Vol. 13 •Issue 8 • Page 24
Drug Data
Inhaled Corticosteroids Phobia and Childhood Asthma: What’s a Doctor to Do?
A 6-year-old child sits on your exam table and coughs uncontrollably, a symptom he’s experienced for the past three days. You note wheezing upon auscultation during the physical exam. Additional history reveals that the child received a diagnosis of asthma a year ago, and he uses nebulized albuterol for symptom relief.
In the past four weeks, he’s required albuterol three times a week, and occasionally two to three nights a week. He’s frequently out of breath or coughs when he runs hard and needs to rest.
Assessment according to the National Heart, Lung, and Blood Institute’s guidelines indicates that your young patient has moderate persistent asthma and should receive a daily controller medication, specifically an inhaled corticosteroid.1,2 However, when you recommend this to the child’s mother, she greets the news with apparent reservation. You’re convinced that this is the best medication for the child, but his mother isn’t so sure and has several questions.
First of all, the parent wants to confirm if this is a “steroid” because she’s heard “bad things” about them. She doubts her child needs so strong a medication and isn’t aware that her child’s asthma warrants this treatment. She wants to know how this will affect his body and his growth. With most concern, she asks if he’ll have to take this medication for the rest of his life.
THE PHYSICIAN’S RESPONSIBILITY
The day is long over when a physician prescribing medications has the privilege of not being challenged by questions as to the efficacy, relative benefits and safety of the medication prescribed. In this situation, the first person to be convinced of the need for inhaled corticosteroids in persistent asthma is the physician.
Despite national guidelines first published in 1991 and revised in 1997 and again in 2002, significant discrepancies continue between the recommendations and clinical management.1-3 Comparisons by specialty and general medicine groups over a five-year interval (1994-1998) reveal that the lowest proportions of inhaled corticosteroid prescriptions for patients with moderate/high risk asthma occurred among pediatric emergency department physicians and pediatricians.3
It should be quite clear by now that inhaled cortico.steroids are the cornerstone of preventive management of childhood asthma and first-line therapy in moderate and persistent asthma. The recently updated national guidelines now recommend that inhaled corticosteroids are the preferred treatment for initiating therapy in children of all ages with persistent asthma.2
To begin appropriate therapy, the level of asthma severity needs to be assessed. In the patient scenario above, it’s clear that the child has persistent asthma. Classifying the level of severity requires knowledge of the guidelines. The proper questions eliciting frequency of symptoms, albuterol used as rescue medication, nighttime symptoms (asked separately from daytime symptoms), and exercise tolerance will determine the level of severity and convince the physician of the need for a controller medication.
RELATIVE BENEFIT AND RISK
The evidence supporting the benefit of daily continuous medication comes from many studies showing that inhaled corticosteroids improve pulmonary function, reduce the need for bronchodilators, improve quality of life, improve exercise tolerance, and reduce hospitalization rates.4 These benefits far outweigh the possibility of risks, and risk is further reduced as doses are stepped down with achievement of adequate control.
The safety issues involving use of inhaled corticosteroids in children primarily concern suppression of the hypothalamic-pituitary adrenal (HPA) axis, growth, and decreased bone mineral density. The evidence on all three accounts is reassuring.
Evidence-based conclusions on inhaled corticosteroids treatment for asthma presented in the December 2003 issue of the journal Chest by the American College of Chest Physicians, the American Academy of Allergy, Asthma and Immunology, and the American College of Allergy, Asthma and Immunology represent the most current informed opinion.5 This publication reviewed the pertinent literature and asked four questions related to children:
• Is there a reduction of bone density in children with asthma using inhaled .corticosteroids?
• Does inhaled corticosteroid therapy affect the rate of growth in asthmatic children?
• Does inhaled corticosteroid therapy affect the final height of children with asthma?
• Do inhaled corticosteroid formulations .differ in their growth-related effects?
The review also considered cataract, glaucoma and skin thinning/easy bruising.
Variables relating to the quality of the reviewed articles were assessed. Grades were given for .reliability in evaluating the relationship between drug and complications. The evidence grades were rated “A” through “F” based on categorical reviews of clinical trials for sufficient and reliable evidence to support the conclusions.
The following findings are pertinent to children:
• Inhaled corticosteroid use in children isn’t associated with a reduction in bone density. (Grade A: An evidence grade of A was based on conclusions derived from at least two high quality, blinded, randomized clinical trials and might be further supported by observational studies.)
• There’s a decrease in short-term growth rates in children, but the overall effect is small and may not be sustained with long-term inhaled corticosteroid therapy. (Grade A.)
• The adult height attained by asthmatic children treated with inhaled corticosteroids isn’t different from that of nonasthmatic children. (Grade C: Conclusions supported by a preponderance of evidence, but there exists high quality conflicting evidence.)
• There’s insufficient information on the .difference between steroid formulations (flutica.sone propionate, beclomethasone dipropionate, budesonide) to derive definitive conclusions .concerning growth-related effects. (Grade C.)
• The risk of subcapsular and nuclear cataracts associated with inhaled corticosteroid therapy is negligible in young asthmatics. (Grade C.)
• The risk of glaucoma associated with inhaled corticosteroids use is likely to be small, but further study is warranted. (Grade F: Indicates that the question failed evidence review, and no evidence-based conclusion could be derived.) The overall conclusion is that ocular complications haven’t been clearly associated with inhaled corticosteroid use.
The risk of skin thinning and easy bruising is elevated in patients receiving inhaled corticosteroids, but duration of treatment and possibly female gender are important variables affecting the overall risk. In this regard, a study of 157 children 3 to 6 years old showed that three to six years of inhaled budesonide treatment at an average daily dosage of 500 mcg, compared with age-matched asthmatic children who had never received treatment with a corticosteroid, didn’t incur increased incidence of posterior subcapsular cataract, bruises, tendency to bruise, hoarseness or other noticeable voice changes.6
Most important is the summary statement that the “preponderance of evidence supports a conclusion that the proven efficacy of inhaled corticosteroid treatment in asthma outweighs the proven risks.”5
SUPPORTING STUDIES
Additional reviews of growth effects buttress these conclusions.7-9 That is, there may be a reduction in short-term growth velocity that isn’t sustained, and in the long-term, final adult height is preserved. The supporting evidence for this conclusion is particularly well-considered in a very thoughtful review of whether inhaled corticosteroids inhibit growth in children.8
After an extensive consideration of the data focused on short-term, intermediate and long-term studies of growth in asthmatic children receiving inhaled corticosteroids, the author concluded that no controlled studies have reported any statistically or clinically significant adverse effect on growth with orally inhaled corticosteroid at the usual childhood doses of 100 to 200 mcg per day.8
Growth retardation may be seen with all inhaled corticosteroids when a sufficiently high dose is administered without any adjustment for disease severity and control. Growth suppression in both short- and intermediate-term studies is dose dependent.8,9
The growth retarding effects of inhaled corticosteroid treatment seem to be more marked at the beginning of treatment, and in some way become attenuated with continued treatment. The corticosteroid-induced changes in growth rate during the first one to two years of treatment don’t predict adult height. Children with asthma treated with inhaled corticosteroids have been found consistently to attain normal final adult height.8
Relevant to this point is the Childhood Asthma Management Program (CAMP) where budesonide was used for four years with slowing of growth by 1 cm in the first year compared with nedocromil and placebo.10 Thereafter, there was no difference in growth rate in subsequent years. The lost 1 cm wasn’t regained by the end of the study (mean duration of 4.3 years), but the predicted final adult height was based on bone age and came within target genetic predicted height.10 This study is currently in a continuation phase and will eventually be the first to report height based on direct measurement of children followed from childhood through adolescence and final adult height.
Several other reviews have considered possible occurrence of additional adverse effects. Oral and dental health problems may occur and need attention.7 Dysphonia and oral candidiasis is uncommon in children but may be seen with high doses and poor technique and lack of mouth rinsing after use. Dental decay and erosion has been noted to be more frequent in children with asthma and may be correlated with dry powder formulations.
Reports of adrenal suppression have appeared, the largest series being a national survey in the United Kingdom in which 33 cases of acute adrenal insufficiency, of which 28 were children, were reported.11 In 28 of the 33 patients, fluticasone propionate was the only inhaled corticosteroid used with dosages ranging from 500 to 2,000 mcg per day. Only one adult and 13 children were described as having severe asthma by British Thoracic Society guidelines. Furthermore, in the United Kingdom, fluticasone propionate accounts for only 15 percent of all inhaled corticosteroid prescriptions, and 31 of the 33 patients were receiving fluticasone propionate.
This brings up several important points: Patients must be accurately characterized as to severity; parents should be warned to the potential risk of adrenal insufficiency when using very high doses; and repeated follow-up is necessary to titrate the dosage downward once adequate .control is achieved.
The physician should be aware of the possibility of symptoms related to adrenal insufficiency in an acutely ill child especially with vomiting or diarrheal illness as there may also be idiosyncratic responses. The majority, though, would be expected to occur only with very high doses.
A current report from the CAMP study cohort is reassuring.12 A comparison of three treatment groups, budesonide (400 mcg/day), nedocromil (16 mg/day) or placebo for 63 children with mild to moderate asthma within the CAMP study was undertaken to evaluate the effect upon HPA axis function. No effect was found for chronic budesonide treatment at the study dose upon HPA axis function, and the absence of a cumulative effect was demonstrated over a three-year period.
COMMUNICATION AND REASSURANCE
How does a physician explain all this to the parent? The disease process has to be understood as a chronic inflammatory process that’s present even when symptoms aren’t apparent.
Try using this analogy: Asthma’s inflammatory process smolders along silently but is ready to be set ablaze whenever sparked by exposure to inciting agents such as allergens, respiratory viral infections, exertion, weather changes and even emotional events. This inflammatory process needs to be continually dampened by daily inhaled corticosteroid medication in order to prevent triggering of symptom exacerbations.
Parental anxiety is best addressed when efficacy and safety issues have been explained. It gives them reassurance to know that inhaled corticosteroids are designed to be a local, topical application to the lung where very little is .available for absorption into the blood stream. This minimizes the potential systemic effects .of HPA suppression, adverse growth and decrease in bone mineralization.7
Make sure parents know ahead of time what is to be monitored and what information will be recorded to ensure safety as well as benefit. The usual practice is to initiate treatment with a relatively high dose to bring symptoms under control. Follow-up visits are scheduled for the purpose of stepping down the dosage pending good control, and parents can be assured that the lowest effective dose will be used.
As the child is seen on follow-up visits, specific questions are addressed to assess the current clinical status. These questions follow the guidelines and inquire about the frequency of albuterol use, symptoms, nocturnal symptoms (separately from daytime symptoms) and exercise symptoms or limitations. Appropriate control measured by the response to these questions allows the physician to titrate to the lowest dose maintaining good control.
At the same time, the child’s height is measured and recorded on a standardized growth chart. When parents are able to observe your careful approach to monitoring their child’s status, to hear your explanation of the required dose, and to know that you’re addressing their concerns, they’ll gain confidence in adhering to the treatment course. And you’ll find cooperation and partnership in a satisfactory therapeutic relationship.
Dr. Bloomberg is associate professor of pediatrics at Washington University School of Medicine, St. Louis, in the division of allergy and pulmonary medicine at St. Louis Children’s Hospital.
For a list of references, please call John Crawford at (610) 278-1400, ext. 1499, or visit www.advanceweb.com/respmanager.
