Objective. To determine the safety of long-term (36 months) administration of an inhaled corticosteroid (budesonide) on hypothalamic-pituitary-adrenal (HPA) axis function in children with mild to moderate asthma.
Methods. This was an ancillary study of the Childhood Asthma Management Program (CAMP). Sixty-three children who had mild to moderate asthma and were enrolled in CAMP underwent evaluation of HPA axis function before and 12 and 36 months after receiving continuous therapy with either an inhaled anti-inflammatory agent (budesonide 400 μg/day or nedocromil 16 mg/day) or placebo. HPA axis function was assessed by serum cortisol levels 30 and 60 minutes after 0.25 mg of adrenocorticotrophic hormone (ACTH) and 24-hour urinary free cortisol excretion.
Results. There were no differences in serum cortisol levels after ACTH stimulation between treatment groups, regardless of time after ACTH administration or months of follow-up. Urinary cortisol excretion per body surface area was similar in both treatment groups at 36 months, after adjusting for age at randomization, race, gender, and clinic. Cumulative inhaled corticosteroid exposure did not influence serum cortisol response to ACTH or urinary free cortisol excretion at 36 months.
Conclusions. We found no effects of chronic budesonide treatment at a dose of 400 μg/day on HPA axis function in children with mild to moderate asthma and demonstrated the absence of a cumulative effect on HPA axis function over a 3-year period.
Measures of area under the serum cortisol concentration time curves and 24-hour urinary free cortisol (UFC) excretion are the most sensitive indicators of systemic activity of ICSs.3,4 UFC excretion often has been used in pediatric studies of the HPA axis because of its noninvasive nature. However, stimulation tests of the HPA axis provide more relevant measures of clinically significant suppression.
A number of clinical trials have suggested that both beclomethasone dipropionate and budesonide (Bud) at doses of 400 μg daily over 2 weeks to 3.5 years can produce a decrease in sensitive measures of HPA axis, indicating systemic activity.5–16 Most long-term studies of ICSs on HPA axis function are cross-sectional, retrospective, or not controlled by a placebo arm and thus are of limited value. No change in HPA axis function measured by basal cortisol was reported in children who received open-label Bud 400 μg/day after 12 months.17 However, a cumulative suppression was suggested in a randomized, placebo-controlled trial when a mixed group of adults and children received beclomethasone dipropionate 336 μg/day for 1 year.8 It is unknown whether short-term studies predict safety with long-term (≥1 year) use and whether ICSs can cause a cumulative suppression of HPA axis over time.
Here we report the effect of Bud 400 μg daily via Turbuhaler given over a 3-year period on HPA axis function measured by standard cortisol stimulation tests and UFC excretion. The children who were studied in this report are a subgroup of patients who are enrolled in the Childhood Asthma Management Program (CAMP), a multicenter, masked, randomized, placebo-controlled clinical trial conducted in children who are aged 5 to 12 years and have mild to moderate asthma. CAMP was designed to determine the long-term effects of 3 treatments (2 classes of anti-inflammatory agents [Bud or nedocromil (Ned)] and placebo) over a 4- to 6-year period. The purpose of this ancillary study was to assess the safety of long-term administration of Bud on the HPA axis in a subset of CAMP participants, because performing measures of the HPA axis was not feasible for all 1041 CAMP participants.
Criteria for inclusion and exclusion from CAMP have been reported elsewhere.18 Patients from the Albuquerque and St Louis sites who met all of the entry criteria for CAMP were given the option to participate in this ancillary study. Sixty-three patients from these 2 CAMP clinical sites (Albuquerque, n = 31; and St Louis, n = 32) were enrolled into the HPA axis study before randomization in the main CAMP trial. Each parent or guardian signed an informed consent statement, and participants signed an assent statement approved by each clinical center’s Institutional Review Board.
Tests of HPA axis function were performed at baseline (prerandomization), 12 months, and 36 months. All patients completed a 28-day screening period during which they demonstrated stable asthma controlled by as-needed albuterol alone. Randomization occurred ∼2 weeks after completion of this 28-day period. The baseline HPA axis visit occurred 1 day before the randomization visit on average (range: 0-14 days). During the period between completion of the 28-day screening period and randomization, patients could receive oral corticosteroids if an asthma exacerbation occurred but could not be receiving oral corticosteroids on the day of randomization. Six participants were prescribed oral corticosteroids between the final screening visit and the HPA baseline visit (range: 20-41 days between visits).
Patients were hospitalized overnight in the local General Clinical Research Center. Morning serum cortisol (obtained between 7:00 am and 9:00 am) was measured after an overnight fast. Urine was collected over a 24-hour period at the 0-, 12-, and 36-month visits.
For determining HPA responsiveness, a standard adrenocorticotrophic hormone (ACTH) stimulation test was performed (Package Insert, Cortrosyn; Organon Inc, Bedford, OH). After insertion of an indwelling catheter and drawing of blood for morning cortisol determination, ACTH 0.25 mg was administered intravenously. Blood was drawn again 30 and 60 minutes after ACTH administration.
All patients had serum cortisol levels assayed at their local site laboratory at baseline and 12- and 36-month visits. Serum cortisol levels were measured by commercially available radioimmunoassay kits at each site (St Louis site: DiaSorin, Stillwater, MN; Albuquerque site: Diagnostic Product Corp, Los Angeles, CA). Serum cortisol values from 4 patients were removed from the analysis at the 12-month visit because they were noted to be biologically implausible. The detailed reasons for removal of these 4 patients are as follows: in 2 patients (both in Ned group), serum cortisol was highest at the time 0-minute sample and decreased after ACTH in both patients at times 30 and 60 minutes. The third patient (placebo group) had an elevated serum cortisol at time 0 (20.9 μg/dL) that decreased to 7.7 μg/dL 30 minutes after ACTH and increased to 29.9 μg/dL at 60 minutes. The fourth patient (Ned group) demonstrated a baseline serum cortisol of 22.3 μg/dL that increased to 25.3 μg/dL 30 minutes after ACTH, then decreased to 16.0 μg/dL 60 minutes after ACTH. These were likely attributable to technical problems with sample handling and/or labeling.
UFC (24-hour sample) was measured by high-performance liquid chromatography. Separate laboratories analyzed the baseline and 12-month UFC samples from each clinic, because the results were expected to be similar. During preliminary analysis of baseline and 12-month data, it was determined that the UFC results from the 2 laboratories were substantially different and thus not directly comparable. For comparing UFCs between the 2 groups, all UFC levels from the 36-month visit were stored at −70°C and analyzed at a single commercial laboratory (chosen at random) as a single batch. Because no remaining aliquots of the baseline and 12-month samples were available for analysis at a single laboratory, the data from the baseline and 12-month visits were removed from the analyses.
A sample size of 60 patients (18 Bud, 18 Ned, and 24 placebo) had 80% power to detect a difference between treatment groups (Bud vs Ned/placebo) of 2.4 μg/dL in serum cortisol 60 minutes after ACTH infusion.19 The assumptions used in the sample size calculation were 2-sided type I error of .05, standard deviation of 3 μg/dL for baseline serum cortisol, and an intraclass correlation coefficient of 0.5 for baseline and follow-up measures.
The primary outcome variable in this analysis is the serum cortisol level. Analyses were completed for measurements made at 0 minutes and 30 minutes and 60 minutes after ACTH stimulation. A secondary outcome was 24-hour UFC excretion per body surface area (UFC/BSA; μg/m2/24 hours).
The 2 placebo groups (placebo-Bud and placebo-Ned) were comparable in terms of age, ethnicity, gender, asthma severity, duration of asthma, prebronchodilator forced expiratory volume in 1 second, methacholine reactivity, steroid use before randomization, body mass index, BSA, and Tanner stage. Thus, they were pooled into one placebo group for comparison with Bud and Ned. Furthermore, there were no significant differences between the Ned and placebo groups in terms of age, ethnicity, gender, asthma severity, airway responsiveness to methacholine, body mass index, or Tanner stage. Thus, the Ned group and the placebo group were combined into a single placebo/Ned group and compared with the Bud group as the primary comparison of interest was the effect of Bud.
Analysis of covariance was used to compare the effects of treatment on cortisol levels at baseline, 12 months, and 36 months in the intention-to-treat analysis. Log-transformed serum cortisol levels were used in the analyses. Models were adjusted for age at randomization, race (white vs minority), gender, clinic, and baseline plasma cortisol (at 12 and 36 months).
In addition to the intention-to-treat analysis, we performed “treatment-received” analyses using the same models as described above. First, ICS use was dichotomized as any ICS use versus no ICS use. This was done because patients were allowed to add open-label beclomethasone dipropionate as step-up therapy per protocol if their asthma was not well controlled. They could also receive other ICSs or have study medication discontinued depending on whether their asthma was poorly controlled or very well controlled. Second, oral corticosteroid use was dichotomized as any oral corticosteroid use versus no oral corticosteroid use. Short bursts of oral corticosteroids (prednisone 2 mg/kg/day [maximum 60 mg] for 2 days followed by 1 mg/kg/day [maximum 30 mg] for 2 days) were prescribed for asthma exacerbations throughout CAMP. Data were analyzed using SAS (Version 8; SAS Institute, Cary, NC).
Sixty-three children were enrolled in this ancillary study. Children in the Bud (n = 18) and placebo/Ned (n = 45) groups were similar in age, ethnicity, gender, age of asthma diagnosis, duration of asthma, and asthma severity (Table 1). These groups were also similar in terms of prebronchodilator forced expiratory volume in 1 second percentage predicted, airways hyperresponsiveness to methacholine, body mass index, BSA, and Tanner stage. Although a similar proportion of children in the Bud and placebo/Ned groups received oral corticosteroids in the 6 months preceding the CAMP screening interview, a higher percentage of children in the Bud group reported taking an ICS in the 6 months before screening (55.6% vs 22.2%; P = .01). Oral corticosteroids were prescribed to 6 HPA study participants during the period between the final screening visit and randomization (3 in Bud group, 3 in placebo/Ned group).
At the baseline visit, all 63 patients were able to provide samples of morning cortisol and cortisol levels 30 and 60 minutes after ACTH stimulation. Reasons for missing samples at 12- and 36-month visits are summarized in Table 2. Urinary samples were not available for 7 patients at the 36-month visit (5 missed 36-month visits, 2 inadequate samples [1 Bud, 1 Ned]).
We examined cortisol levels after ACTH stimulation at each testing time for individual patients to identify children with abnormal HPA responsiveness. Four children demonstrated abnormal cortisol levels during ACTH stimulation test, as defined as a 30-minute cortisol <18 μg/dL and a 60-minute cortisol <20 μg/dL.4 All 4 children were in the placebo/Ned group. One child demonstrated a below-normal cortisol level in response to ACTH at both the baseline (0 minutes: 12.1 μg/dL; 30 minutes: 16.3 μg/dL; 60 minutes: 19.6 μg/dL) and 12-month (0 minutes: 4.2 μg/dL; 30 minutes: 16.8 μg/dL; 60 minutes: 18.8 μg/dL) visits but missed CAMP visits from 28 to 40 months of the trial. This child received daily cromolyn and 5 days of prednisone in the 6 months before CAMP enrollment and Ned alone in the 4 months preceding the 12 month visit. A second child in the Ned group demonstrated below-normal cortisol levels in response to ACTH at the 36-month visit (0 minutes: 0.8 μg/dL; 30 minutes: 6.6 μg/dL; 60 minutes: 10.6 μg/dL) and was receiving fluticasone propionate (1760 μg/day) as step-up therapy for uncontrolled asthma during the 4 months preceding the visit. Two children in the placebo group displayed low cortisol levels after ACTH stimulation at the 36-month visit; 1 received beclomethasone dipropionate (336 μg/day) step-up and 1 course of oral prednisone (34 days before HPA 36-month visit) in the preceding 4 months (0 minutes: 10.8 μg/dL; 30 minutes: 17.2 μg/dL; 60 minutes: 19.3 μg/dL), and the second child received 1 course of prednisone (105 days before HPA visit) but no supplemental ICS during the previous 4 months (0 minutes: 10.7 μg/dL; 30 minutes: 17.2 μg/dL; 60 minutes: 18.3 μg/dL).
After adjusting for age at randomization, race, gender, clinic, BSA, and baseline serum cortisol level, there were no significant differences in serum cortisol levels during the ACTH stimulation test between the treatment groups, regardless of the time point during the ACTH stimulation test and months of follow-up in the intention-to-treat analysis (Fig 1). Over the course of the study, serum cortisol levels at all times collected (0 minutes, 30 minutes, and 60 minutes) tended to decrease, but this decrease was noted in both the Bud and placebo/Ned groups.
Serum cortisol concentration by time after ACTH stimulation and treatment group at baseline, 12 months, and 36 months (intention-to-treat). Values are geometric means (95% confidence intervals) from regression models of treatment group on serum cortisol level (μg/dL). Models were adjusted for age at randomization, race (white vs nonwhite), gender, clinic, BSA, and baseline serum cortisol concentration. Differences between treatment groups in serum cortisol concentrations were not significant at any time point (P > .05).
Six (33%) of the 18 children in the Bud group received supplemental ICS during CAMP, whereas 24 (53%) of the children in the placebo/Ned group received supplemental ICS for uncontrolled asthma at some point during the trial. Given the potential effect of supplemental ICS therapy on HPA function, we examined the effect of recent use of ICS on cortisol levels after ACTH stimulation. Patients who received any ICS in the 6 months preceding the baseline visit or in the 4 months preceding visits at 12 and 36 months had similar serum cortisol levels in the ACTH stimulation test to those children who did not receive any ICS (Fig 2). Furthermore, using total ICS dose in the 4 months preceding the 12- and 36-month visits as a continuous variable, ICS dose was not predictive of serum cortisol level before or after ACTH (P > .05; data not shown).
Serum cortisol concentration by time after ACTH stimulation and inhaled steroid use in the 6-month period before CAMP screening and the 4-month period preceding 12- and 36-month visits at baseline, 12 months, and 36 months, respectively. Inhaled steroid use 4 months before visit (6 months before baseline visit). Values are geometric means (95% confidence intervals) from regression models of inhaled steroid use (yes vs no) on serum cortisol level (μg/dL). Models were adjusted for age at randomization, race (white vs nonwhite), gender, clinic, BSA, and baseline serum cortisol. Differences between groups in serum cortisol concentrations were not significant at any time point (P > .05).
The proportion of patients who received prednisone for acute exacerbations during the first 36 months of CAMP was similar in the Bud (72% of patients) and the placebo/Ned (89%) groups. However, the number of prednisone courses per patient was greater in the placebo/Ned group than in the Bud group (6.2 ± 8.2 vs 3.8 ± 2.0; P = .03). The effects of oral corticosteroids on HPA axis function were considered in several ways, including oral corticosteroids used at any time during the 36-month study period or during the 4 months preceding the 12- and 36-month visits and 6 months preceding CAMP screening. Patients who received oral corticosteroids during the 6 months before CAMP screening had statistically lower levels of serum cortisol 30 and 60 minutes after ACTH stimulation at the baseline visit (P = .03 and P = .01, respectively) but did not differ in terms of 0-minute cortisol levels (P = .52; Fig 3). Only 1 patient (Ned group) exhibited abnormal cortisol levels after ACTH at the baseline visit (0 minutes: 12.1 μg/dL; 30 minutes: 16.3 μg/dL; 60 minutes: 19.6 μg/dL). This patient received 5 days of oral corticosteroid during the 6 months before CAMP but did not receive oral corticosteroids between the final screening visit and the baseline HPA visit. Oral corticosteroid use in the 4 months preceding the 12- and 36-month visits did not alter cortisol levels after ACTH administration (Fig 3).
Serum cortisol concentration by time after ACTH stimulation and prednisone use in the 6-month period before CAMP screening and the 4-month period preceding 12- and 36-month visits at baseline, 12 months, and 36 months, respectively. Prednisone use 4 months before visit (6 months before baseline screening visit). Values are geometric means (95% confidence intervals), from regression models of prednisone use (yes vs no) on serum cortisol level (μg/dL). Models were adjusted for age at randomization, race (white vs nonwhite), gender, clinic, BSA, and baseline serum cortisol level. At baseline, there were significant differences between patients who had used prednisone and those who had not in serum cortisol concentration at 30 minutes and 60 minutes after ACTH administration (P = .03 and P = .01, respectively).
In an attempt to eliminate the confounding effect of supplemental corticosteroid use on cortisol levels after ACTH stimulation, we performed a series of subgroup analyses. To eliminate the effect of supplemental ICS use on cortisol levels, we excluded patients who received ICS other than Bud in the 6 months preceding the 12- and 36-month visits and did not detect a difference in cortisol levels after ACTH between the Bud and placebo/Ned groups (data not shown). To eliminate the effect of oral corticosteroids on cortisol levels after ACTH, we examined patients who did not receive oral corticosteroids during the 6 months preceding the baseline visit and the 4 months preceding the 12- and 36-month visits and did not detect a difference in serum cortisol levels between the Bud and placebo/Ned groups (data not shown). To evaluate for the effect of oral corticosteroids and supplemental ICS, we examined patients who received only Bud or placebo/Ned during the 4 months preceding the 12- and 36-month visits and did not receive supplemental ICS or oral corticosteroids and did not find a difference in cortisol levels after ACTH between the 2 groups (data not shown).
UFC levels were assayed from a 24-hour in-hospital urine collection at the 36-month visit. Urinary cortisol excretion per BSA (μg/m2/24 hours) was similar in both treatment groups after adjusting for age at randomization, race, gender, and clinic (Table 3). Use of any ICS (either Bud or supplemental ICS in the Bud or supplemental ICS in the placebo/Ned group) at any time during the CAMP trial before the 36-month visit did not affect urinary cortisol excretion. However, use of an ICS within the 4 months preceding the 36-month visit was associated with a lower urinary cortisol excretion at a borderline statistically significant level (P = .05). Oral corticosteroid use, either within the preceding 4 months (P = .80) or at any time during CAMP (P = .88), did not affect urinary cortisol excretion at 36 months.
Given the concerns regarding cumulative corticosteroid exposure and HPA function, we examined the relationships between total steroid exposure during CAMP and markers of HPA activity. The correlations between cumulative ICS dose and 30-minute serum cortisol level at 36 months (r = 0.03, P = .78) or UFC/BSA (r = −0.20, P = .14) were low, and there was no significant correlation between cumulative prednisone exposure and serum cortisol (r = 0.13, P = .33) or UFC/BSA (r = −0.01, P = .92).
In this report, we have demonstrated that therapy with an inhaled corticosteroid (Bud) at a dose of 400 μg/day for up to 36 months is not associated with alteration of HPA axis responsiveness to ACTH stimulation. The addition of supplemental ICS during the CAMP trial did not alter this finding, neither did the use of oral corticosteroids in the 4 months preceding the 12- and 36-month visits. Furthermore, there was no evidence of a long-term cumulative effect of steroid therapy (inhaled or oral) on HPA responsiveness to ACTH stimulation.
Although comparison of group means failed to demonstrate evidence of HPA axis suppression, 4 children exhibited decreased responsiveness to ACTH in this study. These 4 children were randomized to the placebo (2 children) or Ned (2 children) group. All of these instances involved recent use of supplemental corticosteroids. It is unlikely that the oral corticosteroids influenced these results, as previous studies have failed to demonstrate HPA suppression after short courses of oral corticosteroids.20–22 Furthermore, the magnitude of suppression of the cortisol response was small, generally <2 μg/dL below the criteria for a normal response.
Interpretation of the existing literature regarding ICS use and HPA axis function is complicated by the wide variety of methods available for measuring HPA axis status and/or function (reviewed in4,23), along with other factors that may influence systemic side effects of ICS, such as disease severity, concomitant medication use, duration of therapy, and drug delivery systems. In this study, we have demonstrated that consistent use of Bud via dry-powder inhaler (Turbuhaler) in a low to medium dose in children24 does not impair baseline serum cortisol levels or alter the HPA response to stimulation after 3 years of therapy.
Serum cortisol levels showed a tendency to decrease over the 36-month period, both at baseline and after ACTH stimulation. This effect was present in both the Bud and placebo/Ned groups. The downward trend of cortisol levels may have resulted from increasing familiarity and decreasing stress response associated with clinic visits and intravenous insertion, resulting in lower cortisol levels. Alternatively, over the 36 months of the study, patients gained both height and weight and, thus, BSA but received a constant dose of ACTH (0.25 mg). Thus, over time, the dose of ACTH relative to BSA decreased, potentially reducing the magnitude of cortisol response. Lashansky et al25 also demonstrated a trend toward decreasing cortisol levels after ACTH stimulation as children progressed from infancy to early puberty, an effect more prominent in girls than in boys. However, correcting cortisol levels for age, gender, and BSA did not eliminate the trend toward decreasing cortisol levels over time observed in our study.
In addition to measuring HPA function after ACTH stimulation, we assayed for urinary excretion of cortisol over a 24-hour period in hospital at the 36-month visit. The results of the UFC studies are consistent with the findings after ACTH stimulation—UFC did not differ between the 2 treatment groups in both the intention-to-treat analysis and the analysis of use of ICS at any time during the first 36 months of CAMP. We did detect, however, a borderline decrease in 24-hour UFC/BSA among patients who received any ICS in the 4 months preceding the visit compared with patients who did not receive any ICS. This is consistent with the greater sensitivity of UFC as a marker of systemic activity from ICSs. However, the lack of effect on the standard ACTH stimulation suggests that the small perturbation of the UFC test is clinically insignificant.
We found no effect of chronic use of Bud at a dose of 400 μg/day on HPA axis function in children with mild to moderate asthma. We extend the findings of short-term studies by demonstrating prospectively the absence of a cumulative effect over a 3-year period despite using a dose that clearly produces some systemic exposure and activity.
The Childhood Asthma Management Program is supported by contracts N01-HR-16044, 16045, 16046, 16047, 16048, 16049, 16050, 16051, and 16052 with the National Heart, Lung, and Blood Institute and General Clinical Research Center at the St Louis and Albuquerque sites. This study was supported by grants M01 RR00051, M01 RR0099718-24, M01 RR02719-14, and RR00036 from the National Center for Research Resources.
Drs Bacharier and Kelly are on the speaker’s bureau for Astra-Zeneca, and Drs Kelly and Raissy receive research funding from Astra-Zeneca.