Approximately one third of children experience an episode of wheezing during the first 3 years of life, and nearly half of these children have recurrent wheezing episodes.1–3In spite of the substantial morbidity associated with this common condition, the optimal approach to management of acute wheezing episodes in young children is not known. Although short-acting β agonists and corticosteroids are frequently used, the effects of these medications in children younger than 3 years of age are less predictable than in school-aged children and adolescents.4 In addition, inhaled and systemic corticosteroids can be associated with harms, so effective corticosteroid-sparing therapies may be preferable.5,6Tiotropium, a selective long-acting anticholinergic agent, has been studied in older children and adults, mostly as adjunctive therapy in patients with moderate-to-severe asthma.7–12 Although not rigorously studied in young children, its anticholinergic mechanism of action offers potential benefits over—or in addition to—β agonists and corticosteroids by simultaneously promoting bronchodilation and preventing mucous secretion.In this issue of Pediatrics, Kotaniemi-Syrjänen et al report results from a randomized, open-label, controlled study of intermittent tiotropium for recurrent acute wheezing episodes in 80 children ages 6 to 35 months.13 Participants with 2 to 4 prior episodes of wheezing were randomized to receive either (1) tiotropium 5 µg once daily for 7 to 14 days, (2) fluticasone 125 µg twice daily for 7 to 14 days, or (3) albuterol 0.2 mg as needed 4 to 6 times daily, each at the onset of an acute respiratory tract infection. Participants in the tiotropium and fluticasone groups also used albuterol as needed. The primary outcome was the proportion of symptom-free days during the 48-week follow-up period, and secondary outcomes were the number of albuterol doses used and the number of adverse events requiring medical attention.Although recruitment was terminated early because of financial, logistical, and ethical reasons, the investigators found that treatment with tiotropium was associated with a greater proportion of symptom-free days (97%) compared with fluticasone (87%) or as-needed albuterol (88%). The differences in the primary outcome between the tiotropium group and the fluticasone and albuterol groups remained statistically significant after a 2-way factorial analysis of variance, accounting for baseline differences across groups. Because the distribution of the number of illness episodes was similar across study groups, the measured effect of tiotropium was attributed to less severe symptoms during illness episodes rather than to less frequent occurrence of illness. Patients in the tiotropium group used albuterol less frequently during illness episodes than those in fluticasone or albuterol groups, and all treatments were found to be safe.The investigators acknowledge important limitations of the study, including the small sample size, which—although not sufficiently small to obscure a difference in the main outcome measure across study groups—limited the study’s power to detect differences in rarer outcomes and may have contributed to imbalances in important baseline characteristics across groups. In addition, the lack of blinding may have led to biased measurement of treatment effects, particularly since the primary outcome was a parent-reported symptom score rather than an objective measure of lung function. Finally, some of the included patients who were less than 24 months of age may have had viral bronchiolitis, for which routine pharmacologic treatment has not been shown to be effective.14Despite these limitations, the investigators deserve praise for conducting an important exploratory study. Their results support prior findings that tiotropium is likely safe in young children15 and provide preliminary evidence that its intermittent use during respiratory tract infections could improve symptoms. If replicated in larger blinded studies, these results suggest that intermittent tiotropium use could prevent, on average, approximately 5 weeks of symptoms per year in young children with recurrent wheezing.This study also highlights the importance of ongoing work to define clinically useful phenotypes in young children with recurrent wheezing episodes. Existing classification systems define wheezing phenotypes according to epidemiologic characteristics, symptoms over time, genetics, and environmental factors.3,4,16–23 Although some of these tools have proven helpful to predict a future diagnosis of asthma, young children may express different phenotypes over time, and whether specific treatments are more effective among patients with different phenotypes is uncertain. In this way, studying the problem through the lens of precision medicine may help to better define which patients with wheezing are most likely to benefit from specific therapies.
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Jan 1, 2023
Samer Alkhuja + 1
Open Access
