Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 143, Issue 3, Pages 940-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2018.06.043
Keywords
Asthma; steroid resistance; corticosteroids; glucocorticoid receptor
Categories
Funding
- National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services [HHSN272200900052C, HHSN272201000052I, 1UM1AI114271-01]
- National Center for Research Resources (NCRR), NIH [NCRR/NIH UL1TR001079, UL1TR000451, UL1RR025780, UL1TR000075]
- National Center for Advancing Translational Sciences, NIH [NCATS/NIH UL1TR000154, UL1TR001082, UL1TR000077-04, UL1TR000040, UL1TR000150, UL1TR001105]
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Background: Variability in response to inhaled corticosteroids (ICSs) can result in less than optimal asthma control. Development of biomarkers assessing the therapeutic efficacy of corticosteroids is important. Objective: We sought to examine whether in vitro PBMC responses to corticosteroids relate to the clinical ICS response. Methods: PBMCs were collected from 125 children with asthma (6-17 years) at enrollment (visit 0 [V0]) and after 1 year of bimonthly guidelines-based management visits (visit 6 [V6]). Difficult-to-control and easy-to-control asthma were defined as requiring daily therapy with 500 mu g or more of fluticasone propionate (FLU) with or without a long-acting beta-agonist versus 100 mu g or less of FLU in at least 4 visits. mRNA levels of glucocorticoid receptor alpha and corticosteroid transactivation (FK506-binding protein 5) and transrepression markers (IL-8 and TNF-alpha) were measured by using RT-PCR in freshly isolated cells and in response to 10(-8) mol/L FLU. Results: Compared with PBMCs from patients with easy-tocontrol asthma, PBMCs from those with difficult-to-control asthma had significantly lower glucocorticoid receptor a levels at V0 (P = .05). A 30% increase in IL-8 suppression by FLU (P = .04) and a trend for increased TNF-alpha suppression by FLU between V0 and V6 (P = .07) were observed in patients with easy-to-control asthma. In contrast, no changes between V0 and V6 in IL-8 and TNF-alpha suppression by FLU were observed in patients with difficult-to-control asthma. Corticosteroidmediated transactivation (FK506-binding protein 5 induction by FLU) increased in the PBMCs of patients with difficult-tocontrol and easy-to-control asthma between V0 and V6 (P = .05 and P = .03, respectively). Conclusions: PBMCs of children with difficult-to-control asthma treated with guidelines-based therapy and requiring high-dose ICSs had reduced in vitro responsiveness to corticosteroids.
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