Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial

Abstract

Importance: Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed.

Objective: To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes.

Design, setting, and participants: A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment.

Intervention: Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child's signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period.

Main outcomes and measures: The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures.

Results: A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed.

Conclusions and relevance: Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy.

Trial registration: clinicaltrials.gov Identifier: NCT01272635.

Figure 1. Flow Diagram of the Study Enrollment and Outcomes for Preschool Children With a History of Respiratory Tract Illness

LRTI indicates lower respiratory tract illness. No information was recorded on potential participants screened but not enrolled. ^a Presence of excessive asthma symptoms was defined as, on average, more than 4 days per week or more than 1 nighttime awakening requiring albuterol during the 2-week run-in period (for controller naïve children) or during the latter 2 weeks of a 4 week run-in period (for children receiving low-dose inhaled corticosteroids or montelukast monotherapy at enrollment).

Figure 2. Cumulative Risk of Experiencing an Episode of Severe LRTI Across Treated RTIs for Preschool Children With a History of Severe LRTI

RTI indicates respiratory tract illness; SLRTI, severe lower RTI. Shown are risks and 95% CIs based on the discrete-time proportional hazards model of treatment effect adjusted for clinical site, age, modified Asthma Predictive Index status, season during which the treated RTI occurred, and whether the child enrolled before or after the study was extended to 78 weeks.

Figure 3. Potential Treatment-Effect Differences in Prespecified Subgroups for Risk of an Episode of Severe LRTI Among Preschool Children With a History of Severe LRTI

IL-8 indicates interleukin-8 gene; LRTI, lower respiratory tract illness; mAPI, modified Asthma Predictive Index. Estimates and CIs were obtained separate discrete-time proportional hazards models, each incorporating an interaction between treatment and the factor indicated on the y-axis. All models included adjustments for clinical site, age, modified API status, season during which the treated respiratory tract illness occurred, and whether the child enrolled before or after the study was extended to 78 weeks. No significant differences between treatment effects (blue circles) are noted between subgroups. ^a IL-8 rs4073 genotype results shown include only Hispanic and non-Hispanic white participants with an adjustment for ethnicity. ^b Other virus indicates coronaviruses; adenoviruses B, C, and E; influenza A and B; parainfluenza viruses I-IV; respiratory syncytial virus A and B; metapneumovirus; and bocavirus. ^c A participant was classified as having a positive mAPI if the individual had experienced at least 4 wheezing episodes in the past year and had 1 major criterion (physician-diagnosed atopic dermatitis, parental history of asthma, or allergic sensitization to ≥1 aeroallergen) or 2 minor criteria (wheezing unrelated to colds, blood eosinophils ≥4%, or allergic sensitization to milk, eggs, or peanuts).

Figure 4. Symptom Scores Over the Duration of Treated RTIs Among Preschool Children With a History of Severe LRTI

LRTI indicates lower respiratory tract illness; PAD, Preschool Asthma Diary. P values are based on repeated measures analysis of variance with compound symmetry (RTIs not progressing to severe LRTI) or 2-sample t test (RTIs progressing to severe LRTI). The bottom and top edges of the box indicate the first and third quartiles, respectively. The line inside the box indicates the median. The error bars that extend from each end of the box indicate the range of values that are outside of the interquartile range, but not more than 1.5 times the interquartile range above the third quartile. Circles indicate values that are more than 1.5 times the interquartile range above the third quartile. ^a The PAD was completed daily starting on the first day an illness kit was used and continued until the participant was symptom-free for 2 days. It contains questions of frequency of respiratory symptoms, each scored on a scale of 1 through 7, with higher scores representing increasingly frequent symptoms, with daily scores ranging from 0 (asymptomatic) to a maximum of 102. The total PAD score is the sum of the daily individual symptom scores over the duration of the illness, with higher scores representing more frequent symptoms.