Asthma Update: Part II.

Medical Management
MATTHEW MINTZ, M.D., The George Washington University School of Medicine and Health Sciences, Washington, D.C.

The National Asthma Education and Prevention Program recently

updated its guidelines for the management of asthma. An evidence-
based approach was used to examine several key issues regarding
appropriate medical therapy for patients with asthma. The updated
guidelines have clarified these issues and should alter the way physi-
cians prescribe asthma medications. Chronic inhaled corticosteroid
use is safe in adults and children, and inhaled corticosteroids are rec-
ommended as first-line therapy in adults and children with persistent
asthma, even if the disease is mild. Other medications, such as cromolyn,
theophylline, and leukotriene modifiers, now are considered alternative
treatments and should have a more limited role in the management of
persistent asthma. The addition of a long-acting beta2 agonist to an
inhaled corticosteroid is superior to all other combinations as well as to
higher dosages of inhaled corticosteroids alone. Combination therapy
with an inhaled corticosteroid and a long-acting beta2 agonist is the
preferred treatment for adults and children with moderate to severe
asthma. Antibiotic therapy offers no additional benefit in patients with
asthma exacerbations. (Am Fam Physicians 2004;70:1061-6. Copy-
right© 2004 American Academy of Family Physicians.)

T
This is part II of a two- he 1997 guidelines from the and in children was controversial. In the
part article on asthma National Asthma Education and recent guidelines update,2 the NAEPP Expert
treatment recommenda-
tions. Part I, “Diagnosis, Prevention Program (NAEPP)1 Panel examined data comparing chronic use
Monitoring, and noted that inhaled corticosteroid of inhaled corticosteroids and other agents
Prevention of Disease therapy offered multiple benefits in patients in adults and children with mild or moderate
Progression,” appeared
with persistent asthma, but some uncertainty persistent asthma. An overwhelming amount
in the September 1, 2004,
issue of AFP. remained about its use in certain patients. of the data showed that inhaled corticoste-
The NAEPP’s recent update2 of the 1997 roids improve asthma control in children
See page 1011 for
definitions of strength-of- guidelines clarifies such treatment issues and with mild or moderate persistent asthma,
recommendation labels. should significantly change the way asthma as measured by improvements in symptoms
An article about how
is treated. Part I3 of this two-part article and forced expiratory volume in one second
to design systems to reviewed diagnosis, monitoring, and pre- (FEV1) and reductions in airway hyperre-
improve asthma care in vention of disease progression in patients sponsiveness, emergency department visits,
your practice will appear with asthma. Part II reviews updated rec- hospitalizations, and use of oral corticoste-
next month in the October
2004 issue of AFP’s sis- ommendations for the treatment of asthma roids. No other medications (i.e., cromolyn
ter publication, Family and discusses areas of controversy, including [Intal], nedocromil [Tilade], theophylline,
Practice Management. combination therapy and the use of antibiot- leukotriene modifiers) are as effective as
ics for asthma exacerbations. inhaled corticosteroids in the long-term con-
trol of asthma.
Inhaled Corticosteroids
The previous NAEPP guidelines1 stated TREATMENT RECOMMENDATIONS

that inhaled corticosteroids were superior Children. The new asthma treatment recom-
to other agents in the treatment of asthma. mendations2 represent a major change from
However, use of inhaled corticosteroids as the previous guidelines, which had recom-
initial therapy in patients with mild disease mended cromolyn as initial maintenance

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 Regular use of inhaled
therapy in children.1 Inhaled Unfortunately, there have been few stud-
corticosteroids can reduce
corticosteroids now are recom- ies in children younger than five years,
mended in children older than and the diagnosis of asthma in infants and
hospital admissions and
five years with mild persistent children is complicated by the difficulty
dramatically decrease
asthma (Table 1).2 According to of obtaining objective measures of lung
deaths from asthma.
data from Merck & Co., Inc., the function.4 Many children wheeze during
use of leukotriene modifiers also the first years of life and do not progress to
is common, particularly in children (July asthma,5 and there are no reliable predictors
2003). However, the updated guidelines2 for determining which children will develop
state that leukotriene modifiers should not asthma. However, physicians who are reluc-
be used as first-line therapy; rather, they are tant to diagnose infants or young children
considered second-line or alternative treat- with asthma may be denying these patients
ment, as are cromolyn, nedocromil, and theo- life-saving and perhaps disease-modifying
phylline. In children five years and younger, medications. To address this problem, the
the guidelines also recommend inhaled corti- updated guidelines2 recommend that physi-
costeroids (via dry powder inhaler, nebulizer, cians strongly consider starting long-term
or metered-dose inhaler with a face mask) therapy for the control of asthma in infants
as first-line therapy, although cromolyn and and young children with four or more epi-
leukotriene modifiers remain alternatives.2 sodes of wheezing in the past year if the

TABLE 1
Preferred Medical Treatment Using a Stepwise Approach
for Managing Asthma in Adults and Children

Clinical features before treatment or adequate control

Asthma
classification Symptom frequency Lung function* Medications required to maintain long-term control

Mild Daytime: 2 days per week PEF or FEV1: 80 percent or No daily medication needed
intermittent or less more of predicted function
Nighttime: 2 nights per
month or less
Mild Daytime: more than 2 days PEF or FEV1: 80 percent or Low-dose inhaled corticosteroid (delivered by
persistent per week, but less than more of predicted function nebulizer or metered-dose inhaler with holding
one time per day chamber, with or without a face mask, or by dry
Nighttime: more than powder inhaler in children 5 years and younger)
2 nights per month
Moderate Daytime: daily PEF or FEV1: 60 to 80 percent Children 5 years and younger: low-dosage inhaled
persistent Nighttime: more than of predicted function corticosteroid and long-acting beta2 agonist or
1 night per week medium-dosage inhaled corticosteroid
Adults and children older than 5 years: low- to
medium-dosage inhaled corticosteroid and long-
acting inhaled beta2 agonist
Severe Daytime: continual PEF or FEV1: 60 percent or less High-dosage inhaled corticosteroid and long-
persistent Nighttime: frequent of predicted function acting beta2 agonist

PEF = peak expiratory flow; FEV1 = forced expiratory volume in one second.
*—Lung function measurements are used only in patients older than 5 years.
Adapted from National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma:
update on selected topics—2002. Bethesda, Md.: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health,
National Heart, Lung, and Blood Institute, 2003; NIH publication no. 02-5074:115.

1062 American Family Physician www.aafp.org/afp Volume 70, Number 6 � September 15, 2004
 Asthma

agents for treating asthma, concerns about

TABLE 2 adverse effects remained. Studies of older
Goals of Asthma Therapy inhaled corticosteroids such as beclometha-
Maintain normal activity levels sone10 showed a small reduction in children’s
Maintain normal pulmonary function growth after 12 months of use, but other
Prevent chronic symptoms studies of newer, more potent agents showed
Prevent recurrent exacerbations no such risk.11,12
Provide optimal pharmacotherapy with In the past, physicians may have erred on
minimal or no adverse events the side of caution by using the less potent
Information from reference 1.
agents in patients with mild dis-
ease. However, based on a review Inhaled corticosteroids
of clinical trials that followed are recommended as first-
children for up to six years, the line therapy in all patients
wheezing lasted more than one day and NAEPP panel2 found strong evi- with persistent asthma.
affected sleep and if the patient has risk dence that the use of inhaled
factors for the development of asthma (i.e., corticosteroids in recommended
parental history of asthma, atopic dermati- dosages does not have long-term, clinically
tis, allergic rhinitis, or wheezing).2 Table 2 significant, or irreversible adverse effects.
lists the goals of asthma therapy.1 The most significant evidence cited by
Adults. The treatment recommendations the NAEPP panel came from the Childhood
for adults also have changed. The previous Asthma Management Program (CAMP)
guidelines1 noted that the use of inhaled study,13 which followed more than 1,000
corticosteroids was preferred in patients with children taking the inhaled corticosteroid
moderate or severe asthma but stopped short budesonide, the mast-cell stabilizer nedo-
of recommending these agents as first-line cromil, or placebo for an average of six years.
therapy in patients with mild asthma. In Although the CAMP study and other studies
addition to the previously known benefits reviewed by the panel showed that low to
of inhaled corticosteroid therapy in patients medium dosages of inhaled corticosteroids
with asthma, recent data6,7 show that regular decreased growth velocity in children (caus-
use of inhaled corticosteroids can reduce hos- ing a small difference in the rate of growth
pital admissions and dramatically decrease [approximately 1 cm per year] in the first
deaths from asthma. One study8 found that year of use), this effect was not sustained,
compliance with low-dosage inhaled cortico- and there was no difference in target adult
steroid therapy virtually eliminated the risk height by the end of the study. A similar
of death from asthma. study,14 which included fewer children but
The NAEPP panel2 reviewed 12 studies of followed them for more than 10 years, found
the leukotriene modifiers montelukast and similar results. Not surprisingly, children
zafirlukast and found that outcome mea- with mild asthma who were taking inhaled
sures “clearly and significantly” favored ther- corticosteroids had superior outcomes in
apy with inhaled corticosteroids.8 A recent both studies.13,14 Thus, the negligible risk of
Cochrane review9 concluded that leukotriene growth reduction is far outweighed by the
modifiers have only marginal benefit and positive effects of inhaled corticosteroid use
should not be recommended as first-line in children.
therapy or add-on therapy. Thus, inhaled The NAEPP panel2 also reviewed 16 stud-
corticosteroids are recommended as first- ies that examined bone mineral density,
line therapy in all patients with persistent subcapsular cataracts, glaucoma, and hypo-
asthma.2 thalamic-pituitary-adrenal axis suppression
in adults and children treated with cortico-
SAFETY steroids; these studies also showed negligible
Although the previous guidelines1 noted that adverse effects from corticosteroid use. A
inhaled corticosteroids are the most effective recent study15 of women 18 to 45 years of age

September 15, 2004 � Volume 70, Number 6 www.aafp.org/afp American Family Physician 1063
 who were taking high dosages of triamcino- bronchodilators. 23 However, long-acting
lone found a potential statistically signifi- beta2 agonists should not be used alone;
cant decrease in bone mineral density in the studies have shown that asthma worsens
hip (but not the spine) in the older women. when these agents are taken without an
However, the decrease was not clinically sig- inhaled corticosteroid.24,25
nificant because the rate of loss was very low, One study26 published since the updated
and this study has been criticized.16 Thus, guidelines were released found that the addi-
the NAEPP panel2 concluded that inhaled tion of a long-acting beta 2 agonist to an
corticosteroids are safe and recommends inhaled corticosteroid allows physicians to
them as first-line therapy for children and lower the corticosteroid dosage and still
adults with persistent asthma. maintain asthma control. Thus, combina-
tion therapy can be steroid-sparing.
Combination Therapy Although the safety of inhaled cortico-
The NAEPP panel2 also considered whether steroid therapy has been established, physi-
the addition of another long-term asthma- cians should prescribe the lowest dosage
control agent to inhaled corticosteroids possible. In addition, there may be a need to
would improve outcomes in increase the corticosteroid dosage and add a
The addition of a long- patients with moderate per- long-acting beta2 agonist in patients at high
acting beta2 agonist to a sistent asthma. The previous risk for exacerbations, such as those with
1
low or medium dosage of guidelines offered several sug- a history of hospitalizations or emergency
an inhaled corticosteroid gestions but did not recom- department visits because of asthma.27,28
improves lung function and mend a specific agent. There is Combination therapy with an inhaled cor-
symptoms and reduces the
now strong evidence that the ticosteroid and a long-acting beta2 agonist
addition of a long-acting beta2 is more cost effective than treatment with
need for use of a short-act-
agonist to a low or medium an inhaled corticosteroid plus a leukotriene
ing beta2 agonist.
dosage of an inhaled cortico- modifier.29
steroid improves lung function The use of long-acting beta2 agonists has
and symptoms and reduces the need for use been questioned recently because of results
of a short-acting beta2 agonist.2 Doubling from the Salmeterol Multi-center Asthma
the dosage of the inhaled corticosteroid or Research Trial (SMART).30 The SMART
adding a leukotriene modifier, theophylline, study was designed to assess the safety of
or cromolyn also improves outcomes, but the addition of salmeterol to current asthma
not as substantially as the combination of therapy in patients who had never taken
an inhaled corticosteroid and a long-acting a long-acting beta2 agonist. This study of
beta2 agonist. 26,353 patients was stopped after 28 weeks
Individual studies17,18 and a meta-analy- because of concerns in a subset of patients.
sis19 comparing combined long-acting beta 2 There were no significant differences be-
agonists and inhaled corticosteroids with the tween salmeterol and placebo in the primary
doubling of the dosage of inhaled corticoste- end point of respiratory-related deaths and
roids have shown that combination therapy life-threatening events requiring interven-
reduces asthma exacerbations. The combi- tions (e.g., intubation, ventilation). How-
nation of a beta2 agonist and an inhaled cor- ever, the number of asthma-related deaths
ticosteroid also has been proved superior to was significantly higher in the patients who
the addition of a leukotriene modifier.20-22 were taking salmeterol (13 patients) than in
The benefits of combination therapy make those who received placebo (four patients).
sense pathophysiologically because of the There was no difference between salmeterol
dual components of asthma: airway inflam- and placebo in the number of deaths among
mation and smooth muscle dysfunction. white patients, but eight black patients tak-
Inhaled corticosteroids are clearly the most ing salmeterol died compared with one black
potent anti-inflammatory agents,1 and long- patient who received placebo.
acting beta2 agonists are the most potent Although the findings of the SMART

1064 American Family Physician www.aafp.org/afp Volume 70, Number 6 � September 15, 2004
 Asthma

study30 are of potential concern, it should

be noted that the number of asthma-related Strength of Recommendation
deaths was significantly lower in the patients
taking inhaled corticosteroids (six of 12,254 Key clinical recommendations Label References
compared with 11 of 14,099 nonusers), Inhaled corticosteroids are more effective than B 2
cromolyn (Intal), nedocromil (Tilade),
regardless of treatment with salmeterol.
theophylline, and leukotriene modifiers for the
Asthma-related deaths also occurred more long-term control of asthma.
frequently in patients taking salmeterol who Inhaled corticosteroids are recommended as first- A 2 ,8, 9
did not use an inhaled corticosteroid. Black line treatment in children with acute asthma.
patients, who have been shown to have more The combination of a beta2 agonist and an inhaled A 2, 20-22
severe asthma and a higher risk for seri- corticosteroid is superior to the addition of a
ous outcomes,31 were less likely than white leukotriene modifier.
patients to use inhaled corticosteroids (38 Adding an antibiotic to usual care is not C 2
percent compared with 49 percent). Thus, recommended in patients with asthma.
the SMART study30 proved that long-acting
beta2 agonists should not be used without
inhaled corticosteroids, that asthma is a not support the use of antibiotics in patients
serious and life-threatening disease, and with asthma, even when clinical suspicion of
that black patients seem to be at increased bacterial infection is high.
risk for serious outcomes.
The NAEPP recommendations for mod- The author indicates that he does not have any con-
flict of interest. Dr. Mintz is a member of the advisory
erate persistent asthma have therefore been board for GlaxoSmithKline and the speaker’s bureaus
revised.2 The preferred treatment for adults for GlaxoSmithKline, Aventis Pharmaceuticals Inc., and
and children older than five years is a com- AstraZeneca Pharmaceuticals LP. Sources of funding:
bination of a long-acting beta2 agonist and none reported.
a low to medium dosage of inhaled cortico-
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1066 American Family Physician www.aafp.org/afp Volume 70, Number 6 � September 15, 2004