Individual Benefit vs Societal Effect of Antibiotic Prescribing for Preschool Children With Recurrent Wheeze

Wheezing is prevalent in early childhood, with 50% of US children having at least 1 episode before 6 years of age1 and one-third of preschool children having an episode within the prior 6 months.2 Rates for wheezing-related emergency department visits are highest among children younger than 5 years, and severe wheezing episodes are a common cause of hospitalization in this age group,3 reflecting the therapeutic challenges in managing these episodes. Several groups of investigators have tried to determine which therapies might be most effective for young children with recurrent wheeze. In the last decade, clinical trials have focused on using conventional asthma therapies, such as inhaled corticosteroids or montelukast, either continuously for long periods of time as a preventive approach4,5 or intermittently in the setting of acute episodes.6 Many of those studies explicitly targeted children at high risk of developing asthma because of strong family history or mild to moderate symptoms between episodes. In contrast, the National Heart, Lung, and Blood Institute’s Childhood Asthma Research and Education (CARE) Network’s Acute Intervention Management Strategies (AIMS) trial7 enrolled a particularly challenging group of young children: those who experience severe recurrent wheezing episodes in the setting of lower respiratory tract illnesses (LRTIs) but who, in-between episodes, are generally asymptomatic. They compared initiation of inhaled budesonide or oral montelukast with placebo at the onset of symptoms that had previously precipitated severe wheezing and found no differences across the 3 groups in terms of episode-free days, oral steroid courses, health care utilization, or quality of life over the year of the trial, suggesting that traditional asthma therapy is not an effective approach for all young children with intermittent LRTI-associated wheeze. Mechanistic studies of viral respiratory tract illnesses (RTIs) offer clues as to why traditional asthma treatments may be suboptimal for this patient population. Respiratory syncytial virus (RSV) bronchiolitis has been associated with increased expression of interleukin 17A in the airways of affected patients, leading to increased levels of interleukin 8 (IL-8) and neutrophilic airway inflammation,8 which is less responsive to corticosteroids than asthma characterized by eosinophilic inflammation. In addition, infants with RSV bronchiolitis demonstrate increased expression of glucocorticoid receptor β,9 which has been associated with glucocorticoid insensitivity in prior studies. Human rhinovirus infection has also been associated with increased production of pro-inflammatory cytokines that promote neutrophilic airway inflammation.10 In this issue of JAMA, Bacharier and colleagues11 present the results of the Azithromycin for Preventing the Development of Upper Respiratory Tract Illness Into Lower Respiratory Tract Symptoms in Children (APRIL) trial, which addresses this group of children with severe intermittent LRTI-associated wheezing. The APRIL trial randomized children aged 12 through 71 months with recurrent wheezing episodes to receive 5 days of either azithromycin or placebo (in addition to supportive care and albuterol) at the onset of symptoms that had previously led to a severe LRTI. Participants needed to meet a minimum number of prior episodes that defined recurrent wheezing, but if they had more than 2 prior hospitalizations, more than 4 courses of oral steroids, had been using more than low-dose controller monotherapy at the time of enrollment, or had been using a controller for more than 8 months, they were deemed to have disease that was too severe for inclusion. Forty percent of the study population was atopic, and 47% were considered to be at high risk for developing asthma, based on having a positive modified Asthma Predictive Index (API). Of the 607 children enrolled, 443 children experienced 937 RTIs and 92 severe LRTIs. A significantly decreased risk of progressing to a severe LRTI (defined as exceeding a specified amount of rescue albuterol use or having “moderate to severe” cough and wheeze for 5 days or more) was demonstrated among the azithromycin group compared with the placebo group (hazard ratio, 0.64 [95% CI, 0.410.98], P = .04), as well as decreased illness severity during episodes that progressed to LRTI. In contrast to the AIMS trial, there was no difference in treatment effects between those with and without a positive modified API. The efficacy of azithromycin in this population contrasts with the lack of benefit of traditional asthma therapy and suggests a different pathophysiology despite overlapping acute signs and symptoms. The finding that macrolides may be helpful in this challenging population potentially reflects both their antimicrobial effects (atypical bacteria do play a significant role in some LRTIs in young children12) and, more likely, their antiinflammatory effects. In mouse models of infection-induced neutrophilic airway inflammation, treatment with azithromycin attenuated pro-inflammatory cytokine expression Related article page 2034 Opinion