title: Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Bacteria and viruses are equally associated with the risk of acute episodes of asthma-like symptoms in young children, suggesting antibiotics as a potential treatment for such episodes. We aimed to assess the effect of azithromycin on the duration of respiratory episodes in young children with recurrent asthma-like symptoms, hypothesising that it reduces the duration of the symptomatic period.
  
  
  METHODS
  In this randomised, double-blind, placebo-controlled trial, we recruited children aged 1-3 years, who were diagnosed with recurrent asthma-like symptoms from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort; a birth cohort consisting of the general Danish population of Zealand, including Copenhagen. Exclusion criteria were macrolide allergy, heart, liver, neurological, and kidney disease, and, before each treatment, one or more clinical signs of pneumonia (respiratory frequency of ≥50 breaths per min; fever of ≥39°C; C-reactive protein concentration of ≥476·20 nmol/L [≥50 mg/L]). Each episode of asthma-like symptoms lasting at least 3 days was randomly allocated to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo after thorough examination by a study physician at the Copenhagen Prospective Studies on Asthma research unit. Each episode was randomly allocated independently of previous treatment from a computer-generated list of random numbers in blocks of ten (generated at the Pharmacy of Glostrup). Investigators and children were masked until the youngest child turned 3 years of age and throughout the data validation and analysis phases. The primary outcome was duration of the respiratory episode after treatment, verified by prospective daily diaries and analysed with Poisson regression. Analyses were per protocol (excluding those without a primary outcome measure or who did not receive treatment). This trial is registered with ClinicalTrials.gov, number NCT01233297.
  
  
  RESULTS
  Between Nov 17, 2010, and Jan 28, 2014, we randomly allocated 158 asthma-like episodes in 72 children (79 [50%] to azithromycin and 79 [50%] to placebo). The mean duration of the episode after treatment was 3·4 days for children receiving azithromycin compared with 7·7 days for children receiving placebo. Azithromycin caused a significant shortening of the episode of 63·3% (95% CI 56·0-69·3; p<0·0001). The effect size increased with early initiation of treatment, showing a reduction in episode duration of 83% if treatment was initiated before day 6 of the episode compared with 36% if initiated on or after day 6 (p<0·0001). We noted no differences in clinical adverse events between the azithromycin (18 [23%] of 78 episodes included in final analysis) and placebo (24 [30%] of 79) groups (p=0·30), but we did not investigate bacterial resistance patterns after treatment.
  
  
  CONCLUSIONS
  Azithromycin reduced the duration of episodes of asthma-like symptoms in young children, suggesting that this drug could have a role in acute management of exacerbations. Further research is needed to disentangle the inflammatory versus antimicrobial aspects of this relation.
  
  
  BACKGROUND
  Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation.
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Naestved Hospital, Naestved, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Stokholm
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bo L
authors.initials: BL
authors.lastname: Chawes
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nadja H
authors.initials: NH
authors.lastname: Vissing
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Naestved Hospital, Naestved, Denmark.
authors.forename: Elín
authors.initials: E
authors.lastname: Bjarnadóttir
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Naestved Hospital, Naestved, Denmark.
authors.forename: Tine M
authors.initials: TM
authors.lastname: Pedersen
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Naestved Hospital, Naestved, Denmark.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Vinding
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ann-Marie M
authors.initials: AM
authors.lastname: Schoos
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Helene M
authors.initials: HM
authors.lastname: Wolsk
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Sunna
authors.initials: S
authors.lastname: Thorsteinsdóttir
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henrik W
authors.initials: HW
authors.lastname: Hallas
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lambang
authors.initials: L
authors.lastname: Arianto
authors.affiliation: Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schjørring
authors.affiliation: Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Krogfelt
authors.affiliation: Department of Microbiological Diagnostics and Virology, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Thea K
authors.initials: TK
authors.lastname: Fischer
authors.affiliation: Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christian B
authors.initials: CB
authors.lastname: Pipper
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Bønnelykke
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.
authors.forename: Hans
authors.initials: H
authors.lastname: Bisgaard
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D017963:Azithromycin / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000276:immunology; D002675:Child, Preschool; D003371:Cough / Q000188:drug therapy* / Q000276:immunology; D003718:Denmark; D004311:Double-Blind Method; D004417:Dyspnea / Q000188:drug therapy* / Q000276:immunology; D061345:Early Medical Intervention; D005260:Female; D006760:Hospitalization; D006801:Humans; D007223:Infant; D008297:Male; D012135:Respiratory Sounds; D013997:Time Factors
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D002097:C-Reactive Protein