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Disease Summaries

Treatment of Asthma in Children 5 Years and Under, Based on Different Global Guidelines

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Posted: November 2009

Paul C. Potter, MD
Director & Head: Allergy Diagnostic & Clinical Research Unit
University of Cape Town Lung Institute, George Street, Mowbray, 7700, South Africa
Email: Paul.Potter@uct.ac.za

 

 

Introduction

Asthma guidelines have been developed during the past 15 years to increase awareness of this disease among physicians and other healthcare professionals, to improve its management, and to evaluate published reports and promote international collaboration in asthma research. This commentary focuses on the highlights of the diagnosis and treatment recommendations included in four recent "global" guidelines published between 2007 and 2009 for children 5 years and under. These guidelines include: The Practical Allergy PRACTALL guidelines1; the European Respiratory Society Task Force (ERS) paediatric asthma guidelines2; the Global Initiative for Asthma (GINA) paediatric guidelines3; and the guidelines for diagnosis and management of asthma by an Expert Panel Report of the National Asthma Education and Prevention Programme (NAEPP) of the U.S. Department of Health and Human Services4.

The first evidence-based guidelines for asthma were published under GINA in 1995. These were revised in 2006 (www.ginasthma.org). The prevalence of asthma in children ranged between 1 and 30% globally, and symptoms of asthma were defined as wheezing, breathlessness, chest tightness and coughing at night or in the morning. Risk factors, such as allergens, viral infections, exercise, and emotional and chemical irritants were identified, and guidelines were provided to diagnose and treat the disease.

While the 2006 GINA guidelines provided evidence based treatment of asthma for children over 5 years, it was felt that there was insufficient information to diagnose and manage asthma in children 5 years and under. General principles in the updated guidelines applicable to the management of asthma of all ages include the importance of a partnership for education between physicians and other healthcare professionals and the patient, and a stepwise pharmacological approach for treatment. A classification by "level of control" was proposed as being more practically relevant, bearing in mind the variability of disease. This classification was considered to be more useful than previous classifications based on "severity". In clinical practice, the "severity" of the patient's asthma changes in response to treatment. As a result, patients may present initially with severe asthma, according to a severity classification, but a good response to treatment could move them into a "moderate" or "mild" symptom category at the next visit. Thus, treatment adjustments, according to GINA guidelines, are based on the "level of control" rather than an initial severity grading.

There is an assumption in applying the 2006 GINA guidelines that the diagnosis of asthma is accurate. However, in children 5 years and younger, the diagnosis can be difficult. In some children the disease evolves from a wheezing illness to "asthma," while in other children who experience wheezing "asthma" never develops. There are also children 5 years and younger who wheeze episodically or have episodic cough and do not have asthma, but they have an alternative diagnosis such as gastroesophageal reflux, cystic fibrosis, aspiration, immune deficiency, congenital heart disease, tuberculosis or bronchopulmonary dysplasia.

The PRACTALL Guidelines

Since the updated 2006 GINA guidelines for the 5 years and younger age group were deficient in addressing the needs of children with "wheezy illnesses," pediatricians convened in Europe to prepare opinion based guidelines more applicable to young children. The PRACTALL guidelines for asthma were published under the auspices of Charite University of Berlin in 20081 by an expert team nominated by the European Academy of Allergy and Clinical Immunology (EAACI) and the American Academy of Allergy Asthma and Immunology (AAAAI).

In these guidelines, at least four patterns of wheezing were proposed. These include: "transient wheezing", in the first 2 years of life only; "non atopic wheezing," triggered by viral infections and remitting in later childhood; "persistent asthma" with atopy, eosinophilia, food allergy, a positive parental history and high indoor exposure to allergens; and "severe intermittent wheezing", with infrequent episodes with minimal morbidity between episodes but with atopic characteristics.

Risk factors identified in the PRACTALL guidelines for persistent asthma and exacerbations include: more severe symptoms in the first 2 years of life, high exposure to indoor allergens in infancy, human rhinovirus infections, passive tobacco smoke exposure, lack of exercise, excessive weight gain, psychological stress and food allergy, for children 4 years or older.

These guidelines recommend a step-up treatment for preventive pharmacological treatment for asthma in children older than 2 years of age. The treatment algorithm commences with an option of inhaled corticosteroids (ICS), beclomethasone dipropionate (BDP), 200µg equivalent or the leukotriene receptor antagonist (LTRA) montelukast, 4mg for 2-4 years and 5mg for 5 years and upwards. In this guideline the term LTRA is used, but "evidence" in each case is only provided for montelukast. If control is insufficient, the ICS can be increased to BDP, 400µg equivalent or add an ICS to montelukast. Should this step not lead to control of symptoms, the ICS can be increased to BDP 800µg equivalent or montelukast can be added to the higher dose ICS. A long acting beta2-agonist also can be added to the ICS before considering other options such as theophylline, oral corticosteroids or omalizumlab.

The European Respiratory Society (ERS) Task Force Paediatric Guideline

The ERS Task Force published a document later in 20082, using an "evidence based approach" in an attempt to improve guidelines for the management in children 5 years or less with wheezy illnesses2, 5. These guidelines stress that there is poor2, 5 agreement on the definitions of different phenotypes for preschool wheezing disorders, that patients may move from one phenotype to another, and that it is difficult to make a firm recommendation for asthma treatments in children under 5 years of age, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach3, 5.

The authors therefore propose that wheeze in young children, 5 years or less in age, should be classified as "episodic" (viral) or "multiple trigger" wheeze, which are not mutually exclusive. They also draw attention to the fact that the GINA definition of asthma requires the presence of "inflammation" of the airways, and since there is very little published data on biopsy findings of the airways in young children and infants with wheezy illnesses, that the term "asthma" should probably not be used for preschool children, especially since data concerning "underlying inflammation" is lacking.

The 2008 ERS guidelines recommend that for children 5 years or less with "multiple trigger wheeze", treatment should be initiated with a trial of an ICS, up to BDP, 400µg equivalent, or fluticasone, 200µg per day for a period of about 3 months. A systematic review of randomized double-blind placebo controlled trials of ICS in preschool children with multiple-trigger wheeze has shown significant improvements in important health outcomes including symptoms, exacerbation rates, lung function and airway hyperresponsiveness4, 6. However, marked variations in responses occur between patients. Those patients with frequent symptoms aged 2 years or older and with a family history of asthma respond best to treatment with ICS. Children aged 2 years or younger without a family history of asthma and less frequent symptoms have no significant treatment effect2, 7.

If there is a good clinical response to treatment, the ICS should be withdrawn, to confirm the need for its ongoing use and to check for spontaneous remission. The rationale behind this strategy is to avoid ICS unnecessarily for extended periods when a subject only has a short wheezy illness, since prolonged use may affect the hypophyseal-pituitary-adrenal axis (HPA). For children who have "episodic viral wheeze", these ERS guidelines note that the use of ICS in preschool children does not reduce the risk of persistent wheeze at the age of 6 years and that symptoms return when glucocorticoid therapy is discontinued. Daily use of montelukast over a one-year period in these children reduced wheezy episodes by 32% and resulted in a 30% reduction in unscheduled health visits but had no effect on hospitalisations compared with placebo.

The 2009 GINA Paediatric Guidelines

GINA published a new guideline in 2009 specifically addressing the management of asthma in children 5 years and younger www.ginasthma.org3. This comprehensive guideline deals specifically with risk factors associated with the development, diagnosis, management, and treatment (education, control, pharmacotherapy for chronic and acute exacerbations) of asthma in young children. Table 1 demonstrates the levels of control defined in the 2009 GINA guidelines3.

TABLE 1: Levels of Asthma Control in Children 5 Years and Younger*

Characteristic Controlled
(All of the following)
Partly Controlled
(Any measure present in any week)
Uncontrolled
(3 or more of features of partly controlled asthma in any week)
Daytime symptoms: wheezing, cough, difficult breathing None
(less than twice/week, typically for short periods on the order of minutes and rapidly relieved by use of a rapid acting bronchodilator)
More than twice/week
(typically for short periods on the order of minutes and rapidly relieved by use of a rapid-acting bronchodilator)
More than twice/week
(typically last minutes or hours or recur, but partially or fully relieved with rapid-acting bronchodilator)
Limitations of activities None
(child is fully active, plays and runs without limitations or symptoms)
Any
(may cough, wheeze, or have difficulty breathing during exercise, vigorous play, or laughing)
Any
(may cough, wheeze or have difficulty breathing during exercise, vigorous play, or laughing)
Nocturnal symptoms/awakening None
(including no nocturnal coughing during sleep)
Any
(typically coughs during sleep or wakes with cough, wheezing, and/or difficult breathing)
Any
(typically coughs during sleep or wakes with cough, wheezing, and/or difficult breathing)
Need for reliever/rescue treatment ≤2 days/week >2 days/week >2 days/week

The 2009 GINA guidelines rank the evidence for recommendations into four categories, A to D, in which level A is from randomized controlled trials with a rich body of data. Level B is from randomized controlled trials for which there is a limited body of data including subgroup or meta-analyses of randomized controlled trials. Level C evidence is from observational studies or non-randomized trials and Level D is evidence from a panel consensus based on clinical experience, where provision of some guidance was deemed valuable but the clinical literature addressing the subject was insufficient to justify placement in one of the other categories.

These guidelines indicate that for prevention or management of asthma there is mixed evidence for house dust mite avoidance measures. A Cochrane Analysis questions the effectiveness of house dust mite avoidance for the treatment of established asthma8, and there is no evidence that anti-house dust mite measures prevent the onset of asthma9. There is insufficient evidence to recommend for, or against a pet in the home, unless the child is sensitised to the pet10. There is increased evidence for sensitization to Alternaria11 and cockroach species12 as risk factors for severity, no evidence for protective effects of diet in pregnancy and lactation13, some evidence for tobacco avoidance as a risk factor for early wheezing and no evidence for probiotic administration to prevent asthma in this age group14. Maternal "distress" and caesarean section were identified as probable risk factors for asthma, and broad spectrum antibiotics should be used with circumspection in young children and only for recognised indications (Evidence D).

The newest GINA guidelines highlight the difficulties in differentiating a viral respiratory infection from asthma in children 5 years or younger in age. Factors which support a diagnosis of "asthma" include recurrent symptoms of wheeze/cough, especially during sleep and with exercise, laughing or crying, as well as an atopic family history and evidence of allergic sensitization. There is no role for pulmonary lung function tests in this age group except for research, and a chest x-ray is recommended only if the diagnosis is in doubt or a complication suspected.

These same guidelines also recognise the wheezy phenotypes described by the ERS2 Task Force as episodic wheeze or multiple trigger wheeze as well as the retrospective wheezy phenotypes reported by Martinez (1995): "transient wheeze", which stops before 3 years of age; "persistent wheeze", which continues after 3 years of age; and "late onset wheeze", which begins after 3 years.

Asthma may present with any of these wheezy patterns, but asthma occurs more rarely in the episodic wheeze and transient wheeze phenotypes compared to the other phenotypes3. Asthma predictive indices (APIs), referred to in the GINA guideline, have been published by Arshad15. For the 5 years and under age group, ICS remain the corner stone of treatment for asthma (Evidence A). Asthma management plans based on respiratory symptoms versus monitoring lung function are equally effective (Evidence B).

Defining "control", based on the 2006 GINA guidelines16 for older children and adults, is difficult for children 5 years or less in age, since measuring lung function is not possible. There are no validated measurements for children 4 years or less and "control of symptoms" is dependant upon parental observation. An asthma control test has been developed for children of ages 4 to 11 years17.

Characteristics and levels of control included in the 2009 GINA guidelines for children 5 years and younger are shown in Table 1. An increase in daytime cough, wheeze at night and night time use of a short-acting beta2 agonist is a strong predictor of exacerbation, with a positive predictive value of 70% and a low false positive rate of 14%6 in children of 2 to 5 years of age18.

The management of asthma in this age group is also challenging with respect to the delivery of medication. A pressured metered dose inhaler with a dedicated valved spacer and mouthpiece is preferable in children 4 to 5 years of age (Evidence A) and with a face mask in children under four years.

The dose response relationships for ICS are not adequately studied. The 2009 GINA Guidelines provide Evidence A for the efficacy of ICS in controlling asthma symptoms in the 5 years or less age group but no evidence that these medications induce a remission. Low dose ICS are safe (Evidence A). Low daily doses are defined for the 5 year or younger age group as BDP, 100 µg; budesonide MDI with spacer, 200 µg; budesonide nebulised, 500 µg; and fluticasone fuorate, 100 µg. Twice the recommended initial low dose of ICS results in near maximum benefit in most children and the dose can be decreased once control is achieved.

The GINA guidelines recognize that leukotriene receptor antagonists such as montelukast improve asthma outcomes in children 5 years and younger (Evidence A). Although this leukotriene modifier reduced viral induced asthma symptoms in children 2 to 5 years with a history of intermittent wheezing, it did not reduce hospitalization or use of an oral systemic glucocorticosteroid, such as prednisone. In the GINA guidelines "anti-leukotrienes" are referred to as "leukotriene modifiers", but the references provided for children with asthma or wheezy illnesses only refer to montelukast.

Long acting bronchodilators (Evidence D) and cromolyn (Evidence A) are not recommended for treatment, and allergen immunotherapy is not recommended for the prophylaxis or treatment of asthma in children 5 years or younger.

The asthma management approach recommended by the 2009 GINA paediatric guidelines, based on control for children 5 years and younger, stresses the importance of asthma education, environmental control, where appropriate and feasible, and the use of as needed short-acting beta2 agonists as a first step. A low dose ICS is recommended as the preferred initial treatment to control asthma in children 5 years and younger (Evidence A). The initial treatment should be given for at least 3 months to establish efficacy. Doubling the initial dose of ICS should be considered if the initial low dose does not control symptoms. The addition of a leukotriene modifier, such as montelukast, to the low dose ICS may also be considered although this has not been studied in this group (Evidence D). If partial control or no control occurs on low dose ICS,the child's inhalation technique and compliance with medication should be carefully assessed and monitored as these are common problems in this age group.

Children 5 years and younger with intermittent wheezing should be treated with a short-acting beta2 agonist every 4 to 6 hours for a day or more (Evidence A) until symptoms disappear. The 2009 GINA guidelines express uncertainty about the addition of other medications, especially when the nature of the episodes is unclear. If a detailed history suggests the diagnosis of asthma and wheezing episodes are frequent (e.g. three in a season) then regular ICS should be initiated (Evidence D).

The NHLBI Expert Panel Report

The 2007 Expert Panel Report 35 National Heart, Lung and Blood institution (NHLBI) USA Guidelines were published before the PRACTALL, ERS and GINA 2009 guidelines. These comprehensive guidelines for the diagnosis and management of asthma applicable to all age groups review a very large data base, and address complexity and broad issues relating to pathophysiology, natural history, management, education and control of environmental factors. There also is a special section on management of children, 0-4 years.

The NHLBI Expert Panel Report 3 describes the management of children 0-4 years separately from the management of children 5-11 years, providing a stepwise approach for the treatment of chronic symptoms and exacerbations for both age groups.

These guidelines stress that 50-80% of children who have asthma develop symptoms before their fifth birthday, but the disease is not often diagnosed as such. They caution about prescribing ICS to young children who may not have asthma. A therapeutic trial with asthma medications may assist to confirm the diagnosis in some cases.

Guilbert et al, 200619 found that children under 3 years of age who have more than four episodes of wheezing in the past year which affects sleep are more likely to develop persistent asthma after the age of 5, particularly if there is a parental history of asthma, evidence of food sensitisation, a greater than 4% peripheral blood eosinophilia or wheezing apart from colds. ICS should be used in these children to improve their quality-of-life.

Treatment intervention with ICS appears important in the first 3-5 years of life since most loss of lung function occurs at this time. However, although ICS control symptoms, a follow up of the Childhood Asthma Management Programme (CAMP) study indicates that a subset of participants in both treatment and placebo groups experienced progressive reductions in lung growth compared to predicted measures20. The Expert Panel Report 3 guidelines stress the importance of "reducing impairment" by decreased symptoms, maintaining normal airway function, reducing the need for short acting bronchodilators, and maintaining normal activity levels, exercise and school attendance. "Reducing risk" is an additional concept in asthma management outlined in these guidelines. The concept of "reducing risk" in these guidelines includes the "prevention of recurrent exacerbations", "preventing progressive loss of lung function", "prevention of reduced lung growth" and the prescription of pharmacotherapy with "minimal or no adverse events".

The distinction between reducing impairment and reducing risk emphasises a multifaceted approach to the treatment of childhood asthma, but aspects of risk are not yet validated in prospective clinical trials (Evidence D). Initiating long term control therapy in children 0-4 years is recommended for reducing impairment and risk of exacerbations in infants and children who have had four or more episodes of wheezing in the past year lasting more than one day, have asthma which affects their sleep and have a risk factor for asthma. These risk factors include a parental history of asthma, a physician diagnosis of atopic dermatitis or evidence of sensitisation to aeroallergens or 2 of the following: evidence of sensitization to foods, >4% peripheral eosinophilia or wheezing apart from colds (Evidence A).

Although consideration should be given to reducing risk in infants who have a second exacerbation requiring systemic corticosteroids within 6 months by prescribing daily low dose ICS, the evidence is low (Evidence Level D). The report also draws attention to the fact that since there are seasonal variations among children, such as occur in seasons when there are increased upper respiratory infections, it is possible that "some of these children may only require daily treatment during previously documented periods of increased risk of exacerbations" for that individual.

The guidelines stress that if there is a clear response to therapy for at least 3 months, a step down in therapy is recommended to a dose which maintains control. Reduction should be gradual and based on clinical judgement, since guidelines for step-down therapy are not validated. Age appropriate dietary intake of calcium and vitamin D are appropriate for children who are required to receive high-dose ICS or systemic corticosteroids. This should be reviewed with the child's parents or caregivers (Evidence D) and slit lamp examination and bone densitometry periodically obtained. Alternative treatment includes montelukast (Evidence A). Theophylline is not recommended for children 5 years and younger.

These guidelines also stress the importance of appropriate delivery devices depending on the age of the child. They recommend montelukast as an add on therapy in the 0-4 year age group and also permit the use of a long-acting beta-agonist (LABA) as add on treatment. There are no studies on the efficacy or safety of LABA as add on treatment in young children in the 0-4 year old group, and thus the stepwise addition of other medications to ICS lacks evidence-based medicine and is extrapolated from studies in older children (5-11 years) or adults. Thus, although the Expert Panel 3 Report provides very detailed treatment protocols and classifications of impairment, risk and severity for young children, validation of these guidelines is necessary and further studies are required to provide strong evidence for implementation of many of the specific management steps.

The treatment algorithms in these guidelines are detailed and more complex and comprehensive than others, making them a bit more difficult to follow in every day clinical practice. However, they do provide excellent details helpful for clinicians to consider when to make a therapeutic decision, particularly when a diagnosis of asthma is under question in the 5 year or younger age group. These guidelines also provide useful checklists for parents when children are discharged from the hospital, information on the practical use of spacers and inhalers, and a very comprehensive reference list for publications on the management of asthma.

Conclusion

In conclusion, the availability of these new guidelines has led to a better understanding of the heterogeneity of wheezy illness in the 5 year or younger age group and the availability of evidence based data for several treatment modalities. While some of the recommendations in the guidelines are evidence based, others are opinion based since published evidence is lacking for several recommendations. The decision to treat a young child with wheezy illness, in particular, with pharmacotherapy, must take into consideration the differential diagnosis of wheezing, the presence of risk factors, the evidence for efficacy and safety of prescribed therapy and the need to consistently follow the patient until the diagnosis of asthma can be confirmed.

Although there are differences in classification and treatment algorithms among the four guidelines reviewed, there is consistency for Level A evidence for the use of ICS in children 5 years and younger in whom there is good clinical evidence for asthma. Montelukast is recommended in all of the new guidelines as a possible alternative to ICS, particularly in children with a milder form of asthma, although not all children will respond to it. More studies are necessary to identify those children likely to respond to montelukast. Additional studies are also needed to provide evidence bases for the appropriate treatment of other wheezy illnesses of childhood, adjustment of therapy, and whether treatment of concurrent allergic rhinitis is beneficial in the management of asthma in young children, as illustrated in adults. Studies are also needed to assess the role for allergen immunotherapy in young children with allergen induced asthma.

Although there are differences in the approach of each of these guidelines,1,2,3,5 all contribute to a better understanding of asthma in the 5 year or younger age group and all provide useful practical information for clinicians and patients. All have identified areas for further research. Guideline implementation is a complex process influenced by the evidence-based medicine but also by the social, organizational, economic and political considerations in implementing strategies21.

It is these broader aspects which influence the prescribing of asthma medications which are partially addressed by the GRADE5 methodology for treatment recommendations now utilised by the World Health Organization for other diseases. These aspects also influence asthma management at a regional level and in some regions have necessitated the adaption of global guidelines to more applicable "regional asthma guidelines", particularly in less developed regions22.

References

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