Perspectives on Growth Effects of Inhaled Corticosteroids
- List the mechanisms of growth suppression by glucocorticoids
- Describe individual patient and inhaled corticosteroid drugdevice characteristics that affect risk for growth suppression
- Recommend strategies for safe use and patient acceptance of inhaled corticosteroid treatment
Inhaled corticosteroids (ICS) remain the most effective treatment for helping children with asthma live healthier and more active lives. ICS currently approved for children with asthma include beclomethasone dipropionate (BDP), budesonide, fluticasone propionate (FP), mometasone furoate, and ciclesonide. Potential growth-suppressing effects of ICS continue to concern prescribers and families. Importantly, however, with regular reassessment of asthma control and dose reduction to the lowest effective dose, ICS can be used safely and provide the best available option for optimal control of persistent asthma.
A 9-year, 10-month-old boy treated with ICS for asthma was referred for evaluation of slowed growth. He began taking a dry powder ICS preparation twice daily when he was 4-years-old and, for the next 2 years, growth continued along the 75th percentile. At six years of age, treatment was changed to an equivalent dosage of the same medication, but administered via a hydrofluoroalkane (HFA) inhaler twice daily. One year later, his height percentile had fallen to the 50th percentile. At that time, methylphenidate treatment for attention deficit hyperactivity disorder (ADHD) was added. During the subsequent two years, his asthma was well controlled, but his height percentile continued to decline to the 20th percentile. Following return to equal dosage dry powder ICS treatment, normal growth resumed.
Glucocorticoids suppress the growth axis at multiple levels Glucocorticoids (GC) in excess of normal physiologic production (e.g. systemically absorbed ICS) can suppress linear growth at multiple levels of a child’s linear growth axis (Figure 1).
Centrally, GC diminish pulsatile GH secretion and, peripherally, reduce GH-receptor expression in growth plates and liver and reduce the production and bioactivity of its secondary messenger, insulin-like growth factor-1 (IGF-1). These effects inhibit growth plate chondrocyte proliferation and collagen synthesis necessary for normal linear growth. Susceptibility to ICS-mediated growth suppression can be increased in children with delayed growth patterns (i.e., “late bloomers”) and/or children treated with other growth-affecting medications (e.g., stimulant medications for ADHD).
ICS Treatment Can Slow Childhood Growth Rate
Reduction in linear growth rate is a very sensitive indicator of ICS systemic effects. Case reports and well-designed prospective trials in pre-pubertal children have clearly shown that ICS treatment can cause dose-dependent slowing of growth rate. Furthermore, prior assumptions regarding a lack of any noticeable effect of ICS on growth during early life and adolescence have recently been challenged by studies showing 1) detectable growth-inhibition in toddlers receiving drug-device treatments that enhance ICS delivery, and 2) a slight, but detectable reduction in adult height compared to expected following long-term use of ICS during childhood and adolescence (discussed more below/online). These observations have prompted debate whether, for some children with asthma, judicious use of prompt intermittent ICS rescue for exacerbations rather than continuous ICS use is a reasonable option for disease management that would further reduce risk for growth inhibition. Regardless of daily or rescue use of ICS therapy, it must be emphasized that the safety profile of ICS treatment to achieve good asthma control far exceeds that of either reliance on oral corticosteroid therapy or morbidity of inadequately treated asthma. Consequently, it is important to be familiar with both ICS and patient characteristics which influence risk for growth effects and strategies to minimize or prevent such effects.
ICS Systemic Exposure Depends on Drug and Delivery Device Characteristics
ICS are highly potent glucocorticoids, with receptor binding affinities that are 4 to 14 times that of dexamethasone. Systemic exposure to a particular ICS depends upon dosage, bioavailability of swallowed ICS, delivery to the lungs, potency in the systemic circulation, and pharmacokinetic features such as volume of distribution, clearance, and half-life (Figure 2).
Figure 2. Effects of drug and device characteristics on systemic bioavailability of a conceptual 100 mg dose of various ICS preparations. BDP, beclomethasone diproprionate; BMP, beclomethasone monopropionate (active metabolite of BDP); BUD, budesonide; FP, fluticasone propionate; GI, gastrointestinal. From Allen, JPeds 2014.
Low bioavailability of swallowed ICS reduces risk for systemic adverse effects by limiting ICS access to the systemic circulation only through the target organ (lung) without additional absorption of drug through a non-therapeutic (intestinal) route. This is important because percentages of swallowed ICS absorbed into the systemic circulation vary widely – BDP 25-40%, budesonide 10%, and FP, mometasone, and ciclesonide < 1%.
These differences help to explain variations in first-year growth suppression observed during treatment with dosages of different ICS estimated to be clinically equivalent at controlling asthma. However, because all ICS are efficiently absorbed from the lungs into the systemic circulation, sufficient dosage of any ICS can inhibit growth.
Reduction in ICS particle size is a key medication modification that increases the efficiency of drug delivery to small airways for the same nominal dosage, leading to increased systemic absorption, and, therefore, potential systemic effects. In response to the 2010 prohibition of chlorofluorocarbon (CFC) propellants by the Food and Drug Administration (FDA) for environmental concerns, manufacturers turned to hydrofluoroalkane (HFA) propellants which – due to greater solubility - allow formulation of compounds as a solution (not a suspension like CFC) with smaller and more consistent particle size. As a result, most HFA ICS preparations show both increased systemic bioavailability and improved therapeutic effects when compared to equal dosage CFC preparations due to more efficient delivery to and absorption within small airways. For instance, HFA BDP administration leads to plasma BDP-metabolite concentrations ~ 3 fold greater than with same-dose CFC-based BDP therapy, and to detectable growth slowing (mean 1.1 cm/year) in children at the very low dose of 40 mcg twice daily (i.e. approximately 20% of the nominal dose utilized in prior CFC BDP growth studies).
Particle size and efficiency of lung delivery can also vary significantly for the same drug depending on administration via dry power (DPI) versus meter-dose (MDI) inhalers. For example, DPI FP 100mcg twice daily had minimal effect on growth in pre-pubertal children whereas toddlers receiving MDI FP 88mcg twice daily showed noticeable growth attenuation, particular in the smallest and youngest study participants. The case vignette above also illustrates effects of increased systemic ICS exposure resulting from a switch from DPI to MDI treatment at the same nominal dosage. To avoid excessive dosage of and unnecessary risk for systemic effects from ICS, therefore, it is important for providers to take into account differences in efficiency of ICS delivery to the lung – either in adjusting prior CFC-based dosages to newer HFA formulations or in switching from dry powder to meter-dose inhalation - in selecting initial ICS dosage and subsequently tapering to lowest effective dosage.
High Treatment Adherence: A “Risk Factor” for ICS-mediated Growth Suppression
In the authors’ experience, one attribute common to most children experiencing unwanted systemic effects from ICS treatment is high adherence to the prescribed treatment regimen. Since compliance with twice daily prescribed ICS administration declines to an average of 50-60% during the first year of treatment, it is likely that typically prescribed dosages often exceed that needed to control asthma when compliance is 100%. As a result, exceptional adherence to the prescribed treatment plan by patients or parents should be considered an additional factor influencing closeness of follow-up for growth assessment and dosage reduction opportunities.
ICS Therapy Effects on Adult Height: Detectable But Small
It was previously assumed that growth slowing due to ICS treatment during childhood represented delayed growth that would correct during adolescence to yield an adult height unaffected by prior ICS exposure. However, a recent study of nearly 1000 subjects showed that differences in growth observed between ICS-treated and control children persisted into adulthood. Specifically, the reduction in adult height in the ICS-treated group compared with the placebo group (−1.3 cm; 95% CI, −1.7 to −0.9) was similar to that seen after the first 2 years of treatment, and was most pronounced in those who were pre-pubertal at that time. Importantly, while the decrease in attained height associated with ICS use in pre-pubertal children persisted as a small reduction in adult height, the decrease was not progressive or cumulative and the quality of life enjoyed by children with better controlled asthma likely exceeded the potential benefit of being ½ to 1 inch taller without ICS therapy.
Relevance for Care of Children with Asthma
Normal growth of a child, including those with asthma, is of paramount concern to families, therefore, introducing a possible risk to growth makes it challenging to inspire acceptance of and confidence in initiating ICS therapy. The following key points can help to foster appropriate perspective for families balancing the significance of ICS growth effects with the importance of asthma control:
- Reinforce that asthma is a potentially disabling and serious disease, for which optimal control is the first priority. ICS offer effective, targeted treatment with a high benefit to risk ratio, particularly when compared to oral corticosteroid treatment.
- Acknowledge slight slowing of growth during childhood as a possible effect of treatment, but one that is favorably balanced by freedom from asthma symptoms and, in severe cases, prevention of life-threatening episodes. Inform parents that, even with long-term use, there is potential for only a slight reduction in adult height of less than one inch on average.
- Reassure parents that proper drug selection, monitoring, and dose-adjustment will prevent or minimize growth effects of ICS. Steps include: 1) selecting ICS preparations with low oral bioavailability to minimize exposure to non-therapeutic (i.e. swallowed) corticosteroid, 2) adjusting dosage for differences in drug delivery to the lung provided by the specific drug/delivery device, and 3) dose titration to lowest dose effective to control asthma.
- Plan follow-up appointments for asthma, growth assessment, and ICS dose adjustment (e.g., every 4 months), particularly for toddlers and children requiring high ICS dosages, already demonstrating short stature due to constitutional growth delay, or receiving other steroid treatments or medications (e.g., stimulants) with potential growth suppressing effects. Consult a growth expert if growth slowing occurs in spite of efforts to titrate to the lowest-effective ICS dosage, to evaluate for other potential causes of growth inhibition, and/or other systemic effects of ICS, such as adrenal axis suppression.
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