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Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma.

ABSTRACT: 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.

SUBMITTER: Kachroo P

PROVIDER: S-EPMC9350737 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma.

Kachroo Priyadarshini P Stewart Isobel D ID Kelly Rachel S RS Stav Meryl M Mendez Kevin K Dahlin Amber A Soeteman Djøra I DI Chu Su H SH Huang Mengna M Cote Margaret M Knihtilä Hanna M HM Lee-Sarwar Kathleen K McGeachie Michael M Wang Alberta A Wu Ann Chen AC Virkud Yamini Y Zhang Pei P Wareham Nicholas J NJ Karlson Elizabeth W EW Wheelock Craig E CE Clish Clary C Weiss Scott T ST Langenberg Claudia C Lasky-Su Jessica A JA

Nature medicine 20220321 4

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 as ...[more]

PMID: 35314841

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Project description:ObjectiveTo describe recovery of adrenal insufficiency in asthmatic children treated with inhaled corticosteroids (ICS) and cortisol replacement therapy.DesignRetrospective, observational study.PatientsA total of 113 patients, 74 male; age 10.4 (3.3-16.5) years; beclomethasone-equivalent ICS dose, 800 μg, (100-1,000), tested by low dose short Synacthen (tetracosactide) test (LDSST), were studied. Test results were classified by basal and peak cortisol concentration: "normal" (basal >100 nmol/L, peak >500 nmol/L), "suboptimal" (basal >100 nmol/L, peak 350-499 nmol/L), "abnormal" (basal <100 nmol/L and/or peak <350 nmol/L). Patients with suboptimal results received hydrocortisone during periods of stress only, and those with abnormal responses received daily hydrocortisone, increased during periods of stress. A total of 73 patients (68%) had ≥2 LDSSTs over 2.2 years (0.2-7.7).MeasurementsChange in cortisol response to repeat LDSST (movement between diagnostic groups, difference in basal and peak cortisol >15% [2× the inter-assay coefficient of variation]), change in BMI and height standard deviation score (SDS).ResultsBaseline test results were abnormal in 17 patients (15%) and all of them had repeat tests. In 13 patients (76%), test results improved (normal in six, suboptimal in seven) and four (24%) remained abnormal. Baseline tests results were suboptimal in 54 patients (48%), of whom 50 (93%) were retested. Repeat tests were normal in 36 patients (72%), remained suboptimal in 11 (22%), and were abnormal in three (6%). Baseline tests results were normal in 42 patients, of whom six patients (14%) were retested. Results remained normal in three (50%), were suboptimal in two (33%), and abnormal in one (17%). Basal and peak cortisol levels increased by >15% in 33/73 (45%) and 42/73 (57%) patients, respectively, and decreased by >15% in 14/73 (19%) and 7/73 (10%), respectively. There was no significant change in height or BMI SDS.ConclusionRecovery of adrenal function is common and occurs during continued ICS and cortisol replacement therapy.

Project description:BackgroundA serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression.MethodsWe enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), as part of the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. We included two validation cohorts, one comprising children with asthma (PASS study) and the other consisting of adults with chronic obstructive pulmonary disorder (COPD) who were recruited from two UK centres for the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. Participants underwent a low-dose short synacthen test. Adrenal suppression was defined as peak cortisol less than 350 nmol/L (in children) and less than 500 nmol/L (in adults). A case-control genome-wide association study was done with the control subset augmented by Wellcome Trust Case Control Consortium 2 (WTCCC2) participants. Single nucleotide polymorphisms (SNPs) that fulfilled criteria to be advanced to replication were tested by a random-effects inverse variance meta-analysis. This report presents the primary analysis. The PASS study is registered in the European Genome-phenome Archive (EGA). The PASS study is complete whereas the PASIC study is ongoing.FindingsBetween November, 2008, and September, 2011, 499 children were enrolled to the discovery cohort. Between October, 2011, and December, 2012, 81 children were enrolled to the paediatric validation cohort, and from February, 2010, to June, 2015, 78 adults were enrolled to the adult validation cohort. Adrenal suppression was present in 35 (7%) children in the discovery cohort and six (7%) children and 17 (22%) adults in the validation cohorts. In the discovery cohort, 40 SNPs were found to be associated with adrenal suppression (genome-wide significance p<1 × 10-6), including an intronic SNP within the PDGFD gene locus (rs591118; odds ratio [OR] 7·32, 95% CI 3·15-16·99; p=5·8 × 10-8). This finding for rs591118 was validated successfully in both the paediatric asthma (OR 3·86, 95% CI 1·19-12·50; p=0·02) and adult COPD (2·41, 1·10-5·28; p=0·03) cohorts. The proportions of patients with adrenal suppression by rs591118 genotype were six (3%) of 214 patients with the GG genotype, 15 (6%) of 244 with the AG genotype, and 22 (25%) of 87 with the AA genotype. Meta-analysis of the paediatric cohorts (discovery and validation) and all three cohorts showed genome-wide significance of rs591118 (respectively, OR 5·89, 95% CI 2·97-11·68; p=4·3 × 10-9; and 4·05, 2·00-8·21; p=3·5 × 10-10).InterpretationOur findings suggest that genetic variation in the PDGFD gene locus increases the risk of adrenal suppression in children and adults who use corticosteroids to treat asthma and COPD, respectively.FundingDepartment of Health Chair in Pharmacogenetics.

Dataset Information

Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma.

Publications

Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma.

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