Asthma Management Handbook

Reviewing initial treatment in children aged 6 years and over

Recommendations

When prescribing any preventer medicine for a child, consider each adjustment to the regimen as a treatment trial: monitor response continually, review within 4–6 weeks (or earlier as needed in response to parents’ concerns), and adjust treatment according to response.

Table. Reviewing and adjusting preventer treatment for children aged 6–11 years Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/table/show/26

Figure. Stepped approach to adjusting asthma medication in children aged 6-11 years Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/figure/show/120

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Last reviewed version 2.0

If good asthma symptom control has not been achieved by an initial low dose of inhaled corticosteroids, do not increase the dose or change the regimen until you have (all of):

  • checked adherence to the inhaled corticosteroid
  • checked the child’s inhaler technique
  • assessed exposure to environmental triggers (e.g. allergens, cigarette smoke)
  • reviewed the diagnosis (consider whether symptoms may be due to a comorbidity or alternative diagnosis such as rhinosinusitis, de-conditioning, obesity or upper airway dysfunction).

Table. Definitions of ICS dose levels in children

Inhaled corticosteroid

Daily dose (microg)

Low

High

Beclometasone dipropionate

100–200

>200 (maximum 400)

Budesonide

200–400

>400 (maximum 800)

Ciclesonide

80–160

>160 (maximum 320)

Fluticasone propionate

100–200

>200 (maximum 500)

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate)

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: 
http://www.thoracic.org.au/clinical-documents/area?command=record&id=14

Last reviewed version 2.0

Asset ID: 21

Close
How this recommendation was developed

Adapted from existing guidance

Based on reliable clinical practice guideline(s) or position statement(s):

  • van Asperen et al. 20101

Last reviewed version 2.0

If asthma is not well controlled by regular low-dose inhaled corticosteroid treatment (and adherence is good, inhaler technique is correct and diagnosis has been confirmed), consider one of the following options:

  • Increase the inhaled corticosteroid dose.
  • Continue low-dose inhaled corticosteroid and add montelukast.
  • Switch to an inhaled corticosteroid/long-acting beta2 agonist combination at low dose.

Note: TGA-registered indications for inhaled corticosteroid/long-acting beta2 agonist combinations differ between products.

  • Advise parents/carers about potential adverse psychiatric effects of montelukast.

Table. Definitions of ICS dose levels in children

Inhaled corticosteroid

Daily dose (microg)

Low

High

Beclometasone dipropionate

100–200

>200 (maximum 400)

Budesonide

200–400

>400 (maximum 800)

Ciclesonide

80–160

>160 (maximum 320)

Fluticasone propionate

100–200

>200 (maximum 500)

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate)

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: 
http://www.thoracic.org.au/clinical-documents/area?command=record&id=14

Last reviewed version 2.0

Asset ID: 21

Close
How this recommendation was developed

Consensus recommendation following inconclusive literature search

Based on clinical experience and expert opinion after literature review yielded insufficient evidence for an evidence-based recommendation

Key evidence considered:

  • Stempel et al. 20162
  • Chang et al. 20143
  • Malka et al. 20144
  • Rabinovitch et al. 20145
  • van Asperen et al. 20101
  • Lemanske et al. 20106
  • Papadopoulos et al. 20097

Last reviewed version 2.0

In children taking regular inhaled corticosteroid treatment, the dose of inhaled corticosteroid should be adjusted to the lowest dose needed to maintain control.

How this recommendation was developed

Adapted from existing guidance

Based on reliable clinical practice guideline(s) or position statement(s):

  • van Asperen et al. 20101

Last reviewed version 2.0

Long-acting beta2 agonists for children must not be prescribed in a separate inhaler, but only as a fixed-dose combination with an inhaled corticosteroids.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Last reviewed version 2.0

When reviewing treatment for a child taking a combination of inhaled corticosteroid and long acting beta2 agonist, ask parents/carers whether symptoms of wheeze or breathlessness resolve rapidly when the child is given short-acting beta2 agonist reliever.

If you suspect reduced response to short-acting beta2 agonist in a child treated with combination inhaled corticosteroid and long-acting beta2 agonist, consider obtaining a specialist opinion.

How this recommendation was developed

Consensus recommendation following inconclusive literature search

Based on clinical experience and expert opinion after literature review yielded insufficient evidence for an evidence-based recommendation

Key evidence considered:

  • Carroll et al. 20108
  • Fogel et al. 20109
  • Adler et al. 200610
  • PBS 201711

Last reviewed version 2.0

In children with persistent exercise-induced respiratory symptoms despite regular treatment with inhaled corticosteroids, consider adding montelukast (children 6–14 years).

Advise parents/carers that not all children experience asthma improvement with montelukast.

Review response within 4–6 weeks and discontinue if no response.

  • Advise parents/carers about potential adverse psychiatric effects of montelukast
How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to the following source(s):

  • van Asperen et al. 20101
  • Fogel et al. 20109
  • Grzelewski et al. 200912

Last reviewed version 2.0

If treatment-related behavioural and/or neuropsychiatric symptoms are suspected in a child taking montelukast, discontinue treatment and advise parents/carers to monitor and treat asthma symptoms while off treatment.

If unsure whether a change in behaviour could be due to medication, consider stopping for a short time (e.g. 1 week or more) and re-starting to monitor effects.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Last reviewed version 2.0

If parents/carers report behavioural changes possibly related to treatment in a child taking regular inhaled corticosteroids, consider reducing the dose, changing to a different corticosteroid and monitoring effect, or trialling a different preventer.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Last reviewed version 2.0

More information

Approaches to assessment and monitoring of asthma control in children

Assessment of asthma control in children is based mainly on:

  • recent asthma symptom control (assessed by the frequency and severity of symptoms between flare-ups 
  • the degree to which asthma symptoms affect daily activities such as interference with physical activity or missed school days)
  • the frequency of flare-ups
  • spirometry in children who are able to perform the test reliably.

Standardised questionnaires

Questionnaire-based instruments have been validated for assessing asthma control in children:

Lung function tests

Frequent spirometry to guide asthma treatment in children has not been shown to achieve superior outcomes to symptom-based treatment.[REFERENCE1739] Current evidence does not support use of home spirometers to guide asthma treatment in children.18 However, low FEV1 predicts clinically significant flare-ups, so spirometry should be performed at asthma reviews for children who are old enough to do the test.
The quality and utility of spirometry depends on the skill, clinical expertise and experience of the person doing and interpreting spirometry.

The results of one study in children aged 6–16 years with moderate atopic asthma suggest that asthma treatment guided by airway hyperresponsiveness (measured by bronchial provocation testing) may have a benefit over symptom-guided treatment in improving lung, but this effect was lost after 3–7 years of usual care.19, 20 Repeated bronchial provocation testing is not feasible in clinical practice.

Measures of airway inflammation

Measures of airway inflammation (e.g. sputum eosinophil count, exhaled nitric oxide measurement) are not recommended in primary care to guide treatment decisions, but are increasingly used in specialist clinics.

Asthma treatment guided by sputum eosinophil count has been shown to reduce the frequency of flare-ups in adults with asthma, but there is insufficient evidence to ascertain its value for children.21

Exhaled nitric oxide measurement may be useful in guiding asthma management in some children. In children not taking inhaled corticosteroid, a high nitric oxide level probably predicts a good short-term response to inhaled corticosteroid treatment,22 but it does not distinguish between asthma and eosinophilic bronchitis and is often high in children with atopy. There is insufficient evidence to ascertain whether a low exhaled nitric oxide level predicts successful withdrawal from inhaled corticosteroids without asthma relapse,22 or safety of treating asthma without inhaled corticosteroids.

A Cochrane review23 found that exhaled nitric oxide-guided management was significantly better than other approaches to adjusting medicines for reducing the number of children with flare-ups and the number of children who needed oral corticosteroids, but did not reduce the frequency of flare-ups or the rate of flare-ups requiring hospitalisation, improve lung function or symptoms scores, or reduce inhaled corticosteroid doses. The authors concluded that it could not be recommended for all children but may be beneficial for a subset not yet defined.23

Towards personalised asthma care

Emerging understanding of asthma phenotypes and of genetic factors that predict therapeutic response to preventer options is leading to the possibility of personalised, genomics-based treatment for asthma in children.24 In the near future, individual tailored therapy is may replace the standardised step model based on population data.

Last reviewed version 2.0

Close
Classification of recent asthma symptom control in children

Ongoing review of asthma involves both assessing recent asthma symptom control and assessing risks for poor asthma outcomes such as flare-ups and adverse effects of medicines.

Recent asthma symptom control is assessed according to the frequency of asthma symptoms over the previous 4 weeks.

Table. Definition of levels of recent asthma symptom control in children (regardless of current treatment regimen)

Good control Partial control Poor control

All of:

  • Daytime symptoms ≤2 days per week (lasting only a few minutes and rapidly relieved by rapid-acting bronchodilator)
  • No limitation of activities
  • No symptoms§ during night or when wakes up
  • Need for SABA reliever# ≤2 days per week

Any of:

  • Daytime symptoms >2 days per week (lasting only a few minutes and rapidly relieved by rapid-acting bronchodilator)
  • Any limitation of activities*
  • Any symptoms during night or when wakes up††
  • Need for SABA reliever# >2 days per week

Either of:

  • Daytime symptoms >2 days per week (lasting from minutes to hours or recurring, and partially or fully relieved by SABA reliever)
  • ≥3 features of partial control within the same week

SABA: short-acting beta2 agonist

† e.g. wheezing or breathing problems

‡ child is fully active; runs and plays without symptoms

§ including no coughing during sleep

# not including doses taken prophylactically before exercise. (Record this separately and take into account when assessing management.)

​* e.g. wheeze or breathlessness during exercise, vigorous play or laughing

†† e.g. waking with symptoms of wheezing or breathing problems

Notes:

Recent asthma control is based on symptoms over the previous 4 weeks. Each child’s risk factors for future asthma outcomes should also be assessed and taken into account in management.

Validated questionnaires can be used for assessing recent symptom control:
Test for Respiratory and Asthma Control in Kids (TRACK) for children < 5 years
Childhood Asthma Control Test (C-ACT) for children aged 4–11 years

Last reviewed version 2.0

Asset ID: 23

Close

Table. Risk factors for life-threatening asthma flare-ups in children

Asthma-related factors

Poor asthma control

Admission to hospital in preceding 12 months

History of intubation for acute asthma

Over-use of short-acting beta2 agonist reliever

Abnormal spirometry findings

Reversible expiratory airflow limitation on spirometry despite treatment

Poor adherence to preventer

Incorrect inhaler technique for preventer

Poor adherence to asthma action plan

Exposure to clinically relevant allergens

Exposure to tobacco smoke

Other clinical factors

Allergies to foods, insects, medicines

Obesity

Family-related factors

Frequent failure to attend consultations/lack of follow-up after an acute flare-up

Significant parental psychological or socioeconomic problems

Parent/carer unequipped to manage asthma emergency

Last reviewed version 2.0

Asset ID: 116

Close

Last reviewed version 2.0

Close
Montelukast for children: efficacy
  • Montelukast use has been associated with behavioural and/or neuropsychiatric adverse effects, including suicidality.

Overview

Montelukast is a leukotriene receptor antagonist preventer. It is registered by the TGA for the treatment of asthma in children aged 2 years and older, and for the symptomatic treatment of allergic rhinitis.25

Montelukast can be used as an alternative to inhaled corticosteroids or as an add-on treatment in a child already taking regular inhaled corticosteroids.

However, it is not effective for all children. Overall, only approximately 20–30% of children will respond to montelukast treatment. The effect is thought to depend mainly on the child’s genotype.26, 27, 28 Clinically, it is not possible to predict accurately which children will benefit most from montelukast treatment.

Montelukast as first-line preventer in children aged 2–5 years

Viral-induced wheezing

Overall, regular maintenance montelukast treatment does not reduce the risk of wheezing episodes requiring oral corticosteroid treatment among preschool children who only have wheezing episodes when they have viral upper respiratory tract infections.29

However, montelukast may be effective for some children. Some randomised controlled trials have reported a reduction the risk of flare-ups in preschool children with intermittent asthma/wheeze,30, 31 while others have not.32

Persistent asthma or wheezing

A systematic review comparing montelukast with inhaled corticosteroids in preschoolers with asthma or recurrent wheezing requiring daily preventer treatment33 reported that inhaled corticosteroids appeared to achieve better symptom control and reduce flare-ups (including severe flare-ups requiring treatment with systemic corticosteroids). However, results were inconsistent and meta-analysis was not possible due to heterogeneity of outcomes measured in available clinical trials.33

Some preschool children with persistent asthma/wheeze respond to montelukast. A crossover study in preschool children with persistent asthma/wheeze reported that some children showed their best response to montelukast, while most responded better to regular inhaled corticosteroids.34 Predictors of a better response to inhaled corticosteroids than montelukast were aeroallergen hypersensitivity and blood eosinophilia (eosinophil counts ≥ 300/μL).34 However, routine blood eosinophil count is not feasible or recommended for this purpose.

Montelukast as first-line preventer children aged 6 years and over

In school-aged children with persistent asthma, inhaled corticosteroids are more effective overall than montelukast in improving lung function and controlling asthma symptoms.35, 37

However, symptoms will respond to a treatment trial of montelukast in approximately one-quarter to one-third of children,35, 38,39 and some may benefit more than from an inhaled corticosteroid.35 More severe asthma and markers of allergic inflammation may predict a better response to inhaled corticosteroids.35

Montelukast as add-on treatment

A systematic review of studies in children over 6 years and adolescents with mild-to-moderate persistent asthma found that the addition of montelukast to inhaled corticosteroids did reduce flare-ups requiring oral corticosteroids or hospital admissions for asthma, compared with the same or an increased dose.37

In a study comparing step-up treatments in children with asthma symptoms uncontrolled by low-dose inhaled corticosteroids, the addition of a long-acting beta2 agonist was effective in more children than either montelukast or increasing the dose of inhaled corticosteroid for controlling asthma symptoms and preventing flare-ups requiring systemic corticosteroids.4 However, some studies in school-aged children with persistent asthma already taking regular inhaled corticosteroids have reported that add-on montelukast reduced the risk of flare-ups4, 40 and exercise-induced asthma symptoms.40 Not all children will respond.

In a small study in children with persistent asthma already taking regular inhaled corticosteroids who were homozygous for the Arg16 genotype, montelukast was more effective as an add-on therapy than long-acting beta2 agonist in reducing symptoms, reliever use and days absent from school due to asthma, depending on the child’s beta receptor genotype.28 However, children were given inhaled corticosteroid and long-acting beta2 agonists in separate inhalers, which is which is known to be associated with increased risks.

However, genotyping it is not currently feasible in clinical practice. In practice, a treatment trial of 4–6 weeks can determine which preventer is suitable for controlling a child’s asthma symptoms,35 but longer treatment may be required to evaluate effect on flare-ups, because flare-ups may be independent of symptom control.

Exercise-induced symptoms

In school-aged children who experience exercise-induced symptoms despite taking regular inhaled corticosteroids, the addition of montelukast is effective in controlling symptoms, but not all children experience a response.12

See: Investigation and management of exercise-induced bronchoconstriction

Short-term use in the management of flare-ups

Some, but not all studies suggest that a short course of montelukast, introduced at the first signs of an upper respiratory tract infection, may be effective in controlling flare-ups. An Australian study reported that this strategy could achieve a small reduction in symptoms, school absence and medical consultations in preschool and school-aged children with episodic wheeze.41

However, the evidence is inconsistent, with some studies showing no benefit.32,42, 43, 44, 45 The findings of one study suggested that whether or not intermittent montelukast is effective in wheezing children aged 5 years and under depends on genotype.27

Montelukast is not TGA-approved or PBS-subsidised for intermittent use.

Note: PBS status as at March 2019: Montelukast is not subsidised by the PBS for adolescents 15 years and over.

Last reviewed version 2.0

Close
Montelukast for children: behavioural and/or neuropsychiatric adverse effects

Montelukast is generally very well tolerated. Behavioural and psychiatric adverse effects were rare in clinical trials.42, 46 However, post-marketing surveillance reports have identified behavioural and/or neuropsychiatric adverse effects associated with montelukast use in some children.44

Behavioural treatment-associated effects are difficult to assess in young children. No factors have been identified to predict which children are at risk.

Reported adverse events include nightmares, sleep disturbance, anxiety, irritability, aggression and depression.44, 47, 27, 32

Suicidal ideation has been reported in adolescents and adults taking montelukast.32 A nested case-control study concluded that children with asthma aged 5–18 years taking leukotriene receptor antagonists were not at increased risk of suicide attempts.48

Reported adverse effects are usually mild.27 The majority occur within 7–14 days of starting montelukast,44, 27 but some may appear after several months.32

Behavioural and/or neuropsychiatric adverse effects typically disappear within 4 days of stopping montelukast treatment.27 There is no evidence of long term effects.

The TGA recommends that clinicians treating children with montelukast should educate caregivers about these potential adverse effects and should consider providing them with the CMI. Advise them to seek medical advice if they have any concerns.

Last reviewed version 2.0

Close
Inhaled corticosteroids for children: adverse effects

Local adverse effects

Hoarseness and pharyngeal candidiasis are not commonly reported among preschool children or school-aged children talking inhaled corticosteroids. 49, 1, 50

Topical effects can be reduced by use of spacer devices (which reduce oropharyngeal deposition), and by mouth-rinsing and spitting after use.1 Immediate quick mouth-rinsing removes more residual medicine in the mouth than delayed rinsing.51

There is limited evidence that inhaled asthma medication can affect dental health.1, 52 Mouth rinsing might reduce this risk.

Systemic adverse effects

Systemic effects of inhaled corticosteroids in children depend on the dose, but clinically significant adverse effects are uncommon.1

The use of spacers and mouth rinsing will not reduce systemic effects, but the use of a spacer may increase efficacy so that a lower dose is required.

Growth

Short-term suppression of linear growth has been demonstrated in children taking inhaled corticosteroids.53,54 The effect seems to be maximal during the first year of therapy and only one study has reported an effect in subsequent years of treatment.54 A Cochrane systematic review concluded that regular use of inhaled corticosteroid at low or medium daily doses is associated with a mean reduction of 0.48 cm per year in linear growth velocity and 0.61 cm less gain in height during 1 year of treatment in children with mild to moderate persistent asthma.54

One study of patients who participated in a clinical trial of inhaled corticosteroids as children, reported a reduction in adult height of approximately 1 cm,53, 55, 56, 57 whereas several studies have reported that children taking inhaled corticosteroids attained normal adult height.58, 59, 60

The effect is dose-dependent56,57 and may be more likely in children who begin inhaled corticosteroid treatment before age 10.55

Other factors affect growth in children with asthma. Uncontrolled asthma itself reduces growth and final adult height.61 One study found that inhaled corticosteroid equivalent to budesonide 400 microg/day affected growth less than low socioeconomic status.60

Bone density

Inhaled corticosteroids have not been associated with effects on bone density or fractures in children. 1 However, data from a recent study in Australia suggested asthma itself is associated with increased incidence of fractures in children, independent of medication.62

Given that the total dose of corticosteroids (both inhaled corticosteroids and oral corticosteroids) influences bone health, the aim of asthma management is to maintain symptom control using the lowest inhaled corticosteroid dose required, and to avoid repeated courses of oral corticosteroids.

Adrenal suppression

Biochemical testing in a research setting suggests that hypothalamic–pituitary–adrenal axis suppression may occur in up to two-thirds of children treated with inhaled corticosteroids, and may occur at even low doses.63 The risk is higher among children receiving concomitant intranasal steroids and those with lower body mass index,63 and is influenced by genetics.64

Clinical adrenal insufficiency in children taking inhaled corticosteroids is rare but has been reported, 65, 66, 67 including cases in Australia.67 Most cases have involved children given more than 500 microg per day fluticasone propionate.65

Adrenal suppression is associated with hypoglycaemia, hypotension, weakness, failure to grow, and is potentially fatal. Hypothalamic–pituitary–adrenal axis suppression may not be detected until adrenal crisis is precipitated by physical stress.68

Written information (e.g. a steroid alert card) can be prepared for children receiving long-term high-dose inhaled corticosteroids. Parents/carers can be instructed to present the card if the child ever needs to go to the emergency department (for any reason) or be admitted to hospital. A steroid alert card should state that child has asthma and the inhaled corticosteroid dose. A medical alert bracelet could also be considered.

There are no nationally accepted protocols for routine assessment of adrenal function in primary care because it has not yet been possible to identify precisely which children should be tested, to interpret test results reliably, to identify the appropriate interval for retesting, and because a clinical benefit has not been clearly demonstrated.

Regular monitoring of height might help detect adrenal suppression, based on the findings of a study in which a reduction in linear growth velocity occurred before adrenal suppression.69

Table. Definitions of ICS dose levels in children

Inhaled corticosteroid

Daily dose (microg)

Low

High

Beclometasone dipropionate

100–200

>200 (maximum 400)

Budesonide

200–400

>400 (maximum 800)

Ciclesonide

80–160

>160 (maximum 320)

Fluticasone propionate

100–200

>200 (maximum 500)

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate)

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: 
http://www.thoracic.org.au/clinical-documents/area?command=record&id=14

Last reviewed version 2.0

Asset ID: 21

Close

Last reviewed version 2.0

Close
Step-up options in children with asthma that is not controlled by low-dose inhaled corticosteroids

In children whose asthma is inadequately controlled by low-dose inhaled corticosteroids alone (and adherence is good, inhaler technique is correct and diagnosis has been confirmed), treatment options include:

  • increasing the inhaled corticosteroid dose
  • adding montelukast
  • switching to inhaled corticosteroid/long-acting beta2 agonist combination.

Table. Step-up options for children when good asthma control is not achieved with low-dose ICS

Option

TGA-registered indications for add-on therapy

PBS considerations

High-dose ICS

N/A

Subsidised

ICS plus montelukast

2 years and over

2–5 years: not subsidised*

6–14 years: not subsidised unless for exercise-induced bronchoconstriction despite ICS treatment

15 years and over: not subsidised

ICS/long-acting beta2 agonist combination

4 years and over for fluticasone propionate/ salmeterol xinafoate

12 years and over for budesonide/formoterol fumarate dihydrate

Subsidised

  • Advise parents about potential adverse psychiatric effects of montelukast

* Montelukast is not subsidised for use in combination with other preventers or for children who require inhaled corticosteroids.

 Montelukast is subsidised for prevention of exercise-induced asthma if asthma is otherwise well controlled while taking optimal-dose inhaled corticosteroids – it is not otherwise subsidised in combination with inhaled corticosteroids (or inhaled corticosteroid/long-acting beta2 agonist combinations). 

‡ Montelukast is not subsidised for people aged over 15 years.

Asset ID: 27

Close

In the majority of children with persistent asthma that requires preventive treatment, control can be achieved with one of these options.1

Few studies have been conducted in preschool-aged children. The preferred step-up option for children aged 6–12 years is controversial and guidelines differ in their recommendations.2

Increasing inhaled corticosteroid dose versus adding a long-acting beta2 agonist

In school-aged children with persistent asthma taking regular inhaled corticosteroid, the addition of a long-acting beta2 agonist does not reduce the rate of asthma flare-ups requiring systemic steroids compared with the same or higher doses of inhaled corticosteroid.3, 4 However, the long-acting beta2 agonist–inhaled corticosteroid was superior for improving lung function.3  Growth is reduced in children treated with higher-dose inhaled corticosteroid, compared with those taking same dose plus a long-acting beta2 agonist.3 

Adolescents may benefit more from combination inhaled corticosteroid/long-acting beta2 agonist treatment than children under 12 years. In adolescents with persistent asthma that is not controlled by a low dose of inhaled corticosteroids, the combination of a long-acting beta2 agonist and an inhaled corticosteroid is modestly more effective in reducing the risk of flare-ups requiring oral corticosteroids than a higher dose of inhaled corticosteroids.70

Adding montelukast versus adding a long-acting beta-2 agonist or increasing inhaled corticosteroid dose

Children aged 1–5 years

In one study in children aged 5 years or less with persistent asthma/wheeze requiring preventer treatment, raised blood eosinophil levels and atopy predicted better short-term response to high-dose inhaled corticosteroid than to montelukast.29 However, routine eosinophil counts are currently not recommended to guide treatment in children.

In children aged 1–5 years with asthma/wheeze that is not adequately controlled by low-dose inhaled corticosteroid alone, adding montelukast is preferable to increasing the dose of inhaled corticosteroids when the safety profiles of these options are compared.71 Long-acting beta2 agonists are not recommended for this age group.

  • Montelukast use has been associated with behavioural and/or neuropsychiatric adverse effects.

Note: Montelukast is TGA-approved for children aged 2 years and over.

Children aged 6 years and over

Among children 6 years and over with asthma that is not controlled by low-dose inhaled corticosteroids, the optimal regimen varies between individuals.6 In one study of children selected for high adherence with maintenance treatment, short-term responses varied between individuals: in some children the best response was achieved by adding a long-acting beta2 agonist, in others by adding montelukast, and in others by increasing the dose of inhaled corticosteroid.6

Note: The use of inhaled corticosteroids and long-acting beta2 agonists in separate inhalers is not recommended for either children or adults because of the potential for increased risk due to selective non-adherence to the inhaled corticosteroid.8

Overall, the addition of montelukast to an inhaled corticosteroid does not reduce the need for rescue oral corticosteroids or hospital admission, compared with the same or an increased dose of inhaled corticosteroids, in children aged 6 years and over or adolescents with mild-to-moderate asthma.72

For children aged 6–14 years with persistent asthma and exercise-induced bronchoconstriction, adding montelukast is more effective in protecting against exercise-induced bronchoconstriction than switching to a combination of inhaled corticosteroid and a long-acting beta2 agonist.73 The use of montelukast also avoids beta-receptor tolerance associated with long-acting beta2 agonists, so a short-acting beta2 agonist taken after exercise produces a greater bronchodilator response than it does in children taking regular long-acting beta2 agonist.73

A treatment trial of montelukast for 4–6 weeks is the best option when effects on exercise-induced symptoms and safety are also considered.71

  • Montelukast use has been associated with behavioural and/or neuropsychiatric adverse effects.

See: Investigation and management of exercise-induced bronchoconstriction

 

Genetic influence on effect of long-acting beta2 agonists

Clinical response to long-acting beta2 agonists partly depends on genetics. A beta2receptor genotype  (Arg16 polymorphism in the beta2 receptor gene) pre-disposes children with asthma to down-regulation of the beta2 receptor and increased susceptibility to flare-ups during regular treatment with regular long-acting beta2agonists.74 However, routine genetic testing to tailor asthma therapy is not yet available in clinical practice.

Last reviewed version 2.0

Close
Inhaled corticosteroid/long-acting beta-2 agonist combinations for children aged 4–11 years

The combination of salmeterol plus fluticasone propionate in a single inhaler is TGA-registered for use in children 4 years and older.

Efficacy

A very large (n=6208) randomised controlled trial in children aged 4–11 years reported that, unlike in adults, the combination of inhaled corticosteroid and long-acting beta2 agonist was not associated with a significant reduction in severe flare-ups, compared with inhaled corticosteroid alone.2 Combination treatment was not associated with an increase in in symptom-free days or a reduction in reliever use, compared with inhaled corticosteroid alone.2

Safety

Clinical response to long-acting beta2 agonists partly depends on genetics. A beta2receptor genotype (Arg16 polymorphism in the beta2 receptor gene) pre-disposes children with asthma to down-regulation of the beta2 receptor and increased susceptibility to flare-ups during regular treatment with regular long-acting beta2agonists.28 [REPLACE THIS REF] However, routine genetic testing to tailor asthma therapy is not yet available in clinical practice.

Earlier systematic reviews and meta-analyses led to concern about the possibility that the use of long-acting beta-agonists (even in combination with inhaled corticosteroids) might even increase the risk of flare-ups that require treatment with oral steroids or hospital admission, or of severe flare-ups.1,71, 75 A meta-analysis commissioned by the US Food and Drug Administration found that the use of long-acting beta2 agonists was associated with increased risk of severe asthma-associated adverse events (both overall and among the subset of people using concomitant inhaled corticosteroid and long-acting beta2 agonist), and that this risk was greatest in children aged 4–11 years.75 However, the increased risk was only seen in studies where inhaled corticosteroid was not provided, or where inhaled corticosteroid and long-acting beta2 agonist were not combined in a single inhaler (i.e. where there was the possibility of selective non-adherence to the inhaled corticosteroid).

The PBAC Post-market review of medicines used to treat asthma in children11 concluded that there was insufficient evidence to ascertain whether tolerance to long-acting beta2 agonist could explain why it is less effective than montelukast and inhaled corticosteroids in managing exercise-induced asthma symptoms.11

A very large randomised controlled trial of children aged 4–11 years, stratified by asthma symptom control and pre-study treatment, found no increased risk of serious adverse outcomes with combination fluticasone propionate and salmeterol in a single inhaler, compared with fluticasone propionate alone.2 Subsequent to the publication of this and similar studies in adults,[CHECK THIS REF] regulators in the USA and Australia removed previous ‘black box’ warnings from combination inhaled corticosteroid–long-acting beta2 agonist products for asthma.[CHECK THIS REF]

PBS status as at March 2019: All formulations that contain a combination of inhaled corticosteroid plus long-acting beta2 agonist are listed as ‘Authority  required - streamlined’. Patient using these combinations for asthma must have previously had frequent episodes of asthma while receiving treatment with oral corticosteroids or optimal doses of inhaled corticosteroids.

Last reviewed version 2.0

Close

References

  1. van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: https://www.thoracic.org.au/journal-publishing/command/download_file/id/25/filename/The_role_of_corticosteroids_in_the_management_of_childhood_asthma_-_2010.pdf
  2. Stempel, D. A., Szefler, S. J., Pedersen, S., et al. Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med. 2016; 375: 840-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27579634
  3. Chang, T. S., Lemanske, R. F., Jr., Mauger, D. T., et al. Childhood asthma clusters and response to therapy in clinical trials. J Allergy Clin Immunol. 2014; 133: 363-9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24139497/
  4. Malka J, Mauger DT, Covar R, et al. Eczema and race as combined determinants for differential response to step-up asthma therapy. J Allergy Clin Immunol. 2014; 134: 483-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24835502
  5. Rabinovitch, N., Mauger, D. T., Reisdorph, N., et al. Predictors of asthma control and lung function responsiveness to step 3 therapy in children with uncontrolled asthma. J Allergy Clin Immunol. 2014; 133: 350-6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24084071/
  6. Lemanske RF, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010; 362: 975-985. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1001278#t=article
  7. Papadopoulos, N. G., Philip, G., Giezek, H., et al. The efficacy of montelukast during the allergy season in pediatric patients with persistent asthma and seasonal aeroallergen sensitivity. J Asthma. 2009; 46: 413-20. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19484680
  8. Carroll, W. D., Jones, P. W., Boit, P., et al. Childhood evaluation of salmeterol tolerance–a double-blind randomized controlled trial. Pediatr Allergy Immunol. 2010; 21: 336-44. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19725893
  9. Fogel, R. B., Rosario, N., Aristizabal, G., et al. Effect of montelukast or salmeterol added to inhaled fluticasone on exercise-induced bronchoconstriction in children. Ann Allergy Asthma Immunol. 2010; 104: 511-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20568384
  10. Adler, A., Uziel, Y., Mei-Zahav, M., Horowitz, I.. Formoterol induces tolerance to the bronchodilating effect of Salbutamol following methacholine-provocation test in asthmatic children. Pulm Pharmacol Ther. 2006; 19: 281-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16169761
  11. Pharmaceutical Benefits Scheme,. Post-market review. PBS medicines used to treat asthma in children. Report to PBAC. Final Report. 2017.
  12. Grzelewski, T, Stelmach, I. Exercise-induced bronchoconstriction in asthmatic children: a comparative systematic review of the available treatment options. Drugs. 2009; 69: 1533-1553. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19678711
  13. Murphy KR, Zeiger RS, Kosinski M, et al. Test for respiratory and asthma control in kids (TRACK): a caregiver-completed questionnaire for preschool-aged children. J Allergy Clin Immunol. 2009; 123: 833-9. Available from: http://www.jacionline.org/article/S0091-6749(09)00212-7/fulltext
  14. Zeiger RS, Mellon M, Chipps B, et al. Test for Respiratory and Asthma Control in Kids (TRACK): clinically meaningful changes in score. J Allergy Clin Immunol. 2011; 128: 983-8. Available from: http://www.jacionline.org/article/S0091-6749(11)01287-5/fulltext
  15. Liu AH, Zeiger R, Sorkness C, et al. Development and cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol. 2007; 119: 817-25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17353040
  16. Liu AH, Zeiger RS, Sorkness CA, et al. The Childhood Asthma Control Test: retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma. J Allergy Clin Immunol. 2010; 126: 267-73, 273.e1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20624640
  17. NSW Child Death Review Team,. NSW Child Death Review Team annual report 2016–17. NSW Ombudsman, Sydney, 2017.
  18. The Consultative Council on Obstetric and Paediatric Mortality and Morbidity,. Victoria’s mothers, babies and children 2014 and 2015. Victoria State Government Health and Human Services, Melbourne, 2017.
  19. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. 2018. Available from: https://ginasthma.org/
  20. Quezada, W., Kwak, E. S., Reibman, J., et al. Predictors of asthma exacerbation among patients with poorly controlled asthma despite inhaled corticosteroid treatment. Ann Allergy Asthma Immunol. 2016; 116: 112-7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/26712474/
  21. Stanford, R. H., Shah, M. B., D'Souza, A. O., et al. Short-acting beta-agonist use and its ability to predict future asthma-related outcomes. Ann Allergy Asthma Immunol. 2012; 109: 403-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23176877
  22. Suissa, S, Ernst, P, Benayoun, S, et al. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med. 2000; 343: 332-336.
  23. Issa-El-Khoury K, Kim H, Chan ES, et al. CSACI position statement: systemic effect of inhaled corticosteroids on adrenal suppression in the management of pediatric asthma. Allergy Asthma Clin Immunol. 2015; 11: 9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25802532/
  24. Szefler, SJ, Phillips, BR, Martinez, FD, et al. Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol. 2005; 115: 233-242. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15696076
  25. Bush A. Montelukast in paediatric asthma: where we are now and what still needs to be done? Paediatr Respir Rev. 2015; 16: 97-100. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25499571
  26. Nwokoro C, Pandya H, Turner S, et al. Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial. Lancet Respir Med. 2014; 2: 796-803. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25212745
  27. Lipworth BJ, Basu K, Donald HP, et al. Tailored second-line therapy in asthmatic children with the Arg(16) genotype. Clin Sci (Lond). 2013; 124: 521-528. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23126384
  28. Brodlie M, Gupta A, Rodriguez-Martinez CE, et al. Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children. Cochrane Database Syst Rev. 2015; Issue 10: CD008202. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26482324
  29. Bisgaard H, Zielen S, Garcia-Garcia ML, et al. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med. 2005; 171: 315-322. Available from: http://ajrccm.atsjournals.org/content/171/4/315.long
  30. Nagao M, Ikeda M, Fukuda N, et al. Early control treatment with montelukast in preschool children with asthma: a randomized controlled trial. Allergol Int. 2018; 67: 72-78. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28526210
  31. Valovirta, E., Boza, M. L., Robertson, C. F., et al. Intermittent or daily montelukast versus placebo for episodic asthma in children. Ann Allergy Asthma Immunol. 2011; 106: 518-26. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21624752
  32. Castro-Rodriguez JA, Rodriguez-Martinez CE, Ducharme FM. Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: A systematic review. Pediatr Pulmonol. 2018; Epub ahead of print 6 November. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30394700
  33. Fitzpatrick AM, Jackson DJ, Mauger DT et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol. 2016; 138: 1608-18.e12. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27777180
  34. Jartti T. Inhaled corticosteroids or montelukast as the preferred primary long-term treatment for pediatric asthma? Eur J Pediatr. 2008; 167: 731-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18214538
  35. Benard, B., Bastien, V., Vinet, B., et al. Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice. Eur Respir J. 2017; 50: . Available from: https://www.ncbi.nlm.nih.gov/pubmed/28818882
  36. Chauhan BF, Ben Salah R, Ducharme FM. Addition of anti-leukotriene agents to inhaled corticosteroids in children with persistent asthma. Cochrane Database Syst Rev. 2013; Issue 10: CD009585. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24089325
  37. Maspero, J, Guerra, F, Cuevas, F, et al. Efficacy and tolerability of salmeterol/fluticasone propionate versus montelukast in childhood asthma: a prospective, randomized, double-blind, double-dummy, parallel-group study. Clin Ther. 2008; 30: 1492-1504.
  38. Pedersen S, Maspero J, Gul N, Sharma R. Components of asthma control and treatment response of individual control criteria in children: analysis of the PEACE study. Pediatr Pulmonol. 2011; 46: 1182-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21751432
  39. Stelmach I, Ozarek-Hanc A, Zaczeniuk M et al. Do children with stable asthma benefit from addition of montelukast to inhaled corticosteroids: randomized, placebo controlled trial. Pulm Pharmacol Ther. 2015; 31: 42-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25640020
  40. Robertson CF, Price D, Henry R, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med. 2007; 175: 323-329. Available from: http://ajrccm.atsjournals.org/content/175/4/323.long
  41. Watts, K, Chavasse, R J P G. Leukotriene receptor antagonists in addition to usual care for acute asthma in adults and children. Cochrane Database Syst Rev. 2012; Issue 5: . Available from: http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD006100.pub2/full
  42. Capsomidis, A., Tighe, M.. Archimedes. Question 2. Is oral montelukast beneficial in treating acute asthma exacerbations in children?. Arch Dis Child. 2010; 95: 948-50. Available from: http://adc.bmj.com/content/95/11/948.long
  43. Schuh, S, Willan, AR, Stephens, D, et al. Can montelukast shorten prednisolone therapy in children with mild to moderate acute asthma? A randomized controlled trial. J Pediatr. 2009; 155: 795-800. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19656525
  44. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008; 122: 1127-1135. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18973936
  45. Philip G, Hustad CM, Malice MP, et al. Analysis of behavior-related adverse experiences in clinical trials of montelukast. J Allergy Clin Immunol. 2009; 124: 699-706.e8. Available from: http://www.jacionline.org/article/S0091-6749(09)01248-2/fulltext
  46. Robertson, CF, Price, D, Henry, R, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med. 2007; 175: 323-329. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17110643
  47. Harmanci, K, Bakirtas, A, Turktas, I, Degim, T. Oral montelukast treatment of preschool-aged children with acute asthma. Ann Allergy Asthma Immunol. 2006; 96: 731-735. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16729788
  48. Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008; 32: 1096-1110. Available from: http://erj.ersjournals.com/content/32/4/1096.full
  49. Cazeiro C, Silva C, Mayer S et al. Inhaled corticosteroids and respiratory infections in children with asthma: a meta-analysis. Pediatrics. 2017; 139. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28235797
  50. Yokoyama H, Yamamura Y, Ozeki T, et al. Effects of mouth washing procedures on removal of budesonide inhaled by using Turbuhaler. Yakugaku Zasshi. 2007; 127: 1245-1249. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17666876
  51. Godara N, Godara R, Khullar M. Impact of inhalation therapy on oral health. Lung India. 2011; 28: 272-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22084541
  52. Loke YK, Blanco P, Thavarajah M, Wilson AM. Impact of inhaled corticosteroids on growth in children with asthma: systematic review and meta-analysis. PloS One. 2015; 10: e0133428. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26191797
  53. Zhang L, Prietsch SO, Ducharme FM. Inhaled corticosteroids in children with persistent asthma: effects on growth. Cochrane Database Syst Rev. 2014: Cd009471. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25030198
  54. Kelly HW, Sternberg AL, Lescher R, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med. 2012; 367: 904-12. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1203229
  55. Pruteanu AI, Chauhan BF, Zhang L et al. Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth. Cochrane Database Syst Rev. 2014: Cd009878. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25030199
  56. De Leonibus C, Attanasi M, Roze Z et al. Influence of inhaled corticosteroids on pubertal growth and final height in asthmatic children. Pediatr Allergy Immunol. 2016; 27: 499-506. Available from:https://www.ncbi.nlm.nih.gov/pubmed/26919136
  57. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003; 361: 1071-1076. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12672309
  58. Pedersen S. Do inhaled corticosteroids inhibit growth in children? Am J Respir Crit Care Med. 2001; 164: 521-35. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11520710
  59. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med. 2000; 343: 1064-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11027740
  60. Garcia Garcia, ML, Wahn, U, Gilles, L, et al. Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: The MOSAIC Study. Pediatrics. 2005; 116: 360-369. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16061590
  61. Degabriele EL, Holloway KL, Pasco JA et al. Associations between asthma status and radiologically confirmed fracture in children: A data-linkage study. J Paediatr Child Health. 2018; 54(8): 855-860. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29614205
  62. Zöllner EW, Lombard CJ, Galal U, et al. Hypothalamic-adrenal-pituitary axis suppression in asthmatic school children. Pediatrics. 2012; 130: e1512-19. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23147980
  63. Hawcutt DB, Francis B, Carr DF et al. Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study. Lancet Respir Med. 2018; 6:442-450. Available from: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(18)30058-4/fulltext
  64. Ahmet A, Kim H, Spier S. Adrenal suppression: A practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy. Allergy Asthma Clin Immunol. 2011; 7: 13. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177893/
  65. Priftis, K N, Papadimitriou, A, Anthracopoulos, M B, Fretzayas, A, Chrousos, G P. Endocrine-immune interactions in adrenal function of asthmatic children on inhaled corticosteroids. Neuroimmunomodulation 2008; 16: 333-339.
  66. Macdessi JS, Randell TL, Donaghue KC, et al. Adrenal crises in children treated with high-dose inhaled corticosteroids for asthma. Med J Aust. 2003; 178: 214-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12603184
  67. Rao Bondugulapati LN, Rees DA. Inhaled corticosteroids and HPA axis suppression: how important is it and how should it be managed? Clin Endocrinol (Oxf). 2016; 85: 165-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27038017
  68. Liddell BS, Oberlin JM, Hsu DP. Inhaled corticosteroid related adrenal suppression detected by poor growth and reversed with ciclesonide. J Asthma. 2017; 54: 99-104. Available from:https://www.ncbi.nlm.nih.gov/pubmed/27284755
  69. Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database Syst Rev. 2010; Issue 5: CD005535. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005535.pub2/full
  70. van Asperen PP. Long-acting beta agonists for childhood asthma. Aust Prescr. 2012; 35: 111-3. Available from: https://www.nps.org.au/australian-prescriber/articles/long-acting-beta2-agonists-for-childhood-asthma
  71. Philip, G., Hustad, C. M., Malice, M. P., et al. Analysis of behavior-related adverse experiences in clinical trials of montelukast. J Allergy Clin Immunol. 2009; 124: 699-706. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19815116
  72. Gibson, Peter G, Chang, Anne B, Glasgow, Nicholas J, et al. CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement. Med J Aust. 2010; 192: 265-271. Available from: [Full guideline available at:](Full guideline available at:)
  73. Kew, KM; Quinn, M; Quon, B. S; Ducharme, FM;. Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children. Cochrane Database Syst Rev. 2016; Issue 6: CD007524: . Available from: https://www.ncbi.nlm.nih.gov/pubmed/27272563
  74. McMahon AW, Levenson MS, McEvoy BW, et al. Age and risks of FDA-approved long-acting β2-adrenergic receptor agonists. Pediatrics. 2011; 128: e1147-1154. Available from: http://pediatrics.aappublications.org/content/128/5/e1147.long
  75. Akashi K, Mezawa H, Tabata Y, et al. Optimal step-down approach for pediatric asthma controlled by salmeterol/fluticasone: A randomized, controlled trial (OSCAR study). Allergol Int. 2016; 65: 306-11. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27155753
  76. Rank, M. A., Branda, M. E., McWilliams, D. B., et al. Outcomes of stepping down asthma medications in a guideline-based pediatric asthma management program. Ann Allergy Asthma Immunol. 2013; 110: 354-358.e2. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23622006