Managing severe asthma in children aged 1–5 years
If asthma symptoms remain uncontrolled (persisting symptoms or flare-ups) despite maximal regular preventer treatment:
- assess adherence
- check inhaler technique
- review the diagnosis
- assess comorbidity (e.g. allergic rhinitis)
- check whether the child is exposed to environmental triggers (e.g. allergens, cigarette smoke)
- check that the dose and regimen is appropriate.
Table. Reviewing and adjusting preventer treatment for children aged 1–5 years Please view and print this figure separately: http://www.asthmahandbook.org.au/table/show/25
Figure. Stepped approach to adjusting asthma medication in children aged 1-5 years Please view and print this figure separately: http://www.asthmahandbook.org.au/figure/show/18
If good asthma control is still not achieved after eliminating common reasons for treatment failure, consider referral to a paediatric respiratory physician or paediatrician.
- How this recommendation was developed
Based on clinical experience and expert opinion (informed by evidence, where available).
Last reviewed version 2.0
- 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.
In the majority of children with persistent asthma that requires preventive treatment, control can be achieved with one of these options.4
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.5
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.6, 7 However, the long-acting beta2 agonist–inhaled corticosteroid was superior for improving lung function.6 Growth is reduced in children treated with higher-dose inhaled corticosteroid, compared with those taking same dose plus a long-acting beta2 agonist.6
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.8
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.9 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.10 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.11 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.11
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.12
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.13
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.14 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.14
A treatment trial of montelukast for 4–6 weeks is the best option when effects on exercise-induced symptoms and safety are also considered.10
- Montelukast use has been associated with behavioural and/or neuropsychiatric adverse effects.
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.15 However, routine genetic testing to tailor asthma therapy is not yet available in clinical practice.
Last reviewed version 2.0Close
- Definitions of severe and difficult-to-treat asthma
Although most people's asthma can be effectively treated with currently available medicines, a substantial subset of people have uncontrolled asthma (as indicated by persisting symptoms, low lung function and/or flare-ups) despite treatment. These patients are described as having difficult-to-treat asthma.
Some patients with difficult-to-treat asthma have severe asthma. Asthma severity is classified retrospectively according to the level of treatment needed to achieve or maintain good asthma control, rather than by the intensity or frequency of symptoms.16 International guidelines have been published for the assessment and management of patients with severe asthma.1 'Severe asthma' (also called severe refractory asthma' or 'severe treatment-resistant asthma') is defined as asthma for which good control is not achieved despite the highest level of recommended treatment, or asthma for which control can be maintained only with the highest level of recommended treatment.1 It is estimated that 5-10% of patients with asthma have severe asthma.1
Not all patients with difficult-to-treat asthma have severe asthma. 'Difficult-to-treat asthma' includes asthma that is uncontrolled due to adherence issues, inappropriate or incorrect use of medicines, environmental triggers or comorbidities. Patients whose asthma control improves rapidly with correction of such problems are not considered to have severe asthma.1
Treatment-resistant asthma or severe refractory asthma can only be diagnosed after confirming the diagnosis, confirming good adherence to high-dose inhaled corticosteroid and correct inhaler technique, excluding alternative or overlapping diagnoses, identifying and minimising exposure to preventable triggers including allergens, irritants and medicines that cause bronchoconstriction, managing comorbidities, and closely monitoring for at least 6 months.17, 1
Omalizumab is a treatment option for some adults, adolescents and children with severe asthma.
The definition of severe asthma proposed by the World Health Organization (WHO) Consultation on Severe Asthma for global use is 'uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)'.18 The WHO definition of severe asthma includes a category called 'severe untreated asthma', a term recommended only for use in countries that lack access to standard asthma medications such as inhaled corticosteroids.
Patients with severe symptoms due to untreated asthma may be found, after starting regular treatment, to have mild asthma (i.e. asthma that is easily controlled with low-dose inhaled corticosteroids).16Close
- Common reasons for poor response to preventer treatment
Apparent lack of response to asthma treatment is commonly due to one or more of the following:3
- poor adherence (which may be due to lack of perceived need for the medication, concern about potential or actual side-effects, cost of medicines, a busy lifestyle, misunderstanding of the purpose and effects of asthma medicines, or inability to follow the medical instructions)
- poor inhaler technique
- mishandling devices (e.g. failure to clean spacer, allowing mouthpiece of dry-powder inhalers to become blocked)
- incorrect dose or frequency
- empty inhaler
- expired medicines
- continued exposure to smoke or allergen triggers.
Failure to identify these causes before adjusting medicines could result in over-medication with preventers.
Last reviewed version 2.0Close
- Correct use of inhaler devices
Checking and correcting inhaler technique is essential to effective asthma management.
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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- 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.
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.29 Combination treatment was not associated with an increase in in symptom-free days or a reduction in reliever use, compared with inhaled corticosteroid alone.29
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.15, 30 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.4,10, 12 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.12 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 children31 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.31
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.29 Subsequent to the publication of this and similar studies in adults,32 regulators in the USA and Australia removed previous ‘black box’ warnings from combination inhaled corticosteroid–long-acting beta2 agonist products for asthma.33
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.
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- Specific allergen immunotherapy (desensitisation)
- Specific allergen immunotherapy should not be started unless the patient has stable asthma, including spirometry-demonstrated forced expiratory volume in 1 second (FEV1) greater than 80% predicted for subcutaneous immunotherapy and greater than 70% predicted for sublingual immunotherapy.34, 35 For patients with unstable asthma (e.g. frequent symptoms, marked variability in airflow measured by spirometry or peak flow monitor), the risks of treatment should be considered. These patients will need specialist supervision during treatment.
Options available in Australia
Two forms of specific allergen immunotherapy are available:
- sublingual immunotherapy
- subcutaneous immunotherapy.
Both forms of specific allergen immunotherapy require 3–5 years of treatment. Specific allergy immunotherapy can be repeated.
Although some specific allergen therapies can be prescribed by primary care health professionals, it is recommended that they are initiated under the care of an allergy specialist (allergist or clinical immunologist), where possible.
Commercial allergen preparations for immunotherapy are available in Australia for aeroallergens including house dust mite, pollens (e.g. grass, tree and weed pollens), animal dander and moulds.
Overview of efficacy
There is strong evidence that allergen immunotherapy is effective in the treatment of seasonal and perennial allergic rhinitis.36, 37, 38 There is less evidence supporting specific allergen immunotherapy in children than in adults.37 Specific allergen immunotherapy in children with seasonal allergic rhinoconjunctivitis might prevent development of asthma.39, 40, 41
Single-allergen specific allergen immunotherapy is effective in patients sensitised to one allergen and those sensitised to multiple allergens.42, 43, 44 In selected cases more than one allergen may be administered as separate extracts. There is weak evidence for the efficacy of allergen mixes.45
A systematic review of studies directly comparing subcutaneous immunotherapy and sublingual immunotherapy in the treatment of allergic rhinoconjunctivitis and asthma found:46
- low-grade evidence that subcutaneous immunotherapy is more effective than sublingual immunotherapy for reducing asthma symptoms and for reducing a combined measure of rhinitis symptoms and medication use
- moderate-grade evidence that subcutaneous immunotherapy is more effective than sublingual immunotherapy for reducing nasal and/or eye symptoms.
Sublingual immunotherapy (self-administered at home) is effective for the treatment of allergic rhinitis in adults and children.50, 51 The greatest benefits have been demonstrated in those with allergies to temperate grass pollens or house dust mite.51 Therapeutic Goods Administration (TGA)-approved indications for commercially available preparations vary according to age group.
The extract must be held under the tongue without swallowing for 2 minutes (liquid extracts) or 1 minute (tablets).
Sublingual immunotherapy is generally well tolerated.50 Local adverse effects are common in children receiving sublingual immunotherapy.47 Systemic adverse reactions, such as anaphylaxis, are very rare.47 The majority of adverse events occur soon after beginning treatment.51
Asthma: Acarizax (house dust mite) is indicated for adults 18–65 years with house dust mite allergic asthma that is not well controlled by inhaled corticosteroids and is associated with mild-to-severe house dust mite allergic rhinitis.52 It is contraindicated in patients with FEV1 <70% predicted after adequate treatment, and for patients who have experienced a severe flare-up within the previous 3 months.52
Allergic rhinitis: Several commercial preparations of aeroallergens for sublingual immunotherapy in patients with allergic rhinitis are used in Australia, including:
- Acarizax (house dust mite) – indicated for adults 18–65 years with persistent moderate to severe house dust mite allergic rhinitis despite symptomatic treatment.52
- Actair (house dust mite) – indicated for the treatment of house dust mite allergic rhinitis with or without conjunctivitis in adults and adolescents over 12 years diagnosed with house dust mite allergy.53
- Grazax (Timothy grass [Phleum pratense] pollen extract) – indicated for adults, adolescents and children older than 5 years with allergic rhinitis induced by Timothy grass54
- Oralair tablets (mix of grass pollens) – indicated for adults and children over 5 years with grass pollen allergic rhinitis.55
Various single allergens and/or multiple allergen mixes are available for use as advised by the treating allergist, available as liquid extracts. Age restrictions vary between products.
Note: PBS status as at October 2016: Treatment with sublingual immunotherapy specific allergen preparations is not subsidised by the PBS.
Subcutaneous immunotherapy involves injections in which the dose is gradually increased at regular intervals (usually weekly), or until a therapeutic/maintenance dose is reached. This can take approximately 3–6 months.56 Treatment is then continued for a further 3–5 years.
Subcutaneous immunotherapy is generally not suitable for younger children (e.g. less than 7 years) because they may not be able to tolerate frequent injections.
Several commercial preparations of aeroallergens for subcutaneous immunotherapy are available in Australia, including various single allergens and/or multiple allergen mixes for use as advised by the treating allergist. Age restrictions vary between products.
Subcutaneous immunotherapy is effective for the treatment of allergic rhinitis and asthma, particularly when single-allergen immunotherapy regimens are used.48 There is strong evidence that it reduces asthma symptoms, asthma medication usage, rhinitis/rhinoconjunctivitis symptoms, conjunctivitis symptoms, and rhinitis/rhinoconjunctivitis disease-specific quality of life, in comparison to placebo or usual care.48 There is also moderate evidence that subcutaneous immunotherapy reduces rhinitis/rhinoconjunctivitis medication usage.48
Subcutaneous immunotherapy is associated with local adverse effects (e.g. injection-site swelling) and, less frequently, serious systemic adverse effects.47, 51 The most common systemic reactions are respiratory symtoms. There have been few reports of anaphylaxis.47
Note: PBS status as at March 2019: Treatment with subcutaneous specific allergen immunotherapy preparations is not subsidised by the PBS.
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- Oral corticosteroids for children: adverse effects
Oral corticosteroids may have adverse psychiatric effects in children, including aggression and hyperactivity.57 Effects in the general population include euphoria, hypomania, depression, disturbances of mood, cognition, sleep and behaviour.58
A short course of oral corticosteroid therapy (less than 2 weeks) is associated with little risk of long-term suppression of the hypothalamus–pituitary–adrenal axis.4 However, risk can accumulate if frequent courses (four or more per year) are given.4
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- Bush, A, Pedersen, S, Hedlin, G, et al. Pharmacological treatment of severe, therapy-resistant asthma in children: what can we learn from where?. Eur Respir J. 2011; 38: 947-958. Available from: http://erj.ersjournals.com/content/38/4/947.long
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- 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
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- Chauhan BF, Chartrand C, Ni Chroinin M et al. Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children. Cochrane Database Syst Rev 2015; Volume 11: CD007949. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26594816
- Castro-Rodriguez, J. A., Rodrigo, G. J., Rodriguez-Martinez, C. E.. Principal findings of systematic reviews for chronic treatment in childhood asthma. J Asthma. 2015; 52: 1038-45. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26303207
- 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
- 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
- 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
- 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
- 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
- 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
- Fogel RB, 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
- 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
- Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009; 180: 59-99. Available from: http://ajrccm.atsjournals.org/content/180/1/59.long
- Bel EH, Sousa A, Fleming L, et al. Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI). Thorax. 2011; 66: 910-917. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21106547
- Bousquet J, Mantzouranis E, Cruz AA, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010; 126: 926-38. Available from: http://www.jacionline.org/article/S0091-6749(10)01126-7/fulltext
- 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
- 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
- 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
- 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
- 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
- Levy ML, Dekhuijzen PN, Barnes PJ, et al. Inhaler technique: facts and fantasies. A view from the Aerosol Drug Management Improvement Team (ADMIT). NPJ Prim Care Respir Med. 2016; 26: 16017. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27098045
- Haughney, J., Price, D., Barnes, N. C., et al. Choosing inhaler devices for people with asthma: current knowledge and outstanding research needs. Respiratory medicine. 2010; 104: 1237-45. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20472415
- Giraud, V., Roche, N.. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. The European respiratory journal. 2002; 19: 246-51. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11866004
- Harnett, C. M., Hunt, E. B., Bowen, B. R., et al. A study to assess inhaler technique and its potential impact on asthma control in patients attending an asthma clinic. J Asthma. 2014; 51: 440-5.
- Hardwell, A., Barber, V., Hargadon, T., et al. Technique training does not improve the ability of most patients to use pressurised metered-dose inhalers (pMDIs). Prim Care Respir J. 2011; 20: 92-6. Available from: http://www.nature.com/articles/pcrj201088
- 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
- Finkelstein Y, Bournissen FG, Hutson JR, Shannon M. Polymorphism of the ADRB2 gene and response to inhaled beta- agonists in children with asthma: a meta-analysis. J Asthma 2009; 46: 900-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19905915
- Pharmaceutical Benefits Scheme,. Post-market review. PBS medicines used to treat asthma in children. Report to PBAC. Final Report. 2017.
- Busse WW, Bateman ED, Caplan AL et al. Combined analysis of asthma safety trials of long-acting beta2-agonists. N Engl J Med 2018; 378: 2497-505. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29949492
- Seymour SM, Lim R, Xia C et al. Inhaled corticosteroids and LABAs - removal of the FDA's boxed warning. N Engl J Med 2018; 378: 2461-3. Available from: https://www.nejm.org/doi/10.1056/NEJMp1716858
- Ciolkowski, J., Mazurek, H., Stasiowska, B.. Evaluation of step-down therapy from an inhaled steroid to montelukast in childhood asthma. Allergol Immunopathol (Madr). 2014; 42: 282-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23684855
- 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
- Kew KM, Beggs S, Ahmad S. Stopping long-acting beta2-agonists (LABA) for children with asthma well controlled on LABA and inhaled corticosteroids. Cochrane Database Syst Rev. 2015; Issue 5: CD011316. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25997166
- 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
- Basheti, IA; Obeidat, NM; Reddel, HK;. Effect of novel inhaler technique reminder labels on the retention of inhaler technique skills in asthma: a single-blind randomized controlled trial.. NPJ Prim Care Respir Med. 2017; 27: 9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28184045
- Rank, M. A., Johnson, R., Branda, M., et al. Long-term outcomes after stepping down asthma controller medications: a claims-based, time-to-event analysis. Chest. 2015; 148: 630-639. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556120/
- Jacobsen, L., Niggemann, B., Dreborg, S., et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007; 62: 943-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17620073
- Pike, K. C., Akhbari, M., Kneale, D., Harris, K. M.. Interventions for autumn exacerbations of asthma in children. Cochrane Database Syst Rev. 2018; Issue 3: Cd012393. Available from: http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD012393.pub2/full
- Mann, RD; Pearce, GL; Dunn, N; Shakir, S. Sedation with "non-sedating" antihistamines: four prescription-event monitoring studies in general practice. BMJ (Clinical research ed). 2000; 320: 1184-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10784544
- Ducharme, F. M., Noya, F. J., Allen-Ramey, F. C., et al. Clinical effectiveness of inhaled corticosteroids versus montelukast in children with asthma: prescription patterns and patient adherence as key factors. Curr Med Res Opin. 2012; 28: 111-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22077107
- 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
- Fonseca-Aten, M, Okada, P J, Bowlware, K L, et al. Effect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2006; 97: 457-463.
- 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
- Brożek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 Revision. J Allergy Clin Immunol. 2010; 126: 466-476. Available from: http://www.jacionline.org/article/S0091-6749(10)01057-2/fulltext
- 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
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- 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
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- Seqirus. Product Information: Acarizax (standardised allergen extract from the house dust mites. Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/
- Stallergenes. Product Information: Actair Initiation Sublingual Tablets 100 IR & 300 IR and Actair Continuation Treatment Sublingual Tablets 300 IR (mixture of. Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/
- Seqirus. Product Information: Grazax. Therapeutic Goods Administration, Canberra, 2017. Available from: https://www.ebs.tga.gov.au
- Stallergenes. Product Information: Oralair (allergen pollen extract of five grasses). Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/
- Australasian Society of Clinical Immunology and Allergy (ASCIA). Allergen Immunotherapy. ASCIA, Sydney, 2013. Available from: http://www.allergy.org.au/patients/allergy-treatment/immunotherapy
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- Australian Medicines Handbook. Last modified July 2018: Australian Medicines Handbook Pty Ltd. 2018
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