Addition of antileukotriene agents to inhaled corticosteroids in children with persistent asthma

BackgroundIn the treatment of children with mild persistent asthma, low-dose ICS are recommended as the preferred monotherapy (referred to as step 2 of therapy). In children with inadequate asthma control on low doses of ICS (step 2), asthma management guidelines recommend adding an LTRA to existing ICS as one of three therapeutic options to intensify therapy (step 3).MethodsSearch strategy: Trials were identified from the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographical databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, AMED and CINAHL, and a manual search of respiratory journals and meeting abstracts, as well as the web-site www.clinicaltrials.gov. The search was conducted until January 2013.Selection criteria: Randomized controlled trials (RCTs) that involved children and adolescents one to 18 years of age, with asthma, who remained symptomatic despite the use of a stable maintenance dose of ICS, and in whom LTRAs were added to ICS and compared with the same, an increased or a tapering dose of ICS for at least four weeks were considered for inclusion.ResultsFive paediatric (parallel group or cross-over) trials met the inclusion criteria. Two (40%) trials were considered to be at a low risk for bias. Four published trials, representing 559 children (≥6 years of age) and adolescents with mild-to-moderate asthma, contributed data to the review. No trial enrolled preschool-age children. All trials used montelukast as the LTRA, administered for between four and 16 weeks. Three trials evaluated the combination of LTRAs and ICS compared with the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (n=268 participants; RR 0.80 [95% CI 0.34 to 1.91]). There was also no statistically significant difference in percent change in forced expiratory volume in 1 s (FEV₁) in this trial, with a mean difference (MD) of 1.3 (95% CI −0.09 to 2.69); however, a significant group difference was observed in the morning and evening peak expiratory flow rates: n=218 participants; MD 9.70 L/min (95% CI 1.27 L/min to 18.13 L/min) and MD 10.70 L/min (95% CI 2.41 L/min to 18.99 L/min), respectively. One trial compared the combination of LTRAs and ICS with a higher dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over a 16-week period (n=182 participants; RR 0.82 [95% CI 0.54 to 1.25]), nor was there any significant difference in exacerbations requiring hospitalization. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding LTRAs as a means to taper the dose of ICS.ConclusionsThe addition of LTRAs to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared with the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although LTRAs have been licensed for use in children for >10 years, the paucity of paediatric trials, the absence of data regarding preschool-age children and the variability in the reporting of relevant clinical outcomes considerably limit firm conclusions. At present, there is no firm evidence to support the efficacy and safety of LTRAs as add-on therapy to ICS as a step 3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low-dose ICS.The full text of the Cochrane Review is available in The Cochrane Library (1).     

Update on leukotriene receptor antagonists in preschool children wheezing disorders

ABSTRACT: Asthma is the most common chronic disease in young children. About 40% of all preschool children regularly wheeze during common cold infections. The heterogeneity of wheezing phenotypes early in life and various anatomical and emotional factors unique to young children present significant challenges in the clinical management of this problem. Antiinflammatory therapy, mainly consisting of inhaled corticosteroids (ICS), is the cornerstone of asthma management. Since Leukotrienes (LTs) are chemical mediators of airway inflammation in asthma, the leukotriene receptor antagonists (LTRAs) are traditionally used as potent anti-inflammatory drugs in the long-term treatment of asthma in adults, adolescents, and school-age children. In particular, montelukast decreases airway inflammation, and has also a bronchoprotective effect. The main guidelines on asthma management have confirmed the clinical utility of LTRAs in children older than five years. In the present review we describe the most recent advances on the use of LTRAs in the treatment of preschool wheezing disorders. LTRAs are effective in young children with virus-induced wheeze and with multiple-trigger disease. Conflicting data do not allow to reach definitive conclusions on LTRAs efficacy in bronchiolitis or post-bronchiolitis wheeze, and in acute asthma. The excellent safety profile of montelukast and the possibility of oral administration, that entails better compliance from young children, represent the main strengths of its use in preschool children. Montelukast is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who show adverse effects related to long-term steroid therapy.     

Periodic use of inhaled steroids in children with mild persistent asthma: what are pediatricians recommending?

Although asthma treatment guidelines recommend daily inhaled corticosteroid (ICS) use for all persistent asthma, pediatricians may recommend alternative treatment plans for children with mild persistent disease. The authors administered a survey of pediatricians to describe prescribing patterns for mild persistent asthma. More than 99% of providers agreed that periodic ICS could be effective for some asthma patients. Overall, 129/251 providers (51%) reported prescribing daily ICS to most patients with mild persistent asthma, whereas 78 (31%) reported recommending periodic ICS for most such patients. Providers with patient populations > or = 25% black were significantly less likely to report prescribing daily ICS (odds ratio, 0.3; 95% confidence interval, 0.2-0.6) for mild persistent asthma. Further research is needed on the effectiveness of periodic ICS use for children with mild persistent asthma and on underlying reasons for differing provider practice patterns.     

Background severity of asthma in children discharged from the emergency department

OBJECTIVE: Attendance at an Emergency Department (ED) with an acute attack of asthma may be indicative of undertreatment of persistent disease. However, many presentations are in children with infrequent episodic asthma. The aim of this study was to characterize the pattern of asthma of children discharged from ED to determine whether there was potential to improve underlying disease control. METHODOLOGY: This was a cohort study. Three hundred and ten parental caretakers of 1 to 15-year-old children, attended and discharged from an ED with asthma, completed an asthma control questionnaire, an asthma knowledge questionnaire and a caregiver's quality of life questionnaire. Background severity of asthma was classified and medication history was assessed. Also included were those with their first attack of asthma. RESULTS: One hundred and thirty-two (43%) children had infrequent episodic asthma, 105 (34%) frequent episodic, 40 (13%) persistent asthma and 33 (11%) first attack asthma. Thirty-nine per cent of children were not receiving preventer therapy and this seemed appropriate; 14% of children with frequent episodic and persistent asthma were not receiving appropriate preventer therapy; and a further 34% had frequent symptoms despite receiving preventer therapy. CONCLUSIONS: We observed deficiencies in use of preventer medications, use of written asthma management plans and lack of parental knowledge in some children with established asthma who presented to an ED. There was also a large number of children who did not have frequent background symptoms or who presented with their first episode.     

Montelukast in pediatric asthma management

Leukotriene modifiers (receptor antagonist and biosynthesis inhibitor) represent the first mediator specific therapeutic option for asthma. Montelukast, a leukotriene receptor antagonist is the only such agent approved for use in pediatric patients. Montelukast modifies action of leukotrienes, which are the most potent bronchoconstrictors, by blocking Cysteinyl leukotriene receptors. Systemic drug like mountelukast can reach lower airways and improves the peripheral functions which play a crucial role in the evolution of asthma. Review of existing literature showed that montelukast compared to placebo has proven clinical efficacy in better control of day time asthma symptoms, percentage of symptom free days, need for rescue drugs and improvement in FEV₁. Studies also demonstrated improvement in airway inflammation as indicated by reduction in fractional exhaled nitric oxide, a marker of inflammation. Studies comparing low dose inhaled corticosteroids (ICS) with montelukast are limited in children and conclude that it is not superior to ICS. For moderate to severe persistent asthma, montelukast has been compared with long acting beta agonists (LABA) as an add-on therapy to ICS, montelukast was less efficacious and less cost-effective. It has beneficial effects in exercise induced asthma and aspirin-sensitive asthma. Montelukast has onset of action within one hour. Patient satisfaction and compliance was better with montelukast than inhaled anti-inflammatory agents due to oral, once a day administration. The recommended doses of montelukast in asthma arechildren 1–5 years: 4 mg chewable tablet, children 6–14 years: 5mg chewable tablet, adults: 10 mg tablet; administered once daily. The drug is well tolerated. Based on the presently available data montelukast may be an alternative treatment for mild persistent asthma as monotherapy where ICS cannot be administered. It is also an alternative to LABA as an add-on therapy to ICS for moderate to severe persistent asthma. The other indications for use of montelukast include: allergic rhinitis, exercise induced bronchoconstriction and aspirin-induced asthma.     

Inhaled corticosteroids or montelukast as the preferred primary long-term treatment for pediatric asthma?

According to current guidelines, inhaled corticosteroids (ICS) are the preferred primary long-term treatment for asthmatic children of all age groups, but leukotriene receptor antagonists can be considered to be an alternative treatment for mild persistent asthma. In this article, all randomized double-blind efficacy studies comparing the long-term (>4-week) treatment using a leukotriene receptor antagonist with an inhaled corticosteroid in asthmatic children were critically reviewed. In school-aged children, five reports with an adequate study design were available. All of these studies compared montelukast with inhaled fluticasone. The meta-analysis of the two main outcome measures, forced expiratory volume in 1 s (weighted mean difference, 4.6% predicted, 95% confidence interval: 3.5–5.5) and asthma control days (respectively, 5.6%, 4.3–6.9) demonstrated the superiority of fluticasone over montelukast. Many other clinical and pulmonary outcomes also consistently showed that low-dose inhaled fluticasone was more effective than montelukast in the long-term management of mild to moderate persistent asthma. A more favorable response to fluticasone over montelukast was associated with more severe disease or markers of allergic inflammation. About a quarter of patients benefited more from montelukast than fluticasone. In children under school age, no comparative studies were available. However, long-term montelukast treatment was found to be effective in placebo-controlled studies in asthmatic children aged >2 years. These findings support the present international recommendations for ICS as the preferred first-line controller therapy for mild to moderate persistent childhood asthma. If montelukast is selected as a monotherapy and asthma is not adequately controlled within 4–6 weeks, the treatment should be discontinued and the preferred medication initiated. Supported by the Academy of Finland. The author has no conflict of interest in connection with this paper. An erratum to this article can be found at     

Current management of allergic asthma in children

Asthma in children is characterized by recurring symptoms such as wheezing, breathlessness, and cough, by airflow obstruction and bronchial hyperresponsiveness, and by underlying inflammation. The presence of allergic sensitization, and allergic rhinitis in particular, is strongly associated with asthma. The goal of management of asthma is to achieve and maintain control of the clinical manifestations of the disease. This can be obtained by drug treatment, education of patients and care givers, and, in allergic asthma, by allergen avoidance and specific immunotherapy. The drugs used in asthma can be classified as controllers - such as inhaled corticosteroids (ICS) and leukotriene receptor antagonists - or relievers (bronchodilators to be used during acute exacerbations of asthma). ICS are the most effective anti-inflammatory controllers for the management of persistent asthma in children of all ages, but there is no consensus about the optimal starting dose. Dose-response studies reported marked and rapid improvement in clinical symptoms and lung function at low doses of ICS, and mild asthma is well controlled by such doses in most children, this ensuring good safety. If there is no improvement with the initial low dose of ICS, an increased ICS dose or additional therapy with leukotriene receptor antagonists or long-acting inhaled β2-agonists should be considered. When asthma is caused by allergy to aeroallergens, specific immunotherapy must be taken into account, in its two forms of subcutaneous or sublingual immunotherapy. The former has complete evidence of efficacy, but the sublingual route is safer and more easily accepted by children.     

Update on National Asthma Education and Prevention Program pediatric asthma treatment recommendations

The National Asthma Education and Prevention Program (NAEPP) published an update on selected topics from the 1997 Guidelines for the Diagnosis and Management of Asthma and provided new evidence-based recommendations for asthma treatment. Selected topics on the long-term management of asthma in children addressed the efficacy of inhaled corticosteroids (ICSs) compared with other asthma medications (i.e., as-needed beta(2)-adrenergic agonists and other controllers) in mild and moderate persistent asthma and the safety of long-term ICS use. The effects of early intervention with ICSs on asthma progression also were evaluated. An important new aspect of the treatment update entails the recommendation of ICSs as the controller medication of choice for all severities of persistent asthma in children. Additionally, on the basis of studies in adults, the Expert Panel suggested that long-acting beta(2)-adrenergic agonists are now the preferred adjunct to ICSs in children with moderate or severe persistent asthma. Based on long-term data in children, ICS therapy was deemed safe in terms of growth, bone mineral density, ocular effects, and hypothalamic pituitary adrenal axis function. Although members of the NAEPP Expert Panel determined that the effects of early intervention with ICSs on decline in lung function have not been adequately studied, they found that the effects on asthma control were substantial.     

Inhaled corticosteroid-phobia and childhood asthma: Current understanding and management implications

Asthma is the most prevalent chronic disease in children. Inhaled corticosteroids (ICS) is the first-line controller therapy for children with persistent asthma, however, suboptimal compliance to ICS therapy remains as a major obstacle in paediatric asthma management. Steroid-phobia, the fear of side-effects and subsequent aversion of ICS, has been widely reported in parents of asthmatic children. The reported prevalence of steroid-phobia varies widely from 19% to 67% in different populations. The concerns about ICS frequently raised by parents include growth suppression, weight gain, bone weakness, addiction and psychiatric disturbances. Outside of growth suppression, which is statistically significant yet mild in clinical studies, the other concerns are not evidence-based and are misconceptions. Conflicting results have been reported regarding the impact of steroid-phobia on ICS compliance. In contrast, steroid-phobia has consistent and negative effects on asthma control in children. While asthma educational programmes have demonstrable benefits in general paediatric populations, the generalisability of such programmes to steroid-phobic parents remains undetermined. There is a paucity of data on specific educational programmes to clear misconceptions and reduce steroid-phobia. Given the continually raising prevalence of paediatric asthma, high-quality studies are warranted to investigate the prevalence and impact of steroid-phobia, with an ultimate goal of developing effective strategies to tackle steroid-phobia and improve asthma care in children.     

Systemic effects of inhaled corticosteroids in children

PURPOSE OF REVIEW: Inhaled corticosteroids (ICS) are first-line therapy for persistent asthma in children. Major safety concerns about long-term ICS therapy include suppression of adrenal function, growth, and bone development. Proper interpretation of ICS safety studies requires knowledge of differences between various ICS drug/delivery device systems. RECENT FINDINGS: Dosage, type of inhaler device used, patient technique, and characteristics of the individual drug influence systemic effects of ICS. Reports of adrenal insufficiency occur but are rare and are confined to children receiving high doses of ICS. Dose-related inhibition of growth is detectable as ICS dosage increases, but appears temporary, more pronounced in childhood, and is not associated with reduction in final height. Moderate-dose ICS therapy is not associated with significant changes in measurements of bone density, but more studies of high doses and of therapy in adolescents are needed. SUMMARY: Recent studies confirm that benefits of ICS, properly prescribed and used, clearly outweigh not only their potential adverse effects but also the risks associated with poorly controlled asthma.     

槐杞黄颗粒联合吸入糖皮质激素治疗儿童支气管哮喘有效性的随机对照多中心临床研究

目的　观察槐杞黄颗粒联合吸入性糖皮质激素（ICS）对儿童支气管哮喘的疗效。方法　收集2016年9月至2017年2月国内四家医院哮喘门诊就诊的轻度持续哮喘儿童180例。按照就诊时间顺序依据DAS 3.0软件产生的各中心随机编号分为3组, A组60例（ICS+槐杞黄）、 B组60例（ICS）、 C组60例（按需ICS）。治疗前及治疗3个月后分别进行测定第1秒用力呼气容积占预测值百分比（FEV1%pred）、 呼气峰流速占预测值百分比（PEF%pred）、 呼出气一氧化氮（FeNO）调查, 并分析比较。结果　180例患儿退出21例, 实际收集有效病例159例,其中A组60例, B组58例, C组41例。A组、 B组治疗后FEV1%pred、 PEF%pred、 FeNO均较治疗前有改善（P＜0.05）, C组治疗后FEV1%pred、 PEF%pred、 FeNO与治疗前比较差异无统计学意义（P＞0.05）。治疗3个月后,A 组FEV1%pred、 PEF%pred上升及FeNO值降低更明显, 与B、 C 组比较差异有统计学意义（P＜0.05）。B组FEV1%pred、 PEF%pred 上升及FeNO值降低与C组比较差异有统计学意义（P＜0.05）。结论　轻度持续哮喘患儿需要长期规范化ICS治疗, 槐杞黄颗粒联合ICS可以更大程度改善哮喘儿童肺功能及临床症状。     

Advances in the management of childhood asthma

For children with daily asthma symptoms, the most effective preventative therapy is inhaled corticosteroids (ICS). Most children experience good symptom control on relatively low doses (<400 μg/day). If frequent symptoms persist despite treatment with ICS 400 μg/day, beneficial add-on therapies include long-acting beta-2 agonists, leukotriene receptor antagonists and slow-release theophyllines. These should be tried sequentially before the dose of ICS is increased.Non-atopic children with episodic viral-triggered wheezing are extremely unlikely to respond to regular ICS. They might best be treated with ‘when-required’ high-dose beta-2 agonists with or without oral steroids.Children with frequently recurrent or chronic non-specific coughing are unlikely to have asthma. However, a clear response of symptoms to a trial of inhaled steroids and relapse when stopping therapy remains useful in identifying those with true cough-variant asthma.It remains to be seen how effective anti-IgE antibody therapy will be.     

Inhaled corticosteroids in childhood asthma: the story continues

Inhaled corticosteroids (ICS) are the most effective anti-inflammatory drugs for the treatment of persistent asthma in children. Treatment with ICS decreases asthma mortality and morbidity, reduces symptoms, improves lung function, reduces bronchial hyperresponsiveness and reduces the number of exacerbations. The efficacy of ICS in preschool wheezing is controversial. A recent task force from the European Respiratory Society on preschool wheeze defined two different phenotypes: episodic viral wheeze, wheeze that occurs only during respiratory viral infections, and multiple-trigger wheeze, where wheeze also occurs in between viral episodes. Treatment with ICS appears to be more efficacious in the latter phenotype. Small particle ICS may offer a potential benefit in preschool children because of the favourable spray characteristics. However, the efficacy of small particle ICS in preschool children has not yet been evaluated in prospective clinical trials. The use of ICS in school children with asthma is safe with regard to systemic side effects on the hypothalamic–pituitary–adrenal axis, growth and bone metabolism, when used in low to medium doses. Although safety data in wheezing preschoolers is limited, the data are reassuring. Also for this age group, adverse events tend to be minimal when the ICS is used in appropriate doses.     

Anti-inflammatory drug therapy in asthma

Asthma is a disease with chronic inflammation of the airways and and-inflammatory treatment is a logical treatment. Inhaled corticosteroids [ICS] remain the cornerstone of anti-inflammatory therapy in recent international guidelines. Asthma cannot be cured by any medication: if the drug is discontinued, the disease manifestations return. This has been proven at all ages. In preschool children the diagnosis of asthma is difficult to establish. In this heterogeneous group ICS or leukotriene receptor antagonists [LTRA] are just as effective as placebo; in the future it will hopefully be possible to describe characteristics of responders. LTRA are an alternative in mild asthma, especially when mono-triggered viral related wheeze is present. Theophylline is effective and also has bronchodilatory properties, which need to be balanced against the relatively frequent side effects. The working mechanisms of anti-inflammatory asthma medications including ICS, LTRA, cromones, macrolides and theophylline are described.     

Six-year follow-up of an intervention to improve the management of preschool children with asthma

Aims:  In a randomized controlled study involving 60 preschool children with asthma, an intervention with extra information and support to parents in the form of group discussions was performed. An earlier follow-up after 18 months revealed an improved adherence and a reduction of exacerbation days. This is a 6-year follow-up.
Methods:  Fifty-four children performed clinical examinations, blood tests, measurements of exhaled nitric oxide, spirometry, bronchial provocation with dry air and skin prick tests. Data from the patients' records and questionnaires were obtained.
Results:  Twenty-nine per cent had no current signs of asthma, whereas 43% exhibited persistent and 28% intermittent asthma. The burden on the healthcare system was minimal. Intermittent inhaled corticosteroid (ICS) therapy was used by 81%. The intervention group (IG) had fewer contacts with nurses. Their parents had a better quality of life. Interviewing children separately contributed in identification of children needing treatment. More children in the IG had to restart ICS as they had signs of worse asthma control.
Conclusion:  Straightforward and timely support to parents of children with asthma can have long-term positive effects by strengthening the ability of parents to treat their children at home, although parents may also develop an underestimation of mild symptoms. It is important to directly ask children about their disease and to maintain regular follow-up visits.     

Asthmakontrolle

The current article presents the concept of asthma control introduced in national and international guidelines, which envisages treatment according to a step-wise plan depending on the degree of asthma control. To assess the latter, short and simple questionnaires, such as the Asthma Control Test, are available and also validated for use in children. Inhaled corticosteroids (ICS) are still considered the basis of antiinflammatory therapy. Children with poorly controlled asthma under monotherapy with safely dosed ICS may be treated concurrently with a long-acting inhaled β2-agonist. In this context, fixed combinations of active substances should be preferred for reasons of compliance, while type and quantity should be adjusted to asthma control regularly in order to avoid long-term overtreatment.     

Role of leukotriene inhibitors in the treatment of childhood asthma]

Leukotriene inhibitors are new pharmacological agents for the treatment of mild to moderate persistent asthma and exercise-induced asthma (EIA). Studies concerning their use in children remain scarce. Available data in the treatment of persistent asthma in children suggest that they could be an alternative to long-acting beta 2-agonists when asthma control cannot be obtained with inhaled steroids alone. Their main advantages are first that they are given orally once daily; second, that they do not induce tachyphylaxis to bronchoprotection against EIA, unlike long-acting beta 2-agonists. Studies specifically conducted in children are necessary to best describe their place in pediatric asthma treatment.     

Activity-induced asthma

Exercise is the most common trigger of persistent childhood asthma. The history for EIA can be complicated by the lack of perception of significant airway obstruction during exercise. One must carefully identify those children with EIA from the group of children who report low level of activity because of lack of interest or because they are out of shape. Baseline spirometry of children with persistent asthma is frequently normal. Spirometry is important to identify those children with EIA who underrecognize their disease, but normal results should not be used as evidence of absence of disease. Formal exercise testing should be considered when the diagnosis is unclear or if there seems to be a lack of bronchoprotection with inhaled albuterol. The goal of treatment of EIA should be the attainment of a normal activity level for children and adolescents. Identification of the limits imposed by EIA and establishment of goals of therapy with the child and family should be the initial action. Inactivity or reduced exertion, in the presence of this diagnosis. should not be accepted. Therapy for EIA starts with control of the underlying persistent asthma. Inhaled corticosteroids are the most effective initial treatment of both EIA and persistent asthma in children and adolescents. Exercise-induced asthma is a common aspect of a prevalent disease that warrants proper diagnosis and treatment. With appropriate therapy, children with EIA should be able to participate in sports and maintain normal activity. They should strive to compete in the same playing field as their peers and have the same goals as those children and athletes who do not have exercise-induced asthma.     

Low-dose theophylline in childhood asthma: a placebo-controlled, double-blind study

Regular anti-inflammatory treatment is essential in treating persistent asthma. Most commonly, inhaled corticosteroids (ICS) are used. However, especially in children, there is concern about the long-term safety of ICS such that doses should be kept to a minimum. The use of theophylline has decreased because of frequent side-effects in therapeutic doses. In adults, there have been reports about an immunomodulatory effect of low-dose theophylline. To study the clinical and immunomodulatory effect in children, 36 patients (mean age 12.5 SD 2.4 years) with moderate, persistent asthma on regular ICS were recruited into a placebo-controlled, double-blind study. After a 6-week run-in period, patients received either theophylline 10 mg/kg bodyweight or placebo for 12 weeks. Diary cards, lung function, peripheral blood lymphocyte subpopulations and serum eosinophil cationic protein (sECP) were assessed. In the treatment group, mean serum theophylline was 7.1 mg/l. There was no change in symptoms or use of rescue medication. Mean (SD) peak expiratory flow (PEF) increased from 86% (24) to 95% (18) predicted. sECP decreased from 43.2 μg/l (32.5) to 26.5 μg/l (16.9) (p = 0.02). Lymphocyte subpopulations did not change. The study failed to show a beneficial clinical or an immunomodulatory effect of theophylline when used in low doses. These results do not support a more important role of theophylline in the long-term treatment of moderate childhood asthma.