Study Says ICS Use for Asthma Is Linked With Adrenal Suppression

The largest metabolomic study of asthma to date investigated the effect of inhaled corticosteroid (ICS) use to clarify their role in adrenal suppression (AS), a condition characterized by the inability to produce adequate amounts of cortisol, which is needed to help regulate the physiological response to stress.

Asthma is the most common noncommunicable chronic disease worldwide; in the United States, it is linked with more than $80 billion in costs annually. While ICS treatment has been a mainstay of asthma therapy for years, the last update to the Global Initiative for Asthma (GINA) asthma guidelines recommended that low-dose ICS can be used as needed for mild asthma.

The complex interplay of genetic factors and the environment affect not only asthma development but also the response to medication and the function of the adrenal glands and the rest of the endocrine system. Initial AS symptoms are subtle and often overlooked, but continued progression can lead to fatigue, headache, abdominal pain, vomiting, and psychiatric symptoms. To date, research on ICS usage and AS has been limited and produced conflicting findings.

In this study, researchers, led by Brigham and Women’s Hospital and the University of Cambridge, turned to studying the metabolome through the use of metabolomics, the systematic analysis of small molecules within cells, tissues, and biofluids in order to profile the genetic, transcriptomic, proteomic, and environmental interactions. It is more precise than phenotyping asthma alone.

The investigators used 4 epidemiological study cohorts along with clinical tests available in the electronic medical record (EMR), analyzing blood plasma of 14,000 individuals.

The 4 groups were the European Prospective Investigation of Cancer discovery cohort (EPIC-Norfolk; n = 10,754), the Mass General Brigham Biobank-Asthma replication cohort (MGBB-Asthma; n = 610), a 4-year randomized clinical trial to validate the ICS effect (Childhood Asthma Management Program (CAMP; n = 1,120), and the assessment of ICS effect using clinical cortisol measurements extracted from EMRs (EMR-Cortisol, which had 25 years' worth of data; n = 2,235).

The team found reduced levels of 17 endogenous steroid metabolites that are linked with asthma, including DHEA-S and cortisol, which are 2 primary hypothalamic–pituitary–adrenal axis steroid hormones that are biomarkers for AS.

This reduction of cortisol is strongly linked with ICS use for asthma, the researchers said, even among patients taking low-dose ICS. This finding is new, they said.

In addition, some of the observed reduction of cortisol was “independent of ICS use, suggesting that the reduced steroid levels also represent a fundamental characteristic of pathophysiology of asthma as a disease,” the wrote.

The researchers also found significant associations between adrenal insufficiency symptoms, including fatigue and anemia, in patients using ICS compared with those who were not.

The findings highlight the possibilities of metabolomics research, as well as considerations that should be further researched to see if they should be incorporated into clinical practice. "Existing evidence suggests that the impact of ICS use might be even more extreme for individuals with genetic susceptibility to corticosteroid-induced adrenal suppression," the researchers noted.

More personalized approaches to ICS use should be considered, they said, especially in light of the revised GINA guidelines, which shifted away from the use of short-acting beta agonists to ICS.

“The use of ICS has been instrumental in reducing asthma exacerbations and improving overall quality of life. However, while their effectiveness should not be understated, our findings suggest that the risks of ICS usage must also be considered,” co-senior author Jessica Lasky-Su, ScD, of the Channing Division of Network Medicine at the Brigham, said in a statement.

“Our work suggests that simple measures, such as regular cortisol monitoring and prescription of the lowest effective ICS dose, may help to mitigate the systemic side effects of ICS use,” said co-senior author Claudia Langenberg, MD, PhD, of the MRC Epidemiology Unit at the University of Cambridge, UK, and Berlin Institute of Health at Charité Universitätsmedizin, Germany.

Reference

Kachroo P, Stewart ID, Kelly RS, et al. Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma. Nat Med. Published online March 21, 2022. doi:10.1038/s41591-022-01714-5