Early intervention of recent onset mild persistent asthma in children aged under 11 yrs: the Steroid Treatment As Regular Therapy in early asthma (START) trial

Inhaled corticosteroids are known to be effective in persistent asthma, but their long-term effect in mild persistent disease of recent onset, which is particularly relevant in children, requires clarification. The objective of this study was to determine the long-term efficacy of regular inhaled low-dose budesonide in children aged <11 yrs with mild persistent asthma with onset within 2 yrs of enrollment. Children aged 5–10 yrs formed part of the population of the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study, and they were randomized in a double-blind manner to treatment with once daily budesonide 200  μ g or placebo via Turbuhaler^TM in addition to usual clinical care and other asthma medication. The double-blind treatment phase continued for 3 yrs. Of the 1974 children, 1000 in the budesonide group and 974 in the placebo group, were analyzed for efficacy. Addition of once-daily budesonide to usual care was associated with a significant increase in the time to first severe asthma-related event (SARE) and significantly reduced risk of SARE over 3 yrs. The hazard ratio relative to usual care (placebo) was 0.60 (95% confidence interval: 0.40–0.90; p = 0.012), with a relative risk reduction of 40%. Children receiving budesonide also needed significantly less intervention with other inhaled corticosteroids (12.3% vs. 22.5% over 3 yrs; p < 0.01), with trends towards decreased usage of oral/systemic corticosteroids and inhaled short-acting β ₂-agonists. Budesonide treatment also had a significant beneficial effect on lung function relative to placebo. In conclusion, early intervention adding once-daily budesonide to usual care in children with mild, persistent asthma of recent onset reduces the long-term risk and frequency of SAREs and improves lung function compared with usual care alone.     

That ICS should be first line therapy for asthma--con

Asthma is a heterogeneous disease and it is therefore unrealistic to expect that inhaled corticosteroids (ICS) would be appropriate first line preventer therapy for all children with asthma. There is good theoretical and clinical trial evidence demonstrating that leukotriene receptor antagonists (LTRAs) are more effective than ICS for viral induced wheezing and equivalent to ICS for mild persistent asthma in children. LTRAS do not have the systemic adverse effects of ICS, are generally well tolerated and their once daily oral administration enhances adherence. LTRAs should therefore be first line preventer therapy for children with frequent intermittent or mild persistent asthma while ICS should be reserved as first line treatment for children with moderate to severe persistent asthma. Given the skew in paediatric asthma severity towards the milder end, this effectively means that LTRAs should be tried first in 2 of every 3 children with asthma requiring preventer treatment.     

Corticoïdes inhalés dans l’asthme : quelle tolérance en 2009 ?

Asthmatic syndrome, better definition of asthma, is an inflammatory chronic disease, probably the most frequent in pediatrics. An important characteristic of asthma is the bronchial inflammation with a complex network of cells and inflammatory mediators of pivotal importance in the pathogenesis. The long term control and treatment of this disease are cardinal points of the management of asthmatic syndrome. Inhaled corticosteroids (ICS) are the first-line treatment for persistent asthma in children of any age. The adverse events of the inhaled steroids on growth, bone mineralization, and hypothalamic-pituitary adrenal (HPA) axis function are the main concerns for the pediatricians. The long-term effects on growth and bone mineralization are actually reassuring. Good tolerance is achieved on hypothalamic-pituitary adrenal axis function with low to moderate doses in children. Scientific and clinical researches are pointed to find out molecules able to improve clinical efficacy of ICS with better tolerance and higher reduction of adverse events.     

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.     

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.     

Preschool children with high adherence to inhaled corticosteroids for asthma do not show behavioural problems

Aim: To assess prevalence of behavioural problems in preschool children with asthma with electronically verified exposure to inhaled corticosteroids (ICS). Methods: Cross‐sectional study of 81 children 2–5 years of age using daily ICS for persistent asthma. During 3 months’ follow‐up, adherence to ICS treatment was recorded by an electronical logging device (Smartinhaler^®). Parents completed the Child Behavior Checklist 1.5–5 years (CBCL 1.5–5) to assess behavioural problems; results were compared to a published reference group of healthy children. Results: The median (interquartile range) adherence to ICS was 92 (78–97) %. There was no difference in total CBCL score between children with asthma on ICS (mean, [SD] 32.10 [1.99]) and the reference group (33.30 [1.87], 95% CI for difference ?6.62 to 4.22). Children with asthma were more likely to have somatic complaints (95% CI for difference 0.64 to 1.96) and less likely to have anxious/depressive symptoms (95% CI for difference ?1.57 to ?0.25) than the reference group. CBCL scores were not significantly related to the electronically measured adherence rates. Conclusions: Maintenance treatment with ICS, taken daily as prescribed, is not associated with an increased risk of behavioural problems in preschool children.     

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.     

Eosinophil cationic protein, myeloperoxidase and tryptase in children with asthma and atopic dermatitis

Serum levels of eosinophil cationic protein (ECP), myeloperoxidase (MPO), tryptase, total IgE and differential blood cell counts were studied in atopic children with: 1) moderate to severe asthma using inhaled steroids and symptom-free for the last 3 weeks (n= 13), 2) mild asthma with sporadic symptoms, using only inhaled β₂-agonists < 3 times/week (n= 15), 3) acute asthmatic attacks admitted to hospital (n= 12), 4) mild to moderate atopic dermatitis (n= 14). Fifteen children without any history of atopy served as controls. ECP, MPO, tryptase and IgE were measured in serum by radioimmunoassays (RIA). The symptom-free children with inhaled steroids had similar median ECP and MPO values as the controls, 8.0 and 360 μg/l, vs. 9.0 and 310 μg/l, while both ECP and MPO were significantly (p < 0.001) increased in the symptom-free children without anti-inflammatory treatment, 32 and 887 μg/l and in those with acute asthma, 28 and 860 μg/l. The children with atopic dermatitis had increased ECP but normal MPO levels, 16.0 and 455 μg/l. Tryptase in serum was not measurable in any patient. All groups except the control group had significantly elevated total IgE levels. The results indicate that in atopic children serum ECP is a good marker of ongoing asthma or atopic dermatitis. The normal levels of ECP and MPO in the children with asthma using inhaled steroids seem to reflect successful anti-inflammatory treatment. The increased levels of ECP and MPO in the children with mild asthma and no anti-inflammatory treatment may indirectly reflect airway inflammation.     

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.     

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.     

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.     

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     

Long-term safety of Mometasone Furoate administered via a dry powder inhaler in children: Results of an open-label study comparing Mometasone Furoate with Beclomethasone Dipropionate in children with persistent asthma

Background  

To assess the long-term pediatric safety of 2 doses of mometasone furoate administered via a dry powder inhaler (MF-DPI) for mild-to-moderate persistent asthma and compare them with that of beclomethasone dipropionate administered via a metered dose inhaler (BDP-MDI) in the treatment of persistent asthma. Both MF-DPI doses tested are twice the approved pediatric dosage of 100 μg once-daily (QD) for children aged 4–11 years.     

Safety of inhaled corticosteroids in children with asthma.

Inhaled corticosteroids (ICS) have become the mainstay of therapy in chronic childhood asthma. Despite the long history and the documented efficacy of these drugs in controlling asthma, concerns still abound regarding the safety of these drugs in children, most specifically related to the potential for adrenal suppression and growth retardation. Recently published studies suggest that adrenal function remains intact when low and moderate doses of these drugs are used. Long-term studies of growth in children suggest that despite an initial decrease in growth velocity, ultimate adult height is not affected significantly by the use of ICS. Other complications of glucocorticoids are not usually seen with low and moderate doses. With proper monitoring and follow-up observation, asthma control can be achieved with these drugs in a safe and effective manner.     

Reduced basal salivary cortisol in children with asthma and allergic rhinitis

Aim: Reduced basal cortisol is reported in allergic disease. We investigated if basal salivary cortisol levels were reduced in children with asthma or allergic rhinitis, controlling for inhaled corticosteroids (ICS) use. Methods: Morning and evening saliva of asthmatic children aged 7–12 years (n = 50) and that of controls (n = 52) were sampled. A total of 19 asthmatics and four controls had allergic rhinitis. Healthy children were controls without rhinitis. Of all, 14 asthmatic children used low, and 12 used moderate or high doses of ICS. Cortisol was analysed by radioimmunoassay. Results: Morning salivary cortisol median (95% CI) was lower in asthmatics (8.7 (7.1, 9.7)) compared with that in controls (10.4 (9.6, 11.8); p = 0.006), which was similar for evening cortisol levels. Regression analyses demonstrated that asthmatics using moderate or high doses of ICS had reduced morning salivary cortisol adjusted (for age and gender) odds ratio (aOR) (95% CI) (0.54 (0.37, 0.80); p = 0.002) and reduced evening cortisol aOR (0.09 (0.01, 0.6); p = 0.02) compared with that in healthy children. Asthmatics with rhinitis on no or low doses of ICS had reduced morning cortisol aOR (0.73 (0.56, 0.96); p = 0.02) compared with that in healthy children. Conclusion: Asthmatic children on moderate or high doses of inhaled corticosteroids had reduced salivary cortisol, but co‐morbidity of asthma and rhinitis was also associated with reduced cortisol levels.     

Monitoring long-term therapy with theophylline preparations in children with asthma

In 78 children (4 to 17 years of age) with moderate or severe asthma who were additionally treated with sustained-release theophylline preparations, different ways of drug monitoring were examined. Analysis of plasma and saliva theophylline was performed by means of high performance liquid chromatography. Saliva theophylline turned out to permit a reliable prediction of plasma theophylline, if an individual regression is calculated for each patient, basing on 3 simultaneously performed measurements of theophylline levels in saliva and plasma within the therapeutic range of 8 to 20 mg/l. In 25 patients theophylline levels were determined in venous and capillary blood. There was an excellent agreement (r = 0.97). Thus, a convenient monitoring of theophylline treatment in children is possible.     

达良好控制哮喘患儿停用低剂量吸入性糖皮质激素的临床随访研究

目的 通过随访达良好控制哮喘患儿停用低剂量吸入性糖皮质激素（ICS）后哮喘急性发作情况,以及实验室指标的动态变化,以期为哮喘患儿的长期控制最佳方案提供依据。方法 根据家长意愿,将63例达到良好控制的哮喘患儿分为ICS治疗组（n=35）和停药组（n=28）,进行18个月随访,每3个月进行评估,观察哮喘急性发作情况,并动态监测两组患儿肺功能和呼出气一氧化氮（FeNO）浓度,以及儿童哮喘控制测试（C-ACT）评分等指标进行分析。结果 随访第3、6、9、12个月时,FeNO在两组间比较差异无统计学意义（P > 0.05）;但在随访第15、18个月时,停药组FeNO显著高于治疗组（P < 0.05）。6次随访时点内C-ACT在两组间比较差异无统计学意义（P > 0.05）。随访第3、6、9、12个月时,第1秒用力呼气容积占预计值的百分比（FEV1%）、第1秒用力呼气量占用力肺活量比值（FEV1/FVC%）、最大呼气中期流速占预计值百分比（MMEF%）、最大呼气50%肺活量的瞬间流速（MEF50%）等指标在两组间比较差异无统计学意义（P > 0.05）;但在随访第15、18个月时,治疗组MMEF%、MEF50%显著高于停药组（P < 0.05）。治疗组随访期间有3例（9%）患儿哮喘发作,停药组有8例（29%）患儿哮喘发作,停药组哮喘复发率高于治疗组（P=0.0495）。结论 持续吸入低剂量ICS可维持哮喘患儿肺功能稳定,减少哮喘发作。     

Effects of nebulized corticosteroids therapy on hypothalamic–pituitary–adrenal axis in young children with recurrent or persistent wheeze

Inhaled corticosteroids (ICS) are preferred drugs for the long-term treatment of all severities of asthma in children. However, data about the safety of ICS in infants is lacking. So, it is essential to do further clinical studies to examine the safety and efficacy of ICS in this population. In this study, the effects of nebulized budesonide and nebulized fluticasone propionate suspensions on hypothalamic–pituitary–adrenal axis is examined in infants with recurrent or persistent wheeze. Thirty-one children aged 6–24 months admitted to our hospital between January and December 2005 with symptoms of recurrent or persistent wheeze were included in the study. The patients were randomly allocated to receive 0.25 mg BUD or 0.25 mg fluticasone propionate twice daily for 6 wk and half dose for another 6 wk with a jet nebulizer at home. Blood samples for basal cortisol concentration, adrenocarticotropic hormone, glucose, HbA1c and electrolytes were obtained at the beginning and at the end of the study. Adrenal function assessment was based on changes in cosyntropin-stimulated plasma cortisol levels. The study was completed with 31 patients, 16 of whom received BUD and 15 FP. All patients except one had plasma cortisol concentrations above 500 nmol/l (18 μg/dl) or had an incremental rise in cortisol of >200 nmol/l after stimulation. Although nebulized steroids seem to be safe in infancy, we recommend that adrenal functions should be tested periodically during long-term treatment with nebulized steroids.     

Nitrites in induced sputum as a simple and cheap non-invasive marker of airway inflammation for asthmatic schoolchildren

To determine if there are differences in the nitric oxide metabolites (nitrites) in sputum of patients with persistent asthma and healthy schoolchildren, we performed a case-control study in a tertiary care hospital in Arequipa, Perú. Nitrites in induced sputum samples were measured using the Griess assay in 30 persistent asthmatics (mean age of 10.1 yr) and 30 controls (mean age of 11.9 yr). The mean ± s.d. of nitrites among asthmatics was significantly higher than the controls (16.30 ± 8.6 vs. 10.25 ± 4.68 nmol/ml, respectively, p = 0.001). Moreover, the nitrite level in the sputum in children with severe persistent asthma was higher than in the level found in the moderate and mild asthmatics (32.83 ± 9.48 vs. 18.10 ± 1.96 vs. 11.84 ± 4.73 nmol/ml, respectively, p < 0.01 for linear trend). This study showed for the first time in children that asthmatics have significantly higher levels of nitrites in induced sputum than healthy controls and that the level of nitrite correlates with the severity of the asthma. Nitrite levels in sputum, a simple and cheap, non-invasive method, may be a good alternative to measure the severity of inflammation in asthmatic children.