REVIEW ARTICLE
Drugs 2000; 59 Suppl. 1: 9-14 0012-6667/00/0001-0009/$25.00/0 © Adis International Limited. All rights reserved.
Inhaled Corticosteroids in Childhood Asthma Growing Concerns Kimberley A. Witzmann and Robert J. Fink Department of Allergy, Immunology, and Pulmonary Medicine, Children’s National Medical Center, George Washington University, Washington, DC, USA
Abstract
Inhaled corticosteroids (ICS) are an established treatment for asthma in childhood. Recent data bring to light growing concerns that ICS may have significant effects on growth velocity in children. The Food and Drug Administration (FDA) recently convened a joint meeting to review these data, and to release new class labelling for ICS that notes this potential adverse effect. Additional concerns regarding ICS are also discussed, including other potential adverse effects, difficulty of use, noncompliance, and patient and parental concerns with the safety of ICS. The aim of this article is as follows: to describe the rationale for the use of ICS in children with asthma; to delineate the association of ICS with potential growth suppression in children; to discuss recent FDA class labelling for use of ICS in children; to describe other potential long term effects of ICS in children; and to detail compliance issues in children with asthma treated with ICS.
Asthma is currently the most common chronic disease of childhood, affecting almost 5 million children in the US. It is responsible for 5000 deaths annually,[1] with the highest mortality rates in those aged 15 to 24 years, and Blacks.[2] In 1991 and again in 1997, the National Institutes of Health (NIH) released clinical practice guidelines for the diagnosis and management of asthma in response to growing concerns that asthma was being undertreated. Goals for asthma therapy identified in the guidelines include preventing chronic symptoms and exacerbations, maintaining pulmonary function and activity levels, meeting the expectations of the patient and family, and providing optimal pharmacotherapy.[2] 1. Rationale for the Use of ICS Optimal pharmacotherapy of asthma is difficult to achieve for a number of reasons. It is clear that
asthma is a chronic inflammatory disease and that prevention is the best way to manage exacerbations. The Global Initiative for Asthma guidelines, which were issued in 1995, state that, ‘any asthma more severe than mild, intermittent (FEV1 ≥ 80% predicted, intermittent symptoms less than one time per week, and nighttime symptoms less than two times per month) is more effectively controlled by treatment to suppress and reverse the inflammation than by treatment only of acute bronchoconstriction’.[3] These guidelines consider inhaled corticosteroids (ICS) to be the most effective antiinflammatory medication. In fact, worldwide, ICS are a mainstay of both adult and paediatric therapy for moderate to severe asthma. The efficacy of ICS has been well documented, and many national and international treatment guidelines recommend their use as first-line therapy in all but mild asthma.[4-6] It is not necessary to argue the benefits
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of ICS in asthma management, since these are widely known and include the following: a decrease in the need for oral corticosteroids; a decrease in airway reactivity; a reduction in the frequency of acute exacerbations; and a reduction in the need for concurrrent medications.[7] There is no doubt that ICS decrease chronic inflammatory changes in the lungs, and that, especially in adults, they do not seem to have significant adverse effects on the hypothalamic-pituitary-adrenal (HPA) axis, or other serious systemic adverse effects.[8] In 1997 the NIH group recommended the use of ICS in children with asthma to fight lung inflammation. Their rationale was that ICS were the most potent anti-inflammatory agents available and that early intervention with these drugs could improve control of the disease process and lung function, and might prevent irreversible injury. They stated that, ‘higher doses [of ICS] may be associated with possible, but not predictable, growth retardation in children’.[2] They recommended that ICS be used as first-line, anti-inflammatory therapy in children with mild persistent, moderate, and severe asthma.[2] The potential risk of growth delay associated with ICS was felt to be justified by the overall benefits of these drugs, which include an overall decrease in morbidity from asthma, and because there was no better anti-inflammatory drug at that time. However, since early 1997, because of the availability of more data relevant to the adverse effects of ICS together with growing patient and parental reservations, caregivers are increasingly questioning the use of ICS as a first-line agent. 2. Growth and ICS During the last 30 years, a number of studies have examined the effects of ICS on growth in children with asthma. Of approximately 53 publications identified in a recent review,[9] 24 showed suppressive effects on growth. These studies are somewhat difficult to interpret, however, because of varying study designs, lack of blinding, variations in dosage, concomitant use of systemic corticosteroids, and no uniformity in the measurement of growth. In children, interpreting growth data is © Adis International Limited. All rights reserved.
difficult because there is a natural deceleration in the growth rate prior to an acceleration in early puberty.[10] These expected velocity changes may skew growth data in either direction, depending on the age of the patients and the duration of the study. To avoid confounding, studies should focus on girls aged <10 years and boys aged <12 years, prior to any change in Tanner staging, which indicates the onset of puberty. Most studies of growth velocity have not recorded Tanner stages and, since the children’s ages have varied widely, it is difficult to tease out what proportion of a change in growth is due to a drug or due to puberty. Because of the recent increase in the use of ICS, studies have examined these issues. Crowley and colleagues examined the effects of ICS on growth in UK children.[11] They studied 56 prepubertal children aged 4.4 to 11.7 years. After 12 months, 20% of children using inhaled budesonide (BUD), 50% of those using inhaled beclomethasone dipropionate (BDP), and 70% of those using an ICS in conjunction with systemic corticosteroids had decreased growth velocities compared with controls. These data are somewhat difficult to interpret because of the variety of ICS used, their dosages, and the age of the children. In 1997, the Dutch Paediatric Asthma Study Group published their initial findings comparing the use of ICS versus inhaled salmeterol for long term therapy. Although ICS were more effective than salmeterol, the group receiving ICS had significantly slower growth rates than those receiving salmeterol.[12] The Canadian group led by Simons[13] compared BDP, salmeterol and placebo, and, during their 1-year study period, BDP provided superior asthma control, but was associated with decreased linear growth in children. Heuck and colleagues[14] examined markers of collagen turnover and dosage effects in children using ICS, and found that twice-daily ICS suppressed the lower leg growth rate, as well as collagen markers, when compared with once-daily morning treatment. Unfortunately, this study did not include a control group. These studies establish a Drugs 2000; 59 Suppl. 1
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clear association between decreased growth rate and the use of ICS in children. 3. Variations between ICS Some ICS seem to have a stronger suppressive effect on growth than others. MacKenzie et al.[15] compared inhaled fluticasone propionate (FP) 200 μg/day with BDP 400 μg/day, and found that BDP significantly reduced lower leg growth, but that lower doses of FP did not. They concluded that the effect of early intervention with ICS on growth in children with asthma warrants further investigation. The Fluticasone Asthma Study Group in Madison demonstrated that lower dosages of FP did not significantly change growth velocity when compared with controls, but that there was a downward trend. Children were treated with FP 50 or 100μg, or placebo twice daily. The mean (± standard error) height increase after 1 year was 6.15 ± 0.17cm in the placebo group, 5.94 ± 0.16cm in the 50μg group, and 5.73 ± 0.13cm in the 100μg group.[16] 4. Duration of Growth Velocity Changes Since ICS do affect growth velocity, some studies have examined the duration of these suppressive effects. Doull and colleagues[17] noted that growth suppression was most marked in children during the initial 6 weeks of treatment, was present during the first 18 weeks of treatment, but, thereafter, growth rates were similar to those when the children were not receiving treatment. Saha et al.[18] examined catch-up growth after discontinuation of ICS in 30 children who had evidence of growth suppression and who had received at least 2 years of treatment with ICS. They found an increase in growth velocity in a majority of children, while 2 showed no change, and 3 continued to have decreased growth velocity despite a change to nonsteroidal medications. The effects of ICS on growth may not be permanent. A study from the Mayo Clinic compared the adult heights of children with asthma treated with corticosteroids, children with asthma not treated with corticosteroids, and age- and gendermatched controls, and found no significant differ© Adis International Limited. All rights reserved.
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ences in the final adult height after correction for mid-parental height.[19] Despite this hopeful outcome, however, many clinicians have concerns about over-utilising ICS as first-line therapy for the treatment of asthma in children.[20] 5. FDA Class Labelling Concerns about the growth suppressive effects of ICS were brought into the spotlight when, in July 1998, the Food and Drug Administration (FDA) convened a joint meeting of the Pulmonary and Allergy Drug Advisory Committee and the Endocrine and Metabolic Drug Advisory Committee. In the Committees’ review of proprietary studies, they noted that ‘mean growth velocity decreased in active treatment [phases] in all these studies’.[9] They also noted a trend toward decreasing growth velocities with higher doses of ICS. Standard HPAaxis analyses were not predictive of lower growth velocity in these patients.[9] As recommended by the Advisory Committee, the FDA implemented ICS class labelling in November 1998. The labelling states, ‘controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients’. They continue, ‘The long term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including impact on final adult height, are unknown. The potential for "catch up" growth...has not been adequately studied... The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the availability of safe and effective non-corticosteroid treatment alternatives’.[21] 6. Other Potential Adverse Effects In addition to potential growth suppressive effects, there are other concerns regarding ICS. Two common adverse effects of ICS are thrush and dysphonia. Thrush appears to be related to the dosage and frequency of use. The proper use of spacer devices and mouth rinsing after use decrease the incidence of thrush.[22] Dysphonia occurs in as many as 20 to 30% of patients treated with ICS, but is not ameliorated by the use of spacers. Although Drugs 2000; 59 Suppl. 1
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dysphonia resolves on discontinuation of therapy, typically it will recur with reintroduction of an ICS.[22] Other adverse effects include decreased bone mass,[23] a potential association with severe viral infections[24] and reduced collagen turnover in children treated with ICS.[25] Ocular effects such as cataract formation and ocular hypertension are not seen in children; low to moderate ICS use has not significantly contributed to their development in adults.[10] 7. Compliance Issues with ICS Noncompliance or poor compliance with ICS is another concern regarding use of these drugs as first-line treatment. Milgrom and colleagues[26] found that more than 90% of patients in their study group exaggerated reports of ICS use, and that compliance was only 13% in those with exacerbations, compared with 68% in those patients who did not experience exacerbations. Kelloway and colleagues[27] also studied noncompliance with asthma medication, and found that 70% of patients taking oral theophylline were compliant, compared with only approximately 30% of patients using inhaled therapies. Bender et al.[28] noted that patients rarely took all their medications as prescribed, and failed to take daily ICS on a median of 41.8% of days. They also noted that noncompliance was linked to decreased knowledge of asthma and to family dysfunction. Celano and colleagues[29] found similar results in children from low income families; mean use of ICS was 44% of prescribed doses, and in half of the households there were cigarette smokers. They also noted that 27% of children demonstrated metered-dose inhaler (MDI)/spacer technique that was likely to prevent drug delivery. The difficulty of teaching and learning proper inhalation technique is a disadvantage of the use of MDIs. In a study by Chapman,[30] it was found that up to one-third of paediatric, teen, and adult patients had inadequate inhaler technique. This was also reflected in a study by Van Beerendonk et al.,[31] who found that in a group of 316 adults 89% made at least one mistake in MDI/spacer © Adis International Limited. All rights reserved.
technique. The most common errors were not continuing to inhale once the medicine was dispensed (70%), and forgetting to exhale fully prior to inhalation of the drug (66%). Despite initial education in their use, not only is it difficult to use the proper technique with the MDI/spacer apparatus, but compliance rates with these complicated devices are rather low as well. These difficulties can only increase when we take into account the multiple MDI medications with different instructions, and MDI versus dry powder inhaler (DPI) techniques. Parental concern is another reason for decreased compliance with paediatric ICS use. A study from Singapore in 1996 reported that 36% of parents were opposed to ‘inhaler therapy’, or preferred oral medications.[32] Reasons for parental reluctance to use ICS included fear of dependence, concerns with adverse effects and overdosage, and the child’s dislike of inhaler devices. A more recent Canadian study published in 1998[33] demonstrated that a large proportion of adult patients had misconceptions and fears regarding therapy with ICS, which reduced their willingness to use them. More than half the patients were concerned about using ICS on a regular basis and stated fears of adverse effects on habitus and bone density, and decreased efficacy over time. Two-thirds of these patients had not discussed their concerns with their physician. Another recent study conducted in an emergency department examined parental attitudes. Adverse effects of medications were a concern for 81% of compliant and 90% of noncompliant families. Doubts regarding usefulness were recorded in 34% and 54%, respectively, of compliant versus noncompliant families. Medications were forgotten some of the time by 42% of the children, and 53% actively avoided taking their asthma medicines.[34] By addressing issues of noncompliance, physicians can facilitate more efficient targeting of behavioural interventions, which will result in better disease control and lower requirements for urgent interventions. Drugs 2000; 59 Suppl. 1
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8. Conclusions ICS play a major role in the treatment of moderate to severe asthma in children, and are the best studied class of drugs for controlling chronic airway inflammation in children. ICS are a mainstay of our pharmacological armamentarium against childhood asthma, but their use is not without risk. There are many unresolved issues surrounding the use of ICS, namely, adverse effects, compliance and safety. Especially in paediatrics, we need to develop effective asthma treatment regimens that are simple for the child and family members to utilise, that will not require frequent administration at school (which might affect school performance), and that do not have potentially serious adverse effects on growth velocity. This opens the door for other medications, especially those that encourage improved adherence by being ‘userfriendly’, that are perceived as safe by parents, and, because they are compatible with the child’s and the family’s lifestyle, pave the way for the future medical management of paediatric asthma into the twenty-first century.
References 1. Sly RM. Changing asthma mortality. Ann Allergy 1994; 73: 259-68 2. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 2: guidelines for the diagnosis and management of asthma. NIH Publication no. 97-4051. Bethesda, MD: National Institutes of Health, 1997: 1-50 3. National Heart, Lung, and Blood Institute and World Health Organization. Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH Publication no. 95-3659. Bethesda, MD: National Institutes of Health,1995: 1-48 4. International consensus report on diagnosis and treatment of asthma. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. Publication no. 92-3091, March 1992. Eur Respir J 1992; 5: 601-41 5. British Thoracic Society. Guidelines for Management of Asthma. Thorax 1993; 48 Suppl.: S1-24 6. The British Guidelines on Asthma Management. 1995 Review and Position Statement. Thorax 1997; 52 Suppl. 1 7. Condemi JJ, Chervinsky P, Goldstein MF, et al. Fluticasone propionate powder administered through Diskhaler versus triamcinolone acetonide aerosol administered through metereddose inhaler in patients with persistent asthma. J Allergy Clin Immunol 1997; 100 (4): 467-74
© Adis International Limited. All rights reserved.
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8. Ayres JG, Bateman ED, Lundback B, et al. High dose fluticasone propionate, 1 mg daily, versus fluticasone propionate, 2 mg daily, or budesonide, 1.6 mg daily, in patients with chronic severe asthma. International Study Group. Eur Respir J 1995; 8: 579-86 9. FDA Joint Meeting of the Pulmonary and Allergy Drug Advisory and the Endocrine and Metabolic Drug Advisory Committees. [Transcript] 1998 Jul 28-29; Day #2: 16 10. Sorkness CA. Comparisons of systemic activity and safety among different inhaled corticosteroids. J Allergy Clin Immunol 1998; 102 (4): S52-64 11. Crowley S, Hindmarsh PC, Matthews DR, et al. Growth and growth hormone axis in prepubertal children with asthma. J Pediatr 1995 Feb; 126 (2): 297-303 12. Verberne AA, Frost C, Roorda RJ, et al. One year treatment with salmeterol compared with beclomethasone in children with asthma. The Dutch Paediatric Asthma Study Group. Am J Respir Crit Care Med 1997 Sep: 156 (3 Pt 1): 688-95 13. Simons FE. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group. N Engl J Med 1997 Dec 4; 337 (23): 1659-65 14. Heuck C, Wolthers OD, Kollerup G, et al. Adverse effects of inhaled budesonide on growth and collagen turnover in children with asthma: a double-blind comparison of once-daily versus twice-daily administration. J Pediatr 1998 Nov; 133 (5): 608-12 15. MacKenzie C. Effects of inhaled corticosteroids on growth. J Allergy Clin Immunol 1998 Apr; 101 (4 Pt 2): S451-5 16. Allen DB, Bronsky EA, LaForce CF, et al. Growth in asthmatic children treated with fluticasone propionate. Fluticasone Propionate Asthma Study Group. J Pediatr 1998 Mar; 132 (3 Pt 1): 472-7 17. Doull IJ, Campbell MJ, Holgate ST. Duration of growth suppressive effects of regular inhaled corticosteroids. Arch Dis Child 1998 Feb; 78 (2): 172-3 18. Saha MT, Laippala P, Lenko HL. Clinical observations on catch-up growth in asthmatic children following withdrawal of inhaled glucocorticoids. Pediatr Pulmonol 1998 Oct; 26 (4): 292-4 19. Silverstein MD, Yunginger JW, Reed CW, et al. Attained adult height after childhood asthma: effect of glucocorticoid therapy. J Allergy Clin Immunol 1997 Apr; 99 (4): 466-74 20. Van Bever HP, Desager KN, Lijssens N, et al. Does treatment of asthmatic children with inhaled corticosteroids affect their adult height? Pediatr Pulmonol 1999; 27: 369-75 21. Class Labeling for Intranasal and Orally Inhaled Corticosteroid Containing Products Regarding the Potential for Growth Suppression in Children; Division of Pulmonary Drug Products. US FDA Class labeling; 1998 Nov 11. Available from: http://www.fda.gov/cder/news/cs-label.htm 22. Pedersen SE. Chapter 22: efficacy and safety of inhaled corticosteroids in children. In: Schleimer RP, Busse WW, O’Byrne PM, editors. Inhaled glucocorticoids in asthma: mechanisms and clinical actions. New York: Marcel Dekker, Inc, 1997: 586 23. Martinati LC, Bertoldo F, Gasperi E, et al. Longitudinal evaluation of bone mass in asthmatic children treated with inhaled beclomethasone dipropionate or cromolyn sodium. Allergy 1998 Jul; 53 (7): 705-8 24. Welch MJ. Inhaled steroids and severe viral infections. J Asthma 1994; 31 (1): 43-50
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25. Crowley S, Trivedi P, Riseli L, et al. Collagen metabolism and growth in prepubertal children with asthma treated with inhaled steroids. J Pediatr 1998 Mar: 132 (3 Pt 1): 409-13 26. Milgrom H, Bender B, Ackerson L, et al. Noncompliance and treatment failure in children with asthma. J Allergy Clin Immunol 1996 Dec; 98 (6 Pt 1): 1051-7 27. Kelloway JS, Wyatt RA, Adlis SA. Comparison of patients’ compliance with prescribed oral and inhaled asthma medications. Arch Intern Med 1994 Jun; 154 (12): 1349-52 28. Bender B, Milgrom H, Rand C, et al. Psychological factors associated with medication nonadherence in asthmatic children. J Asthma 1998; 35 (4): 347-53 29. Celano M, Geller RJ, Phillips KM, et al. Treatment adherence among low-income children with asthma. J Pediatr Psychol 1998 Dec; 23 (6): 345-9 30. Chapman KR. The choices of inhalers in adults and children over six. J Aerosol Med 1995 Summer; 8 Suppl. 2: S27-36 31. Van Beerendonk I, Mesters I, Mudde AN, et al. Assessment of the inhalation technique in outpatients with asthma or chronic obstructive pulmonary disease using a metered-dose inhaled or dry powder device. J Asthma 1998; 35 (3): 273-9
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32. Lim SH, Goh DY, Tan AY, et al. Parents’ perceptions towards their child’s use of inhaled medication for asthma therapy. J Pediatr Child Health 1996 Aug; 32 (4): 306-9 33. Boulet LP. Perception of the role and potential side effects of inhaled corticosteroids among asthmatic patients. Chest 1998 Mar; 113 (3): 587-92 34. Leickly FE, Wade SL, Crain E, et al. Self-reported adherence, management behavior, and barriers to care after emergency department visit by inner city children with asthma. Pediatrics 1998 May; 101 (5): E8
Correspondence and offprints: Dr K.A. Witzmann, Department of Allergy, Immunology, and Pulmonary Medicine, Children’s National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010, USA. E-mail:
[email protected] [email protected]
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