Published May 18, 2026
N Engl J Med 2026;395:753-764
DOI: 10.1056/NEJMoa2516505
Abstract
Background
Wheezing illnesses are a leading cause of hospitalization for preschool-age children and are frequently treated with antibiotics. Observational studies have shown more frequent isolation of three pathogenic bacteria (Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae) from nasopharyngeal samples from children with recurrent episodes of wheezing than from those without such illnesses.
Methods
In this multicenter trial, we randomly assigned patients 18 to 59 months of age who presented to an emergency department with a moderate-to-severe episode of wheezing to receive azithromycin once daily at a dose of 12 mg per kilogram of body weight or matching placebo for 5 days. The primary outcome was the sum of scores on the Asthma Flare-up Diary for Young Children (ADYC) over 5 days. Primary-outcome scores could range from 5 to 35, with higher scores indicating more severe wheezing-related symptoms. Efficacy was assessed separately in patients who tested positive for pathogenic bacteria (the positive cohort) and in those who tested negative (the negative cohort). Secondary outcomes were length of stay in the emergency department, length of hospital stay, and return emergency department visits or hospitalizations within 72 hours. Bacterial clearance and antimicrobial resistance were measured at follow-up visits 1 to 3 weeks after randomization.
Results
Among 840 patients who underwent randomization, 521 tested positive for pathogenic bacteria. The trial was stopped for futility by the data and safety monitoring board after a planned interim analysis. ADYC scores did not differ significantly between the azithromycin and placebo groups in either the positive cohort (median, 9.59 [interquartile range, 7.29 to 12.60] vs. 9.72 [interquartile range, 7.66 to 12.17]; P=0.70) or the negative cohort (median, 9.30 [interquartile range, 6.97 to 11.62] vs. 9.10 [interquartile range, 7.19 to 11.45]; P=0.69). In the positive cohort, bacterial clearance was 58.7% in the azithromycin group and 11.4% in the placebo group. Secondary outcomes appeared to be similar in the two groups for both cohorts, as did the development of bacterial resistance and the incidence of adverse events.
Conclusions
Azithromycin did not lead to a greater reduction in the severity of wheezing-related symptoms than placebo in preschool-age children who presented to the emergency department with moderate-to-severe acute wheezing. (Funded by the National Heart, Lung, and Blood Institute and others; AZ-SWED ClinicalTrials.gov number, NCT04669288.)
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Notes
The content and conclusions are those of the authors and should not be construed as the official position or policy of, nor should any endorsements be inferred by, the Health Resources and Services Administration, the Department of Health and Human Services, or the U.S. Government.
This article was published on May 18, 2026, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award numbers UG3/UH3HL147016 for the trial and U24HL147018 for the data coordinating center at the University of Utah, and by the Pediatric Emergency Care Applied Research Network (PECARN). PECARN is supported by the Maternal and Child Health Bureau in the Health Resources and Services Administration of the U.S. Department of Health and Human Services under the Emergency Medical Services for Children (EMSC) program through the following cooperative agreements: EMSC Data Center–University of Utah (UJ5MC30824); Great Lakes–Atlantic Children’s Emergency Research (GLACiER) Node–Nationwide Children’s Hospital (U03MC28844); Hospitals of the Midwest Emergency Research Node (HOMERUN)–Cincinnati Children’s Hospital Medical Center (U03MC22684); Pediatric Emergency Medicine Northeast, West, and South (PEM-NEWS)–Columbia University Medical Center (U03MC00007); Pediatric Research in Injuries and Medical Emergencies (PRIME)–University of California at Davis Medical Center (U03MC00001); Charlotte, Houston, and Milwaukee Prehospital (CHaMP) Research Node–State University of New York at Buffalo (U03MC33154); Seattle, Texas, Los Angeles Research (STELAR) Node–Seattle Children’s Hospital (U03MC33156); and San Francisco–Oakland, Providence, Atlanta Research Collaborative (SPARC) Node–Emory University School of Medicine (U03MC49671).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank Elizabeth Beckett Firmage, B.S., from the Arizona Clinical Coordinating Center, University of Arizona, and Krista M. Ellis, M.S., from the Utah Data Coordinating Center, University of Utah, for their assistance with trial management; the research coordinators in PECARN, without whom this trial would not have been possible; the clinicians in PECARN who enrolled children in the trial; the pharmacists who prepared the trial drug and placebo on site; the members of the data and safety monitoring board (Bonnie W. Ramsey, M.D. [chair], Allan Becker, M.D., Michelle Cloutier, M.D., Jeremy Garrett, Ph.D., Haley Hedlin, Ph.D., Carlos Camargo, M.D., Ph.D., and Thomas Terndrup, M.D.); and Francine Ducharme, M.D., for granting permission to use the Pediatric Respiratory Assessment Measure and the Asthma Flare-up Diary for Young Children.
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Published online: May 18, 2026
Published in issue: August 20, 2026
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- No to Azithromycin for Preschoolers with Acute Wheezing in the Emergency Department, New England Journal of Medicine, 395, 8, (818-820), (2026)./doi/full/10.1056/NEJMe2606675
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Facts Only
* Patients aged 18 to 59 months with moderate-to-severe wheezing.
* Azithromycin administered at 12 mg per kilogram of body weight once daily for 5 days.
* Matching placebo administered for 5 days.
* Primary outcome measured by the Asthma Flare-up Diary for Young Children (ADYC).
* 840 patients underwent randomization.
* 521 patients tested positive for pathogenic bacteria.
* Pathogenic bacteria tracked included *Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae*.
* Bacterial clearance was 58.7% in the azithromycin group and 11.4% in the placebo group.
* P-values for primary outcomes were 0.70 for the positive cohort and 0.69 for the negative cohort.
* Funded by the National Heart, Lung, and Blood Institute and PECARN.
* Trial stopped for futility by the data and safety monitoring board.
Executive Summary
Preschool-age children presenting to emergency departments with moderate-to-severe wheezing are frequently treated with antibiotics, despite uncertainty regarding efficacy. A multicenter trial investigated whether a five-day course of azithromycin (12 mg/kg daily) reduces symptom severity compared to a placebo in children aged 18 to 59 months. The study specifically analyzed two groups: those who tested positive for pathogenic bacteria (*S. pneumoniae, M. catarrhalis, and H. influenzae*) and those who tested negative.
The trial was terminated early for futility following an interim analysis. Data indicated no significant difference in wheezing-related symptom scores, as measured by the Asthma Flare-up Diary for Young Children, between the azithromycin and placebo groups in either the positive or negative cohorts. While azithromycin significantly increased the rate of bacterial clearance in the positive cohort (58.7% vs. 11.4%), this biological effect did not translate into clinical improvement. Secondary outcomes, including hospital stay length and the development of antimicrobial resistance, remained similar across all groups.
Full Take
This study employs a robust randomized controlled trial (RCT) design with a clear primary endpoint and a pre-specified interim analysis for futility, which protects patients from ineffective treatments. A peer reviewer would note the strength of the "positive vs. negative" cohort stratification, which directly addresses the biological hypothesis that bacterial colonization drives wheezing. However, the discrepancy between biological success (high bacterial clearance) and clinical failure (no reduction in symptoms) is the most critical finding. It suggests that while the antibiotic performs its mechanical function of killing bacteria, those bacteria may not be the primary drivers of the acute wheezing episodes in this population.
The findings challenge the common clinical instinct to treat presumed bacterial colonization in pediatric respiratory distress. The framing is proportionate; the authors do not overreach, acknowledging that bacterial clearance occurred but correctly concluding that this did not lead to clinical benefit. This fits into a broader medical shift toward antimicrobial stewardship, reducing the use of broad-spectrum antibiotics to prevent the rise of resistant strains.
For these findings to alter global practice, clinicians must accept that "clearing the bacteria" is not synonymous with "treating the patient." The real-world implication is a potential reduction in unnecessary antibiotic prescriptions for preschoolers in emergency settings.
Bridge Questions:
1. Does the lack of efficacy in acute episodes extend to the prevention of recurrent wheezing over a longer duration?
2. Would a different class of antibiotics or a different dosing schedule produce a clinical response, or is the underlying pathology fundamentally non-bacterial?
Counterstrike Scan: A coordinated influence campaign against antibiotics would use this data to advocate for the total removal of antibiotics from pediatric respiratory protocols regardless of presenting comorbidities. The actual content is a disciplined clinical trial that limits its conclusions to acute wheezing in a specific age group, maintaining professional nuance.