severe persistent not respond adequately to treatment and therefore not be
asthma.1,2 The most widely disseminated of these—from well controlled.
the Global Initiative for Asthma—describe patients with Asthma guidelines highlight consistently the aims and
mild persistent asthma as having symptoms more than objectives of treatment: (1) to minimise or eliminate
once a week but less than daily, nocturnal symptoms asthma symptoms; (2) to achieve the best possible lung
more than twice a month but less than once a week, and function; (3) to prevent asthma exacerbations; (4) to do
with typical lung function (forced expired volume in 1 s the above with the fewest drugs; (5) to keep short-term
[FEV1] or peak expiratory flow >80%) between asthma and long-term adverse effects to a minimum; and (6) to
episodes. Individuals with moderate persistent asthma educate the patient about the disease and goals of
have symptoms daily, nocturnal symptoms at least once a management. One other important objective should be
week, exacerbations that can affect activity and sleep, and prevention of decline in lung function and development
FEV1 or peak expiratory flow of less than 80% but more of fixed airflow obstruction, which happens in some
than 60% predicted. However, if these markers arise patients with asthma. In addition to these goals and
while on treatment, the degree of disease severity is objectives, in each of the guideline documents,
increased from mild to moderate and from moderate to researchers have described what is meant by the term
severe. Furthermore, asthma severity must be asthma control. This definition includes the above
differentiated from asthma control.3 For example, a objectives and additional aims to decrease need for rescue
patient who presents with severe asthma symptoms and treatment—such as inhaled β2 agonists—to less than
airflow obstruction might be well controlled once they daily use, to reduce variability of flow rates that is
characteristic of asthma, and to have usual activities of
Search strategy and selection criteria daily living. Achievement of this level of asthma control
should be an objective from the very first visit of the
We searched the Cochrane library (update May, 2006), MEDLINE (1965–2006), patient to the treating doctor.
OLDMEDLINE (1950–65), EMBASE (1980–April, 2006), and CINAHL (1956–April, 2006) Despite publication of these guidelines, asthma is
with the search terms “asthma”, OR “wheeze*” OR “hyperresponsiveness”. We then sometimes undertreated. Evidence to lend support to this
restricted the results with the terms “clinical trial” OR “treatment” in the electronic search, statement has existed since Turner-Warwick4 reported a
and by hand-searching for “mild” OR “moderate” asthma. We restricted our search to survey of patients managed in primary-care practice.
English language publications. We largely selected publications in the past 10 years but did Findings of telephone surveys in Europe,5 Asia,6 the
not exclude commonly referenced and highly regarded older publications. We also USA,6 and Canada7 have all shown that most people with
searched the reference lists of articles identified by this search strategy and selected those asthma are not ideally controlled. The reasons for this
we judged relevant. Decisions to include specific references were based on authors’ situation are complex, but one possible explanation is
knowledge of published work, participation in expert meetings, and many years of research unawareness by patients (including many with mild
on the subject. Thus, this work is not an exhaustive systematic review of the pharmacology persistent asthma) and their managing doctors that good
and effectiveness of all drugs that have been used to treat asthma. Rather, it is an overview asthma control can and should be achieved. In this
of current best practice strategy based on research evidence, clinical reasoning, theory, and Review, we discuss the effectiveness of current
heuristics. We did not review studies on alternative treatments for asthma. pharmacological treatments for mild and moderate
persistent asthma. Management of mild intermittent

794 www.thelancet.com Vol 368 August 26, 2006

 Review

asthma and mechanisms of action of anti-asthma drugs

O’Byrne15 Pauwels16 Boushey17 Zeiger18 Garcia19
are not included.
Total patients (n) 698 7241 225 400 994

Management of mild persistent asthma FEV₁ (% predicted) 89–90% 86% 88–91% 93–95% 87–88%

Patients with mild persistent asthma form a sizable Days with symptoms per week 3 4 4 3·6 NA

proportion of people with asthma (up to 70%);8 these
individuals could be called the silent majority because
they rarely visit their family doctor with symptoms of the
disease and are seldom seen in a secondary or tertiary
health-care setting, in which most doctors with a focused
interest in asthma management are based. Partly for this
reason, very little attention has been paid to morbidity
associated with mild persistent asthma and in very few
reports have researchers assessed patients’ responses to
treatment. Indeed, most studies that claim to have
studied people with mild-to-moderate asthma have not
included many (or any) individuals with mild disease, as
indicated by the mean FEV1, which is usually around 70%
predicted normal, rescue β2 agonist use of 2–3 puffs per
day, or both.9–14 This situation makes results presented in
these reports of little or no value for evaluation of
treatment strategies for patients with mild persistent
asthma. Fortunately, this omission has been rectified in
the past 4–5 years (table).
The standard of care for patients with mild persistent
asthma in the past was to recommend regular use of
inhaled short-acting β2 agonists.20 However, monotherapy
with these drugs results in deterioration of overall asthma
control21 and in an increased risk for death,22 and this
treatment approach is no longer recommended in
national or international guidelines. Subsequently,
researchers are investigating the benefits of inhaled
corticosteroids, which are the pre-eminent anti-
inflammatory treatment for asthma,23 in patients’ with
mild persistent disease. Findings of these studies have
lead to some controversy.
In the OPTIMA trial,15 the researchers’ objective was to
assess whether the benefits of adding a long-acting
inhaled β2 agonist (formoterol) to inhaled corticosteroids
(budesonide), particularly for reduction of mild and
severe asthma exacerbations, which had been reported in
people with moderate persistent asthma,24–26 also were
apparent in patients with mild persistent asthma. In
Nocturnal symptoms per week <1 NA NA <1 NA
β2 agonist use (inhalations per week) 7 NA NA 7 5
Values are either taken from or calculated (where available) from information presented in tables of baseline
characteristics. NA=information not available.
Table: Baseline characteristics of patients in clinical trials of mild persistent asthma
benefit when compared with budesonide alone. The
researchers showed that, for patients with mild persistent
asthma, low-dose inhaled corticosteroids alone are the
preferred treatment option. By contrast, in the same
study, another population of patients (group B), who had
moderate persistent asthma and used inhaled
corticosteroids at study entry, did show a striking and
significant difference in asthma exacerbations when
formoterol was added to budesonide (figure 1). The
findings suggested that combination treatment is not
appropriate for all patients with persistent asthma and
that benefit is only seen in those not ideally controlled on
low doses of inhaled corticosteroids alone.
Another large study, in which patients with mild
persistent asthma were given inhaled corticosteroids, is
the START trial.16 These investigators looked at whether
early intervention with inhaled corticosteroids (again,
budesonide) prevented progression of asthma in adults
and children aged 5–11 years with newly diagnosed, mild,
persistent asthma (table). The outcome was measured by
time to first very severe exacerbation, which needed a
visit to the emergency room or admission, and by decline
in post-bronchodilator FEV1. Patients were treated with
low-dose budesonide or placebo for 3 years. During the
first year, almost 34% of individuals in the placebo arm
needed additional treatment with inhaled corticosteroids
and 4% had a severe asthma exacerbation. This proportion
was reduced in the budesonide arm to 20% needing
1·0
(number per patient per year)

OPTIMA, two groups of patients were selected: the first 0·8

Rate of exacerbations

(group A) consisted of almost 700 individuals with mild

persistent asthma who had never used inhaled 0·6
corticosteroids (table). In this group, budesonide alone
0·4
(200 μg/day) was compared with the same dose of
budesonide plus formoterol or placebo for 1 year of
0·2
treatment. The primary outcome was rate of severe
asthma exacerbations; this rate was 0·77 per patient per 0·0
year in the placebo-treated group, falling to 0·29 per
9
a

00 0

00

00 0
9

00

18

00 00
18
Pl

or
0
or
B2

B2

8
or

or
B4

B2
+F
+F

patient per year with low-dose budesonide alone (figure 1).

+F

+F
00
B4
B2

B2

B8

All other study outcomes, including days with asthma

symptoms and nights with nocturnal symptoms, were Optima A Optima B FACET

improved by budesonide treatment. The combination of Figure 1: Rate of severe asthma exacerbations in OPTIMA and FACET studies
budesonide and formoterol did not provide any additional Pla=placebo. B200=budesonide 200 μg/day. For9=formoterol 9 μg/day.

www.thelancet.com Vol 368 August 26, 2006 795

 Review
additional inhaled corticosteroids and 2% with a severe
exacerbation. By year 3 of the study, 50% of patients
allocated placebo who had not used inhaled corticosteroids
at the start of the study were being treated with this drug
and 6% of the population had a severe asthma
exacerbation. In the budesonide arm, 30% were given
additional inhaled corticosteroids and 3% had a severe
asthma exacerbation. Changes in both pre-bronchodilator
and post-bronchodilator FEV1, although significant, were
small at the end of 3 years of treatment. Thus, early
intervention with low doses of inhaled corticosteroids did
prevent progression of asthma, but the effects were—
particularly in the case of lung function—incomplete.
The Childhood Asthma Management Plan (CAMP)
study is a large prospective trial.27 The researchers aimed
to assess whether treatment with either inhaled
corticosteroids or nedocromil prevented decline in lung
function in children with asthma. 1041 children aged
5–12 years with mild-to-moderate asthma were randomly
allocated either 200 μg of budesonide, 8 mg of nedocromil,
or placebo twice daily for 4–6 years. The primary outcome
was change in FEV1 predicted after administration of a
bronchodilator; this measure was not improved by either
active treatment. However, no decline happened in FEV1
over the 4 years of study in children allocated placebo.
Despite the lack of effect on post-bronchodilator FEV1,
compared with those allocated nedocromil, children who
received budesonide had a significantly smaller decline
in ratio of FEV1 to forced vital capacity and improved
airway responsiveness to methacholine, fewer
admissions, fewer urgent visits to a caregiver, greater
reduction in need for rescue treatment for symptoms,
fewer courses of prednisone, and fewer days on which
additional asthma drugs were needed.
In the IMPACT study, researchers assessed intermittent
short-course inhaled corticosteroids, guided by a
symptom-based action plan, alone or in addition to daily
treatment with either budesonide or an anti-leukotriene,
zafirlukast, in 225 adult patients with mild persistent
asthma for 1 year.17 This population was almost identical
in baseline characteristics to those of OPTIMA and
START (table), albeit with a much longer duration of
asthma than in these studies. Findings of IMPACT
indicated that patients with mild persistent asthma could
be treated with intermittent courses of inhaled or oral
corticosteroids, together with an action plan. This
conclusion was reached despite the fact that regular use
of inhaled budesonide was significantly better than
intermittent use in improving pre-bronchodilator FEV1,
asthma control scores, number of symptom-free days,
airway hyper-responsiveness, and markers of airway
inflammation (sputum eosinophils and exhaled nitric
oxide). Outcomes that were not better were asthma
quality-of-life scores, measurements of morning peak
expiratory flow, and post-bronchodilator FEV1. Importantly,
the proportion of patients with severe asthma
exacerbations did not differ between groups. However,
796
the proportion needing a course of prednisone throughout
the year was very low and much lower than previously
described in similar populations,11 making finding a
treatment effect for regular budesonide in a study of this
size almost impossible.
Is regular use of inhaled corticosteroids in mild
persistent asthma worthwhile?
The most widely used primary outcome variables in
asthma drug trials—improvements in FEV1 or morning
peak expiratory flow—are not the best choice in studies of
patients with mild persistent asthma, because these
measurements will generally be normal or close to normal
in this population. Since this group of patients are
asymptomatic some of the time, use of symptom scores,
control questionnaires, or quality-of-life methods—which
are better choices for primary outcome—needs large
sample sizes to be adequately powered because of the
small size of change likely to be seen. Therefore, the
benefits reported in large trials of low-dose daily inhaled
corticosteroids can seem not worth the effort needed to
achieve them. However, patients with mild persistent
asthma have, by definition, persistent symptoms every
week, with nocturnal symptoms occasionally, and rates of
severe asthma exacerbations, if untreated, that are higher
than expected before the above studies were undertaken.
A trial of low doses of inhaled corticosteroids in patients
with mild persistent asthma should last for at least
3 months to obtain most therapeutic benefit18 and could
provide the size of benefit that will ensure that individuals
will continue to use the drug. If this benefit is not
achieved, the patient is unlikely to continue to use inhaled
corticosteroids on a regular basis, and will revert to
intermittent use. However, if a therapeutic trial is not
attempted, clinical effectiveness will never be known. All
patients with mild persistent asthma deserve the
opportunity to decide whether the benefit from use of
inhaled corticosteroids, usually only once daily, is worth
the effort.
A trial of inhaled corticosteroids is frequently
recommended for children with intermittent wheezing
to help in establishing a diagnosis of asthma when
opinion is uncertain. Most episodes of wheezing in
infants and young children could be due to viral
bronchitis. Findings of a study have shown that twice-
daily administration of inhaled corticosteroids for 2 years,
compared with placebo, controlled symptoms but had an
effect only during the treatment period, with no carryover
effect after the drug was stopped (during the third study
year).28 Intermittent treatment with inhaled corticosteroids
during episodes of wheezing was also not effective at
preventing future episodes of wheezing.29
Another issue that needs to be considered when
making a decision to start treatment with inhaled
corticosteroids in mild asthma is the potential for side-
effects. These drugs are not metabolised in the lungs and
every molecule of corticosteroid that is administered is
www.thelancet.com Vol 368 August 26, 2006

absorbed into the systemic circulation. All studies in
patients with mild persistent asthma have used low doses
of inhaled corticosteroids (maximum dose 400 μg/day).
A wealth of data is available showing the safety of these
low doses, even when used long term, in adults.30
However, in both the START trial16 and the CAMP study,27
a significant reduction in growth velocity of children of
1·0–1·5 cm was reported over 3–5 years of treatment
with budesonide (200–400 μg/day). This finding is
unlikely to have any effect on the final height of these
children, because one study—in which children treated
with inhaled budesonide were followed up to final
height—did not show any detrimental effect, even with
an average dose of 500 μg/day.31 Also, the low doses of
budesonide used in the CAMP study over 3 years did not
have any measurable effect on hypothalamic-pituitary-
adrenal axis function.32
Other treatment options for mild persistent
asthma
Leukotriene receptor antagonists, which have both
bronchodilator and anti-inflammatory properties,33,34 have
been assessed and compared with inhaled corticosteroids
in adults18 and children19 with mild persistent asthma. In
both studies, a leukotriene receptor antagonist,
montelukast, was compared with a low-dose inhaled
corticosteroid (fluticasone, 200 μg/day). In these studies,
both drugs improved most asthma-control measures, but
fluticasone was significantly better for most outcomes.
This outcome was especially true in patients who had
eosinophilic bronchitis. Responses to treatment differed
within and between individuals.35 Although, on average,
inhaled corticosteroids improve almost all asthma
outcomes, more so than leukotriene receptor antagonists,
some patients might show a greater response to leukotriene
receptor antagonists. Currently, accurate identification of
these responders—based on their clinical, physiological,
or pharmacogenomic characteristics—is not possible.
Thus, although leukotriene receptor antagonists are
regarded as a treatment option for patients with mild
persistent asthma, they are not as effective as low doses of
inhaled corticosteroids.
Management of moderate persistent asthma
Patients with moderate persistent asthma are described as
those whose disease is not well controlled on low doses of
inhaled corticosteroids (≤500 μg of beclometasone or
equivalent dose for other corticosteroids in adults, and
≤250 μg in children). Asthma-treatment guidelines
recommend a combination of inhaled corticosteroid and a
long-acting inhaled β2 agonist in these people.1,2 This
recommendation stems from findings of the FACET
study,25 which compared a low dose of inhaled corticosteroid
rising to a four-fold increase, with and without a long-
acting β2 agonist, in patients with moderate-to-severe
persistent asthma. The investigators showed that a four-
fold boost in dose of inhaled corticosteroid (budesonide,
www.thelancet.com Vol 368 August 26, 2006
Review
from 200 μg/day to 800 μg/day) improved all outcomes,
but addition of long-acting β2 agonist to the highest dose
of inhaled corticosteroid was the most effective strategy,
particularly for reduction of severe asthma exacerbations
(figure 1). Researchers on several subsequent studies could
not show any benefit of a two-fold rise in dose of inhaled
corticosteroid for most outcomes assessed, including
reduction of the rate of asthma exacerbations15 or
prevention of exacerbations.36–38 By contrast, addition of a
long-acting β2 agonist to the inhaled corticosteroid did
improve most outcomes,26 including lessening of asthma
exacerbations.15,25,39 Use of a combination of inhaled
corticosteroid and long-acting β2 agonist for patients with
moderate persistent asthma has also been shown to
improve all indicators of asthma control, when compared
with a corticosteroid alone,15,40,41
In the GOAL study,41 researchers investigated how
frequently ideal asthma control can be achieved in three
groups of patients, who mostly had moderate-to-severe
asthma (only 10% of participants had mild persistent
disease). The three groups consisted of people not using
inhaled corticosteroids at study entry (steroid-naive), and
those taking low-dose or moderate-dose inhaled
corticosteroids at study entry, but who were not well
controlled. The study population was randomly allocated
either increasing doses of inhaled corticosteroid alone (to
a maximum of 1000 μg/day of fluticasone) or similar
doses together with the long-acting β2 agonist salmeterol
for 1 year. Phase I of the study was dose escalation,
whereby the dose was stepped up until total asthma
control was achieved or until the maximum dose
(fluticasone 1000 μg or fluticasone 1000 μg and salmeterol
100 μg daily dose) was reached. Phase II was after total
control was achieved or after 12 weeks on the maximum
dose of drug. Findings suggested that total asthma
control—which was identified by the patient having no
symptoms, normal lung function, and no limitation of
activities—could be achieved in some patients but in less
than 50% of the overall population and less than 30% of
those already taking moderate doses of inhaled
corticosteroids at randomisation, even with the highest
doses of combination treatment. However, well controlled
asthma—defined by the presence of mild occasional
symptoms—was achieved in up to 78% of patients not
receiving inhaled corticosteroids before study entry and
in 62% of those already on moderate doses of these drugs
(figure 2). The combination of inhaled corticosteroid and
long-acting β2 agonist was significantly better than
inhaled corticosteroid alone.
We should note that evidence for the enhanced benefit
of combined inhaled corticosteroids and long-acting β2
agonists in patients with moderate persistent asthma
exists mainly in adults. Findings of a systematic review of
eight randomised controlled trials of long-acting β2
agonists to treat symptoms in children using inhaled
corticosteroids showed no apparent protection from
asthma exacerbation in those on a β2 agonist compared
797
 Review

Fluticasone phase II Fluticasone and salmeterol phase II non-significant) numbers of asthma-related deaths were
Fluticasone phase I Fluticasone and salmeterol phase I recorded with regular use of salmeterol. The population
80 in the US surveillance study had, in general, very poorly
controlled asthma, yet less than 50% of these patients
Proportion of patients

60 reported being treated with inhaled corticosteroids. The

40
20
0
Steroid–naive Low–dose
inhaled
corticosteroid
Figure 2: Proportion of patients achieving good asthma control after 1 year
of treatment with fluticasone either alone or in combination with
salmeterol in the GOAL study
Modified from reference 41 with permission of the American Thoracic Society.
with children using a comparison treatment (mainly
placebo).42
Despite evidence for effectiveness when used in
combination with inhaled corticosteroids in adults with
moderate asthma, considerable concern has been voiced
about the safety of long-acting β2 agonists. This situation
arose after publication of a surveillance study, which was
mandated after the long-acting β2 agonist salmeterol was
approved for use in the USA.43 Researchers identified an
increased risk of respiratory-related mortality or life-
threatening events with salmeterol compared with placebo
in a population of patients with asthma, and these
differences were significant for the African-American
subset of study participants. The findings accorded with
those of another post-marketing surveillance study
undertaken in the UK,44 in which numerically higher (but
280 4×BUD+SABA
200 (294 events)
120
40
0 rescue treatment was compared with a four-fold higher
Number of exacerbations
African-American population had even less well controlled
asthma, with lower lung function and even fewer patients
prescribed inhaled corticosteroids. Although long-acting
β2 agonists are effective for symptom relief in asthma,
they have not been reported to have clinically important
Moderate–dose anti-inflammatory effects. Therefore, their use as
inhaled monotherapy in patients with poorly controlled asthma is
corticosteroid
not recommended in any treatment guidelines, and it
seems to be associated with an increased risk of severe
asthma outcomes and disease-related deaths. Although
no long-term surveillance study has been undertaken of a
combination of corticosteroid and long-acting β2 agonist
in one inhaler, this treatment strategy, as described above,
reduces severe asthma exacerbations and improves
asthma control in all studies in which it has been assessed
in adults, with no concerns raised about the safety of these
combinations.
Another treatment approach described for management
of moderate asthma is use of an inhaler containing a
combination of the corticosteroid budesonide and the
long-acting β2 agonist formoterol, for both maintenance
and rescue therapy.14,40,45 This approach is possible because
formoterol is an inhaled β2 agonist, which has a rapid
onset and a long duration of action46 and acts as a
bronchodilator as the dose increases.47 The drug can,
therefore, be effectively used as relief treatment for
asthma.48 The idea of using formoterol in combination
with an inhaled corticosteroid as both maintenance and
rescue treatment for asthma patients was initially assessed
by comparing this approach with high-dose inhaled
corticosteroids as maintenance and a short-acting inhaled
β2 agonist as rescue.14,45 Subsequently, a study was reported
in which the strategy of combined maintenance and

dose of inhaled corticosteroids as maintenance and a

280 BUD/Form+SABA short-acting β2 agonist as rescue.40 Findings of these
200 (330 events)
studies show that use of this combination as both
120 maintenance and rescue greatly reduces risk for severe
40 asthma exacerbations when compared with other
0
approaches (figure 3), with an associated reduction in oral
280 BUD/Form maintenance and corticosteroid use. Thus, for some patients who need
200 reliever maintenance treatment with a combination inhaler
(160 events)*
120 containing budesonide and formoterol, the inhaler can
also be used as rescue when needed, thereby allowing the
40
0 patient to manage their asthma with one inhaler. The
0 3 6 9 12 15 19 23 27 31 35 39 43 47 51 55 reason for this benefit is not yet clear, but it could happen
Weeks since randomisation because of early administration of the inhaled
corticosteroid, given as part of the rescue treatment, at the
Figure 3: Number of severe asthma exacerbations needing medical intervention (oral or systemic time of worsening asthma control.
corticosteroid treatment) over 1 year in the STAY study
BUD=budesonide. Form=formoterol. SABA=short-acting inhaled β2 agonist Every exacerbation is represented by a The cost-effectiveness of using combinations of inhaled
line. The first exacerbation is the upper line and any subsequent event a patient had is recorded below. *Rate corticosteroids and long-acting β2 agonists to treat
reduction 46% to 53% versus both groups; p<0·001. moderate persistent asthma has been investigated.49–51

798 www.thelancet.com Vol 368 August 26, 2006


A B
Figure 4: Induced sputum specimens from patients with eosinophilic airway inflammation (A) or neutrophilic airway inflammation (B)
Magnification is ×40 (A) and ×25 (B).
Findings have shown improved effectiveness at partial or
complete offset of costs or at modest additional cost.
Although addition of a long-acting β2 agonist to inhaled
corticosteroids improves clinically relevant outcomes in
most patients with moderate asthma more so than
further increases in dose of inhaled corticosteroid,52 the
size of benefit is reduced in people with severe asthma.
This finding is highlighted in a meta-analysis,53 in which
researchers described that the combination of long-acting
β2 agonists and inhaled corticosteroids resulted in
greater improvement in lung function and symptoms
when compared with a 2–2·5-fold higher dose of inhaled
corticosteroids. However, in 15 trials in which outcomes
of exacerbation were reported, no group difference was
recorded (2% [95% CI 0–4]) in absolute risk of patients
having moderate exacerbations. Authors of this meta-
analysis did not look at the differences between formoterol
and salmeterol as add-on treatments. Nevertheless, this
analysis points out that, despite our current best
strategies, many patients do not have well controlled
asthma. Therefore, other approaches to improve asthma
control in these individuals need to be investigated.
Use of biomarkers to guide treatment of
moderate asthma
Markers of inflammation could help to guide use of anti-
inflammatory treatment. Currently, two tests are available
clinically: total and differential cell counts in sputum54
and fraction of nitric oxide in exhaled breath55 are both
reliable and reproducible. Normal values for sputum cell
counts have been established,56 and this method provides
the most direct and fairly non-invasive assessment of
airway inflammation. Sputum cell counts help to identify
whether exacerbations of asthma are associated with
eosinophilic, neutrophilic, or a combined pattern of
www.thelancet.com Vol 368 August 26, 2006
Review
bronchitis (figure 4). Occasionally, no cellular
inflammation will be present.57 Eosinophilic bronchitis is
steroid responsive,58 whereas non-eosinophilic bronchitis
is usually not.59 In the same patient, the nature of
inflammation can change with time depending on the
cause of the exacerbation. For example, an exacerbation
due to allergen exposure or reduction of dose of inhaled
corticosteroid is usually eosinophilic and responds to an
increase in dose of the inhaled drug; addition of a long-
acting β2 agonist is not necessary. Long-acting β2
agonists become effective for management of symptoms
if the individual continues to be hyper-responsive despite
adequate control of eosinophilic inflammation.
Eosinophilic bronchitis in an asymptomatic patient is
predictive of an exacerbation60 and therefore needs to be
suppressed by boosting the dose of inhaled corticosteroid.
While trying to work out the minimum dose of inhaled
corticosteroid for an individual, maintaining the dose in
a patient whose asthma is well controlled would be
prudent if the eosinophil count is greater than 2%.61 An
exacerbation due to a viral or bacterial infection is usually
neutrophilic. A viral infection resolves spontaneously
with supportive additional treatment with a short-acting
or long-acting bronchodilator; increasing doses of inhaled
corticosteroids are not necessary and are usually not
effective. A bacterial infection requires an antibiotic.
Researchers on two randomised clinical trials tested the
principles of individualised treatment by comparing this
strategy of asthma management with approaches based
on national guidelines. In one trial, 74 patients with
asthma were randomly assigned either a management
strategy aimed at maintaining their sputum eosinophil
count below 3% or standard clinical care based on the
British Thoracic Society’s guidelines.62 Individuals in the
sputum management group had significantly fewer
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severe asthma exacerbations than those in the standard

care group, and significantly fewer participants were 100
Sputum strategy

Proportion free of exacerbation (%)

admitted to hospital with asthma. The reduction in Conventional strategy
80
exacerbations was achieved without an increase in total
corticosteroid dose in the sputum group. In a larger 60 p=0·04
multicentre Canadian study, 107 patients were randomly
assigned either clinical guideline-based treatment or a 40
strategy to maintain sputum eosinophils below 2% after
establishing the minimum treatment to maintain 20

control.63 Primary outcomes were relative risk reduction

0
for occurrence of the first exacerbation and length of time 0 100 200 300 400 500 600 700 800
without exacerbation. Compared with participants in the Days from maintenance
guideline-based group, patients allocated sputum Number at risk
management had longer time to first exacerbation (by
Sputum strategy 48 41 38 33 27 20 13 5 0
213 days), lower relative risk reduction (by 49%; figure 5),
Conventional 52 42 33 26 19 16 12 9 0
and fewer exacerbations needing prednisone (5 vs 15). strategy
This benefit was seen mainly in patients needing
treatment with inhaled steroid in a daily dose equivalent Figure 5: Kaplan-Meier survival curve of patients free of asthma
to fluticasone 250 μg. The cumulative dose of inhaled exacerbations over 2 years in the Canadian study63

corticosteroid during the trial was similar in both groups.
Reduction of non-eosinophilic exacerbations and
lengthening of time free of exacerbation by treatment
with a long-acting β2 agonist were outcomes seen only in
the sputum strategy arm. Since these events were not
recorded in patients receiving a long-acting β2 agonist in
the clinical strategy, possibly, when eosinophilic
inflammation is under control, this drug might prevent
deterioration of asthma caused by a viral or bacterial
infection. However, this analysis was secondary and needs
prospective assessment. Use of strategies such as sputum
cell counts seems prudent to limit administration of
additional drugs to patients whose variability in airflow
obstruction and airway hyper-responsiveness are
uncontrolled despite adequate control of their eosinophilic
bronchitis. Also, whether dose-titration of corticosteroids
to completely abolish luminal (or tissue) eosinophils
would further improve asthma outcomes remains to be
seen. Although the contribution of airway eosinophils to
asthma exacerbations is arguable, their measurement has
consistently been proven to be beneficial in guiding
asthma treatment. The sputum strategy was not superior
to clinical guideline-based therapy in patients with mild
asthma and therefore is probably not necessary.
A raised fraction of nitric oxide in exhaled breath is
associated with loss of asthma control during reductions
in dose of inhaled corticosteroids64 and correlates
moderately with eosinophilic bronchitis.65 Titration of the
dose of inhaled corticosteroids based on measurements
of the fraction of exhaled nitric oxide in children is
associated with improvements in airway hyper-
responsiveness.66 However, this measure is less able to
discriminate eosinophilic from non-eosinophilic airway
inflammation in patients receiving inhaled
corticosteroids.67 The fraction of nitric oxide in exhaled
breath typically falls before airway eosinophilia is
controlled.68 Also, exhaled nitric oxide concentrations
indicate activity of the nitric oxide synthase enzyme in
several cells in the airway, notably airway epithelium, and
are non-specific. The fraction of exhaled nitric oxide can
also rise with non-eosinophilic bronchitis. In a randomised
controlled trial, investigators looked at whether amounts
of exhaled nitric oxide could be used to guide asthma
treatment.69 97 patients with mild to moderate asthma
were randomly allocated to one of two strategies, whereby
dose of inhaled corticosteroid was adjusted every 4 weeks
to either keep the fraction of nitric oxide in exhaled breath
at less than 15 ppb or to prevent loss of asthma control as
defined by Global Initiative for Asthma guidelines. Rates
of exacerbation did not differ between the two groups.
However, the nitric oxide strategy enabled a significant
reduction in the maintenance dose of inhaled
corticosteroid. Whether a raised fraction of exhaled nitric
oxide in asymptomatic patients needs any treatment
action is not clear. Thus, although the measurement is
easy to use, especially in children, its precise role in
improving treatment of moderate asthma needs further
assessment, particularly when it is associated with non-
eosinophilic bronchitis.
Other treatments
In several studies, researchers have investigated clinical
benefit when leukotriene receptor antagonists are added
to inhaled corticosteroids in adults and children with
moderate persistent asthma. However, authors of a meta-
analysis of benefits achieved have concluded that addition
of these drugs to inhaled corticosteroids might modestly
improve asthma control compared with inhaled
corticosteroids alone, but this strategy cannot be
recommended as a substitute for increasing the dose of
inhaled corticosteroids.70 Furthermore, leukotriene
receptor antagonists have been shown to be less effective
than long-acting β2 agonists when combined with inhaled
corticosteroids.71
Data for the effectiveness of immunotherapy in patients
with moderate asthma are scarce. Hence, no firm

800 www.thelancet.com Vol 368 August 26, 2006


conclusions can be drawn or recommendations made on
such an approach for patients who need a moderate dose
of inhaled corticosteroids to maintain symptom control.
Low-dose theophylline has also been assessed as add-on
therapy to inhaled corticosteroids.72 The size of benefit
achieved is less than for long-acting β2 agonists. Another
potential treatment option for patients with moderate
asthma is omalizumab, which is a recombinant humanised
monoclonal antibody against IgE. This anti-IgE forms
complexes with free IgE, thus blocking the interaction
between the immunoglobulin and effecter cells, decreases
concentrations of free IgE in serum, and thus lessens early
and late asthmatic responses after allergen inhalation.73
When compared with placebo in patients on moderate-to-
high doses of inhaled corticosteroids, omalizumab reduced
asthma exacerbations and enabled a small decline in dose
of inhaled corticosteroid.74 However, this drug is expensive
and it has not been compared with proven additive
treatments such as long-acting β2 agonists, which are
cheaper. Therefore, this strategy is not currently
recommended in international guidelines for patients
with moderate asthma.
Future research directions
Despite abundant evidence that currently available
treatments are very effective and can provide good asthma
control for most patients with mild or moderate persistent
asthma, several important issues still need to be clarified
about pharmacological management. In a few studies,
researchers have shown that individuals with asthma lose
lung function at a greater rate than non-smoking healthy
people,1,75 and this finding has been corroborated in
children and adults with newly diagnosed, mild asthma.76
Early intervention with inhaled corticosteroids reduces,
but does not prevent, this accelerated decline in lung
function.16 The effect of other anti-asthma drugs (eg, anti-
leukotrienes) has not been assessed for this issue.
Moreover, we do not yet know how early to begin anti-
inflammatory treatment in asthma patients. Whereas
inhaled corticosteroids do not seem to prevent development
of asthma in at-risk infants,28 the potential for anti-
leukotrienes, which can reduce allergen-induced airway
eosinophilia,34 bone-marrow eosinophil production,34 and
dendritic-cell trafficking,78 to do so is unknown. Also, as far
as we know, no studies have assessed the benefits of anti-
inflammatory treatment in mild intermittent asthma.
Lastly, the goal of individualising treatment on the basis of
pharmacogenetics—that is, identification of the best
treatment option based on knowledge of a patient’s
genotype or of the inflammatory state of their airway—is
an important area for current and future research. Already,
findings have suggested that patients with an Arg-Arg
polymorphism at position 16 of the β2 receptor could be at
greater risk of adverse effects from regular use of β2
agonists,79 and changing treatment based on control of
airway eosinophils can reduce asthma exacerbations;62,63
however, the relative effectiveness of this approach
www.thelancet.com Vol 368 August 26, 2006
Review
compared with best pharmacological treatment for
reduction of asthma exacerbations (currently a combination
of inhaled corticosteroid and long-acting β2 agonist) has
not been assessed.
Conclusions
Most patients with asthma have mild intermittent and
persistent disease. Those with mild persistent asthma
are usually not well controlled. Low doses of inhaled
corticosteroids can generally provide ideal disease control
and reduce risk for severe asthma exacerbations in both
children and adults. Intermittent inhaled corticosteroid
treatment at the time of an exacerbation has also been
suggested as a strategy for mild persistent asthma, but it
is less effective than low-dose regular treatment for most
outcomes. Leukotriene receptor antagonists are another
treatment option for this population, but they are also
less effective than low-dose inhaled corticosteroids.
Patients with moderate persistent asthma can be
regarded as those who are not ideally controlled on low-
dose inhaled corticosteroids. In adults, the combination
of a corticosteroid and long-acting β2 agonist (usually in
one inhaler) is better than doubling the dose of inhaled
corticosteroid to achieve better asthma control and reduce
exacerbation risks. In children, much less evidence is
available that a combination is more effective than an
increased dose of inhaled corticosteroid. One of the
combinations available to treat asthma (budesonide and
formoterol) has also been assessed as both maintenance
and rescue therapy. This approach further reduces risks
for severe exacerbations. If asthma control is not
achieved despite the patient taking effective treatment,
measurement of the inflammatory response in the airway
in sputum or exhaled breath might be helpful to guide
management. Allergen immunotherapy and cytokine-
targeted treatment and monoclonal antibodies are not
routinely indicated, but might be effective in selected
patients. Pharmacotherapy should always be accompanied
by patient’s education about the disease and use of
inhalers and allergen avoidance (when indicated) and a
written management plan.
Conflict of interest statement
POB is a consultant for, has received speaker’s fees from, or holds grants-
in-aid from Altana, AstraZeneca, Biolipox, Boehringer, GlaxoSmithKline,
IVAX, and Topigen in the past 2 years. He does not own any shares,
stocks, or options in any company. KP holds grants-in-aid from
GlaxoSmithKline and Sepracor for investigator-initiated studies and has
received honoraria from Merck, Altana, and AstraZeneca in the past
2 years for lectures. He does not own any shares, stocks or options in any
company. He did not receive any fees for contributing to this article.
Acknowledgments
KP is supported by a Canada research chair in airway regulation and
inflammation.
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