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Update on National Asthma Education and Prevention Program Pediatric Asthma Treatment Recommendations

Posted on: Saturday, 18 December 2004, 03:00 CST

Summary:The National Asthma Education and Prevention Program (NAEPP) published an update on selected topics from the 1997 Guidelines for the Diagnosis and Management of Asthma and provided new evidence-based recommendations for asthma treatment. Selected topics on the long-term management of asthma in children addressed the efficacy of inhaled corticosteroids (ICSs) compared with other asthma medications (i.e., as-needed β^sub 2^-adrenergic agonists and other controllers) in mild and moderate persistent asthma and the safety of long-term ICS use. The effects of early intervention with ICSs on asthma progression also were evaluated. An important new aspect of the treatment update entails the recommendation of ICSs as the controller medication of choice for all severities of persistent asthma in children. Additionally, on the basis of studies in adults, the Expert Panel suggested that long- acting β^sub 2^-adrenergic agonists are now the preferred adjunct to ICSs in children with moderate or severe persistent asthma. Based on long-term data in children, ICS therapy was deemed safe in terms of growth, bone mineral density, ocular effects, and hypothalamic pituitary adrenal axis function. Although members of the NAEPP Expert Panel determined that the effects of early intervention with ICSs on decline in lung function have not been adequately studied, they found that the effects on asthma control were substantial. Clin Pediatr. 2004;43:793-802

Introduction

Asthma is a leading cause of chronic childhood illness in the United States.1,2 In 2001, an estimated 6.3 million children were diagnosed with asthma.1 Children between the ages of 5 and 17 years have the highest asthma prevalence rate as well as the highest 12- month asthma attack rate.1 Asthma-related morbidity is considerable in children, as evidenced by an estimated 14 million missed school days each year due to asthma at a cost of approximately $1,389 million in 2002.1,2

In 2002, the National Asthma Education and Prevention Program (NAEPP) conducted a systematic review of the literature and published an update on selected topics from the 1997 NAEPP Guidelines for the Diagnosis and Management of Asthma. A major focus of the review was the relative efficacy of long-term controller medications in children and the safety of long-term inhaled corticosteroid (ICS) use in this population. Findings of the 2002 NAEPP Expert Panel Report are reviewed here with a focus on evidence- based changes to previous NAEPP treatment recommendations. Panel findings on ICS safety and the effects of early ICS intervention also are reviewed.

Pathogenesis of Asthma

Chronic airway inflammation plays a central role in the pathogenesis of asthma.3,4 In susceptible individuals, inflammation leads to recurrent wheeze, breathlessness, chest tightness, and cough, with variable airway obstruction and an increased susceptibility to bronchospasm.5

Asthma medications are classified as "quick-relief" or "controller" medications. Symptoms arising from bronchospasm respond rapidly to the as-needed use of quick-relief medications (i.e., short-acting β^sub 2^-adrenergic agonists [SABAs], anticholinergics, systemic corticosteroids). Long-term controller medications (i.e., ICSs, leukotrieno modifiers, long-acting β^sub 2^-adrenergic agonists [LABAs], cromolyn sodium, nedocromil sodium, theophylline) are taken on a daily basis to reduce the frequency and severity of exacerbations and to reverse airflow obstruction. Antiinflammatory agents are considered the most effective asthma controller medications.5 The broad range of antiinflammatory activity demonstrated by ICSs5 may explain their potent and consistent effectiveness in controlling asthma.5

Asthma Diagnosis

The diagnosis of asthma is based on the presence of recurrent symptoms of airflow obstruction, partially reversible airflow limitation, and the exclusion of other diagnoses. Other causes of childhood and infantile wheeze include other inflammatory disorders such as cystic fibrosis and bronchopulmonary dysplasia; infectious conditions such as tracheitis, bronchiolitis, pertussis, and Chlamydia infection; feeding and gastrointestinal problems such as acid reflux, formula intolerance, milk or food allergies, aspiration, tracheoesophageal fistula, and laryngeal cleft; congenital malformations such as vascular ring or sling, airway anomalies, and esophageal cysts; and finally, any airway compression by a foreign body or a lymphadenopathy.5

For children 5 years of age or younger, symptom similarity to other childhood illnesses, the absence of wheeze in some instances, and the lack of objective measures to assess lung function complicate the diagnosis of asthma. The most common cause of asthma symptoms in younger children is viral respiratory infection.3 Some infants and children who wheeze with respiratory infections may show a remission of symptoms in preschool years, whereas others may develop persistent asthma. Children at a high risk of developing persistent symptoms can be identified based on frequency of symptoms and other high-risk factors (Table 1).3,7

Table 1

NAEPP CRITERIA FOR INITIATION OF CONTROLLER THERAPY IN INFANTS AND YOUNG CHILDREN3,7

NAEPP Stepwise Approach to Asthma Treatment

NAEPP treatment recommendations for asthma follow a stepwise approach that is based on disease severity (i.e., mild intermittent to mild, moderate, and severe persistent). Criteria for assessing the severity of asthma in children are based on the frequency of symptoms (Table 2). For children older than 5 years, criteria also include objective measures of lung function. For patients with mild intermittent asthma, the use of a SABA is recommended as needed for symptom relief. For all patients with persistent asthma, daily controller medication is required.

The stepwise approach to asthma treatment is based on the rapid achievement of asthma control using a short course of systemic corticosteroids, if needed, followed by maintenance of asthma control with daily controller treatment. A review of treatment every 1 to 6 months is recommended to enable a gradual step-down in controller medication to the minimal effective dose. If control is not maintained, a step-up in medication may be required, but only after a thorough review of environmental control measures and medication administration technique and adherence.

NAEPP Recommendations for Long-term Control of Persistent Asthma

The NAEPP recommendations for the use of controller medications in children aged 5 years and younger and those older than 5 years with persistent asthma are summarized in Tables 3 and 4, respectively. Previous (1997) and updated (2002) recommendations are compared for both patient populations. The updated recommendations reflect 2 key changes: availability of a wider range of controller medications approved for use in preschool-aged children (Table 5) and recognition of ICSs as the controllers of choice for all severities of persistent asthma.

Table 2

NAEPP CRITERIA FOR ASTHMA SEVERITY CLASSIFICATION3

Effectiveness of ICSs Compared With Other Asthma Medications

Ten studies enrolling 2,210 patients were included in the Expert Panel's determination of the relative effectiveness of ICSs compared with as-needed SABAs or other controllers.3 Of these studies, the Childhood Asthma Management Program (CAMP) study was the most comprehensive study evaluated.

Evidence for the efficacy of ICS treatment over as-needed SABA use in children older than 5 years was obtained from 6 studies enrolling a total of 652 control patients and 790 children treated with ICSs.3,8-13 Overall, greater asthma control was shown with ICSs versus as-needed SABAs with no controller medication. Children receiving ICSs experienced improvements in prebronchodilator forced expiratory volume in 1 second (FEV^sub 1^), airway hyperresponsiveness, and asthma symptoms, as well as reduced hospitalizations and need for rescue medication, compared with control patients.3

Consistent with results in children older than 5 years, 2 small trials enrolling a total of 69 children 5 years old and younger demonstrated improved asthma control with ICSs versus placebo.14,15 These studies highlight the need for daily controller treatment, in particular ICSs, in children with persistent asthma.

Results of the CAMP study provide clear evidence of the greater efficacy of ICSs over nedocromil.8 This randomized, placebo- controlled study compared the efficacy of inhaled budesonide (200 g twice daily [b.i.d.]) and nedocromil (8 mg b.i.d.) with placebo over a 4- to 6-year period in 1,041 children aged 5 to 12 years with mild to moderate persistent asthma. In this study, children receiving budesonide demonstrated significant improvements in asthma control compared with placebo, whereas patients receiving nedocromil showed only marginal improvement in 2 outcomes (prednisone requirement and urgent care visits). From these results, the Expert Panel concluded that ICSs are more effective than nedocromil in reducing the frequency and severity of symptoms, the frequency of asthma-related hospitalizations, and the use of supplemental SABA.3,8 In children 5 years old and younger, nedocromil has not been adequately studied. Acco\rdingly, the Expert Panel recommendation for nedocromil is limited to that of an alternative to the preferred use of ICSs in children older than 5 years.3 The Expert Panel considers cromolyn an alternative option for the maintenance of mild or moderate persistent asthma treatment in children of all ages, based on 1 published systematic review of data on the effectiveness of cromolyn sodium.16

Table 3

NAEPP TREATMENT RECOMMENDATIONS FOR LONG-TERM CONTROL OF ASTHMA IN CHILDREN ≤5 YEARS OF AGE3,5

Table 4

NAEPP TREATMENT RECOMMENDATIONS FOR LONG-TERM CONTROL OF ASTHMA IN CHILDREN >5 YEARS OF AGE3,5

Consistent with these recommendations, a recently published study found that nebulized budesonide inhalation suspension resulted in greater symptom improvement and significantly lower rates of asthma exacerbations, urgent care visits, and oral prednisone use compared with nebulized cromolyn in 335 children 2 to 6 years of age with persistent asthma.17

Leukotriene modifiers include the leukotriene receptor antagonists (LTRAs) zafirlukast and montelukast, and the 5- lipoxygenase inhibitor zileuton. When used as monotherapy, LTRAs are associated with modest improvements in lung function in children as young as 6 years and in asthma control outcomes in children as young as 2 years.3 In adolescents and adults, ICSs are superior to LTRAs for most outcomes.3,18,19 Low-dose fluticasone propionate (88 g b.i.d.) provided significantly greater improvements in lung function, rescue medication use, asthma symptoms, and nighttime awakenings compared with montelukast (10 mg once daily) and zafirlukast (20 mg b.i.d.) in patients aged 15 years and older and 12 years and older, respectively. Updated NAEPP recommendations for the preferred use of ICSs over LTRAs in young children are based on extrapolation of data from older patients.3

Table 5

ASTHMA CONTROLLER MEDICATIONS APPROVED FOR USE IN CHILDREN

LABAs are not recommended as monouierapy for the treatment of persistent asthma. Two studies enrolled a total of 116 children treated with ICSs, 112 treated with a LABA, and 80 treated with placebo. Results showed greater improvements in lung function and some asthma symptoms and less need for additional asthma medication with ICS treatment than with either LABA or placebo treatment.3,10,20 In 1 study, salmeterol rnonotherapy led to a deterioration in FEV^sub 1^.3,20 In another study that enrolled 164 patients aged 12 to 65 years, a switch from ICS to LABA treatment was associated with a significant increase in asthma exacerbations and treatment failures.3,21

For use as add-on treatment, studies in adults and children older than 5 years support the addition of LABAs to low- to medium-close ICSs. Evidence favoring the addition of a leukotriene modifier or theophylline or doubling the dose of an ICS is not as substantial. Thus, for children 5 years and older, the preferred treatment for moderate persistent asthma is the addition of a LABA to ICS therapy.3

Although comparative studies in older children and adults favor the use of combination ICS plus LABA treatment, this combination has not been studied in children 5 years old and younger, and there are no studies evaluating the use of LABAs in children 4 years and younger. However, studies have shown that ICSs, within the medium- dose range, are effective in the treatment of moderate and severe persistent asthma in preschool-aged children. From this finding and extrapolation of data supporting combination therapy in older children, the Expert Panel recommends the use of low-dose ICS plus a LABA or increased ICS dose (medium-dose range) as preferred treatment for children 5 years and younger with moderate persistent asthma not controlled with low-dose ICSs.3

Only 1 published study compared the effectiveness of ICS versus theophylline treatment in children.3,22 Results showed a greater reduction in symptoms and bronchial hyperresponsiveness and a reduced need for β^sub 2^-adrenergic agonists and oral corticosteroids with ICS treatment, prompting recommendations for theophylline as an alternative controller only in children older than 5 years with mild persistent asthma, and as an alternative add- on treatment in children with moderate disease.

Safety of Long-term ICS Use in Children

A review of the safety of long-term ICS use also was undertaken by the NAEPP. Safety was determined based on vertical growth, bone mineral density, ocular toxicity, and hypothalamic pituitary adrenal (HPA) axis function.

In a meta-analysis of data from 5 randomized, controlled studies enrolling a total of 855 children (mean age, 9.5 years), patients treated with ICSs for 1 year grew, on average, about 1 cm less than patients not receiving ICSs.23 CAMP study results are consistent with those of short-term growth studies in showing decreased growth velocity in children receiving inhaled budesonide primarily during the first year of treatment.8 However, during subsequent years, the difference in growth velocity was not sustained. At the end of the 4- to 6-year treatment period, the mean height increase with budesonide was 1.1 cm less than with placebo.8

Three cohort studies assessing final adult height in children who were treated with ICSs also were reviewed. One study showed a slight difference in final adult height between patients treated with ICSs and corticosteroid-nave patients, but the difference was less than expected based on reported short-term changes in growth velocity.3,24 The remaining 2 studies showed no effect of ICS use on final adult height.25,26 In 1 of these studies, Agertoft and Pedersen25 reported achievement of predicted adult height despite initial growth velocity reductions in children who had been treated with inhaled budesonide (mean daily dose, 412 g) for a mean of 9.2 years. Although not reviewed by the Panel, 1 final study showed no significant difference in final adult height among asthmatic children receiving a long-term ICS (beclomethasone dipropionate 400- 600 g once daily), sodium cromoglycate, or sodium cromoglycate plus bronchodilator treatment.27 From these studies, the Expert Panel concluded that the potential but small risk of delayed growth due to ICS use in children is balanced by the effectiveness of these agents in treating mild or moderate persistent asthma.

From evaluation of data from clinical studies that monitored children for up to 6 years, the Expert Panel determined that low to medium doses of ICSs appear Lo have no long-term or clinically significant adverse effects on bone mineral density or the development of subcapsular cataracts or glaucoma in children.3,8 Moreover, the Panel concluded that the effects of low to medium doses of ICSs on the HPA axis are usually clinically insignificant but that some children may be more sensitive to these effects.3 A recent collaborative effort of the American College of Chest Physicians; the American Academy of Allergy, Asthma and Immunology; and the American College of Allergy, Asthma and Immunology undertaken to evaluate the potential risks of ICS use determined that the preponderance of evidence confirms that the clinical effectiveness of ICSs outweighs any risk of treatment.28

Effects of Early ICS Treatment on Asthma Progression

Accumulating evidence suggests that structural changes in airways (airway remodeling) can occur secondary to the inflammatory process in patients with asthma.4 It has been suggested that progressive airway remodeling in conjunction with airway inflammation may cause permanent declines in lung function.4

Support for early and long-term ICS treatment comes from a recent randomized, double-blind, placebo-controlled study showing greater improvements in airway remodeling and associated bronchial hyperresponsiveness with prolonged (12 months vs 3 months) use of fluticasone propionate in 35 patients with mild to moderate persistent asthma.29 Only about one third of the demonstrated improvement in hyperresponsiveness was associated with early inflammatory changes, whereas the rest was associated with later improvement in airway remodeling.29 Of note, significant airway remodeling may occur even in the absence of continuing symptoms (Figure 1), further supporting the need for continued antiinflammatory treatment.30

Figure 1. Reticular basement membrane (RBM) thickness was used as a measure of airway remodeling in patients with asthma. Thickness of RBM in biopsy specimens is shown in currently asthmatic patients, patients in clinical remission of atopic asthma, and healthy control subjects. Horizontal bars represent median values. Mean age ranged from 21 to 24 years across the 3 groups. (Reprinted with permission from Van Den Toorn LM, Overbeek SE, De Jongste JC, Leman K, Hoogsteden HC, Prins J-B. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med. 2001;164:2107-2113.) Official journal of the American Thoracic Society American Thoracic Society.30

Despite a lack of definitive evidence that ICSs prevent progressively decreasing lung function, improved asthma control supports early ICS use in persistent asthma. Long-term studies indicate that asthma progression, measured by declines in lung- function, varies in different age groups.3,8,31,32 In childhood asthma, lung function declines occur mostly in preschool-aged children with symptom onset before 3 years of age.3,31 Results of the CAMP study demonstrated no progressive decline in lung function (postbronchodilator FEV^sub 1^) among children 5 to 12 years of age with mild to moderate persistent asthma who received placebo, and no significant improvement from baseline among children who received budesonide.3,8

Recent results of the randomized, double-blind, placebo- controlled Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study,33 which enrolled more than 7,000 patients aged 5 to 66 years with recent-on-set, mild, persistent asthma, did de\monstrate loss of pulmonary function. Furthermore, once-daily administration of budesonide (200 or 400 g) significantly improved postbronchodilator FEV^sub 1^ over 3 years, although the difference from placebo diminished with time. When broken down by age, treatment with inhaled budesonide did not significantly improve postbronchodilator FEV^sub 1^ in children aged 11 to 17 years (n = 1,221).33 Treatment with budesonide did provide significantly greater asthma control, however, with a 44% reduced risk of severe asthma exacerbation.33

Providing a Continuum of Care

Although regular use of ICSs can substantially reduce hospital admissions and readmissions among patients with asthma,34-36 substantial numbers of pediatric patients continue to be readmitted to the hospital for asthma exacerbations. In a retrospective study by Bloomberg and colleagues,37 30% of children hospitalized for asthma over 10 years had at least 1 readmission for asthma within the 10-year period; these readmissions accounted for more than 40% of total asthma admissions. In general, children with asthma underuse controller medications.38 Among those children hospitalized with asthma, few may receive written management plans or education, and few may be discharged on a regimen of ICSs.39 Asthma-related hospitalizations and emergency department visits represent opportunities to assess whether children have been receiving appropriate ICS therapy and, if not, to initiate therapy. Many patients fail to follow up with their primary care physicians after an emergency department visit, and in many instances, opportunities to start preventive medications are missed at follow-up.40 Therefore, a focus on the chronic nature of asthma, with the need for long-term treatment, is needed to ensure a continuum of asthma care after discharge from an emergency department or hospital. This approach may reduce the risk of readmission and decrease asthma morbidity.

Summary

The evidence-based NAEPP guidelines update reinforces the importance of ICS treatment for the control of persistent asthma in children. On the basis of studies comparing ICSs with other controller medications, the NAEPP Expert Panel recommends the preferred use of ICSs for persistent asthma regardless of disease severity.3 For older children with moderate or severe disease, the addition of a LABA to ICS treatment is appropriate to minimize the ICS dose requirement.3 In terms of vertical growth, bone mineral density, ocular toxicity, and HPA axis function, the NAEPP Expert Panel reported that ICS use, at recommended doses, is not associated with long-term, clinically significant, or irreversible adverse effects.3 Moreover, although the prevention of decreasing lung function by ICSs has not been adequately studied, recent data confirm that early intervention and long-term ICS treatment offer substantial benefit to children with asthma in terms of asthma control and potential airway remodeling.31

Acknowledgments

The author acknowledges Sudha Vemuri, PhD, and Leslie Sell, PhD, for their assistance in the preparation of this manuscript.

Disclosure

Dr. Nemr Eid serves on the Speaker Bureau of AstraZeneca.

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18. Busse W, Raphael GD, Galant S, et al, for the Fluticasone Propionate Clinical Research Study Group. Low-dose fluticasone propionate compared with montelukast for first-line treatment of persistent asthma: a randomized clinical trial. J Allergy Clin Immunol. 2001;107:461-468.

19. Busse W, Wolfe J, Storms W, et al. Fluticasone propionate compared with zafirlukast in controlling persistent asthma. A randomized, double-blind, placebo controlled trial. J Fam Pract. 2001;50:595-602.

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29. Ward C, Pais M, Bish R, et al. Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax. 2002;57:309-316.

30. Van Den Toorn LM, Overbeck SE, De Jongste JC, et al. Airway inflammation is present during clinical remission of a topic asthma. Am J Respir Crit Care Med. 2001;164:2107-2113.

31. Zeiger RS, Dawson C, Weiss S. Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol. 1999;103:376- 387.

32. Xuan W, Peat JK, Toelle BG, et al. Lung function growth and its relation to airway hyperresponsiveness and recent wheeze. Results from a longitudinal population study. Am J Respir Care Med. 2000;161:1820-1824.

33. Pauwels RA, Pedersen S, Busse WW, et al, on behalf of the START Investigators Group. Early intervention with budesonide in mild persistent asthma. Lancet. 2003;361:1071-1076.

34. Biais L, Ernst P, Boivin J-F, Suissa S. Inhaled corticosteroids and the prevention of readmission to hospital for asthma. Am J Respir Crit Care Med. 1998;158:126-132.

35. Sin DD, Man SF. Low-dose inhaled corlicosicroid therapy and risk of emergency department visits for asthma. Arch Intern Med. 2003;162: 1591-1595.

36. Suissa S, Ernst P, Kezonh A. Regular use of \inhaled corticosleroids and the long term prevention of hospitalisation for asthma. Thorax. 2003;57:880-884.

37. Bloomberg GR, Trinkaus KM, Fisher EB, et al. Hospital readmissions for childhood asthma. A 10-year metropolitan study. Am J Respir Crit Care Med. 2002;167:1068-1076.

38. Adams RJ, Fuhlbrigge A, Finkelstein JS, et al. Use of inhaled anti-inflammatory medication in children with asthma in managed care settings. Arch Pediatr Adolesc Med. 2001;155:501-507.

39. Fawcelt WA, Gaddis SE. Mild asthma accounts for the majority of pediatric hospital admissions due to chronic disease. Poster presented at: American College of Allergy, Asthma and Immunology Annual Meeting; November 7-12, 2003; New Orleans, LA.

40. Zorc JJ, Scarfone RJ, Li Y, et al. Scheduled follow-up after emergency department visit for asthma: a randomized trial. Pediatrics. 2003;111:495-502.

Nemr S. Eid, MD

This manuscript was supported by AstraZeneca LP.

Reprint requests and correspondence to: Nemr S. Eid, MD, Professor of Pediatrics, Director, Pediatric Pulmonary Medicine and The Childhood Asthma Care and Education Center and The Cystic Fibrosis Center, 571 South Floyd Street, Suite 414, Louisville, KY 40202.

2004 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.

Copyright Westminster Publications, Inc. Nov/Dec 2004

Source: Clinical Pediatrics

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