Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
22
02
2021
accepted:
24
01
2022
pubmed:
23
3
2022
medline:
22
4
2022
entrez:
22
3
2022
Statut:
ppublish
Résumé
The application of large-scale metabolomic profiling provides new opportunities for realizing the potential of omics-based precision medicine for asthma. By leveraging data from over 14,000 individuals in four distinct cohorts, this study identifies and independently replicates 17 steroid metabolites whose levels were significantly reduced in individuals with prevalent asthma. Although steroid levels were reduced among all asthma cases regardless of medication use, the largest reductions were associated with inhaled corticosteroid (ICS) treatment, as confirmed in a 4-year low-dose ICS clinical trial. Effects of ICS treatment on steroid levels were dose dependent; however, significant reductions also occurred with low-dose ICS treatment. Using information from electronic medical records, we found that cortisol levels were substantially reduced throughout the entire 24-hour daily period in patients with asthma who were treated with ICS compared to those who were untreated and to patients without asthma. Moreover, patients with asthma who were treated with ICS showed significant increases in fatigue and anemia as compared to those without ICS treatment. Adrenal suppression in patients with asthma treated with ICS might, therefore, represent a larger public health problem than previously recognized. Regular cortisol monitoring of patients with asthma treated with ICS is needed to provide the optimal balance between minimizing adverse effects of adrenal suppression while capitalizing on the established benefits of ICS treatment.
Identifiants
pubmed: 35314841
doi: 10.1038/s41591-022-01714-5
pii: 10.1038/s41591-022-01714-5
pmc: PMC9350737
mid: NIHMS1825621
doi:
Substances chimiques
Adrenal Cortex Hormones
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
814-822Subventions
Organisme : Medical Research Council
ID : MC_UU_00006/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : K01 HL153941
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL123915
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL155742
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_12015/1
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : K23 AI130408
Pays : United States
Organisme : Medical Research Council
ID : MR/N003284/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0401527
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L00002/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1000143
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : L40 AI138248
Pays : United States
Organisme : Cancer Research UK
ID : 14136
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : K23 HL151819
Pays : United States
Organisme : Medical Research Council
ID : MC-UU_12015/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : K01 HL146980
Pays : United States
Organisme : NHLBI NIH HHS
ID : K99 HL159234
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141826
Pays : United States
Organisme : Cancer Research UK
ID : C864/A14136
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL139634
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Type : CommentIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Global Initiative for Asthma. Global strategy for asthma management and prevention. https://ginasthma.org/ (2021).
Masoli, M., Fabian, D., Holt, S. & Beasley, R. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59, 469–478 (2004).
pubmed: 15080825
doi: 10.1111/j.1398-9995.2004.00526.x
Becker, A. B. & Abrams, E. M. Asthma guidelines: the Global Initiative for Asthma in relation to national guidelines. Curr. Opin. Allergy Clin. Immunol. 17, 99–103 (2017).
pubmed: 28118238
doi: 10.1097/ACI.0000000000000346
Centers for Disease Control and Prevention. Data, Statistics, and Surveillance: Asthma Surveillance Data. https://www.cdc.gov/asthma/asthmadata.htm
Greally, M., Jagoe, W. S. & Greally, J. The genetics of asthma. Ir. Med. J. 75, 403–405 (1982).
pubmed: 7174257
Dold, S., Wjst, M., von Mutius, E., Reitmeir, P. & Stiepel, E. Genetic risk for asthma, allergic rhinitis, and atopic dermatitis. Arch. Dis. Child. 67, 1018–1022 (1992).
pubmed: 1520004
pmcid: 1793604
doi: 10.1136/adc.67.8.1018
Jenkins, M. A., Hopper, J. L. & Giles, G. G. Regressive logistic modeling of familial aggregation for asthma in 7,394 population-based nuclear families. Genet. Epidemiol. 14, 317–332 (1997).
pubmed: 9181360
doi: 10.1002/(SICI)1098-2272(1997)14:3<317::AID-GEPI9>3.0.CO;2-1
Sharma, S. et al. The genomic origins of asthma. Thorax 69, 481–487 (2014).
pubmed: 24668408
doi: 10.1136/thoraxjnl-2014-205166
Louisias, M., Ramadan, A., Naja, A. S. & Phipatanakul, W. The effects of the environment on asthma disease activity. Immunol. Allergy Clin. North Am. 39, 163–175 (2019).
pubmed: 30954168
pmcid: 6452888
doi: 10.1016/j.iac.2018.12.005
Reinke, S. N. et al. Metabolomics analysis identifies different metabotypes of asthma severity. Eur. Respir. J. 49, 1601740 (2017).
Kelly, R. S. et al. Asthma metabolomics and the potential for integrative omics in research and the clinic. Chest 151, 262–277 (2017).
pubmed: 27776981
doi: 10.1016/j.chest.2016.10.008
Kelly, R. S. et al. Plasma metabolite profiles in children with current asthma. Clin. Exp. Allergy 48, 1297–1304 (2018).
pubmed: 29808611
pmcid: 6160355
doi: 10.1111/cea.13183
McGeachie, M. J. et al. The metabolomics of asthma control: a promising link between genetics and disease. Immun. Inflamm. Dis. 3, 224–238 (2015).
pubmed: 26421150
pmcid: 4578522
doi: 10.1002/iid3.61
Adamko, D. J., Sykes, B. D. & Rowe, B. H. The metabolomics of asthma: novel diagnostic potential. Chest 141, 1295–1302 (2012).
pubmed: 22553262
doi: 10.1378/chest.11-2028
Bush, A. Translating asthma: dissecting the role of metabolomics, genomics and personalized medicine. Indian J. Pediatr. 85, 643–650 (2018).
pubmed: 29185231
doi: 10.1007/s12098-017-2520-0
Snowden, S., Dahlen, S. E. & Wheelock, C. E. Application of metabolomics approaches to the study of respiratory diseases. Bioanalysis 4, 2265–2290 (2012).
pubmed: 23046268
doi: 10.4155/bio.12.218
Checkley, W. et al. Identifying biomarkers for asthma diagnosis using targeted metabolomics approaches. Respir. Med. 121, 59–66 (2016).
pubmed: 27888993
pmcid: 5516646
doi: 10.1016/j.rmed.2016.10.011
Pite, H., Morais-Almeida, M. & Rocha, S. M. Metabolomics in asthma: where do we stand? Curr. Opin. Pulm. Med. 24, 94–103 (2018).
pubmed: 29059088
doi: 10.1097/MCP.0000000000000437
Crompton, G. A brief history of inhaled asthma therapy over the last fifty years. Prim. Care Respir. J. 15, 326–331 (2006).
pubmed: 17092772
pmcid: 6730840
doi: 10.1016/j.pcrj.2006.09.002
Duplantier, J. E., Nelson, R. P. J., Morelli, A. R., Good, R. A. & Kornfeld, S. J. Hypothalamic–pituitary–adrenal axis suppression associated with the use of inhaled fluticasone propionate. J. Allergy Clin. Immunol. 102, 699–700 (1998).
pubmed: 9802384
doi: 10.1016/S0091-6749(98)70292-1
Guilbert, T. W. et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N. Engl. J. Med. 354, 1985–1997 (2006).
pubmed: 16687711
doi: 10.1056/NEJMoa051378
Allen, D. B. Effects of inhaled steroids on growth, bone metabolism and adrenal function. Expert Rev. Respir. Med. 1, 65–74 (2007).
pubmed: 20477267
doi: 10.1586/17476348.1.1.65
Lapi, F., Kezouh, A., Suissa, S. & Ernst, P. The use of inhaled corticosteroids and the risk of adrenal insufficiency. Eur. Respir. J. 42, 79–86 (2013).
pubmed: 23060630
doi: 10.1183/09031936.00080912
Gurnell, M., Heaney, L. G., Price, D. & Menzies-Gow, A. Long-term corticosteroid use, adrenal insufficiency and the need for steroid-sparing treatment in adult severe asthma. J. Intern. Med. 290, 240–256 (2021).
pubmed: 33598993
pmcid: 8360169
doi: 10.1111/joim.13273
Todd, G. R., Wright, D. & Ryan, M. Acute adrenal insufficiency in a patient with asthma after changing from fluticasone propionate to budesonide. J. Allergy Clin. Immunol. 103, 956–957 (1999).
pubmed: 10329837
doi: 10.1016/S0091-6749(99)70447-1
Drake, A. J. et al. Symptomatic adrenal insufficiency presenting with hypoglycaemia in children with asthma receiving high dose inhaled fluticasone propionate. BMJ 324, 1081–1082 (2002).
pubmed: 11991916
pmcid: 1123030
doi: 10.1136/bmj.324.7345.1081
Todd, G. R. G. et al. Acute adrenal crisis in asthmatics treated with high-dose fluticasone propionate. Eur. Respir. J. 19, 1207–1209 (2002).
pubmed: 12108877
doi: 10.1183/09031936.02.00274402
Macdessi, J. S. et al. Adrenal crises in children treated with high-dose inhaled corticosteroids for asthma. Med. J. Aust. 178, 214–216 (2003).
pubmed: 12603184
doi: 10.5694/j.1326-5377.2003.tb05165.x
Santiago, A. H. & Ratzan, S. Acute adrenal crisis in an asthmatic child treated with inhaled fluticasone proprionate. Int. J. Pediatr. Endocrinol. 2010, 749239 (2010).
Smith, R. W. et al. Prevalence of hypothalamic–pituitary–adrenal axis suppression in children treated for asthma with inhaled corticosteroid. Paediatr. Child Health 17, e34–e39 (2012).
pubmed: 23633903
pmcid: 3381924
doi: 10.1093/pch/17.5.e34
Hay, C. M. & Spratt, D. I. Adrenal insufficiency in a woman secondary to standard-dose inhaled fluticasone propionate therapy. Endocrinol. Diabetes Metab. Case Rep. 2014, 130080 (2014).
pubmed: 24683484
pmcid: 3965276
Keeley, D. Inhaled corticosteroids for asthma: guidance is inconsistent. BMJ 367, l6934 (2019).
pubmed: 31843748
doi: 10.1136/bmj.l6934
Meyers, D. A., Bleecker, E. R., Holloway, J. W. & Holgate, S. T. Asthma genetics and personalised medicine. Lancet Respir. Med. 2, 405–415 (2014).
pubmed: 24794577
pmcid: 4768462
doi: 10.1016/S2213-2600(14)70012-8
Keskin, O. et al. Genetic associations of the response to inhaled corticosteroids in asthma: a systematic review. Clin. Transl. Allergy 9, 2 (2019).
pubmed: 30647901
pmcid: 6327448
doi: 10.1186/s13601-018-0239-2
Hernandez-Pacheco, N., Pino-Yanes, M. & Flores, C. Genomic predictors of asthma phenotypes and treatment response. Front. Pediatr. 7, 6 (2019).
pubmed: 30805318
pmcid: 6370703
doi: 10.3389/fped.2019.00006
Vijverberg, S. J. H., Farzan, N., Slob, E. M. A., Neerincx, A. H. & Maitland-van der Zee, A. H. Treatment response heterogeneity in asthma: the role of genetic variation. Expert Rev. Respir. Med. 12, 55–65 (2018).
pubmed: 29115880
doi: 10.1080/17476348.2018.1403318
Cazzola, M., Rogliani, P., Calzetta, L. & Matera, M. G. Pharmacogenomic response of inhaled corticosteroids for the treatment of asthma: considerations for therapy. Pharmgenomics. Pers. Med. 13, 261–271 (2020).
pubmed: 32801837
pmcid: 7414974
Figueiredo, R. G., Costa, R. S., Figueiredo, C. A. & Cruz, A. A. Genetic determinants of poor response to treatment in severe asthma. Int. J. Mol. Sci. 22, 4251 (2021).
Hawcutt, D. B. et al. Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study. Lancet Respir. Med. 6, 442–450 (2018).
pubmed: 29551627
pmcid: 5971210
doi: 10.1016/S2213-2600(18)30058-4
Frey, L. J. Data integration strategies for predictive analytics in precision medicine. Per. Med. 15, 543–551 (2018).
pubmed: 30387695
pmcid: 6277956
doi: 10.2217/pme-2018-0035
Donovan, B. M., Bastarache, L., Turi, K. N., Zutter, M. M. & Hartert, T. V. The current state of omics technologies in the clinical management of asthma and allergic diseases. Ann. Allergy Asthma Immunol. 123, 550–557 (2019).
pubmed: 31494234
pmcid: 6931133
doi: 10.1016/j.anai.2019.08.460
Akbaraly, T. et al. Association of circulating metabolites with healthy diet and risk of cardiovascular disease: analysis of two cohort studies. Sci. Rep. 8, 8620 (2018).
pubmed: 29872056
pmcid: 5988716
doi: 10.1038/s41598-018-26441-1
Bakkeheim, E., Mowinckel, P., Carlsen, K. H., Burney, P. & Lødrup Carlsen, K. C. Reduced basal salivary cortisol in children with asthma and allergic rhinitis. Acta Paediatr. 99, 1705–1711 (2010).
pubmed: 19912147
doi: 10.1111/j.1651-2227.2009.01598.x
Shin, Y. S. et al. The impact of asthma control on salivary cortisol level in adult asthmatics. Allergy Asthma Immunol. Res. 6, 463–466 (2014).
pubmed: 25229005
pmcid: 4161689
doi: 10.4168/aair.2014.6.5.463
Dorsey, M. J., Cohen, L. E., Phipatanakul, W., Denufrio, D. & Schneider, L. C. Assessment of adrenal suppression in children with asthma treated with inhaled corticosteroids: use of dehydroepiandrosterone sulfate as a screening test. Ann. Allergy Asthma Immunol. 97, 182–186 (2006).
pubmed: 16937748
doi: 10.1016/S1081-1206(10)60010-5
Svendsen, U. G. et al. High-dose inhaled steroids in the management of asthma. A comparison of the effects of budesonide and beclomethasone dipropionate on pulmonary function, symptoms, bronchial responsiveness and the adrenal function. Allergy 47, 174–180 (1992).
pubmed: 1514669
doi: 10.1111/j.1398-9995.1992.tb00960.x
Boe, J., Bakke, P., Rodolen, T., Skovlund, E. & Gulsvik, A. High-dose inhaled steroids in asthmatics: moderate efficacy gain and suppression of the hypothalamic–pituitary–adrenal (HPA) axis. Research Council of the Norwegian Thoracic Society. Eur. Respir. J. 7, 2179–2184 (1994).
pubmed: 7713201
doi: 10.1183/09031936.94.07122179
Afilalo, M. et al. Efficacy of inhaled steroids (beclomethasone dipropionate) for treatment of mild to moderately severe asthma in the emergency department: a randomized clinical trial. Ann. Emerg. Med. 33, 304–309 (1999).
pubmed: 10036345
doi: 10.1016/S0196-0644(99)70367-7
Chang, C. C. & Tam, A. Y. Suppression of adrenal function in children on inhaled steroids. J. Paediatr. Child Health 27, 232–234 (1991).
pubmed: 1659840
doi: 10.1111/j.1440-1754.1991.tb00398.x
Kannisto, S., Korppi, M., Remes, K. & Voutilainen, R. Adrenal suppression, evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids. J. Clin. Endocrinol. Metab. 85, 652–657 (2000).
pubmed: 10690871
Ahmet, A., Kim, H. & Spier, S. Adrenal suppression: a practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy. Allergy Asthma Clin. Immunol. 7, 13 (2011).
pubmed: 21867553
pmcid: 3177893
doi: 10.1186/1710-1492-7-13
Aalbers, R., Vogelmeier, C. & Kuna, P. Achieving asthma control with ICS/LABA: a review of strategies for asthma management and prevention. Respir. Med. 111, 1–7 (2016).
pubmed: 26614594
doi: 10.1016/j.rmed.2015.11.002
O’Byrne P., Fabbri L. M., Pavord I. D., Papi A., Petruzzelli S. & Lange, P. Asthma progression and mortality: the role of inhaled corticosteroids. Eur. Respir. J. 54, 1900491 (2019).
Cho, M. H. & Tantisira, K. G. Adrenal insufficiency and ICS: genetics takes a breath. Lancet Respir. Med. 6, 407–408 (2018).
pubmed: 29551625
doi: 10.1016/S2213-2600(18)30101-2
Wenzel, S. E. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat. Med. 18, 716–725 (2012).
pubmed: 22561835
doi: 10.1038/nm.2678
Suissa, S., Ernst, P., Benayoun, S., Baltzan, M. & Cai, B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N. Engl. J. Med. 343, 332–336 (2000).
pubmed: 10922423
doi: 10.1056/NEJM200008033430504
Wade, M. et al. Technical details influence the diagnostic accuracy of the 1 microg ACTH stimulation test. Eur. J. Endocrinol. 162, 109–113 (2010).
pubmed: 19797501
doi: 10.1530/EJE-09-0746
Holt, S. et al. Dose–response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ 323, 253–256 (2001).
pubmed: 11485952
pmcid: 35344
doi: 10.1136/bmj.323.7307.253
Sannarangappa, V. & Jalleh, R. Inhaled corticosteroids and secondary adrenal insufficiency. Open Respir. Med. J. 8, 93–100 (2014).
pubmed: 25674179
pmcid: 4319207
doi: 10.2174/1874306401408010093
Day, N. et al. EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br. J. Cancer 80, 95–103 (1999).
pubmed: 10466767
Yu, S. et al. Toward high-throughput phenotyping: unbiased automated feature extraction and selection from knowledge sources. J. Am. Med. Inform. Assoc. 22, 993–1000 (2015).
pubmed: 25929596
pmcid: 4986664
doi: 10.1093/jamia/ocv034
Kelly, R. S. et al. Metabolomic profiling of lung function in Costa-Rican children with asthma. Biochim. Biophys. Acta. Mol. Basis Dis. 1863, 1590–1595 (2017).
pubmed: 28188833
doi: 10.1016/j.bbadis.2017.02.006
The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Childhood Asthma Management Program Research Group. Control. Clin. Trials 20, 91–120 (1999).
Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N. Engl. J. Med. 343, 1054–1063 (2000).
Strunk, R. C. et al. Long-term budesonide or nedocromil treatment, once discontinued, does not alter the course of mild to moderate asthma in children and adolescents. J. Pediatr. 154, 682–687 (2009).
pubmed: 19167726
pmcid: 2942076
doi: 10.1016/j.jpeds.2008.11.036
Kelly, R. S. et al. An integrative transcriptomic and metabolomic study of lung function in children with asthma. Chest 154, 335–348 (2018).
pubmed: 29908154
pmcid: 6689076
doi: 10.1016/j.chest.2018.05.038
R Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2020).
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B Methodol. 57, 289–300 (1995).
Haynes, W. Tukey’s test. In: Encyclopedia of Systems Biology (eds Dubitzky, W., Wolkenhauer, O., Cho, K.-H. & Yokota, H.) 2303–2304 (Springer, 2013).
Neary, N. & Nieman, L. Adrenal insufficiency: etiology, diagnosis and treatment. Curr. Opin. Endocrinol. Diabetes Obes. 17, 217–223 (2010).
pubmed: 20375886
pmcid: 2928659
doi: 10.1097/MED.0b013e328338f608
Pazderska, A. & Pearce, S. H. Adrenal insufficiency—recognition and management. Clin. Med. 17, 258–262 (2017).
doi: 10.7861/clinmedicine.17-3-258