Choosing a Long-term Controller Medication in Childhood Asthma
The Proverbial Two-edged Sword

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The treatment of persistent asthma challenges the clinician with a number of options, the choice of which depends on the age of the patient, the pharmacologic profile, the dosing interval, the delivery system, the risk/benefit ratio, and the cost effectiveness of each medication, either alone or in various combinations. According to various international guidelines for asthma management, patients with either mild or moderate persistent asthma should receive both a long-term controller and a quick relief medication for optimal disease control. The choice of a quick relief medication is relatively easy since most available products are within the same class of compounds (beta-adrenergic agonists), share relatively the same pharmacologic profiles, and differ only in their delivery systems (metered-dose inhalers, breath-actuated inhalers, dry powder formulations, nebulizer solutions, parenteral forms). In contrast, the choice of long-term controller medications is more complicated since it involves numerous classes of compounds, including methylxanthines, long-acting beta agonists, leukotriene antagonists, antiallergic compounds, and inhaled corticosteroids (ICS)s, which differ markedly in their various pharmacologic and clinical properties.

The concept of a "controller" medication means different things to different people. To the patient, the relevant definition most frequently cited is symptom control; to the clinician, the most important feature is disease control. Optimally, a medication would satisfy both definitions simultaneously. Classifying a medication as such has been difficult because the terms "symptom control" and "disease control" have yet to be satisfactorily defined. Clinical trials are being designed to address these important considerations.

With the advent of intermediate (e.g., albuterol) and long-acting beta agonists (e.g., salmeterol), the ability of the clinician to provide adequate symptom control became possible in many patients (1). However, therapy with beta agonists came under scrutiny when chronic regular use was associated with either poorer overall asthma control (2) or increased morbidity and mortality (3). These, as well as other observations regarding the loss of the bronchoprotective effect to methacholine, allergen, or exercise provocation after chronic administration of beta agonists, elicited a series of debates as to the clinical relevance of these findings, whether the observations were causally linked or were confounded by disease severity, and whether the outcomes observed could be applied to all patients with asthma regardless of their underlying disease severity (4, 5).

One argument put forth against the regular use of beta agonists has been that they treat the symptoms of asthma while permitting the underlying inflammatory process to continue. If correct, one would anticipate that in patients with disease activity suboptimally controlled who were already receiving ICS therapy, the most effective intervention would be to give higher doses of ICSs. However, two studies have demonstrated that the addition of salmeterol at this juncture is more efficacious than more than doubling the dose of ICSs (6, 7). Moreover, despite improvement in symptom control, markers of airway inflammation do not change (8). Thus, we are left with the paradox that in some cases beta-agonist therapy is potentially harmful, whereas in others it is helpful, in the treatment of mild to moderate persistent asthma.

In this issue, Verberne and coworkers (9) approach the issue of the proper choice of long-term controller medications using a different experimental design. In a 1-yr prospective double-blind, randomized clinical trial, they compared the efficacy and side effects of two long-term controller medications, an ICS [beclomethasone dipropionate (BDP)], 200 µg twice a day, and a long-acting beta agonist (salmeterol, 50 µg twice a day), both using Rotadisks in combination with a Diskhaler, when used as monotherapy in children (mean age, 10.5 yr) with mild to moderate persistent asthma. After 1 yr of therapy, the improvement in certain outcome variables (improvements in FEV₁, methacholine airway responsiveness, rescue beta agonist use) was significantly greater in the BDP than in the salmeterol group. Morning and evening PEF, and daytime and nighttime symptoms, improved in both groups, with a tendency for more improvement in the BDP group. Asthma exacerbations, for which prednisolone was needed, were more frequent in the salmeterol group (17 versus two), as were the number of withdrawals because of exacerbations (six versus one).

Although many of these outcomes support the use of BDP rather than salmeterol as the long-term controller monotherapy of choice in this patient population, one important observation complicates this conclusion. In the BDP-treated children, average annual growth was significantly reduced (difference of 1.4 cm/yr, resulting in 0.28 height SDS). When added to the findings of two recent studies (10, 11), which also demonstrated growth-retarding effects of this magnitude during BP treatment, the conclusion that ICSs are capable of adversely affecting growth appears incontrovertible.

On the one hand, this should not be surprising since glucocorticoids are potent inhibitors of virtually every component of the growth axis, including growth hormone secretion and action, insulin like growth factor-1 bioactivity, collagen synthesis, and adrenal androgen production (12). Because all three studies demonstrating significant effects on growth used inhaled BDP, one could consider the possibility of a drug-specific rather than a class-specific effect. Indeed, BDP theoretically could have a greater systemic effect than other ICSs (on a microgram for microgram basis) because of intrapulmonary metabolism to beclomethasone monopropionate, a potent corticosteroid with a prolonged half-life. However, sufficient doses of any ICS, which are readily absorbed into the systemic circulation from the lungs, could exert this effect. On the other hand, the clinical relevance (as opposed to statistical significance) of growth suppression by ICSs depends more on the ultimate effect on height and the balance between the individual need for disease control in mild and moderate asthma and the risk of drug side effects.

Determining the clinical relevance of the effects of ICSs on growth is complicated by the complexities of studying growth in children with asthma, a disease that fluctuates in severity and retards growth and development independent of drugs used to treat it. Although Verberne and coworkers (9) address the problems of many previous studies (e.g., lack of control groups, inadequate duration of evaluation, failure to segregate by pubertal status or sex at baseline), the growth data remain compromised by a study design primarily oriented toward analysis of drug efficacy rather than growth. Information regarding the precise number of children in prepubertal and pubertal subgroups, method of pubertal staging during the trial, and the handling of children experiencing pubertal transition during the study is lacking. Also, individual patient data are not provided, a critical factor when the numbers of patients per subgroup is relatively small. For example, with a mean study patient age of 10.5 yr (range, 6 to 16 yr), it is likely that 50% of female patients in the study were pubertal. This yields only five to six female patients per subgroup (i.e., pubertal or prepubertal) upon which analysis of BDP effect based on sex could be made. A few patients experiencing either midstudy pubertal growth acceleration or marked growth deceleration signifying completion of female pubertal growth could have significantly affected mean subgroup growth velocity. Also, presentation of individual patient data aids in distinguishing profound idiosyncratic responses of select patients to growth-suppressing effects of ICSs (13) versus a pervasive, and therefore, more predictable effect.

This study and others (11) suggest that the potential for growth inhibition by ICSs is greatest in prepubertal children, particularly during the years immediately preceding (an often delayed) puberty. Growth velocity and GH secretion temporarily decline during this period, and evidence suggests that in the setting of delayed stimulation by either adrenal or gonadal steroids, sensitivity of the growth axis to inhibition is increased. Unless carefully controlled for, the slowed growth relative to peers often experienced by early adolescent asthmatic children with delayed growth and development can be mistaken for ICS effect, when in fact subsequent growth acceleration occurs during continued ICS treatment (14). Supporting this observation are studies showing no effect of moderate dose BDP therapy (i.e.,  400 µg/d) on childhood (15) or final adult height (16, 17). Furthermore, long-term studies of similar doses of budesonide show no change in height SDS over several years (18). Consequently, the potential for a decline in growth rate is not a priori a clinically relevant adverse effect that should limit use of BDP or other ICSs. For asthma requiring anti-inflammatory therapy, the relative safety of ICSs vis-à-vis oral corticosteroids is unquestioned.

How can the recent prospective studies showing growth suppression by inhaled BDP be reconciled with retrospective studies showing minimal or no effect on growth rate or height? One explanation returns to the differences between physician and patient in defining disease versus symptom control, which are as relevant to drug adverse effects as they are to drug efficacy. For example, this study and other well designed studies (11), which achieve disease control with closely monitored and consistent dosing, indicate that BDP inhaled at a dosage of 400 µg every day is capable of suppressing prepubertal growth. Most patients, however, reduce drug exposure by titrating medication to achieve symptom control, rather than disease control, perhaps accounting for the lack of effect of "real life" prescriptions of BDP 400 µg/d on retrospective growth rates or final adult stature. Whether long-term uninterrupted inhalation of BDP or other ICSs at a dosage sufficient to achieve the clinician's definition of disease control could have a clinically relevant adverse effect on final height remains unknown.

Consequently, determining an individual patient's minimal dose of ICS effective in controlling both symptoms and disease while avoiding excess corticosteroid exposure and lowering the risk for adverse effects remains an important challenge. Moreover, since the growth-inhibiting effects of glucocorticoids vary not only with dosage but with dose frequency and total time of exposure, receptor affinity, drug absorption and metabolism, lipophilicity, and other factors, each new strategy in ICS treatment (e.g., higher dosage, institution earlier in life, use of more potent formulations) requires that questions regarding glucocorticoid side effects be addressed anew. What the findings of Verberne and coworkers do strongly support is the importance of carefully monitoring growth in every child treated with ICSs. Only then can growth suppression be detected and reduction in dosage with the introduction of adjuctive therapy with other long-term controller medications be instituted (6, 7). If these interventions are not helpful in eliminating the growth suppression, referral to a growth specialist should be considered (12).

The treatment of mild and moderate persistent asthma in children provides the clinician with numerous challenges. The multiple nuances of individual drug effects, interactive effects, and the individual patient's response both from a therapeutic and an adverse effects standpoint are all relevant issues for the physician caring for asthmatic children. Until the heterogenous nature of asthma can be separated into individual phenotypes based on biologic, physiologic, immunologic, or pharmacologic characteristics, resulting in the development of more specific therapies, treatment options for long-term control will continue to be a "two-edged sword" in many cases.

Division of Allergy
Departments of Pediatrics and Medicine
University of Wisconsin Medical School
Madison, Wisconsin

DAVID B. ALLEN, M.D.

Division of Endocrinology
Department of Pediatrics
University of Wisconsin Medical School
Madison, Wisconsin

	Footnotes

Correspondence and requests for reprints should be addressed to Robert F. Lemanske, Jr., M.D., University of Wisconsin Children's Hospital, 600 Highland Avenue H4/432, Madison, WI 53792.

Acknowledgments: Supported by Grants A134891 and HL56396 from the National Institutes of Health.

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