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Inhaled corticosteroids for subacute cough in children

  1. Sophie Anderson-James1,*,
  2. Julie M Marchant1,
  3. Jason P Acworth1,2,
  4. Cathy Turner3,
  5. Anne B Chang1,4,5

Editorial Group: Cochrane Airways Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 12 MAR 2012

DOI: 10.1002/14651858.CD008888.pub2


How to Cite

Anderson-James S, Marchant JM, Acworth JP, Turner C, Chang AB. Inhaled corticosteroids for subacute cough in children. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD008888. DOI: 10.1002/14651858.CD008888.pub2.

Author Information

  1. 1

    The University of Queensland, Queensland Children's Medical Research Institute, Brisbane, Queensland, Australia

  2. 2

    Royal Children's Hospital, Emergency Medicine, Brisbane, Australia

  3. 3

    The University of Queensland, School of Nursing & Midwifery, Herston, Queensland, Australia

  4. 4

    Charles Darwin University, Menzies School of Health Research, Casuarina, Northern Territories, Australia

  5. 5

    Royal Children's Hospital, Queensland Children's Respiratory Centre, Brisbane, Queensland, Australia

*Sophie Anderson-James, Queensland Children's Medical Research Institute, The University of Queensland, Herston Road, Herston, Brisbane, Queensland, 4029, Australia. Sophie_Anderson-James@health.qld.gov.au.

Publication History

  1. Publication Status: New
  2. Published Online: 28 FEB 2013

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Characteristics of included studies [ordered by study ID]
Fox 1999

MethodsDual-centre double-blind randomised controlled trial comparing budesonide 200 µg or 1 puff twice daily (via metered dose inhaler (MDI) with modified spacer and mask) versus placebo in infants admitted to hospital with acute bronchiolitis

At baseline participants had a medical history, nasopharyngeal swab and clinical examination performed

Randomisation occurred when infants were considered ready for discharge. Method of sequence generation and allocation concealment not described


Participants60 infants, aged median (range) 11 (1 to 42) weeks, with clinical diagnosis of acute viral bronchiolitis requiring hospital admission were included. There were no significant differences in any patient characteristics between the 2 groups

Inclusion criteria: infants aged less than 12 completed months with a clinical diagnosis of acute viral bronchiolitis

Exclusion criteria: children with underlying cardiopulmonary disease, including congenital heart disease, bronchopulmonary disease and cystic fibrosis, and those who experienced respiratory problems in the neonatal period, or required mechanical ventilation during current illness

Follow-up data at 1 month were available for 54 of the 60 infants initially randomised. Budesonide group N = 26 (20 males), placebo group N = 28 (14 males)

1 participant was excluded after randomisation but before receiving any study medication as required mechanical ventilation, 1 participant was excluded at the first follow-up appointment due to poor compliance, and 4 additional participants failed to attend any follow-up appointments

8 included infants had been born prematurely between 32 and 37 weeks' gestation, with 6 randomised to the placebo group; however, the difference between groups was non-significant


InterventionsTreatment group received inhaled budesonide 200 µg or 1 puff twice daily (via MDI with spacer and mask) for 8 weeks, versus placebo control group

Additional medications received by participants during the next 12-month follow-up period included cough suppressants, oral and inhaled bronchodilators, and inhaled and systemic corticosteroids.


OutcomesPrimary outcome: reduction in incidence of coughing and wheezing episodes requiring treatment by a general practitioner (GP) or emergency department during a 12-month follow-up period

Parent-completed diary card record of respiratory symptoms (episodes of coughing and wheezing), GP and hospital visits, and medication prescribed and used over a 12-month follow-up period

Clinical examinations occurred at 1, 2, 6 and 12 months post discharge.

2 adverse events were recorded; however, these were unrelated to study medication. 1 infant was admitted to hospital with viral gastroenteritis and 1 infant was re-admitted with mild coughing and wheezing


NotesOnly episodes of cough and wheeze that required treatment by a GP or emergency department were included in the statistical analysis

Written communication with the author did not provide further differentiated cough symptom data

Study funded by grants from the National Asthma Campaign and The St Thomas's Hospital Special Trustees


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised to receive either budesonide or placebo (30 to each group). Method of sequence generation not described

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated double blind

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear who was the assessor

Incomplete outcome data (attrition bias)
All outcomes
High riskReasons for withdrawals and missing data described; however, not included in final analysis

Selective reporting (reporting bias)Low riskLimitations of study discussed. Authors suggested possible Type 1 error due to more males in the treatment group

Other biasUnclear riskPossible selection bias in recruitment, as number of potentially eligible participants not described. Additional medications allowed during the follow-up period included inhaled and systemic corticosteroids

Wong 2000

MethodsSingle-centre, double-blind randomised controlled trial comparing fluticasone propionate 150 µg (3 puffs of a 50 µg inhaler) twice daily (via metered dose inhaler (MDI) with low volume spacer and mask) versus placebo, in infants admitted to hospital for first documented episode of acute bronchiolitis

Nasopharyngeal aspirates were sent for immunofluorescent study and viral culture. A detailed history was obtained and documented with examination findings and treatments

Randomisation occurred when infants were considered ready for discharge. Method of sequence generation and allocation concealment not described

Statistical analysis was performed on an intention-to-treat basis


Participants48 infants aged 2 to 52 weeks, with first documented episode of acute bronchiolitis requiring admission

Inclusion criteria: infants admitted with first episode of lower respiratory tract infection, diagnosed by 1 investigator as having acute bronchiolitis using COURT criteria. Specific inclusion ages not stated

Exclusion criteria: birth before 36 weeks' gestation; congenital heart disease or syndromic abnormalities; established systemic or chronic illnesses; treatment with corticosteroids or mechanical ventilation before entering the study. Those who were unable to master the required medication delivery technique after education were also excluded

Follow-up data at 3 weeks were available for 44 of the 48 infants initially randomised. Fluticasone propionate group N = 21, placebo group N = 23. The demographic data were similar in the 2 groups

2 participants in the treatment group were withdrawn due to distress resulting from the application of the face mask, with a third participant withdrawn due to social reasons. 1 participant in the placebo group was withdrawn for non-compliance after the treatment period


InterventionsTreatment group received 150 µg fluticasone propionate via MDI with low-volume spacer and mask for 3 months, versus placebo control group

Prescription of additional medications by independent doctors included beta2-agonists, corticosteroids and antibiotics


OutcomesPrimary outcome: reduction in overnight cough rate from pre-treatment baseline levels

Overnight cough recordings using a voice-activated tape recorder, attempted at baseline and at each of the 6 follow-up visits. During the treatment period, 87% of attempted cough recordings were technically successful. Not attempted on 10 occasions. Weighted mean change in cough rate was used to compare reductions in cough rate between treatment groups

Percentages of infants cough free (based on overnight recording) at each home visit were reported

Overnight oxygen saturation measurements were also conducted at time of cough recording

Data on symptom frequency, use of rescue respiratory medications, hospital admissions was collected. Follow-up clinical examinations occurred on 6 occasions over 12 months. Clinical decisions about need for additional treatments were made by family practitioners and hospital doctors. Family doctor and hospital records were examined at the end of the study for collaborative information

Parents completed symptom diaries scoring cough, wheeze and general well-being for both day and night; however, data were reported as percentage of days over 3 months for each symptom score

Lung function was measured 6 months after hospital discharge (3 months after the treatment period), therefore could not be included in this review


NotesWritten communication with the study author did not provide further differentiated cough symptom data

Project funded by GlaxoWellcome


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; however, method of sequence generation not described

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated double blind

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskPrimary outcome measure overnight cough rate (objective measure); however, unclear who was the assessor

Incomplete outcome data (attrition bias)
All outcomes
High riskDrop-outs and withdrawals described, and included in final analysis up until withdrawal date. Participants with no overnight cough data following the baseline cough recordings were eliminated from the analysis

Selective reporting (reporting bias)Low riskLimitations of study discussed

Other biasUnclear riskPossible selection bias in recruitment, as number of potentially eligible participants not described. Prescription of additional medications by independent doctors included bronchodilators, corticosteroids and antibiotics. More infants in the placebo group received bronchodilators/corticosteroids, but not antibiotics

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Davies 1999Double-blind randomised controlled trial of inhaled fluticasone propionate versus placebo. Cough duration was ≥ 6 weeks, although inclusion criteria was > 3 weeks. Excluded from review as chronic cough, not subacute cough

Evald 1989Randomised controlled trial of inhaled beclomethasone dipropionate versus placebo. Cross-over occurred at 2 weeks. Excluded from review as chronic cough, not subacute cough, cross-over study design, and participants were adults, not children

Jartti 2007Randomised controlled trial of oral prednisolone versus placebo. Excluded from review as oral prednisolone, not inhaled corticosteroids, and investigating effect on wheezing in virus-positive children, not cough

Kooi 2008Double-blind randomised controlled trial of inhaled fluticasone propionate, montelukast or placebo in children with asthma-like symptoms. Study inclusion criteria does not comply as no separate cough symptom data, and daily symptoms were not required for inclusion. Run-in period of 2 weeks implemented. Excluded from review as chronic cough, not subacute cough

Kwon 2006Not a randomised controlled trial (RCT). Study of adults with cough duration of 3 to 8 weeks who underwent bronchoprovocation and induced sputum tests to determine treatment with inhaled corticosteroids. Excluded from review as not an RCT, subacute and chronic cough, and adults, not children

Moskovljevic 2009Double-blind randomised controlled trial of inhaled fluticasone propionate, montelukast or placebo in children aged 8 to 18. Excluded from review as study inclusion criteria do not comply, as participants had asthma-like symptoms, and no short-term data were available (collected at baseline and after 3 months)

Pelkonen 2009Randomised controlled trial of inhaled budesonide or placebo in children aged 3 to 26 months with abnormal lung function. Lower range of cough duration was 2 months, therefore excluded from review as chronic cough, not subacute cough, and abnormal lung function suggesting underlying condition

Ponsioen 2005Double-blind randomised controlled trial of inhaled fluticasone propionate versus placebo in adults with cough duration ≥ 2 weeks. Excluded as adult participants, not children

Pornsuriyasak 2005Double-blind randomised controlled trial of inhaled budesonide or placebo in participants with persistent post upper respiratory tract infection cough. All participants were aged ≥ 18 years, although inclusion criteria was > 15 years (as per written communication with author). Excluded from review as adult participants, not children

Profita 2010Double-bind randomised controlled trialof inhaled beclomethasone dipropionate versus placebo in children with clinical diagnosis of intermittent asthma. Excluded from review as study inclusion criteria does not comply as participants had asthma

Puhakka 1998Double-blind randomised controlled trial of intranasal fluticasone propionate versus placebo in adults for common cold. Excluded from review as adults, not children, and intranasal not inhaled corticosteroids, cough symptom data not differentiated

Ribeiro 2007Double-blind randomised controlled trial of inhaled beclomethasone dipropionate versus placebo in adults with chronic cough (duration of ≥ 8 weeks). Excluded from review as chronic cough, not subacute cough and adults, not children

Rytila 2000Single-blind randomised controlled trial of inhaled beclomethasone dipropionate versus placebo in adults with asthma. Excluded from review as adults, not children, and participants with asthma

Yuksel 1992Double-blind randomised controlled trial of inhaled beclomethasone dipropionate versus placebo in premature infants. Cough duration was greater than 4 weeks. Excluded from review as chronic cough, not subacute

 
Comparison 1. Inhaled corticosteroids versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical failure298Odds Ratio (M-H, Fixed, 95% CI)0.61 [0.24, 1.55]

 
Summary of findings for the main comparison. Inhaled corticosteroids for subacute cough

Inhaled corticosteroids for subacute cough

Patient or population: children with subacute cough following acute bronchiolitis
Settings: treatment given at discharge
Intervention: inhaled corticosteroids compared to placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlInhaled corticosteroids

Clinical failure (proportion of participants who were not cured or substantially improved (> 70% reduction in cough severity measure) at follow-up).
Follow-up: 3 to 4 weeks
41 per 10030 per 100
(14 to 52)
OR 0.61
(0.24 to 1.55)
98
(2 studies)
⊕⊕⊝⊝
low1,2,3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Allocation concealment and blinding was unclear in both included studies. Randomisation sequence generation was not described.
2 In both included studies there was a limitation in the directness of the answers to the review question, due to the distinct patient population as defined by age (< 12 months) and illness (post acute bronchiolitis).
3 Both included studies had relatively few patients and few study events, resulting in wide CIs.