Impaired growth in children with asthma during treatment with conventional doses of inhaled corticosteroids

We describe 6 (4F, 2M) prepubertal children with moderate asthma diagnosed at a mean age of 2.8 years. All patients were treated with inhaled corticosteroids in a dose of between 300 and 800 mcg of beclomethasone diproprionate (becotide) daily, given either as an aerosol or rotahaler. Mean height velocity SDS decreased from −0.8(range +0.5 to −2.0)to −3.2(range −1.3 to −4.8) when the dose was increased. Alternatively, when the dose was reduced or stopped, mean height velocity SDS increased from −3.2 (range −2.0 to −4.8) to +0.8 (range −1.2 to +2.7). Careful assessment of height velocity is indicated in all children receiving treatment with inhaled corticosteroids.     

Potential adverse endocrine effects of inhaled corticosteroids

Abstract: Evidence exists for a potential role for inhaled corticosteroids, particularly when used in high dose to cause growth impairment, delayed maturation and adrenal suppression in children and adolescents with asthma. The functional significance of biochemical adrenal suppression remains uncertain. Similarly, there is as yet insufficient evidence to determine whether inhaled corticosteroids may adversely affect bone mineral density in children and adolescents with asthma.     

Increased glycosaminoglycans in the urine of asthmatic children on inhaled corticosteroids

Increased extracellular matrix (ECM) deposition in the airway wall contributes to the airway remodeling in asthmatics. Glycosaminoglycans (GAGs) are polysaccharides attached to a protein core in order to form proteoglycans, a component of the ECM. In this study, we investigated the possible influence of long-term treatment with inhaled corticosteroids (ICS) on urinary GAGs levels of asthmatic children. Seventy asthmatic children (41 boys), aged 6.8-12.5 yr, participated in the study. About 44 were treated with inhaled budesonide via turbuhaler for 2-35 months (median 12 months) and 26 were on relief medications. About 30 healthy controls were also studied. GAGs were precipitated from early morning urine samples, collected, isolated and quantified using uronic acid-carbazole reaction and expressed as uronic acid (UA) in microg/g/Cr(u)/m2. Urinary GAGs values did not differ significantly between controls and asthmatics but significant differences were found between children on ICS and asthmatics on relief medications (p < 0.001). There was a positive correlation between the daily dose of inhaled budesonide and the urinary GAGs values (r = 0.32, p = 0.037) whereas a threshold distinguishing 'low' vs. 'high' doses of ICS was found to be at 300 microg/m2 per day with a significant difference in urinary GAGs secretion (p = 0.006). Our data show that urinary GAGs secretion is reduced in asthmatic children that used only relief medication but it is increased in those on long-term treatment with ICS. A dose dependent effect of ICS was also detected.     

Prophylactic intermittent treatment with inhaled corticosteroids of asthma exacerbations due to airway infections in toddlers

The aim of this study was to investigate whether budesonide, for 10 d, administered at the first sign of an upper respiratory tract infection, could reduce asthma symptoms in 1-3-y-old children with asthma during infections. The primary efficacy variable was symptom scores. The study had a multicentre, randomized, double-blind, placebo-controlled design with parallel groups. Fifty-five children with a mean age of 26 months received either budesonide or placebo via a spacer with a facemask. Each child was monitored for 1 y. Budesonide was given 400 microg q.i.d. for the first 3 d and b.i.d. for 7 d. Symptoms (cough, wheeze, noisy breathing and breathlessness) were scored (0-3) daily by the parents. Asthma symptom scores were lower in children treated with budesonide than in those given placebo. The effect was most pronounced for cough and noisy breathing, but it did not affect the need for hospital care. In conclusion, treatment with budesonide, started at the first sign of a respiratory infection, reduced asthma symptoms in toddlers with episodic asthma.     

Growth impairment and adrenal suppression on low-dose inhaled beclomethasone

Growth impairment and adrenal suppression secondary to inhaled corticosteroids (ICS) is a well-recognised phenomenon. We report a 13-year-old boy, treated long-term for asthma, who presented with short stature while on low-dose inhaled corticosteroid (beclomethasone 200 microg/d). Investigations revealed evidence of severe adrenal suppression. Weaning off the steroid treatment resulted in recovery of adrenal activity and rapid growth. While low-dose ICS are normally considered to have few side effects, this case illustrates the extreme variability of individual sensitivity and the need for careful surveillance of all children treated with long-term steroids.     

Early use of inhaled corticosteroids in infancy

The inability to accurately predict the outcome of infants with recurrent wheezy bronchitis makes the early use of inhaled corticosteroids (ICS) controversial. Data from bronchoalveolar lavages and epidemiological surveys suggest a persistent inflammation of the airways in the more severe cases. Prospective studies, mostly with nebulized corticosteroids, have demonstrated clinical efficacy on daytime and nightime symptoms, reduced requirements for rescue bronchodilators and a real steroid sparing effect. In infants with episodic viral-associated wheeze with or without interval symptoms, ICS use carries the risk of overtreatment and of adverse effects. Long-term prospective studies are urgently required to assess the efficacy and safety of ICS and their possible effects on the natural history of infantile asthma.     

Use of inhaled corticosteroids decreases hospital admissions for asthma in young children

Background  An active use of inhaled corticosteroids for asthma has been associated with less asthma exacerbations and hospital admissions in children aged more than 2 years. The present study aimed to investigate hospital admission rates in young children from two populations in relation to the age-specific use of maintenance medication for asthma. Methods  Annual data on children aged less than 24 months treated for asthma, including data on the use of maintenance medication based on the purchases of prescribed medications, and annual numbers of admissions to hospital and proportions of readmissions, were collected from 1995 to 1999 in two provinces of Finland. The inclusion criteria, three or more doctor-diagnosed wheezing episodes, were individually checked by the authors in each case. The mean number of children aged less than 24 months during the years of the study was 5490 in Kuopio and 9914 in Oulu area. Results  In the Kuopio area, during the years of the study, 16.5/1000 children aged less than 24 months were on maintenance medication for asthma, and 90% of them were receiving inhaled corticosteroids. In the Oulu area, the respective figures were 13.5/1000 (P<0.001) and 99%. The average admission rate was 7.9/1000 in the Kuopio area and 8.7/1000 in the Oulu area (P<0.05). The readmissions indicated the higher admission rates in the Oulu (40% of all admissions) than in the Kuopio (28%) area (P<0.01). Conclusion  Active use of maintenance therapy by inhaled corticosteroids was associated with a decreased need of hospital treatment in young children <24 months old with asthma, mainly because of less readmissions.     

Growth of asthmatic children is slower during than before treatment with inhaled glucocorticoids

Reports on the influence of inhaled glucocorticoids on growth have been controversial. We studied the growth of prepubertal asthmatic children prior to and during glucocorticoid therapy. We collected retrospectively the notes of 201 asthmatic children aged 1–11 years receiving inhaled beclomethasone dipropionate or budesonide. We calculated their height and height velocity standard deviation scores (HSDS and HVSDS, respectively) before the treatment and up to 5 years during the treatment and compared those with the growth of healthy peers. The dose of the medication was calculated and the severity of asthma was assessed. The asthmatic children grew similarly to their healthy peers before treatment with inhaled glucocorticoids: the mean HSDS was +0.02 and the mean HVSDS +0.01 for boys and -0.16 and +0.13 for girls, respectively. Growth retardation took place soon after the start of the treatment, the most profound decrease in the growth velocity (the change in the mean HVSDS from +0.05 to -0.88) occurring during the first year of treatment. The growth-retarding effect of inhaled glucocorticoids was not dose dependent. In the covariance analysis the increasing severity of asthma had a significant interaction with repeated measurements, showing more growth retardation along with more severe asthma, especially during long-term treatment. Asthma per se does not impair growth, but inhaled glucocorticoids may do so. Careful monitoring of the growth of all asthmatic children receiving inhaled glucocorticoids is necessary because the growth-retarding effect of the medication is not dose dependent. Individual sensitivity might explain the differences seen in the growth patterns of children receiving inhaled glucocorticoids.     

Repeatability of the low-dose ACTH test in asthmatic children on inhaled corticosteroids

Aim:  To assess the repeatability of low-dose Synacthen test (LDST) in asthmatic children receiving high-dose fluticasone propionate (FP).
Methods:  Low-dose Synacthen test was performed on 18 children with stable chronic asthma treated with FP at a constant daily dose of ≥500 μg and repeated 1 month later. Repeatability was assessed using the Kappa statistic for categorical variables.
Results:  Fifteen patients had consistent results (either two normal or two abnormal responses) and three patients had inconsistent results (one normal and one abnormal response). The Kappa statistic was 0.56 indicating fair to good agreement between the tests.
Conclusion:  The results of adrenal function testing in patients on inhaled steroids can have major implications for patient management, making it important to use a test with excellent repeatability. The LDST conducted using our protocol does not fulfil this criterion.     

Lower leg growth suppression caused by inhaled glucocorticoids is not accompanied by reduced thickness of the cutis or subcutis

Background: Exogenous glucocorticoids suppress short-term lower leg growth in children as assessed by knemometry. The knemometric measurements, however, may be confounded by reductions in the thickness of the cutis and subcutis over the knee. Aim: To assess whether inhaled glucocorticoid-induced suppression of short-term growth is accompanied by changes in the thickness of the cutis and subcutis. Methods: The study was a randomized, controlled, crossover trial with 1 wk treatment, run-in and washout periods. Active treatment was inhaled budesonide 200 μg twice daily. Short-term growth was assessed by knemometry, and the thickness of the cutis and subcutis over the knee, on the volar forearm and abdomen was measured by 20 MHz B-mode ultrasound. Material: Nineteen children with asthma aged 7 to 13 y. Results: Lower leg growth was significantly reduced during budesonide treatment (0.27 mm/wk) compared to the treatment-free period (0.54 mm/wk) (p = 0.02, 95%: -0.50 to -0.05). Variations in the thickness of the cutis were seen during budesonide treatment (mean ± SEM): -0.01 ± 0.03 mm over the knee, -0.02 ± 0.02 mm on the forearm and 0.01 ± 0.02 mm on the abdomen. The variations in the total thickness of the cutis and subcutis were -0.05 ± 0.12 mm, 0.06 ± 0.12 mm and -0.06 ± 0.10 mm during budesonide treatment. The variations in thickness of the cutis or subcutis were not statistically different during budesonide treatment and the treatment free period in any anatomical location.

Conclusions: Short-term lower leg growth suppression induced by inhaled glucocorticoids is not confounded by variations in thickness of cutis or subcutis. The present observations further establishes knemometry as a reliable tool for assessment of the risk of growth suppression of inhaled glucocorticoids in children with asthma.     

Eformoterol Turbohaler® compared with salmeterol by dry powder inhaler in asthmatic children not controlled on inhaled corticosteroids

The aim of the study was to compare the efficacy of the inhaled long‐acting β₂‐agonists eformoterol and salmeterol when added to existing inhaled corticosteroid (ICS) therapy in symptomatic asthmatic children. This randomized, 12‐week, parallel‐group study, performed in a primary care setting, included 156 children and adolescents (aged 6–17 years) with moderate persistent asthma. Patients were randomized to open‐label eformoterol (Oxis^®) Turbohaler^® 9 μg (delivered dose) or salmeterol Accuhaler^® 50 μg, both b.i.d, added to current ICS. Assessments included: changes in daytime reliever β₂‐agonist therapy (primary variable), total 24‐h reliever use, lung function, clinic and diary symptom scores, patient and carer health‐related quality of life (HRQL) and adverse events. Daytime reliever use decreased significantly (p < 0.001) from baseline by 65% and 52%, respectively in the eformoterol and salmeterol treatment groups. Compared with salmeterol, eformoterol produced a greater decrease in daytime (?0.46 inhalations/day; p = 0.081) and 24‐h (?0.70 inhalations/day; p = 0.043) reliever use. The percentage of patients who did not require any reliever medication during the study was significantly higher in the eformoterol group (p < 0.05 vs. salmeterol at weeks 8 and 12). Clinic and diary card peak expiratory flow and symptom measures all improved from baseline in both treatment arms. There was a significantly greater effect in favour of eformoterol for the reduction in clinic‐assessed overall night‐time symptoms (p < 0.05 vs. salmeterol). Clinically relevant improvements in patient‐assessed HRQL occurred during treatment with eformoterol and salmeterol, but carer‐assessed HRQL was improved to a clinically relevant extent, only with eformoterol. Both treatments were well tolerated. In children and adolescents with moderate persistent asthma, add‐on therapy with eformoterol was well tolerated and at least as effective as salmeterol.     

轻-中度哮喘患儿气道炎症类型与病情、糖皮质激素疗效的关系

目的探讨轻-中度支气管哮喘患儿初始治疗前气道炎症类型与病情及吸入糖皮质激素治疗反应的关系。方法以87例轻-中度哮喘患儿作为研究对象,在糖皮质激素吸入治疗(ICS)前进行痰液诱导及诱导痰细胞学分析,酶联免疫荧光法测定痰液嗜酸粒细胞阳离子蛋白(ECP)、ELISA法检测痰液IL-8、TGF-β1,儿童肺功能仪检测基础肺功能和小气道通气指标、乙酰甲胆碱(Mch)支气管激发试验测定气道高反应性(AHR)。20例健康体检儿童作为对照组,应用SPSS13.0软件进行统计学分析。结果87例轻-中度哮喘患儿根据诱导痰液EOS%分为嗜酸性粒细胞哮喘组(EA)64例,非嗜酸性粒细胞哮喘组(NEA)23例,EA与NEA组ICS治疗前痰液细胞学构成比、诱导痰上清液ECP、IL-8差异有统计学意义(P<0.05);两组间FEV1%预测值(FEV1%pred)、PEF%pred、中-重度AHR%、小气道阻塞(%)、痰液TGF-β1水平等指标差异有统计学意义(P<0.05)。ICS治疗4周后EA组基础肺功能指标、气道高反应性、小气道通气功能明显改善,而NEA组改善不明显。多元逐步回归分析结果表明初治痰液EOS%、FEV1%预测值、痰液TG...     

Inhaled corticosteroids for maintenance treatment in childhood pulmonary sarcoidosis

We present our experience with sequential oral and inhaled corticosteroid therapy in childhood pulmonary sarcoidosis. Fifteen children were followed-up for a mean of 7y. Treatment consisted of oral prednisolone 2mg/kg/d on initial diagnosis. After remission was reached, alternate day therapy with 1 mg/kg was continued. The dose was tapered to a maintenance dose which controlled the activity of the disease. When patients were free of symptoms and had no clinical and laboratory findings, inhaled corticosteriod treatment was started. Relapse treatment consisted of cessation of inhaled corticosteroids and start of oral corticosteroids at a dosage of 2 mg/kg/d and then a tapered dose. Five patients were given oral corticosteroids only. Nine patients were given inhaled steroids after oral corticosteroid therapy had been discontinued. Clinical and radiological remissions were achieved in every patient.
Conclusion : Sequential oral and inhaled corticosteroid therapy may be an alternative treatment regimen for sarcoidosis in children.     

Unexpected side-effects of inhaled steroids: A case report

An asthmatic child is presented who developed a cushingoid appearance with evidence of adrenal suppression and growth impairment while on low dose inhaled topical steroids. When the inhaled steroids were replaced by inhaled sodium cromoglycate his adrenal function recovered while his appearance and growth returned to normal. This report indicates that there are some children who are at risk of developing side-effects on doses of inhaled topical steroids normally considered to be entirely safe.     

Glucocorticoids and growth in asthmatic children

The effects of asthma and oral and inhaled glucocorticoid therapy on growth in children are reviewed. Previous reports have shown that asthma itself may delay the onset of puberty, an effect which may masquerade as growth suppression. Oral glucocorticoids appear to impair growth; however, lower doses and alternate-day therapy may have less risk of this effect. While a controversial topic, inhaled glucocorticoids in lower doses appear to be associated with a small risk of adverse effects on growth. Minimal data are available for higher doses. Knemometry, a relatively new technique used for measuring small changes in growth, has detected short-term effects with both oral and inhaled glucocorticoids therapy. However, a number of limitations are associated with short-term growth studies. Clinicians should be aware of the potential for growth impairment with glucocorticoid therapy so adequate monitoring can be undertaken and appropriate intervention introduced when deemed necessary.     

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目的探讨长期吸入糖皮质激素对哮喘患儿粘附因子系统与补体激活片段的影响。方法采用酶联免疫吸附法(ELISA),检测了2002-01—2004-12于青岛大学医学院附属医院儿科就诊的26例哮喘患儿吸入糖皮质激素治疗前及治疗后3个月、6个月、12个月后血清细胞间粘附因子-1(sICAM-1)、血管内皮细胞粘附因子-1(sVCAM-1)和补体激活片段(sC5b-9)的质量浓度变化,并与28名健康儿童比较。结果哮喘患儿治疗前血清sICAM-1、sVCAM-1和sC5b-9质量浓度明显高于对照组;吸入糖皮质激素后血清sICAM-1、sVCAM-1和sC5b-9质量浓度逐渐下降,吸入时间越长,sICAM-1、sVCAM-1和sC5b-9质量浓度降低越明显;吸入糖皮质激素12个月后血清sICAM-1、sVCAM-1和sC5b-9质量浓度与正常对照组比较差异无显著性。结论粘附因子和补体激活片段在哮喘的发病中可能起了一定的作用。长时间吸入糖皮质激素可降低sICAM-1、sVCAM-1和sC5b-9的水平。测定血清sICAM-1、sVCAM-1和sC5b-9水平可用于吸入糖皮质激素抗炎疗效的判断,也可作为哮喘病情和治疗临床观察的指标。     

The insulin–like growth factor axis and collagen turnover in asthmatic children treated with inhaled budesonide

Serum concentrations of growth hormone–dependent insulin–like growth factor I (IGF–I) and insulinlike growth factor binding protein–3 (IGFBP–3), the carboxy terminal propeptide of type I procollagen (PICP), the carboxy terminal pyridinoline cross–linked telopeptide of type I collagen (ICTP) and the amino terminal propeptide of type III procollagen (PIIINP) were studied in 14 prepubertal children with asthma (mean age 9.7 years) during treatment with inhaled budesonide. The study design was a randomized, crossover trial with two double–blind treatment periods (200 and 800 μg) and one open, non–randomized treatment period (400 μg ). All periods were 18 days'duration. Budesonide treatment was associated with a dose–related suppressive trend in serum concentrations of PIIINP when the 400 μg period was included (p < 0.01; z =–2.7) and when it was excluded from the calculations (p < 0.01; z =–2.6), indicating reduced synthesis of type III collagen. A similar trend was observed in ICTP levels when the 400 μg period was excluded from the calculations (p = 0.05; z =–1.9). No other statistically significant variations were seen.     

Short-term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydroflouroalkane-134a

Inhaled beclomethasone dipropionate (BDP) with the propellant hydrofluoroalkane-134a (HFA) has been designed to be equivalent in terms of safety to chlorofluorocarbon (CFC)-formulated metered dose inhalers (MDI). The aim was to assess whether BDP HFA MDI 100 microg twice daily was equivalent to BDP CFC MDI 100 microg twice daily in terms of effects on short-term lower leg growth rate (LLGR) and measures of hypothalamic-pituitary-adrenal (HPA) function. The study consisted of a randomized double-blind cross-over trial with three active, a run-in and two wash-out periods each consisting of 2 wk. The place of study was a secondary referral outpatient clinic. The subjects involved were 14 boys and 10 girls with asthma, aged 7-12 yr. They were all administered BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily. The outcome measures included LLGR and 24-h urine-free cortisol (UFC) and total cortisol metabolites (TCM). Mean (SD) LLGR during run-in and BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily periods were 0.43 (0.23), 0.09 (0.29), 0.10 (0.45) and 0.08 (0.27) mm/wk. The one-sided 97.5% confidence interval for the difference in LLGR between BDP HFA 100 microg and BDP CFC 100 microg was 0.24, thus, below the predefined criterion of 0.20 mm/week. Inter-period comparisons of active treatments showed no differences between means of LLGR, UFC or TCM. Though non-inferiority between BDP HFA and CFC 100 microg twice daily in terms of effects on LLGR was not found, equivalence was suggested by comparisons of LLGR during run-in and active treatments and by HPA function measures.     

Asthma hospitalizations continue to decrease in schoolchildren but hospitalization rates for wheezing illnesses remain high in young children

Aim: To analyse changes in hospitalization rates for asthma in children during recent years. Methods: In a population‐based analysis, changes in asthma hospitalization rates were studied in children in Göteborg (Gothenburg), the second largest city in Sweden, during 1985‐2000. The changes in different age groups have been correlated with the delivery of inhaled corticosteroids to the age groups. Results: In the 5 to 18‐y age group, there was a continuous, significant decrease in number of hospital days, admissions and individual patients admitted for asthma not only for the entire study period, 1985‐2000, but also during the past 10‐y period. The number of hospital days in the year 2000 was only 6% of the figure for 1985. An inverse correlation between delivery of inhaled corticosteroids and hospitalization for asthma was seen not only during 1985‐1995, when use of inhaled corticosteroids became widespread (r_S=?0.95, p= 0.007 for hospital days), but also when the entire period from 1985 to 2000 was analysed. Conversely, in the 0 to 1‐y and 2 to 4‐y age groups, there was no decrease in hospitalizations for wheezing illnesses or asthma‐like symptoms during the past 10‐y period, 1991‐2000. Conclusion: During the period 1985‐2000 the number of hospital days owing to asthma decreased by more than 90% in the 5 to 18‐y age group. The marked decrease in asthma hospitalization rates among schoolchildren represents a great advance in paediatric respiratory medicine, which has been continuous during the past 10‐y period. However, in young children admissions for wheezing have apparently not decreased.