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Authors: Avraham Beigelman, Leonard B. Bacharier
Journal: Journal of Allergy and Clinical Immunology (2015)

We thank McCallum and her colleagues1McCallum G.B. Chang A.B. Grimwood K. Further clinical trials on macrolides for bronchiolitis in infants are unnecessary.J Allergy Clin Immunol. 2015; 136: 1134-1135Google Scholar for their interest in our study.2Beigelman A. Isaacson-Schmid M. Sajol G. Baty J. Rodriguez O.M. Leege E. et al.Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis.J Allergy Clin Immunol. 2015; 135: 1171-1178.e1Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar They raise the concern that based on the previously published negative studies of azithromycin in the setting of bronchiolitis, our finding of a decreased likelihood of post–respiratory syncytial virus (RSV) recurrent wheezing (RW)2Beigelman A. Isaacson-Schmid M. Sajol G. Baty J. Rodriguez O.M. Leege E. et al.Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis.J Allergy Clin Immunol. 2015; 135: 1171-1178.e1Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar does not warrant further follow-up studies. As indicated by McCallum et al,1McCallum G.B. Chang A.B. Grimwood K. Further clinical trials on macrolides for bronchiolitis in infants are unnecessary.J Allergy Clin Immunol. 2015; 136: 1134-1135Google Scholar 3 trials have evaluated “long-term” outcomes of macrolide therapy, including a small (n = 21) trial from Turkey3Tahan F. Ozcan A. Koc N. Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomised, placebo-controlled trial.Eur Respir J. 2007; 29: 91-97Crossref PubMed Scopus (93) Google Scholar using clarithromycin2Beigelman A. Isaacson-Schmid M. Sajol G. Baty J. Rodriguez O.M. Leege E. et al.Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis.J Allergy Clin Immunol. 2015; 135: 1171-1178.e1Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar and 2 from McCallum et al,4McCallum G.B. Morris P.S. Chatfield M.D. Maclennan C. White A.V. Sloots T.P. et al.A single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis: a randomised, placebo-controlled trial.PLoS One. 2013; 8: e74316Crossref PubMed Scopus (38) Google Scholar, 5McCallum G.B. Morris P.S. Grimwood K. Maclennan C. White A.V. Chatfield M.D. et al.Three-weekly doses of azithromycin for indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial.Front Pediatr. 2015; 3: 32Crossref Scopus (25) Google Scholar which found that 14McCallum G.B. Morris P.S. Chatfield M.D. Maclennan C. White A.V. Sloots T.P. et al.A single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis: a randomised, placebo-controlled trial.PLoS One. 2013; 8: e74316Crossref PubMed Scopus (38) Google Scholar or 35McCallum G.B. Morris P.S. Grimwood K. Maclennan C. White A.V. Chatfield M.D. et al.Three-weekly doses of azithromycin for indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial.Front Pediatr. 2015; 3: 32Crossref Scopus (25) Google Scholar doses of azithromycin did not improve acute bronchiolitis severity and did not prevent respiratory readmission during the following 6 months. Potential reasons for the disparate findings between these reports are multifactorial, including differences in outcome measures, durations of follow-up, dosing regimens, the baseline risk for future respiratory morbidity of study participants, and different causative viruses. We suspect that major explanations for the differences between our findings2Beigelman A. Isaacson-Schmid M. Sajol G. Baty J. Rodriguez O.M. Leege E. et al.Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis.J Allergy Clin Immunol. 2015; 135: 1171-1178.e1Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar and those of others4McCallum G.B. Morris P.S. Chatfield M.D. Maclennan C. White A.V. Sloots T.P. et al.A single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis: a randomised, placebo-controlled trial.PLoS One. 2013; 8: e74316Crossref PubMed Scopus (38) Google Scholar, 5McCallum G.B. Morris P.S. Grimwood K. Maclennan C. White A.V. Chatfield M.D. et al.Three-weekly doses of azithromycin for indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial.Front Pediatr. 2015; 3: 32Crossref Scopus (25) Google Scholar relate to the duration of follow-up and the indicator of long-term efficacy. In our study,2Beigelman A. Isaacson-Schmid M. Sajol G. Baty J. Rodriguez O.M. Leege E. et al.Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis.J Allergy Clin Immunol. 2015; 135: 1171-1178.e1Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar we found (Fig 1) that the azithromycin and placebo groups did not differ in risk of recurrent wheezing after 6 months of follow-up (P = .07), but after 12 months of follow-up, there was a significant reduction in risk among azithromycin-treated children (P = .048), indicating that the major effect of azithromycin therapy is not related to wheezing illnesses shortly after bronchiolitis but rather illnesses more than 6 months after the initial bronchiolitis. In addition, the outcome of readmission was not a sensitive marker for azithromycin efficacy in our study because readmission was very uncommon, with only 3 of 39 infants readmitted over 12 months. In contrast, nearly 30% of the population in the studies by McCallum et al4McCallum G.B. Morris P.S. Chatfield M.D. Maclennan C. White A.V. Sloots T.P. et al.A single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis: a randomised, placebo-controlled trial.PLoS One. 2013; 8: e74316Crossref PubMed Scopus (38) Google Scholar, 5McCallum G.B. Morris P.S. Grimwood K. Maclennan C. White A.V. Chatfield M.D. et al.Three-weekly doses of azithromycin for indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial.Front Pediatr. 2015; 3: 32Crossref Scopus (25) Google Scholar required readmission over 6 months, which suggests differing susceptibility to respiratory morbidity between the study populations, which likely contributes to differences in the overall findings. Although our study participants were otherwise healthy infants hospitalized for acute RSV bronchiolitis, almost 90% of the population in studies by McCallum et al4McCallum G.B. Morris P.S. Chatfield M.D. Maclennan C. White A.V. Sloots T.P. et al.A single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis: a randomised, placebo-controlled trial.PLoS One. 2013; 8: e74316Crossref PubMed Scopus (38) Google Scholar, 5McCallum G.B. Morris P.S. Grimwood K. Maclennan C. White A.V. Chatfield M.D. et al.Three-weekly doses of azithromycin for indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial.Front Pediatr. 2015; 3: 32Crossref Scopus (25) Google Scholar included indigenous infants from Australia and New Zealand. Indigenous infants have greater lung morbidity than do nonindigenous infants,5McCallum G.B. Morris P.S. Grimwood K. Maclennan C. White A.V. Chatfield M.D. et al.Three-weekly doses of azithromycin for indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial.Front Pediatr. 2015; 3: 32Crossref Scopus (25) Google Scholar with higher rates of airway bacterial colonization resulting in recurrent pneumonia and bronchiectasis. Finally, although all patients in our study experienced bronchiolitis due to RSV infection,2Beigelman A. Isaacson-Schmid M. Sajol G. Baty J. Rodriguez O.M. Leege E. et al.Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis.J Allergy Clin Immunol. 2015; 135: 1171-1178.e1Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar only 44% of the patients in the studies by McCallum et al4McCallum G.B. Morris P.S. Chatfield M.D. Maclennan C. White A.V. Sloots T.P. et al.A single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis: a randomised, placebo-controlled trial.PLoS One. 2013; 8: e74316Crossref PubMed Scopus (38) Google Scholar, 5McCallum G.B. Morris P.S. Grimwood K. Maclennan C. White A.V. Chatfield M.D. et al.Three-weekly doses of azithromycin for indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial.Front Pediatr. 2015; 3: 32Crossref Scopus (25) Google Scholar had confirmed RSV infection. If our findings are specific to RSV bronchiolitis, Dr McCallum's trials demonstrating no long-term effects of azithromycin may reflect lack of efficacy in the setting of non-RSV bronchiolitis. In summary, although it is clear that macrolides do not improve acute bronchiolitis severity, our pilot study strongly suggested that azithromycin during RSV bronchiolitis may be an effective intervention to attenuate the outcome of post-RSV RW and potentially asthma. Because asthma carries a significant burden on affected individuals and society, and because up to 13% of childhood asthma cases are attributable to severe RSV bronchiolitis,6James K.M. Gebretsadik T. Escobar G.J. Wu P. Carroll K.N. Li S.X. et al.Risk of childhood asthma following infant bronchiolitis during the respiratory syncytial virus season.J Allergy Clin Immunol. 2013; 132: 227-229Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar azithromycin as a potential disease-modifying approach to attenuate, and even prevent, post-RSV RW should be further investigated in a more definitive trial. Further clinical trials on macrolides for bronchiolitis in infants are unnecessaryJournal of Allergy and Clinical ImmunologyVol. 136Issue 4PreviewWe read with interest results of the randomized controlled trial (RCT) conducted by Beigelman et al1 involving 40 hospitalized infants with respiratory syncytial virus (RSV) bronchiolitis. They report that compared with placebo, a 2-week course of once-daily azithromycin reduced IL-8 levels in nasal lavage fluid, but not in serum. Although no significant between-group differences were observed in the proportions of infants experiencing 2 or more parent-reported wheezing episodes in the subsequent 50 weeks, there was some evidence that those treated with azithromycin took longer to have a third episode of wheezing and they had fewer days with respiratory symptoms during follow-up. Full-Text PDF