Early Tx reduces risk of LRTI disease progression

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Among young children with histories of recurrent severe lower respiratory tract illness (LRTI), the use of azithromycin early during an apparent RTI compared with placebo significantly reduced the risk of experiencing progression to severe LRTI.

Acute episodes of severe LRTI are common among pre-schoolers, and up to 14% to 26% of pre-schoolers present with recurrent wheezing during the first 6 years of life. These severe episodes are often associated with substantial illness, and may result in visits to urgent care and emergency departments. Although viral infections are often present, bacteria may also contribute to illness development. Identification of treatment approaches that lessen the severity of these recurrent episodes would provide substantial benefit to preschool children with recurrent severe LRTI, according to background information in the article.

Dr Leonard B Bacharier, of the Washington University in St Louis School of Medicine, and colleagues randomly assigned 607 children (age 12 months through 71 months) with histories of recurrent, severe LRTIs to receive the antibiotic azithromycin (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 individualised action plans. The trial was conducted across 9 academic US medical centres in the National Heart, Lung, and Blood Institute’s AsthmaNet network.

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). The azithromycin group experienced a significantly lower risk of progressing to severe LRTI than the placebo group. Adverse events were infrequently observed.

Although limited to 86 participants at a single study site, the researchers found numerically higher rates of acquisition of azithromycin-resistant organisms in oropharyngeal samples in participants receiving azithromycin and those who did not, along with evidence of acquisition of azithromycin-resistant organisms even in participants not treated with azithromycin. “Real-world rates of development of azithromycin-resistant organisms may be greater, potentially due to failure to complete the full duration of therapy often seen in clinical practice. Given the small sample size, further studies are needed to assess the potential increased risk of antibiotic resistance vs the comparative effectiveness of azithromycin with respect to other asthma medications to prevent severe LRTI,” the authors write.

“In children with the phenotype of wheezing studied herein, clinicians may consider a therapeutic trial of azithromycin early in the course of RTIs based on a parent-initiated individualised plan. Children who demonstrate an azithromycin response, as reflected by less-severe episodes of RTI, may benefit from repeating such therapy with subsequent illnesses.

“Studies replicating the findings reported herein would provide further support to this conclusion, and future studies comparing the relative benefits of early azithromycin therapy with either daily or intermittent high-dose inhaled corticosteroids may help determine the relative efficacies of these treatment strategies.”

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.

JAMA material
JAMA abstract
JAMA editorial


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