Asthma Management Handbook

Prescribing reliever and considering regular preventer treatment for children aged 1–5 years

Recommendations

For children with recurrent wheezing, when the diagnosis of asthma is uncertain, ask parents/carers about the frequency and severity of symptoms and what seems to trigger them.

Identify:

  • whether wheezing only occurs for a few days at a time when the child has a cold, or if the child coughs or wheezes at other times (e.g. when playing actively or laughing)
  • whether there is increased work of breathing at these times (e.g. increased respiratory rate, tracheal tug, subcostal and intercostal recession, shortness of breath).

Table. Classification of preschool wheeze and indications for preventer treatment in children aged 1–5

Severity of flare-ups

Frequency of symptoms

Symptoms every 6 months or less

Symptoms every 3–4 months

Symptoms every 4–6 weeks

Symptoms at least once per week

Mild flare-ups

(managed with salbutamol in community)

Not indicated

Not indicated

Consider

Indicated

Moderate–severe flare-ups

(require ED care/oral corticosteroids)

Indicated

Indicated

Indicated

Indicated

Life-threatening flare-ups

(require hospitalisation or PICU)

Indicated

Indicated

Indicated

Indicated

PICU: paediatric intensive care unit; ED: emergency department

Indicated: Prescribe preventer and monitor as a treatment trial. Discontinue if ineffective.

Not indicated: Preventer is unlikely to be beneficial

Consider prescribing preventer according to overall risk for severe flare-ups

Symptoms: wheeze, cough or breathlessness. May be triggered by viral infection, exercise or inhaled allergens

Flare-up: increase in symptoms from usual day-to-day symptoms (ranging from worsening asthma over a few days to an acute asthma episode)

Preventer options: an inhaled corticosteroid (low dose) or montelukast

[!] Advise parents/carers about potential adverse behavioural and/or neuropsychiatric effects of montelukast

Notes:
Preventer medication is unlikely to be beneficial in a child whose symptoms do not generally respond to salbutamol

In children taking preventer, symptoms should be managed with a short-acting inhaled beta2 agonist reliever (e.g. when child shows difficulty breathing).

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How this recommendation was developed

Adapted from existing guidance

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

  • Brand et al. 20081
  • Brand et al. 20142

Last reviewed version 2.0

When the diagnosis of asthma is more certain, assess the frequency and severity of wheezing, other symptoms and flare-ups.

Table. Classification of preschool wheeze and indications for preventer treatment in children aged 1–5

Severity of flare-ups

Frequency of symptoms

Symptoms every 6 months or less

Symptoms every 3–4 months

Symptoms every 4–6 weeks

Symptoms at least once per week

Mild flare-ups

(managed with salbutamol in community)

Not indicated

Not indicated

Consider

Indicated

Moderate–severe flare-ups

(require ED care/oral corticosteroids)

Indicated

Indicated

Indicated

Indicated

Life-threatening flare-ups

(require hospitalisation or PICU)

Indicated

Indicated

Indicated

Indicated

PICU: paediatric intensive care unit; ED: emergency department

Indicated: Prescribe preventer and monitor as a treatment trial. Discontinue if ineffective.

Not indicated: Preventer is unlikely to be beneficial

Consider prescribing preventer according to overall risk for severe flare-ups

Symptoms: wheeze, cough or breathlessness. May be triggered by viral infection, exercise or inhaled allergens

Flare-up: increase in symptoms from usual day-to-day symptoms (ranging from worsening asthma over a few days to an acute asthma episode)

Preventer options: an inhaled corticosteroid (low dose) or montelukast

[!] Advise parents/carers about potential adverse behavioural and/or neuropsychiatric effects of montelukast

Notes:
Preventer medication is unlikely to be beneficial in a child whose symptoms do not generally respond to salbutamol

In children taking preventer, symptoms should be managed with a short-acting inhaled beta2 agonist reliever (e.g. when child shows difficulty breathing).

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How this recommendation was developed

Consensus

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

Last reviewed version 2.0

If the diagnosis of asthma was made in the past or elsewhere, confirm the diagnosis, if possible.

How this recommendation was developed

Consensus

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

Last reviewed version 2.0

Discuss the goals of asthma treatment with the child’s parents/carers. Explain that the overall aims of treatment are to reduce the risk of flare-ups, make sure asthma does not interfere with play or preschool attendance, and minimise the side effects of treatment by using the lowest level of medication required to maintain good asthma control.

Ask parents about their own goals for the child’s health and about their beliefs and concerns about medication.

How this recommendation was developed

Consensus

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

Last reviewed version 2.0

For all children with asthma or salbutamol-responsive preschool wheeze, prescribe a reliever suitable for the child’s age: salbutamol 2–4 puffs (100 microg per puff) as needed via pressurised metered-dose inhaler plus spacer and face mask for children aged 1–2 years or pressurised metered-dose inhaler plus spacer for children aged 3–5 years (if able to cooperate).

Educate parents/carers how and when to give reliever, and advise them to carry reliever (and spacer, if needed) at all times to use when needed to manage symptoms.

  • Reliever should be used when wheezing episodes are associated with increased work of breathing. It should not be used for cough in the absence of other symptoms. In infants, it should not be used for noisy breathing when the child shows no increased work of breathing.
How this recommendation was developed

Consensus

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

Last reviewed version 2.0

Consider regular preventer treatment according to the child’s age, frequency of symptoms, severity of flare-ups, and risk factors for severe flare-ups.

Consider regular preventer treatment for children with frequent symptoms (e.g. wheeze, cough or breathlessness at least once per week) or a history of severe flare-ups (e.g. requiring emergency department visits, intensive care or hospitalisation)

  • Regular preventer is not recommended for children younger than 12 months, except on the advice of a specialist.

Note: This assessment should be based on overall pattern of symptoms including frequency of flare-ups and symptoms between flare-ups, not on symptoms seen during a flare-up.

Table. Classification of preschool wheeze and indications for preventer treatment in children aged 1–5

Severity of flare-ups

Frequency of symptoms

Symptoms every 6 months or less

Symptoms every 3–4 months

Symptoms every 4–6 weeks

Symptoms at least once per week

Mild flare-ups

(managed with salbutamol in community)

Not indicated

Not indicated

Consider

Indicated

Moderate–severe flare-ups

(require ED care/oral corticosteroids)

Indicated

Indicated

Indicated

Indicated

Life-threatening flare-ups

(require hospitalisation or PICU)

Indicated

Indicated

Indicated

Indicated

PICU: paediatric intensive care unit; ED: emergency department

Indicated: Prescribe preventer and monitor as a treatment trial. Discontinue if ineffective.

Not indicated: Preventer is unlikely to be beneficial

Consider prescribing preventer according to overall risk for severe flare-ups

Symptoms: wheeze, cough or breathlessness. May be triggered by viral infection, exercise or inhaled allergens

Flare-up: increase in symptoms from usual day-to-day symptoms (ranging from worsening asthma over a few days to an acute asthma episode)

Preventer options: an inhaled corticosteroid (low dose) or montelukast

[!] Advise parents/carers about potential adverse behavioural and/or neuropsychiatric effects of montelukast

Notes:
Preventer medication is unlikely to be beneficial in a child whose symptoms do not generally respond to salbutamol

In children taking preventer, symptoms should be managed with a short-acting inhaled beta2 agonist reliever (e.g. when child shows difficulty breathing).

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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

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How this recommendation was developed

Adapted from existing guidance

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

  • van Asperen et al. 20103
  • Brand et al. 20142

Last reviewed version 2.0

For children aged 12 months to less than 2 years, consider a treatment trial with a low dose of inhaled corticosteroids only if any of the following apply:

  • Symptoms (wheezing, cough, breathlessness) occur at least once per week and frequently disrupt child’s sleeping or play.
  • Flare-ups are generally severe enough to require ED or oral corticosteroids.
  • The child has had a flare-up that required hospitalisation or ICU.

Table. Classification of preschool wheeze and indications for preventer treatment in children aged 1–5

Severity of flare-ups

Frequency of symptoms

Symptoms every 6 months or less

Symptoms every 3–4 months

Symptoms every 4–6 weeks

Symptoms at least once per week

Mild flare-ups

(managed with salbutamol in community)

Not indicated

Not indicated

Consider

Indicated

Moderate–severe flare-ups

(require ED care/oral corticosteroids)

Indicated

Indicated

Indicated

Indicated

Life-threatening flare-ups

(require hospitalisation or PICU)

Indicated

Indicated

Indicated

Indicated

PICU: paediatric intensive care unit; ED: emergency department

Indicated: Prescribe preventer and monitor as a treatment trial. Discontinue if ineffective.

Not indicated: Preventer is unlikely to be beneficial

Consider prescribing preventer according to overall risk for severe flare-ups

Symptoms: wheeze, cough or breathlessness. May be triggered by viral infection, exercise or inhaled allergens

Flare-up: increase in symptoms from usual day-to-day symptoms (ranging from worsening asthma over a few days to an acute asthma episode)

Preventer options: an inhaled corticosteroid (low dose) or montelukast

[!] Advise parents/carers about potential adverse behavioural and/or neuropsychiatric effects of montelukast

Notes:
Preventer medication is unlikely to be beneficial in a child whose symptoms do not generally respond to salbutamol

In children taking preventer, symptoms should be managed with a short-acting inhaled beta2 agonist reliever (e.g. when child shows difficulty breathing).

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How this recommendation was developed

Consensus

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

Last reviewed version 2.0

For children aged 2 years and older with frequent symptoms (e.g. wheeze, cough or breathlessness at least once per week) or a history of severe flare-ups (e.g. requiring emergency department visits or oral corticosteroids), consider a treatment trial of regular preventer with either of:

  • montelukast
  • an inhaled corticosteroid (low dose).
  • Advise parents/carers about potential adverse behavioural and/or neuropsychiatric effects of montelukast.

Table. Classification of preschool wheeze and indications for preventer treatment in children aged 1–5

Severity of flare-ups

Frequency of symptoms

Symptoms every 6 months or less

Symptoms every 3–4 months

Symptoms every 4–6 weeks

Symptoms at least once per week

Mild flare-ups

(managed with salbutamol in community)

Not indicated

Not indicated

Consider

Indicated

Moderate–severe flare-ups

(require ED care/oral corticosteroids)

Indicated

Indicated

Indicated

Indicated

Life-threatening flare-ups

(require hospitalisation or PICU)

Indicated

Indicated

Indicated

Indicated

PICU: paediatric intensive care unit; ED: emergency department

Indicated: Prescribe preventer and monitor as a treatment trial. Discontinue if ineffective.

Not indicated: Preventer is unlikely to be beneficial

Consider prescribing preventer according to overall risk for severe flare-ups

Symptoms: wheeze, cough or breathlessness. May be triggered by viral infection, exercise or inhaled allergens

Flare-up: increase in symptoms from usual day-to-day symptoms (ranging from worsening asthma over a few days to an acute asthma episode)

Preventer options: an inhaled corticosteroid (low dose) or montelukast

[!] Advise parents/carers about potential adverse behavioural and/or neuropsychiatric effects of montelukast

Notes:
Preventer medication is unlikely to be beneficial in a child whose symptoms do not generally respond to salbutamol

In children taking preventer, symptoms should be managed with a short-acting inhaled beta2 agonist reliever (e.g. when child shows difficulty breathing).

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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

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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):

  • Castro-Rodriguez et al. 20184
  • Fitzpatrick et al. 20165
  • Szefler et al. 20136
  • Bacharier et al. 20087
  • Kooi et al. 20088
  • Knorr et al. 20019
  • Brodlie et al. 201510

Last reviewed version 2.0

An inhaled corticosteroid should be considered as the first choice preventer for those with symptoms that are frequent (e.g. daytime or night-time symptoms at least once per week), symptoms that restrict activity or sleep), or a history of severe flare-ups (e.g. requiring treatment in the emergency department or hospital admission).

An inhaled corticosteroid could also be preferable when either of the following are present:

  • atopy
  • raised blood eosinophil count (if known; this test is  not recommended routinely).

When starting preventer for the first time for a child aged 2 years or over, the choice of agent can be guided by the following considerations.

Montelukast might be considered as alternative to an inhaled corticosteroid when any of the following apply:

  • The child is unable or refuses to use to pMDI + spacer/mask.
  • The child has significant allergic rhinitis that requires treatment.
  • Parents, despite education about risks and benefits,  decline inhaled corticosteroids or are significantly concerned about their adverse effects (poor adherence is likely in this context).

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

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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):

  • Castro-Rodriguez et al. 20184
  • Fitzpatrick et al. 20165
  • Szefler et al. 20136
  • Bacharier et al. 20087
  • Kooi et al. 20088
  • Knorr et al. 20019
  • Brodlie et al. 201510

Last reviewed version 2.0

For children aged 2 years and older with symptoms that are frequent (e.g. every day, or night-time symptoms at least once per week), symptoms that restrict activity or sleep), or a history of severe flare-ups (e.g. requiring treatment in the emergency department or hospital admission), consider an inhaled corticosteroid (low dose) as first-choice preventer.

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

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How this recommendation was developed

Adapted from existing guidance

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

  • van Asperen et al. 20103
  • Brand et al. 20142

Last reviewed version 2.0

When prescribing montelukast, start as a treatment trial. Review effects at 4–6 weeks and discontinue if no response.

How this recommendation was developed

Evidence-based recommendation

Based on literature search and formulated by multidisciplinary working group

Key evidence considered:

  • Fitzpatrick et al. 20165
  • Szefler et al. 20136
  • Bacharier et al. 20087
  • Kooi et al. 20088
  • Knorr et al. 20019
  • Brodlie et al. 201510

Last reviewed version 2.0

When prescribing montelukast, warn parents/carers that behavioural and/or neuropsychiatric  effects of montelukast are possible, but do not occur in the majority of children. Explain that if these adverse effects occur, they are typically seen within the first 2 weeks of starting regular treatment but resolve soon after discontinuing.

When dispensing montelukast in pharmacies, counsel parents/carers about behavioural and/or neuropsychiatric  effects of montelukast and provide the consumer medicines information leaflet.

How this recommendation was developed

Evidence-based recommendation

Based on literature search and formulated by multidisciplinary working group

Key evidence considered:

  • Bernard et al. 201711
  • Aldea Perona et al. 201612
  • Wallerstedt et al. 200913
  • Philip et al. 200914
  • Philip et al. 200915
  • Ali et al. 201516
  • Therapeutic Goods Administration17
  • Schumock et al. 201218

Last reviewed version 2.0

When prescribing regular inhaled corticosteroids, begin with a low dose.

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

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How this recommendation was developed

Adapted from existing guidance

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

  • van Asperen et al. 20103

Last reviewed version 2.0

More information

Short-acting beta-2 agonist relievers for children: 1–5 years

Infants under 12 months

In infants under 12 months, bronchiolitis is the most likely cause of acute respiratory distress. Bronchodilators are not recommended in children under 12 months old, consistent with current guidelines for the management of acute bronchiolitis.19

Children aged 1–5 years

Inhaled short-acting beta2 agonists are effective bronchodilators in children aged 1–5 years.1

Short-acting beta2 agonists may be less effective for wheezing in children under 2 years old than in older children.20 However, many clinical trials in infants have included those with bronchiolitis, so there is limited evidence for the effects of short-acting beta2 agonists specifically in asthma.20 Studies conducted in emergency departments have shown that short-acting beta2 agonists are more effective than placebo in controlling acute wheeze in children under 2 years, but may not achieve clinically significant improvements.20

Inhaled short-acting beta2 agonists are generally well tolerated in children aged 1–5 years.1 Adverse effects can include muscle tremor, headache, palpitations and agitation. Muscle tremor and agitation are common with initial use of standard doses, but often settle over time. Serious adverse effects such as hypokalaemia have been reported at very high doses.1

Oral short-acting beta2 agonists are associated with adverse effects1 and should not be used for the treatment of asthma in any age group.

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Administration of inhaled medicines in children: 6 years and over

Parents, carers and children need training to use inhaler devices correctly, including inhaler technique, and care and cleaning of inhalers and spacers.

School-aged children (depending on the child’s age, ability, and with individualised training) can learn to use a range of inhaler types, including manually actuated pressurised metered-dose inhalers with spacers, breath-actuated pressurised metered-dose inhalers (e.g. Autohaler), and dry-powder inhalers (e.g. Accuhaler, Turbuhaler).21, 22, 23, 24, 25

Table. Types of inhaler devices for delivering asthma and COPD medicines Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/table/show/75

A pressurised metered-dose inhaler and spacer is an appropriate first choice for most children.23

School-aged children are unlikely to use their inhaler device correctly without careful training and repeated checking.26

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Correct use of inhaler devices

Checking and correcting inhaler technique is essential to effective asthma management.

Most patients with asthma or COPD do not use their inhalers properly,27, 28,2929, 30 and most have not had their technique checked or corrected by a health professional.

Incorrect inhaler technique when using maintenance treatments increases the risk of severe flare-ups and hospitalisation for people with asthma or COPD.27, 28, 31, 32, 33, 34

Poor asthma symptom control is often due to incorrect inhaler technique.35, 36

Incorrect inhaler technique when using inhaled corticosteroids increases the risk of local side effects like dysphonia and oral thrush.

The steps for using an inhaler device correctly differ between brands. Checklists of correct steps for each inhaler type and how-to videos are available from the National Asthma Council website.

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Preparation of new spacers before first use

Spacers are made of plastic, antistatic polymer/polycarbonate polyurethane, or cardboard.

Plastic spacers (e.g. Breath-A-Tech, Volumatic)

Electrostatic surface charge on new spacers made of plastic (e.g. Breath-A-Tech, Volumatic) reduces the proportion of medicine available for delivery to the airway. This charge can be reduced by washing the plastic spacer in dishwashing liquid and allowing it to air dry or drip-dry without rinsing or wiping.1

Alternatively, priming the spacer by actuating the device several times into the spacer also overcomes the charge, but this wastes medicine. The optimal number of actuations for priming is not known and the findings of in vitro studies vary widely. One study (using older, CFC-based formulations of asthma medicines) reported that up to 40 actuations fired into a new plastic spacer overcame the effect of the electrostatic charge.37 Others have concluded that the electrostatic charge on plastic spacers does not reduce in vivo efficacy of bronchodilator therapy in children with asthma.38 The number of actuations necessary may be known when the results of recent studies become available.

When a new plastic spacer must be used immediately (e.g. for a person with asthma symptoms), patients, parents and carers should follow the manufacturer's priming instructions. In hospitals and emergency departments, a new spacer that has not been pre-treated by washing can be primed using multiple (at least 10) puffs of salbutamol. (This is an arbitrary number of actuations in the absence of evidence that would enable a precise guideline.)

Non-plastic spacers

Disposable cardboard spacers (e.g. DispozABLE, LiteAire) and polyurethane/antistatic polymer spacers (e.g. Able A2A, AeroChamber Plus, La Petite E-Chamber, La Grande E-Chamber) do not require preparation before first use.1

Note: The term 'priming' is also used for the preparation process that is necessary for new pressurised metered-dose inhalers that have not been used for more than a week. This involves first actuating the inhaler into the air (away from the patient). Users should follow the manufacturer’s instructions for the particular brand of inhaler, which specify the number of actuations required.

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Classification of symptom patterns in children

The pattern and severity of symptoms in a child with asthma or preschool wheeze is a guide to initial treatment.

Table. Classification of preschool wheeze and indications for preventer treatment in children aged 1–5

Severity of flare-ups

Frequency of symptoms

Symptoms every 6 months or less

Symptoms every 3–4 months

Symptoms every 4–6 weeks

Symptoms at least once per week

Mild flare-ups

(managed with salbutamol in community)

Not indicated

Not indicated

Consider

Indicated

Moderate–severe flare-ups

(require ED care/oral corticosteroids)

Indicated

Indicated

Indicated

Indicated

Life-threatening flare-ups

(require hospitalisation or PICU)

Indicated

Indicated

Indicated

Indicated

PICU: paediatric intensive care unit; ED: emergency department

Indicated: Prescribe preventer and monitor as a treatment trial. Discontinue if ineffective.

Not indicated: Preventer is unlikely to be beneficial

Consider prescribing preventer according to overall risk for severe flare-ups

Symptoms: wheeze, cough or breathlessness. May be triggered by viral infection, exercise or inhaled allergens

Flare-up: increase in symptoms from usual day-to-day symptoms (ranging from worsening asthma over a few days to an acute asthma episode)

Preventer options: an inhaled corticosteroid (low dose) or montelukast

[!] Advise parents/carers about potential adverse behavioural and/or neuropsychiatric effects of montelukast

Notes:
Preventer medication is unlikely to be beneficial in a child whose symptoms do not generally respond to salbutamol

In children taking preventer, symptoms should be managed with a short-acting inhaled beta2 agonist reliever (e.g. when child shows difficulty breathing).

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Table. Definitions of asthma patterns in children aged 6 years and over not taking regular preventer

Category

Pattern and intensity of symptoms (when not taking regular treatment)

Infrequent intermittent asthma †

Symptom-free for at least 6 weeks at a time (flare-ups up to once every 6 weeks on average but no symptoms between flare-ups)

Frequent intermittent asthma

Flare-ups more than once every 6 weeks on average but no symptoms between flare-ups

Persistent asthma

Mild

FEV1 ≥80% predicted and at least one of:

  • Daytime symptoms more than once per week but not every day
  • Night-time symptoms more than twice per month but not every week

Moderate

Any of:

  • FEV1 <80% predicted
  • Daytime symptoms daily
  • Night-time symptoms more than once per week
  • Symptoms sometimes restrict activity or sleep

Severe

Any of:

  • FEV1 ≤60% predicted
  • Daytime symptoms‡ continual
  • Night-time symptoms frequent
  • Flare-ups frequent
  • Symptoms frequently restrict activity or sleep

† It may not be appropriate to make the diagnosis of asthma in children aged 6 or older who wheeze only during upper respiratory tract infections. These children can be considered to have episodic (viral) wheeze.

‡ Symptoms between flare-ups. A flare-up is defined as a period of worsening asthma symptoms, from mild (e.g. symptoms that are just outside the normal range of variation for the child, documented when well) to severe (e.g. events that require urgent action by parents and health professionals to prevent a serious outcome such as hospitalisation or death from asthma).

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Table. Classification of asthma and indications for initiating preventer treatment in children aged 6–11

 

 

 

 

 

 

Severity of flare-ups

Average frequency of flare-ups and symptoms between flare-ups

Infrequent intermittent
Flare-ups every 6 weeks or less and no symptoms between flare-ups

Frequent intermittent
Flare-ups more than once every 6 weeks and no symptoms between flare-ups

Persistent
Between flare-ups (any of):

  • Daytime symptoms‡ more than once per week
  • Night-time symptoms‡ more than twice per month
  • Symptoms restrict activity or sleep

Mild flare-ups

(almost always managed with salbutamol in community)

 

Not indicated

 

Consider

 

Indicated

Moderate–severe flare-ups

(>2 in past year requiring ED or oral corticosteroids)

 

Consider

 

Indicated

 

Indicated

Life-threatening flare-ups

(require hospitalisation or PICU)

 

Indicated

 

Indicated

 

Indicated

 

Preventer should be started as a treatment trial. Assess response after 4–6 weeks and review before prescribing long term.

ED: emergency department

Indicated: Prescribe preventer and monitor as a treatment trial. At follow-up, discontinue if ineffective

Not indicated: Preventer is unlikely to be beneficial

Consider prescribing preventer according to overall risk for severe flare-ups

‡ Symptoms between flare-ups. A flare-up is defined as a period of worsening asthma symptoms, from mild (e.g. symptoms that are just outside the normal range of variation for the child, documented when well) to severe (e.g. events that require urgent action by parents/carers and health professionals to prevent a serious outcome such as hospitalisation or death from asthma).

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For children already taking regular preventer treatment, adjustments to the treatment regimen are based on finding the lowest dose of medicines that will maintain good control of symptoms.

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Wheezing phenotypes in preschool children

Longitudinal population-based cohort studies3940 of preschool children with wheezing have identified various long-term patterns (wheezing phenotypes).1

Table. Systems for retrospectively classifying the duration of childhood wheeze

Classification system/source Phenotypes identified Description
Tucson Children’s Respiratory Study † ‡ Transient wheeze

Wheezing commences before the age of 3 years and disappear by age 6 years

Persistent wheeze

Wheezing continues until up to or after age 6 years

Late-onset wheeze

Wheezing starts after age 3 years.

Avon Longitudinal Study of Parents and Children § Transient early wheeze

Wheezing mainly occurs before 18 months, then mainly disappears by age 3.5 years

Not associated with hypersensitivity to airborne allergens

Prolonged early wheeze

Wheezing occurs mainly between age 6 months and 4.5 years, then mainly disappears before child’s 6th birthday

Not associated with hypersensitivity to airborne allergens

Associated with a higher risk of airway hyperresponsiveness and reduced lung function at age 8–9 years, compared with never/infrequent wheeze phenotype

Intermediate-onset wheeze

Wheezing begins sometime after age 18 months and before 3.5 years.

Strongly associated with atopy (especially house mite, cat allergen), higher risk of airway hyperresponsiveness and reduced lung function at age 8–9 years, compared with never/infrequent wheeze phenotype

Late-onset wheeze

Wheezing mainly begins after age 3.5 years

Strongly associated with atopy (especially house mite, cat allergen, grass pollen)

Persistent wheeze

Wheezing mainly begins after 6 months and continues through to primary school

Strongly associated with atopy

Notes

Terms can only be identified after the child has stopped wheezing for several years and cannot be applied to a preschool child.

Transient wheeze, persistent wheeze and late-onset wheeze can be episodic or multiple-trigger wheeze.#

Sources

† Martinez FD, Wright AL, Taussig LM et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995; 332: 133-8. Available from: http://www.nejm.org/doi/full/10.1056/NEJM199501193320301#t=article

‡ Morgan WJ, Stern DA, Sherrill DL et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med 2005; 172: 1253-8. Available from: http://ajrccm.atsjournals.org/content/172/10/1253.long

§ Henderson J, Granell R, Heron J et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax 2008; 63: 974-80. Available from: http://thorax.bmj.com/content/63/11/974.long

# Brand PL, Baraldi E, Bisgaard H et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach [European Respiratory Society Task Force]. Eur Respir J 2008; 32: 1096-110. Available from: http://erj.ersjournals.com/content/32/4/1096.full

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Early childhood wheezing phenotypes cannot be recognised or applied clinically, because they are recognised retrospectively.1 In an individual child with episodic wheeze, it is not possible to accurately predict epidemiological phenotype from clinical phenotype.1

Currently available tools for predicting whether a wheezing preschool child will have asthma at school age (e.g. the Asthma Predictive Index41) have limited clinical value.42

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Inhaled corticosteroids for children: efficacy

Role in treatment asthma in children

The effectiveness of ICS in children appears to depend on several factors including the child’s age, which triggers are causing symptoms, wheezing phenotype, tobacco smoke exposure and genotype.43 Overall, inhaled corticosteroids seem to be more effective in older children and those with more severe disease.3

Early introduction of inhaled corticosteroid for children with recurrent wheeze does not prevent airway remodelling, improve long-term lung function or prevent the onset of persistent asthma, according to current evidence from long-term randomised controlled clinical trials in preschool children and school-aged children with intermittent or mild persistent asthma.3

Current evidence does not support planned seasonal use of inhaled corticosteroids in children not taking preventer at other times.44

Children aged 1–5 years

Intermittent wheeze/asthma

In preschool children who only have wheezing episodes with viral respiratory infections, limited available evidence suggests that regular treatment with inhaled corticosteroids does not reduce the risk of hospitalisation, flare-ups that require oral corticosteroid use, or reduce the frequency and duration of acute episodes.4345 Inhaled corticosteroid treatment does not reduce these children’s risk of developing persistent wheeze by age 6 years.1

Persistent wheeze/asthma

In preschool children who have episodes of wheezing from time to time, but also cough and wheezes at other times when they do not have a viral cold (e.g. when cries, plays or laughs), regular inhaled corticosteroids are moderately effective in controlling symptoms, though less effective than in older children.1 When wheeze improves markedly during a short treatment trial (e.g. 3 months), it is not possible to tell whether improvement was due to the treatment or spontaneous resolution of symptoms.1 However, this can be clarified by stopping inhaled corticosteroid treatment, monitoring symptoms, and re-starting.

In infants and preschoolers with persistent wheezing or asthma of at least 6 months’ duration, regular treatment with inhaled corticosteroids improves wheezing, asthma symptoms and lung function, and reduces flare-ups.346 

Children aged 6 years and over

Most clinical trials of regular inhaled corticosteroid treatment in children have been conducted among children with asthma symptoms every week or more often (‘persistent asthma’).3 

Beclometasone dipropionate, budesonide, ciclesonide and fluticasone propionate have all been shown to be effective in children. There have been relatively fewer studies of ciclesonide in children,3 but, overall, randomised clinical trials show that it is equally effective as budesonide or fluticasone propionate in improving asthma symptoms and reducing flare-ups.47 In some studies, ciclesonide was associated with less adrenal suppression or height than comparator inhaled corticosteroids.47

In a study of school-aged children with more than 2 days per week with symptoms, night waking more than twice per month due to asthma symptoms, or needing regular preventer, regular low-dose daily inhaled corticosteroid treatment reduced the rate of flare-ups that require treatment with oral corticosteroids, compared with no regular preventer treatment and as-needed short-acting beta2agonist for wheezing episodes.48

In a study of children aged 4–11 years with asthma diagnosed within the previous 2 years and symptoms more than weekly in the previous 3 months, regular preventer was associated with a reduction in serious flare-ups, school absence due to asthma, an increase in symptom-free days, and improved lung function, compared with placebo.4950

The Thoracic Society of Australia and New Zealand’s current position statement on the use of inhaled corticosteroids in children3 recommends regular treatment with inhaled corticosteroid:

  • as a first-choice preventer for children with asthma symptoms at least daily or night-time symptoms at least twice per week between flare-ups
  • as an alternative to cromones (nedocromil or sodium cromoglycate) or montelukast in children with any daytime or night-time symptoms between flare-ups, or those with flare-ups every 6 weeks or more.

Doses

In the majority of children, asthma control can be achieved with any of the following initial doses:3

  • budesonide up to 400 microg/day
  • beclometasone (Qvar) up to 200 microg/day
  • ciclesonide up to 160 microg/day
  • fluticasone propionate up to 200 microg/day.

If these doses do not achieve control of symptoms, possible explanations include alternative diagnoses, adherence, incorrect inhaler technique, psychosocial factors and exposure to tobacco smoke or other triggers such as allergens.3

Dose–response studies of inhaled corticosteroids show that the maximal efficacy is generally achieved at a dose equivalent to approximately 200 microg/day fluticasone propionate,3 while the risk of adrenal suppression increases exponentially at doses above 500 microg/day.3 Therefore (based on theoretical equivalents between different agents), upper limits of daily doses for children are:

  • budesonide 800 microg/day
  • beclometasone dipropionate [Qvar] 400 microg/day
  • ciclesonide 320 microg/day
  • fluticasone propionate 500 microg/day.

Higher doses are unlikely to be more effective, and are likely to cause systemic effects.3

Most studies of inhaled corticosteroids in children have used twice-daily dosing.3 Fluticasone propionate is only approved for twice-daily dosing, but the other inhaled corticosteroids are approved for once daily dosing. Ciclesonide is effective when given once daily.3

Note: Do not use beclometasone dose recommendations from outdated or overseas guidelines based on older formulations containing CFC propellant – doses are different.

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

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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. 1, 3, 51

Topical effects can be reduced by use of spacer devices (which reduce oropharyngeal deposition), and by mouth-rinsing and spitting after use.3 Immediate quick mouth-rinsing removes more residual medicine in the mouth than delayed rinsing.52

There is limited evidence that inhaled asthma medication can affect dental health.3, 53 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.3

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.54,55 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.55 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.55

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,54, 56, 57, 58 whereas several studies have reported that children taking inhaled corticosteroids attained normal adult height.59, 60, 61

The effect is dose-dependent57,58 and may be more likely in children who begin inhaled corticosteroid treatment before age 10.56

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

Bone density

Inhaled corticosteroids have not been associated with effects on bone density or fractures in children. 3 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

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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.70

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.71, 72, 73 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.10

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,74, 75 while others have not.76

Persistent asthma or wheezing

A systematic review comparing montelukast with inhaled corticosteroids in preschoolers with asthma or recurrent wheezing requiring daily preventer treatment4 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.4

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.5 Predictors of a better response to inhaled corticosteroids than montelukast were aeroallergen hypersensitivity and blood eosinophilia (eosinophil counts ≥ 300/μL).5 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.77, 78

However, symptoms will respond to a treatment trial of montelukast in approximately one-quarter to one-third of children,77, 79,80 and some may benefit more than from an inhaled corticosteroid.77 More severe asthma and markers of allergic inflammation may predict a better response to inhaled corticosteroids.77

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.78

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.81 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-ups81, 82 and exercise-induced asthma symptoms.82 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.73 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,77 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.8384

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.85

However, the evidence is inconsistent, with some studies showing no benefit.76,86, 87, 88, 7 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.72

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.

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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.89, 90 However, post-marketing surveillance reports have identified behavioural and/or neuropsychiatric adverse effects associated with montelukast use in some children.13

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.13, 911112

Suicidal ideation has been reported in adolescents and adults taking montelukast.12 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.93

Reported adverse effects are usually mild.11 The majority occur within 7–14 days of starting montelukast,1311 but some may appear after several months.12

Behavioural and/or neuropsychiatric adverse effects typically disappear within 4 days of stopping montelukast treatment.11 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.

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'Wheeze-detecting' devices

Some hand-held devices and smart phone applications are marketed for detecting and measuring wheeze by audio recording and analysis.

There is not enough evidence to recommend these devices and apps for use in monitoring asthma symptoms or asthma control in adults or children, or in distinguishing wheeze from other airway sounds in children.

  • Reliance on these devices could result in over- or under-treatment.

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References

  1. 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
  2. Brand PL, Caudri D, Eber E et al. Classification and pharmacological treatment of preschool wheezing: changes since 2008. Eur Respir J. 2014; 43: 1172-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24525447
  3. 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
  4. 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
  5. 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
  6. Szefler, S. J., Carlsson, L. G., Uryniak, T., Baker, J. W.. Budesonide inhalation suspension versus montelukast in children aged 2 to 4 years with mild persistent asthma. J Allergy Clin Immunol Pract. 2013; 1: 58-64. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24229823
  7. 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
  8. Kooi, EM, Schokker, S, Marike Boezen, H, et al. Fluticasone or montelukast for preschool children with asthma-like symptoms: randomized controlled trial. Pulm Pharmacol Ther. 2008; 21: 798-804. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18647656
  9. Knorr, B, Franchi, LM, Bisgaard, H, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pedriatrics. 2001; 108: E48. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11533366
  10. 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
  11. 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
  12. Aldea Perona, A., Garcia-Saiz, M., Sanz Alvarez, E.. Psychiatric disorders and montelukast in children: a disproportionality analysis of the VigiBase®. Drug Saf. 2016; 39: 69-78. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26620206
  13. Wallerstedt, S. M., Brunlof, G., Sundstrom, A., Eriksson, A. L.. Montelukast and psychiatric disorders in children. Pharmacoepidemiol Drug Saf. 2009; 18: 858-64. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19551697
  14. Philip, G, Hustad, C, Noonan, G, et al. Reports of suicidality in clinical trials of montelukast. J Allergy Clin Immunol. 2009; 124: 691-696. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19815114
  15. 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
  16. Ali, M. M., O'Brien, C. E., Cleves, M. A., Martin, B. C.. Exploring the possible association between montelukast and neuropsychiatric events among children with asthma: a matched nested case-control study. Pharmacoepidemiol Drug Saf. 2015; 24: 435-45. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25683909
  17. Therapeutic Goods Administration,. Montelukast – neuropsychiatric risks. Aust Prescr. 2013; 36: 168-171. Available from: https://www.nps.org.au/australian-prescriber/articles/medicines-safety-update-2-58#article
  18. Schumock, G T, Stayner, L T, Valuck, R J, et al. Risk of suicide attempt in asthmatic children and young adults prescribed leukotriene-modifying agents: a nested case-control study. J Allergy Clin Immunol. 2012; 130: 368-375. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22698520
  19. Paediatric Research in Emergency Departments International Collaborative. Australasian bronchiolitis guideline. PREDICT; 2016. Available from: http://www.predict.org.au/publications/2016-pubs/
  20. Chavasse RJ, Bara A, McKean MC. Short acting beta2-agonists for recurrent wheeze in children under two years of age. Cochrane Database Syst Rev. 2002; Issue 2: CD002873. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002873/full
  21. Gillette, C., Rockich-Winston, N., Kuhn, J. A., et al. Inhaler technique in children with asthma: a systematic review. Acad Pediatr. 2016; 16: 605-15. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27130811
  22. Capanoglu, M., Dibek Misirlioglu, E., Toyran, M., et al. Evaluation of inhaler technique, adherence to therapy and their effect on disease control among children with asthma using metered dose or dry powder inhalers. J Asthma. 2015; 52: 838-45. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26037396
  23. Ram, F S F, Brocklebank, D D M, White, J, et al. Pressurised metered dose inhalers versus all other hand-held inhaler devices to deliver beta-2 agonist bronchodilators for non-acute asthma. Cochrane Database Syst Rev. 2002; Issue 2: .
  24. Nikander, K, Turpeinen, M, Pelkonen, A S, et al. True adherence with the Turbuhaler in young children with asthma. Arch Dis Child. 2011; 96: 168-173.
  25. Pedersen, S., Mortensen, S.. Use of different inhalation devices in children. Lung. 1990; 168 Suppl: 653-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/2117175
  26. Sleath, B, Ayala, G X, Gillette, C, et al. Provider demonstration and assessment of child device technique during pediatric asthma visits. Pediatrics. 2011; 127: 642-648.
  27. The Inhaler Error Steering Committee,, Price, D., Bosnic-Anticevich, S., et al. Inhaler competence in asthma: common errors, barriers to use and recommended solutions. Respir Med. 2013; 107: 37-46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23098685
  28. Bjermer, L.. The importance of continuity in inhaler device choice for asthma and chronic obstructive pulmonary disease. Respiration; international review of thoracic diseases. 2014; 88: 346-52. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25195762
  29. Basheti, I A, Armour, C L, Bosnic-Anticevich, S Z, Reddel, H K. Evaluation of a novel educational strategy, including inhaler-based reminder labels, to improve asthma inhaler technique. Patient Educ Couns. 2008; 72: 26-33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18314294
  30. Bosnic-Anticevich, S. Z., Sinha, H., So, S., Reddel, H. K.. Metered-dose inhaler technique: the effect of two educational interventions delivered in community pharmacy over time. The Journal of asthma : official journal of the Association for the Care of Asthma. 2010; 47: 251-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20394511
  31. Melani AS, Bonavia M, Cilenti V, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011; 105: 930-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21367593
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