You are on page 1of 15

Pediatr Clin N Am 50 (2003) 577 – 591

Identifying the child in need of asthma therapy

Stanley J. Szef ler, MDa,b,*
Department of Pediatrics, Divisions of Pediatric Clinical Pharmacology and Allergy and Immunology,
National Jewish Medical and Research Center, 1400 Jackson St., Room B121,
Denver, CO 80206, USA
Department of Pediatrics and Pharmacology,
University of Colorado Health Sciences Center, Denver, CO 80262, USA

It is encouraging that the trend of increasing asthma mortality and morbidity

has now reached a plateau [1]. The next challenge is to establish a decline in
mortality and other risks resulting from undertreatment of asthma (Box 1).
This reduction might be achieved by developing a proactive approach to
recognize patients at risk for persistent asthma and to intervene early. Methods to
intervene in the natural history of asthma may also limit deleterious outcomes.
Asthma is currently considered a chronic inflammatory disease with intermit-
tent exacerbations. Inhaled glucocorticoids, the most potent anti-inflammatory
asthma medication, are considered the cornerstone for managing persistent
asthma even in young children [2– 4]. Over the last 10 years new medications
and delivery systems have been introduced including a nebulized inhaled
glucocorticoid for children as young as 1 year of age [5]. New initiatives to
improve medication labeling for young children have now made it possible to
intervene at a very early age [6]. These initiatives have improved the overall
management of childhood asthma [7].
New directions in the management of childhood asthma include early
recognition and early intervention with environmental control and administration
of long-term control therapy [8,9]. It is hoped that this movement will result in

This work was supported in part by Public Health Services Research Grants 1NO1-HR-16048,
HL36577, HL 51834, General Clinical Research Center Grant 5 MO1 RR00051 from the Division
of Research Resources, and the NICHHD Pediatric Pharmacology Research Unit Network Grant
The author has served as a consultant for drug development and received research support from
several pharmaceutical firms that provide medications currently used or in development for the
treatment of asthma including Astra Zeneca, Aventis, Genentech, Glaxo Smith Kline, Merck,
Novartis, and 3M.
* National Jewish Medical and Research Center 1400 Jackson St., Rm. B121 Denver, Colo-
rado 80206.
E-mail address:

0031-3955/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved.
578 S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591

Box 1. Risks related to the undertreatment of asthma

Respiratory arrest
Acute exacerbation
Emergency department visit
Course of systemic glucocorticoid therapy
Nocturnal symptoms
Breakthrough symptoms – spontaneous or activity-induced
Variability in pulmonary function caused by airway sensitivity
School absence
Reduced quality of life
Reduced activity level
Poor self-image
Progression as indicated by
Loss of pulmonary function
Increasing symptoms
Increasing medication requirements
Persistent inflammation
Airway remodeling and irrecoverable loss of pulmonary function
Adverse effects related to overuse of rescue therapy
(eg, bronchodilators and systemic glucocorticoids)

improved methods to diagnose asthma and the identification of methods to alter

the natural history of asthma. Although inhaled glucocorticoid therapy improves
asthma control, it is not clear whether the use of glucocorticoids can prevent
progression of asthma and thus alter the natural history of asthma [10,11].
This article summarizes the population of patients that merit consideration for
asthma therapy and then reviews the current approaches to asthma management.
New directions in understanding the response to treatment are also presented,
because this information could lead to new approaches to individualize therapy
and thus optimize response and minimize the risk for adverse effects.

Who needs intervention?

Asthma guidelines currently recommend intervention at several points [2].
First, intervention with bronchodilators for symptoms and with systemic gluco-
corticoids for significant exacerbations pertains to asthma management for all age
groups. Second, intervention with long-term control therapy is recommended in
children when symptoms occur more than two times per week, when nocturnal
symptoms occur more than two times per month, and when pulmonary function
with either forced expiratory volume in 1 second (FEV1) or peak expiratory flow
S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591 579

is less than 80% predicted or if peak flow variability within 1 day exceeds 20%.
In addition, when significant acute exacerbations recur within 6 weeks in young
children, intervention with long-term controller therapy should be considered.
Another consideration for intervention with long-term therapy is the young child
who is at risk for persistent asthma and has demonstrated frequent exacerbations,
for example, more than three within a 1-year period. This area was recently
addressed in the revisions to the National Asthma Education and Prevention
Program (NAEPP) asthma guidelines [4] and is discussed in more detail.

Changing features of asthma therapy

Less than 50 years ago, the treatment of asthma was focused on relieving
episodes of bronchospasm with short-acting bronchodilators, such as epineph-
rine, isoproterenol, and metaproterenol. Further structural modifications of
epinephrine led to the introduction of the currently preferred b2-adrenergic
agonists albuterol, terbutaline, and pirbuterol. Theophylline, a long-acting bron-
chodilator, was the preferred maintenance therapy for asthma in 1970s and 1980s.
Alteration of oral release characteristics provided products that could be admin-
istered two or even one time per day and offered benefits in preventing nocturnal
asthma episodes. In the 1980s, it was recognized that inhaled cromolyn could
block the early and late pulmonary response to an allergen challenge in a
sensitized patient and thus serve as a preventative therapy. It was also observed
that cromolyn could block the resultant airway hyperresponsiveness that followed
an allergen challenge in a sensitized patient. This key observation ushered in the
era of preventive therapy for asthma.
The benefits of inhaled glucocorticoid therapy dosing were recognized in the
late 1970s, and this recognition was followed by a series of studies that
demonstrated unquestionable efficacy in the long-term management of asthma
for both adults and children [9]. Recently, several new classes of medications
have been introduced including the long-acting b2-adrenergic agonists and the
leukotriene modifiers. The long-acting b2-adrenergic agonists salmeterol and
formoterol have a 12-hour duration of action and are currently approved for use
in children 4 years of age and older. One of the oral leukotriene antagonists,
montelukast, has emerged as a popular first-line long-term control therapy in
children with asthma because of the availability of dosage guidelines and
the demonstration of safety in children as young as 6 months of age. To limit
the adverse effects of short-acting b-agonists, the stereoisomer of albuterol,
levalbuterol, was developed and introduced. Also, renewed interest has
developed for the combination of medications in one formulation, such as an
inhaled steroid and a long-acting b-adrenergic agonist, based on evidence of
additive effects, convenience for the patient, and the potential to reduce further
the risk for significant exacerbation [12]. Combination therapy is currently only
approved for use in children 12 years of age and older, however. Physicians now
have the opportunity to individualize the patient’s treatment plan with this
580 S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591

selection of medications to take into account such features as taste, inhalation

technique, and ability to swallow an oral formulation that are unique to children.

Current approach to managing asthma in children

Current guidelines for asthma management emphasize diagnosis and identifica-
tion of asthma triggers, attention to environmental control, objective monitoring
with peak flow and spirometry, asthma education, and pharmacotherapy [2– 4].
Asthma is classified as intermittent, mild persistent, moderate persistent, and severe
persistent based on the frequency of daytime and nighttime symptoms and
pulmonary function variability and level. The Global Initiative for Asthma and
the National Heart, Lung, and Blood Institute (NHLBI) guidelines for the diagnosis
and management of asthma have recently been updated [3,4].
In particular, the revised NAEPP guidelines address the needs of childhood
asthma through a careful evidence-based review of critical issues such as the time
of intervention, the safety and limitations of inhaled glucocorticoids, and the
preferred medication for additive therapy to inhaled glucocorticoids [4]. Informa-
tion related to asthma management for children less than 5 years of age is weak
because of the small number of studies in this age group. Therefore, many
assumptions for the design of treatment regimens in young children are based
primarily on adult studies. It is hoped that investigators and the pharmaceutical
industry will fill the gaps in information and also develop new medications for
younger children.
Inhaled glucocorticoids are the preferred first-line treatment in both children
and adults [3,4]. The preferred additive therapy for inadequate control with low-
to medium-dose inhaled glucocorticoid is a long-acting b-adrenergic agonist [4].
Leukotriene antagonists, as well as cromolyn, nedocromil, and theophylline, are
considered alternative first-line therapy to inhaled glucocorticoids and alternative
additive therapy to long-acting b2-adrenergic agonists once treatment with
inhaled glucocorticoids has been initiated [4].
Several recent studies solidify the role of inhaled glucocorticoids as first-line
therapy in the management of persistent asthma and also identify some limi-
tations in the efficacy of inhaled glucocorticoids, such as failure to eradicate acute
exacerbations and to prevent loss in pulmonary function [7,11]. Treatment
strategies must address the limitations of inhaled glucocorticoids in preventing
asthma progression and reversing pulmonary function in long-standing, poorly
controlled asthma.
The outcome study report from the NHLBI Childhood Asthma Management
Program (CAMP) Research Group establishes the efficacy of inhaled glucocorti-
coids as first-line long-term control therapy in children 5 to 12 years of age with
mild to moderate persistent asthma [11]. The CAMP clinical trial was initiated in
1991 to determine whether continuous long-term treatment with either an inhaled
glucocorticoid (budesonide) or an inhaled nonsteroid (nedocromil) control
medication could improve lung growth safely over a 4- to 6-year treatment
S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591 581

period as compared with treatment with albuterol and oral prednisone as needed
based on the frequency and severity of symptoms.
Postbronchodilator percent predicted FEV1 was identified as the primary
measure of lung growth because it reflects maximal lung capacity. The CAMP
trial showed that the inhaled glucocorticoid treatment increased postbronchodila-
tor percent predicted FEV1 from a mean of 103.2% predicted to 106.8% predicted
within 2 months; however postbronchodilator percent predicted FEV1 gradually
diminished to 103.8% predicted by the end of the treatment period (Fig. 1A) and
did not differ significantly from that in the placebo group. Postbronchodilator

Fig. 1. Results of the Childhood Asthma Management Program (CAMP). (A) The change in
postbronchodilator FEV1 during the duration of the study. There was an initial improvement in
postbronchodilator FEV1 in patients receiving budesonide, but by the end of the study, there were no
differences between the three treatment groups. (B) The change in prebronchodilator therapy.
Budesonide resulted in a modest, yet statistically significant improvement in prebronchodilator FEV1
throughout the treatment period compared with placebo. (C) The change in methacholine responsiveness
over time. Note that all subjects had improvement in bronchial hyperresponsiveness (BHR) as indicated
by the increase in the provocative methacholine concentration needed to produce a decreae in FEV1 over
the 4 to 6 years of the trial. Patients randomly assigned to treatment with budesonide had a significantly
greater reduction in BHR than the placebo-treated patients. (D) A Kaplan-Meier curve describing the
cumulative probability of a first course of prednisone during 4 years of follow up in the budesonide-,
nedocromil-, and placebo-treated children. (Adapted from The Childhood Asthma Management
Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma.
N Engl J Med 2000;343:1054 – 63; with permission.)
582 S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591

percent predicted FEV1 in the nedocromil group was similar to that measured in
the placebo group throughout the study period.
The finding that neither budesonide nor nedocromil provided significant
benefit over placebo for the postbronchodilator percent predicted FEV1 was
unexpected based on a previous study of early intervention with inhaled
glucocorticoids in childhood asthma [13]. This study, however, did not examine
postbronchodilator FEV1 as an outcome measure, and it was not conducted in a
randomized, controlled design. Because a decline in percent predicted FEV1 did
not occur in the placebo group, the CAMP study results raise questions whether
airway remodeling is occurring in this population of mild to moderate persistent
asthma and whether inhaled glucocorticoids have any effect on preventing this
change in airway pathology. A decline in postbronchodilator percent predicted
FEV1 in the budesonide treatment arm and a requirement for supplementary
therapy suggests asthma may be progressing despite continuous therapy. Ongoing
analysis in these patients will determine whether this progression could be caused
by poor adherence to the treatment regimen.
Because a decline in postbronchodilator percent predicted FEV1 was not
observed in the CAMP study, questions have been raised about whether airway
remodeling is occurring in this patient population. It is possible that percent
predicted FEV1 may not be sufficiently sensitive to detect the process of airway
remodeling. It is also possible that the study did not include patients who are the
most susceptible to airway remodeling because it was limited to participants with
mild to moderate asthma. Participants most susceptible to a progressive loss in
percent predicted FEV1 might have been excluded for this study. It is also possible
that the most significant effect on FEV1 decline occurred before the participants
entered the study [14,15]. The mean duration of asthma in the CAMP participants
was 5 years, and the most significant effect on airway structure might occur shortly
after the onset of the disease. If so, early diagnosis and prompt intervention are
necessary to prevent airway remodeling and long-term consequences of this airway
reaction, such as impairment in lung growth or airway hyperresponsiveness.
Other measures of postbronchodilator pulmonary function were not signifi-
cantly different on completion of the treatment phase of the CAMP study. In the
treatment group several measurements of pulmonary function obtained before
bronchodilator administration differed from placebo. The difference in prebron-
chodilator percent predicted FEV1 following inhaled budesonide treatment as
compared with baseline exceeded that in the placebo group (2.9 versus 0.9,
P = 0.02) (Fig. 1B). This observation might indicate that functional airway
caliber in the budesonide group was greater than that in the placebo arm.
Although the difference was statistically significant, it was small in magnitude.
For inhaled nedocromil, the only difference in pulmonary function when
compared with the placebo group was prebronchodilator FEV1 (liters). All
pulmonary function values were similar for all treatment groups 4 months after
discontinuing active study medication. This observation suggests that any
beneficial effect observed on a pulmonary function parameter because of active
treatment was lost a short time after discontinuing treatment. This key obser-
S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591 583

vation suggests that inhaled glucocorticoids do not have a long-term effect on

altering the natural history of asthma if administered later in the course of the
disease. Once again, this observation prompts a study of earlier intervention.
The most remarkable effect of inhaled glucocorticoid treatment was the
significant reduction in airway hyperresponsiveness (Fig. 1C). On the other
hand, there was no effect of inhaled nedocromil on this treatment measure when
compared with placebo. Although inhaled budesonide reduced airway hyper-
responsiveness during treatment, the methacholine concentration that produced a
20% decrease in FEV1 (FEV1PC20) was similar in all three groups after study
medication was discontinued. This finding is another indication that long-term
outcomes of asthma may not be altered by even the best form of treatment.
For clinical outcomes, the most significant treatment effect was observed with
the inhaled glucocorticoid treatment arm as compared with placebo. Hospital-
izations, urgent care visits, and prednisone courses were approximately 45%
lower in the inhaled budesonide group as compared with the placebo group. The
inhaled budesonide group also had significantly lower symptom scores, a higher
number of episode-free days per month, and fewer albuterol inhalations per week
than the placebo group. The inhaled nedocromil group had a reduction only in
urgent care visits and prednisone courses when compared with the placebo group;
there was no difference in the other clinical outcome measures.
In addition, the time to the first significant asthma exacerbation that required
systemic glucocorticoid (prednisone) therapy and the time for intervention with
supplementary inhaled glucocorticoid therapy were longer for the inhaled
budesonide group than for the placebo group, with no difference noted for the
nedocromil group when compared with the placebo group (Fig. 1D). The
proportion of patients requiring either intervention was much lower in the inhaled
budesonide group than in the placebo group; the inhaled nedocromil group was
comparable with the placebo group for these measures.
The CAMP results differ significantly from observations obtained from studies
of short duration, for example 1 year or less, particularly in measures of pulmonary
function and body growth. Although the study reduced concern regarding the
long-term effect of inhaled glucocorticoid therapy on linear growth, it raised
questions regarding the effect of inhaled glucocorticoids on the natural history of
asthma. The CAMP study showed that the only detectable adverse effect of long-
term treatment with inhaled budesonide was a transient reduction in growth
velocity that was limited to 1 cm in the first year of treatment that was persistent
but not progressive. Based on the calculated projection of final growth, the final
height in all three treatment groups would be similar once the participants reached
final height. Agertoft and Pedersen [16] confirmed this projection with a report of
long-term follow up in young adults who had received inhaled glucocorticoid
therapy during childhood. Long-term follow up in a prospective study population
such as the CAMP study will be necessary to relieve any lingering concerns
regarding persistent effects of inhaled glucocorticoid therapy on final height. This
study is currently in progress with the CAMP study population, and the results
should be available within a few years. Also, the medications evaluated in the
584 S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591

CAMP study did not completely eliminate the morbidity associated with asthma,
and thus there is still room for improvement in overall asthma management. This
improvement might come through the use of combination therapy with available
medications, through the introduction of new medications such as the immuno-
modulators, or through earlier intervention with available medications such as
inhaled glucocorticoids or even leukotriene antagonist [12,17]. Some of these
avenues are already being pursued in studies that are in progress.

Managing asthma in young children

An area that requires additional research is the appropriate time to initiate
long-term control therapy. Several medications are now labeled for use in young
children. Specifically, nebulized budesonide is authorized for use in children as
young as 1 year of age, and use of montelukast is authorized in children 2 years
old. Currently there is no long-acting b-adrenergic agonist with specific labeling
for use in children less than 4 years of age. Because treatment plans are based on
the assumption that chronic inflammation is a major feature of asthma and that
persistent asthma can occur early in life, there is a movement toward earlier
recognition and earlier intervention. It remains to be seen whether earlier
recognition and earlier treatment can modify the natural history of asthma. This
question should be addressed with the design of appropriate prospective,
randomized, controlled intervention studies evaluating environmental control,
pharmacotherapy, or immune modulation [4].
For the most part, asthma management in young children is based on
experience derived from studies conducted in older children and adults [4,18].
This reliance on experience with other populations arises primarily from the
limitations in the diagnosis and assessment of asthma control in young children,
including the dependence on following symptoms to assess control. It is difficult
but not impossible to measure pulmonary function reliably in young children.
Measures of pulmonary function are currently limited to research settings but
could be more readily available with advancing technology.
Once allergen sensitivity is defined and allergen exposure are confirmed,
environmental control measures can be applied. Additional control measures
include reducing exposure to viral respiratory infections. Both of these steps are
almost impossible to apply, given the multiple (home, day care, and school) settings
in which children are exposed. Furthermore, some have argued that limiting such
exposure may paradoxically increase the risk of developing asthma [19].
Pharmacotherapy in young children can also be a challenge because of
limitations in the route of administration for inhaled medication and dependence
on patient cooperation [18]. Information regarding the appropriate dose of
medications for children less than 5 years of age is available for some, but not
all, medications. These issues have been addressed given the current limitations
in the recent update to the NAEPP guidelines for the diagnosis and management
of asthma [4].
S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591 585

The updated guidelines suggest that first-line therapy could begin with low-
dose inhaled glucocorticoid administered by nebulizer or alternatively by a
spacer/holding chamber and face mask [4]. A nebulized budesonide preparation
has been recently approved for use in children as young as 1 year of age with
dosage guidelines for this age group [5]. Other alternatives include the use of
montelukast that is now available in a formulation that can be administered to
children as young as 2 years of age. Comparative studies are needed to determine
whether an inhaled glucocorticoid administered by pressurized metered-dose
inhaler and spacer/face mask is equivalent to nebulized administration. Currently,
no inhaled glucocorticoid in the dry powder or metered-dose inhaler formulation
available in the United States is approved for use in children less than 4 years of
age. Furthermore, it is rare that a dry powder formulation can be administered to a
young child because it requires the generation of a sufficient inspiratory flow rate.
It will therefore be important to evaluate the new hydrofluoroalkane-based
metered-dose inhalers along with spacer/face mask for use in young children.
A recent study that compared nebulized budesonide with inhaled cromolyn
administered by nebulizer clearly demonstrated superior asthma control with the
nebulized budesonide formulation in measures of symptom control and time for
supplementary medication. Hospitalizations and emergency department visits
were similar in both treatment groups, however [7].
For the treatment of moderate persistent asthma in young children, it is now
recommended that one consider a medium dose of inhaled glucocorticoid or the
addition of a long-acting b-adrenergic agonist [4]. This recommendation is
primarily based on conclusions derived from adult studies in the absence of
controlled studies in this age group. Furthermore, there is currently no long-
acting b-adrenergic agonist formulation approved for use in children less than
4 years of age. Consequently, this lack of approval results in the undesirable
alternative of using an approved medication, such as a metered-dose inhaler along
with a spacer, for an age group in which there are no dosing guidelines.
Obviously, it would also be desirable to test the available chlorofluorocarbon-
based formulation in young children or to develop a nebulized form of a long-
acting b-adrenergic agonist for patients unable to cooperate with the metered dose
inhaler and spacer. Alternatively, an approved form of a leukotriene antagonist
could be added to the inhaled glucocorticoid [4].
High-dose inhaled glucocorticoids are recommended for more severe asthma.
If needed, systemic glucocorticoid can be added with adjustment to the lowest
dose required to stabilize symptoms. This treatment guideline will obviously be
adjusted as available medications are studied and as new medications are
introduced for the management of asthma in young children.
There is also a movement to consider early intervention in young children who
are at risk for persistent asthma. Recent studies from the Tucson Children’s
Respiratory Study, which has followed respiratory patterns in children for the first
15 years of life, now indicate that children who wheeze during lower respiratory
tract illnesses in the first 3 years of life and who still wheeze at age 6 (persistent
wheezers) have slightly but not significantly lower levels of pulmonary function
586 S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591

than children who have not had wheezing illness before age 6 years. In this long-
term study it also seems that the lowest levels of lung function in early childhood
are observed among children who wheeze before age 3 years and are not current
wheezers at age 6 years. These patients are considered transient wheezers as
compared with the persistent wheezers who have comparably normal pulmonary
function in the first 3 years of life but lower pulmonary function thereafter [15,20].
This finding prompts the question whether the decline in pulmonary function in
persistent wheezers can be deterred through early intervention with either
environmental control or therapy that is directed to alter the course of the disease.
This natural history study also proved useful in identifying risk factors for
persistent asthma [21]. Castro-Rodriguez et al [21] introduced the concept of an
Asthma Predictive Index suggesting that frequent wheezing during the first
3 years of life along with either one major risk factor (parental history of asthma
or eczema in the child) or two of three minor risk factors (eosinophilia > 4%,
wheezing without colds, and allergic rhinitis) were associated with the persistence
of asthma.
Based on limited evidence, it is thought that a loss of pulmonary function over
time is associated with airway remodeling [22]. This remodeling is somewhat
similar to the pattern that is observed in chronic obstructive pulmonary disease in
adults and cystic fibrosis in children. It is also projected that the consequent
alteration in lung growth could have an overall effect on long-term outcomes.
Overall, patients differ markedly in their clinical presentation and their suscep-
tibility to this potential alteration in lung growth. Although it has been proposed
that early intervention with inhaled glucocorticoid therapy can be effective in
preventing the progression of the disease and the risk for irreversible changes in
the airways, this hypothesis remains to be proven. There is no doubt, however,
that intervention with inhaled glucocorticoids offers the best opportunity to
improve asthma control based on well-controlled studies in younger and older
children including adolescents [7,11]. The NHLBI Childhood Asthma Research
and Education Network is currently conducting an early intervention study in
young children using the Asthma Predictive Index [21] as an entry criterion. This
study should answer a number of questions regarding the effect of early
intervention with inhaled glucocorticoid therapy on the natural history of asthma.

New developments that could affect the future management of

childhood asthma
The NHLBI Asthma Clinical Research Network described recently the
significant variability in response to inhaled glucocorticoids in adults with
reduced pulmonary function and persistent asthma [23]. The effect of increasing
doses of inhaled glucocorticoids were evaluated in 30 adult subjects with
persistent asthma and percent predicted FEV1 between 55% and 85%.
This study reported several key observations related to the multiple measures
of response. Near maximal FEV1 and methacholine PC20 effects were attained
S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591 587

with low to medium doses of both inhaled fluticasone propionate and inhaled
beclomethasone dipropionate when they were administered with a metered dose
inhaler and a spacer device. The highest dose of each inhaled glucocorticoid did
not significantly increase either efficacy measure but did result in increased
systemic effect as determined by overnight plasma cortisol levels. In addition,
there was significant variability in response among the subjects, and this
variability was observed with both inhaled glucocorticoids. It was noted that
caution should be used in applying these results, because higher doses of inhaled
glucocorticoids may be necessary to manage more severe patients or to prevent
significant asthma exacerbations.
It was also observed that about one third of the subjects had a good pulmonary
response as determined by greater than 15% improvement in FEV1; another third
had a marginal response, between 5% to 15% increase in FEV1; another third
failed to respond, showing a less than 5% increase in FEV1. A similar pattern was
observed with the methacholine PC20 measure of improvement. The FEV1
improvement did not correlate to the PC20 improvement, and therefore patients
can improve with one measure of response while showing no effect with another
measure of response. Thus, the magnitude of a specific set of responses can vary
within the same patient. Certain biomarkers, specifically exhaled nitric oxide and
sputum eosinophils, along with asthma characteristics including duration of
asthma and bronchodilator response, were associated with these two response
parameters [23]. Additional studies will be conducted by the NHLBI Asthma
Clinical Research Network to determine the mechanisms of poor response to
inhaled glucocorticoid therapy.
The NHLBI Childhood Asthma Research and Education Network is also
conducting a study to determine if poor response to inhaled glucocorticoid
therapy can occur in children and whether the biomarkers that predict response
are the same as in adults. A unique feature of this study will be determining
whether the response to an inhaled glucocorticoid is proportional to the response
to a leukotriene antagonist. An assessment of asthma phenotypic characteristics
and a genotypic analysis will be conducted in these children to identify further
predictors of response to these two medications.
There are also continuing advances in the evaluation of asthma medications
and appropriate labeling for all age groups likely to use these medicines. A
review by Payne and Balfour-Lynn [24] provides a summary of the current
understanding of the management of severe persistent asthma in children. They
proposed that tools to measure airway inflammation such as exhaled nitric oxide,
induced sputum, bronchoalveolar lavage, and biopsy could be used to assist in
decisions centered around pursuing more aggressive forms of anti-inflammatory
therapy or bronchodilator therapy. Other measures of airway inflammation, such
as interleukin (IL)-4 and interferon-g, can be measured in exhaled condensates
[25]. Unfortunately, there is very little evidence in children that these indicators
of airway inflammation can be reliably applied to make decisions in asthma
management. Sont et al [26] indicated that a treatment plan based on measures of
airway hyperresponsiveness for inhaled glucocorticoid dosing could lead to
588 S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591

improved asthma control. They also noted a reduction in airway collagen

deposition suggesting a reversal in features of airway remodeling. The studies
from the Asthma Clinical Research Network [23] add a note of caution in
applying this approach, because patients may not achieve a reduction in airway
hyperresponsiveness or improvement in pulmonary function with inhaled gluco-
corticoid doses that exceed the low to medium dose range. It is not clear whether
these patients have persistent inflammation or perhaps have structural airway
changes that are not responsive to any form of available treatment. Perhaps new
medications or new approaches to treatment combinations will benefit these
refractory patients.
In patients classified as having severe steroid-resistant asthma, Chan et al [27]
found that there are at least two different patterns of pulmonary function
following high-dose daily oral glucocorticoid therapy. One group of patients
with low pulmonary function failed to improve despite high-dose systemic
glucocorticoid therapy, whereas another group had a pattern of variable pulmo-
nary function. African Americans had a greater prevalence of steroid-resistant
asthma, as defined by failure to improve FEV1, than whites. It will be important
to understand the underlying mechanisms for these two patterns of steroid
resistance along with the reason for an apparently high prevalence of steroid
resistance in the African American population.
Research that incorporates bronchoscopy, bronchoalveolar lavage, biopsy,
molecular biology, and noninvasive measures of airway inflammation has
stimulated new applications for available medications and ideas for the devel-
opment of new medications. The recognition that mediators, such as IL-4, IL-5,
IL-13, and interferon-g, are associated with airway inflammation has resulted in
the development of new treatments to block or enhance these mediators [28].
DNA vaccine therapy with antisense oligonucleotides is also being tested in an
attempt to block the inflammatory response [29]. The immunomodulator med-
ication that is closest to approval is anti-IgE. Phosphodiesterase 4 inhibitors are
also undergoing early clinical trials.
Pharmacogenetics promises to provide information on the relationships of
genetics to medication response [30 –32]. Advances in this area could help define
relevant asthma phenotypes and genotypes for associations with response to
medications and assist in defining individualized treatment approaches. The
response to medications could be related to genetic polymorphisms altering the
site of action or drug metabolism pathways [32] or asthma-associated disease
features that could affect the response to these medications [33 –42]. This progress
could offer promising opportunities to understand the variability in response to
treatment as well as new methods to individualize treatment programs.

Based on the results of the long-term CAMP clinical trial in childhood asthma
[11], the benefits of continuous long-term use of inhaled glucocorticoids on
S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591 589

asthma control are clear. Studies are in progress to evaluate whether early
intervention with inhaled glucocorticoids can alter the natural history of asthma.
Indicators are now being defined to identify the patient at risk for persistent
asthma and thus to identify candidates for early intervention. Given the right
medication and the patient profile, it may be possible to induce remission or even
a cure. Patients with severe asthma have low pulmonary function that is difficult
to improve, however. It will be important to recognize patients at risk for severe
asthma and to intervene more effectively to prevent asthma progression.
None of these advances will be possible without a comprehensive approach to
asthma care including the ready access to health care. Although it seems that the
rise in asthma mortality and morbidity has reached a plateau [1], there are
significant racial and ethic disparities in asthma health care use and mortality
[43]. The goal should now be to strive for a reduction in asthma morbidity and
mortality. A high proportion of asthma morbidity among inner-city children may
be related to nonadherence; therefore targeting management approaches to
improve adherence could prove effective in reducing morbidity [44]. Recom-
mendations have been made to integrate available resources in the United States
to improve overall asthma outcomes for children [45].

The author thanks Gretchen Czapla for assistance in the manuscript preparation.

[1] Mannino DM, Homa DM, Akinbami LJ, et al. Surveillance for asthma – United States, 1980 –
1999. MMWR Morb Mortal Wkly Rep 2002;51:1 – 13.
[2] National Institutes of Health/National Heart, Lung, and Blood Institute. National asthma educa-
tion and prevention program expert panel report 2: guidelines for the diagnosis and management
of asthma. Bethesda: National Institutes of Health; 1997. Publication #97 – 4051.
[3] National Institutes of Health/National Heart, Lung, and Blood Institute. Global Initiative for
Asthma. Global strategy for asthma management and prevention. Bethesda: National Institutes of
Health; 2002. Publication #02 – 3659.
[4] National Asthma Education and Prevention Program Report. Guidelines for the diagnosis and
management of asthma update on selected topics 2002. J Allergy Clin Immunol 2002;110:
S141 – 219.
[5] Szefler SJ, Eigen H. Budesonide inhalation suspension: a nebulized corticosteroid for persistent
asthma. J Allergy Clin Immunol 2002;109:730 – 42.
[6] Szefler SJ. Meeting the needs of the modernization act: challenges in developing pediatric
therapies. J Allergy Clin Immunol 2000;106(3 Suppl):115 – 7.
[7] Lefein JG, Szefler SJ, Murphy KR, et al. Nebulized budesonide inhalation suspension compared
with cromolyn sodium nebulizer solution for asthma in young children: results of a randomized
outcome trial. Pediatrics 2002;109:866 – 72.
[8] Naspitz C, Szefler SJ, Tinkelman D, et al, editors. Textbook of pediatric asthma. London:
Martin-Dunitz; 2001.
[9] Spahn JD, Szefler SJ. Childhood asthma: new insights into management. J Allergy Clin Immunol
2002;109:3 – 13.
590 S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591

[10] Suissa S, Ernst P. Inhaled corticosteroids: impact on asthma morbidity and mortality. J Allergy
Clin Immunol 2001;107:937 – 44.
[11] The Childhood Asthma Management Program Research Group. Long-term effects of budesonide
or nedocromil in children with asthma. N Engl J Med 2000;343:1054 – 63.
[12] Matz J, Emmett A, Rickard K, et al. Addition of salmeterol to low-dose fluticasone versus
higher-dose fluticasone: an analysis of asthma exacerbations. J Allergy Clin Immunol 2001;
107:783 – 9.
[13] Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth
and pulmonary function in asthmatic children. Respir Med 1994;88:373 – 81.
[14] Martinez FD, Wright AL, Taussig LM, et al. The Group Health Medical Associates. Asthma and
wheezing in the first six years of life. N Engl J Med 1995;332:133 – 8.
[15] Phelan PD, Robertson CF, Olinsky A. The Melbourne asthma study: 1964 – 1999. J Allergy Clin
Immunol 2002;109:189 – 94.
[16] Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in
children with asthma. N Engl J Med 2000;343:1064 – 9.
[17] Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces exacerbations and
steroid requirement in allergic asthmatics. Eur Respir J 2001;18:254 – 61.
[18] Spahn JD, Covar RA, Gleason MC, et al. Pharmacologic management of asthma in infants and
small children. In: Naspitz CK, Szefler SJ, Tinkelman D, et al, editors. Textbook of pediatric
asthma. London: Martin Dunitz; 2001. p. 121 – 47.
[19] Liu AH. Endotoxin exposure in allergy and asthma: reconciling a paradox. J Allergy Clin
Immunol 2002;109:379 – 92.
[20] Martinez FD. Development of wheezing disorders and asthma in preschool children. Pediatrics
2002;109:362 – 7.
[21] Castro-Rodriguez JA, Holberg CJ, Wright AL, et al. A clinical index to define risk of asthma in
young children with recurrent wheezing. Am J Respir Crit Care Med 2000;162:1403 – 6.
[22] Rasmussen F, Taylor DR, Flannery EM, et al. Risk factors for airway remodeling in asthma
manifested by a low postbronchodilator FEV1/vital capacity ratio. Am J Respir Crit Care Med
2002;165:1480 – 8.
[23] Szefler SJ, Richard J, Martin RJ, et al, for the Asthma Clinical Research Network of the National
Heart, Lung, and Blood Institute. Significant variability in response to inhaled corticosteroids for
persistent asthma. J Allergy Clin Immunol 2002;109:410 – 8.
[24] Payne DNR, Balfour-Lynn IM. Children with difficult asthma: a practical approach. J Asthma
2001;38:189 – 203.
[25] Shahid SK, Kharitinov SA, Wilson NM, et al. Increased interleukin-4 and decreased interferon-
gamma in exhaled breath condensate of children with asthma. Am J Respir Crit Care Med 2002;
165:1290 – 3.
[26] Sont JK, Willems LNA, Bel EH, et al and the Asthma Management Project University Leiden
Study Group. Clinical control and histopathologic outcome of asthma when using airway hyper-
responsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999;
159:1043 – 51.
[27] Chan MT, Leung DYM, Szefler SJ, et al. Difficult-to-control asthma: clinical characteristics of
steroid- insensitive asthma. J Allergy Clin Immunol 1998;101(5):594 – 601.
[28] Barnes P. New targets for future asthma therapy. In: Yeadon M, Diamont Z, editors. New and
exploratory therapeutic agents for asthma, lung biology in health and disease, vol. 139. New
York: Marcel Dekker; 2000. p. 361 – 89.
[29] Kline JN. DNA therapy for asthma. Curr Opin Allergy Immunol 2002;2:69 – 73.
[30] Ober C, Moffatt ME. Contributing factors to the pathobiology: the genetics of asthma. Clin Chest
Med 2000;21:245 – 61.
[31] Fenech A, Hall IP. Pharmacogenetics of asthma. Br J Clin Pharmacol 2002;53:2 – 15.
[32] Palmer LJ, Silverman ES, Weiss ST, et al. Pharmacogenetics of asthma. Am J Respir Crit Care
Med 2002;165:861 – 6.
[33] Marsh DG, Neely JD, Breazeale DR, et al. Linkage analysis of IL4 and other chromosome
S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591 591

5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994;264:

1152 – 6.
[34] Borish L, Mascali JJ, Klinnert M, et al. SSC polymorphisms in interleukin genes. Hum Mol
Genet 1995;4:974.
[35] Rosenwasser LJ, Klemm DJ, Dresback JK, et al. Promoter polymorphisms in the chromosome
5 gene cluster in asthma and atopy. Clin Exp Allergy 1995;25(Suppl 2):74 – 8; discussion 95 – 6.
[36] Burchard EG, Silverman EK, Rosenwasser LJ, et al. Association between a sequence variant in
the IL-4 gene promoter and FEV(1) in asthma. Am J Respir Crit Care Med 1999;160:919 – 22.
[37] Hershey GK, Friedrich MF, Esswein LA, et al. The association of atopy with a gain-of-function
mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med 1997;337:1720 – 5.
[38] Rosa-Rosa L, Zimmermann N, Bernstein JA, et al. The R576 IL-4 receptor alpha allele correlates
with asthma severity. J Allergy Clin Immunol 1999;104:1008 – 14.
[39] Martinez FD. Maturation of immune responses at the beginning of asthma. J Allergy Clin
Immunol 1999;103:355 – 61.
[40] Spahn JD, Szefler SJ, Surs W, et al. A novel action of IL-13: induction of diminished monocyte
glucocorticoid receptor-binding affinity. J Immunol 1996;157:2654 – 9.
[41] Kam JC, Szefler SJ, Surs W, et al. Combination IL-2 and IL-4 reduces glucocorticoid receptor
binding affinity and T cell response to glucocorticoids. J Immunol 1993;151:3460 – 6.
[42] Sher ER, Leung DYM, Surs W, et al. Steroid resistant asthma: cellular mechanisms contributing
to inadequate response to glucocorticoid therapy. J Clin Invest 1994;93:33 – 9.
[43] Akinbami LJ, Schoendorf KC. Trends in childhood asthma: prevalence, health care utilization,
and mortality. Pediatrics 2002;110:315 – 22.
[44] Bauman LJ, Wright E, Leickly FE, et al. Relationship of adherence to pediatric asthma morbidity
among inner-city children. Pediatrics 2002;110(1):1 – 7. Available at:
cgi/content/full/110/1/e6. Accessed July 1, 2002.
[45] Lara M, Rosenbaum S, Rachelefsky G, et al. Improving childhood asthma outcomes in the
United States: a blueprint for policy action. Pediatrics 2002;109:919 – 30.