Azithromycin in Preschoolers with Severe Wheezing Episodes Diagnosed at the Emergency Department (AZ-SWED): A Randomized, Placebo-Controlled, Precision-Medicine Trial

Abstract Background and rationale. Over 2.2 million children aged 2-5 years have wheezing illnesses (WI) that are severe enough to require Emergency Department (ED) visits each year in the United States, and 15% of these children require hospitalization. There is new evidence suggesting an association between isolation of three pathogenic nasopharyngeal (NP) bacteria (3PB)(Neisseria catarrhalis, Hemophilus influenzae, Streptococcus pneumoniae)and preschool WI, but demonstration of a causal relation is lacking. Many patients with WI are treated with antibiotics, with scanty evidence supporting this approach. There is concern that excessive use of antibiotics promotes bacterial resistance. Two high profile, phase II clinical trials (PMID:26575060, PMID:26704020) performed in outpatient clinics recently showed significant reduction in WI symptoms when children were treated with Azithromycin (AZ) either before or soon after symptoms started, but whether AZ is effective in more severe cases requiring ED visits, is unknown. Another trial (PMID:28771627) analyzed 222 preschool children with wheeze in the ED and treated them with AZ or placebo, demonstrating no difference in duration of short-acting beta agonist use between groups. The study was discontinued prior to enrollment of the targeted sample size. No studies have assessed whether AZ could be differentially effective in WI with or without concomitant isolation of the 3PB. Study design. AZ-SWED is a parallel group, randomized(1:1), double-blind placebo-controlled trial testing the hypothesis that, in the ED setting, AZ can decrease symptoms of moderate to severe WI (i.e., those with a Pediatric Respiratory Assessment Measure [PRAM] score ≥4) during the five days following the ED visit, as assessed by the previously validated Asthma Flare-up Diary for Young Children (ADYC) instrument. The results were analyzed separately in the 3PB positive and in the 3PB negative groups, with power calculated assuming an effect on the ADYC score that was similar to that observed for fluticasone in a trial using the same ADYC instrument(PMID:26341275). A subgroup of participants was followed for an additional 3 weeks after the ED visit, providing additional NP swabs to assess clearance of the pathogenic bacteria and development of antibiotic resistance. Results. Recruitment started in September 2021, and on December 10, 2024, the NHLBI, under recommendation from the trial DSMB, stopped the AZ-SWED trial for futility. A total of 840 participants were randomized, of which 521 (62%) had an NP swab that was positive for at least one of the3PB. A total of 209 of those positive for one of the 3PB were followed for an additional 3 weeks. For the 3PBpositive group, the median (IQR) sum ADYC over 5 days was 9.59 (7.29,12.60) in the AZ arm and 9.72 (7.66,12.17) in the placebo arm (p=0.7). Similarly, in the 3PB negative group, the median (IQR) was 9.30 (6.97,11.62) in the AZ arm and 9.10 (7.19,11.45) in the placebo arm (p=0.7). Secondary outcomes of ED length of stay, hospital length of stay, and return visits within 72hours of the initial visit were similar between the two arms in both 3PBgroups. Analyses by sex and race showed no difference in effect of AZ across subgroups. Of 116 3PB positive subjects who returned for 1-week follow-up, 27/46(58.7%) in the AZ arm and 8/70 (11.4%) in the placebo arm were found to be negative for the 3PB after one week. Development of bacterial resistance was similar in the two arms. Significance of the study. Azithromycin did not decrease the severity of wheezing illnesses in 18 to <60-month-olds regardless of the presence or absence of H influenzae, M catarrhalis, or S pneumonia isolated from the participants’ nasopharynx at the time of the illness.