CAMP: Long Term Effects of Asthma Therapy
The Childhood Asthma Management Program (CAMP) Study
Case Study Summary
Questions Arising From the Case
Physicians today have a variety of medications to offer children with asthma, but little data documenting the long-term outcomes of any given treatment plan. This is disconcerting to both physicians and parents as they attempt to select the best course of treatment for an affected child, knowing that he/she probably faces years on medication to control the chronic inflammatory processes underlying asthma. For example, treatment with inhaled corticosteroids has been highly recommended as one option for improved control of asthma, but concerns have arisen over adverse effects in children, especially effects on growth. Short-term studies have demonstrated a decrease in growth during the first year on inhaled corticosteroids, but long-term data have been lacking. Other concerns exist as well, including the possibility of cataract. Balanced against these concerns are the desires to reduce urgent care visits and hospitalizations, to improve or slow the decline of lung function, and to improve quality of life for both child and the family. And, while nedocromil, cromolyn, or a leukotriene inhibitor provide other choices, the same basic question of long-term risk versus benefit still exists for each of them as well.
The Childhood Asthma Management Program (CAMP) Study
The Childhood Asthma Management Program (CAMP) was a multicenter, randomized, double-masked clinical trial designed to answer just such questions by determining long-term effects of treatment for mild-to-moderate childhood asthma. Three daily inhaled treatments were compared: (1) budesonide, a glucocorticoid, 200 µg twice daily; (2) nedocromil, a nonsteroidal anti-inflammatory, 8 mg twice daily; and (3) placebo, twice daily. All participants also used albuterol, a short-acting beta-agonist bronchodilator, as needed for symptom control.
1,041 children ages 5 through 12 were enrolled at eight centers between December 1993 and September 1995 and followed from four to six years (Table 1). Follow-up visits were held two and four months after randomization and at four-month intervals until March through June 1999. The children discontinued study medications at this point and then returned two to four months later for final testing. The study results were summarized in an article in The New England Journal of Medicine.
One of the unique features of the CAMP trial is that for the first time a study provides a comprehensive picture of the outcomes of selecting a medication, with key information about clinical impact, changes in pulmonary function, and adverse effects (Table 2). Clinical indices included urgent care visits and hospitalizations, episode-free days, use of prednisone or albuterol, nighttime awakenings, compliance, daily symptom score, and psychologic testing scores. Measures of pulmonary function consisted of FEV1, FEV1/FVC, and methacholine challenge. Indicators of adverse effect comprised changes in actual and projected height; bone density, fractures, and age; development of cataract; and Tanner score.
As shown in Table 1, the three treatment groups had similar baseline characteristics and the same length follow-up [mean = 4.3 years]. Typically, the children were first diagnosed with asthma at age three, approximately five years prior to entering the study. Slightly more than half of each group had moderate asthma; the rest had mild asthma. During the six months prior to enrollment, they had used one or more treatment regimens: inhaled corticosteroid [36 to 41% of each study group], cromolyn or nedocromil [38 to 47%], or oral corticosteroid [30 to 39%]. They had an average of only 10 symptom-free days per month, needed albuterol several times per week to treat symptoms, and recorded approximately one nighttime awakening per month due to asthma. The hospitalization rates were also similar.
The CAMP study compared the results of long-term treatment with budesonide or nedocromil versus placebo (Table 2). Three areas were evaluated: pulmonary function, clinical outcomes, and adverse effects: Pulmonary function: None of the groups demonstrated a long-term effect on FEV1 after administration of bronchodilator, possibly because an irreversible change in lung function may have already occurred in the patients prior to the study. The children had already had asthma for a mean of five years before enrollment, while some studies recommend treatment start within two to three years after onset of disease to minimize changes in lung function. However, airway responsiveness did improve in all groups, with significantly greater improvement in the budesonide-treated group. Nedocromil was similar to placebo in this category.
Budesonide treatment was associated with a sharp reduction in hospitalization [43% lower], urgent care visits [45% lower], and use of prednisone [43% lower] compared with placebo. Nedocromil use was similar to placebo in rate of hospitalization, although it was associated with a lower rate of urgent care visits [27%] and use of prednisone [16%]. Budesonide was also associated with the most improvement in control of asthma, including fewer symptoms, less use of albuterol, more episode-free days, longer times to treatment with prednisone or other nonassigned asthma medication, and number of days on which another asthma medication was prescribed. Nedocromil treatment was similar to placebo in most of these categories, although courses of prednisone were reduced relative to placebo [p<0.01], but not as much as with budesonide use. Compliance was similar with budesonide and placebo, but lower in the nedocromil group [p<0.01].
The only significant adverse effect noted was a reduction in rate of growth in the budesonide-treated group, a mean of 1.1 cm difference in height. This reduction in height occurred primarily in the first year of treatment and did not worsen with continued use of budesonide. Nedocromil was not associated with a reduction in height. Other measures, including bone age, projected final height, and Tanner stage, were similar in all three treatment groups at the end of the study. One child in the budesonide group developed a "questionable posterior subcapsular cataract." This study participant had also received beclomethasone, oral prednisone, and intranasal corticosteroids during the study.
Case Study Summary
The following case history will illustrate how this information can be applied in the clinical setting.
David is an 8-year-old male with mild persistent asthma that has been worsening.
David reports problems with nighttime awakenings [approximately once or twice a month] and asthma symptoms when he plays sports at school. He currently uses his albuterol inhaler almost daily [approximately 8 to 14 puffs per week]. A new patient, he recently moved to the area, has had difficulty adjusting to the move, and wants to play sports again "like the other kids." His prior treatment consisted of albuterol inhaler as needed, with occasional visits to the emergency room when the inhaler did not resolve his asthma symptoms. The parents previously refused to consider any type of long-term treatment with a steroid, including inhaled corticosteroids, because they have heard that "steroids are harmful" and that they "stunt growth."
The husband recently transferred here and his wife now has a new job. They are especially concerned with David's health, but also with the constant disruption to family life, loss of sleep, and lost time on the job. His physical exam is normal except for some indications of allergic symptoms, edematous nasal passages with thin secretions and allergic shiners. His pulmonary function was FEV1 89% predicted with a reversal by 15% with 2 inhalations of albuterol. His FEV1/FVC ratio was 0.83. After performing an exercise challenge in the office, his FEV1 decreased by 20% and there were diffuse expiratory wheezes on auscultation after he finished the challenge. This was quickly relieved with 2 inhalations of albuterol.
Questions Arising From the Case
What options for David's treatment can you recommend to the parents?
What results do you anticipate for the clinical outcome, pulmonary function, and risk factors for each of these?
How should you address the parental concerns about the use of inhaled corticosteroids?
Four basic approaches can be suggested for David's treatment.
David could continue with the current treatment plan. However, his asthma is obviously not under good control. The primary reason he is not receiving additional medication is his parents' lack of knowledge about other options, including detailed information on the risks and benefits.
If David were to continue with this approach, the CAMP study results suggest the following outcomes (Table 2):
Continued symptoms of respiratory distress occurring several times per week and after exercise
Possible need for a course of treatment with prednisone for more significant exacerbations
Some improvement in nighttime awakenings and use of albuterol if he is closely monitored and uses the inhaler properly [that is, if his follow-up mimics that of a child enrolled in the clinical trial]
No significant improvement in episode-days
No improvement in FEV1
Some improvement in airway responsiveness to methacholine challenge as he grows older
No increased risk for delayed growth or cataractsThis option offers little clinical or pulmonary improvement and does not address the parents' concerns over disruptions in the family's daily lives. In addition, it puts David at continued risk for breakthrough symptoms, difficulty with exercise, and risk for nighttime episodes and emergency care visits. It does not address David's stated desire to play sports, a goal that might help him better comply with a treatment plan.
David could receive nedocromil, one of the drugs evaluated in the CAMP study.
Nedocromil is an inhaled anti-inflammatory drug for the treatment of asthma that is not a steroid. The children in the CAMP study received 8 mg, twice daily, delivered by four 2-mg actuations of a pressurized metered-dose inhaler. After four to six years of treatment, the study group demonstrated no improvement in FEV1, but this was true for the budesonide and placebo groups as well. Airway responsiveness did improve [ratio 1.8, follow-up: baseline] but the degree of improvement was the same in the placebo group [ratio 1.9], indicating that the nedocromil was not responsible. Unfortunately, similar information about the long-term effects of cromolyn, a nonsteroidal anti-inflammatory agent like nedocromil, is not available to help determine if it is a good alternative. To ensure the most improvement in David's respiratory function, the inhaled corticosteroid budesonide should be considered in place of nedocromil.
Nedocromil treatment would probably improve two important clinical outcomes for David: urgent care visits and the need for prednisone, both of which are major parental concerns about David's illness. However, hospitalizations for asthma will not be any better than just treating symptomatically. Long-term treatment with nedocromil is also unlikely to improve other key aspects of asthma control [compared with placebo treatment], including number of symptoms, nighttime awakenings, use of albuterol, number of episode-free days, and number of days on which another asthma medication is needed. This suggests that nedocromil will not satisfactorily address the parents' desire for David's successful treatment to be accompanied by a reduction in disruptions to family life. One potential complication of treatment with nedocromil is its association with reduced adherence to the treatment schedule, usually attributed to the taste of the medication. Therefore, careful monitoring of medication administration will be necessary.
Nedocromil treatment would ease the parental concerns over adverse effects of long-term medication. It is not associated with decreased growth or with other adverse effects over the four to six years of this study.
David could be treated with an inhaled corticosteroid such as budesonide, which was evaluated in the CAMP study.
Budesonide, an inhaled corticosteroid, appears to give David the best chance for improvements in both respiratory function and clinical outcomes but does carry a risk of a small reduction in growth during the first year of treatment. [Children in the CAMP study received 400 µg budesonide daily with a breath-actuated metered-dose inhaler.]The CAMP study used FEV1 measurement after bronchodilator use as the best indicator of improved lung function and this did not improve with budesonide, nedocromil, or placebo use. (The possible reasons for this are discussed in more detail in reference 2 [CAMP Group, 2000].) Budesonide does offer David the most improvement in airway responsiveness; a three-fold increase over baseline values [significantly greater than that seen with placebo or nedocromil treatment] was noted in the CAMP study. David would likely see the most improvement in a wide variety of clinical outcome measures with budesonide as well. He could expect fewer hospitalizations or urgent care visits, factors that should assist the family's goal for reduced disruptions to daily life. He could expect better asthma control in general, with fewer symptoms, reduced use of his albuterol inhaler, more episode-free days, and less need for treatment with prednisone or other additional asthma medication.
A major concern of his parents, however, is the use of any steroid. They will need additional information explaining the distinction between use of a daily inhaled corticosteroid such as budesonide and use of a systemic drug such as prednisone. The results of the CAMP study should allay their fears about reductions in growth rate, in particular. David can expect a slight reduction in growth during the first year of treatment [approximately 1 cm] and that small change can be demonstrated to the parents with a ruler. Secondly, they should be reassured by the fact that this reduced growth velocity does not continue during subsequent years of treatment. In fact, David can expect to attain his full projected adult height. No other adverse risks were associated with long-term budesonide treatment, which will also greatly reassure the parents that this medication is safe for David to take on a daily basis.
David could receive another medication, such as a leukotriene blocker.
While clinical studies address the general efficacy of leukotriene inhibitors, no similar data are available addressing long-term effects of four to six years of treatment. David's parents would not have their concerns about long-term safety addressed, nor could they receive valuable information about long-term results for effectiveness of this treatment option. Such information is sorely needed to help both the physician and the parents select the best treatment option for David
The selection of the optimal treatment plan for children with mild or moderate asthma can be simplified and enhanced using the results of the recently concluded CAMP study. This long-term, comprehensive picture of treatment with placebo, nedocromil, or budesonide answers many questions about predicted improvement in respiratory function, changes in clinical outcomes, and risk of adverse effects. These types of data are badly needed for other available and investigational medications as well, as physicians and parents search for the best therapeutic option.
It should be noted that the results of the CAMP study that was conducted at National Jewish Health as one of the eight study centers had a significant impact on the recent revisions made to the National Asthma Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma. Largely due to the findings in this study, inhaled steroids are now recognized as the preferred medication for the management of persistent asthma in both children and adults. A detailed discussion of the rationale for this approach was recently summarized in a supplement to the Journal of Allergy and Clinical Immunology (3).
Stanley J. Szefler, MD acknowledges the assistance of Mary E. King PhD in the preparation of this article.
The Childhood Asthma Management Program Research Group. The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Control Clin Trials 1999;20:91-120
The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. New Engl J Med 2000;343:1054-63
National Asthma Education and Prevention Program Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics 2002, J Allergy Clin Immunol 110:1A-8A, S141-S219, 2002.
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This information has been approved by Stanley Szefler, MD (August 2003). Original publication Spring 2001; updated August 2003.