Function in Children With Mild to Moderate Asthma Long-Term Effect of Budesonide on Hypothalamic-Pituitary-Adrenal Axis

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 g/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 g/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. Pediatrics 2004;113: 1693–1699; asthma, inhaled corticosteroids, hypothalamic-pituitary-adrenal axis, children, cortisol. ABBREVIATIONS. ICS, inhaled corticosteroid; HPA, hypothalamic-pituitary-adrenal; UFC, urinary free cortisol; Bud, budesonide; CAMP, Childhood Asthma Management Program; Ned, nedocromil; ACTH, adrenocorticotrophic hormone; BSA, body surface area. Inhaled corticosteroids (ICSs) have become widely recognized as the preferred therapeutic modality for persistent asthma. However, concerns regarding the shortand long-term safety of these agents likely contribute to their underutilization.1 An area of particular concern to physicians who care for children with asthma includes the effect of ICS therapy on hypothalamic-pituitary-adrenal (HPA) axis function. The effects of ICS therapy on HPA axis function must be interpreted with the understanding that the systemic effect of exogenous corticosteroid administration (including ICS) results in biochemically detectable HPA axis suppression that must be distinguished from clinically relevant HPA axis suppression.2 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 g 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 openlabel Bud 400 g/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 g/day for 1 year.8 It is unknown whether short-term studies predict safety with longterm ( 1 year) use and whether ICSs can cause a cumulative suppression of HPA axis over time. Here we report the effect of Bud 400 g 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 From the *Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine and St Louis Children’s Hospital, St Louis, Missouri; ‡Department of Pediatrics, The University of New Mexico Health Science Center, Albuquerque, New Mexico; and §Johns Hopkins Bloomberg School of Hygiene and Public Health, Balti-