PEDIATRICS Vol. 121 No. 1 January 2008, pp. 179-180 (doi:10.1542/peds.2007-2751)
COMMENTARY |
Safer Inhaled Corticosteroid Therapy for Asthma
Asthma and Airway Centre, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada
When symptoms of childhood asthma are persistent and intrusive, no therapy restores control more reliably than the inhalation of topically effective corticosteroids. Within days, nocturnal symptoms of cough and wheeze become infrequent or disappear. When measured, lung function shows improvement and diurnal fluctuations in airway caliber show a decrease. In the ensuing weeks, daytime episodes of asthma will become less frequent, and laboratory measures of nonspecific bronchial hyperresponsiveness will improve. Underlying these changes is the restoration of normal airway histology. Bronchial biopsies in the patient with uncontrolled asthma show infiltration of the mucosa by eosinophils, disruption of the airway epithelium, and elaboration of tenacious mucous. This inflamed and edematous airway becomes more normal in appearance with several weeks of inhaled corticosteroid therapy such that bronchial biopsies in the steroid-treated patient appear normal or nearly so.1 Understandably, national and international guidelines for the management of pediatric and adult asthma postulate that inhaled corticosteroids are the most reliable foundation of pharmacotherapy in persistent disease.2
Regrettably, the parents of children with asthma and many clinicians who treat children with asthma are often reluctant to consider the use of inhaled corticosteroids.3 Many parental concerns are ill-informed and can be addressed by education. For example, parents may confuse the antiinflammatory corticosteroids for asthma care with the masculinizing steroids often abused by professional athletes or will express fears that their child will become "dependent" on an inhaler. Other concerns are dismissed less easily. Parents often question the potential for systemic impact when a corticosteroid is inhaled. Although the risk seems minimal with low-dose inhaled corticosteroids, there is ample evidence that corticosteroids can and do have measurable systemic effects in some settings. Among adults, the inhalation of available corticosteroids is associated with reduced bone density, hip fracture, and cataract formation.4–7 Among the parents of children with asthma, the most commonly expressed concern is that the regular use of inhaled corticosteroids will slow growth, a phenomenon that has been reported by several investigators who have studied available agents.8 We have been reassured that this slowing of growth seems to be transient and that normal adult height is likely to be attained.9,10 Nonetheless, many parents find these reassurances unconvincing.
Pharmaceutical chemists have attempted to address these concerns by developing safer corticosteroids for inhalation. One such agent is ciclesonide, the most recently introduced inhaled corticosteroid (now available in many countries by the trade name Alvesco).11,12 Ciclesonide is described as a "prodrug," which means that it is not active pharmacologically until metabolized at the intended site of action.13 Ciclesonide has little effect until cleaved by esterases present in the lung, wherein it becomes the active antiinflammatory compound, des-ciclesonide. Tight protein binding of ciclesonide in the serum further diminishes the likelihood for systemic impact of any trace amounts of ciclesonide that make their way into the systemic circulation.14
In this issue of Pediatrics Electronic Pages, Skoner et al15 provide additional reassurance concerning the safety of ciclesonide in the treatment of childhood asthma. The investigators studied 661 children with mild asthma and assigned them in random, double-blind fashion to therapy for 1 year with 160 µg of ciclesonide per day, 40 µg of ciclesonide per day, or matching placebo. During this treatment period, they tracked linear growth with 4 stadiometer measurements and could find no measurable impact of ciclesonide on the linear growth of these children as compared with placebo. By contrast, both beclomethasone and budesonide have been reported to slow linear growth in previous studies that used similar technology in similar populations. Additional reassurance was provided in the Skoner et al trial by the absence of any measurable effect on urinary free cortisol levels.
The study was not without its limitations. The findings are reassuring only if one believes that the majority of children inhaled most doses of the study drug given to them and that their inhalation technique was good enough to deposit medication in the lower airway. However, the children described by Skoner et al had very mild disease, and one might even question whether all the children actually had asthma. Concurrent therapy was allowed, and approximately half of the children were using another controller therapy in the form of the oral antileukotriene agent montelukast. It is plausible (if not probable) that many children inhaled the study medication only intermittently or perhaps not at all. The investigators relied on diary-card records of medication use and canister weights; ultimately, such compliance data are unconvincing. To cause additional concern, we cannot be sure how successfully ciclesonide was inhaled from "press-end-breathe" aerosol inhalers used without spacing devices. Patient handling of these devices is notoriously poor, and one might argue that some of the study medication that patients attempted to inhale never reached the lower airway, let alone the systemic circulation.16 To support this contention, the study failed to show any pulmonary-function or asthma-control benefit of ciclesonide. Ultimately, the study by Skoner et al would have been more convincing if ciclesonide's lack of impact on linear growth had been seen side-by-side with measurable growth-retarding effects of an active comparator such as budesonide or beclomethasone. For the present, Skoner et al have provided us with the best "real-world" data to reassure us that the use of "safer" inhaled corticosteroids really is safer.
Proponents of inhaled corticosteroid use to treat pediatric asthma would argue that additional reassurance about the safety of a particular inhaled corticosteroid is unnecessary. Asthma in children and adults can be controlled with relatively low doses of inhaled corticosteroid regardless of whether it is given alone or in combination with adjunctive agents so that the risk of systemic impact is low. They would remind us that slowed linear growth in children does not seem to lead to decreases in adult height.17 They also might remind us of the nonpharmacologically steroid-sparing strategies such as removal of offending allergens and diminished exposure to secondhand tobacco smoke. Although these proponents of inhaled corticosteroid use needed no convincing, many parents of children with asthma do. We now have additional arguments for fearful parents who are reluctant to consider using an inhaled corticosteroid to achieve optimal asthma control.
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FOOTNOTES |
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Accepted Sep 17, 2007.
Address correspondence to Kenneth R. Chapman, MD, MSc, FRCPC, FACP, FCCP, Asthma and Airway Centre, University Health Network, Toronto Western Hospital, Room 7-451 East Wing, 399 Bathurst St, Toronto, Ontario, Canada M5T 2S8. E-mail: kchapman{at}ca.inter.net
Financial Disclosure: The author has indicated that he has served as a consultant for Altana, Astra Zeneca, Biovail, Boehringer-Ingelheim, Genpharm, GlaxoSmithKline, Hoffman LaRoche, Merck Frosst, Novartis, Pfizer, Roche, Schering Plough, and Telacris; has been involved in continuing medical education with 3M, Altana, AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck Frosst, Novartis, Pfizer, and Telacris; and has received research grants and/or contracts from 3M, Altana, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, GlaxoSmithKline, Hoffman LaRoche, Merck Frosst, Novartis, Roche, Telacris, and Theratechnologies.
Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.
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[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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