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.

Extended Data Fig. 1. Plasma metabolites in EPIC-Norfolk cohort.

A. Manhattan plot of metabolites sorted by their pathways on x-axis and negative log10 of P-value on the y-axis. The cut off horizontal lines on the y-axis highlight the metabolites significantly associated with asthma outcome at a P-value <0.05 and at the Bonferroni threshold (n=35 metabolites, P-value<5.14x10⁻⁵). The legend key shape and color show the direction of effect for the metabolites and the main pathway they belong to, respectively. B. Volcano Plot showing the effect size of the metabolites with OR on the x-axis and negative log10 of P-value on the y-axis. The metabolites colored in red are significant at a Bonferroni threshold of P-value<5.14x10⁻⁵. Multivariable logistic regression models were used to obtain odds ratio and p-values comparing asthma cases with controls (A, B).

Extended Data Fig. 2. Principal steroid hormone biosynthesis pathways with mineralocorticoid, glucocorticoid and androgen metabolites highlighting the replicated metabolites between EPIC-Norfolk cohort and Mass General Brigham Biobank.

Our annotated metabolites colored in red have been mapped to these pathways with their precursors or intermediates. Abbreviations: CRH: Corticotropin releasing hormone; ACTH: Adrenocorticotropic hormone

Fig. 1.. Overall study design.

The study incorporates four independent cohorts: the EPIC Norfolk cohort, the Mass General Brigham Biobank (MGBB)-Asthma cohort, the CAMP randomized controlled trial (RCT) and the EMR-Cortisol cohort. The cohorts were utilized sequentially to identify prevalent asthma metabolites, validate significant metabolites, assess the effect of inhaled corticosteroids (ICS) on the steroid metabolites, and evaluate the utility of cortisol as a biomarker of adrenal suppression among asthmatics on ICS. The details of our approach for each cohort are illustrated. Abbreviations: MGBB-A, Mass General Brigham Biobank (MGBB)-Asthma; RCT, Randomized Controlled Trial; CAMP, Childhood Asthma Management Program; ICS, inhaled corticosteroids; EMR, Electronic Medical health Record; RPDR, Research Patient Data Registry

Fig. 2.. Plasma steroid metabolite associations in EPIC-Norfolk cohort and Mass General Brigham Biobank (MGBB)-Asthma cohort.

A. Plasma metabolites significantly associated with asthma in the EPIC-Norfolk cohort and replicated in the MGBB-Asthma cohort (n=17 metabolites). The dotted line indicates the cut off for odds ratio (OR) < or >1 for direction of effect. Metabolite names with an asterisk * indicate that the metabolite has not been officially confirmed based on a standard. B. Steroid metabolite associations between asthma cases and controls; asthma cases with ICS treatment and controls; asthma cases not treated with ICS and controls; and asthma cases with ICS treatment and not treated with ICS in the MGBB-Asthma cohort. The dotted line indicates the cut off for OR< or >1 for direction of effect. Individual values shown for each metabolite as odds ratios along with their lower and upper 95% confidence intervals in A and B. The legend key color shows the sub-pathway they belong to (A, B). Generalized linear model was used to compare groups (A, B); Statistical significance was determined using a bonferroni threshold and false discovery rate of 0.05 (A, B). Abbreviations: Ast, asthma cases; ICS, inhaled corticosteroids

Fig. 3.. Quantification of Cortisol in the EMR-Cortisol cohort.

Top, histogram showing the frequency of subjects during the indicated times of sample collection (24-hour daily period) on the x-axis of the bottom graph. Bottom, graph showing the aggregated minimum cortisol levels for four groups of subjects during the indicated times of sample collection on the x-axis. Subjects were binned into three time categories (04:00-12:00, 12:00-18:00, 18:00-04:00) based on the availability of subjects and smoothed using loess curve fitting. Legend label is colored based on four categories: Ast_ICS: asthma cases with ICS treatment (Average=4.2 mcg/dL; SD=5.2); Ast_No_ICS: Asthma cases without ICS treatment (Average=6.03 mcg/dL; SD=5.1); Controls_ICS: Controls with ICS treatment (Average=5.58 mcg/dL; SD=4.6); Controls_No_ICS: Controls without ICS treatment (Average=7.02 mcg/dL; SD=5.8). P-value for asthma cases with ICS treatment compared to controls without ICS treatment (Mean difference=−2.80 mcg/dL; 95% CI=−1.4, −4.2; P=1.9x10⁻⁶). Tukey’s HSD test was used to identify significant differences between the asthma/ICS subgroups. Pairwise comparisons between the subgroups were also performed using generalized linear models, adjusted for collection time, age, gender and race. Abbreviations: Ast, Asthma cases; ICS, inhaled corticosteroids