Systemic effects of inhaled corticosteroids in children

PURPOSE OF REVIEW: Inhaled corticosteroids (ICS) are first-line therapy for persistent asthma in children. Major safety concerns about long-term ICS therapy include suppression of adrenal function, growth, and bone development. Proper interpretation of ICS safety studies requires knowledge of differences between various ICS drug/delivery device systems. RECENT FINDINGS: Dosage, type of inhaler device used, patient technique, and characteristics of the individual drug influence systemic effects of ICS. Reports of adrenal insufficiency occur but are rare and are confined to children receiving high doses of ICS. Dose-related inhibition of growth is detectable as ICS dosage increases, but appears temporary, more pronounced in childhood, and is not associated with reduction in final height. Moderate-dose ICS therapy is not associated with significant changes in measurements of bone density, but more studies of high doses and of therapy in adolescents are needed. SUMMARY: Recent studies confirm that benefits of ICS, properly prescribed and used, clearly outweigh not only their potential adverse effects but also the risks associated with poorly controlled asthma.     

Inhaled corticosteroids in childhood asthma: the story continues

Inhaled corticosteroids (ICS) are the most effective anti-inflammatory drugs for the treatment of persistent asthma in children. Treatment with ICS decreases asthma mortality and morbidity, reduces symptoms, improves lung function, reduces bronchial hyperresponsiveness and reduces the number of exacerbations. The efficacy of ICS in preschool wheezing is controversial. A recent task force from the European Respiratory Society on preschool wheeze defined two different phenotypes: episodic viral wheeze, wheeze that occurs only during respiratory viral infections, and multiple-trigger wheeze, where wheeze also occurs in between viral episodes. Treatment with ICS appears to be more efficacious in the latter phenotype. Small particle ICS may offer a potential benefit in preschool children because of the favourable spray characteristics. However, the efficacy of small particle ICS in preschool children has not yet been evaluated in prospective clinical trials. The use of ICS in school children with asthma is safe with regard to systemic side effects on the hypothalamic–pituitary–adrenal axis, growth and bone metabolism, when used in low to medium doses. Although safety data in wheezing preschoolers is limited, the data are reassuring. Also for this age group, adverse events tend to be minimal when the ICS is used in appropriate doses.     

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

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

Update on National Asthma Education and Prevention Program pediatric asthma treatment recommendations

The National Asthma Education and Prevention Program (NAEPP) published an update on selected topics from the 1997 Guidelines for the Diagnosis and Management of Asthma and provided new evidence-based recommendations for asthma treatment. Selected topics on the long-term management of asthma in children addressed the efficacy of inhaled corticosteroids (ICSs) compared with other asthma medications (i.e., as-needed beta(2)-adrenergic agonists and other controllers) in mild and moderate persistent asthma and the safety of long-term ICS use. The effects of early intervention with ICSs on asthma progression also were evaluated. An important new aspect of the treatment update entails the recommendation of ICSs as the controller medication of choice for all severities of persistent asthma in children. Additionally, on the basis of studies in adults, the Expert Panel suggested that long-acting beta(2)-adrenergic agonists are now the preferred adjunct to ICSs in children with moderate or severe persistent asthma. Based on long-term data in children, ICS therapy was deemed safe in terms of growth, bone mineral density, ocular effects, and hypothalamic pituitary adrenal axis function. Although members of the NAEPP Expert Panel determined that the effects of early intervention with ICSs on decline in lung function have not been adequately studied, they found that the effects on asthma control were substantial.     

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.     

Current management of allergic asthma in children

Asthma in children is characterized by recurring symptoms such as wheezing, breathlessness, and cough, by airflow obstruction and bronchial hyperresponsiveness, and by underlying inflammation. The presence of allergic sensitization, and allergic rhinitis in particular, is strongly associated with asthma. The goal of management of asthma is to achieve and maintain control of the clinical manifestations of the disease. This can be obtained by drug treatment, education of patients and care givers, and, in allergic asthma, by allergen avoidance and specific immunotherapy. The drugs used in asthma can be classified as controllers - such as inhaled corticosteroids (ICS) and leukotriene receptor antagonists - or relievers (bronchodilators to be used during acute exacerbations of asthma). ICS are the most effective anti-inflammatory controllers for the management of persistent asthma in children of all ages, but there is no consensus about the optimal starting dose. Dose-response studies reported marked and rapid improvement in clinical symptoms and lung function at low doses of ICS, and mild asthma is well controlled by such doses in most children, this ensuring good safety. If there is no improvement with the initial low dose of ICS, an increased ICS dose or additional therapy with leukotriene receptor antagonists or long-acting inhaled β2-agonists should be considered. When asthma is caused by allergy to aeroallergens, specific immunotherapy must be taken into account, in its two forms of subcutaneous or sublingual immunotherapy. The former has complete evidence of efficacy, but the sublingual route is safer and more easily accepted by children.     

Inhaled corticosteroids and growth]

Inhaled corticosteroids are effective in patients with asthma by reducing the chronic inflammatory changes. They are widely prescribed in children and even in infants. The potential adverse effects of inhaled corticosteroids on statural growth have been the matter of numerous past and present controversies. Asthma itself can delay growth. The majority of studies demonstrate that the growth impairment is dose-dependent and that moderate doses of inhaled corticosteroids are safe. Monitoring statural growth of asthmatic children, whether they are treated or not with inhaled corticosteroids is mandatory. The treatment must be adapted to the severity of asthma, and overtreatment must be avoided. Inhalation techniques minimizing systemic absorption must be used. Addition of other antiasthmatic drugs to moderate doses of inhaled corticosteroids should be preferred to high doses of inhaled corticosteroids alone.     

Montelukast in pediatric asthma management

Leukotriene modifiers (receptor antagonist and biosynthesis inhibitor) represent the first mediator specific therapeutic option for asthma. Montelukast, a leukotriene receptor antagonist is the only such agent approved for use in pediatric patients. Montelukast modifies action of leukotrienes, which are the most potent bronchoconstrictors, by blocking Cysteinyl leukotriene receptors. Systemic drug like mountelukast can reach lower airways and improves the peripheral functions which play a crucial role in the evolution of asthma. Review of existing literature showed that montelukast compared to placebo has proven clinical efficacy in better control of day time asthma symptoms, percentage of symptom free days, need for rescue drugs and improvement in FEV₁. Studies also demonstrated improvement in airway inflammation as indicated by reduction in fractional exhaled nitric oxide, a marker of inflammation. Studies comparing low dose inhaled corticosteroids (ICS) with montelukast are limited in children and conclude that it is not superior to ICS. For moderate to severe persistent asthma, montelukast has been compared with long acting beta agonists (LABA) as an add-on therapy to ICS, montelukast was less efficacious and less cost-effective. It has beneficial effects in exercise induced asthma and aspirin-sensitive asthma. Montelukast has onset of action within one hour. Patient satisfaction and compliance was better with montelukast than inhaled anti-inflammatory agents due to oral, once a day administration. The recommended doses of montelukast in asthma arechildren 1–5 years: 4 mg chewable tablet, children 6–14 years: 5mg chewable tablet, adults: 10 mg tablet; administered once daily. The drug is well tolerated. Based on the presently available data montelukast may be an alternative treatment for mild persistent asthma as monotherapy where ICS cannot be administered. It is also an alternative to LABA as an add-on therapy to ICS for moderate to severe persistent asthma. The other indications for use of montelukast include: allergic rhinitis, exercise induced bronchoconstriction and aspirin-induced asthma.     

Reduced basal salivary cortisol in children with asthma and allergic rhinitis

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

Effects of inhaled or nasal glucocorticosteroids on adrenal function and growth

Inhaled and nasal glucocorticosteroids (GCS) have being shown to be very effective in the treatment of persistent asthma and allergic rhinitis. However, there has been great concern about the possible effects of these inhaled or nasally administered drugs upon the growth of patients of pediatric age. One of the possible glucocorticoid actions of GCS is reflected by the suppression of adrenal function, suggesting a peripheral direct effect of circulating GCS on the cartilage. The present review addresses the safety of inhaled and nasal GCS by assessing the literature on their effects on adrenal gland function and on growth in children and adolescents. It can be concluded that, at recommended doses, adrenal function is rarely suppressed. High doses of inhaled GCS seem to decrease short-term prepubertal growth, but available studies of final height show that it is not affected at licensed doses. Despite these observations, physicians should monitor the growth of their patients, particularly when a new drug is introduced.     

The effect of asthma and its treatment on growth

Asthma has little, if any, significant effect on attained adult height. Untreated asthma results in a delay of puberty by approximately 1.3 years, and pubertal delay is likely to explain the majority of apparent growth failure in asthmatics. All currently available inhaled corticosteroids (ICS) result in growth suppression at conventional doses (400 microg/day of beclomethasone dipropionate equivalent), but the growth suppressive effects are relatively short lived, after which growth reverts to pretreatment levels. Younger, prepubertal children, appear more sensitive to the growth suppressive effects of ICS. Asthmatic children receiving conventional doses of ICS (400 microg/day of BDP equivalent) will attain an adult height indistinguishable from their predicted adult height (based on their mid parental height), and no different from non-asthmatics. Adult height could possibly be decreased in severe asthmatics, but this is unlikely to be greater than a 1.2 cm decrement. Recent longitudinal studies offer reassurance that at conventional doses ICS do not have significant long term effects on growth, and that their benefits consistently outweigh their side effects.     

The effect of asthma and its treatment on growth.

Asthma has little, if any, significant effect on attained adult height. Untreated asthma results in a delay of puberty by approximately 1.3 years, and pubertal delay is likely to explain the majority of apparent growth failure in asthmatics. All currently available inhaled corticosteroids (ICS) result in growth suppression at conventional doses (400 microg/day of beclomethasone dipropionate equivalent), but the growth suppressive effects are relatively short lived, after which growth reverts to pretreatment levels. Younger, prepubertal children, appear more sensitive to the growth suppressive effects of ICS. Asthmatic children receiving conventional doses of ICS (400 microg/day of BDP equivalent) will attain an adult height indistinguishable from their predicted adult height (based on their mid parental height), and no different from non-asthmatics. Adult height could possibly be decreased in severe asthmatics, but this is unlikely to be greater than a 1.2 cm decrement. Recent longitudinal studies offer reassurance that at conventional doses ICS do not have significant long term effects on growth, and that their benefits consistently outweigh their side effects.     

Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom.

BACKGROUND: Until recently, only two cases of acute adrenal crisis associated with inhaled corticosteroids (ICS) had been reported worldwide. We identified four additional cases and sought to survey the frequency of this side effect in the United Kingdom. METHODS: Questionnaires were sent to all consultant paediatricians and adult endocrinologists registered in a UK medical directory, asking whether they had encountered asthmatic patients with acute adrenal crisis associated with ICS. Those responding positively completed a more detailed questionnaire. Diagnosis was confirmed by symptoms/signs and abnormal hypothalamic-pituitary-adrenal axis function test results. RESULTS: From an initial 2912 questionnaires, 33 patients met the diagnostic criteria (28 children, five adults). Twenty-three children had acute hypoglycaemia (13 with decreased levels of consciousness or coma; nine with coma and convulsions; one with coma, convulsions and death); five had insidious onset of symptoms. Four adults had insidious onset of symptoms; one had hypoglycaemia and convulsions. Of the 33 patients treated with 500-2000 micro g/day ICS, 30 (91%) had received fluticasone, one (3%) fluticasone and budesonide, and two (6%) beclomethasone. CONCLUSIONS: The frequency of acute adrenal crisis was greater than expected as the majority of these patients were treated with ICS doses supported by British Guidelines on Asthma Management. Despite being the least prescribed and most recently introduced ICS, fluticasone was associated with 94% of the cases. We therefore advise that the licensed dosage of fluticasone for children, 400 micro g/day, should not be exceeded unless the patient is being supervised by a physician with experience in problematic asthma. We would also emphasise that until adrenal function has been assessed patients receiving high dose ICS should not have this therapy abruptly terminated as this could precipitate adrenal crisis.     

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

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

Low-dose theophylline in childhood asthma: a placebo-controlled, double-blind study

Regular anti-inflammatory treatment is essential in treating persistent asthma. Most commonly, inhaled corticosteroids (ICS) are used. However, especially in children, there is concern about the long-term safety of ICS such that doses should be kept to a minimum. The use of theophylline has decreased because of frequent side-effects in therapeutic doses. In adults, there have been reports about an immunomodulatory effect of low-dose theophylline. To study the clinical and immunomodulatory effect in children, 36 patients (mean age 12.5 SD 2.4 years) with moderate, persistent asthma on regular ICS were recruited into a placebo-controlled, double-blind study. After a 6-week run-in period, patients received either theophylline 10 mg/kg bodyweight or placebo for 12 weeks. Diary cards, lung function, peripheral blood lymphocyte subpopulations and serum eosinophil cationic protein (sECP) were assessed. In the treatment group, mean serum theophylline was 7.1 mg/l. There was no change in symptoms or use of rescue medication. Mean (SD) peak expiratory flow (PEF) increased from 86% (24) to 95% (18) predicted. sECP decreased from 43.2 μg/l (32.5) to 26.5 μg/l (16.9) (p = 0.02). Lymphocyte subpopulations did not change. The study failed to show a beneficial clinical or an immunomodulatory effect of theophylline when used in low doses. These results do not support a more important role of theophylline in the long-term treatment of moderate childhood asthma.     

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??Objective??To investigate the effects of long-term inhalation of corticosteroids at low dose on the height of Chinese children with mild to moderate asthma. Methods??From August 2015 to July 2016??a total of 966 prepubertal children aged 3.0 to 9.5 years from the Cooperative Group of Asthma??the Subspecialty Group of Respiration??the Society of Pediatrics??Chinese Medical Association were enrolled for the analysis of the cross-sectional questionnaire survey??in which 173 were asthmatic children who had received at least 12-month ICS treatment at low dose and stopped the ICS treatment at least 6 months before enrollment??415 were asthmatic children who had received any ICS treatment for no more than 2 months in a year or who didn’t receive ICS treatment??and 378 were healthy controls. The analysis of variance??ANOVA?? test was used to compare height standard deviation score??SDS??and height velocity among these three groups. The t test was used to analyze changes of height indicators across time in the long-term ICS treatment group. Results??No difference was found in the height SDS and weight SDS at enrollment??or in the height SDS and weight SDS one year before enrollment??or in growth velocity and weight velocity among these three groups. In the long-term ICS treatment group??the height SDS slightly decreased at withdrawal of ICS treatment??-0.62±2.75?? compared to that at the start of ICS treatment??-0.23±1.71?? and one year before enrollment??-0.20±2.91????but significantly increased after at least six monthsof withdrawalofICS??enrollment????0.15±1.39??. The height SDS after five years of treatment with ICS was -0.95±1.41??which was significantly reduced compared to the height SDS after one to three years of treatment??0.17±1.40??P??0.020?? or three to five years of treatment??0.32±1.27??P??0.013??. Conclusion??Long-term treatment????five years?? with ICS at low dose is not associated with height reduction in prepubertal children with mild to moderate asthma.     

Inhaled corticosteroid-phobia and childhood asthma: Current understanding and management implications

Asthma is the most prevalent chronic disease in children. Inhaled corticosteroids (ICS) is the first-line controller therapy for children with persistent asthma, however, suboptimal compliance to ICS therapy remains as a major obstacle in paediatric asthma management. Steroid-phobia, the fear of side-effects and subsequent aversion of ICS, has been widely reported in parents of asthmatic children. The reported prevalence of steroid-phobia varies widely from 19% to 67% in different populations. The concerns about ICS frequently raised by parents include growth suppression, weight gain, bone weakness, addiction and psychiatric disturbances. Outside of growth suppression, which is statistically significant yet mild in clinical studies, the other concerns are not evidence-based and are misconceptions. Conflicting results have been reported regarding the impact of steroid-phobia on ICS compliance. In contrast, steroid-phobia has consistent and negative effects on asthma control in children. While asthma educational programmes have demonstrable benefits in general paediatric populations, the generalisability of such programmes to steroid-phobic parents remains undetermined. There is a paucity of data on specific educational programmes to clear misconceptions and reduce steroid-phobia. Given the continually raising prevalence of paediatric asthma, high-quality studies are warranted to investigate the prevalence and impact of steroid-phobia, with an ultimate goal of developing effective strategies to tackle steroid-phobia and improve asthma care in children.     

Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom

Background: Until recently, only two cases of acute adrenal crisis associated with inhaled corticosteroids (ICS) had been reported worldwide. We identified four additional cases and sought to survey the frequency of this side effect in the United Kingdom. Methods: Questionnaires were sent to all consultant paediatricians and adult endocrinologists registered in a UK medical directory, asking whether they had encountered asthmatic patients with acute adrenal crisis associated with ICS. Those responding positively completed a more detailed questionnaire. Diagnosis was confirmed by symptoms/signs and abnormal hypothalamic-pituitary-adrenal axis function test results. Results: From an initial 2912 questionnaires, 33 patients met the diagnostic criteria (28 children, five adults). Twenty-three children had acute hypoglycaemia (13 with decreased levels of consciousness or coma; nine with coma and convulsions; one with coma, convulsions and death); five had insidious onset of symptoms. Four adults had insidious onset of symptoms; one had hypoglycaemia and convulsions. Of the 33 patients treated with 500–2000 µg/day ICS, 30 (91%) had received fluticasone, one (3%) fluticasone and budesonide, and two (6%) beclomethasone. Conclusions: The frequency of acute adrenal crisis was greater than expected as the majority of these patients were treated with ICS doses supported by British Guidelines on Asthma Management. Despite being the least prescribed and most recently introduced ICS, fluticasone was associated with 94% of the cases. We therefore advise that the licensed dosage of fluticasone for children, 400 µg/day, should not be exceeded unless the patient is being supervised by a physician with experience in problematic asthma. We would also emphasise that until adrenal function has been assessed patients receiving high dose ICS should not have this therapy abruptly terminated as this could precipitate adrenal crisis.     

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.     

Fluticasone in the therapy of asthmatic children: short-term effects on growth

AIM: Inhaled corticosteroids (ICS), for years used in the therapy of low-moderate bronchial asthma, reduce the rate of asthmatic attack with improved pulmonary functioning and quality of life. Clinical trials have been addressed mainly to study the efficacy rather than the safety of drugs, so that the side effects of these drugs have not yet been accurately defined. Clinical experience shows that growth delay appears in the first months of therapy with ICS. The aim of the study was to evaluate the influence of the therapy with spacer-administered inhaled corticosteroid on short-term auxological development in prepubertal children. METHODS: In a group of children with low asthma, height and weight have been evaluated before and after six months of inhaled therapy with dipropionate fluticasone at a dose of 100 microg per day. RESULTS: Twenty-five patients (19 males and 6 females; age 5.5+/-1.6 years; range: 2.6-7.8 years) showed a regular growth during the six months of therapy (mean height 0.8 standard deviation score [SDS] before therapy and 0.8 SDS after therapy), while 21 (17 males and 4 females; age 10.0+/-1.5 years; range 8.0-12.7 years) showed an increment of growth rate (mean height from 0.5 SDS to 0.7 SDS, respectively). CONCLUSION: Spacer-administered low dose fluticasone does not negatively influence short-term growth rate, regardless of the age of the patients.