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BMJ Clin Evid. 2012; 2012: 0302.
Published online 2012 January 18.
PMCID: PMC3285219

Asthma and other recurrent wheezing disorders in children (chronic)

Stephen William Turner, MBBS, MRCP, FRCPCH, MD, Senior Clinical Lecturer in Child Health and Honorary Consultant Paediatrician,# Amanda Jane Friend,# and Augusta Okpapi, Speciality Trainee in Paediatrics#

Abstract

Introduction

Childhood asthma is the most common chronic paediatric illness. There is no cure for asthma but good treatment to palliate symptoms is available. Asthma is more common in children with a personal or family history of atopy, increased severity and frequency of wheezing episodes, and presence of variable airway obstruction or bronchial hyperresponsiveness. Precipitating factors for symptoms and acute episodes include infection, house dust mites, allergens from pet animals, exposure to tobacco smoke, and exercise.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of single-agent prophylaxis in children taking as-needed inhaled beta2 agonists for asthma? What are the effects of additional prophylactic treatments in childhood asthma inadequately controlled by standard-dose inhaled corticosteroids? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 48 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta2 agonists (long-acting), corticosteroids (inhaled standard or higher doses), leukotriene receptor antagonists (oral), omalizumab, and theophylline (oral).

Key Points

Childhood asthma can be difficult to distinguish from viral wheeze and can affect up to 20% of children.

Regular monotherapy with inhaled corticosteroids improves symptoms, reduces exacerbations, and improves physiological outcomes in children with asthma symptoms requiring regular short-acting beta2 agonist treatment. Their effect on final adult height is minimal and when prescribed within recommended doses have an excellent safety record. Regular monotherapy with other treatments is not superior to low-dose inhaled corticosteroids.

Leukotriene receptor antagonists may have a role as first-line prophylaxis in very young children.

There is consensus that long-acting beta2 agonists should not be used for first-line prophylaxis.

  • CAUTION: Monotherapy with long-acting beta2 agonists does not reduce asthma exacerbations but may increase the chance of severe asthma episodes.

Theophylline was used as first-line prevention before the introduction of inhaled corticosteroids. Although there is weak evidence that theophylline is superior to placebo, theophylline should no longer be used as first-line prophylaxis in childhood asthma because of clear evidence of the efficacy and safety of inhaled corticosteroids.

  • Theophylline has serious adverse effects (cardiac arrhythmia, convulsions) if therapeutic blood concentrations are exceeded.

When low-dose inhaled corticosteroids fail to control asthma, most older children will respond to one of the add-on options available, which include addition of long-acting beta2 agonists, addition of leukotriene receptor antagonists, addition of theophylline, or increased dose of inhaled corticosteroid. However, we don't know for certain how effective these additional treatments are because we found no/limited RCT evidence of benefit compared with adding placebo/no additional treatments.

  • Addition of long-acting beta2 agonists may reduce symptoms and improve physiological measures compared with increased dose of corticosteroids in older children. Long-acting beta2 agonists are not currently licensed for use in children under 5 years of age.
  • Consensus suggests that younger children are likely to benefit from addition of leukotriene receptor antagonists.
  • Although there is weak evidence that addition of theophylline to inhaled corticosteroids does improve symptom control and reduce exacerbations, theophylline should only be added to inhaled corticosteroids in children aged over 5 years when the addition of long-acting beta2 agonists and leukotriene receptor antagonists have both been unsuccessful.

Omalizumab may be indicated in the secondary care setting for older children (aged over 5 years) with poorly controlled allergic asthma despite use of intermediate- and high-dose inhaled corticosteroids once the diagnosis is confirmed and compliance and psychological issues are addressed. However, we need more data to draw firm conclusions.

About this condition

Definition

Asthma is characterised by episodic wheeze, cough, and shortness of breath in association with exposure to multiple factors including rhinovirus, exercise, and allergens. The diagnosis remains entirely based on the history coupled with a positive response to treatment. Childhood asthma can affect up to 20% of children and can be difficult to diagnose in preschool children, where many individuals have acute episodic wheeze/viral-induced wheeze. Examination of the child with asthma is invariably normal and although physiological testing will characteristically find reversible airway obstruction and atopy, these tests lack precision for asthma and have no benefit in the majority of children. The absence of a widely accepted definition for asthma, a diagnostic test, and lack of a biomarker with which to objectively monitor the condition can make childhood asthma a clinical challenge, especially in young children. In cases of clinical uncertainty or where symptoms persist despite adequate treatment, referral for specialist opinion should be sought. This review deals with pharmacological management of chronic asthma in children only. For information on the management of acute asthma in children see review on Asthma and other recurrent wheezing disorders in children (acute).

Incidence/ Prevalence

Asthma prevalence rose in the UK and other Western countries during the 1980s and 1990s, but recent evidence suggests that asthma prevalence is falling; however, lifetime asthma prevalence is still reported as 24% in children aged 9 to 12 years in the UK. Genetic factors are thought to account for 60% of asthma causation, but genetic change cannot explain the rise in asthma prevalence from 4% in 1964 to present day values. The reasons for the rise and early fall in asthma prevalence are not understood but are likely to involve epigenetics and interactions between genetic predispositions and environmental exposures, including tobacco smoke.

Aetiology/ Risk factors

Asthma is a typical complex condition where genetic and environmental factors interact, often at critical stages of development. Genetic factors explain approximately 60% of asthma causation, but there is no single "asthma gene" — rather there are approximately 10 genes, each of which confer a modest increased risk for asthma. Environmental factors implicated in asthma causation include exposure to tobacco smoke, diet (including non-breast feeding), early respiratory infection, and indoor and outdoor air quality. Other non-modifiable risk factors include sex (asthma is more common in boys than girls but more common in women than men) and age (many children apparently "grow out of" their asthma).

Prognosis

A UK longitudinal study of children born in 1970 found that 29% of 5-year-olds wheezing in the past year were still wheezing at the age of 10 years. Another study followed a group of children in Melbourne, Australia, from the age of 7 years (in 1964) into adulthood. The study found that a large proportion (73%) of 14-year-olds with infrequent symptoms had few or no symptoms by the age of 28 years, whereas two-thirds of those 14-year-olds with frequent wheezing still had recurrent attacks at the age of 28 years.

Aims of intervention

To reduce or abolish cough and wheeze; to attain best possible lung function; to reduce the risk of severe attacks; to minimise sleep disturbance and absence from school; to minimise adverse effects of treatment; and to allow normal growth.

Outcomes

By contrast with other chronic conditions, there is no gold standard outcome for asthma in clinical trials; this can make for difficulties in comparing and contrasting similar clinical trials. We have separated outcomes into 4 domains: symptom control (clinical assessments): daily symptom score, daily use of short-acting beta2 agonist, exertional and nocturnal symptoms; physiological measures: FEV1, peak flow, bronchial hyperreactivity; exacerbations: hospital admission, rescue course of oral corticosteroids, unscheduled presentation to primary care, accident and emergency attendance, and hospitalisation. Adverse effects.

Methods

Clinical Evidence search and appraisal June 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2010, Embase 1980 to June 2010, and The Cochrane Database of Systematic Reviews, May 2010 [online, searched 2 June 2010] (1966 to date of issue). When editing this review we used The Cochrane Database of Systematic Reviews 2010, Issue 3. An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. We included studies in children aged 1 to 12 years with asthma or recurrent wheeze of unspecified origin. We included studies including older children (>12 years) or younger children (<1 year) if the mean age of children in the study was between 1 and 12 years, or where the majority of children (at least 80%) were aged between 1 and 12 years. We excluded studies mainly in children with wheeze due to other specific respiratory disorders (e.g., bronchiolitis). Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language. RCTs had to be at least single blinded, and contain 20 or more individuals, of whom 80% or more were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as “open”, “open label”, or not blinded. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table
GRADE Evaluation of interventions for Asthma and other recurrent wheezing disorders in children (chronic).

Glossary

Forced expiratory volume in 1 second (FEV1)
The volume breathed out in the first second of forceful blowing into a spirometer, measured in litres.
High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
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.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Orciprenaline
This is known as metaproterenol in the USA; it is a non-selective beta agonist.
Peak expiratory flow rate (PEFR)
The maximum rate that gas is expired from the lungs when blowing into a peak flow meter or a spirometer. It is measured at an instant, but the units are expressed as litres per minute.
Salbutamol
This is known as albuterol in the USA; it is a short-acting selective beta2 agonist.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Notes

Bronchiolitis

Contributor Information

Stephen William Turner, University of Aberdeen, Aberdeen, UK.

Amanda Jane Friend, University of Aberdeen, Aberdeen, UK.

Augusta Okpapi, Royal Aberdeen Children's Hospital, Aberdeen, UK.

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2012; 2012: 0302.
Published online 2012 January 18.

Corticosteroids (inhaled)

Summary

Regular monotherapy with inhaled corticosteroids improves symptoms, reduces exacerbations, and improves physiological outcomes in children with asthma symptoms requiring regular short-acting beta 2 agonist treatment. Their effect on final adult height is minimal and when prescribed within recommended doses have an excellent safety record.

Regular monotherapy with other treatments (long-acting beta 2 agonists, leukotriene receptor antagonists, or oral theophylline) is not superior to low-dose inhaled corticosteroids.

Benefits and harms

Inhaled corticosteroids versus placebo:

We found three systematic reviews (search dates 1996, 24 RCTs [10/24 RCTs in preschool children]; search date 2007, 13 RCTs; and search date 2008, 14 RCTs in children). The reviews applied different inclusion criteria. The first and second systematic reviews included RCTs on any inhaled corticosteroid versus placebo in children, and identified different RCTs. The third systematic review included RCTs on inhaled fluticasone versus placebo. It identified one RCT in common with the first review, and three RCTs in common with the second review. The first and third reviews pooled the data from the included RCTs. The second review reported the results of the RCTs narratively and did not pool the data, and so we have only reported on those additional RCTs in this review that met Clinical Evidence inclusion criteria for this question, and were not included in the meta-analyses of the other systematic reviews. One of these RCTs was reported in multiple publications. We found three subsequent RCTs and three additional RCTs. For further information on adverse effects from observational studies, see comment.

Symptom control (clinical assessments)

Compared with placebo Regular inhaled corticosteroids seem more effective at improving symptom scores and days without symptoms, and at reducing beta2 agonist use in children with asthma (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Asthma symptoms

Systematic review
744 children; all receiving usual care, including as-needed inhaled beta2 agonists
15 RCTs in this analysis
Symptom score 4 to 88 weeks
with regular inhaled corticosteroids (betamethasone, beclometasone, budesonide, flunisolide, or fluticasone)
with placebo
Absolute results not reported

Improvement with corticosteroids 50%
95% CI 49% to 51%
Effect size not calculatedcorticosteroids plus usual care

RCT
160 children aged 12 to 47 months, with persistent asthma symptoms % symptom-free 24-hour periods 12 weeks
with fluticasone propionate (inhaled, 100 micrograms twice daily)
with placebo
Absolute results not reported

OR 0.53
95% CI 0.29 to 0.95
P = 0.035
Small effect sizefluticasone

Systematic review
353 children with asthma (no oral corticosteroids)
2 RCTs in this analysis
Change in daily symptom scores from baseline 12 weeks
with fluticasone (inhaled, 100 micrograms/day)
with placebo
Absolute results not reported

SMD –0.52
95% CI –0.73 to –0.31
Effect size not calculatedfluticasone

Systematic review
1083 children with asthma (no oral corticosteroids)
5 RCTs in this analysis
Change in daily symptom scores from baseline 12 weeks
with fluticasone (inhaled, 200 micrograms/day)
with placebo
Absolute results not reported

SMD –0.34
95% CI –0.46 to –0.22
Effect size not calculatedfluticasone

RCT
3-armed trial
276 children aged 1 to 4 years, with frequent wheezing % of symptom-free days 12 weeks
70% with beclometasone (inhaled using nebuliser, 400 micrograms twice daily) plus salbutamol (inhaled using nebuliser, 2500 micrograms taken as required)
61% with placebo plus salbutamol (inhaled using nebuliser, 2500 micrograms taken as required)

P = 0.034
Effect size not calculatedregular beclometasone plus as-needed salbutamol

RCT
3-armed trial
1041 children aged 5 to 12 years, with mild to moderate asthma, mean pre-study FEV1 94% predicted, all using salbutamol for asthma symptoms
In review
Change in symptom score, assessed by daily diary-card measures 4 to 6 years
–0.44 with budesonide (inhaled, 200 micrograms twice daily)
–0.37 with placebo

P (budesonide v placebo) = 0.005
Effect size not calculatedbudesonide

RCT
3-armed trial
63 children aged 2 to 6 years with asthma-like symptoms Change in symptom scores from baseline 3 months
with fluticasone (inhaled, 100 micrograms twice daily)
with placebo (oral, once daily)
Absolute results reported graphically

P = 0.021
RCT may have been underpowered; see further information on studies
Effect size not calculatedfluticasone

RCT
3-armed trial
238 children aged 12 to 59 months with 2 or more episodes of wheeze in the past year Proportion of episode-free days, assessed by diary cards over 12 months
76% with budesonide (inhaled by nebuliser, 1.0 mg twice daily) plus placebo (oral)
74% with placebo (oral and inhaled)
Absolute results not reported

Direct statistical comparison between budesonide and placebo not reported

RCT
3-armed trial
353 children aged 5 to 12 years, with moderate symptomatic asthma, receiving short-acting beta2 agonist on as-needed basis
In review
% of days free from asthma symptoms week 12
29.4% with beclometasone dipropionate (inhaled via extrafine aerosol, 160 micrograms/day)
17.6% with placebo

Reported as not significant
Not significant

RCT
3-armed trial
353 children aged 5 to 12 years, with moderate symptomatic asthma, receiving short-acting beta2 agonist on as-needed basis
In review
% of days free from asthma symptoms week 12
32.1% with beclometasone dipropionate (inhaled via extrafine aerosol, 80 micrograms/day)
17.6% with placebo

P less-than or equal to 0.05
Effect size not calculatedbeclometasone dipropionate (80 micrograms/day)

RCT
4-armed trial
1031 children aged 4 to 11 years with persistent asthma Mean change from baseline in asthma symptom scores (24-hour) 12 weeks
with ciclesonide (inhaled, 40 micrograms once daily)
with placebo (inhaled, once daily)
Absolute results reported graphically

P <0.01
Effect size not calculatedciclesonide (40 micrograms daily)

RCT
4-armed trial
1031 children aged 4 to 11 years with persistent asthma Mean change from baseline in asthma symptom scores (24-hour) 12 weeks
with ciclesonide (inhaled, 80 micrograms once daily)
with placebo (inhaled, once daily)
Absolute results reported graphically

P <0.001
Effect size not calculatedciclesonide (80 micrograms daily)

RCT
4-armed trial
1031 children aged 4 to 11 years with persistent asthma Mean change from baseline in asthma symptom scores (24-hour) 12 weeks
with ciclesonide (inhaled, 160 micrograms once daily)
with placebo (inhaled, once daily)
Absolute results reported graphically

P <0.001
Effect size not calculatedciclesonide (1600 micrograms daily)
Beta-agonist use

Systematic review
722 children; all receiving usual care, including as-needed inhaled beta2 agonists
14 RCTs in this analysis
Beta2 agonist use 4 to 88 weeks
with regular inhaled corticosteroids (betamethasone, beclometasone, budesonide, flunisolide, or fluticasone)
with placebo
Absolute results not reported

Relative decrease with corticosteroids 37%
95% CI 36% to 38%
Moderate effect sizecorticosteroids plus usual care

RCT
3-armed trial
241 children aged 6 to 14 years with clinically stable asthma and <1 month of prior corticosteroid use Days and nights without need for salbutamol
92% with beclometasone (81 children)
83% with placebo (80 children)

P less-than or equal to 0.001
Effect size not calculatedbeclometasone

Exacerbations

Compared with placebo Regular inhaled corticosteroids seem more effective at reducing oral corticosteroid use in children with asthma, and at reducing treatment withdrawals due to exacerbation, hospital admissions, and severe asthma-related events at up to 3 years, in children aged over 5 years (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Asthma exacerbation

RCT
3-armed trial
353 children aged 5 to 12 years, with moderate symptomatic asthma, receiving short-acting beta2 agonist on as-needed basis
In review
Time to onset of first asthma exacerbation or increased asthma symptoms week 12
with beclometasone dipropionate (inhaled via extrafine aerosol, 160 micrograms/day)
with beclometasone dipropionate (inhaled via extrafine aerosol, 80 micrograms/day)
with placebo
Absolute results reported graphically

No significant difference among the 3 groups (P = 0.18, Kaplan-Meier analysis)
Not significant

RCT
1981 children aged 5 to 10 years with mild persistent asthma, 1974 children included in analysis
In review
Subgroup analysis
Time to first severe asthma-related event
with budesonide (inhaled, 200 micrograms once daily) added to usual care
with placebo (inhaled, once daily) added to usual care
Absolute results not reported

Reported as significantly increased with budesonide
P value not reported
Effect size not calculatedbudesonide

RCT
1981 children aged 5 to 10 years with mild persistent asthma, 1974 children included in analysis
In review
Subgroup analysis
Number of severe asthma-related events 3 years
52 (in 40 children) with budesonide (inhaled, 200 micrograms once daily) added to usual care
82 (in 63 children) with placebo (inhaled, once daily) added to usual care

Reported as significantly reduced risk with budesonide
P value not reported
Effect size not calculatedbudesonide
Hospital admissions

RCT
3-armed trial
1041 children aged 5 to 12 years, with mild to moderate asthma, mean pre-study FEV1 94% predicted, all using salbutamol for asthma symptoms
In review
Hospital admissions due to asthma per 100 person-years 4 to 6 years
2.5 with budesonide (inhaled, 200 micrograms twice daily) (311 children)
4.4 with placebo (418 children)

P (budesonide v placebo) = 0.04
Effect size not calculatedbudesonide

RCT
3-armed trial
1041 children aged 5 to 12 years, with mild to moderate asthma, mean pre-study FEV1 94% predicted, all using salbutamol for asthma symptoms
In review
Urgent care visits due to asthma per 100 person-years 4 to 6 years
12 with budesonide (inhaled, 200 micrograms twice daily) (311 children)
22 with placebo (418 children)

P (budesonide v placebo) <0.001
Effect size not calculatedbudesonide
Need for oral corticosteroids

Systematic review
487 children; all receiving usual care, including as-needed inhaled beta2 agonists
12 RCTs in this analysis
Oral corticosteroid use 4 to 88 weeks
with regular inhaled corticosteroids (betamethasone, beclometasone, budesonide, flunisolide, or fluticasone)
with placebo
Absolute results not reported

Relative decrease with corticosteroids 68%
95% CI 66% to 70%
Effect size not calculatedcorticosteroids plus usual care

RCT
3-armed trial
1041 children aged 5 to 12 years, with mild to moderate asthma, mean pre-study FEV1 94% predicted, all using salbutamol for asthma symptoms
In review
Prednisolone courses per 100 person-years 4 to 6 years
70 with budesonide (inhaled, 200 micrograms twice daily)
122 with placebo

P (budesonide v placebo) <0.001
Effect size not calculatedbudesonide
Treatment withdrawal due to exacerbations

RCT
3-armed trial
241 children aged 6 to 14 years Treatment withdrawals because of exacerbations
5 with beclometasone (81 children)
15 with placebo (80 children)

P = 0.03
Effect size not calculatedbeclometasone

No data from the following reference on this outcome.

Physiological measures

Compared with placebo Regular inhaled corticosteroids seem more effective at improving peak expiratory flow rate and FEV1 in children with asthma, and at improving airway hyperresponsiveness, assessed by methacholine challenge test, in children aged 6 to 14 years with clinically stable asthma. We don't know whether regular inhaled corticosteroids are more effective at improving lung function, assessed by interrupter technique (Rint), in children aged 2 to 6 years with asthma-like symptoms (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Peak expiratory flow

Systematic review
372 children; all receiving usual care, including as-needed inhaled beta2 agonists
5 RCTs in this analysis
Peak expiratory flow rate 4 to 12 weeks
with regular inhaled corticosteroids (betamethasone, beclometasone, budesonide, flunisolide, or fluticasone)
with placebo
Absolute results not reported

Weighted mean improvement: 11% predicted
95% CI 9.5% to 12.5%
Effect size not calculatedcorticosteroids plus usual care
Forced expiratory volume

RCT
3-armed trial
1041 children aged 5 to 12 years, with mild to moderate asthma, mean pre-study FEV1 94% predicted, all using salbutamol for asthma symptoms
In review
Change in FEV1 (% of predicted) from baseline: before bronchodilator use 4 to 6 years
2.9% with budesonide (inhaled, 200 micrograms twice daily)
0.9% with placebo

P = 0.02 (budesonide v placebo)
Effect size not calculatedbudesonide

RCT
3-armed trial
241 children aged 6 to 14 years with clinically stable asthma and <1 month of prior corticosteroid use Mean change in FEV1 as % of predicted 1 year
10% with beclometasone (81 children)
5% with placebo (80 children)

P = 0.001 (beclometasone v placebo)
Effect size not calculatedbeclometasone

RCT
4-armed trial
1031 children aged 4 to 11 years with persistent asthma Change in % FEV1 from baseline 12 weeks
22.88% with ciclesonide (inhaled, 40 micrograms once daily)
21.36% with placebo (inhaled, once daily)

Reported no significant difference between groups
Not significant

RCT
4-armed trial
1031 children aged 4 to 11 years with persistent asthma Change in % FEV1 from baseline 12 weeks
26.13% with ciclesonide (inhaled, 80 micrograms once daily)
21.36% with placebo (inhaled, once daily)

P <0.05
Effect size not calculatedciclesonide (80 micrograms daily)

RCT
4-armed trial
1031 children aged 4 to 11 years with persistent asthma Change in % FEV1 from baseline 12 weeks
27.38% with ciclesonide (inhaled, 160 micrograms once daily)
21.36% with placebo (inhaled, once daily)

P <0.01
Effect size not calculatedciclesonide (160 micrograms daily)

RCT
3-armed trial
353 children aged 5 to 12 years, with moderate symptomatic asthma, receiving short-acting beta2 agonist on as-needed basis
In review
Mean change in FEV1 from baseline (% predicted) week 12
9.2% with beclometasone dipropionate (inhaled via extrafine aerosol, 80 micrograms/day)
3.9% with placebo

P less-than or equal to 0.01
Effect size not calculatedbeclometasone dipropionate (80 micrograms/day)

RCT
3-armed trial
353 children aged 5 to 12 years, with moderate symptomatic asthma, receiving short-acting beta2 agonist on as-needed basis
In review
Mean change in FEV1 from baseline (% predicted) week 12
10.0% with beclometasone dipropionate (inhaled via extrafine aerosol, 160 micrograms/day)
3.9% with placebo

P less-than or equal to 0.01
Effect size not calculatedbeclometasone dipropionate (160 micrograms/day)
Lung function assessed by Rint

RCT
3-armed trial
63 children aged 2 to 6 years with asthma-like symptoms Lung function, assessed by airway resistance (Rint)
with fluticasone (inhaled, 100 micrograms twice daily)
with placebo (oral, once daily)
Absolute results not reported

Reported no significant difference between groups
RCT may have been underpowered; see further information on studies
Not significant
Airway hyperresponsiveness

RCT
3-armed trial
241 children aged 6 to 14 years with clinically stable asthma and <1 month of prior corticosteroid use Methacholine PC20, measured 36 hours after study medication 12 months
with beclometasone
with placebo
Absolute results reported graphically

P = 0.001 (beclometasone v placebo)
Effect size not calculatedbeclometasone

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adrenal function

Systematic review
Children, all receiving usual care, including as-needed inhaled beta2 agonists
12 RCTs in this analysis
Adrenal function
with inhaled corticosteroids (betamethasone, budesonide, flunisolide, or fluticasone)
with placebo
Absolute results not reported

Significance assessment not reported
Oral candidiasis

RCT
7221 people with mild persistent asthma for <2 years, including 3210 children aged 17 years or younger Oral candidiasis 3 years
1.2% with once-daily budesonide (200 micrograms once daily from dry-powder inhaler if aged <11 years and 400 micrograms once daily if >11 years)
0.5% with placebo
Absolute numbers not reported

Systematic review
Children, all receiving usual care, including as-needed inhaled beta2 agonists
4 RCTs in this analysis
Oral candidiasis
with inhaled corticosteroids (betamethasone, budesonide, flunisolide, or fluticasone)
with placebo
Absolute results not reported
Growth suppression

RCT
3-armed trial
1041 children aged 5 to 12 years, with mild to moderate asthma, mean pre-study FEV1 94% predicted, all using salbutamol for asthma symptoms
In review
Mean increase in height 4 to 6 years
22.7 cm with budesonide 400 micrograms
23.8 cm with placebo

P = 0.005
Effect size not calculatedplacebo

RCT
3-armed trial
241 children aged 6 to 14 years Mean increase in height
3.96 cm with beclometasone
5.04 cm with placebo

P = 0.018
Effect size not calculatedplacebo

RCT
94 children aged 7 to 9 years with recurrent viral-induced wheeze
In review
Growth 7-month treatment period
with inhaled beclometasone 400 micrograms/day
with placebo
Absolute results not reported

Mean difference in growth: –1 cm
95% CI –1.4 cm to –0.6 cm
P <0.0001
No significant catch-up growth during a follow-up 4-month washout period
Effect size not calculatedplacebo

RCT
3195 children aged 5 to 17 years with mild asthma Growth rate 3 years
with budesonide
with placebo
Absolute results not reported

Mean difference in growth per year: –0.43 cm
95% CI –0.54 cm to –0.32 cm
P <0.0001
Effect size not calculatedplacebo

RCT
Children aged <11 years with mild asthma
Subgroup analysis
Growth rate 3 years
with budesonide (200 micrograms/day)
with placebo
Absolute results not reported

Differences in growth rate: –0.45 cm/year
95% CI –0.56 cm/year to –0.34 cm/year
P <0.0001
Effect size not calculatedplacebo

RCT
Children aged >11 years with mild asthma
Subgroup analysis
Growth rate 3 years
with budesonide (400 micrograms/day)
with placebo
Absolute results not reported

Difference in growth rate: –0.40 cm/year
95% CI –0.66 cm/year to –0.14 cm/year
P = 0.003
Effect size not calculatedplacebo

RCT
Children aged <11 years with mild asthma
Subgroup analysis
Growth rate year 1
with budesonide (200 micrograms/day)
with placebo
Absolute results not reported

Difference in growth rate: –0.58 cm/year
95% CI –0.76 cm/year to –0.40 cm/year
P <0.0001
Effect size not calculatedplacebo

RCT
Children aged <11 years with mild asthma
Subgroup analysis
Growth rate year 3
with budesonide (200 micrograms/day)
with placebo
Absolute results not reported

Difference in growth rate: –0.33 cm/year
95% CI –0.52 cm/year to –0.14 cm/year
P = 0.0005
Effect size not calculatedplacebo

Systematic review
1087 children, 10/24 RCTs in preschool children, all receiving usual care, including as-needed inhaled beta2 agonists
8 RCTs in this analysis
Growth velocity
with inhaled corticosteroids
with placebo
Absolute results not reported

Reported no significant difference between groups
Not significant

Inhaled corticosteroids versus oral leukotriene receptor antagonists:

See option on leukotriene receptor antagonists (oral).

Inhaled corticosteroids versus inhaled long-acting beta2 agonist:

See option on long-acting beta2 agonists (inhaled).

Inhaled corticosteroids versus oral theophylline:

See option on theophylline (oral).

Further information on studies

The RCT reported that it was unable to recruit the number of children (198) required by its power calculation to reach 90% power.

Comment

A further publication of the START trial reported on a 2-year open-label treatment extension phase with budesonide. A total of 5146 people (aged 5–66 years) from the 3-year double-blind phase of the RCT continued into this extension phase and were treated with budesonide (200 micrograms/day if <11 years, 400 micrograms/day for others). It analysed results over the full 5 years of the study. It found that both groups (budesonide for 5 years and placebo for 3 years followed by budesonide for 2 years) increased % FEV1 by an average of 3.24%. It found no significant difference between groups. It found that the cumulative risk of severe asthma-related events after 5 years was significantly lower in people treated with budesonide for 5 years compared with people treated with placebo for 3 years followed by budesonide for 2 years.

Adverse effects of inhaled corticosteroids from observational studies:

Observational studies have found little or no biochemical evidence of change in bone metabolism with inhaled corticosteroids. Case reports and a national survey of paediatricians and endocrinologists have indicated the possibility of adrenal suppression leading to adrenal crisis associated with hypoglycaemia in children on high-dose inhaled corticosteroids. Most cases involved fluticasone in daily doses of 500 to 2000 micrograms. Two cross-sectional studies using a slit lamp to screen for lenticular changes in children taking long-term inhaled corticosteroids (beclometasone, budesonide) found no posterior subcapsular cataracts.

One systematic review (search date 1993, 12 studies, 331 children with asthma treated with inhaled beclometasone) found no evidence of growth impairment with inhaled beclometasone. Two related controlled prospective studies assessed the effects of inhaled budesonide on growth. The first study compared 216 children treated with budesonide (400–600 micrograms/day) versus 62 children treated with theophylline or sodium cromoglicate over 3 to 5 years of follow-up. No significant changes in growth velocity were found at doses up to 400 micrograms daily (5.5 cm/year with budesonide v 5.6 cm/year with controls).The adult height of 142 of these budesonide-treated children (mean treatment period 9.2 years, mean dosage 412 micrograms/day) was compared with 18 controls never treated with inhaled corticosteroids and 51 healthy siblings. No significant differences were found. Children in all groups attained their target adult height (mean difference between measured and target adult height: +0.3 cm, 95% CI –0.6 cm to +1.2 cm for budesonide-treated children; –0.2 cm, 95% CI –2.4 cm to +2.1 cm for control children with asthma; +0.9 cm, 95% CI –0.4 cm to +2.2 cm for healthy siblings).

Starting dose of inhaled corticosteroid:

We found one systematic review (search date not reported, 5 RCTs in children, 4 RCTs in infants) examining the effects of different initiation doses of inhaled corticosteroids. The review found no significant difference between intermediate-dose and low-dose inhaled corticosteroid in exacerbations (2 RCTs [1 RCT in children, mean age approximately 9 years; 1 RCT in infants, age range 12–47 months]: proportion of children with exacerbation: 18/193 [9%] with intermediate dose v 23/200 [13%] with low dose; RR 0.82, 95% CI 0.47 to 1.43). It found that high-dose budesonide significantly reduced airway hyperresponsiveness, assessed by post-exercise fall in FEV1, compared with low-dose budesonide (1 RCT, 19 children; absolute numbers not reported in review; P <0.0001).

Inhaled corticosteroids versus placebo post exercise:

We found one crossover RCT (25 children aged 5–14 years) that only assessed post-exercise symptoms. It compared hydrofluoroalkane beclometasone dipropionate (50 or 100 micrograms) once in the evening by autohaler versus placebo. Treatment periods lasted 4 weeks with a 1-week washout period between. The RCT did not report pre-crossover results, but it found no evidence of a carry-over or period effect. It found that both doses of beclometasone significantly reduced the percentage fall in FEV1 after exercise compared with placebo. It found few adverse effects during treatment with low-dose (50 or 100 micrograms) hydrofluoroalkane beclometasone dipropionate by autohaler or during treatment with placebo.

Clinical guide:

The dose of inhaled corticosteroids should be reviewed at least once every 3 months. If symptoms are controlled, the inhaled corticosteroid dose can be halved or if very low, discontinuation can be considered. Annual measurement of height with plotting on height centile charts should be undertaken in all children receiving treatment with inhaled corticosteroids. Children requiring long-term use of high-dose (off-licence) inhaled corticosteroids should be referred to a specialist.

Substantive changes

Corticosteroids (inhaled) New evidence added. Categorisation unchanged (Beneficial).

2012; 2012: 0302.
Published online 2012 January 18.

Leukotriene receptor antagonists (oral)

Summary

Regular monotherapy with oral leukotriene receptor antagonists is not superior to low-dose inhaled corticosteroids. Leukotriene receptor antagonists may have a role as first-line prophylaxis in very young children.

Benefits and harms

Oral leukotriene receptor antagonists versus placebo:

We found no systematic review. We found 8 RCTs.

Symptom control (clinical assessments)

Compared with placebo Regular treatment with oral montelukast may be more effective at improving some measures of asthma control (assessed by daily beta2 agonist use) in children aged 6 to 16 years at 8 weeks, but we don't know whether it is more effective at improving other measures (daytime symptom score or nocturnal awakenings). Regular treatment with oral montelukast may be more effective at improving daytime symptom scores in children aged 2 to 5 years at 12 weeks, but we don't know whether it is more effective at improving symptom scores in children aged 2 to 6 years at 12 weeks or at improving days without beta2 agonists in children aged 6 to 24 months at 6 weeks. Intermittent treatment with oral montelukast (treatment at the onset of upper respiratory tract infection or asthma symptoms) may be more effective at improving symptom scores and reducing proportion of nights disturbed in children aged 2 to 14 years with intermittent asthma at 12 months (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptom scores

RCT
336 children aged 6 to 16 years with mean FEV1 72% predicted, concomitant inhaled corticosteroid treatment in 33% of placebo group and 39% of montelukast group Daytime asthma symptom score 8 weeks
with montelukast (oral, 5 mg/day)
with placebo
Absolute results not reported

Reported no significant difference between groups
Not significant

RCT
336 children aged 6 to 16 years with mean FEV1 72% predicted, concomitant inhaled corticosteroid treatment in 33% of placebo group and 39% of montelukast group Nocturnal awakenings with asthma 8 weeks
with montelukast (oral, 5 mg/day)
with placebo
Absolute results not reported

Reported no significant difference between groups
Not significant

RCT
689 children aged 2 to 5 years, concomitant inhaled corticosteroid treatment in 29% of placebo group, 27% of montelukast group, 2:1 ratio montelukast:placebo group Improvement in average daytime symptom scores (6-point scale) 12 weeks
0.37 with montelukast (oral, 4 mg/day)
0.26 with placebo

P = 0.003
Effect size not calculatedmontelukast

RCT
689 children aged 2 to 5 years, concomitant inhaled corticosteroid treatment in 29% of placebo group, 27% of montelukast group, 2:1 ratio montelukast:placebo group Average overnight asthma symptom scores 12 weeks
with montelukast (oral, 4 mg/day)
with placebo
Absolute results not reported

Reported no significant difference between groups
Not significant

RCT
24 children aged 10 to 26 months with probable early childhood asthma, defined as recurrent wheeze, atopy on skin testing, elevated exhaled nitric oxide, and a positive family history of asthma Median symptom score (change from baseline)
From 5.5 to 1.5 with montelukast (4 mg)
From 3.0 to 4.0 with placebo

Change from baseline with montelukast: P = 0.04
Change from baseline with placebo: P = 0.35

RCT
220 children aged 2 to 14 years, with intermittent asthma Symptom score (mean total symptom score for each episode, assessed by diary cards) 12 months
37 with montelukast
43 with placebo

P = 0.049
Effect size not calculatedmontelukast

RCT
220 children aged 2 to 14 years, with intermittent asthma Proportion of nights disturbed per days at risk 12 months
1010/29,816 (3.4%) with montelukast
1105/29,840 (3.7%) with placebo

Reported 8.6% reduction with montelukast
P = 0.043
Effect size not calculatedmontelukast

RCT
Crossover design
26 children, aged 3 to 6 years, with mild asthma in analysis; unclear how many children randomised Change in daytime symptom score from baseline
From 0.98 to 0.63 with montelukast
Not reported with placebo

Reported that montelukast reduced symptoms by 35% compared with placebo, P = 0.033
However, it was unclear from the RCT whether this was an analysis of the change from baseline with montelukast or a direct comparison between montelukast and placebo
Effect size not calculatedmontelukast

RCT
Crossover design
26 children, aged 3 to 6 years, with mild asthma in analysis; unclear how many children randomised Change in night-time symptom score from baseline
From 0.38 to 0.14 with montelukast
Not reported with placebo

Reported that montelukast reduced symptoms by 63% compared with placebo, P = 0.022
However, it was unclear from the RCT whether this was an analysis of the change from baseline with montelukast or a direct comparison between montelukast and placebo
Effect size not calculatedmontelukast

RCT
3-armed trial
63 children aged 2 to 6 years with asthma-like symptoms Change in symptom scores from baseline 3 months
with montelukast (oral, 4 mg/day)
with placebo (oral, once daily)
Absolute results reported graphically

Reported no significant difference between fluticasone and montelukast
P value not reported
RCT may have been underpowered; see further information on studies
Not significant

RCT
3-armed trial
238 children aged 12 to 59 months with 2 or more episodes of wheeze in the past year Proportion of episode-free days, assessed by diary cards over 12 months
73% with montelukast (oral, 4 mg once daily) plus placebo (inhaled)
74% with placebo (oral and inhaled)
Absolute results not reported

Direct statistical comparison between montelukast and placebo not reported
Need for beta2 agonist

RCT
336 children aged 6 to 16 years with mean FEV1 72% predicted, concomitant inhaled corticosteroid treatment in 33% of placebo group and 39% of montelukast group Total daily beta2 agonist use 8 weeks
Reduced by 13% with montelukast (oral, 5 mg/day)
Increased by 10% with placebo

P = 0.01
Effect size not calculatedmontelukast

RCT
256 children aged 6 to 24 months with mild asthma Days without beta2 agonists 6 weeks
with montelukast (4 mg oral granules)
with placebo
Absolute results not reported

Mean difference: +7.4 days
95% CI –0.9 days to +15.6 days
Not significant

Exacerbations

Compared with placebo Regular treatment with oral montelukast may be more effective at reducing the proportion of children aged 6 to 16 years with an asthma exacerbation at 8 weeks, but we don't know whether it is more effective at reducing the use of oral corticosteroids in these children. Regular treatment with oral montelukast may be more effective at reducing the use of rescue oral corticosteroids at 12 weeks in children aged 2 to 5 years, but we don't know whether it is more effective at reducing asthma attack or unscheduled physician visit for asthma at 6 weeks in children aged 6 to 24 months. Intermittent treatment with oral montelukast (treatment at the onset of upper respiratory tract infection or asthma symptoms) may be more effective at reducing unscheduled acute healthcare resource utilisation, time off school/childcare, and parental time off work in children aged 2 to 14 years with intermittent asthma at 12 months (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations

RCT
336 children aged 6 to 16 years with mean FEV1 72% predicted, concomitant inhaled corticosteroid treatment in 33% of placebo group and 39% of montelukast group Proportion of children with an asthma exacerbation 8 weeks
84.8% with montelukast (oral, 5 mg/day)
95.5% with placebo
Absolute numbers not reported

P = 0.002
Effect size not calculatedmontelukast

RCT
256 children aged 6 to 24 months with mild asthma AR for at least 1 asthma attack 6 weeks
16.7% with montelukast (4 mg oral granules)
18.5% with placebo

P = 0.72
Not significant

RCT
3-armed trial
63 children aged 2 to 6 years with asthma-like symptoms Withdrawal due to asthma exacerbation 3 months
1 with montelukast (oral, 4 mg daily)
2 with placebo (oral, once daily)
Absolute results reported graphically

Significance assessment not reported
Unscheduled visit to primary care/hospital

RCT
256 children aged 6 to 24 months with mild asthma AR for at least 1 unscheduled physician visit for asthma 6 weeks
10% with montelukast (4 mg oral granules)
15% with placebo

P = 0.12
Not significant

RCT
220 children aged 2 to 14 years, with intermittent asthma Unscheduled acute healthcare resource utilisation specific for asthma 12 months
163 with montelukast
228 with placebo

Rate reduction (adjusted for patient cluster, number of days in the study, and rhinitis history) 0.65
95% CI 0.47 to 0.89
P = 0.007
Effect size not calculatedmontelukast
Rescue oral corticosteroid use

RCT
336 children aged 6 to 16 years with mean FEV1 72% predicted, concomitant inhaled corticosteroid treatment in 33% of placebo group and 39% of montelukast group Proportion of children with rescue oral corticosteroid use 8 weeks
12.1% with montelukast (oral, 5 mg/day)
15.8% with placebo
Absolute numbers not reported

P = 0.41
Not significant

RCT
689 children aged 2 to 5 years, concomitant inhaled corticosteroid treatment in 29% of placebo group, 27% of montelukast group, 2:1 ratio montelukast:placebo group Need for rescue oral corticosteroid courses 12 weeks
19% with montelukast (oral, 4 mg/day)
28% with placebo
Absolute numbers not reported

P = 0.008
Effect size not calculatedmontelukast
Time off school/work

RCT
220 children aged 2 to 14 years, with intermittent asthma Time off school/childcare (proportion of days absent per days at risk) 12 months
349/29,816 (1.2%) with montelukast
552/29,840 (1.8%) with placebo

Reported reduced by 37% with montelukast
P <0.0001
Effect size not calculatedmontelukast

RCT
220 children aged 2 to 14 years, with intermittent asthma Parental time off work (proportion of days absent per days at risk) 12 months
416/29,816 (1.4%) with montelukast
622/29,840 (2.1%) with placebo

Reported reduced by 33% with montelukast
P <0.0001
Effect size not calculatedmontelukast

No data from the following reference on this outcome.

Physiological measures

Compared with placebo Regular treatment with oral montelukast may be more effective at improving mean morning lung function (measured by FEV1) at 8 weeks in children aged 6 to 16 years. Regular treatment with oral montelukast may be more effective at improving bronchial hyperreactivity (assessed by methacholine challenge test) at 4 weeks in children aged 3 to 6 years, but we don't know whether it is more effective at improving lung function, assessed by airway resistance, at 3 months in children aged 2 to 6 years (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Forced expiratory volume

RCT
336 children aged 6 to 16 years with mean FEV1 72% predicted, concomitant inhaled corticosteroid treatment in 33% of placebo group and 39% of montelukast group Mean morning FEV1 8 weeks
8.2% with montelukast (oral, 5 mg/day)
3.6% with placebo

P <0.001
Effect size not calculatedmontelukast

RCT
24 children aged 10 to 26 months with probable early childhood asthma, defined as recurrent wheeze, atopy on skin testing, elevated exhaled nitric oxide, and a positive family history of asthma Mean FEV0.5 (change from baseline)
189 mL to 214 mL with montelukast (4 mg)
161 mL to 166 mL with placebo

Change from baseline with montelukast: P = 0.038
Change from baseline with placebo: P = 0.26
Lung function, assessed by Rint

RCT
3-armed trial
63 children aged 2 to 6 years with asthma-like symptoms Lung function, assessed by airway resistance (Rint) 3 months
with montelukast (oral, 4 mg daily)
with placebo (oral, once daily)
Absolute results reported graphically

Reported no significant difference between montelukast and placebo
P value not reported
RCT may have been underpowered; see further information on studies
Not significant
Airway hyperresponsiveness

RCT
Crossover design
26 children, aged 3 to 6 years, with mild asthma in analysis; unclear how many children randomised Bronchial hyperreactivity (assessed by methacholine challenge test) 4 weeks
4.79 mg/mL with montelukast
2.07 mg/mL with placebo

P = 0.001
Effect size not calculatedmontelukast

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
336 children aged 6 to 16 years with mean FEV1 72% predicted, concomitant inhaled corticosteroid treatment in 33% of placebo group and 39% of montelukast group Adverse effects
with montelukast (oral, 5 mg/day)
with placebo

No significant difference reported in the incidence of adverse effects with montelukast versus placebo
Not significant

RCT
689 children aged 2 to 5 years, concomitant inhaled corticosteroid treatment in 29% of placebo group, 27% of montelukast group, 2:1 ratio montelukast:placebo group Adverse effects
with montelukast (oral, 4 mg/day)
with placebo

No significant difference reported in the incidence of adverse effects with montelukast versus placebo
Not significant

RCT
256 children aged 6 to 24 months with mild asthma Overall treatment-related adverse effects 6 weeks
with montelukast (4 mg oral granules)
with placebo
Absolute results not reported

Reported as no significant difference
Not significant

RCT
256 children aged 6 to 24 months with mild asthma Upper respiratory tract infection 6 weeks
with montelukast (4 mg oral granules)
with placebo
Absolute results not reported

Mean difference +11.0%
95% CI –1% to +21%
Not significant

RCT
256 children aged 6 to 24 months with mild asthma Fever 6 weeks
with montelukast (4 mg oral granules)
with placebo
Absolute results not reported

Mean difference –0.4%
95% CI –11% to +8%
Not significant

RCT
256 children aged 6 to 24 months with mild asthma Diarrhoea 6 weeks
with montelukast (4 mg oral granules)
with placebo
Absolute results not reported

Mean difference –2%
95% CI –11% to +6%
Not significant

RCT
256 children aged 6 to 24 months with mild asthma Vomiting 6 weeks
with montelukast (4 mg oral granules)
with placebo
Absolute results not reported

Mean difference –3%
95% CI –12% to +5%
Not significant

No data from the following reference on this outcome.

Oral leukotriene receptor antagonists versus inhaled corticosteroids:

We found 9 RCTs reported in 10 publications.

Symptom control (clinical assessments)

Compared with inhaled corticosteroids Oral montelukast may be less effective than inhaled fluticasone at improving symptom scores, proportion of parents and physicians reporting satisfaction, and rescue medication-free days at up to 12 weeks, and at improving the composite outcomes of rescue-free days or asthma control days over 48 weeks to 12 months in children aged 6 years or over with asthma. However, we don't know how effective oral montelukast and inhaled budesonide are, compared with each other, at improving episode-free days over 12 months in younger children, aged 1 to 5 years, with asthma (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptom score

RCT
342 children aged 6 to 12 years with chronic asthma for at least 6 months and FEV1 60% to 80% of predicted Mean change in night-time asthma symptom score 12 weeks
–0.19 with oral montelukast (5 mg chewable tablet once daily)
–0.40 with fluticasone propionate (50 micrograms twice daily by multi-dose powder inhaler)

P <0.001
Moderate effect size fluticasone

RCT
3-armed trial
51 newly diagnosed mildly asthmatic children aged 6 to 18 years who were sensitive to house dust mites Mean symptom score 6 months
1.9 with montelukast (oral, 5 mg/day for children aged 6–14 years, 10 mg/day for older children)
1.9 with low-dose budesonide (inhaled, 400 micrograms/day by dry-powder inhaler)

P >0.12 for each dose of budesonide v montelukast
Not significant

RCT
3-armed trial
51 newly diagnosed mildly asthmatic children aged 6 to 18 years who were sensitive to house dust mites Mean symptom score 6 months
1.9 with montelukast (oral, 5 mg/day for children aged 6–14 years, 10 mg/day for older children)
2.2 with high-dose budesonide (inhaled, 800 micrograms/day by dry-powder inhaler)

P >0.12 for each dose of budesonide v montelukast
Not significant

RCT
342 children aged 6 to 12 years with chronic asthma for at least 6 months and FEV1 60% to 80% of predicted Proportion of parents "very satisfied" 12 weeks
42% with montelukast (oral, 5 mg chewable tablet once daily)
58% with fluticasone propionate (inhaled, 50 micrograms twice daily)

P = 0.006
Effect size not calculated fluticasone

RCT
342 children aged 6 to 12 years with chronic asthma for at least 6 months and FEV1 60% to 80% of predicted Proportion of physicians "very satisfied" 12 weeks
29% with montelukast (oral, 5 mg chewable tablet once daily)
48% with fluticasone propionate (inhaled, 50 micrograms twice daily)

P = 0.016
Effect size not calculated fluticasone

RCT
62 children aged 5 to 15 years with newly diagnosed mild, persistent asthma Symptom score 12 weeks
with montelukast (oral, 5 mg/day) plus placebo inhaler
with budesonide (inhaled, 200 micrograms twice daily) plus placebo tablets
Absolute results not reported

Reported no significant difference between groups
P value not reported
Not significant

RCT
Crossover design
144 children aged 6 to 17 years, with mild to moderate persistent asthma; using only as-needed bronchodilators
Further report of reference
Asthma control days last 4 weeks of 8 weeks' treatment
2.1 days/week with montelukast (oral, 5–10 mg [dose dependent on age] at night)
2.8 days/week with fluticasone (inhaled, 100 micrograms twice daily)

P <0.001
Effect size not calculatedfluticasone

RCT
3-armed trial
238 children aged 12 to 59 months with 2 or more episodes of wheeze in the past year Proportion of episode-free days, assessed by diary cards over 12 months
73% with montelukast (oral, 4 mg once daily) plus placebo (inhaled)
76% with budesonide (inhaled by nebuliser, 1.0 mg twice daily) plus placebo (oral)
Absolute results not reported

Direct statistical comparison between budesonide and montelukast not reported

RCT
3-armed trial
63 children aged 2 to 6 years with asthma-like symptoms Change in symptom scores from baseline 3 months
with montelukast (oral, 4 mg/day)
with fluticasone (inhaled, 100 micrograms twice daily)
Absolute results reported graphically

Reported no significant difference between fluticasone and montelukast
P value not reported
RCT may have been underpowered; see further information on studies
Not significant

RCT
994 children aged 6 to 14 years, with mild persistent asthma, average FEV1 87.2% predicted % rescue-free days over 12 months
84.0% with montelukast (oral, 5 mg)
86.7% with fluticasone (inhaled, 50 micrograms twice daily)

Least-squares mean difference –2.8%
95% CI –4.7% to –0.9%
P = 0.003
However, non-inferiority satisfied (see further information on studies)
Effect size not calculatedfluticasone

RCT
3-armed trial
285 children aged 6 to 14 years, with mild to moderate persistent asthma, using only as-needed salbutamol before randomisation % asthma control days 48 weeks
52.5% with montelukast (oral, 5 mg once daily)
64.2% with fluticasone (inhaled, 100 micrograms twice daily)

Difference 11.8%
95% CI 3.7% to 19.8%
P = 0.004 (fluticasone monotherapy v montelukast)
Effect size not calculatedfluticasone
Need for beta2 agonist

RCT
342 children aged 6 to 12 years with chronic asthma for at least 6 months and FEV1 60% to 80% of predicted Mean change in daily puffs of salbutamol 12 weeks
–1.23 with montelukast (oral, 5 mg chewable tablet once daily)
–1.43 with fluticasone propionate (50 micrograms twice daily by multi-dose powder inhaler)

P = 0.18
Not significant

RCT
342 children aged 6 to 12 years with chronic asthma for at least 6 months and FEV1 60% to 80% of predicted Rescue medication-free days 12 weeks
35% with montelukast (oral, 5 mg chewable tablet once daily)
45% with fluticasone propionate (inhaled, 50 micrograms twice daily)

P = 0.002
Effect size not calculated fluticasone

RCT
Crossover design
144 children aged 6 to 17 years, with mild to moderate persistent asthma; using only as-needed bronchodilators
Further report of reference
Salbutamol use last 4 weeks of 8 weeks' treatment
4.4 puffs/weeks with montelukast (oral, 5–10 mg [dose dependent on age] at night)
3.1 puffs/week with fluticasone (inhaled, 100 micrograms twice daily)

P = 0.0305
Effect size not calculatedfluticasone

No data from the following reference on this outcome.

Exacerbations

Compared with inhaled corticosteroids Oral montelukast may be less effective than inhaled fluticasone at reducing the number of children aged 6 years or over who withdraw due to asthma exacerbation up to 12 to 16 weeks, the proportion with an asthma attack up to 12 months, and oral prednisolone use over 48 weeks (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations

RCT
342 children aged 6 to 12 years with chronic asthma for at least 6 months and FEV1 60% to 80% of predicted Withdrawal due to asthma exacerbation 12 weeks
14/170 (8%) with oral montelukast (5 mg chewable tablet once daily)
9/172 (5%) with fluticasone propionate (50 micrograms twice daily by multi-dose powder inhaler)

Statistical assessment not performed

RCT
Crossover design
144 children aged 6 to 17 years, with mild to moderate persistent asthma; using only as-needed bronchodilators Number of people who withdrew due to asthma exacerbation 16 weeks
10 with montelukast (oral, 5 mg or 10 mg)
2 with fluticasone (100 micrograms twice daily)

P = 0.019
Effect size not calculatedfluticasone

RCT
994 children aged 6 to 14 years, with mild persistent asthma, average FEV1 87.2% predicted Proportion of people with an asthma attack over 12 months
32.2% with montelukast (oral, 5 mg)
25.6% with fluticasone (inhaled, 50 micrograms twice daily)
Absolute numbers not reported

RR 1.26
95% CI 1.04 to 1.52
Small effect sizefluticasone

RCT
3-armed trial
285 children aged 6 to 14 years, with mild to moderate persistent asthma, using only as-needed salbutamol before randomisation Proportion of people not having oral prednisolone over 48 weeks
with montelukast (oral, 5 mg once daily)
with fluticasone (inhaled, 100 micrograms twice daily)
Absolute results reported graphically

P = 0.002
Effect size not calculatedfluticasone

No data from the following reference on this outcome.

Physiological measures

Compared with inhaled corticosteroids Oral montelukast may be less effective than inhaled fluticasone at improving morning peak expiratory flow (PEF) and FEV1 measures in children aged 6 years or over with asthma; however, we don't know whether it is more or less effective at improving lung function, assessed by airway resistance (Rint). We don't know how effective oral montelukast and inhaled budesonide are, compared with each other, at improving lung function, assessed by Rint, at 4 weeks in younger children, aged 2 to 6 years, with asthma-like symptoms (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Forced expiratory volume

RCT
342 children aged 6 to 12 years with chronic asthma for at least 6 months and FEV1 60% to 80% of predicted Proportion with >5% increase in FEV1 12 weeks
43% with oral montelukast (5 mg chewable tablet once daily)
63% with fluticasone propionate (50 micrograms twice daily by multi-dose powder inhaler)

P = 0.002
Effect size not calculatedfluticasone

RCT
3-armed trial
51 newly diagnosed mildly asthmatic children aged 6 to 18 years who were sensitive to house dust mites FEV1 as % predicted 6 months
90.9% with montelukast (oral, 5 mg/day for children aged 6–14 years, 10 mg/day for older children)
93.4% with low-dose budesonide (400 micrograms/day by dry-powder inhaler)

P >0.07 for each dose of budesonide v montelukast
Not significant

RCT
3-armed trial
51 newly diagnosed mildly asthmatic children aged 6 to 18 years who were sensitive to house dust mites FEV1 as % predicted 6 months
90.9% with montelukast (oral, 5 mg/day for children aged 6–14 years, 10 mg/day for older children)
93.0% with budesonide (inhaled, 800 micrograms/day)

P >0.07 for each dose of budesonide v montelukast
Not significant

RCT
Crossover design
144 children aged 6 to 17 years, with mild to moderate persistent asthma; using only as-needed bronchodilators Improvement in FEV1 last 4 weeks of 8 weeks' treatment
1.9% with montelukast (oral, 5–10 mg [dose dependent on age] at night)
6.8% with fluticasone (inhaled, 100 micrograms twice daily)

P <0.0001
Effect size not calculatedfluticasone

RCT
62 children aged 5 to 15 years with newly diagnosed mild, persistent asthma Change in FEV1, % predicted, from baseline 12 weeks
with montelukast (oral, 5 mg/day) plus placebo inhaler
with budesonide (inhaled, 200 micrograms twice daily) plus placebo tablets
Absolute results reported graphically

Reported no significant difference between groups
Not significant

RCT
994 children aged 6 to 14 years, with mild persistent asthma, average FEV1 87.2% predicted Change in FEV1, % of predicted from baseline over 12 months
0.6% with montelukast (oral, 5 mg)
2.7% with fluticasone (inhaled, 50 micrograms twice daily)
Absolute numbers not reported

Least-squares mean difference –2.2%
95% CI –3.6% to –0.7%
P = 0.004
Small effect sizefluticasone

RCT
3-armed trial
285 children aged 6 to 14 years, with mild to moderate persistent asthma, using only as-needed salbutamol before randomisation Change in (pre-bronchodilator) FEV1, % of predicted from baseline 48 weeks
–0.58% with montelukast (oral, 5 mg once daily)
6.32% with fluticasone (inhaled, 100 micrograms twice daily)

Difference 6.90%
95% CI 3.92% to 9.88%
P <0.001
Effect size not calculatedfluticasone
Peak expiratory flow

RCT
342 children aged 6 to 12 years with chronic asthma for at least 6 months and FEV1 60% to 80% of predicted Mean change in morning peak expiratory flow (PEF) 12 weeks
23.0 L/minute with oral montelukast (5 mg chewable tablet once daily)
39.9 L/minute with fluticasone propionate (50 micrograms twice daily by multi-dose powder inhaler)

P = 0.004
Effect size not calculatedfluticasone

RCT
3-armed trial
285 children aged 6 to 14 years, with mild to moderate persistent asthma, using only as-needed salbutamol before randomisation Mean change in morning PEF, % predicted 48 weeks
0.65% with montelukast (oral, 5 mg once daily)
5.18% with fluticasone (inhaled, 100 micrograms twice daily)

Difference 4.54%
95% CI 1.67% to 7.41%
P = 0.002
Effect size not calculatedfluticasone
Lung function, assessed by Rint

RCT
5-armed trial
145 children aged 6 to 18 years with moderate atopic asthma, which was stable for the previous 6 months treated with inhaled corticosteroid and long-acting beta2 agonist Pulmonary function, % of predicted value as assessed by resistance by the interrupter technique (Rint) 4 weeks
126.0% with montelukast (oral, 5 mg once daily for children aged 6–14 years or 10 mg once daily for adolescents aged >14 years)
120.5% with budesonide (inhaled, 200 micrograms per day)

Between-group statistical assessment not reported

RCT
3-armed trial
63 children aged 2 to 6 years with asthma-like symptoms Lung function, assessed by airway resistance (Rint)
with montelukast (oral, 4 mg/day)
with fluticasone (inhaled, 100 micrograms twice daily)
Absolute results not reported

Reported no significant difference between groups
RCT may have been underpowered; see further information on studies
Not significant

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
342 children aged 6 to 12 years with chronic asthma for at least 6 months and FEV1 60% to 80% of predicted Treatment-related adverse events
6% with montelukast
7% with fluticasone

Statistical assessment not performed

RCT
342 children aged 6 to 12 years with chronic asthma for at least 6 months and FEV1 60% to 80% of predicted Withdrawals due to adverse effect
2% with montelukast
2% with fluticasone

Statistical assessment not performed

RCT
994 children aged 6 to 14 years, with mild persistent asthma, average FEV1 87.2% predicted Adverse effects (considered drug-related) over 12 months
22/495 (4%) with montelukast (oral, 5 mg)
16/499 (3%) with fluticasone (inhaled, 50 micrograms twice daily)

RCT
994 children aged 6 to 14 years, with mild persistent asthma, average FEV1 87.2% predicted Overall growth rate over 12 months
6.18 cm/year with montelukast (oral, 5 mg)
5.81 cm/year with fluticasone (inhaled, 50 micrograms twice daily)

Difference 0.41 cm/year
95% CI 0.07 cm/year to 0.75 cm/year
Effect size not calculatedmontelukast

RCT
62 children aged 5 to 15 years with newly diagnosed mild, persistent asthma Adverse effects 12 weeks
with montelukast (oral, 5 mg/day) plus placebo inhaler
with budesonide (inhaled, 200 micrograms twice daily) plus placebo tablets
Absolute results reported graphically

Significance assessment not reported

RCT
3-armed trial
285 children aged 6 to 14 years, with mild to moderate persistent asthma, using only as-needed salbutamol before randomisation Linear growth 48 weeks
5.72 cm with montelukast (oral, 5 mg once daily)
5.32 cm with fluticasone (inhaled, 100 micrograms twice daily)

Difference –0.40 cm
95% CI –0.93 cm to +0.13 cm
P = 0.13
Not significant

No data from the following reference on this outcome.

Further information on studies

The RCT reported that it was unable to recruit the number of children (198) required by its power calculation to reach 90% power. The RCT found that only montelukast significantly decreased circulating eosinophils from baseline. It found that montelukast significantly reduced eosinophils compared with placebo (P = 0.045).

The RCT calculated a non-inferiority limit for the treatment difference of –7% points corresponding to approximately 2 asthma rescue-free days in 1 month.

The RCT did not include a washout period but used the first 4 weeks of each treatment period as a "pseudo-washout" period. Only results from the second 4 weeks of each treatment period were included in the analysis. The RCT also reported on the proportion of people who responded to treatment (defined as >7.5% improvement in FEV1). It found that 17% of people responded to both treatments, 23% of people responded only to fluticasone, 5% only to montelukast, and 55% responded to neither; most individuals respond to neither treatment.

Comment

We found another RCT (395 children aged 2–8 years with mild asthma or recurrent wheezing) comparing budesonide versus montelukast, which did not satisfy Clinical Evidence inclusion criteria because it was an open-label trial. However, we have included a comment on this study because it reported on exacerbations as an outcome and there was a paucity of such data for this comparison. It found that budesonide (inhaled via nebuliser, 500 micrograms/day) significantly reduced exacerbations compared with montelukast (oral, 4 mg/day or 5 mg/day) over 52 weeks.

Clinical guide:

In older children, leukotriene receptor antagonists are less effective than inhaled corticosteroids as monotherapy for control of symptoms and preventing exacerbations.

Substantive changes

Leukotriene receptor antagonists (oral) New evidence added. Categorisation unchanged (Likely to be beneficial).

2012; 2012: 0302.
Published online 2012 January 18.

Long-acting beta2 agonists (inhaled)

Summary

There is consensus that long-acting beta 2 agonists should not be used for first-line prophylaxis.

CAUTION: Monotherapy with long-acting beta 2 agonists does not reduce asthma exacerbations but may increase the chance of severe asthma episodes when those episodes occur.

Benefits and harms

Inhaled long-acting beta2 agonist versus placebo:

We found one systematic review (search date 2008, 40 RCTs, 9 RCTs in children and adolescents), which reported on asthma exacerbations with long-acting beta2 agonist versus placebo. Some of the RCTs in the review included children who were taking additional asthma medications and the review did not present a separate analysis for children who were only using as-needed beta2 agonist. The review also did not report on the outcomes of symptoms or physiological measures and so we have additionally reported these outcomes from those RCTs included in the review that also satisfied Clinical Evidence inclusion criteria for this question. We found another two systematic reviews (search dates 2008) assessing serious adverse effects associated with regular treatment with salmeterol compared with placebo and with regular treatment with formoterol compared with placebo.

Symptom control (clinical assessments)

Compared with placebo We don't know whether adding inhaled salmeterol to usual care is more effective than placebo added to usual care at reducing salbutamol use or the number of nights without awakenings in children aged over 4 years (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptoms/night-time awakening

RCT
207 children aged 4 to 11 years with asthma diagnosed according to American Thoracic Society (ATS) guidelines, receiving as-needed inhaled beta2 agonists, FEV1 (without medication) 50% to 80% predicted
In review
Number of nights without awakenings 12 weeks
with salmeterol (inhaled, 50 micrograms twice daily)
with placebo
Absolute results not reported

Reported no significant difference between groups
Not significant
Need for beta2 agonist

RCT
3-armed trial
241 children aged 6 to 14 years with clinically stable asthma and <1 month of prior corticosteroid use
In review
Days and nights without need for salbutamol
88% with salmeterol (80 children)
83% with placebo (80 children)

P = 0.09
Not significant

RCT
207 children aged 4 to 11 years with asthma diagnosed according to ATS guidelines, receiving as-needed inhaled beta2 agonists, FEV1 (without medication) 50% to 80% predicted
In review
Change in supplemental salbutamol use 12 weeks
–0.8 with salmeterol (inhaled, 50 micrograms twice daily)
–0.3 with placebo

P = 0.004
Effect size not calculatedsalmeterol

No data from the following reference on this outcome.

Exacerbations

Compared with placebo We don't know whether long-acting beta2 agonists (salmeterol or formoterol) are more effective at reducing exacerbations requiring systemic corticosteroids in children with asthma who are/are not taking additional asthma medications (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations

Systematic review
Children with asthma, unclear how many RCTs or children included in analysis Exacerbations requiring systemic corticosteroids
with long-acting beta2 agonist (salmeterol or formoterol)
with placebo
Absolute results not reported

RR 0.99
95% 0.80 to 1.22
See further information on studies
Not significant

Physiological measures

Compared with placebo Adding inhaled salmeterol to usual care is more effective than adding placebo to usual care at improving FEV1 at 1 year and mean morning and evening peak expiratory flow rate (PEFR) at 12 weeks, in children aged over 4 years (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Forced expiratory volume

RCT
3-armed trial
241 children aged 6 to 14 years with clinically stable asthma and <1 month of prior corticosteroid use
In review
Mean change in FEV1 as % of predicted 1 year
10% with salmeterol (80 children)
5% with placebo (80 children)

P <0.001
Effect size not calculatedsalmeterol
Peak expiratory flow rate

RCT
207 children aged 4 to 11 years with asthma diagnosed according to American Thoracic Society (ATS) guidelines, receiving as-needed inhaled beta2 agonists, FEV1 (without medication) 50% to 80% predicted
In review
Mean morning peak expiratory flow rate (PEFR) 12 weeks
25 L/minute with salmeterol (inhaled, 50 micrograms twice daily)
13.2 L/minute with placebo

P <0.001
Effect size not calculatedsalmeterol

RCT
207 children aged 4 to 11 years with asthma diagnosed according to ATS guidelines, receiving as-needed inhaled beta2 agonists, FEV1 (without medication) 50% to 80% predicted
In review
Mean evening PEFR 12 weeks
20 L/minute with salmeterol (inhaled, 50 micrograms twice daily)
10.1 L/minute with placebo

P = 0.01
Effect size not calculatedsalmeterol

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
1333 children aged 4 to 16 years, concurrent inhaled corticosteroid use varied from 0% to 57% and concurrent cromones 0% to 25% in included studies
5 RCTs in this analysis
Non-fatal serious adverse effects
46/725 (6.3%) with salmeterol
34/608 (5.6%) with placebo

OR 1.30
95% CI 0.82 to 2.05
Not significant

Systematic review
1335 children aged 5 to 17 years, concurrent inhaled corticosteroid use varied from 0% to 100% in included studies
5 RCTs in this analysis
Non-fatal serious adverse effects
34/843 (4%) with formoterol
6/492 (1%) with placebo

OR 2.48
95% CI 1.27 to 4.83
Moderate effect sizeplacebo

No data from the following reference on this outcome.

Inhaled long-acting beta2 agonists versus inhaled corticosteroids:

We found two RCTs.

Symptom control (clinical assessments)

Compared with corticosteroids We don't know how inhaled salmeterol and beclometasone compare at increasing the proportion of children who are asymptomatic, but salmeterol may be less effective than beclometasone at reducing the need for beta2 agonists after 1 year, in children aged over 6 years with asthma (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Asthma symptoms

RCT
67 children aged 6 to 16 years (mean age about 10.5 years), with mild to moderate asthma, not currently using inhaled corticosteroids Proportion of children asymptomatic (change from before trial) 1 year
From 3% to 36% with salmeterol (inhaled, 50 micrograms twice daily)
From 6% to 55% with beclometasone (inhaled, 200 micrograms twice daily)
Absolute numbers not reported

Significance assessment not reported
Need for beta2 agonists

RCT
3-armed trial
241 children aged 6 to 14 years with clinically stable asthma and <1 month of prior corticosteroid use Days and nights without need for salbutamol
88% with salmeterol (80 children)
92% with beclometasone (81 children)

Between-group significance assessment not reported

RCT
67 children aged 6 to 16 years (mean age about 10.5 years), with mild to moderate asthma, not currently using inhaled corticosteroids Use of rescue salbutamol 54 weeks
0.44 uses/day with salmeterol (inhaled, 50 micrograms twice daily)
0.07 uses/day with beclometasone (inhaled, 200 micrograms twice daily)

P less-than or equal to 0.001
Effect size not calculatedbeclometasone

Exacerbations

Compared with inhaled corticosteroids We don't know how inhaled salmeterol and beclometasone compare at reducing exacerbations requiring oral corticosteroids or exacerbations requiring withdrawal from the study in children aged over 6 years, because the RCTs did not present a direct statistical comparison; however, a higher number of exacerbations were found with salmeterol (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations requiring oral corticosteroids

RCT
67 children aged 6 to 16 years (mean age about 10.5 years), with mild to moderate asthma, not currently using inhaled corticosteroids Exacerbations requiring oral corticosteroid treatment 1 year
17/32 (53%) with salmeterol (inhaled, 50 micrograms twice daily)
2/35 (6%) with beclometasone (inhaled, 200 micrograms twice daily)

Significance assessment not reported
Treatment withdrawals because of exacerbations

RCT
3-armed trial
241 children aged 6 to 14 years with clinically stable asthma and <1 month of prior corticosteroid use Treatment withdrawals because of exacerbations
15 with salmeterol (80 children)
5 with beclometasone (81 children)

Between-group significance assessment not reported

RCT
67 children aged 6 to 16 years (mean age about 10.5 years), with mild to moderate asthma, not currently using inhaled corticosteroids Treatment withdrawals because of exacerbations 1 year
6/32 (19%) with salmeterol (inhaled, 50 micrograms twice daily)
1/35 (3%) with beclometasone (inhaled, 200 micrograms twice daily)

Significance assessment not reported

Physiological measures

Compared with inhaled corticosteroids We don't know how inhaled salmeterol and beclometasone compare at improving FEV1 or peak expiratory flow rate after about 1 year in children aged over 6 years with asthma. However, inhaled salmeterol may be less effective than inhaled beclometasone at improving airway hyperresponsiveness to methacholine (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Forced expiratory volume

RCT
3-armed trial
241 children aged 6 to 14 years with clinically stable asthma and <1 month of prior corticosteroid use Mean change in FEV1 , as % of predicted 1 year
10% with salmeterol (80 children)
10% with beclometasone (81 children)

Between-group significance assessment not reported

RCT
67 children aged 6 to 16 years (mean age about 10.5 years), with mild to moderate asthma, not currently using inhaled corticosteroids Mean change of FEV1 predicted 54 weeks
–4.5% with salmeterol (inhaled, 50 micrograms twice daily)
+10% with beclometasone (inhaled, 200 micrograms twice daily)

Mean difference beclometasone v salmeterol: 14.2%
95% CI 8.3% to 20.0%
Effect size not calculatedbeclometasone
Peak expiratory flow rate

RCT
67 children aged 6 to 16 years (mean age about 10.5 years), with mild to moderate asthma, not currently using inhaled corticosteroids Improvement in morning peak expiratory flow rate 1 year
49 L/minute with salmeterol (inhaled, 50 micrograms twice daily)
61 L/minute with beclometasone (inhaled, 200 micrograms twice daily)

Reported no significant difference between groups
Not significant
Airway hyperresponsiveness

RCT
3-armed trial
241 children aged 6 to 14 years with clinically stable asthma and <1 month of prior corticosteroid use Methacholine PC20 36 hours after study medication 12 months
with salmeterol
with beclometasone
Absolute results reported graphically

P = 0.009
Effect size not calculatedbeclometasone

RCT
67 children aged 6 to 16 years (mean age about 10.5 years), with mild to moderate asthma, not currently using inhaled corticosteroids Airway responsiveness end of the treatment period
–0.73 doubling dose with salmeterol (inhaled, 50 micrograms twice daily)
+2.02 doubling dose with beclometasone (inhaled, 200 micrograms twice daily)

Difference between groups 2.79 doubling dose
95% CI 1.75 to 3.84
P <0.0001
See further information on studies
Effect size not calculatedbeclometasone

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Growth suppression

RCT
67 children aged 6 to 16 years (mean age about 10.5 years), with mild to moderate asthma, not currently using inhaled corticosteroids Linear growth 1 year of treatment
5.4 cm with salmeterol (inhaled, 50 micrograms twice daily)
4.0 cm with beclometasone (inhaled, 200 micrograms twice daily)

P = 0.004
Effect size not calculatedsalmeterol

RCT
3-armed trial
241 children aged 6 to 14 years with clinically stable asthma and <1 month of prior corticosteroid use Linear growth 1 year of treatment
6.1 cm with salmeterol (80 children)
4.7 cm with beclometasone (81 children)

P = 0.007 (beclometasone v salmeterol)
Effect size not calculatedsalmeterol

Further information on studies

Some of the RCTs in the review included children who were taking additional medications including inhaled corticosteroids, sodium cromoglicate, and others. The review carried out an indirect comparison and interactive test examining whether long-acting beta2 agonists increased exacerbations in children compared with adults. It found increased exacerbation rates requiring systemic corticosteroids in children compared with adults; however, this was of borderline significance (number of RCTs and people in analysis not reported; RR 1.26, 95% CI 1.00 to 1.60; absolute numbers not reported).

Symptom improvement in the salmeterol group was accompanied by significant deterioration in bronchial reactivity, indicating a failure to control underlying bronchial inflammation.

Comment

Clinical guide:

Given 1) the lack of clear superiority of long-acting beta2 agonists over inhaled corticosteroid monotherapy, 2) the effectiveness and safety of low-dose inhaled corticosteroid monotherapy, and 3) the concern about increased exacerbations associated with long-acting beta2 agonist monotherapy (extrapolated from adult studies), consensus is that long-acting beta2 agonists should not be used first line as monotherapy in any age group.

Substantive changes

Long-acting beta2 agonists New evidence added. Categorisation changed (from Trade-off between benefits and harms to Likely to be ineffective or harmful).

2012; 2012: 0302.
Published online 2012 January 18.

Theophylline (oral)

Summary

Theophylline was used as first-line prevention before the introduction of inhaled corticosteroids. Although there is weak evidence that theophylline is superior to placebo, theophylline should no longer be used as first-line prophylaxis in childhood asthma because of clear evidence of the efficacy and safety of inhaled corticosteroids.

Theophylline has serious adverse effects (cardiac arrhythmia, convulsions) if therapeutic blood concentrations are exceeded.

Benefits and harms

Oral theophylline versus placebo:

We found one RCT comparing once daily oral sustained-release theophylline (mean theophylline level of 11.2 mg/L) versus placebo for 6 weeks. We found one systematic review (search date not reported, 12 studies) assessing the behavioural and cognitive effects of theophylline.

Symptom control (clinical assessments)

Compared with placebo Oral theophylline added to usual care including as-needed inhaled beta2 agonists may be more effective than adding placebo to usual care at reducing the mean number of doses of bronchodilator used in children aged 6 to 15 years experiencing at least 2 night awakenings per week; however, evidence is weak (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Need for other asthma medications

RCT
Crossover design
24 children aged 6 to 15 years experiencing at least 2 night awakenings/week, receiving usual care, including as-needed inhaled beta2 agonists Mean number of doses of bronchodilator used
6.5 with once-daily oral sustained release theophylline (mean theophylline level of 11.2 mg/L)
23.7 with placebo

P <0.001
Effect size not calculatedtheophylline

Exacerbations

Compared with placebo Oral theophylline added to usual care including as-needed inhaled beta2 agonists may be more effective than adding placebo to usual care at reducing the mean number of acute night-time attacks in children aged 6 to 15 years experiencing at least 2 night awakenings per week; however, evidence is weak (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations

RCT
Crossover design
24 children aged 6 to 15 years (mean age 9.2 years) experiencing at least 2 night awakenings/week, receiving usual care, including as-needed inhaled beta2 agonists Mean number of acute night-time attacks
3.2 with once-daily oral sustained release theophylline (mean theophylline level of 11.2 mg/L)
10.7 with placebo

P <0.001
Effect size not calculatedtheophylline

Physiological measures

Compared with placebo Oral theophylline added to usual care including as-needed inhaled beta2 agonists may be more effective than adding placebo to usual care at increasing mean morning peak expiratory flow rate in children aged 6 to 15 years experiencing at least 2 night awakenings per week; however, evidence is weak (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Peak expiratory flow

RCT
Crossover design
24 children aged 6 to 15 years experiencing at least 2 night awakenings/week, receiving usual care, including as-needed inhaled beta2 agonists Mean morning peak expiratory flow rate
244 L/minute with once-daily oral sustained release theophylline (mean theophylline level of 11.2 mg/L)
207 L/minute with placebo

P <0.001
Effect size not calculatedtheophylline

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
24 children aged 6 to 15 years experiencing at least 2 night awakenings/week, receiving usual care, including as-needed inhaled beta2 agonists Gastric symptoms (including dyspepsia, nausea, and vomiting)
30% with oral sustained-release theophylline
6% with placebo
Absolute numbers not reported

P <0.001
Effect size not calculatedplacebo

Systematic review
340 children Adverse effects
with theophylline

Oral theophylline versus inhaled corticosteroids:

We found no systematic review. We found one RCT, which compared oral theophylline versus inhaled beclometasone.

Symptom control (clinical assessments)

Compared with inhaled corticosteroids We don't know how oral theophylline and inhaled beclometasone compare at improving asthma symptom score in children aged 6 to 16 years with asthma (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptom score

RCT
195 children aged 6 to 16 years (mean age 11.9 years) receiving usual care, including as-needed inhaled beta2 agonists, followed for 12 months
Subgroup analysis
Mean asthma symptom score (change from baseline) 12 months
From 0.6 to 0.9 with theophylline (oral)
From 0.5 to 0.8 with beclometasone (inhaled, 360 micrograms/day)

Reported no significant difference between groups
Not significant

Exacerbations

Compared with inhaled corticosteroids We don't know how oral theophylline and inhaled beclometasone compare at reducing the proportion of children, aged 6 to 16 years, with one or more emergency department visits or hospital admissions for asthma (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations

RCT
195 children aged 6 to 16 years (mean age 11.9 years) receiving usual care, including as-needed inhaled beta2 agonists, followed for 12 months
Subgroup analysis
Proportion of children with 1 or more emergency department visits or hospital admissions for asthma 12 months
11.8% with theophylline (oral)
4.9% with beclometasone (inhaled, 360 micrograms/day)
Absolute numbers not reported

Reported no significant difference between groups
Not significant

Physiological measures

Compared with inhaled corticosteroids We don't know how oral theophylline and inhaled beclometasone compare at improving FEV1 or methacholine sensitivity in children aged 6 to 16 years with asthma (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Forced expiratory volume

RCT
195 children aged 6 to 16 years (mean age 11.9 years) receiving usual care, including as-needed inhaled beta2 agonists, followed for 12 months
Subgroup analysis
Pre-bronchodilator mean FEV1 (% predicted) 36 weeks
with beclometasone (inhaled, 360 micrograms/day)
with theophylline (oral)
Absolute results reported graphically

Reported no significant difference between groups
Not significant
Airway hyperresponsiveness

RCT
195 children aged 6 to 16 years (mean age 11.9 years) receiving usual care, including as-needed inhaled beta2 agonists, followed for 12 months
Subgroup analysis
Change in methacholine sensitivity from baseline 6 weeks
0.48 with beclometasone (inhaled, 360 micrograms/day)
0 with theophylline (oral)

Reported no significant difference between groups
Not significant

RCT
195 children aged 6 to 16 years (mean age 11.9 years) receiving usual care, including as-needed inhaled beta2 agonists, followed for 12 months
Subgroup analysis
Methacholine sensitivity (PD20) final visit
14.79 with beclometasone (inhaled, 360 micrograms/day)
8.71 with theophylline (oral)

Reported no significant difference between groups
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Growth suppression

RCT
195 children aged 6 to 16 years (mean age 11.9 years) receiving usual care, including as-needed inhaled beta2 agonists, followed for 12 months
Subgroup analysis
Mean rate of growth in prepubescent boys 1 year
6.2 cm/year with oral theophylline
4.3 cm/year with inhaled beclometasone 360 micrograms/day

Further information on studies

None.

Comment

Theophylline has serious adverse effects (cardiac arrhythmia, convulsions) if therapeutic blood concentrations are exceeded.

Clinical guide:

Theophylline was used as first-line prevention before the introduction of corticosteroids; however, it is not to be used first line any more. There is no evidence of superiority between inhaled corticosteroids and theophylline monotherapy. Given 1) the lack of clear superiority of theophylline over inhaled corticosteroid monotherapy, 2) the effectiveness and safety of low-dose inhaled corticosteroid monotherapy, and 3) the long-recognised adverse effects associated with theophylline treatment (at therapeutic levels nausea and at toxic levels cardiac arrhythmias and convulsions), consensus is that theophylline should not be used as monotherapy in any age group.

Substantive changes

Theophylline (oral) No new evidence added but existing evidence re-evaluated. Categorisation changed (from Trade-off between benefits and harms to Likely to be ineffective or harmful).

2012; 2012: 0302.
Published online 2012 January 18.

Increased dose of inhaled corticosteroid

Summary

When low-dose inhaled corticosteroids fail to control asthma, most older children will respond to one of the add-on options available, which include addition of long-acting beta 2 agonists, addition of leukotriene receptor antagonists, addition of theophylline, or increased dose of inhaled corticosteroid. However, we don't know for certain how effective these additional treatments are because we found no/limited RCT evidence of benefit compared with adding placebo/no additional treatments.

Increasing the dose of corticosteroids in older children may be less effective than adding long-acting beta2 agonists for reducing symptoms and improving physiological measures.

Benefits and harms

Increased dose of inhaled corticosteroid versus low-dose corticosteroid:

We found two systematic reviews (search dates 1999 and 2008). The first systematic review examined different doses of inhaled beclometasone versus each other. It included only two RCTs in children and did not pool the data. We have therefore reported directly from the one RCT that satisfied Clinical Evidence inclusion criteria. The second systematic review examined the effects of different doses of inhaled fluticasone versus each other in adults and children. The review did not present a separate analysis based on previous inhaled corticosteroid use, and so we have only included the analyses where the majority of children were from RCTs that specified previous inhaled corticosteroid use.

Symptom control (clinical assessments)

Increased dose of inhaled corticosteroid versus low-dose corticosteroid We don't know whether adding a higher dose of inhaled beclometasone is more effective than adding placebo in children aged 6 to 16 years with asthma, who were already taking low-dose inhaled beclometasone (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptom scores

RCT
3-armed trial
177 children aged 6 to 16 years, mean pre-bronchodilator FEV1 86% predicted Proportion of children with no symptoms 1 year
39% with additional beclometasone (200 micrograms twice daily)
35% with placebo
Absolute results not reported

No direct comparison of increased corticosteroid versus placebo
No significant difference among groups was found in these children, whose compliance with pre-existing medication was good

Exacerbations

Increased dose of inhaled corticosteroid versus low-dose corticosteroid We don't know whether a second dose of inhaled beclometasone is more effective than adding placebo at reducing exacerbations at 1 year, in children aged 6 to 16 years with asthma, who were already taking inhaled beclometasone twice daily. Increased dose of inhaled fluticasone (400–500 micrograms/day) seems no more effective than lower dose of inhaled fluticasone (200 micrograms/day) at reducing exacerbations requiring oral corticosteroids in children with asthma who were all previously using inhaled corticosteroids (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations

RCT
3-armed trial
177 children aged 6 to 16 years, mean pre-bronchodilator FEV1 86% predicted Exacerbation rates 1 year
with additional beclometasone (200 micrograms twice daily)
with placebo
Absolute results not reported

No direct comparison of increased corticosteroid versus placebo
No significant difference among groups was found in these children, whose compliance with pre-existing medication was good

Systematic review
883 children (aged 4–11 years or about 8 years) with asthma, all using inhaled corticosteroids and either remaining symptomatic or with at least 1 asthma exacerbation in the previous 12 months
2 RCTs in this analysis
Exacerbations requiring oral corticosteroids
33/442 (7.5%) with fluticasone (200 micrograms/day)
28/441 (6.3%) with fluticasone (400–500 micrograms/day)

OR 1.21
95% CI 0.72 to 2.05
Not significant

Physiological measures

Increased dose of inhaled corticosteroid versus low-dose corticosteroid We don't know whether a second dose of inhaled beclometasone is more effective than adding placebo at improving lung function assessed by FEV1, bronchial reactivity, or airway responsiveness at 1 year, in children aged 6 to 16 years with asthma, who were already taking inhaled beclometasone twice daily. Increased dose of inhaled fluticasone (400–500 micrograms/day) may be more effective than lower dose of inhaled fluticasone (200 micrograms/day) at improving mean morning peak expiratory flow rate in children with asthma who were all previously using inhaled corticosteroids; however, we don't know whether increased dose is more effective at improving FEV1 in children with asthma, the majority of whom were previously using inhaled corticosteroids (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Forced expiratory volume

RCT
3-armed trial
177 children aged 6 to 16 years, mean pre-bronchodilator FEV1 86% predicted Lung function (mean change in FEV1) at 1 year
5.8% predicted with additional beclometasone (200 micrograms twice daily)
4.3% predicted with placebo

No direct comparison of increased corticosteroid versus placebo
No significant difference among groups was found in these children, whose compliance with pre-existing medication was good

Systematic review
114 children
2 RCTs in this analysis
FEV1, % predicted
with fluticasone (200 micrograms/day)
with fluticasone (400–500 micrograms/day)
Absolute results not reported

WMD –2.48
95% CI –8.60 to +3.64
Not significant
Peak expiratory flow

Systematic review
876 children (aged 4–11 years or about 8 years) with asthma, all using inhaled corticosteroids and either remaining symptomatic or with at least 1 asthma exacerbation in the previous 12 months
2 RCTs in this analysis
Change in morning peak expiratory flow rate (PEFR) from baseline
with fluticasone (200 micrograms/day)
with fluticasone (400–500 micrograms/day)
Absolute results not reported

Difference –7.9 L/minute
95% CI –12.9 L/minute to –2.9 L/minute
Effect size not calculatedfluticasone (400–500 micrograms/day)
Airway hyperresponsiveness

RCT
3-armed trial
177 children aged 6 to 16 years, mean pre-bronchodilator FEV1 86% predicted Bronchial reactivity 1 year
with additional beclometasone (200 micrograms twice daily)
with placebo
Absolute results not reported

No direct comparison of increased corticosteroid versus placebo
No significant difference among groups was found in these children, whose compliance with pre-existing medication was good

RCT
3-armed trial
177 children aged 6 to 16 years, mean pre-bronchodilator FEV1 86% predicted Changes in airway responsiveness 1 year
with additional beclometasone (200 micrograms twice daily)
with placebo
Absolute results not reported

No direct comparison of increased corticosteroid versus placebo
No significant difference among groups was found in these children, whose compliance with pre-existing medication was good

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Growth suppression

RCT
3-armed trial
177 children aged 6 to 16 years, mean pre-bronchodilator FEV1 86% predicted Mean height increase 1 year
3.6 cm with additional beclometasone (200 micrograms twice daily)
4.5 cm with placebo

P = 0.02
Effect size not calculatedplacebo

Increased dose of inhaled corticosteroid versus adding beta2 agonist:

See option on addition of long-acting beta2 agonist.

Increased dose of inhaled corticosteroid versus adding oral leukotriene receptor antagonists:

See option on addition of oral leukotriene receptor antagonists.

Further information on studies

None.

Comment

Doses of inhaled corticosteroids are often increased from low dose to higher doses despite lack of evidence of benefit. For the population as a whole, there is likely to be a ceiling effect where total daily doses in excess of 400 micrograms budesonide (or equivalent) do not provide benefit. There have been case reports of serious adrenal crisis in children receiving high doses of inhaler corticosteroid, principally fluticasone in doses above 500 micrograms.

Substantive changes

Increased dose of inhaled corticosteroid New evidence added. Categorisation unchanged (Unknown effectiveness) because evidence remains insufficient to assess the effects of this intervention.

2012; 2012: 0302.
Published online 2012 January 18.

Addition of regular (daily) long-acting beta2 agonist

Summary

When low-dose inhaled corticosteroids fail to control asthma, most older children will respond to one of the add-on options available, which include addition of long-acting beta 2 agonists, addition of leukotriene receptor antagonists, addition of theophylline, or increased dose of inhaled corticosteroid. However, we don't know for certain how effective these additional treatments are because we found no/limited evidence of benefit compared with adding placebo/no additional treatments.

Addition of long-acting beta 2 agonists may reduce symptoms and improve physiological measures compared with increased dose of corticosteroids in older children.

Long-acting beta 2 agonists are not currently licensed for use in children under 5 years of age.

Long-acting beta 2 adrenergic agonists may increase the chance of severe asthma episodes.

Benefits and harms

Addition of long-acting beta2 agonist versus addition of placebo to inhaled corticosteroid:

We found one systematic review (search date 2008, 16 RCTs, 24 comparisons, 4625 children) comparing adding regular long-acting beta2 agonist to inhaled corticosteroid versus adding placebo to the same dose of inhaled corticosteroid. For further information on adverse effects, see long-acting beta2 agonists (inhaled) under question on prophylaxis and comments below.

Symptom control (clinical assessments)

Addition of regular (daily) long-acting beta2 agonist compared with adding placebo Adding long-acting beta2 agonist to inhaled corticosteroid seems no more effective than adding placebo to the same dose of inhaled corticosteroid at improving symptom scores in children aged 4 to 16 years with persistent seasonal asthma, who were previously treated with inhaled corticosteroids (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptom scores

Systematic review
1119 children with persistent asthma who received daily inhaled corticosteroid (ICS) for at least 28 days before study entry
4 RCTs in this analysis
Mean change in symptom scores
with ICS plus long-acting beta2 agonist (LABA; salmeterol or formoterol)
with ICS plus placebo
Absolute results not reported

SMD –0.04
95% CI –0.16 to +0.08
Not significant

Exacerbations

Addition of regular (daily) long-acting beta2 agonist compared with adding placebo Adding long-acting beta2 agonist to inhaled corticosteroid is no more effective than adding placebo to the same dose of inhaled corticosteroid at reducing exacerbations requiring oral corticosteroids in children with persistent asthma, who were previously treated with inhaled corticosteroids (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations requiring oral corticosteroids

Systematic review
1084 children with persistent asthma who received daily inhaled corticosteroid (ICS) for at least 28 days before study entry
7 RCTs in this analysis
Proportion of children with exacerbation requiring oral corticosteroids
34/540 (6%) with ICS plus long-acting beta2 agonist (LABA; salmeterol or formoterol)
37/544 (7%) with ICS plus placebo

RR 0.92
95% CI 0.60 to 1.40
Not significant

Physiological measures

Addition of regular (daily) long-acting beta2 agonist compared with adding placebo Adding long-acting beta2 agonist to inhaled corticosteroid seems more effective than adding placebo to the same dose of inhaled corticosteroid at improving FEV1 in children with persistent asthma, who were previously treated with inhaled corticosteroids (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Forced expiratory volume

Systematic review
1235 children with persistent asthma who received daily inhaled corticosteroid (ICS) for at least 28 days before study entry
9 RCTs in this analysis
Improvement in FEV1 from baseline
with ICS plus long-acting beta2 agonist (LABA; salmeterol or formoterol)
with ICS plus placebo
Absolute results not reported

Difference 80 mL
95% CI 60 mL to 110 mL
Effect size not calculatedaddition of LABA

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
3-armed trial
177 children aged 6 to 16 years, 1 year of follow-up, mean pre-bronchodilator FEV1 86% predicted
In review
Mean height increase 1 year
5.1 cm with additional salmeterol (50 micrograms twice daily)
4.5 cm with placebo

Between-group significance assessment not reported

Systematic review
3284 children with persistent asthma who received daily inhaled corticosteroid (ICS) for at least 28 days before study entry
15 RCTs in this analysis
Overall adverse effects
1054/1855 (57%) with ICS plus long-acting beta2 agonist (LABA; salmeterol or formoterol)
782/1429 (55%) with ICS plus placebo

RR 1.04
95% 0.98 to 1.10
Not significant

Systematic review
1155 children with persistent asthma who received daily ICS for at least 28 days before study entry
2 RCTs in this analysis
Oral candidiasis
5/677 (0.7%) with ICS plus LABA (salmeterol or formoterol)
1/478 (0.2%) with ICS plus placebo

RR 3.78
95% CI 0.63 to 22.75
The review advised that results should be interpreted with caution because of a large confidence interval and small number of reporting trials
Not significant

Systematic review
1467 children with persistent asthma who received daily ICS for at least 28 days before study entry
4 RCTs in this analysis
Tremor
3/777 (0.4%) with ICS plus LABA (salmeterol or formoterol)
0/690 (0%) with ICS plus placebo

RR 3.07
95% CI 0.38 to 25.05
The review advised that results should be interpreted with caution because of a large confidence interval and small number of reporting trials
Not significant

Systematic review
1052 children with persistent asthma who received daily ICS for at least 28 days before study entry
2 RCTs in this analysis
Palpitations
1/575 (0.2%) with ICS plus LABA (salmeterol or formoterol)
2/477 (0.4%) with ICS plus placebo

RR 0.4
95% CI 0.05 to 3.25
The review advised that results should be interpreted with caution because of a large confidence interval and small number of reporting trials
Not significant

Systematic review
2966 children with persistent asthma who received daily ICS for at least 28 days before study entry
14 RCTs in this analysis
Headache
200/1645 (12%) with ICS plus LABA (salmeterol or formoterol)
144/1321 (11%) with ICS plus placebo

RR 1.10
95% CI 0.90 to 1.33
Not significant

Addition of long-acting beta2 agonist versus increased dose of corticosteroid:

We found one systematic review (search date 2008, 7 RCTs, 1048 children) comparing addition of long-acting beta2 agonist to inhaled corticosteroid treatment versus increased dose of inhaled corticosteroid in the control group. We found two subsequent RCTs. For further information on adverse effects (death and hospital admission) with formoterol, see comments.

Symptom control (clinical assessments)

Addition of regular (daily) long-acting beta2 agonist compared with adding increased dose of inhaled corticosteroid Adding salmeterol to fluticasone may be more effective than increased dose of fluticasone at improving some symptom measures including symptom-free days and days without salbutamol in children aged 4 to 16 years with symptomatic persistent seasonal or perennial asthma, previously treated with inhaled corticosteroids, and at improving the composite outcome of best response to treatment in children aged 6 to 17 years with mild to moderate asthma (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptoms

RCT
283 children and adolescents, aged 4 to 16 years (mean age 9.5 years), with symptomatic persistent seasonal or perennial asthma; all children previously treated with inhaled corticosteroids % of symptom-free days
41.5% with salmeterol (50 micrograms) plus fluticasone (100 micrograms) (inhaled, twice daily)
33.3% with fluticasone (inhaled, 200 micrograms twice daily)

Difference 8.7%
95% CI 1.2% to 16.3%
Intention-to-treat (ITT) analysis (281 people in analysis)
Effect size not calculatedsalmeterol plus fluticasone

RCT
283 children and adolescents, aged 4 to 16 years (mean age 9.5 years), with symptomatic persistent seasonal or perennial asthma; all children previously treated with inhaled corticosteroids % days without salbutamol treatment
with salmeterol (50 micrograms) plus fluticasone (100 micrograms) (inhaled, twice daily)
with fluticasone (inhaled, 200 micrograms twice daily)
Absolute results not reported

Difference 8%
95% CI 0.6% to 15.3%
ITT analysis (281 people in analysis)
Effect size not calculatedsalmeterol plus fluticasone

RCT
Crossover design
3-armed trial
182 children aged 6 to 17 years with mild to moderate asthma; asthma uncontrolled while receiving fluticasone (100 micrograms twice daily) Proportion of children with best response to each treatment
54% with fluticasone (100 micrograms) plus salmeterol (50 micrograms) (inhaled, twice daily)
32% with fluticasone (250 micrograms; inhaled, twice daily)
Absolute results reported graphically

P = 0.004
Effect size not calculatedfluticasone plus salmeterol

No data from the following reference on this outcome.

Exacerbations

Addition of regular (daily) long-acting beta2 agonist compared with adding increased dose of inhaled corticosteroid We don't know whether adding long-acting beta2 agonist (salmeterol or formoterol) to inhaled corticosteroid is more or less effective than increased dose of inhaled corticosteroid at reducing exacerbations requiring oral corticosteroids, in children with persistent asthma previously treated with inhaled corticosteroids (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations

Systematic review
441 children with persistent asthma and having received daily inhaled corticosteroid (ICS) treatment for at least 28 days before study entry
2 RCTs in this analysis
Proportion of children with exacerbation requiring oral corticosteroids
12/220 (5%) with ICS plus long-acting beta2 agonist (salmeterol or formoterol)
8/221 (4%) with increased dose of ICS plus placebo

RR 1.50
95% CI 0.65 to 3.48
Not significant

RCT
283 children and adolescents, aged 4 to 16 years (mean age 9.5 years), with symptomatic persistent seasonal or perennial asthma; all children previously treated with ICS Exacerbations
3 with salmeterol (50 micrograms) plus fluticasone (100 micrograms) (inhaled, twice daily)
6 with fluticasone (inhaled, 200 micrograms twice daily)

Significance assessment not reported

No data from the following reference on this outcome.

Physiological measures

Addition of regular (daily) long-acting beta2 agonist compared with adding increased dose of inhaled corticosteroid Adding long-acting beta2 agonist (salmeterol or formoterol) to inhaled corticosteroid may be more effective than increased dose of inhaled corticosteroid at improving peak expiratory flow measurements in children with symptomatic persistent seasonal or perennial asthma or persistent asthma previously treated with inhaled corticosteroids. However, we don't know whether it is more or less effective at improving FEV1 measurements (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Forced expiratory volume measures

Systematic review
526 children with persistent asthma and having received daily inhaled corticosteroid (ICS) treatment for at least 28 days before study entry
2 RCTs in this analysis
Change from baseline in FEV1
with ICS plus long-acting beta2 agonist (LABA; salmeterol or formoterol)
with increased dose of ICS plus placebo
Absolute results not reported

WMD +0.01
95% CI –0.03 to +0.05
Not significant
Peak expiratory flow measures

Systematic review
1002 children with persistent asthma and having received daily ICS treatment for at least 28 days before study entry
4 RCTs in this analysis
Change in morning peak expiratory flow (L/minute)
with ICS plus LABA (salmeterol or formoterol)
with increased dose of ICS plus placebo
Absolute results not reported

WMD 7.55
95% CI 3.57 to 11.53
Effect size not calculatedICS plus LABA

RCT
283 children and adolescents, aged 4 to 16 years (mean age 9.5 years), with symptomatic persistent seasonal or perennial asthma; all children previously treated with ICS Change in morning peak flow from baseline week 8
24.6 L/minute with salmeterol (50 micrograms) plus fluticasone (100 micrograms) (inhaled, twice daily)
16.0 L/minute with fluticasone (inhaled, 200 micrograms twice daily)

Difference 8.6 L/minute
95% CI 1.3 to 15.9 L/minute
Intention-to-treat analysis (281 people in analysis)
Effect size not calculatedsalmeterol plus fluticasone

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
283 children and adolescents, aged 4 to 16 years (mean age 9.5 years), with symptomatic persistent seasonal or perennial asthma; all children previously treated with inhaled corticosteroids (ICS) Adverse effects, considered to be drug related
with salmeterol (50 micrograms) plus fluticasone (100 micrograms) (inhaled, twice daily)
with fluticasone (inhaled, 200 micrograms twice daily)

Systematic review
814 children with persistent asthma and having received daily ICS treatment for at least 28 days before study entry
4 RCTs in this analysis
Overall adverse effects
254/403 (63%) with ICS plus long-acting beta2 agonist (LABA; salmeterol or formoterol)
256/411 (62%) with increased dose of ICS plus placebo

RR 1.05
95% CI 0.90 to 1.23
Not significant

Systematic review
790 children with persistent asthma and having received daily ICS treatment for at least 28 days before study entry
3 RCTs in this analysis
Headache
66/391 (17%) with ICS plus LABA (salmeterol or formoterol)
49/399 (12%) with increased dose of ICS plus placebo

RR 1.37
95% CI 0.98 to 1.90
Not significant

Systematic review
Children with persistent asthma and having received daily ICS treatment for at least 28 days before study entry
2 RCTs in this analysis
Linear growth 1 year
with ICS plus LABA (salmeterol or formoterol)
with increased dose of ICS plus placebo
Absolute results not reported

WMD 1.2 cm/year
95% CI 0.72 cm/year to 1.7 cm/year
Effect size not calculatedICS plus LABA

No data from the following reference on this outcome.

Addition of long-acting beta2 agonist versus addition of leukotriene receptor antagonist:

We found one RCT.

Symptom control (clinical assessments)

Addition of long-acting beta2 agonist compared with addition of leukotriene receptor antagonist Adding salmeterol to fluticasone may be more effective than adding montelukast to fluticasone at improving the composite outcome of best response to treatment in children aged 6 to 17 years with mild to moderate asthma (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptoms

RCT
Crossover design
3-armed trial
182 children aged 6 to 17 years with mild to moderate asthma; asthma uncontrolled while receiving fluticasone (100 micrograms twice daily) Proportion of children with best response to each treatment
52% with fluticasone (100 micrograms) plus salmeterol (50 micrograms) (both inhaled, twice daily)
34% with fluticasone (inhaled, 100 micrograms twice daily) plus montelukast (orally, 5 mg or 10 mg once daily)
Absolute results reported graphically

P = 0.02
Effect size not calculatedfluticasone plus salmeterol

Exacerbations

No data from the following reference on this outcome.

Physiological measures

No data from the following reference on this outcome.

Further information on studies

The review reported that most RCTs were funded by manufacturers of both long-acting beta2 agonist and inhaled corticosteroid inhalers.

The primary outcome of the trial involved the primary endpoint in the per-protocol population; however, this included only 178/283 (63%) of people who had at least 47 days of treatment without missing diary recordings or protocol deviations, and so did not fulfil Clinical Evidence reporting criteria. The per-protocol analysis found similar results to the intention-to-treat analysis.

Comment

We found another systematic review (search date 2008), which identified 9 RCTs in children, all of which were also identified by the review. This second review pooled the data for addition of long-acting beta2 agonist (LABA) to inhaled corticosteroid (ICS) versus the same dose of ICS and versus an increased dose of ICS. It found no significant difference in exacerbations requiring hospital admission in the subgroup of children with LABA plus ICS compared with ICS alone (3 RCTs; number of children in analysis not reported; RR 3.38, 95% 0.94 to 12.15; absolute numbers not reported). However, it also carried out an indirect comparison and interactive test examining whether adding LABA to ICS increased exacerbations in children versus in adults. It found that the addition of LABA to ICS was associated with increased exacerbation rates in children compared with adults (number of RCTs and people in analysis not reported; RR 6.7; P = 0.004; absolute numbers not reported).

Different dosage regimens of ICS/LABA combinations:

One RCT identified by the review assessed the "SMART" regimen of ICS/LABA. In the SMART regimen an ICS/LABA combination inhaler is used on an as-required basis, depending on symptoms. This differs from the conventional "fixed regimen" for ICS/LABA. The RCT (subgroup analysis of 341 children aged 4–11 years) found that the SMART regimen (once daily plus as-required budesonide/formoterol inhaler combination) was superior to the fixed-combination regimen (once daily budesonide/formoterol combination inhaler), and once daily higher dose ICS (budesonide) in terms of exacerbations and early morning peak expiratory flow. Many of the indices of symptom control (clinical measures) were similar across the three arms of the study, with the exception of night-time awakenings, which were reduced in the SMART group. The children in this RCT had mild disease (<40% had an exacerbation during the 12-month follow-up).

Deaths and asthma-related hospital admission

We found another systematic review (search date 2007), which pooled safety data from AstraZeneca-sponsored RCTs comparing formoterol versus non-LABA treatment. It pooled data on 11,849 children and adolescents treated with formoterol in 41 clinical trials (about 45% of people aged <12 years, about 80% of people taking formoterol in combination with ICS). It found no significant difference in asthma-related hospital admissions between people taking formoterol and people taking non-LABA treatments. It found only one asthma-related death (in the formoterol/ICS group).

Substantive changes

Addition of long-acting beta2 agonist New evidence added. Categorisation changed (from Unknown effectiveness to Likely to be beneficial).

2012; 2012: 0302.
Published online 2012 January 18.

Addition of oral theophylline

Summary

When low-dose inhaled corticosteroids fail to control asthma, most older children will respond to one of the add-on options available, which include addition of long-acting beta 2 agonists, addition of leukotriene receptor antagonists, addition of theophylline, or increased dose of inhaled corticosteroid. However, we don't know for certain how effective these additional treatments are because we found no/limited evidence of benefit compared with adding placebo/no additional treatments.

Although there is weak evidence that addition of theophylline to inhaled corticosteroids does improve symptom control and reduce exacerbations, theophylline should only be added to inhaled corticosteroids in children aged over 5 years when the addition of long-acting beta 2 agonists and leukotriene receptor antagonists have both been unsuccessful.

Theophylline has serious adverse effects (cardiac arrhythmia, convulsions) if therapeutic blood concentrations are exceeded.

Benefits and harms

Addition of oral theophylline versus addition of placebo:

We found no systematic review but found two RCTs.

Symptom control (clinical assessments)

Addition of oral theophylline compared with addition of placebo Adding oral theophylline may be more effective than adding placebo to existing treatment at increasing the mean number of symptom-free days and reducing the use of additional beta2 agonist (orciprenaline), but we don't know whether it is more effective at improving symptoms as recorded on diary cards in children aged 6 years or over with asthma (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptoms

RCT
Crossover design
33 children aged 6 to 19 years, recruited from a hospital asthma clinic; 22 children (mean age 13.6 years) using inhaled beclometasone (mean 533 micrograms/day), 11 children (mean age 11.8 years) using oral prednisolone (mean 30 mg alternate days) Mean number of symptom-free days
63% with addition of oral theophylline (serum concentration 10–20 micrograms/mL) for 4 weeks
42% with placebo
Absolute numbers not reported

P less-than or equal to 0.01
Effect size not calculatedaddition of oral theophylline

RCT
36 children, parallel groups, mean age 12.5 years, using inhaled corticosteroids for at least 6 months before study entry Symptoms (as recorded on diary cards) or use of rescue medication
with adding theophylline (10 mg/kg bodyweight)
with adding placebo
Absolute results not reported

Reported no significant difference between groups
P value not reported
Not significant

RCT
Crossover design
33 children aged 6 to 19 years, recruited from a hospital asthma clinic; 22 children (mean age 13.6 years) using inhaled beclometasone (mean 533 micrograms/day), 11 children (mean age 11.8 years) using oral prednisolone (mean 30 mg alternate days) Need for inhaled beta2 agonist (orciprenaline)
0.5 doses/day with addition of oral theophylline (serum concentration 10–20 micrograms/mL) for 4 weeks
1.0 doses/day with placebo

P less-than or equal to 0.01
Effect size not calculatedaddition of oral theophylline

Exacerbations

Addition of oral theophylline compared with addition of placebo Adding oral theophylline may be more effective than adding placebo to existing treatment at reducing the proportion of children aged 6 years or over needing additional daily prednisolone; however, evidence is weak (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Need for oral corticosteroids

RCT
Crossover design
33 children aged 6 to 19 years, recruited from a hospital asthma clinic; 22 children (mean age 13.6 years) using inhaled beclometasone (mean 533 micrograms/day), 11 children (mean age 11.8 years) using oral prednisolone (mean 30 mg alternate days) Proportion of children needing additional daily prednisolone
3/32 (9%) with addition of oral theophylline (serum concentration 10–20 micrograms/mL) for 4 weeks
10/32 (31%) with placebo

P = 0.02
Effect size not calculatedaddition of oral theophylline

No data from the following reference on this outcome.

Physiological measures

Addition of oral theophylline compared with addition of placebo We don't know whether adding oral theophylline is more effective than adding placebo to existing treatment at improving mean peak expiratory flow in children aged about 12 years (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Peak expiratory flow

RCT
36 children, parallel groups, mean age 12.5 years, using inhaled corticosteroids for at least 6 months before study entry Change in mean peak expiratory flow from baseline 12 weeks
From 85% to 95% with adding theophylline (10 mg/kg bodyweight)
Not reported with adding placebo

No between-group comparison

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
33 children aged 6 to 19 years, recruited from a hospital asthma clinic; 22 children (mean age 13.6 years) using inhaled beclometasone (mean 533 micrograms/day), 11 children (mean age 11.8 years) using oral prednisolone (mean 30 mg alternate days) Adverse effects
with addition of oral theophylline (serum concentration 10–20 micrograms/mL) for 4 weeks
with placebo

RCT
36 children, parallel groups, mean age 12.5 years, using inhaled corticosteroids for at least 6 months before study entry Adverse effects
with adding theophylline (10 mg/kg bodyweight)
with adding placebo

No data from the following reference on this outcome.

Further information on studies

One child was excluded from the analysis because of poor compliance. The RCT was too small and brief to comprehensively assess harms.

The RCT found that serum eosinophilic cationic protein was significantly decreased from baseline with theophylline after 12 weeks, but it found no significant change from baseline with placebo (reported no between-group comparison). The RCT was too small and brief to comprehensively assess harms.

Comment

Theophylline has serious adverse effects (cardiac arrhythmia, convulsions) if therapeutic blood concentrations are exceeded.

Substantive changes

No new evidence

2012; 2012: 0302.
Published online 2012 January 18.

Addition of oral leukotriene receptor antagonists

Summary

When low-dose inhaled corticosteroids fail to control asthma, most older children will respond to one of the add-on options available, which include addition of long-acting beta 2 agonists, addition of leukotriene receptor antagonists, addition of theophylline, or increased dose of inhaled corticosteroid. However, we don't know for certain how effective these additional treatments are because we found no/limited evidence of benefit compared with adding placebo/no additional treatments.

Consensus suggests that younger children are likely to benefit from addition of leukotriene receptor antagonists.

Benefits and harms

Addition of oral leukotriene receptor antagonists versus addition of placebo:

We found one systematic review (search date 2003) examining the addition of leukotriene receptor antagonists to inhaled corticosteroids for chronic asthma in adults and children. It identified two RCTs in children; however, it did not present a separate analysis in children. One of the RCTs was published only in abstract form and so we have not included it in this Clinical Evidence review. The other RCT was a crossover RCT, which compared adding oral montelukast versus adding placebo to inhaled budesonide over 4 weeks. For further information on the risk of suicidality, see comment.

Symptom control (clinical assessments)

Addition of oral leukotriene receptor antagonist compared with addition of placebo We don't know whether adding oral montelukast to inhaled budesonide is more effective than adding placebo to inhaled budesonide at improving global evaluation or quality of life measurements after up to 4 weeks in children, aged 6 to 14 years, with persistent asthma who had been taking inhaled budesonide for at least 6 weeks (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptom scores

RCT
Crossover design
279 children aged 6 to 14 years previously treated with inhaled corticosteroid for at least 6 weeks, with mean FEV1 78% predicted after 1 month run-in with budesonide 200 micrograms Quality of life measurements
with adding oral montelukast to inhaled budesonide over 4 weeks
with adding placebo to inhaled budesonide over 4 weeks
Absolute results not reported

Reported no significant difference between groups
Not significant

RCT
Crossover design
279 children aged 6 to 14 years previously treated with inhaled corticosteroid for at least 6 weeks, with mean FEV1 78% predicted after 1 month run-in with budesonide 200 micrograms Global evaluations
with adding oral montelukast to inhaled budesonide over 4 weeks
with adding placebo to inhaled budesonide over 4 weeks
Absolute results not reported

Reported no significant difference between groups
Not significant

Exacerbations

Addition of oral leukotriene receptor antagonist compared with addition of placebo Adding oral montelukast to inhaled budesonide may be more effective than adding placebo to inhaled budesonide at reducing asthma exacerbation days, but we don't know whether it is more effective at reducing asthma attacks requiring unscheduled medical intervention or treatment with oral corticosteroid after up to 4 weeks in children, aged 6 to 14 years, with persistent asthma who had been taking inhaled budesonide for at least 6 weeks (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations

RCT
Crossover design
279 children aged 6 to 14 years previously treated with inhaled corticosteroid for at least 6 weeks, with mean FEV1 78% predicted after 1 month run-in with budesonide 200 micrograms Asthma attacks requiring unscheduled medical intervention or treatment with oral corticosteroid
with adding oral montelukast to inhaled budesonide over 4 weeks
with adding placebo to inhaled budesonide over 4 weeks
Absolute results not reported

Reported no significant difference between groups
Not significant

RCT
Crossover design
279 children aged 6 to 14 years previously treated with inhaled corticosteroid for at least 6 weeks, with mean FEV1 78% predicted after 1 month run-in with budesonide 200 micrograms Asthma exacerbation days (decrease from baseline peak flow of >20%, or increase from baseline of beta2 agonist use of >70%)
12% with adding oral montelukast to inhaled budesonide over 4 weeks
16% with adding placebo to inhaled budesonide over 4 weeks
Absolute results not reported

P <0.001
Effect size not calculatedaddition of montelukast

Physiological measures

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
279 children aged 6 to 14 years previously treated with inhaled corticosteroid for at least 6 weeks, with mean FEV1 78% predicted after 1 month run-in with budesonide 200 micrograms Adverse effects (asthma exacerbation, upper respiratory tract infection, headache, cough, pharyngitis, and fever)
with adding oral montelukast to inhaled budesonide over 4 weeks
with adding placebo to inhaled budesonide over 4 weeks
Absolute results not reported

Reported no significant difference between groups
Not significant

Addition of oral leukotriene receptor antagonists versus increased corticosteroid dose:

We found one crossover RCT comparing addition of oral montelukast to inhaled corticosteroids versus increasing inhaled corticosteroid dose.

Symptom control (clinical assessments)

Addition of oral leukotriene receptor antagonist compared with increased corticosteroid dose We don't know how effective adding montelukast to fluticasone and increased dose of fluticasone are, compared with each other, at improving the composite outcome of best response to treatment in children aged 6 to 17 years with mild to moderate asthma (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptoms

RCT
Crossover design
3-armed trial
182 children aged 6 to 17 years with mild to moderate asthma; asthma uncontrolled while receiving fluticasone (100 micrograms twice daily) Proportion of children with best response to each treatment
with fluticasone (inhaled, 100 micrograms twice daily) plus montelukast (orally, 5 mg or 10 mg once daily)
with fluticasone (inhaled, 250 micrograms twice daily)
Absolute results reported graphically

Reported as similar for adding montelukast versus increased dose of fluticasone
Significance assessment not reported

Exacerbations

No data from the following reference on this outcome.

Physiological measures

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
Crossover design
3-armed trial
182 children aged 6 to 17 years with mild to moderate asthma Adverse effects
with fluticasone (inhaled, 100 micrograms twice daily) plus montelukast (orally, 5 mg or 10 mg once daily)
with fluticasone (inhaled, 250 micrograms twice daily)

Addition of leukotriene receptor antagonist versus addition of long-acting beta2 agonist:

See option on addition of long-acting beta2 agonist.

Further information on studies

The RCT in children was brief (4 weeks of treatment). The RCT was funded by the manufacturers of montelukast.

Comment

We found two further RCTs, which did not fulfil Clinical Evidence inclusion criteria. However, we have included a brief comment here, because of paucity of data on this intervention in children taking inhaled corticosteroids. The first open-label RCT (84 children aged 6–14 years, on low-dose inhaled corticosteroids) compared addition of montelukast versus addition of theophylline for 4 weeks. It found that additional montelukast significantly improved peak expiratory flow measurements compared with additional theophylline at 4 weeks. However, it found no significant difference between groups in inhaled beta2 agonist use or in mild asthma attacks.

The second RCT (194 children aged 2–14 years with asthma, about 90% currently taking inhaled corticosteroid alone or with long-acting beta2 agonist) compared montelukast versus placebo in addition to usual asthma care, during what is historically know to be a time of increased exacerbation risk (September and October in the USA). It found that montelukast significantly reduced worsening asthma days compared with placebo over 45 days. The number needed to treat was not given and this study was funded by the manufacturer of montelukast.

Risk of suicidality

We found one review (search date 2008,116 RCTs or open-label studies with or without a control group, 37,764 adults or children), which examined adverse effects related to suicidality with montelukast. It found only one case of suicidal ideation with montelukast in paediatric studies. This was in a 12-year-old boy with pre-existing behaviour problems in one open-label study (open-label studies: suicidal ideation: 1/1487 with montelukast v 0/900 with other drugs).

Substantive changes

Addition of oral leukotriene receptor antagonists New evidence added, which identified no new RCTs. New evidence added. Existing evidence re-evaluated and categorisation changed (from Unknown effectiveness to Likely to be beneficial by consensus).

2012; 2012: 0302.
Published online 2012 January 18.

Addition of omalizumab

Summary

Omalizumab may be indicated in the secondary care setting for older children (aged over 5 years) with poorly controlled allergic asthma despite use of intermediate- and high-dose inhaled corticosteroids once the diagnosis is confirmed and compliance and psychological issues are addressed. However, we need more data to draw firm conclusions.

Benefits and harms

Adding omalizumab versus adding placebo:

We found one systematic review (search date 2006), which identified one RCT in children only, which was reported in several publications. We found one subsequent RCT.

Symptom control (clinical assessments)

Addition of omalizumab compared with addition of placebo Adding omalizumab to inhaled corticosteroid seems no more effective than adding placebo to inhaled corticosteroid at improving clinical measures of symptom control including asthma scores, dose of short-acting beta2 agonist, or asthma quality of life scores, in children aged 6 to 12 years with moderate to severe allergic asthma (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Symptom scores

RCT
334 children, aged 6 to 12 years, with moderate to severe allergic asthma, previously treated with inhaled corticosteroids and bronchodilator treatment for at least 3 months Asthma symptom scores 16 weeks
with adding omalizumab (subcutaneous) to beclometasone (inhaled, stable dose for 16 weeks)
with adding placebo to beclometasone (inhaled, stable dose for 16 weeks)
Absolute results not reported

The RCT reported that there was little change in asthma symptom scores during the stable-corticosteroid dose phase, with minimal difference between groups
Significance assessment not reported

RCT
334 children, aged 6 to 12 years, with moderate to severe allergic asthma, previously treated with inhaled corticosteroids and bronchodilator treatment for at least 3 months
Further report of reference
Asthma quality of life, assessed by Paediatric Asthma Quality of Life Questionnaire (PAQLQ) score 16 weeks
with adding omalizumab (subcutaneous) to beclometasone (inhaled, stable dose for 16 weeks)
with adding placebo to beclometasone (inhaled, stable dose for 16 weeks)
Absolute results reported graphically

Reported no significant difference between groups
Not significant

RCT
334 children, aged 6 to 12 years, with moderate to severe allergic asthma, previously treated with inhaled corticosteroids and bronchodilator treatment for at least 3 months
Further report of reference
Proportion of children with a large change (defined as a change in score >1.5) in overall PAQLQ score 16 weeks
9.5% with adding omalizumab (subcutaneous) to beclometasone (inhaled, stable dose for 16 weeks)
6.6% with adding placebo to beclometasone (inhaled, stable dose for 16 weeks)
Absolute numbers not reported

Reported no significant difference between groups
Not significant

RCT
627 children, aged 6 to 12 years, with moderate to severe allergic asthma that was not controlled despite at least fluticasone propionate 200 micrograms daily via dry powder inhaler, or equivalent Change in nocturnal asthma score from baseline 24 weeks
–0.63 with adding omalizumab (subcutaneous) to corticosteroid (inhaled, constant dose unless adjustment for exacerbation, daily)
–0.50 with adding placebo to corticosteroid (inhaled, constant dose unless adjustment for exacerbation, daily)

P = 0.114
Not significant

RCT
627 children, aged 6 to 12 years, with moderate to severe allergic asthma that was not controlled despite at least fluticasone propionate 200 micrograms daily via dry powder inhaler, or equivalent Reduction in number of doses of short-acting beta2 agonist per day 24 weeks
–1.3 with adding omalizumab (subcutaneous) to corticosteroid (inhaled, constant dose unless adjustment for exacerbation, daily)
–1.0 with adding placebo to corticosteroid (inhaled, constant dose unless adjustment for exacerbation, daily)

P = 0.047
Reported as not significant; see further information on studies
Not significant

Exacerbations

Addition of omalizumab compared with addition of placebo Adding omalizumab to fixed-dose inhaled corticosteroid may be more effective than adding placebo to fixed-dose inhaled corticosteroid at reducing exacerbations in children aged 6 to 12 years with moderate to severe allergic asthma (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Exacerbations

RCT
334 children, aged 6 to 12 years, with moderate to severe allergic asthma, previously treated with inhaled corticosteroids and bronchodilator treatment for at least 3 months Proportion of children with exacerbations treated with systemic corticosteroids 16 weeks
28/225 (12%) with adding omalizumab (subcutaneous) to beclometasone (inhaled, stable dose for 16 weeks)
20/109 (18%) with adding placebo to beclometasone (inhaled, stable dose for 16 weeks)

Significance assessment not reported

RCT
627 children, aged 6 to 12 years, with moderate to severe allergic asthma that was not controlled despite at least fluticasone propionate 200 micrograms daily via dry powder inhaler, or equivalent Rate of clinically significant exacerbation during 24 weeks' treatment
0.45 with adding omalizumab (subcutaneous) to corticosteroid (inhaled, constant dose unless adjustment for exacerbation, daily)
0.64 with adding placebo to corticosteroid (inhaled, constant dose unless adjustment for exacerbation, daily)

RR 0.69
95% CI 0.53 to 0.90
P = 0.007
Small effect sizeomalizumab

No data from the following reference on this outcome.

Physiological measures

Addition of omalizumab compared with addition of placebo We don't know whether adding omalizumab to inhaled corticosteroid is more effective than adding placebo to inhaled corticosteroid at improving measures of pulmonary function including peak expiratory flow (PEF), FEV1, FVC, or forced expiratory flow between 25% and 75% of vital capacity (FEF25–75%), in children aged 6 to 12 years with moderate to severe allergic asthma (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Pulmonary function

RCT
334 children, aged 6 to 12 years, with moderate to severe allergic asthma, previously treated with inhaled corticosteroids and bronchodilator treatment for at least 3 months Pulmonary function 16 weeks
with adding omalizumab (subcutaneous) to beclometasone (inhaled, stable dose for 16 weeks)
with adding placebo to beclometasone (inhaled, stable dose for 16 weeks)
Absolute results not reported

The RCT reported that there was little change in peak expiratory flow (PEF), FEV1 , FVC, or forced expiratory flow between 25% and 75% of vital capacity (FEF25–75%) during the stable-corticosteroid dose phase, with minimal difference between groups
Significance assessment not reported

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
334 children, aged 6 to 12 years, with moderate to severe allergic asthma, previously treated with inhaled corticosteroids and bronchodilator treatment for at least 3 months
Further report of reference
Total number of children with an adverse effect 28 weeks
201/225 (89%) with addition of omalizumab (subcutaneous) to beclometasone (inhaled, stable dose for 16 weeks, reducing dose for 12 weeks)
95/109 (87%) with addition of placebo to beclometasone (inhaled, stable dose for 16 weeks, reducing dose for 12 weeks)

No significant difference between groups; see further information on studies
Not significant

No data from the following reference on this outcome.

Further information on studies

The RCT also examined the corticosteroid-sparing effects of omalizumab in a corticosteroid dose-reduction phase (final 12 weeks of the study). During the first 8 weeks of this phase, the dose of inhaled beclometasone was reduced step-wise (reduced by about 25% of the baseline dose every 2 weeks until elimination or worsening of asthma symptoms), to establish the minimum effective dose of beclometasone, which was then maintained for the final 4 weeks of the trial. The RCT found that omalizumab allowed a significantly greater reduction in corticosteroid dose compared with placebo (median reduction: 100% with omalizumab v 67% with placebo; P = 0.001). It also found that a significantly higher proportion of people taking omalizumab were able to stop taking inhaled corticosteroid completely without worsening asthma symptoms (55% with omalizumab v 39% with placebo; P = 0.004). The RCT found that a small number of people withdrew from the trial because of needle fear.

The RCT found no development of anti-omalizumab antibodies or serum sickness during the 28 weeks of the double-blind phase of the trial.

All people in the RCT used fixed-dose inhaled corticosteroid for 24 weeks (constant dose unless adjustment required for exacerbation), and then used adjustable-dose inhaled corticosteroid for 28 weeks (dose reduction allowed dependent on symptoms). The RCT reported that the significance level was set at P <0.025 for all secondary outcomes to take account of multiple testing.

Comment

Clinical guide:

Addition of monthly infusions of omalizumab is associated with reduced inhaled corticosteroid dose and reduced exacerbations. The effect of omalizumab on pulmonary function is not known. Many of the children included in clinical trials were already in receipt of intermediate-dose inhaled corticosteroid and long-acting beta2 agonist, suggesting a potential role for omalizumab in the management of moderate to severe asthma. The efficacy of omalizumab against high-dose inhaled corticosteroid and oral corticosteroids remains unknown. In children with moderate to severe asthma symptoms, issues of diagnostic accuracy, compliance with treatment, and behavioural/psychological problems need to be addressed.

Substantive changes

Addition of omalizumab New option added. Categorised as Unknown effectiveness because evidence from two RCTs, one reported in several publications, is insufficient to assess the effects of this intervention.


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