Leukotriene receptor antagonists in the management of childhood asthma

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1 Information Paper paper for health Health professionals Professionals LTRAs for childhood asthma Leukotriene receptor antagonists in the management of childhood asthma Key points Introduction This information paper outlines the current position of leukotriene receptor antagonists (LTRAs) in the treatment of children with asthma. The leukotrienes are a family of pro-inflammatory mediators that play an important role in the pathophysiology of asthma. Leukotrienes are derived from cell membranes and released following activation of resident airway cells (mast cells) and infiltrating cells (eosinophils and neutrophils). They are involved in both early and late asthmatic airway responses to allergen challenge. Leukotrienes are potent bronchoconstrictors and also cause airway oedema, mucus secretion and recruitment of eosinophils into the airway. Leukotriene receptor antagonists bind to and inhibit specific receptors within the airway. Consider montelukast therapy: as regular preventive therapy in children with frequent intermittent asthma or mild persistent asthma in addition to inhaled corticosteroids (ICS) in children with exerciseinduced asthma that is not controlled by ICS at an optimal dose in children with seasonal allergic rhinitis. There is less evidence to support the use of montelukast as the sole preventive therapy in children with moderate-to-severe persistent asthma. These children are more likely to benefit from ICS therapy. Oral montelukast should not be relied on to manage acute asthma. 1 Montelukast is registered for use in children aged 2 years and over. Revised July 2010 This update is based on clinical literature published up to March 2010 (search strategy described in Appendix 2) Montelukast (Singulair) is the only LTRA registered in Australia for use in children aged 2 and older (see Box 1). Montelukast is an orally active, specific LTRA that protects against early- and late-phase bronchoconstriction response to allergen challenge, and against exercise-induced bronchoconstriction. Diagnostic considerations in children Asthma management in children should be based on a careful assessment of the clinical pattern. Childhood asthma is classified as infrequent intermittent, frequent intermittent, mild persistent, moderate persistent or severe persistent (Figure 1). This classification is based mainly on clinical information, but spirometry and peak expiratory flow (PEF) variability can provide useful additional information in children older than 7 years. The initial assessment should be reviewed regularly. Intermittent asthma accounts for up to 95% of childhood asthma. 2 Because episodes are usually triggered by a viral upper respiratory tract infection, the terms intermittent asthma and virus-associated wheeze or viral-induced wheeze are sometimes used synonymously in clinical literature. 3 Montelukast is currently recommended as a treatment option for children with frequent intermittent asthma or mild persistent asthma. Infants and preschoolers The diagnosis of asthma in infants and preschool children relies on clinical judgement based on a combination of symptoms and physical findings, family history, the presence of other clinical atopic disease (eczema and allergic rhinitis) and response to bronchodilators. Wheezing in infants up to 12 months old is most commonly transient and due to either acute viral bronchiolitis or to the presence of relatively small and/or floppy airways, which produces noisy breathing but no associated morbidity. Neither of these forms of infant wheeze respond to anti-asthma therapy. Cough When cough is the predominant symptom of suspected asthma in a young child, careful assessment is needed to avoid making an incorrect diagnosis of asthma, or instigating inappropriate treatment. 4 The absence of wheeze and/or shortness of breath makes asthma unlikely. Cough alone (recurrent non-specific cough) is most likely due to recurrent viral bronchitis, which is unresponsive to both bronchodilators and preventive therapy including inhaled corticosteroids (ICS). Recurrent non-specific cough usually resolves by age 6 or 7 years and leaves no residual pulmonary pathology. Exercise-induced asthma Exercise-induced symptoms are commonly reported in children with asthma, but are not always due to asthma.

2 LTRAs for childhood asthma Box 1. Registered indication and PBS listing (children) Montelukast sodium (Singulair) is registered for use in children aged 2 years and older for the prophylaxis and treatment of chronic asthma and the symptomatic treatment of seasonal allergic rhinitis. Montelukast is reimbursed by the Pharmaceutical Benefits Scheme. It is available on Streamlined Authority: as a first-line preventer medication in children aged 2 14 years with frequent intermittent asthma or mild persistent asthma as an alternative to sodium cromoglycate or nedocromil sodium (not subsidised for use in combination with other preventer medications). in the prevention of exercise-induced asthma in children aged 6 14 years as an alternative to adding salmeterol xinafoate or eformoterol fumarate, in those whose asthma is otherwise well controlled while receiving optimal-dose inhaled corticosteroid, but who require short-acting beta 2 agonist three or more times per week for prevention or relief of residual exercise-related symptoms. Figure 1. Asthma patterns in children of exercise-induced bronchoconstriction involves the release of inflammatory mediators including cysteinyl leukotrienes in response to airway dehydration during exercise. 6 Safety profile Montelukast is well tolerated. Clinical trials in children have reported montelukast adverse event rates comparable with those in placebo-treated children. 7-9 It does not appear to 10, 11 affect linear growth in pre-pubescent children. Recently, concerns have been raised about behavioural adverse effects in children taking montelukast. These appear to be rare in clinical trials. 12, 13 Since the introduction of montelukast in clinical practice, data from adverse event reports suggest that the use of montelukast in children is associated with a slight increase in the risk of psychiatric disorders, 14 but a clear causal link has not been established due to potentially confounding effects including concomitant medication and the severity of underlying asthma. Cessation of therapy appears to be associated with resolution of symptoms. 14 When prescribing montelukast to children, doctors should advise parents of the potential association of montelukast with behaviour-related adverse events and advise them to cease treatment if behavioural effects are suspected. Convenience An orally administered preventive treatment may be a useful alternative to other treatments, particularly for very young patients who have difficulty using inhalers reliably. Preference for a once-daily oral agent over a multiple-dose inhaled agent is likely to improve adherence. 15 Box 2. Background: viral-induced wheeze Typical patterns of deterioration in symptoms or fall in lung function parameters over time, relative to good asthma control (horizontal lines). Rationale for leukotriene antagonism in childhood asthma The use of LTRAs as preventer therapy in children with asthma is supported by evidence suggesting that persistent elevation of cysteinyl leukotrienes in the serum and urine of children with asthma indicates the presence of an ongoing inflammatory process, which contributes to bronchial hyperresponsiveness. 5 In children with asthma triggered by viral infections (see Box 2), the use of LTRAs as a strategy to reduce airway reactivity is based on the observation that cysteinyl leukotrienes are released in the airway during respiratory syncytial virus infection and are thought to contribute to inflammation. In children with asthma symptoms in response to exercise, the use of LTRAs is based on evidence that the pathophysiology Preventing episodes of viral-induced wheeze or infrequent intermittent asthma has proven to be very difficult. Regular low-dose ICS does not reduce episode frequency or severity in children with episodic viral-induced wheeze. 1 Parents of preschool-aged children with viral-induced wheeze are commonly advised to begin giving their child a short course of oral prednisolone at the onset of an exacerbation. However, current evidence suggests this is not an effective strategy for recurrent viral-induced wheeze, 16 and does not reduce the risk of hospital admission in preschoolers. 17 In school-aged children, a short course of oral prednisolone initiated by parents when their child experiences an episode of acute asthma (triggered by any cause) may reduce asthma symptoms and lost school days, but the benefits need to be balanced against potential adverse effects of repeated corticosteroid courses. 18 Standard current treatment for acute episodes is inhaled short-acting beta 2 agonist bronchodilators. Oral corticosteroids (in addition) remain the treatment of choice in severe acute asthma managed in hospital emergency departments, and are more effective than high-dose ICS in this context. 19 2

3 LTRAs for childhood asthma Dosing and administration Montelukast is administered once daily as a 4 mg (ages 2 5) or 5 mg (ages 6 14) chewable tablet, with or without food. The onset of therapeutic effects occurs within 1 day of commencing treatment. 7 A study that examined the effect of montelukast at 2 and 12 hours in children with mild exerciseinduced asthma found that maximal effect occurs 12 hours after dosing. 20 Studies in children with exercise-induced bronchoconstriction have demonstrated that equal protection against exerciseinduced asthma is achieved when montelukast is taken at night or in the morning. 21 Clinical evidence in children Evidence for the efficacy of montelukast in children with each clinical pattern of asthma is summarised in Appendix 1. Persistent asthma Children with mild persistent asthma should receive regular preventive therapy with LTRAs or low-dose ICS. Regular treatment with an ICS is recommended in children with moderate-to-severe persistent asthma. Large placebo-controlled trials of montelukast once daily in preschoolers and in school-aged children with persistent asthma have demonstrated efficacy on clinical outcomes including increase in proportion of asthma-free days, reduction in daytime and night-time asthma symptoms, and reduction in requirement for short-acting beta 2 agonists and oral corticosteroids. 8, 9 In children old enough to perform spirometry reliably, placebo-controlled trials have also demonstrated efficacy on lung function variables. 9 The onset of action of montelukast is rapid and sustained, with benefits observed within the first day of treatment. 8 Montelukast has been shown to improve lung function, night-time wakening and quality of life in children with relatively mild asthma. 22 In placebo-controlled studies that included children with moderately severe asthma, montelukast did not reduce exacerbation rates or improve parent-reported measures in pre-schoolers 8 or reduce night-time wakening due to asthma, symptoms scores or school absences in school-aged children. 9 Based on data from placebo-controlled trials, it has not been possible to define clinical indicators that predict which children will benefit most from montelukast therapy. 23 In children taking ICS, responses to different add-on therapies differ between individuals. 24 In children with mild persistent asthma, montelukast may be an alternative to low-dose ICS for improving clinically relevant measures of asthma control such as short-acting beta 2 agonist requirement, 11 emergency care visits and hospitalisation rates. 25 However, ICS are more effective than montelukast on a range of outcome measures including lung function measures. 11 In comparative studies that included children with moderate persistent asthma, ICS were superior to montelukast on clinical, lung function and quality-of-life outcome measures Key findings from clinical trials There is substantial evidence that montelukast is an effective preventer therapy, compared with placebo, in children with persistent asthma. Comparative studies suggest that the main role for montelukast is as an alternative to low-dose ICS in children with mild persistent asthma or frequent intermittent asthma. There is good evidence to support the use of montelukast in children to protect against exerciseinduced bronchoconstriction. There is good evidence to support the use of montelukast to manage seasonal allergic rhinitis in children. In children with intermittent asthma or viral-induced wheeze, montelukast may help protect against asthma exacerbations associated with respiratory infections, when given either as continual therapy or as short courses in response to the onset of respiratory tract infections. Intermittent asthma Children with infrequent intermittent asthma require treatment only during episodes. A short course of montelukast, introduced at the first signs of an asthma episode or upper respiratory tract infection, may reduce symptoms. Children with frequent intermittent asthma may benefit from regular preventive therapy with LTRAs or low-dose ICS. Children with frequent intermittent asthma commonly require preventive treatment only during the winter months. Continuous montelukast once daily may reduce exacerbation rates and ICS requirement in pre-school children with intermittent asthma who have a history of recurrent exacerbations associated with respiratory infections. 30 In children with asthma exacerbations associated with respiratory viral infections, the addition of montelukast to usual therapy (including regular ICS for some children) during a predicted season of frequent asthma exacerbations, reduced the duration of asthma symptoms and unplanned visits to doctors. 31 A short course of montelukast, introduced at the first signs of an asthma episode or upper respiratory tract infection, can achieve a small reduction in symptoms, school absence and medical consultations in preschool and school-aged children with intermittent asthma. 3 No comparative studies in children have directly compared the effects of LTRAs, commenced at the onset of exacerbations, with short courses of high-dose ICS. However, a trial comparing low-dose ICS, montelukast and placebo in preschool children with moderate-to-severe intermittent wheezing demonstrated that both ICS and montelukast reduced the severity of symptoms, compared with placebo, but did not reduce the number of event-free days or oral corticosteroid use. 32 3

4 Leukotrine Receptor Antagonists LTRAs for childhood asthma Montelukast does not replace oral prednisolone in stabilising asthma after acute episodes requiring emergency department visits. 33 Exercise-induced asthma Montelukast is an alternative to pre-exercise short-acting beta 2 agonists for exercise-induced asthma prophylaxis. Treatment with LTRAs lessens, but does not completely prevent, the post-exercise fall in FEV 1 that is characteristic of exercise-induced asthma. Like cromones, they enable a more rapid recovery in lung function. 34 Continuous montelukast treatment is effective in reducing exercise-induced bronchoconstriction and fall in lung function in children. 35 Evidence in an adult population suggests that single-dose montelukast can also be effective when taken the night before or at least 2 hours before exercise. 36 Evidence from double-blind, placebo-controlled clinical trials in children with exercise-induced asthma taking ICS suggests that montelukast is more effective than either eformoterol 37 or salmeterol 38 in protecting against exercise-induced bronchoconstriction. Montelukast is an alternative to pre-exercise short-acting beta 2 agonist reliever. Frequent use of relievers before exercise should be avoided due to potential receptor tolerance, which may compromise the therapeutic effect when they are required to relieve exercise-related symptoms. 39 Long-term montelukast use is not associated with tachyphylaxis, unlike short-acting and long-acting beta 2 agonists. 38, 39 No attenuation of the bronchoprotective effect was seen after 4 weeks montelukast treatment in children with asthma and exercise-induced bronchoconstriction in a small (n=32) double-blind randomised clinical trial. 40 Preventive asthma treatment in children In a child with persistent asthma, initial therapy options include low-dose ICS or montelukast (Figure 2). If adequate asthma control is not achieved after a trial period of 2 4 weeks with montelukast, it should be replaced with low-dose ICS (Table 1) and the dose titrated as necessary. If asthma control is not achieved using ICS alone, current evidence 24, suggests the options include the adding a long-acting beta 2 agonist, adding montelukast, or increasing the ICS dose. As with any asthma therapy, commence LTRAs for a trial period of 2 4 weeks then reassess whether the treatment is effective, well tolerated and necessary. Table 2 gives recommendations for commencing or ceasing LTRAs depending on the child s current asthma severity and drug regimen. Other indications Allergic rhinitis Montelukast reduces inflammation and improves nasal and ocular symptoms in children with seasonal allergic rhinitis, compared with placebo. 44, 45 Comparative studies in children with seasonal or perennial allergic rhinitis suggest its efficacy 45, 46 is comparable to that of antihistamines. Intranasal corticosteroids are the most effective pharmacotherapy for allergic rhinitis in children. They control all the major symptoms, including sneezing, itching and nasal congestion. Currently available intranasal corticosteroids Table 1. Indicative ICS dose equivalents (per day) Low High Ciclesonide* < 160 mcg 160 mcg Beclomethasone dipropionate** < 200 mcg 200 mcg Fluticasone propionate** < 200 mcg 200 mcg Budesonide** < 400 mcg 400 mcg *ex actuator dose **ex valve dose Figure 2. Approach to preventive therapy in children Initial therapy (according to severity)* Oral montelukast or Low-dose ICS If control not achieved Stop montelukast and start low-dose ICS If control not achieved Increase ICS dose If control not achieved Add a long-acting beta 2 agonist or Add montelukast or Increase ICS dose If control not achieved Increase ICS to maximal dose *ICS recommended as first-line preventer for children with moderate-to-severe asthma. preparations are only approved for use in children aged 3 years and over. Montelukast might be considered for: those with concurrent asthma those taking high-dose ICS therapy for asthma in whom it would be beneficial to avoid additional corticosteroids children aged between 2 and 3 years children who refuse or are unable to tolerate intranasal corticosteroid sprays. Non-specific cough Non-specific cough, defined as non-productive cough in the absence of identifiable respiratory disease or known aetiology, is common among children. Given that the mechanism of neurogenic chronic cough is thought to involve the leukotriene pathway, the use of LTRAs has been studied as a potential treatment. However, there are currently very limited data evaluating their efficacy in the treatment of children with non-specific cough. 47 4

5 LTRAs for childhood asthma Use in infants Montelukast is currently registered for use in children aged 2 years and older. There is also evidence that it is well tolerated in children aged under 2 years, 48 and may improve lung function, airway inflammation and symptom scores in very young children with early childhood asthma. 49 However, montelukast does not improve symptoms of acute bronchiolitis in infants. 50 Table 2. Starting and stopping LTRA treatment as sole preventer therapy Current Treatment Status Action Recommended If Poor Response Starting LTRA Frequent reliever use, no preventer therapy Start LTRA Trial for 2 4 weeks Start low-dose ICS Sodium cromoglycate or nedocromil sodium Start LTRA and cease cromone abruptly Trial for 2 4 weeks Asthma well controlled on lowest ICS dose for 3 months Start LTRA and cease ICS abruptly. Trial for 2 4 weeks Recommence ICS Stopping LTRA Good control on LTRA for 3 months or end of winter season of frequent intermittent asthma Cease LTRA Recommence LTRA or another preventer Recommendations for starting and stopping LTRA treatment in children with frequent intermittent or mild persistent asthma. Recommendations apply only to montelukast as the sole preventer therapy. For advice on adding montelukast to a regimen that includes ICS, or in the management of allergic rhinitis, refer to the manufacturer s Approved Product Information. Appendix 1. Summary of evidence from selected montelukast randomised controlled clinical trials Persistent asthma Author Design Key findings placebo-controlled trials Knorr et al., Knorr et al., Becker et al., Montelukast 4 mg once daily at bedtime for 12 weeks in pre-school children with mild-tomoderate persistent asthma (n=689) Montelukast 5 mg once daily at bedtime for 8 weeks in school children with persistent asthma (n=336) Included children with moderately severe asthma (FEV % predicted) One-third taking ICS Johnston et al., 6-week trial of montelukast during predictable annual epidemic of asthma exacerbations in children taking usual treatment (n=194) measures: percentage asthma-free days, daytime asthma symptoms, night-time asthma symptoms, days with asthma symptoms, need for SABA or oral corticosteroids, physician s global evaluation No significant difference vs placebo in exacerbations rate, caregiver s global evaluation, quality of life Benefits observed from first day No difference vs placebo in adverse event rate measures: FEV 1 improvement, SABA use, days with asthma exacerbations (21% vs 26%), quality of life No significant difference vs placebo on following outcome measures: absenteeism from school, nocturnal awakening, daytime asthma symptom score Onset of action rapid and sustained No difference vs placebo in adverse event rate In subgroup with milder asthma (FEV 1 > 75% predicted), montelukast superior to placebo on following outcome measures: FEV 1 improvement, PEF, night-time wakening, quality of life measures: reduction in days with worse asthma symptoms and reduction in unscheduled physician visits for asthma Benefit seen in both ICS and non-ics subgroups 5

6 Leukotrine Receptor Antagonists Author Design Key findings comparative trials Intermittent asthma placebo-controlled trials comparative trials Garcia Garcia et al., Exercise-induced asthma Kim et al., placebo-controlled trials Montelukast 5 mg once daily vs fluticasone 100 mcg twice daily in school children with mild persistent asthma for 12 months (n=994) Designed to demonstrate non-inferiority for primary outcome: change from baseline in % days free of rescue medications (e.g. SABA, systemic corticosteroids) Luskin et al., Montelukast vs fluticasone in school children with mild persistent asthma (n=104) 12-month prospective open label observational study Sorkness et al., Montelukast once daily vs fluticasone 100 mcg twice daily for 48 weeks in school children with mild-to-moderate persistent asthma Zeiger et al., Montelukast vs fluticasone for 16 weeks in school children with mild-to-moderate persistent asthma Ostrom et al., Montelukast 5 mg once daily vs fluticasone mcg twice daily for 12 weeks in school children (n=342) with moderate-to-severe persistent asthma (baseline FEV % predicted) Jat et al., Combination montelukast 5 mg once + budesonide 200 mcg daily vs budesonide 400 mcg/day alone in children with moderate persistent asthma Lemanske et al., Comparison of three step-up therapies in random order in children (6 17 years) with uncontrolled asthma despite 200 mcg fluticasone daily (n=182): 500 mcg fluticasone daily vs 200 mcg fluticasone mcg salmeterol daily vs 100 mcg fluticasone + montelukast Bisgaard et al., Long-term (12 months) montelukast in preschool children with intermittent asthma and a history of recurrent viral-induced exacerbations taking ICS (n=549) Robertson et al., 12-month study of parent-initiated montelukast course commenced at onset of viral infection or asthma symptoms in school children with intermittent asthma Bacharier et al., month study of comparing 7-day course of budesonide via nebuliser vs montelukast vs placebo (in addition to SABA) at onset of respiratory infections in preschool children (12 59 months) with moderate-to-severe intermittent wheezing (n=238) Montelukast taken for 8 weeks in children with exercise-induced asthma (n=64) Montelukast not inferior to ICS on primary outcome measure Fluticasone superior on following outcome measures: FEV 1, days without SABA, quality of life, systemic corticosteroid requirement, acute asthma episodes Both montelukast and fluticasone well tolerated Montelukast and fluticasone equally effective on following outcome measures: emergency visits, hospitalisation, symptoms at study completion, SABA use, oral prednisolone use Montelukast superior on adherence Fluticasone superior on following outcome measures: symptom-free days, SABA use, improvement in number of asthma control days, improvement in episode-free days, FEV, morning and evening PEF No difference for growth over 48 weeks Fluticasone superior to montelukast on following outcome measures: number of asthma control days, Asthma Control Questionnaire, SABA use, FEV 1, peak expiratory flow Fluticasone superior to montelukast on following outcome measures: FEV 1, morning and evening PEF, percentage rescue-free days, night-time symptom score, mean total symptom score, SABA use Similar efficacy on: FEV 1, asthma symptom scores Budesonide 400 mcg/day markedly superior to montelukast plus low-dose budesonide on exacerbation rate (33.3% vs 9.1%; P < 0.01) Response to step-up treatments was highly variable Probability of best response greatest with salmeterol (45%), and approximately equal for montelukast (28%) and increased dose of ICS (27%). However, FEV 1 included in the outcome measure, thus favouring the salmeterol arm. measures: exacerbation rate, ICS requirement Number of positive viral tests too low to permit correlation of reduction exacerbations with prevention of viral-induced episodes measures: reduction in symptoms, days off school, need for doctor visits Non-significant trend favouring montelukast for: specialist attendances and hospitalisations, duration of episode, SABA use, prednisolone use No difference between treatment groups on following outcome measures: proportion of episode-free days, oral corticosteroid use, health care use, quality of life, linear growth Both budesonide and montelukast reduced symptoms and interference with activity, compared with placebo Montelukast superior to placebo on protection against exercise-induced bronchoconstriction Bronchoprotective effect sustained for 8 weeks after cessation of treatment 6

7 LTRAs for childhood asthma Author Design Key findings comparative trials Stelmach et al., A 4-week comparison of four treatments: eformoterol + ICS vs montelukast + ICS vs ICS vs montelukast vs placebo in school-aged children with atopic asthma (n=100) Fogel et al., 4-week comparison of montelukast vs salmeterol in addition to ICS in school-aged children with persistent asthma and exercise-induced asthma (n=154) Montelukast + ICS and montelukast monotherapy superior to other treatments on FEV 1 reduction after exercise challenge Montelukast superior to salmeterol on following outcome measures: FEV 1 reduction, use of SABA after exercise challenge FEV 1, Forced expiratory volume in 1 second; ICS, inhaled corticosteroids; PEF, peak expiratory flow; SABA, short-acting beta 2 agonist. Appendix 2. Search strategy A. PubMed 7 April 2010 ( montelukast [Substance Name] OR montelukast [All Fields]) OR ( zafirlukast [Substance Name] OR zafirlukast [All Fields]) AND ( humans [MeSH Terms] AND Randomized Controlled Trial[ptyp] AND ( infant [MeSH Terms] OR child [MeSH Terms] OR adolescent [MeSH Terms]) Limited to published in the last 3 years B. PubMed 8 April 2010 ( montelukast [Substance Name] OR montelukast [All Fields]) AND (allergic[all Fields] AND ( rhinitis [MeSH Terms] OR rhinitis [All Fields])) AND ( humans [MeSH Terms] AND Randomized Controlled Trial[ptyp] AND ( infant [MeSH Terms] OR child [MeSH Terms] OR adolescent [MeSH Terms]) Limited to published in the last 5 years References 1. McKean M, Ducharme F. Inhaled steroids for episodic viral wheeze of childhood. Cochrane Database Syst Rev Henderson J, Knox S, Pan Y, Britt H. Changes in asthma management in Australian general practice. Prim Care Respir J 2004; 13: Robertson C, Price D, Henry R et al. 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Am J Respir Crit Care Med 2008; 178: Acknowledgements This information paper was prepared in consultation with the following health professionals: Professor Peter van Asperen, paediatric respiratory physician Professor Craig Mellis, paediatric respiratory physician Professor Colin Robertson, paediatric respiratory physician Dr Kerry Hancock, general practitioner Suggested citation: National Asthma Council Australia. Leukotriene receptor antagonists in the management of childhood asthma. Melbourne: National Asthma Council Australia, SUPPORT This information paper was supported by an unrestricted educational grant from MSD (Australia). National Asthma Council Australia retained editorial control. PUBLICATION Published by the National Asthma Council Australia Ltd. ACN Suite 104, Park Street South Melbourne Vic 3205 Australia DISCLAIMER Although all care has been taken, this information paper is a general guide only, which is not intended to be a substitute for assessment of appropriate courses of treatment on a case-by-case basis. The National Asthma Council Australia expressly disclaims all responsibility (including for negligence) for any loss, damage or personal injury resulting from reliance on the information contained herein. 2