ACAAI 2011: Evidence-based Treatment for Childhood and Adolescent Wheezing

NOVEMBER 07, 2011
Michael J. Stillman, PhD
Leonard B. Bacharier, MD, Professor of Pediatrics & Medicine at Washington University in St. Louis School of Medicine, and Clinical Director, Division of Allergy, Immunology, & Pulmonary Medicine of Children’s Hospital in St. Louis, presented a lecture evaluating evidence-based treatments for wheezing and asthma in childhood and adolescence at the Annual Meeting of the American College of Allergy, Asthma and Immunology. 
Dr. Bacharier described a recent meta-analysis of 23 studies (3,592 subjects) with 1-23 months of wheezing or asthma for ≥6 months examined whether ICS, when given continuously to preschool children with recurrent wheeze or asthma, reduce exacerbations. The study found that ICS therapy was associated with significantly fewer exacerbations requiring oral corticosteroids (18 vs 32.1%). The number needed to treat (NNT) was 7 (95% CI 6-9), suggesting an effective treatment. Dr. Bacharier noted that when studies were subdivided into early “asthma” or early “wheezing,” there was a greater effect in subjects with asthma. This effect was independent of age, atopy, ICS type, delivery system, and treatment duration, suggesting that ICS treatment does result in exacerbation prevention in preschool children.
Another study evaluated leukotriene receptor antagonists as maintenance therapy in 549 children 2-5 years old with intermittent asthmatic symptoms. In this 12 month double-blind trial, subjects received either montelukast 4 or 5mg daily or placebo. The montelukast subjects showed such benefits as 31.9% lower rate of exacerbations and longer time to first exacerbation. However, the study’s range of exacerbations was quite broad relative to other studies. As there was no difference in OCS use between groups, this suggested that moderate to severe exacerbations were not very well prevented by this strategy.
Dr. Bacharier next discussed alternate strategies to reduce morbidity among preschool episodic wheezers, first describing two trials of early OCS in children with viral associate wheeze. A 1988 study with some limitations (open labeled, non-randomized) showed very impressive effects of OCS on morbidity markers. It took 15 yrs to redo the study, and they found no difference in these morbidity matters. So now there was a challenge. Dr. Bacharier said, “Maybe our gold standard isn't so golden; maybe OCS doesn't reduce morbidity in this population.”
Dr. Bacharier then described a randomized, double-blinded, placebo-controlled study he performed as part of the CARE Network. The study evaluated 238 children, age12-59 months, with moderate-severe recurrent wheezing in the context of a URI. The primary outcome was proportion of episode-free days over 1 year. Dr. Bacharier’s group examined 3 different treatment strategies administered only during a URI. The twist was that they asked the parents to start therapies at the very first hint that their child was starting to become sick. Not every child started with a runny nose or sore throat—the symptoms were individualized. For 7 days they received either: budesonide 1 mg bid + placebo LTRA + β-agonist; montelukast 4 mg daily + placebo ICS + β-agonist; or placebo LTRA + placebo ICS + β-agonist. There were no between-group differences in the proportion of episode free days or in OCS use. 
The question then became which treatment is superior in preschool children with recurrent severe episodes of wheezing and positive APIs—daily low dose ICS therapy or episodic high dose ICS therapy? Another study with the CARE Network in 278 children 12-53 months of age evaluated this. After a 2-week run-in, there were two treatment groups over 52 weeks. Subjects received either budesonide (0.5 mg) or placebo every day. During respiratory tract illnesses, the daily placebo group received high-dose (1.0 mg, BID), whereas the daily low-dose budesonide continued on that same dose. Dr. Bacharier’s group found no significant difference between daily and intermittent ICS therapy in this population in terms of frequency of exacerbations, nor were there differences in time to 1st exacerbation, or other study variables, including growth effects. 
Next, Dr. Bacharier described the BADGER study. In school age (5-11 years) children who received Step 2 care (low-dose ICS; Evidence A) but did not sufficiently improve, what is the next treatment strategy: increased ICS dose (fluticasone 250 μg BID); add a LABA (salmeterol/fluticasone combination); or add a LTRA (montelukast)? Upon study end, each child was identified as either a differential responder (ie, someone who exhibited significantly better outcomes on one treatment than on another) or non-differential treatment responder. The study design was a three treatment period, double blind, 3-way cross-over, randomized to: 2.5 x ICS = fluticasone DPI 250 μg BID; 1 x ICS+LABA = fluticasone/salmeterol DPI 100/50 BID; 1 x ICS+LTRA = fluticasone DPI 100 μg BID + montelukast. Dr. Bacharier said, “The first result shocked us. A differential response occurred in 98% of participants. We found that LABA step-up was more than 1.5 times as likely to produce the best response. So, 45% of children receiving LABA step-up was when they had their best response. But it’s important to realize that 25% to 28% of these patients experienced their best response either when receiving either higher dose ICSs or ICS+LTRA.” 

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