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Efficacy of Macrolides on Acute Asthma or Wheezing Exacerbations in Children with Recurrent Wheezing: A Systematic Review and Meta-analysis

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A Correction to this article was published on 13 March 2020

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Abstract

Introduction

The role of macrolides for treatment of children with acute asthma or wheezing exacerbations is unclear.

Objective

The aim of this systematic review was to evaluate the effectiveness of macrolides in children with recurrent wheezing presenting with acute asthma or wheezing exacerbation.

Methods

We conducted an electronic search in MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL, and ClinicalTrials.gov.

Study selection criteria

Randomized controlled trials of macrolides (any macrolide) compared with placebo or standard treatment in children up to 18 years with recurrent wheezing/asthma presenting with an acute exacerbation.

Outcomes

Primary outcomes were need for hospitalization and/or time of acute asthma/wheezing symptoms resolution; secondary outcomes were duration of stay in the emergency department (ED)/clinic, severity of symptoms of the index episode, use of additional systemic corticosteroids or short active β-2 agonists, changes in lung function measures, ED visit/hospitalization during first week after index episode, time to next exacerbation, or adverse effects (AEs).

Results

Only three studies met the inclusion criteria (n = 334 children, 410 treated episodes); two studies included recurrent wheezers and the third included asthmatic children. There was no difference in hospitalization between groups, but children treated with macrolides had a significantly lower time to symptoms resolution than controls, although the magnitude of benefit remains to be quantified due to no normal distribution data presented. There was no difference in time to next episode of exacerbation (HR 0.96; 95% CI 0.71–1.28; I2 = 0%; p = 0.77). In one study, children receiving macrolides had a significant decrease in the severity of symptoms, decrease use of salbutamol, and another study showed improved lung function. No study evaluated antibiotic resistance development.

Conclusions

Limited evidence support that a macrolide trial could be considered in children with acute asthma or recurrent wheezing exacerbation.

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Change history

  • 13 March 2020

    An Online First version of this article was made available online at https://link.springer.com/article/10.1007/s40272-019-00371-5 on 14 January 2020. An error was subsequently identified in the article, and the following correction should be noted:

References

  1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018. http://www.ginasthma.org. Accessed Nov 2019.

  2. Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018;391(17):783–800.

    PubMed  Google Scholar 

  3. Nunes C, Pereira AM, Morais-Almeida M. Asthma costs and social impact. Asthma Res Pract. 2017;3(1):1.

    PubMed  PubMed Central  Google Scholar 

  4. Nurmagambetov T, Kuwahara R, Garbe P. The economic burden of asthma in the United States, 2008–2013. Ann Am Thorac Soc. 2018;15(3):348–56.

    PubMed  Google Scholar 

  5. Garner R, Kohen D. Changes in the prevalence of asthma among Canadian children. Health Rep. 2008;19(2):45–50.

    PubMed  Google Scholar 

  6. Lougheed MD, Garvey N, Chapman KR, Cicutto L, Dales R, Day AG, et al. The Ontario asthma regional variation study: emergency department visit rates and the relation to hospitalization rates. Chest. 2006;129(4):909–17.

    PubMed  Google Scholar 

  7. Karaca-Mandic P, Jena AB, Joyce GF, Goldman DP. Out-of-pocket medication costs and use of medications and health care services among children with asthma. JAMA. 2012;307(12):1284–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Radhakrishnan DK, Dell SD, Guttmann A, Shariff SZ, Liu K, To T. Trends in the age of diagnosis of childhood asthma. J Allergy Clin Immunol. 2014;134(5):1057–62.

    PubMed  Google Scholar 

  9. Szefler SJ, Zeiger RS, Haselkorn T, Mink DR, Kamath TV, Fish JE, et al. Economic burden of impairment in children with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol. 2011;107(2):110–9.

    PubMed  Google Scholar 

  10. Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis. Pediatrics. 2009;123(3):e519–25.

    PubMed  Google Scholar 

  11. Kaiser SV, Huynh T, Bacharier LB, Rosenthal JL, Bakel LA, Parkin PC, et al. Preventing exacerbations in preschoolers with recurrent wheeze: a meta-analysis. Pediatrics. 2016;137(6):e20154496.

    PubMed  Google Scholar 

  12. Castro-Rodriguez JA, Beckhaus AA, Forno E. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: systematic review with meta-analysis. Pediatr Pulmonol. 2016;51(8):868–76.

    PubMed  PubMed Central  Google Scholar 

  13. Beigelman A, Chipps BE, Bacharier LB. Update on the utility of corticosteroids in acute pediatric respiratory disorders. Allergy Asthma Proc. 2015;36(5):332–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. da Silva Filho LV, Pinto LA, Stein RT. Uso de macrolídeos em doenças pulmonares: controvérsias da literatura recente. J Pediatr (Rio J). 2015;91(6 Suppl 1):S52–60.

    Google Scholar 

  15. Hernando-Sastre V. Macrolide antibiotics in the treatment of asthma. An update. Allergol Immunopathol (Madr). 2010;38(2):92–8.

    CAS  Google Scholar 

  16. Poole NM, Shapiro DJ, Fleming-Dutra KE, Hicks LA, Hersh AL, Kronman MP. Antibiotic prescribing for children in United States emergency departments: 2009–2014. Pediatrics. 2019;143(2):e20181056.

    PubMed  Google Scholar 

  17. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647.

    PubMed  Google Scholar 

  18. Clinical safety data management: definitions and standards for expedited reporting E2A. ICH Harmonised Tripartite Guideline. 1994. https://database.ich.org/sites/default/files/E2A_Guideline.pdf. Accessed Nov 2019.

  19. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

    PubMed  PubMed Central  Google Scholar 

  20. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.

    PubMed  PubMed Central  Google Scholar 

  21. Deeks JJ, Altman DG, Bradburn M. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey G, Altman D, editors. Systematic reviews in health care: meta-analysis in context. 2nd ed. London: BMJ Publishing Group; 2001. p. 285–312.

    Google Scholar 

  22. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to meta-analysis. Chichester: Wiley; 2009.

    Google Scholar 

  23. Volovitz B, Bilavsky E, Nussinovitch M. Effectiveness of high repeated doses of inhaled budesonide or fluticasone in controlling acute asthma exacerbations in young children. J Asthma. 2008;45(7):561–7.

    CAS  PubMed  Google Scholar 

  24. Fonseca-Aten M, Okada PJ, Bowlware KL, Chavez-Bueno S, Mejias A, Rios AM, et al. Effect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2006;97(4):457–63.

    CAS  PubMed  Google Scholar 

  25. Bacharier LB, Guilbert TW, Mauger DT, Boehmer S, Beigelman A, Fitzpatrick AM, et al. 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. JAMA. 2015;314(19):2034–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Koutsoubari I, Papaevangelou V, Konstantinou GN, Makrinioti H, Xepapadaki P, Kafetzis D, et al. Effect of clarithromycin on acute asthma exacerbations in children: an open randomized study. Pediatr Allergy Immunol. 2012;23(4):385–90.

    PubMed  Google Scholar 

  27. Stokholm J, Chawes BL, Vissing NH, Bjarnadóttir E, Pedersen TM, Vinding RK, et al. Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4(1):19–26.

    CAS  PubMed  Google Scholar 

  28. Mandhane PJ, Paredes Zambrano de Silbernagel P, Aung YN, Williamson J, Lee BE, Spier S, et al. Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: a placebo-controlled randomized trial. PLoS One. 2017;12(8):e0182411.

    PubMed  PubMed Central  Google Scholar 

  29. Stokholm J, Chawes BL, Vissing NH, Bjarnadóttir E, Pedersen TM, Vinding RK, et al. Supplement to: azithromycin for episodes with asthma-like symptoms in young children aged 1–3 years: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4(1):19–26.

    CAS  PubMed  Google Scholar 

  30. Normansell R, Sayer B, Waterson S, Dennett EJ, Del Forno M, Dunleavy A. Antibiotics for exacerbations of asthma. Cochrane Database Syst Rev. 2018. https://doi.org/10.1002/14651858.CD002741.pub2.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lei W, Tsai M, Liu S, Yeh T. The effects of macrolides in children with reactive airway disease: a systematic review and meta- analysis of randomized controlled trials. Drug Des Dev Ther. 2018;12:3825–45.

    CAS  Google Scholar 

  32. Lin C, Yeh T, Liu S, Lin H, Cheng Y, Hung H, et al. Effects of macrolide treatment during the hospitalization of children with childhood wheezing disease : a systematic review and meta-analysis. J Clin Med. 2018;7(11):432.

    CAS  PubMed Central  Google Scholar 

  33. Steel HC, Theron AJ, Cockeran R, Anderson R, Feldman C. Pathogen- and host-directed anti-inflammatory activities of macrolide antibiotics. Mediat Inflamm. 2012;2012:17.

    Google Scholar 

  34. Altenburg J, de Graaff CS, van der Werf TS, Boersma WG. Immunomodulatory effects of macrolide antibiotics—part 1: biological mechanisms. Respiration. 2011;81(1):67–74.

    CAS  PubMed  Google Scholar 

  35. Beigelman A, Gunsten S, Mikols CL, Vidavsky I, Cannon CL, Brody SL, et al. Azithromycin attenuates airway inflammation in a noninfectious mouse model of allergic asthma. Chest. 2009;136(2):498–506.

    PubMed  Google Scholar 

  36. Zimmermann P, Ziesenitz VC, Curtis N, Ritz N. The immunomodulatory effects of macrolides-A systematic review of the underlying mechanisms. Front Immunol. 2018;9:302.

    PubMed  PubMed Central  Google Scholar 

  37. Beigelman A, Isaacson-schmid M, Sajol G, Baty J, Rodriguez OM, 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(5):1171–8.

    CAS  PubMed  Google Scholar 

  38. Wong EHC, Porter JD, Edwards MR, Johnston SL. The role of macrolides in asthma: current evidence and future directions. Lancet Respir. 2014;2600(14):1–14.

    Google Scholar 

  39. Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010;23(3):590–615.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Asada M, Yoshida M, Suzuki T, Hatachi Y, Sasaki T, Yasuda H, et al. Macrolide antibiotics inhibit respiratory syncytial virus infection in human airway epithelial cells. Antiviral Res. 2009;83(2):191–200.

    CAS  PubMed  Google Scholar 

  41. Min JY, Jang YJ. Macrolide therapy in respiratory viral infections. Mediat Inflamm. 2012;2012:9.

    Google Scholar 

  42. Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur Respir J. 2010;36(3):646–54.

    CAS  PubMed  Google Scholar 

  43. Papadopoulos NG, Christodoulou I, Rohde G, Agache I, Almqvist C, Bruno A, et al. Viruses and bacteria in acute asthma exacerbations—A GA2LEN-DARE systematic review. Allergy. 2011;66(4):458–68.

    CAS  PubMed  Google Scholar 

  44. Hahn DL, Webley W. Chronic Chlamydia pneumoniae lung infection: a neglected explanation for macrolide effects in wheezing and asthma? Lancet Respir. 2016;4(3):e8.

    Google Scholar 

  45. Rollins DR, Beuther DA, Martin RJ. Update on infection and antibiotics in asthma. Curr Allergy Asthma Rep. 2010;10(1):67–73.

    PubMed  Google Scholar 

  46. Cohen RT, Pelton SI. Individual benefit vs societal effect of antibiotic prescribing for preschool children with recurrent wheeze. JAMA. 2015;314(19):2027–9.

    CAS  PubMed  Google Scholar 

  47. Fleming-Dutra KE, Friedman CR, Hicks LA. Early azithromycin treatment to prevent severe lower respiratory tract illnesses in children. JAMA. 2016;315(19):2121–2.

    PubMed  PubMed Central  Google Scholar 

  48. Hansen MP, Scott AM, McCullough A, Thorning S, Aronson JK, Beller EM, et al. Adverse events in people taking macrolide antibiotics versus placebo for any indication. Cochrane Database Syst Rev. 2019. https://doi.org/10.1002/14651858.CD011825.pub2.

    Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Jose A. Castro-Rodriguez.

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Funding

Dr. Castro-Rodriguez’s contribution was funded in part by CONICYT PIA/ANILLO (Grant no. 170925013) from the Chilean Comisión Nacional de Investigación Científica y Tecnológica (CONICYT).

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The authors have no financial relationships relevant to this article to disclose.

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The authors declare that they have no conflict of interests.

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Pincheira, M.A., Bacharier, L.B. & Castro-Rodriguez, J.A. Efficacy of Macrolides on Acute Asthma or Wheezing Exacerbations in Children with Recurrent Wheezing: A Systematic Review and Meta-analysis. Pediatr Drugs 22, 217–228 (2020). https://doi.org/10.1007/s40272-019-00371-5

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