18 July 2026
SGEM#515: Now the Azithromycin Don’t Work for Preschool Wheeze
The Skeptics Guide to Emergency Medicine
About
Reference: Denninghoff KR et al. Azithromycin for Preschoolers with Wheezing in the Emergency Department. New England Journal of Medicine. May 2026
Date: July 14, 2026
Dr. Zara Ibrahim
Guest Skeptic: Dr. Zara Ibrahim is a pediatric emergency medicine fellow at Children’s National Hospital in Washington DC where she also completed medical school, pediatric residency. Her research interests include AI applications in medicine and health equity. In her time off, Zara likes to read books, travel, go on long walks to explore DC's excellent bakery scene, and do HIIT workouts to balance out the pastries.
Case: A 3-year-old with a history of recurrent wheezing presents to the pediatric emergency department (ED) with cough, rhinorrhea, increased work of breathing, and expiratory wheeze. His Pediatric Respiratory Assessment Measure (PRAM) score is 6. He receives albuterol, ipratropium, and dexamethasone with some improvement. His parents ask: “Last time he was sick, someone gave him antibiotics, I think it was ‘Zith something. Would antibiotics help him get better faster?”
Background: Preschool wheeze is best viewed as a heterogeneous clinical syndrome rather than a single diagnosis. Some of these children wheeze mainly during viral illnesses, some may be manifesting an early asthma phenotype, and a smaller number have alternative causes such as bronchiolitis, foreign-body aspiration, anatomic airway abnormalities, etc. Wheezing and asthma exacerbations are frequent reasons for ED care and hospitalization in children. In U.S. data from 2012 to 2020, asthma hospitalization rates were consistently highest among children aged 0 to 4 years and decreased across successive pediatric age groups.
During an acute asthma-like episode, airway inflammation, mucosal edema, mucus hypersecretion, and bronchial smooth-muscle constriction further narrow the airways. This can produce expiratory wheeze, prolonged expiration, tachypnea, retractions, reduced air entry, and, in more severe episodes, hypoxemia. Viral respiratory infections are the most common triggers of acute wheezing and asthma exacerbations in young children, with rhinovirus and respiratory syncytial virus among the frequently identified pathogens. Because preschool children can’t typically perform reproducible spirometry, emergency clinicians rely on clinical examination, pulse oximetry, and validated bedside severity scores such as the Pediatric Respiratory Assessment Measure, or PRAM. The PRAM is a bedside score from 0 to 12 based on oxygen saturation, suprasternal retractions, scalene-muscle contraction, air entry, and wheezing; higher scores indicate greater severity.
The immediate ED goal is to rapidly assess exacerbation severity, identify impending respiratory failure, and reassess the child’s response to treatment, rather than assign a permanent diagnostic label during a single acute visit. Standard management includes inhaled short-acting beta₂-agonists, early systemic glucocorticoids for moderate-to-severe exacerbations when appropriate, supplemental oxygen for hypoxemia, and repeated clinical assessment. Antibiotics are not routinely recommended for an asthma-like exacerbation unless there is a separate bacterial indication.
Two biologically plausible arguments have been advanced in support of azithromycin.
First, Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae are often detected in the upper airways of young children, and observational studies have associated colonization or microbiome profiles dominated by these organisms with more severe lower respiratory illness and later recurrent wheeze or asthma. These associations raised the hypothesis that bacteria may contribute to some episodes, but nasopharyngeal detection can represent colonization and, by itself, does not establish lower-airway bacterial infection or causation.
Second, macrolides have immunomodulatory and anti-inflammatory actions distinct from their antibacterial activity. Earlier outpatient randomized trials in selected children suggested that azithromycin, particularly when started very early in a respiratory illness before substantial airway obstruction developed, might shorten episodes or reduce progression to severe lower respiratory illness. In contrast, an earlier ED-based placebo-controlled trial found no reduction in symptom duration, short-acting beta₂-agonist use, or time to the next exacerbation. These mixed findings raised an important timing-and-severity question: might azithromycin have a pre-emptive effect early in an illness but little or no effect once moderate-to-severe wheezing is established?
Clinical Question: In preschool children presenting to the ED with moderate-to-severe wheezing, does a 5-day course of azithromycin reduce wheezing-related symptom severity compared with placebo?
Population: Children 18 to 59 months old presenting to one of eight PECARN-affiliated pediatric EDs with moderate-to-severe expiratory wheezing, defined as PRAM score ≥4
Excluded: Children with antibiotics in the prior two weeks, acute infection requiring systemic antibiotics, recent systemic glucocorticoids for wheezing, suspected foreign-body aspiration, prematurity, systemic illness other than allergies, azithromycin allergy, or active COVID-19.
Intervention: Azithromycin 12 mg/kg orally once daily for 5 days.
Comparison: Matching placebo for 5 days
Outcome:
Primary Outcome: Sum of Asthma Flare-up Diary for Young Children scores over 5 days. Scores ranged from 5 to 35, with higher scores indicating worse symptoms.
Secondary Outcomes: ED length of stay, hospital length of stay, return ED visits or hospitalization within 72 hours, bacterial clearance, antimicrobial resistance, and adverse events.
Type of Study: A multicentre, parallel-group, masked, placebo-controlled superiority randomized controlled trial.
Authors’ 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.”
Quality Checklist for Randomized Clinical Trials:
The study population included or focused on those in the emergency department. Yes
The patients were adequately randomized? Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized. Yes
The study patients were recruited consecutively (i.e. no selection bias). No
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
All groups were treated equally except for the intervention. Unsure
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. Yes
The treatment effect was large enough and precise enough to be clinically significant. No
Financial conflicts of interest. The study was funded by NHLBI/NIH and PECARN, and the funders reportedly had no role in design, analysis, interpretation, manuscript writing, or publication decisions.
Results: A total of 840 children were randomized. Of these, 521 (62%) tested positive for at least one of the three pathogenic bacteria, and 312 tested negative. Around half of the patients were hospitalized. The trial was stopped early for futility after an interim analysis
Key Results: Adding five days of azithromycin to standard ED treatment did not reduce wheezing-related symptom severity compared with placebo.
Primary Outcome: ADYC Symptoms Score
There was no significant improvement in wheezing-related symptom severity with azithromycin, whether children had the prespecified bacteria detected or not.
Secondary Outcomes: No meaningful differences were seen in ED length of stay, hospital length of stay, or 72-hour return ED visits/hospitalizations.
Bacterial Clearance: Among bacteria-positive children with follow-up testing, azithromycin cleared the prespecified bacteria more often than placebo: 58.7% vs 11.4%.
Adverse Events and Resistance: Adverse events were similar between groups, and no deaths occurred. Antimicrobial resistance at follow-up was similar among those who returned for follow-up testing, but the bacterial follow-up sample was incomplete
Negative Study:
This was a negative study. This is important because we know there is publication bias, where studies with positive or exciting findings are more likely to be submitted, accepted, published, promoted, and remembered. Negative trials can quietly disappear, leaving clinicians with an inflated sense that an intervention works.
A well-done negative trial can be just as valuable as a positive one because it helps us stop doing things that do not help patients.
Selection Bias/Generalizability:
The flow diagram in Figure 1 provides food for thought. More than 2,600 children were eligible, but only 840 underwent randomization. Among families approached, about 64% declined to consent. In addition, some eligible families were never approached because of staffing, guardian availability, language, or administrative issues. This also included a small group where the provider had a clinical preference.
This introduces selection bias.
The children enrolled in the trial may not perfectly represent all preschoolers with wheezing who show up to the ED. For example, we do not know whether families who declined had strong feelings about antibiotics. Did some parents want azithromycin and not want to risk placebo? Did some parents want to avoid antibiotics and not want to risk receiving azithromycin? Were some families too stressed, too busy, or too overwhelmed to consider research participation? We do not know.
The same question applies to clinicians....
Date: July 14, 2026
Dr. Zara Ibrahim
Guest Skeptic: Dr. Zara Ibrahim is a pediatric emergency medicine fellow at Children’s National Hospital in Washington DC where she also completed medical school, pediatric residency. Her research interests include AI applications in medicine and health equity. In her time off, Zara likes to read books, travel, go on long walks to explore DC's excellent bakery scene, and do HIIT workouts to balance out the pastries.
Case: A 3-year-old with a history of recurrent wheezing presents to the pediatric emergency department (ED) with cough, rhinorrhea, increased work of breathing, and expiratory wheeze. His Pediatric Respiratory Assessment Measure (PRAM) score is 6. He receives albuterol, ipratropium, and dexamethasone with some improvement. His parents ask: “Last time he was sick, someone gave him antibiotics, I think it was ‘Zith something. Would antibiotics help him get better faster?”
Background: Preschool wheeze is best viewed as a heterogeneous clinical syndrome rather than a single diagnosis. Some of these children wheeze mainly during viral illnesses, some may be manifesting an early asthma phenotype, and a smaller number have alternative causes such as bronchiolitis, foreign-body aspiration, anatomic airway abnormalities, etc. Wheezing and asthma exacerbations are frequent reasons for ED care and hospitalization in children. In U.S. data from 2012 to 2020, asthma hospitalization rates were consistently highest among children aged 0 to 4 years and decreased across successive pediatric age groups.
During an acute asthma-like episode, airway inflammation, mucosal edema, mucus hypersecretion, and bronchial smooth-muscle constriction further narrow the airways. This can produce expiratory wheeze, prolonged expiration, tachypnea, retractions, reduced air entry, and, in more severe episodes, hypoxemia. Viral respiratory infections are the most common triggers of acute wheezing and asthma exacerbations in young children, with rhinovirus and respiratory syncytial virus among the frequently identified pathogens. Because preschool children can’t typically perform reproducible spirometry, emergency clinicians rely on clinical examination, pulse oximetry, and validated bedside severity scores such as the Pediatric Respiratory Assessment Measure, or PRAM. The PRAM is a bedside score from 0 to 12 based on oxygen saturation, suprasternal retractions, scalene-muscle contraction, air entry, and wheezing; higher scores indicate greater severity.
The immediate ED goal is to rapidly assess exacerbation severity, identify impending respiratory failure, and reassess the child’s response to treatment, rather than assign a permanent diagnostic label during a single acute visit. Standard management includes inhaled short-acting beta₂-agonists, early systemic glucocorticoids for moderate-to-severe exacerbations when appropriate, supplemental oxygen for hypoxemia, and repeated clinical assessment. Antibiotics are not routinely recommended for an asthma-like exacerbation unless there is a separate bacterial indication.
Two biologically plausible arguments have been advanced in support of azithromycin.
First, Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae are often detected in the upper airways of young children, and observational studies have associated colonization or microbiome profiles dominated by these organisms with more severe lower respiratory illness and later recurrent wheeze or asthma. These associations raised the hypothesis that bacteria may contribute to some episodes, but nasopharyngeal detection can represent colonization and, by itself, does not establish lower-airway bacterial infection or causation.
Second, macrolides have immunomodulatory and anti-inflammatory actions distinct from their antibacterial activity. Earlier outpatient randomized trials in selected children suggested that azithromycin, particularly when started very early in a respiratory illness before substantial airway obstruction developed, might shorten episodes or reduce progression to severe lower respiratory illness. In contrast, an earlier ED-based placebo-controlled trial found no reduction in symptom duration, short-acting beta₂-agonist use, or time to the next exacerbation. These mixed findings raised an important timing-and-severity question: might azithromycin have a pre-emptive effect early in an illness but little or no effect once moderate-to-severe wheezing is established?
Clinical Question: In preschool children presenting to the ED with moderate-to-severe wheezing, does a 5-day course of azithromycin reduce wheezing-related symptom severity compared with placebo?
Population: Children 18 to 59 months old presenting to one of eight PECARN-affiliated pediatric EDs with moderate-to-severe expiratory wheezing, defined as PRAM score ≥4
Excluded: Children with antibiotics in the prior two weeks, acute infection requiring systemic antibiotics, recent systemic glucocorticoids for wheezing, suspected foreign-body aspiration, prematurity, systemic illness other than allergies, azithromycin allergy, or active COVID-19.
Intervention: Azithromycin 12 mg/kg orally once daily for 5 days.
Comparison: Matching placebo for 5 days
Outcome:
Primary Outcome: Sum of Asthma Flare-up Diary for Young Children scores over 5 days. Scores ranged from 5 to 35, with higher scores indicating worse symptoms.
Secondary Outcomes: ED length of stay, hospital length of stay, return ED visits or hospitalization within 72 hours, bacterial clearance, antimicrobial resistance, and adverse events.
Type of Study: A multicentre, parallel-group, masked, placebo-controlled superiority randomized controlled trial.
Authors’ 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.”
Quality Checklist for Randomized Clinical Trials:
The study population included or focused on those in the emergency department. Yes
The patients were adequately randomized? Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized. Yes
The study patients were recruited consecutively (i.e. no selection bias). No
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
All groups were treated equally except for the intervention. Unsure
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. Yes
The treatment effect was large enough and precise enough to be clinically significant. No
Financial conflicts of interest. The study was funded by NHLBI/NIH and PECARN, and the funders reportedly had no role in design, analysis, interpretation, manuscript writing, or publication decisions.
Results: A total of 840 children were randomized. Of these, 521 (62%) tested positive for at least one of the three pathogenic bacteria, and 312 tested negative. Around half of the patients were hospitalized. The trial was stopped early for futility after an interim analysis
Key Results: Adding five days of azithromycin to standard ED treatment did not reduce wheezing-related symptom severity compared with placebo.
Primary Outcome: ADYC Symptoms Score
There was no significant improvement in wheezing-related symptom severity with azithromycin, whether children had the prespecified bacteria detected or not.
Secondary Outcomes: No meaningful differences were seen in ED length of stay, hospital length of stay, or 72-hour return ED visits/hospitalizations.
Bacterial Clearance: Among bacteria-positive children with follow-up testing, azithromycin cleared the prespecified bacteria more often than placebo: 58.7% vs 11.4%.
Adverse Events and Resistance: Adverse events were similar between groups, and no deaths occurred. Antimicrobial resistance at follow-up was similar among those who returned for follow-up testing, but the bacterial follow-up sample was incomplete
Negative Study:
This was a negative study. This is important because we know there is publication bias, where studies with positive or exciting findings are more likely to be submitted, accepted, published, promoted, and remembered. Negative trials can quietly disappear, leaving clinicians with an inflated sense that an intervention works.
A well-done negative trial can be just as valuable as a positive one because it helps us stop doing things that do not help patients.
Selection Bias/Generalizability:
The flow diagram in Figure 1 provides food for thought. More than 2,600 children were eligible, but only 840 underwent randomization. Among families approached, about 64% declined to consent. In addition, some eligible families were never approached because of staffing, guardian availability, language, or administrative issues. This also included a small group where the provider had a clinical preference.
This introduces selection bias.
The children enrolled in the trial may not perfectly represent all preschoolers with wheezing who show up to the ED. For example, we do not know whether families who declined had strong feelings about antibiotics. Did some parents want azithromycin and not want to risk placebo? Did some parents want to avoid antibiotics and not want to risk receiving azithromycin? Were some families too stressed, too busy, or too overwhelmed to consider research participation? We do not know.
The same question applies to clinicians....