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
1-U01-HD37237.
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: szeflers@njc.org
0031-3955/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved.
doi:10.1016/S0031-3955(03)00041-5
578 S.J. Szefler / Pediatr Clin N Am 50 (2003) 577–591
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.
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
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.
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.
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
Summary
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].
Acknowledgment
The author thanks Gretchen Czapla for assistance in the manuscript preparation.
References
[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