PEDIATRIC ASTHMA: Helping Kids Breathe Easier

Schuman Tam, MD

Asthma is a chronic respiratory disease characterized by inflammation of the airway and manifested as wheezing, dyspnea and/or cough. According to the National Center for Health Statistics, pediatric asthma prevalence increased steadily in the decade beginning in 1999 from 108 to 138 cases per 1,000.[1] In 2011, an estimated 9.6% of children aged 0-19 had asthma. The prevalence of asthma is higher in male children, a pattern opposite of that reported in adults. About 40% of pediatric asthma patients had at least one asthma attack during the previous 12-month period. In 2008, children aged 5-17, with at least one asthma attack in the previous year, were reported to have missed 10.5 million school days in the previous year. Childhood asthma is thus a common, disabling and potentially life-threatening chronic condition.

The National Heart, Lung, and Blood Institute helped develop two asthma research networks in the 1990s: the Asthma Clinical Research Network (ACRN) and the Childhood Asthma Research and Education (CARE). The two networks provided a mechanism for an evidence-based approach for evaluating and treating bronchial asthma. The result of these efforts was the National Asthma Education and Prevention Program (NAEPP) guidelines. The most recent guidelines were published in 2007. The next guidelines will likely be based on new data generated by the two research networks. This article discusses the studies that shaped the 2007 NAEPP guidelines and examines recent published studies that likely will shape future care of asthma patients.

In the early 1990s, considerable controversy existed regarding the safety of using regular short-acting beta agonists for asthma. The Beta Agonist Study (BAGS), published in 1996, showed that using 2 puffs of albuterol 4x per day was neither beneficial nor harmful compared to albuterol usage on an as-needed basis.[2] The authors concluded that inhaled albuterol should be prescribed for patients with asthma on an as-needed basis. The limitation of this study was that the subjects were primarily adult patients. The NAEPP incorporated the study findings into its recommendation that as-needed usage of short-acting beta agonist was essential.

In the late 1990s, it was reported that adding salmeterol, a long-acting bronchodilator, to patients who were on inhaled steroid was more effective than increasing the inhaled steroid dose. The Salmeterol or Corticosteroid Study (SOCS), published in 2001, showed that for asthma patients 12 to 65 years old who were controlled on inhaled steroid, switching to long-acting bronchodilator alone or to placebo alone resulted in more frequent treatment failures and exacerbations.[3] The authors concluded that it was inappropriate to use long-acting bronchodilator alone without inhaled steroid. Performed in parallel to the SOCS trial was the Salmeterol +/- Inhaled Corticosteroid (SLIC) trial, also published in 2001.[4] This study of patients with moderate asthma showed that the addition of a long-acting bronchodilator to inhaled steroid allowed up to 50% reduction in inhaled steroid dose; however, the inhaled steroid could not be eliminated without loss of asthma control.

Prior to 2006, it was unknown whether inhaled steroid could modify subsequent development of asthma. To address this question, the CARE network conducted its first trial: the Prevention of Early Asthma in Kids (PEAK).[5] This 3-year-long trial studied 2-3 year olds with positive asthma predictive index. One group was treated with fluticasone 88 mcg 2x per day and another group with placebo 2x per day. After 2 years, treatment was stopped, and subjects were observed the following year. During the 2-year active treatment period, usage of inhaled steroid was associated with a higher proportion of asthma-free days, fewer exacerbations, and a reduced need for supplemental controller medications. During the observation year, after treatment was stopped, there was no significant difference between the groups in asthma-free days, exacerbations or pulmonary function. The authors concluded that children with a high probability of persistent asthma did better in terms of asthma control while actively receiving steroid; but that benefit disappeared soon after the steroid was stopped, and compared to placebo, there was no improvement in lung function. The early usage of inhaled steroid did not have a disease-modifying effect after 2 years, and such usage was unable to alter the natural history of asthma in high-risk preschool children.

The two common controller medications for mild persistent asthma are inhaled steroid and leukotriene modifier. To compare these medications, the CARE network in the early 2000s conducted the Characterizing the Response to a Leukotriene Receptor Antagonist and an Inhaled Corticosteroid (CLIC) trial.[6,7] This randomized crossover trial compared the responses of patients aged 6 to 17 with mild to moderate asthma treated for 2 months with inhaled steroid, fluticasone 100 mcg bid x 2 months, with an age-appropriate montelukast dose administered, resulting in a greater than 7.5% improvement of FEV1. Seventeen percent of the subjects responded to fluticasone or montelukast; 23% responded to fluticasone alone; 5% responded to montelukast alone; 55% responded to neither medication. When other asthma clinical measures were considered, improvement was significantly higher with inhaled steroid treatment than with montelukast treatment.

The CLIC findings support the NAEPP guidelines’ preference of inhaled steroid as first-line therapy for mild to moderate persistent asthma in children. It is also important to remember that 5% of the asthmatic children responded to montelukast and not fluticasone. Therefore, asthmatic patients are heterogeneous, and not all patients respond to one medication. If a patient is not responsive to inhaled steroid, it is appropriate to try an alternative, such as leukotriene modifier.

To further confirm the effectiveness of inhaled steroid, to compare effectiveness between inhaled steroid and leukotriene modifier, and to study the effect of adding a long-acting bronchodilator, the CARE network in 2002 conducted the Pediatric Asthma Controller Trial (PACT) in asthmatic subjects 6-14 years old, with mild persistent asthma.[8] This trial allocated subjects into 3 groups: 1) fluticasone 100 mcg bid; 2) fluticasone 100 mcg qAM and salmeterol 50 mcg bid; 3) montelukast 5 mg qPM.

Group 1 and Group 2 had similar patient-measured outcomes, including percentage of asthma control days and prevention of asthma exacerbations. Group 1 (inhaled steroid only) was superior to Group 3 (montelukast) for asthma control outcomes, including asthma control days and improvement of lung function. Similar to the CLIC study, inhaled steroid was more effective than leukotriene modifier. Similar to the SLIC trial, the PACT trial showed that addition of long-acting bronchodilator in group 2 with half the dose of inhaled steroid, as compared to group 1, could achieve similar asthma control days and improvement of lung function.

In summary, inhaled steroid is statistically more effective than leukotriene modifier, and the addition of long-acting bronchodilator to inhaled steroid may allow practitioners to use a lower dose of inhaled steroid to achieve the same asthma control.

The Childhood Asthma Management Program (CAMP) research group, which conducted a prospective study to investigate the effectiveness and safety of inhaled steroid, reported the results in 2000 and issued a follow-up report in September 2012.[9,10] In late 1993, 1,041 children aged 5-12 with mild to moderate persistent asthma were recruited and randomized to 3 groups: 1) 200 mcg budesonide inhaling bid; 2) 8 mg nedocromil inhaling bid; 3) placebo. Subjects were treated for 4-6 years with the respective drugs and placebo.

After 4 years of active treatment, neither budesonide nor nedocromil were better than placebo in terms of lung function as measured by post-bronchodilator FEV1. Post-bronchodilator FEV1 is a measurement of fixed airway obstruction; therefore, percent-predicted post-bronchodilator FEV1 over time indirectly and non-invasively measure airway remodeling. Neither inhaled budesonide nor nedocromil attenuated airway remodeling compared with placebo. The inhaled budesonide group, however, had better control of asthma than the placebo and nedocromil groups.

Similar to the PEAK trial in younger children, the initial findings for the CAMP trial showed that inhaled steroid could not alter the natural history of asthma, namely airway remodeling with progressive loss of lung function. During active treatment, inhaled steroid was better than placebo for asthma symptom control. Subsequent analysis of the data showed that there was a subgroup (about 25%) among the 1,041 children who seemed to have a more rapid decline in post-bronchodilator FEV1.[11] Therefore, about 25% of the asthmatic children might have progressive deterioration of lung function. Inhaled steroid is unable to revert this natural course, although it can reduce asthma symptoms and exacerbation during treatment. An international study called START also confirmed the finding that inhaled steroid was unable to prevent deterioration of lung function.[12]

Prior to the 13-year follow-up of the CAMP trial, it was generally believed that children who received inhaled steroid were able to achieve adult height. One study concluded that reduction in growth velocity was transient during the early phase of initiation of inhaled steroid.[13] This study, however, was based on a small control group--not on a direct comparison between an inhaled steroid group and a control group.

Investigators in the CAMP trial performed a study on their cohorts 13 years after the 4-year treatment with inhaled steroid, inhaled nedocromil and inhaled placebo.[10] During the 13-year period, the patients were treated by their primary physicians per NAEPP under advisement from CAMP physicians. Follow-ups were done at the CAMP study centers for height and weight measurements 2x per year for the first 4.5 years, and 1x year for the next 8 years. Up to 90% of the original cohorts were successfully retained for measurement of height at adulthood.

Mean adult height was 1.2 cm lower in the group treated with budesonide initially than the group treated with placebo. The initial reduction in growth during the 4-year treatment period during childhood was 1.2 cm, and that reduction persisted into adulthood. It appeared the difference in growth seen in the first two years of assigned treatment in the budesonide group, as compared with placebo group, was primarily among prepubertal participants 5-10 years old.

When treating pediatric asthma patients, practitioners have to weigh the potential growth-reduction side effect with the well-established efficacy of inhaled steroid in controlling persistent asthma. It is appropriate to use the lowest effective dose for symptom control in order to minimize concern about the effects of inhaled steroid on adult height.

The 2007 NAEPP guidelines,[14] driven by data generated by the ACRN and CARE networks, provide a good knowledge base for physicians to follow in treating their asthma patients. It is clear that inhaled steroids are effective in controlling persistent asthma, but not in altering the natural history of asthma--namely progressive deterioration of lung function in certain subgroups of patients with persistent asthma. The daily use in children, especially from ages 5 to 10, can result in a reduction of growth during the first two years of use, and the resulting difference in height persists into adulthood. Therefore, the recommendation of the NAEPP Guideline is appropriate: obtain control, then step down to the lowest dose possible to reduce the risk of the controller medication.

There are many unanswered questions in caring for pediatric asthma patients. In adult asthmatic patients, evidence based on the IMPACT trial and the more recent BASALT trial demonstrated that intermittent usage of inhaled steroid based on symptoms was similar to daily usage of inhaled steroid in patients with mild to moderate asthma.[15,16] Can this same principle be applied to pediatric asthma patients? We need studies similar to the IMPACT and BASALT trials to answer that question. Such studies may help reduce inhaled steroid usage in pediatric asthma patients; they may also become the basis for changes in treatment guidelines for mild persistent asthmatic patients.

Similarly, the adult TALC trial showed that addition of tiotropium inhaler to inhaled steroid was not inferior to adding salmeterol to inhaled steroid in treating adult patients with moderate persistent asthma.[17] Another recent finding is that adding tiotropium to patients on inhaled steroid and long-acting bronchodilator could improve asthma control by reducing the chance of an exacerbation and by improving bronchodilation.[18] We need studies of tiotropium in pediatric asthma patients, which again may help to reduce inhaled steroid usage.

Until the next NAEPP guideline update is available, practitioners should also become familiar with the recent data generated by the CARE network, the ACRN network and the CAMP research group in order to generate appropriate treatment plans for their patients.

 

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Dr. Tam, a clinical professor at UCSF, is an asthma and allergy specialist at the Asthma & Allergy Clinic of Marin & San Francisco. Phone: 415-461-8909

Acknowledgements: I thank Donald German, MD, Lily Lee, PharmD, and Angela Tam for valuable comments on this manuscript.

References

1. Akinbami LJ, et al, “Asthma prevalence, health care use, and mortality: United States, 2005–2009,“ National Health Statistics Reports, No. 32 (Jan. 12, 2011).

2. Drazen JM, et al, “Comparison of regularly scheduled with as-needed use of albuterol in mild asthma,” NEJM, 335:841-847 (1996).

3. Lazarus SC, et al, “Long-acting β2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma,” JAMA, 285:2583-93 (2001).

4. Lemanske RF, et al, “Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol,” JAMA, 285:2594-603 (2001)

5. Guilbert TW, et al, “Long-term inhaled corticosteroids in preschool children at high risk for asthma,” NEJM, 354:1985-97 (2006).

6. Szefler SJ, et al, “Characterization of within-subject responses to fluticasone and montelukast in childhood asthma,” JACI, 115:233-242 (2005).

7. Zeiger RS, et al, “Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma,” JACI, 117:45-52 (2006).

8. Sorkness CA, “Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: The PACT Trial,” JACI, 119:64-72 (2007).

9. CAMP Research Group, “Long-term effects of budesonide or nedocromil in children with asthma,” NEJM, 343:1054-63 (2000).

10. Kelly HW, “Effect of inhaled glucocorticoids in childhood on adult height,” NEJM, 367:904-912 (2012).

11. Covar RA, et al, “Progression of asthma measured by lung function in the Childhood Asthma Management Program,” Am J Respir Crit Care Med, 170:234-241 (2004).

12. Pauwels RA, et al, “Early intervention with budesonide in mild persistent asthma,” Lancet, 361:1071-76 (2003).

13. Agertoft L, Pedersen S, “Effect of long-term treatment with inhaled budesonide on adult height in children with asthma,” NEJM, 343:1064-69 (2000).

14. NAEPP, “Guidelines for the Diagnosis and Management of Asthma,” www.nhlbi.nih.gov/guidelines/asthma (2007).

15. Boushey HA, et al, “Daily versus as-needed corticosteroids for mild persistent asthma,” NEJM, 352:1519-28 (2005).

16. Calhoun WJ, et al, “Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma,” JAMA, 308:987-997 (2012).

17. Peters SP, et al, “Tiotropium bromide step-up therapy for adults with uncontrolled asthma,” NEJM, 363:1715-26 (2010).

18. Kertsjens HA, et al, “Tiotropium in asthma poorly controlled with standard combination therapy,” NEJM, 367:1198-1207 (2012).