Long-term treatment with corticosteroids/ACTH in asthmatic children. IV. Skeletal maturation

Skeletal maturation in severe bronchial asthma was studied in 15 children during and after treatment with depot tetracosactrin and in 6 children during treatment with prednisolone. Attained skeletal maturity before treatment was below the reference mean in the majority of children. Skeletal maturation was enhanced during treatment with depot tetracosactrin, which led to more advanced attained skeletal maturity at withdrawal than at start of treatment. There was a tendency towards larger increases of skeletal maturity than of height. The influence of adrenal androgens, released by ACTH-stimulation and good control of the disease are probably relevant factors for the acceleration of skeletal maturation. After withdrawal of depot tetracosactrin the rate of skeletal maturation normalized. During prednisolone treatment there was a delay of skeletal maturation leading to a progressive relative decrease of attained skeletal maturity, and closely related to a delay in linear growth. Treatment with depot tetracosactrin may thus induce enhancement of skeletal maturation, but with the treatment regimen found to be efficacious in bronchial asthma, the effect is not very pronounced and does not perceptibly affect the ultimate outcome of growth.     

Long-term treatment with glucocorticoids/ACTH in asthmatic children. III. Effects on growth and adult height

The effect on growth of long-term treatment with prednisolone and/or ACTH (tetracosactrin) depot preparation was studied in 40 children with severe bronchial asthma. Height velocity was subnormal before treatment. During treatment the group of 17 children primarily treated with ACTH showed a moderate increase in mean velocity. Their height was not significantly altered, and neither was the age at peak height velocity nor adult height. In the group of 23 children treated with prednisolone the mean velocity decreased, resulting in a relative decrease in height. Peak height velocity was delayed by about 2 years in the boys but occurred at the expected time in the girls, as did menarche. Mean adult height was lower than expected after adjustment for mid-parenteral height. In 10 children ACTH was substituted for prednisolone, and their height velocity increased but not enough to affect adult height, which was just as low as in the patients treated with prednisolone only.     

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.     

Bone density in asthmatic children treated with inhaled corticosteroids.

Volumetric trabecular bone mineral density of the lumbar spine (vTBMD) and distal radius (rTBMD) were measured in 20 prepubertal white asthmatic children treated with moderate to high doses of inhaled corticosteroids. The median standard deviation score for vTBMD (0.20, -0.56 to 2.09) and rTBMD (-0.04, -0.82 to 1.39) were within the normal range.     

Bone density in asthmatic children treated with inhaled corticosteroids

Volumetric trabecular bone mineral density of the lumbar spine (vTBMD) and distal radius (rTBMD) were measured in 20 prepubertal white asthmatic children treated with moderate to high doses of inhaled corticosteroids. The median standard deviation score for vTBMD (0.20, -0.56 to 2.09) and rTBMD (-0.04, -0.82 to 1.39) were within the normal range.     

Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids (Part 2) – the risk as determined by gold standard adrenal function tests: A systematic review

The evidence for hypothalamic-pituitary-adrenal axis (HPA) suppression by inhaled corticosteroids (ICS) was found to be conflicting. Reviewers have not distinguished between gold standard and basal adrenal function tests. The utility of the latter is limited by physiological and pathological variability as well as by methodological concerns. The risk of HPA suppression in asthmatic children and adolescents treated with ICS, as determined by gold standard adrenal function tests, needs to be established. A systematic review of the literature from January 1973 to July 2005 was performed. The Medline and Cochrane databases were searched, the reference lists of retrieved articles were inspected and pharmaceutical companies were approached. Randomized-controlled trials, cohort and case-control studies designed to detect HPA suppression caused by ICS, diagnosed by the insulin tolerance test (ITT) or the metyrapone test, performed on asthmatics of all ages not on oral steroids, were included and assessed for methodological quality. Of the 22 identified studies only four met the criteria for inclusion. All of these were published before 1988 and only one was methodologically sound. The cohort study showed that the baseline risk for HPA suppression is 0% while the absolute risk is 100% in asthmatic children treated with a beclomethasone dipropionate metered dose inhaler at a dose of 250-600 mug/m(2)/day for 6-42 months. As suggested by other observations these results could be generalized to other ICS. They may be of clinical significance especially if children are subjected to stress. Further research is needed to establish the cumulative dose for all ICS at which HPA suppression will be precipitated. Guidelines for future trials are suggested.     

Pulmonary function in asthmatic children during thalassotherapy.

In 39 asthmatic children, 5-14 years of age, sent to the Kinderkurheim Satteldüne for a 6 week course of thalassotherapy, the following pulmonary function studies were tested serially: Vital capacity (VC), one-second forced expiratory volume (FEV1), maximal mid-expiratory flow rate (MMFR) and peak flow rate (PFR). Results expressed as mean values per week of the group as a whole, showed subnormal results at initial testing in all 4 parameters measured. Improvement followed rapidly with the final level generally achieved during week 2. However, statistical analysis showed the differences between the initial and each of the subsequent values to be insignificant with one exception in the FEV1 values. Thus the clinical improvement observed in most patients during thalassotherapy could not be substantiated by pulmonary function tests.     

Long-term Treatment with Glucocorticoids/ACTH in Asthmatic Children III.

ABSTRACT. The effect on growth of long-term treatment with prednisolone and/or ACTH_1-24 (tetracosactrin) depot preparation was studied in 40 children with severe bronchial asthma. Height velocity was subnormal before treatment. During treatment the group of 17 children primarily treated with ACTH showed a moderate increase in mean velocity. Their height was not significantly altered, and neither was the age at peak height velocity nor adult height. In the group of 23 children treated with prednisolone the mean velocity decreased, resulting in a relative decrease in height. Peak height velocity was delayed by about 2 years in the boys but occurred at the expected time in the girls, as did menarche. Mean adult height was lower than expected after adjustment for mid-parenteral height. In 10 children ACTH was substituted for prednisolone, and their height velocity increased but not enough to affect adult height, which was just as low as in the patients treated with prednisolone only.     

Long-term Treatment with Corticosteroids/ACTH in Asthmatic Children

ABSTRACT. Skeletal maturation in severe bronchial asthma was studied in 15 children during and after treatment with depot tetracosactrin and in 6 children during treatment with prednisolone. Attained skeletal maturity before treatment was below the reference mean in the majority of children. Skeletal maturation was enhanced during treatment with depot tetracosactrin, which led to more advanced attained skeletal maturity at withdrawal than at start of treatment. There was a tendency towards larger increases of skeletal maturity than of height. The influence of adrenal androgens, released by ACTH-stimulation and good control of the disease are probably relevant factors for the acceleration of skeletal maturation. After withdrawal of depot tetracosactrin the rate of skeletal maturation normalized. During prednisolone treatment there was a delay of skeletal maturation leading to a progressive relative decrease of attained skeletal maturity, and closely related to a delay in linear growth. Treatment with depot tetracosactrin may thus induce enhancement of skeletal maturation, but with the treatment regimen found to be efficacious in bronchial asthma, the effect is not very pronounced and does not perceptibly affect the ultimate outcome of growth.     

Long-term Treatment with Corticosteroids/ACTH in Asthmatic Children

Hypothalamic-pituitary-adrenal (HPA) function was studied in 23 children with severe bronchial asthma during and after long-term treatment with prednisolone and/or ACTH_1-24 (depot tetracosactrin) by means of ACTH stimulation test and insulin tolerance test. In the 14 children primarily treated with depot tetracosactrin, the Cortisol levels in insulin tests were within normal limits both during and after treatment. An enhanced response to ACTH stimulation was found during the treatment period. During treatment with prednisolone a marked impairment of the adrenocortical function was found, with low basal plasma Cortisol levels and subnormal response to ACTH stimulation, more marked the lower the age at the start of treatment and the higher the dose per kg body weight. After substitution with depot tetracosactrin the HPA-function was restituted, with plasma Cortisol levels within normal limits. Growth hormone levels after insulin induced hypoglycemia were ±7 ng/ml during and after treatment with depot tetracosactrin. As long-term treatment with depot tetracosactrin has little side-effects in terms of suppression of the HPA-axis it is a useful alternative to oral prednisolone in severe asthma in children.     

Adrenal function in asthmatic children treated with inhaled budesonide

The effect of the inhaled topical steroid budesonide on adrenal function was evaluated in 33 children (aged 7-15 years) with moderate bronchial asthma. The trial was designed as a prospective single-blind study of the effect of budesonide in daily doses of 200 microgram through 400 microgram to 800 micrograms in three randomized consecutive periods of 8 weeks. The unstimulated diurnal production of cortisol was assessed by measurement of free cortisol in 24-hour urine samples at the end of each period. No significant dose-related suppression was found. The cortisol production did not differ significantly during treatment with 800 microgram budesonide as compared to treatment with 200 microgram budesonide (95% confidence interval: 74%-112%). It is concluded, that budesonide is a topical steroid with a favourable ratio between topical and systemic effects in asthmatic children.     

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.     

Respiratory function in children of asthmatic mothers

ObjectiveTo evaluate lung function and clinical manifestations suggestive of asthma in children of mothers with a reported medical diagnosis of asthma.MethodsAn observational cross-sectional analytical study nested in a cohort of 4,757 pregnant women. A total of 86 six-year-old children were evaluated, born to mothers with a medical diagnosis of asthma before pregnancy. Information was collected regarding clinical symptoms of atopy and respiratory diseases, as well as socioeconomic and exposure variables; the children were submitted to spirometry.ResultsSpirometric alterations were observed in 30.3% of cases, with a prevalence of asthma in those who had an obstructive pattern. 9.3% of the children had a previous medical diagnosis of asthma; however, the established diagnosis based on the presence and frequency of asthma symptoms was 18.6%. Of the 86 participating children, 37.2% had a score of five or more points in the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, which was associated with spirometry alterations (p = 0.002). After multiple logistic regression analysis, higher paternal education, higher number of bedrooms in the family's home, and mother who did not have “wheezing” episodes during pregnancy were statistically significant as protective factors for the presence of respiratory disorder detected by spirometry.ConclusionsThe frequency of spirometry alterations in children of asthmatic mothers was high; the restrictive pattern was more often observed that the obstructive. There was a higher incidence of obstructive test results in those who presented clinical symptoms of asthma, with a higher frequency of clinical diagnosis of asthma than that found in the literature.     

Long-term pulmonary function in children with Hodgkin's disease

We studied the long-term pulmonary function of 25 patients who were at least 5 years post-treatment for Hodgkin's disease. The mean age of the patients was 17 years (range 9.5–25 years) at the time of study. Twenty-one of the patients were male. All patients received six courses of COPP chemotherapy and, in addition, 8 of the 25 patients received radiotherapy to the mediastinum in low or moderate doses (20–30 Gy). One patient had symptoms of bronchiectasia. The chest radiographs of nine patients (36%) showed minimal abnormalities. We divided patients into two groups while evaluating their pulmonary function tests according to whether they received mantle irradiation or not. In patients who received mantle irradiation, pulmonary function tests showed a minimal decrease in FEV₁. The decrease in FEV₁ indicated an obstructive ventilatory defect. We concluded that our treatment protocols for paediatric Hodgkin's disease were curative, well tolerable and might minimize pulmonary functional changes.     

A 2-year step-down withdrawal from inhaled corticosteroids in asthmatic children receiving immunotherapy

Background

Inhaled corticosteroids (ICSs) for treating asthma are controversial because of their negative effects on the growth of asthmatic children and without clearly defined withdrawal strategy. A 2-year ICS step-down and withdrawal strategy has been developed for asthmatic children receiving 3-year subcutaneous immunotherapy (SCIT).

Methods

Eleven children were included into the SCIT group and 13 children into the ICS group. ICSs were discontinued when children met the following criteria: requiring only 1 puffper day, with good control, for at least 6 months; having a forced expiratory volume in 1 second (FEV₁)/forced vital capacity ≥80%; and SCIT discontinued for ≥24 months. The main endpoints were the results of both the childhood asthma control test (C-CAT) and the methacholine bronchial provocation test.

Results

In the SCIT group, all the 11 children had ICS discontinued, with one child developed asthma attack after pneumonia and received ICS again after completion of SCIT. In the ICS group, five children discontinued ICS and developed asthma attacks later and received ICS again; the other eight children developed severe symptoms during ICS step-down. Thus, the discontinuation of ICS was only achieved in the SCIT group. The dose of methacholine that caused a decrease of 20% in FEV₁ continued to improve after discontinuation of ICS for the SCIT group and presented better results than the ICS group (P=0.050). After completion of SCIT, the C-CAT had improved significantly after 30 months of treatment compared with the ICS group (P<0.05).

Conclusions

In the present study, we developed a 2-year step-down and withdrawal strategy from ICSs strategy for allergic asthma children receiving SCIT; the strategy was efficacious and safe.