Growth and adrenal suppression in asthmatic children on moderate to high doses of fluticasone propionate

OBJECTIVE: Growth and adrenal suppression have been reported in asthmatic children using high-dose inhaled fluticasone propionate (FP). Inhaled FP, given at moderate doses (250-750 microg/day), has not been documented to be associated with growth or adrenal suppression in asthmatic children until recently. We report three cases illustrating these side effects. METHODS: Growth and adrenal suppression, after the introduction of inhaled FP, were observed in three prepubertal young asthmatic children referred to our asthma clinic and growth clinic. Growth centile and velocity were assessed by longitudinal stadiometry height measurements. Early morning plasma cortisol levels, and glucagon stimulation tests were used to assess the pituitary adrenal axis. RESULTS: Severe growth and adrenal suppression were noted in three children while they were on moderate doses of inhaled FP. Improvements in growth and adrenal function were observed following cessation or dose reduction of inhaled FP. CONCLUSIONS: Unexpected growth and adrenal suppression may occur in young asthmatic children using moderate doses of inhaled FP.     

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.     

Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone

Background and Aims

Clinical adrenal insufficiency has been reported with doses of inhaled fluticasone proprionate (FP) >400 μg/day, the maximum dose licensed for use in children with asthma. Following two cases of serious adrenal insufficiency (one fatal) attributed to FP, adrenal function was evaluated in children receiving FP outwith the licensed dose.

Methods

Children recorded as prescribed FP ⩾500 μg/day were invited to attend for assessment. Adrenal function was measured using the low dose Synacthen test (500 ng/1.73 m² intravenously) and was categorised as: biochemically normal (peak cortisol response >500 nmol/l); impaired (peak cortisol ⩽500 nmol/l); or flat (peak cortisol ⩽500 nmol/l with increment of <200 nmol/l and basal morning cortisol <200 nmol/l).

Results

A total of 422 children had been receiving FP alone or in combination with salmeterol; 202 were not investigated (137 FP within license; 24 FP discontinued); 220 attended and 217 (age 2.6–19.3 years) were successfully tested. Of 194 receiving FP ⩾500 μg/day, six had flat responses, 82 impaired responses, 104 were normal, and in 2 the LDST was unsuccessful. Apart from the index child, the other five with flat responses were asymptomatic; a further child with impairment (peak cortisol 296 nmol/l) had encephalopathic symptoms with borderline hypoglycaemia during an intercurrent illness. The six with flat responses and the symptomatic child were all receiving FP doses of ⩾ 1000 μg/day.

Conclusion

Overall, flat adrenal responses in association with FP occurred in 2.8% of children tested, all receiving ⩾1000 μg/day, while impaired responses were seen in 39.6%. Children on above licence FP doses should have adrenal function monitoring as well as a written plan for emergency steroid replacement.     

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.     

Influence of inhaled corticosteroids on growth: a pediatric endocrinologist''s perspective

Given the increasing advocacy for the use of inhaled corticosteroids as a treatment of choice for persistent asthma, growing numbers of children are being exposed to the possible growth-suppressing effects of glucocorticoids. Recent evidence strongly suggests that, when consistently administered at moderate doses, inhaled corticosteroids (IC) are capable of slowing growth in children. Whether such growth suppression would persist and ultimately affect final adult height remains unknown. Therapeutic goals which aim for uninterrupted inflammatory disease control rather than periodic symptom control may increase the occurrence of growth failure in children treated with IC. In this article, current information about the mechanisms of growth suppression by glucocorticoids and the effects of IC on growth is reviewed, and recommendations for designing studies to investigate the effects of drugs on growth are presented.     

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.     

Cushing syndrome, adrenal suppression and local corticosteroid use

Adrenal suppression can occur following use of intra-articular corticosteroid injection for treatment of arthritis. If unrecognised, this can result in major medical illness, shock or death. We report two children who developed Cushingoid features and severe adrenal suppression after joint injection. Paediatricians caring for children who have intra-articular corticosteroid injections should be aware of this potential complication. Monitoring of cortisol levels after injection should be considered.     

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.     

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.     

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.     

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.     

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...     

Growth of the adrenal gland of the normal human fetus during early gestation

The weights of 182 adrenal glands obtained from presumably normal human fetuses delivered by elective abortion between 6 and 17 weeks post-conceptional gestational age were measured. There was little increase in adrenal weight between 6 and 12 weeks gestation. Thereafter, the rate of increase in adrenal weight was rapid. There were no significant differences between the adrenal gland of male and female abortuses of similar gestational ages.     

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.     

Growth in congenital adrenal hyperplasia

Individuals with congenital adrenal hyperplasia (CAH) are shorter, on an average, than the general population. A recent meta analysis of final height in CAH indicated that the height deficit is typically 1 to 2 standard deviations below the mean in both males and females. Growth in CAH due to 21-hydroxylase deficiency is influenced by a number of factors, related both to the underlying disease and its treatment. In general, males with the simple virilising form have the poorest height prognosis. This relates in part to late diagnosis and treatment and the bone age advancement seen in individuals with untreated postnatal androgen excess. Obesity in CAH patients also appears to be correlated with reduced height potential. Glucocorticoid treatment which is vital for cortisol replacement, prevention of adrenal crises and androgen suppression, results in growth inhibition when administered in larger doses. Current evidence suggests that infancy and peripubertal periods are the time periods where heights outcome is most sensitive to glucocorticoid dose. More recent estimates of physiological cortisol secretion rates indicate that standard cortisol replacement schedules may result in overtreatment. In addition, dose titration to achieve complete androgen suppression and normalization of 17-hydroxyprogesterone is likely to result in overtreatment and consequent growth impairment. Optimization of current treatment may lead to further improvements in height prognosis. The potential benefits of more complex treatment regimes, using aromatase inhibitors and antiandrogens, in combination with a reduced glucocorticoid dose remain uncertain.     

Spontaneous recovery of steroid-induced osteopenia

We report a case of an adolescent girl treated with high-dose oral steroids for prolonged coughing thought to be secondary to unstable asthma. Iatrogenic adrenal suppression led to clinical appearance of Cushing syndrome and associated bilateral early post-capsular cataracts, slowing of growth velocity and osteopenia. After weaning off steroids, there was a spontaneous increase in aeral lumbar bone mineral density and also catch-up growth evident over a 5-year period.