Azithromycin Does Not Reduce Acute Wheezing Severity in Preschoolers

Reconsidering Azithromycin for Acute Preschool Wheezing

Acute wheezing episodes in preschool-aged children represent a significant cause of emergency department visits and hospitalizations [1]. While often virally mediated, these events are associated with more frequent nasopharyngeal isolation of pathogenic bacteria like Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae in children with recurrent wheezing [2]. This observation has supported the use of antibiotics such as azithromycin, a practice also bolstered by the drug's known anti-inflammatory and immunomodulatory properties, which could theoretically benefit reactive airway disease beyond its antimicrobial effects [2, 3, 4]. However, existing evidence for this approach has been inconsistent, with meta-analyses showing limited benefit on key outcomes like hospital stay or wheezing recurrence [5, 6, 4]. A recent multicenter, randomized controlled trial was designed to provide definitive evidence on this common clinical question.

Trial Design and Patient Characteristics

To determine the efficacy of azithromycin, investigators conducted a multicenter trial enrolling children 18 to 59 months of age who presented to an emergency department with a moderate-to-severe wheezing episode. A total of 840 patients were randomized to receive either azithromycin at a dose of 12 mg per kilogram of body weight once daily or a matching placebo for 5 days. The study's primary endpoint was the total symptom burden over five days, measured by the Asthma Flare-up Diary for Young Children (ADYC), a validated tool where scores range from 5 to 35 and higher scores indicate more severe symptoms. To account for bacterial involvement, efficacy was assessed separately in patients who tested positive for pathogenic bacteria (the positive cohort, n=521) and those who tested negative (the negative cohort). Secondary outcomes included length of emergency department and hospital stays, and rates of return visits or hospitalizations within 72 hours. The trial was ultimately stopped for futility by its data and safety monitoring board after a planned interim analysis, a step taken when accumulating data show an intervention is highly unlikely to prove effective.

Clinical Outcomes: No Benefit for Wheezing Severity

The trial's primary analysis found that azithromycin provided no significant benefit over placebo in reducing the severity of wheezing symptoms. This lack of effect was consistent across patient groups, regardless of bacterial colonization. In the cohort of children who tested positive for pathogenic bacteria, the median 5-day ADYC symptom score was 9.59 (interquartile range, 7.29 to 12.60) in the azithromycin group, nearly identical to the 9.72 (interquartile range, 7.66 to 12.17) score in the placebo group (P = 0.70). The results were similarly null in the cohort that tested negative for bacteria, with a median ADYC score of 9.30 (interquartile range, 6.97 to 11.62) for azithromycin versus 9.10 (interquartile range, 7.19 to 11.45) for placebo (P = 0.69). Furthermore, the study found no advantage for azithromycin on any secondary measures. The length of stay in the emergency department, length of any subsequent hospital stay, and rates of return visits or rehospitalizations within 72 hours were all similar between the treatment and placebo groups for both cohorts.

Bacterial Clearance and Resistance Profile

A key finding from the study was the stark divergence between azithromycin's microbiological activity and its clinical effect. Among patients in the pathogen-positive cohort, the antibiotic was highly effective at its intended antimicrobial task. Bacterial clearance from the nasopharynx was achieved in 58.7% of children receiving azithromycin, compared to just 11.4% in the placebo group. This demonstrates that the drug successfully reduced the targeted bacterial load. However, this robust microbiological effect did not translate into any measurable improvement in wheezing severity or other clinical outcomes. This disconnect suggests that in the context of an acute wheezing episode, the presence of these bacteria in the nasopharynx may represent colonization rather than the primary driver of the underlying inflammatory process responsible for the child's symptoms. Regarding safety and stewardship, the development of antimicrobial resistance and the incidence of adverse events were found to be similar between the azithromycin and placebo groups within the 1 to 3 week follow-up period.

Clinical Implications for Practice

The findings from this large, multicenter trial argue strongly against the routine use of azithromycin for preschool-aged children presenting with moderate-to-severe acute wheezing. The study demonstrates that a 5-day course of azithromycin provides no clinical benefit over placebo in reducing symptom severity, shortening emergency department or hospital stays, or preventing early return visits. This conclusion holds true even in the 521 children who had nasopharyngeal swabs positive for common pathogenic bacteria like S. pneumoniae, M. catarrhalis, or H. influenzae. While the antibiotic effectively cleared these bacteria, this action had no impact on the clinical course of the wheezing illness. For the practicing physician, this result reinforces antibiotic stewardship principles. It suggests that the presence of these bacteria on a nasopharyngeal test during an acute wheeze should not automatically trigger an antibiotic prescription, as the underlying pathophysiology of the episode appears to be independent of this bacterial carriage. The study (ClinicalTrials.gov: NCT04669288), funded by the National Heart, Lung, and Blood Institute and others, provides clear evidence to support withholding antibiotics in this common clinical scenario.

References

1. Grandinetti R, Fainardi V, Caffarelli C, et al. Risk Factors Affecting Development and Persistence of Preschool Wheezing: Consensus Document of the Emilia-Romagna Asthma (ERA) Study Group. Journal of Clinical Medicine. 2022. doi:10.3390/jcm11216558

2. Lei W, Lin H, Tsai M, et al. The effects of macrolides in children with reactive airway disease: a systematic review and meta-analysis of randomized controlled trials. Drug Design Development and Therapy. 2018. doi:10.2147/dddt.s183527

3. Zimmermann P, Ziesenitz VC, Curtis N, Ritz N. The Immunomodulatory Effects of Macrolides—A Systematic Review of the Underlying Mechanisms. Frontiers in Immunology. 2018. doi:10.3389/fimmu.2018.00302

4. Lin C, Yeh T, Liu S, et al. Effects of Macrolide Treatment during the Hospitalization of Children with Childhood Wheezing Disease: A Systematic Review and Meta-Analysis.. Journal of clinical medicine. 2018. doi:10.3390/jcm7110432

5. Ukkonen R, Renko M, Kuitunen I. Azithromycin for acute bronchiolitis and wheezing episodes in children – a systematic review with meta-analysis. Pediatric Research. 2023. doi:10.1038/s41390-023-02953-z

6. Che S, He H, Deng Y, Liu E. [Clinical effect of azithromycin adjuvant therapy in children with bronchiolitis: a systematic review and Meta analysis].. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2019. doi:10.7499/j.issn.1008-8830.2019.08.014