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Evidence of hypothalamic-pituitary-adrenal axis suppression during moderate-to-high-dose inhaled corticosteroid use

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Abstract

The possible risk of adverse effects due to regular use of inhaled corticosteroids (ICS) is a real concern. Our aim was to describe the factors that have an impact on hypothalamic-pituitary-adrenal axis suppression (HPA-AS) in children and adolescents taking ICS regularly. The HPA axis status of patients who were on moderate-to-high-dose ICS [>176 and >264 μg/day fluticasone propionate-hydrofluoroalkane (FP-HFA) for patients 0–11 and ≥12 years, respectively] was investigated. Various types of ICS were converted to FP-HFA equivalent according to National Asthma Education and Prevention Program (NAEPP) guidelines. Participants with a baseline (8 a.m.) serum cortisol <15 μg/dL underwent a low-dose ACTH stimulation test (LDAT) to diagnose HPA-AS. Among 91 patients, 60 (75.9 %) participants underwent LDAT, and seven (7.7, 95 % CI 3.5–15.3 %) were diagnosed with HPA-AS. Ciclesonide was more frequently used by the participants with HPA-AS compared to patients with a normal HPA axis (42.9 vs. 4.8 %, p = 0.009). Use of ICS at moderate-to-high doses for at least 7 months distinguished participants with HPA-AS from those with a normal HPA axis. Among the duration, type, and dose of ICS, solely the use of ICS with a body mass index (BMI)-adjusted daily dose of ≥22 μg FP was found to increase the risk for HPA-AS (odds ratio (OR) 7.22, 95 % confidence interval (CI) 1.23–42.26, p = 0.028). The receiver operating characteristics (ROC) curve analysis revealed a cutoff value of 291 μg/day FP (area under the curve (AUC) = 0.840, p = 0.003) for predicting HPA-AS

Conclusion: The prevalence of HPA-AS was found to be 7.7 % in children taking not only high-dose ICS but also moderate-dose ICS. Dose alone was found to be an actual risk factor for HPA-AS.

What is Known:

• Inhaled corticosteroids are the current mainstay treatment for persistent asthma.

• The possible risk of systemic side effects due to regular consumption of inhaled corticosteroids (ICS) is a frequent issue of concern for both physicians and parents of patients in the pediatric age group.

What is New:

• The prevalence of hypothalamic-pituitary-adrenal axis suppression was 7.7 % in a group of children taking inhaled corticosteroids not only at high but also at moderate doses.

• Among the duration, type, and dose of inhaled corticosteroids, only the use of fluticasone propionate equivalent metered-dose inhaler at a body mass index-adjusted daily dose of ≥22 μg was found to increase the risk for hypothalamic-pituitary-adrenal axis suppression.

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Abbreviations

ACTH:

Adrenocorticotropic hormone

CI:

Confidence interval

FP:

Fluticasone propionate

HFA:

Hydrofluoroalkane

HPA:

Hypothalamic-pituitary-adrenal axis

HPA-AS:

Hypothalamic-pituitary-adrenal axis suppression

ICS:

Inhaled corticosteroid

LABA:

Long-acting beta-2 agonist

LDAT:

Low-dose ACTH test

LTRA:

Leukotriene receptor antagonist

NPV:

Negative predictive value

OR:

Odds ratio

PPV:

Positive predictive value

References

  1. Agwu JC, Spoudeas H, Hindmarsh PC, Pringle PJ, Brook CG (1999) Tests of adrenal insufficiency. Arch Dis Child 80:330–333

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Barnes PJ, Pedersen S, Busse WW (1998) Efficacy and safety of inhaled corticosteroids. New developments. Am J Resp Crit Care Med 157:S1–53

    Article  CAS  PubMed  Google Scholar 

  3. Broide J, Soferman R, Kivity S, Golander A, Dickstein G, Spirer Z, Weisman Y (1995) Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab 80:1243–1246

    CAS  PubMed  Google Scholar 

  4. Bruni FM, De Luca G, Venturoli V, Boner AL (2009) Intranasal corticosteroids and adrenal suppression. Neuroimmunomodulation 16:353–362

    Article  CAS  PubMed  Google Scholar 

  5. Cetinkaya F, Kayiran P, Memioglu N, Tarim OF, Eren N, Erdem E (2008) Effects of nebulized corticosteroids therapy on hypothalamic-pituitary-adrenal axis in young children with recurrent or persistent wheeze. Pediatr Allergy Immunol 19:773–776

    Article  PubMed  Google Scholar 

  6. Chopra D, Bhandari B, Wardhan N (2012) Ciclesonide—a novel corticosteroid for the management of asthma. Curr Clin Pharmacol 7:73–77

    Article  CAS  PubMed  Google Scholar 

  7. Covar RA, Fuhlbrigge AL, Williams P, Kelly HW the Childhood Asthma Management Program Research Group (2012) The Childhood Asthma Management Program (CAMP): contributions to the understanding of therapy and the natural history of childhood asthma. Curr Resp Care Rep 1:243–250

    Article  Google Scholar 

  8. Drake AJ, Howells RJ, Shield JP, Prendiville A, Ward PS, Crowne EC (2002) Symptomatic adrenal insufficiency presenting with hypoglycaemia in children with asthma receiving high dose inhaled fluticasone propionate. BMJ 324:1081–1082

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Fan Y, Ma L, Pippins J, Limb S, Xu Y, Sahajwalla CG (2013) Impact of study design on the evaluation of inhaled and intranasal corticosteroids’ effect on hypothalamic-pituitary-adrenal axis function, part I: general overview of HPA axis study design. J Pharm Sci 102:3513–3527

    Article  CAS  PubMed  Google Scholar 

  10. Gelfand EW, Georgitis JW, Noonan M, Ruff ME (2006) Once-daily ciclesonide in children: efficacy and safety in asthma. J Pediatr 148:377–383

    Article  CAS  PubMed  Google Scholar 

  11. Georgitis JW (1999) The 1997 asthma management guidelines and therapeutic issues relating to the treatment of asthma. National Heart, Lung, and Blood Institute. Chest 115:210–217

    Article  CAS  PubMed  Google Scholar 

  12. Global Strategy for Asthma Management and Prevention. (GINA updated 2014). Available via http://www.ginasthma.org/. Accessed 10 June 2014.

  13. Goldberg S, Einot T, Algur N, Schwartz S, Greenberg AC, Picard E, Virgilis D, Kerem E (2002) Adrenal suppression in asthmatic children receiving low-dose inhaled budesonide: comparison between dry powder inhaler and pressurized metered-dose inhaler attached to a spacer. Ann Allergy Asthma Immunol 89:566–571

    Article  CAS  PubMed  Google Scholar 

  14. Goldsobel AB, Chipps BE (2010) Cough in the pediatric population. J Pediatr 156:352–358

    Article  PubMed  Google Scholar 

  15. Gonc EN, Kandemir N, Kinik ST (2003) Significance of low-dose and standard-dose ACTH tests compared to overnight metyrapone test in the diagnosis of adrenal insufficiency in childhood. Horm Res 60:191–197

    Article  CAS  PubMed  Google Scholar 

  16. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, Bacharier LB, Lemanske RF Jr, Strunk RC, Allen DB, Bloomberg GR, Heldt G, Krawiec M, Larsen G, Liu AH, Chinchilli VM, Sorkness CA, Taussig LM, Martinez FD (2006) Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 354:1985–1997

    Article  CAS  PubMed  Google Scholar 

  17. Hagg E, Asplund K, Lithner F (1987) Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency. Clin Endocrinol (Oxf) 26:221–226

    Article  CAS  Google Scholar 

  18. Hawcutt DB, Jorgensen AL, Wallin N, Thompson B, Peak M, Lacy D, Newland P, Didi M, Couriel J, Blair J, Pirmohamed M, Smyth RL (2014) Adrenal responses to a low dose short synacthen test in children with asthma. Clin Endocrinol (Oxf) 82:648–656

    Article  Google Scholar 

  19. Heller MK, Laks J, Kovesi TA, Ahmet A (2010) Reversal of adrenal suppression with ciclesonide. J Asthma 47:337–339

    Article  CAS  PubMed  Google Scholar 

  20. Jones SL, Trainer PJ, Perry L, Wass JA, Besser GM, Grossman A (1994) An audit of the insulin tolerance test in adult subjects in an acute investigation unit over one year. Clin Endocrinol (Oxf) 41:123–128

    Article  CAS  Google Scholar 

  21. Lipworth BJ, Clark DJ, McFarlane LC (1997) Adrenocortical activity with repeated twice daily dosing of fluticasone propionate and budesonide given via a large volume spacer to asthmatic school children. Thorax 52:686–689

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group (2000) N Engl J Med 343:1054–1063.

  23. Lougheed MD, Lemiere C, Dell SD, Ducharme FM, Fitzgerald JM, Leigh R, Licskai C, Rowe BH, Bowie D, Becker A, Boulet LP, Canadian Thoracic Society Asthma Management Continuum--2010 Consensus (2010) Summary for children six years of age and over, and adults. Can Respir J 17:15–24

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Miller WL, Achermann JC, Flock CE (2008) The adrenal cortex and its disorders. In: Sperling MA (ed) Pediatric endocrinology, 3rd edn. Saunders, Philadelphia, pp 444–511

    Chapter  Google Scholar 

  25. National Asthma Education and Prevention Program (2007) Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. (NIH publication No. 08–4051). Bethesda, MD: National Institute of Health. Available via http://www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf. Accessed 10 June 2014.

  26. Ozbek OY, Turktas I, Bakirtas A, Bideci A (2006) Evaluation of hypothalamic-pituitary-adrenal axis suppression by low-dose (0.5 microg) and standard-dose (250 microg) adrenocorticotropic hormone (ACTH) tests in asthmatic children treated with inhaled corticosteroid. J Pediatr Endocrinol Metab 19:1015–1023

    Article  CAS  PubMed  Google Scholar 

  27. Sahiner UM, Cetinkaya S, Ozmen S, Arslan Z (2011) Evaluation of adrenocortical function in 3-7 aged asthmatic children treated with moderate doses of fluticasone propionate: reliability of dehydroepiandrosterone sulphate (dhea-s) as a screening test. Allergol Immunopathol 39:154–158

    Article  CAS  Google Scholar 

  28. Shah A, Stanhope R, Matthew D (1992) Hazards of pharmacological tests of growth hormone secretion in childhood. BMJ 304:173–174

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Skoner JD, Schaffner TJ, Schad CA, Kwon AY, Skoner DP (2008) Addressing steroid phobia: improving the risk-benefit ratio with new agents. Allergy Asthma Proc 29:358–364

    Article  CAS  PubMed  Google Scholar 

  30. Smith RW, Downey K, Gordon M, Hudak A, Meeder R, Barker S, Smith WG (2012) Prevalence of hypothalamic-pituitary-adrenal axis suppression in children treated for asthma with inhaled corticosteroid. Paediatr Child Health 17:e34–e39

    PubMed Central  PubMed  Google Scholar 

  31. Schwarz RH, Neacsu O, Ascher DP, Alpan O (2012) Induced symptomatic adrenal suppression: case report and review of the literature. Clin Pediatr 51:1184–1190

    Article  Google Scholar 

  32. Todd GR, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D (2002) Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 87:457–461

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Von Berg A, Engelstatter R, Minic P, Sreckovic M, Garcia Garcia ML, Latos T, Vermeulen JH, Leichtl S, Hellbardt S, Bethke TD (2007) Comparison of the efficacy and safety of ciclesonide 160 microg once daily vs. budesonide 400 microg once daily in children with asthma. Pediatr Allergy Immunol 18:391–400

    Article  Google Scholar 

  34. Wu K, Goyal N, Stark JG, Hochhaus G (2008) Evaluation of the administration time effect on the cumulative cortisol suppression and cumulative lymphocytes suppression for once-daily inhaled corticosteroids: a population modeling/simulation approach. J Clin Pharmacol 48:1069–1080

    Article  CAS  PubMed  Google Scholar 

  35. Zeiger RS, Szefler SJ, Phillips BR, Schatz M, Martinez FD, Chinchilli VM, Lemanske RF, Strunk RC, Larsen G, Spahn JD, Bacharier LB, Bloomberg GR, Guilbert TW, Heldt G, Morgan WJ, Moss MH, Sorkness CA, Taussig LM, Childhood Asthma Research and Education Network of National Heart Lung, and Blood Institute (2006) Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol 117:45–52

    Article  CAS  PubMed  Google Scholar 

  36. Zollner EW (2007) Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids: part 1. Which test should be used? Pediatr Allergy Immunol 18:401–409

    Article  PubMed  Google Scholar 

  37. Zollner EW, Lombard CJ, Galal U, Hough FS, Irusen EM, Weinberg E (2012) Hypothalamic-pituitary-adrenal axis suppression in asthmatic school children. Pediatrics 130:e1512–e1519

    Article  PubMed  Google Scholar 

  38. Zollner EW, Lombard C, Galal U, Hough S, Irusen E, Weinberg E (2011) Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids—more common than expected? J Pediatr Endocrinol Metab 24:529–534

    Article  PubMed  Google Scholar 

  39. Zollner EW, Lombard C, Galal U, Hough S, Irusen E, Weinberg E (2011) Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids: is the early-morning serum adrenocorticotropic hormone (ACTH) a useful screening test? Pediatr Allergy Immunol 22:614–620

    Article  PubMed  Google Scholar 

  40. Zora JA, Zimmerman D, Carey TL, O’Connell EJ, Yunginger JW (1986) Hypothalamic-pituitary-adrenal axis suppression after short-term, high-dose glucocorticoid therapy in children with asthma. J Allergy Clin Immunol 77:9–13

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study includes a retrospective review of patient files that was performed with the approval of the Ethics Committee of Hacettepe University Medical Faculty in accordance with the Helsinki Declaration.

Conflict of interest

The authors declare that they have no competing interests.

Funding

There was no funding source for this study

Authors’ contribution

OC participated in the review of files and data generation, entry, and analysis, prepared the manuscript with BES who contributed the development of design, and approved the manuscript as submitted. DV had responsibility for data review, outcome assessment, and manuscript preparation with BB and EAY. OS had responsibility for management of statistical analysis and for review of statistical accuracy of the data and took part in data generation and interpretation of statistical results with UMS. NK contributed to the review and interpretation of the patient data and revision of the manuscript. All the authors approved the final manuscript as submitted.

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Authors and Affiliations

  1. Department of Pediatric Allergy, Faculty of Medicine, Hacettepe University, Sıhhıye, 06100, Ankara, Turkey

    Ozlem Cavkaytar, Ebru Arik Yilmaz, Betul Buyuktiryaki, Ozge Soyer, Umit M. Sahiner & Bulent E. Sekerel

  2. Department of Pediatric Endocrinology, Faculty of Medicine, Hacettepe University, Sıhhıye, 06100, Ankara, Turkey

    Dogus Vuralli & Nurgun Kandemir

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  1. Ozlem Cavkaytar
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Correspondence to Bulent E. Sekerel.

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Cavkaytar, O., Vuralli, D., Arik Yilmaz, E. et al. Evidence of hypothalamic-pituitary-adrenal axis suppression during moderate-to-high-dose inhaled corticosteroid use. Eur J Pediatr 174, 1421–1431 (2015). https://doi.org/10.1007/s00431-015-2610-9

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