Changes in recommended treatments for mild and moderate asthma

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Applied Evidence

Changes in recommended treatments for mild and moderate asthma

J Fam Pract. 2004 September;53(9):692-700

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References

1. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma. Update on selected topics–2002. J Allergy Clin Immunol 2002;110(5 suppl):S141-S219.

2. National Asthma Education and Prevention Program Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Heart, Lung, and Blood Institute; National Institutes of Health; 1997. Publication 97;4051.-

3. Jadad AR, Moher M, Browman GP, Booker L, Sigouin C, Fuentes M, et al. Systematic reviews and meta-analyses on treatment of asthma: critical evaluation. BMJ 2000;320:537-540.

4. Castro-Rodríguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000;162:1403-1406.

5. Oxford Centre for Evidence-based Medicine Levels of Evidence Available atwww.cebm.net/levels_faq.asp . Accessed January 8, 2004.

6. Connett GJ, Warde C, Wooler E, Lenney W. Use of budes-onide in severe asthmatics aged 1–3 years. Arch Dis Child 1993;69:351-355.

7. de Blic J, Delacourt C, Le Bourgeois M, Mahut B, Ostinelli J, Caswell C, et al. Efficacy of nebulized budesonide in treatment of severe infantile asthma: a double-blind study. J Allergy Clin Immunol 1996;98:14-20.

8. Bisgaard H, Gillies J, Groenewald M, Maden C, . for an International Study Group The effect of inhaled fluticas-one propionate in the treatment of young asthmatic children: a dose comparison study. Am J Respir Crit Care Med 1999;160:126-131.

9. Nielsen KG, Bisgaard H. The effect of inhaled budesonide on symptoms, lung function, and cold air and metha-choline responsiveness in 2- to 5-year–old asthmatic children. Am J Respir Crit Care Med 2000;162:1500-1506.

10. Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054-1063.

11. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994;88:373-381.

12. Hoekstra MO, Grol MH, Bouman K, Stijnen T, Koëter GH, Kauffman HF, et al. Fluticasone propionate in children with moderate asthma. Am J Respir Crit Care Med 1996;154:1039-1044.

13. Jónasson G, Carlsen K-H, Blomqvist P. Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids. Eur Respir J 1998;12:1099-1104.

14. Simons FER and the Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. N Engl J Med 1997;337:1659-1665.

15. Storr J, Lenney CA, Lenney W. Nebulized beclomethasone dipropionate in preschool asthma. Arch Dis Child 1986;61:270-273.

16. Van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, Duiverman EJ, Pocock SJ, Kerrebijn KF. and the Dutch Chronic Non-Specific Lung Disease Study Group Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. Am Rev Respir Dis 1992;146:547-554.

17. Tasche MJA, Uijen JHJM, Bernsen RMD, de Jongste JC, van der Wouden JC. Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma: a systematic review. Thorax 2000;55:913-920.

18. Leflein JG, Szefler SJ, Murphy KR, Fitzpatrick S, Cruz-Rivera M, Miller CJ, et al. Nebulized budesonide inhalation suspension compared with cromolyn sodium nebulizer solution for asthma in young children: results of a randomized outcomes trial. Pediatrics 2002;109:866-872.

19. Verberne AAPH, Frost C, Duiverman EJ, Grol MH, Kerrebijn KF. and the Dutch Paediatric Asthma Study Group Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma. Am J Respir Crit Care Med 1998;158:213-219.

20. Lazarus SC, Boushey HA, Fahy JV, Chinchilli VM, Lemanske RF Jr, Sorkness CA, , et al. for the Asthma Clinical Research Network of the National Heart Lung and Blood Institute. Long-acting 2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001;285:2583-2593.

21. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. and the American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild or moderate persistent asthma. J Allergy Clin Immunol 1998;101:14-23.

22. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;343:1064-1069.

23. National Asthma Education Program (NAEP). Report of the Working Group on Asthma and Pregnancy: Management of Asthma during Pregnancy. Bethesda, Md: National Heart, Lung, and Blood Institute; National Institutes of Health, 1993. NIH Publication No. 96-141593.

24. American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthmaand Immunology (ACAAI). The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000;84:475-480.

25. National Asthma Education and Prevention Program. NAEPP Expert Panel Report. Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment—Update 2004. Bethesda, Md: National Heart, Lung, and Blood Institute; National Institutes of Health. NIH Publication No. 04-5246. March 2004.

26. Källén B, Rydhstroem H, Äberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999;93:392-395.

27. Ericson A, Källén B. Use of drugs during pregnancy—unique Swedish registration method that can be improved. Information From the Swedish Medical Products Agency 1999;1:8-11.

28. Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen Y-Z, Ohlsson SV, et al. for the START Investigators Group. Early intervention with budesonide in mild persistent asthma. Lancet 2003;361:1071-1076.

Topics in the management of asthma in children

Recognizing the need for continual appraisal of the benefits and risks of asthma medications in children, the NAEPP Expert Panel considered new studies comparing the effectiveness of ICS monotherapy with that of as-needed SABAs and other controllers used as monotherapy in children with mild or moderate persistent asthma. In addition, the safety of long-term ICS use in children was evaluated based on vertical growth, bone mineral density, ocular toxicity, and adrenal suppression.

Effectiveness of ICSs compared with other asthma medications

Short-acting β₂-adrenergic agonists. Eight studies met the eligibility criteria for evaluating the effectiveness of ICSs versus as-needed SABAs.^6,10-16 Six studies (4 involving budesonide) in children 5 years and older showed that ICSs improve lung function and symptoms and reduce the need for emergency intervention compared with as-needed SABAs.¹ Among all studies included in the NAEPP update, the Childhood Asthma Management Program (CAMP) Research Group Study,⁹ a placebo-controlled study of inhaled budesonide and nedocromil, contributed the most evidence. Studies with children 5 years and younger are limited to 2 small studies enrolling a total of 69 children.^6,15 Consistent with studies of older children, these studies indicate that ICSs improve asthma control compared with as-needed SABAs.¹

Cromolyn and nedocromil. Despite well-established safety profiles, cromolyn and nedocromil are no longer recommended as first-line therapy for children, even those with mild disease. New recommendations reflect the greater effectiveness of inhaled budesonide compared with nedocromil demonstrated in the CAMP study,¹⁰ and the lack of apparent benefit of cromolyn as maintenance treatment in childhood asthma reported by Tasche and colleagues in a systematic review of the literature.¹⁷

In the CAMP study, children 5 to 12 years of age receiving inhaled budesonide showed greater reductions in symptoms and albuterol use, lower rates of hospitalization and urgent care visits, and less need for additional asthma therapy and oral prednisone compared with placebo over 4 to 6 years of treatment.¹⁰ The marginal effectiveness of nedocromil demonstrated in the CAMP study mirrored that of cromolyn reported in the review of 24 randomized placebo-controlled studies by Tasche and colleagues.^1,17

For children 5 years and younger, the NAEPP Expert Panel took into account 1 randomized placebo-controlled study conducted with children 2 to 5 years of age; it showed improvements in lung function, symptoms, and bronchial hyperre-activity with inhaled budesonide.⁹ Support for the new NAEPP recommendations preferring ICSs for preschool children is found in a more recent open-label study¹⁸ that showed greater symptom improvement and significantly lower rates of asthma exacerbations, urgent care visits, and oral prednisone use with budesonide inhalation suspension, compared with cromolyn sodium nebulizer solution (Intal Nebulizer Solution) in children 2 to 6 years of age with persistent asthma.

Leukotriene modifiers. The LTRAs zafir-lukast and montelukast are approved for use in children. According to the NAEPP Expert Panel, studies have shown only modest improvements in lung function and other asthma control outcomes with LTRA monotherapy in children as young as 6 and 2 years, respectively.¹ Because studies comparing ICSs with LTRAs in children are lacking, findings of greater overall efficacy of ICSs in adults with persistent asthma have been extrapolated for use with children; clear superiority of ICSs versus LTRAs in most outcomes has resulted in the recommendation for ICSs as the preferred treatment for mild persistent asthma in children.

Long-acting β₂-adrenergic agonists. There is no role for LABAs as monotherapy in asthma. No studies have compared the effectiveness of ICS versus LABA monotherapy in children younger than 5 years, and studies in older children have shown greater effectiveness of inhaled beclomethasone versus salmeterol.^14,19 In the study by Verberne and colleagues, salmeterol monotherapy was associated with deterioration in FEV₁.¹⁹ In a more recent study that included patients as young as 16 years, a switch from ICS to LABA treatment was associated with a significant increase in treatment failures and exacerbations.²⁰

Theophylline. Only 1 study has compared outcomes with low-dose ICSs versus theophylline in adults and children.²¹ Although limited, the data support greater effectiveness of ICSs based on symptoms, bronchial hyperresponsiveness, and the need for β₂-adrenergic agonists and oral corticosteroids.¹

Safety of long-term ICS use in children

Systemic corticosteroids have the potential to suppress growth over the long term.² Short-term growth studies with ICSs show an average reduction in growth velocity of 1 cm per year during the first year of treatment, but the CAMP study showed that initial reductions in growth velocity with inhaled budesonide were not maintained over a 4- to 6-year treatment period.^1,10

Although catch-up growth was not observed in the CAMP study, Agertoft and Pedersen reported no effect of long-term treatment with inhaled budesonide (mean 9.2 years) on final adult height.²² Based on these long-term prospective studies of budesonide, showing only a transient reduction in growth velocity and attainment of expected final adult height, and retrospective studies including inhaled beclomethasone, the Expert Panel concluded that the ICS class is safe regarding growth effects.