Serum Fructosamine, Total Cholesterol, and High-Density Lipoprotein in Children with Asthma during Glucocorticoid Treatment.

Background/Aims. Glucocorticoids may have adverse effects on carbohydrate and lipid metabolism. The present study was conducted to investigate possible effects on carbohydrate and lipid metabolism of inhaled and oral glucocorticoids in children with asthma. Methods. Two randomised controlled trials with blinded crossover designs were performed. Active treatment was 400 µ g inhaled budesonide or 5 mg prednisolone orally daily during one week. The budesonide trial included 17 and the prednisolone trial 20 school children. Serum fructosamine, total cholesterol and high-density lipoprotein were assessed. Results. Serum fructosamine was increased during active treatment (prednisolone 252.3 µ M versus placebo 247.3 µ M; P = 0.03 and budesonide 228.1 µ M versus no treatment 223.1 µ M; P = 0.02). Total cholesterol and high-density lipoprotein were not statistically significantly increased. Conclusion. Short-term treatment with oral prednisolone and inhaled budesonide may adversely affect mean blood glucose concentration. Possible long-term consequences require further investigations.

Methodology and implications of knemometry in growth assessment of inhaled glucocorticoids.

When validated recommendations for standardization and measurement procedures are used short-term assessment of lower leg growth by knemometry is a highly accurate and reproducible method for assessment of systemic activity of inhaled glucocorticoids. Crossover and parallel designs applying consistent measurement intervals can be used. Crossover designs with a single-blind run in and washout and double-blind active periods are as sensitive as designs using randomized placebo periods. In populations of children, short-term knemometry appears to be capable of defining specific glucocorticoids, application devices and doses that do not suppress long-term height growth. Although no specific cut-off level can be identified in individuals from the available randomized, double-blind short-term knemometry and intermediate-term height growth rate studies, good evidence have been provided that if the short-term lower leg growth suppression in populations of children is higher than approximately 25%, the risk of intermediate-term growth suppression becomes significant with a mean height growth rate retardation in the range of approximately 0.5-1.5 cm during the first year of treatment. Short-term knemometry should be performed as an integral part of the safety assessments of new inhaled glucocorticoids and inhalation devices in children with asthma, before intermediate-term height growth evaluations are initiated.

Short-term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydrofluoroalkane-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.

Short-term lower leg growth in asthmatic children treated with inhaled beta2-agonists.

BACKGROUND: Knemometry studies of growth suppressive effects of inhaled glucocorticoids in children with asthma usually allow participating children to use concomitant inhaled beta2-agonists. Systemic beta2-agonists, however, have been found to suppress growth hormone secretion and this has caused concern about a possible confounding effect of inhaled beta2-agonists on results of growth studies of exogenous glucocorticoids. AIM: The study evaluated whether inhaled salbutamol adversely affects short-term growth. SUBJECTS AND METHODS: Fifteen children aged 6-12 years with mild asthma were enrolled in a single-blind, randomized crossover study with two 2-week treatment periods and a 1-week run-in. During the active period treatment dry powder salbutamol (Ventoline Diskhaler) 200 microg was inhaled three times a day. During the comparative period no treatment was given. Knemometry of the right lower leg was performed on the first and the last day of each period. RESULTS: Mean lower leg growth rates (SEM) during no-treatment and salbutamol periods were 0.35 (0.06) and 0.42 (0.07) mm per week, respectively (P = 0.35, t = -0.98, 95% CI: 0.25-0.93 mm per week). CONCLUSIONS: Inhaled salbutamol 200 microg three times daily does not suppress short-term growth in asthmatic children. Inhaled beta2-agonists in equipotent doses and regimens can be safely used in short-term knemometric growth studies of exogenous glucocorticoids without any risk of confounding the results.

A questionnaire on factors influencing children's assent and dissent to non-therapeutic research.

BACKGROUND: Knowledge about assent or dissent of children to non-therapeutic research is poor. OBJECTIVES: To assess sociodemographic characteristics in healthy children and adolescents who were invited to participate in non-therapeutic research, to evaluate their motives for assent or dissent and their understanding of the information given. METHODS: A total of 1281 healthy children and adolescents six to sixteen years of age were invited to participate in a non-therapeutic study and a questionnaire. RESULTS: Assenting children were motivated by a desire to help sick children (n = 638, 98%) and to gain experience with participating in a research study (n = 503, 82%). Dissenting children made their decision because of worries about having a blood (n = 193, 46%) or a urine sample (n = 94, 26%) taken or because of worries about a doctor's examination (n = 136, 33%). Fewer children in the assent group (n = 166, 25%) than in the dissent group (136, 33%) worried about the doctor's examination (p = 0.01). In the assent and dissent group, 568 (86%) and 343 (85%) children, respectively, said they were able to understand some or all of the written information (p = 0.42), and 650 (97%) and 330 (98%), respectively, were able to understand some or all of the verbal information (p = 0.07). CONCLUSIONS: Sociodemographic characteristics may not influence healthy children's decision to volunteer for non-therapeutic research. Assenting children have altruistic and educational motives, whereas worries about procedures may cause children to dissent. A great majority of school children and adolescents feel capable of understanding and giving assent or dissent to non-therapeutic research.

Assessment of the relation between short and intermediate term growth in children with asthma treated with inhaled glucocorticoids.

OBJECTIVE: To assess the relation between short-term growth and intermediate term growth in children with asthma treated with inhaled glucocorticoids. DESIGN: An open 12 months parallel group trial with visits to the clinic on day 1, after 2, 4, 8, 12, 20, 28, 36, 44 and 52 weeks. SETTING: Outpatient clinic in a secondary referral centre. SUBJECTS: Sixteen children with asthma aged 9 (6-13) years; 16 matched healthy subjects. METHODS: Knemometry and stadiometry. INTERVENTIONS: Dry-powder inhaled budesonide 200 microg twice daily. PRIMARY OUTCOME MEASURES: Intra-group comparisons of mean lower leg growth rates. SECONDARY OUTCOME MEASURES: Inter-group comparisons of mean lower leg growth rates and intra-group comparisons of mean height-standard deviation scores. RESULTS: One year mean lower leg growth rate (0.36 mm/week) did not differ from the rates during the 2 (0.27 mm/week; P = 0.23), 4 (0.33 mm/week; P = 0.54), 8 (0.36 mm/week; P = 0.79) or 12 (0.33 mm/week; P = 0.49) weeks intervals in the asthma group. Similarly, in the healthy children 2 (0.56 mm/week; P = 0.63), 4 (0.46 mm/week; P = 0.36), 8 (0.43 mm/week; P = 0.49) and 12 (0.43 mm/week; P = 0.66) weeks mean growth rates did not vary statistically significantly from the 1 year growth rate (0.42 mm/week). Mean lower leg growth rates, however, were consistently lower during all periods in the children with asthma (P = 0.02-0.03). At completion of the study mean height-standard deviation score in the asthma group (-0.19) was significantly suppressed as compared with the score at study entry (-0.03) (P = 0.02), whereas no statistically significant variation was detected in the control group. CONCLUSIONS: Short-term lower leg growth rates are consistent with intermediate term growth rates in group studies in children with asthma treated with inhaled dry powder budesonide 400 microg/day. Short-term group knemometry should be an integral part of growth evaluations of new inhaled glucocorticoids, doses and inhalation devices in children with asthma.

Methodological aspects of high-frequency ultrasound of skin in children.

BACKGROUND: High-frequency ultrasound of the skin has recently been introduced for assessment of systemic effects in the cutis and subcutis of oral and inhaled glucocorticoids in children. However, the use of high-frequency skin ultrasound in clinical trials is invalidated because important methodological aspects have not been addressed. The aim of the present study was to evaluate inter- and intraobserver, day to day and diurnal variations of measurement of thickness of cutis and subcutis, and the fraction of low echogenic pixels (fLEP) in the cutis and, furthermore, to assess effects of exercise on the cutis and subcutis and variations in subcutaneous thickness between anatomical locations in children with a high-frequency B-mode ultrasound scanning device. METHODS: Three studies were conducted, each including 10 healthy prepubertal children. High-frequency skin ultrasound was performed with the 20 MHz Dermascan C (Cortex Technology, Hadsund, Denmark). In study 1, the same observer performed five consecutive scannings to assess intraobserver variations. In study two different observers performed scannings at 2 h intervals between 08:00 and 20:00 h, whereby interobserver and diurnal variations were assessed. In study 3, the same observer performed scannings in different anatomical locations on five consecutive days, and on one of these days before and after exercise. Thus day-to-day variations and the effect of exercise were assessed. RESULTS: Low inter- and intraobserver variations were found on assessment of the thickness of cutis and subcutis, whereas high variations were found on evaluation of the dermal water content. Diurnal variations were absent, and day-to-day variations were low. Exercise caused significant increases in the thickness of cutis and subcutis on the thigh. CONCLUSION: Low inter- and intraobserver variations make high-frequency ultrasound a precise and reliable tool for assessment of the cutaneous and subcutaneous thickness in children. In future trials, repetitive scannings need not to be performed at the same time of the day, whereas strenuous physical activity should be avoided on days of examination.

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 microg 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.

Ultrasound of skin in prednisolone-induced short-term growth suppression.

OBJECTIVE: To assess the thickness of the cutis and subcutis in children with prednisolone-induced knemometric growth suppression. DESIGN: A double blind, placebo-controlled crossover trial with two 7-day treatment periods. PATIENTS: Twenty children with asthma aged 7.7 to 13.8 (mean 10.4) years. INTERVENTIONS: 5 mg prednisolone/day. OUTCOME MEASURES: Lower leg growth rate, thickness of cutis and subcutis and the fraction of low echogenic pixels determined by ultrasound. RESULTS: Mean lower leg growth rate was -0.23 during prednisolone, 0.58 mm/week during placebo treatment (p < 0.01). Mean total thickness of cutis and subcutis over the knee was reduced by 0.28 during prednisolone, increased by 0.07 mm/week during placebo treatment (p = 0.04). Lower leg growth rate was positively correlated to changes in thickness of cutis and subcutis (p = 0.04; r = 0.31). CONCLUSIONS: Reductions in thickness of cutis and subcutis may account for some of the lower leg growth suppression caused by systemic glucocorticoids.

Eosinophil granule proteins in the assessment of airway inflammation in pediatric bronchial asthma.

Eosinophil granule proteins such as eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and eosinophil protein X (EPX) in serum and urine are indirect measures of eosinophil activity. The measures have been evaluated for prediction, diagnosis and monitoring of anti-inflammatory treatment modalities in children with asthma. Assessments in serum and urine are highly dependent on sampling procedures and must be performed under strictly controlled conditions using standardized sampling and laboratory procedures. The measures are influenced by circadian and seasonal variations. Measurement of the eosinophil granule proteins does not improve the predictive value of a family history of atopy. Due to insufficient sensitivity and specificity, the measures are not useful in the diagnosis of asthma in children, and the clinical use of eosinophil proteins in the individual child for assessment of asthma severity has not been sufficiently validated. Serum and urine eosinophil granule proteins, however, may be useful in extending our knowledge of suppressive effects on eosinophil activity of various doses, devices and administration regimens of inhaled glucocorticoids in children. Such evaluations may be performed in randomized, double-blind trials of well-defined age groups and they should include measures of compliance. One important aspect to look at would be the distinction between suppressive effects on eosinophil activity and clinically important anti-inflammatory effects. Considering the complexity of airway inflammation and the heterogeneity of childhood asthma, however, it may be too simplistic to look for a single measure of the inflammatory processes. In the future, perhaps, a combination of products of inflammatory cells may give more clinically relevant information with respect to prediction, diagnosis, monitoring and outcome of childhood asthma.

Vitamin D supplementation to healthy children does not affect serum osteocalcin or markers of type I collagen turnover.

AIM: New serum markers have recently been introduced in the assessment of bone turnover. Such measures are osteocalcin, the C-terminal propeptide of type I procollagen (PICP), the N-terminal propeptide of type I procollagen (PINP) and the C-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP). This study aimed to determine whether supplementation with vitamin D3 to healthy children during the winter affects bone turnover in healthy children measured by serum osteocalcin, PICP, PINP or ICTP. METHODS: 12 girls and 8 boys aged 6.2-13.7 (mean 9.8) y, all proven healthy by medical examination and history, were enrolled in a double-blind, randomized, placebo-controlled, cross-over study with two 4 wk treatment periods and 2 wk washout. Vitamin D3 600 IU was given in one tablet of ABCDin daily. On the last day of the 4 wk periods blood was sampled for assessment of serum osteocalcin, PICP, PINP, ICTP, 25-OH-vitamin D, 1,25-diOH-vitamin D and parathyroid hormone (PTH). RESULTS: During supplementation and placebo periods serum osteocalcin (mean +/- SEM) was 53.9 +/- 5.7 and 54.4 +/- 3.8 microg l(-1) (p = 0.70), PICP was 437+/- 44 and 429 +/- 41 microg l(-1) (p = 0.73), PINP was 579 +/- 56 and 619 +/- 64 microg l(-1) (p = 0.33) and ICTP was 13.4 +/- 0.9 and 13.6 +/- 0.7 microg l(-1) (p = 0.52), respectively. Mean +/- SEM serum 25-OH-vitamin D was 47.0 +/- 2.3 and 33.0 +/- 3.0 nmol l(-1) during vitamin D3 supplementation and placebo (p < 0.001, t = 8.10, 95% CI = 10.3 to 17.6 nmol l(-1)), 1,25-diOH-vitamin D and PTH were 87.5 +/- 4.3 and 92.0 +/- 5.3 pmol l(-1) (p = 0.38), and 3.97 +/- 0.5 and 4.21 +/- 0.4 micromol l(-1) (p = 0.37), respectively. CONCLUSION: Supplementation with 600 IU vitamin D3 to healthy children in the winter does not affect bone turnover as measured by serum osteocalcin, PICP, PINP or ICTP. Vitamin D supplementation to healthy children may not be recommended on the ground of concern for bone turnover.

Circadian variations in serum eosinophil cationic protein, and serum and urine eosinophil protein X.

Biochemical evaluation of inflammation may be a useful adjunct to measures of pulmonary function and symptoms in children with asthma. However, little data have been provided to validate the markers in children. The aim of the present study was to assess circadian variations in serum eosinophil cationic protein (ECP), and serum and urine eosinophil protein X (EPX) in children. Five girls and two boys aged 10-14 years were studied. The first sample of urine consisted of urine collected from 24.00 hours the night before until 08.00 hours on the morning of the day of investigation. Thereafter urine was collected at 4-h intervals until 24.00 hours and in another 8-h interval from 24.00 to 08.00 hours. Blood samples for assessment of serum ECP and serum EPX were collected every 2 h during the 24 h. Statistically significant circadian variations in serum ECP (F=3.2, p=0.002), serum EPX (F=3.1, p=0.002) and in urine EPX/creatinine (F=5.4, p=0.003) were detected. The concentrations were higher during the night compared to daytime. Peak levels of serum ECP (mean [+/- SEM]) were found at 06.00 hours (16.3 [5.3] micro g/l), trough levels at 08.00 hours (3.9 [0.7] micro g/l) (p=0.01). Peak levels of serum EPX were seen at 06.00 (43.7 [9.5] micro g/l) with trough levels at 12.00 hours (22.0 [3.5] micro g/l) (p=0.01). Peak levels of urine EPX/creatinine occurred in urine collected from 24.00 to 08.00 hours (90.0 [27.7] micro g/mmol), trough levels in the 16.00-20.00 hours sample (29.7 [8.9] micro g/mmol) (p=0.02). Serum ECP, serum EPX and urine EPX exhibit a circadian variation in children with nocturnal and early morning peak levels. To avoid confounding influence from circadian variations in ECP and EPX in clinical studies blood or urine should be sampled at consistent times.

A randomized, controlled lower leg growth study of vitamin D supplementation to healthy children during the winter season.

BACKGROUND: The deceleration of longitudinal growth in children during winter occurs simultaneously with a decrease in the number of daylight hours and a reduction in vitamin D status. Due to worries about deleterious effects on bone of a relative insufficiency, vitamin D supplementation to healthy children has been suggested. AIM: To see whether supplementation of vitamin D to healthy children during winter affects seasonal growth. SUBJECTS AND METHODS: Twelve girls and eight boys aged 6.2-13.7 (mean 9.8) years, all healthy, were enrolled in a double-blind, randomized, placebo-controlled cross-over study with two 4-week treatment periods and 2-week run-in and wash-out periods. Vitamin D(3) 600 IU was given in one tablet ABCDin daily. Knemometry of the right lower leg was performed on the first and last day of each period. RESULTS: Lower leg growth rates (mean +/- SEM) during placebo and vitamin D(3) administration were identical: 0.28 +/- 0.04 mm per week (p = 0.94, t = 0.1, 95% CI: - 0.12-0.13 mm per week). CONCLUSION: Supplementation with vitamin D(3) 600 IU day(-1) to healthy children during winter may not improve seasonal growth. Therefore, supplementation may not be recommended on the grounds of concerns about growth; however firm conclusions await randomized long-term studies.

Short-term treatment with prednisolone has no lasting effect on serum leptin.

It has been suggested that the leptin-stimulating effect of short-term treatment with systemic glucocorticoids may last several weeks to months. The aim of the present study was to assess serum leptin during and four days after withdrawal of short-term treatment with prednisolone. The study comprised 20 healthy subjects (12 men and 8 premenopausal women aged 19-45 years: mean 31 years). The design was a randomized, double-blind, placebo-controlled, parallel group study with 2 days' run in, 3 days' treatment and 4 days' run out. No medication was given during run in and run out. During the treatment period the subjects took prednisolone, 20 mg twice daily, or placebo. Blood was collected on the last day of each period. In the prednisolone group comparisons of run in (mean serum leptin (+/- SEM) (4.94 (1.31)) with treatment (7.08 (1.39)) and run out (5.20 (1.84)) microg/L) showed a significant stimulating effect of treatment (p=0.03, t=-2.6, 95%, confidence interval -4.0 to -0.25 microg/L), whereas no statistically significant variation between run in and run out was detected (p=0.47, t=0.8, confidence interval -2.63 to 1.35 microg/L). Inter-group comparisons of run in with treatment and run out showed elevated leptin concentrations during prednisolone treatment (p=0.03) but no statistically significant variations between run in and run out data (p=0.88). In healthy adults the stimulating effects on serum leptin of short-term prednisolone seem to last only a few days after withdrawal of treatment.

17-Hydroxylase/17,20 lyase deficiency diagnosed during childhood.

We present a case of familial 17alpha-hydroxylase/17,20 lyase (CYP17) deficiency in which the index case, a 14-year-old XX girl, led to the diagnosis of the condition in a 9-year-old XY sister. No mutations in the CYP 17 gene were found in any of the girls.

Inhaled corticosteroids and growth.

Since inhaled corticosteroids may circulate systemically, a risk of growth suppression in asthmatic children treated with these drugs cannot be ruled out. When assessing the risk, specific drugs, delivery systems, doses, administration regimens, and compliance with treatment regimens must be considered. Although reassuring results have been reported, methodological flaws have meant that the published follow-up evaluations of final height may not be valid for the sound assessment of any growth effects of inhaled corticosteroids. Short-term studies suggest that twice-daily administration of budesonide 200-400 microg delivered from a metered-dose inhaler with a spacer, dry powder budesonide 200 microg, and fluticasone propionate 200 microg per day in children with mild asthma, are not associated with growth-rate effects. The risk may become significant with budesonide 800 microg administered via a metered-dose inhaler with a spacer, and with 400 microg from a dry powder inhaler. The risk of growth suppression can be reduced by dosing once daily in the morning. In children with severe asthma, high doses of inhaled corticosteroids may be potentially lifesaving and thus outweigh the potential risk of mild growth suppression.

Systemic activity versus systemic adverse effects of nasal glucocorticoids in the treatment of allergic rhinitis.

Treatment with nasal glucocorticoids may be associated with systemic activity, which can be detected by sensitive measures of basal adrenal cortisol secretion, bone turnover and short-term growth (knemometry). The detection of systemic activity, however, does not imply that nasal glucocorticoids cause serious adverse systemic effects, such as an inability of the adrenals to react to physiological stress. Studies assessing the ability of the adrenal cortex to react to stimulation have found this to be intact. Long-term assessments of bone density and statural height are needed, and the possibility of additive effects of intranasal glucocorticoids in children receiving concomitant treatment with inhaled glucocorticoids has not yet been studied. Children on long-term treatment with intranasal glucocorticoids should be followed with height measurements every 6 mo.

A randomised controlled trial of short term growth and collagen turnover in asthmatics treated with inhaled formoterol and budesonide.

AIMS: To determine effects on short term growth and collagen turnover of adding formoterol (Eformoterol) to half the glucocorticoid dose in children with asthma, treated with inhaled budesonide (Pulmicort Turbuhaler). DESIGN: A randomised double blind, placebo controlled crossover study with two six-week periods. SETTING: Outpatient clinic in secondary referral centre. SUBJECTS: A total of 27 prepubertal children aged 6-13 years. INTERVENTIONS: Formoterol 12 microg and dry powder budesonide 100 microg twice daily in one period; placebo and dry powder budesonide 200 microg twice daily in the other. OUTCOME MEASURES: Primary outcome measures were lower leg growth rate, and serum and urine markers of type I and type III collagen turnover. Secondary outcome measures were inflammation markers in serum, and parameters of asthma control. RESULTS: During budesonide 200 microg twice daily treatment, mean lower leg growth rate was 0.14 mm/week (p = 0.02) lower than during the formoterol and budesonide period. Similar statistically significant effects on markers of collagen turnover were found, whereas inflammation markers and asthma control did not vary statistically significantly between the two periods. CONCLUSIONS: In children treated with inhaled glucocorticoids, halving the dose and adding formoterol is associated with faster short term growth and an increase in markers of collagen turnover, with no loss of asthma control.

Impact of inhaled and intranasal corticosteroids on the growth of children.

Since inhaled and intranasal corticosteroids may be systemically bioavailable, risk of growth suppression cannot be ruled out in children treated with these compounds. The mechanisms by which exogenous corticosteroids can cause growth suppression may be multifactorial, involving influences on growth hormone secretory profiles and insulin-like growth factor-I activity, direct effects on the epiphyseal growth plate, and effects on bone and collagen turnover. When studies on growth in children treated with inhaled and intranasal corticosteroids are interpreted, it is important to discriminate between data on the final outcome of growth (adult height) and data on growth rate. No firm conclusions can be drawn on adult height from the available data. While the data on children treated with inhaled corticosteroids appear reassuring, there are no peer-reviewed studies on the final height of children treated with intranasal corticosteroids. The possibility of additive effects on the final height or growth rate of children receiving intranasal plus inhaled corticosteroids has also not been studied. When assessing the risk of growth rate suppression, specific corticosteroids, doses and inhaler systems must be evaluated separately. Standard paediatric doses of inhaled corticosteroids (budesonide 200 to 400 microg/day delivered from a metered dose inhaler with a spacer, dry powder budesonide 200 microg/day, or dry powder fluticasone propionate 200 microg/day) do not affect growth rate when a twice daily administration regimen is used. The risk of growth rate suppression in children treated with inhaled budesonide depends on the dosage and may become significant with 800 microg/day administered with a spacer, or with 400 microg/day administered with a dry powder device. When high doses of inhaled corticosteroids are used, the risk of adverse effects on growth rate can be reduced by once daily dosage in the morning. In fact, intranasal mometasone furoate 100 and 200microg from an aqueous pump spray and dry powder budesonide 200 and 400microg once daily in the morning have been found not to affect growth rate. Sensitivity to adverse effects on growth rate may vary between individuals. If growth suppression is detected, 'catch-up growth' may be expected when the dose of the inhaled or intranasal corticosteroid is reduced or other treatment modalities are introduced. Inhaled or intranasal corticosteroids should not be withheld from children with asthma or rhinitis. Topical corticosteroids should be given in doses that control disease symptoms; however, height measurements should be performed regularly in children receiving corticosteroids.