Antibiotics for persistent cough or wheeze following acute bronchiolitis in children

Gabrielle B McCallum; Erin J Plumb; Peter S Morris; Anne B Chang

doi:10.1002/14651858.CD009834.pub3

Antibióticos para las sibilancias o la tos persistente después de la bronquiolitis aguda en niños

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Referencias

References to studies included in this review

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estudios excluidos
otras referencias

McCallum GB, Morris PS, Grimwood K, Maclennan C, White AV, Chang AB, et al. Three‐weekly doses of azithromycin for indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo‐controlled trial. Frontiers in Pediatrics 2015;3:1‐9.

Tahan F, Ozcan A, Koc N. Clarithromycin in the treatment of RSV bronchiolitis: a double‐blind, randomised, placebo‐controlled trial. European Respiratory Journal 2007;29:91‐7.

References to studies excluded from this review

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estudios incluidos
otras referencias

Beigelman A, Isaacson‐Schmid M, Sajol G, Baty J, Rodrigues 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. Journal of Allergy and Clinical Immunology 2015;135(5):1171‐8e1. [CN‐01087161; CN‐01130880; CN‐01136644; P30 CA091842]

Friis B, Anderson P, Brenoe E, Hornsleth A, Jensen A, Knudsen F, et al. Antibiotic treatment of pneumonia and bronchiolitis ‐ a prospective randomised study. Archives of Disease in Childhood 1984;59:1038‐45.

Kabir A, Mollah A, Anwar K, Rahman A, Amin R, Rahman M. Management of bronchiolitis without antibiotics: a multicentre randomized control trial in Bangladesh. Acta Paediatrica 2009;98:1593‐9.

Kneyber MC, Woensel JB, Uitjendaal E, Uiterwaal C, Kimpen J. Azithromycin does not improve disease course in hospitalized infants with respiratory syncytial virus (RSV) lower respiratory tract disease: a randomized equivalence trial. Pediatric Pulmonology 2008;43:142‐9.

Mazumder M, Hossain M, Kabir A. Management of bronchiolitis with or without antibiotics ‐ a randomized control trial. Journal of Bangladesh College of Physicians and Surgeons 2009;27:63‐9.

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McCallum GB, Morris PS, Chatfield MD, Maclennan C, White AV, Chang AB. A single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis: a randomised, placebo‐controlled trial. PloS One 2013;8(9):1‐9.

Pinto LA, Pitrez PM, Luisi F, Mello PP, Gerhardt M, Marostica PJ. Azithromycin therapy in hospitalized infants with acute bronchiolitis is not associated with better clinical outcomes: a randomized, double‐blinded, and placebo‐controlled clinical trial. Journal of Paediatrics 2012;161(6):1104‐8. [RBR‐257ZBC; SN‐1099‐0496]

Additional references

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estudios incluidos
estudios excluidos

Bailey EJ, Maclennan C, Morris PS, Kruske SG, Brown N, Chang AB. Risks of severity and readmission of indigenous and non‐indigenous children hospitalised for bronchiolitis. Journal of Paediatrics and Child Health 2009;45:593‐7.

Blom‐Danielle JM, Ermers M, Bont L, van‐Woensel‐Job BM, van‐Aalderen‐Wim MC. Inhaled corticosteroids during acute bronchiolitis in the prevention of post‐bronchiolitic wheezing. Cochrane Database of Systematic Reviews 2007, Issue 1. [DOI: 10.1002/14651858.CD004881.pub3]

Carroll N, Wu P, Gebretsadik T, Griffin MR, Dupont WD, Mitchel EF, et al. The severity‐dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma. Journal of Allergy and Clinical Immunology 2009;123:1055‐61.

Chang AB, Chang CC, O'Grady K, Torzillo PJ. Lower respiratory tract infections. Pediatric Clinics of North America 2009;56(6):1303‐21.

Chang AB, Oppenheimer JJ, Weinberger M, Rubin BK, Weir K, Irwin RS. Management of children with chronic wet cough and protracted bacterial bronchitis: CHEST Guideline and Expert Panel Report. Chest 2017;151(4):884‐90.

Didierlaurent A, Goulding J, Patel S, Snelgrove R, Low L, Bebien M, et al. Sustained desensitization to bacterial Toll‐like receptor ligands after resolution of respiratory influenza infection. Journal of Experimental Medicine 2008;205(2):323‐9.

Fox GF, Everard ML, Marsh MJ, Milner AD. Randomised controlled trial of budesonide for the prevention of post‐bronchiolitis wheezing. Archives of Disease in Childhood 1999;80(4):343‐7.

Giamarellos‐Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. International Journal of Antimicrobial Agents 2008;31(1):12‐20.

GRADEpro GDT. GRADEpro Guideline Development Tool [Software]. McMaster University, 2015 (developed by Evidence Prime, Inc.). gradepro.org.

Halfhide C, Smythe RL. Innate immune response and bronchiolitis and preschool recurrent wheeze. Paediatric Respiratory Reviews 2008;9(4):251‐62.

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [March 2011]. The Cochrane Collaboration, 2011. www.cochrane‐handbook.org.

Kim CK, Choi J, Kim HB, Callaway Z, Shin BM, Kim JT, et al. A randomized intervention of montelukast for post‐bronchiolitis: effect on eosinophil degranulation. Journal of Pediatrics 2010;156(5):749‐54.

Leach AJ, Boswell JB, Asche V, Nienhuys TG, Mathews JD. Bacterial colonization of the nasopharynx predicts very early onset and persistence of otitis media in Australian aboriginal infants. Pediatric Infectious Disease Journal 1994;13(11):983‐9.

Leconte S, Paulus D, Degryse J. Prolonged cough in children: a summary of the Belgian primary care clinical guideline. Primary Care Respiratory Journal 2008;17(4):206‐11.

Marchant JM, Morris P, Gaffney J, Chang AB. Antibiotics for prolonged moist cough in children. Cochrane Database of Systematic Reviews 2005, Issue 4. [DOI: 10.1002/14651858.CD004822.pub2]

Marchant JM, Masters IB, Champion A, Petsky HL, Chang AB. Randomised controlled trial of amoxycillin‐clavulanate in children with chronic wet cough. Thorax 2012;67(8):689‐93. [DOI: 10.1136/thoraxjnl‐2011‐201506]

McCallum GB, Morris PS, Chang AB. Antibiotics for persistent cough or wheeze following acute bronchiolitis in children. Cochrane Database of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/14651858.CD009834.pub2]

McCallum GB, Chatfield MD, Morris PS, Chang AB. Risk factors for adverse outcomes of Indigenous infants hospitalized with bronchiolitis. Pediatric Pulmonology 2016;51:613‐23.

McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clinical Microbiology Reviews 2006;19:571‐82.

National Institute for Health and Care Excellence (NICE). Bronchiolitis: diagnosis and management in children. www.nice.org.uk/Guidance/NG92015.

Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, Baley JE, Gadomski AM, et al. Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics 2014;134:e1474‐e1502.

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Scottish Intercollegiate Guidelines Network (SIGN). Bronchiolitis in children: a national clinical guideline. Archives of Disease in Childhood Education and Practice Edition 2006;91:1‐46.

Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. American Journal of Respiratory and Critical Care Medicine 2000;161:1501‐7.

Spurling GK, Doust J, Del Mar CB, Eriksson L. Antibiotics for bronchiolitis in children. Cochrane Database of Systematic Reviews 2011, Issue 6. [DOI: 10.1002/14651858.CD005189.pub3]

Su SC, Chang AB. Improving the management of children with bronchiolitis: the updated American Academy of Pediatrics clinical practice guideline. Chest 2014;6:1428‐30.

Google Scholar

Swingler GH, Hussey GD, Zwarenstein M. Duration of illness in ambulatory children diagnosed with bronchiolitis. Archives of Pediatrics and Adolescent Medicine 2000;154:997‐1000.

Wong JY, Rutman A, O'Callaghan C. Recovery of the ciliated epithelium following acute bronchiolitis in infancy. Thorax 2005;60(7):582‐7.

Zarogoulidis P, Papanas N, Kioumis I, Chatzaki E, Maltezos E, Zarogoulidis K. Macrolides: from in vitro anti‐inflammatory and immunomodulatory properties to clinical practice in respiratory diseases. European Journal of Clinical Pharmacology 2011;67:1‐25.

Google Scholar

Characteristics of studies

Characteristics of included studies [ordered by year of study]

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estudios excluidos

Tahan 2007

Methods	Double‐blind, placebo‐controlled, parallel‐group, randomised study
Participants	Inclusion criteria: Infants ≤ 7 months Hospitalised with first‐time episode of wheezing requiring hospitalisation and with respiratory syncytial virus‐confirmed bronchiolitis Exclusion criteria: Cardiac disease Cystic fibrosis Chronic neonatal lung disease associated with prematurity Treatment with corticosteroids within 24 hours or with bronchodilators within 4 hours before presentation to hospital Number screened: not stated Number refused: not stated Number randomised: total n = 30 (intervention group n = 15 and control group n = 15)
Interventions	Oral clarithromycin (15 mg/kg/d) or placebo (15 mg/kg/d) daily for 3 weeks
Outcomes	Primary outcomes Length of hospital stay Supplemental oxygen Wheeze Secondary outcomes Decrease in plasma concentrations (interleukin‐4, interleukin‐8, eotaxin) Enhanced production of interferon‐gamma
Notes	Single site Small sample size High attrition Funding: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on sequence generation provided. Paper describes that participants were "randomised by a single study nurse"
Allocation concealment (selection bias)	Unclear risk	No information provided on how the study nurse randomised each participant and how concealment was maintained
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and families remained blinded to randomisation until end of study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Paper described that investigators remained blinded to randomisation until end of study
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	30 participants were enrolled and randomised. During the study phase, 9 were excluded (30%) because they had received corticosteroids. Groups and outcomes of these infants were not reported
Selective reporting (reporting bias)	Unclear risk	The results table appears to show analysis including only children remaining in the trial (n = 21). ITT was not used
Other bias	Unclear risk	It is unclear whether the trial was registered, and if outcomes were selected a priori

McCallum 2015

Methods	Multi‐centre, double‐blinded, placebo‐controlled, parallel‐group, randomised study
Participants	Inclusion criteria: Indigenous ethnicity defined as Aboriginal, Tores Strait Islander, Maori, and/or Pacifici Islander Infants aged ≤ 24 months Hospitalised with a clinical diagnosis of bronchiolitis Consented within 24 hours of hospitalisation Caregivers required to have mobile phone Exclusion criteria: Chronic lung disease or bronchiectasis Current diagnosis of gastroenteritis Received azithromycin in past 7 days Liver impairment Cyanotic congenital heart disease Received oxygen for longer than 24 hours in admitting hospital Number screened: n = 698 (n = 479 excluded for various reasons) Number refused: n = 89 Number randomised: total n = 219 (intervention group n = 106 and control group n = 113)
Interventions	Oral azithromycin (30 mg/kg once weekly) or placebo (30 mg/kg once weekly) for 3 weeks
Outcomes	Primary outcomes: Length of hospital stay Duration of supplemental oxygen use Secondary outcomes: Respiratory symptoms and signs at day 21 Respiratory rehospitalisation (within 6 months of discharge) Nasopharyngeal bacterial carriage and respiratory virus (obtained from nasopharyngeal swabs collected at admission and 48 hours later)
Notes	International RCT between Australia and New Zealand RCT was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN1261000036099) Funding: National Health and Medical Research Council (605809)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Independent statistician used a computer‐generated, permuted block design to generate randomisation sequences
Allocation concealment (selection bias)	Low risk	Sealed opaque envelopes concealed treatment allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All participants, family, assessor, and hospital staff remained blinded during the study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Neither the study team (researchers hospital staff) nor parents were aware of assigned treatment groups until data analysis was completed
Incomplete outcome data (attrition bias) All outcomes	Low risk	219 participants were randomised and intention‐to‐treat analysis was performed
Selective reporting (reporting bias)	Low risk	All participants were analysed as 'intention‐to‐treat'
Other bias	Low risk	The trial was registered. Details of adverse events were reported ‐ none of the participants discontinued the trial

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos

Study	Reason for exclusion
Beigelman 2015	In this RCT, treatment occurred during the acute phase of bronchiolitis (e.g. ≤ 14 days)
Friis 1984	This open randomised trial included children up to 62 months of age with a diagnosis of pneumonia; treatment provided up to 6 days did not include use of antibiotics beyond the acute period
Kabir 2009	In this RCT, the treatment period lasted only up to 7 days
Kneyber 2008	In this RCT, the treatment period lasted only up to 3 days
Mazumder 2009	Length of treatment period for this RCT is not clear. Analysis describes up to 5 days, thus not eligible for post‐acute bronchiolitis
McCallum 2013	In this RCT, treatment was provided during the acute phase of bronchiolitis (i.e. ≤ 14 days)
Pinto 2012	In this RCT, treatment was provided during the acute phase of bronchiolitis (i.e. ≤ 14 days)

RCT: randomised controlled trial

Data and analyses

Open in table viewer

Comparison 1. Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of participants who were not cured at follow‐up (up to 6 months) Show forest plot	2	249	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.37, 1.28]
Open in figure viewer Analysis 1.1 Comparison 1 Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo), Outcome 1 Number of participants who were not cured at follow‐up (up to 6 months).
2 Number of participants who were rehospitalised within 6 months Show forest plot	2	240	Odds Ratio (M‐H, Random, 95% CI)	0.54 [0.05, 6.21]
Open in figure viewer Analysis 1.2 Comparison 1 Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo), Outcome 2 Number of participants who were rehospitalised within 6 months.
3 Proportion of participants with wheeze (within 6 months of intervention) Show forest plot	2	240	Odds Ratio (M‐H, Random, 95% CI)	0.47 [0.06, 3.95]
Open in figure viewer Analysis 1.3 Comparison 1 Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo), Outcome 3 Proportion of participants with wheeze (within 6 months of intervention).

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.

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Figure 4

Forest plot of comparison: 1 Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo), outcome: 1.1 Number of participants who were not cured at follow‐up (up to 6 months).

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Figure 5

Forest plot of comparison: 1 Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo), outcome: 1.2 Number of participants who were rehospitalised within 6 months.

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Figure 6

Forest plot of comparison: 1 Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo), outcome: 1.3 Proportion of participants with wheeze (within 6 months of intervention).

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Analysis 1.1

Comparison 1 Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo), Outcome 1 Number of participants who were not cured at follow‐up (up to 6 months).

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Analysis 1.2

Comparison 1 Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo), Outcome 2 Number of participants who were rehospitalised within 6 months.

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Analysis 1.3

Comparison 1 Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo), Outcome 3 Proportion of participants with wheeze (within 6 months of intervention).

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Summary of findings for the main comparison. Antibiotics compared with placebo or no treatment for persistent respiratory symptoms following acute bronchiolitis

Antibiotics compared with placebo or no treatment for persistent respiratory symptoms following acute bronchiolitis
Patient or population: children < 24 months with persistent respiratory symptoms following acute bronchiolitis Setting: post‐acute bronchiolitis phase > 14 days Intervention: antibiotics^ Comparison: placebo or no treatment^
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with antibiotics
Number of participants who were not cured at follow‐up Follow‐up: 6 months	234 per 1000	174 per 1000 (102 to 282)	OR 0.69 (0.37 to 1.28)	249 (2 RCTs)	⊕⊕⊝⊝ LOW^a
Number of participants rehospitalised for a respiratory illness Follow‐up: 6 months	238 per 1000	271 per 1000 (173 to 398)	OR 1.19 (0.67 to 2.12)	240 (2 RCTs)	⊕⊕⊝⊝ LOW^a
Proportion of participants with recurrent wheeze Follow‐up: 6 months	123 per 1000	99 per 1000 (47 to 195)	OR 0.47 (0.06 to 3.95)	240 (2 RCTs)	⊕⊕⊝⊝ LOW^a
^Intervention/Comparison group: treatment initiated during child's hospitalisation for acute bronchiolitis *The risk in the intervention group (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) CI: confidence interval; OR: odds ratio
We used GRADEPro software to create this table (GRADEpro GDT 2015) GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aQuality downgraded because of small numbers of studies and participants and high attrition in the Tahan study. Hence, we cannot be confident of the effect estimate

Summary of findings for the main comparison. Antibiotics compared with placebo or no treatment for persistent respiratory symptoms following acute bronchiolitis

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Comparison 1. Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of participants who were not cured at follow‐up (up to 6 months) Show forest plot	2	249	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.37, 1.28]

2 Number of participants who were rehospitalised within 6 months Show forest plot	2	240	Odds Ratio (M‐H, Random, 95% CI)	0.54 [0.05, 6.21]

3 Proportion of participants with wheeze (within 6 months of intervention) Show forest plot	2	240	Odds Ratio (M‐H, Random, 95% CI)	0.47 [0.06, 3.95]

Comparison 1. Prevention of post‐bronchiolitis syndrome (antibiotics vs placebo)

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Referencias

References to studies included in this review

McCallum 2015 {published data only}

Tahan 2007 {published data only}

References to studies excluded from this review

Beigelman 2015 {published data only}

Friis 1984 {published data only}

Kabir 2009 {published data only}

Kneyber 2008 {published data only}

Mazumder 2009 {published data only}

McCallum 2013 {published data only}

Pinto 2012 {published data only}

Additional references

Bailey 2009

Blom‐Danielle 2007

Carroll 2009

Chang 2009

Chang 2017

Didierlaurent 2008

Fox 1999

Giamarellos‐Bourboulis 2008

GRADEpro GDT 2015

Halfhide 2008

Higgins 2011

Kim 2010

Leach 1994

Leconte 2008

Marchant 2005

Marchant 2012

McCallum 2012

McCallum 2016

McCullers 2006

NICE 2015

Ralston 2014

RevMan 2014 [Computer program]

SIGN 2006

Sigurs 2000

Spurling 2011

Su 2014

Swingler 2000

Wong 2005

Zarogoulisidis 2011

Characteristics of studies

Characteristics of included studies [ordered by year of study]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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