Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma
John V. Fahy, Nathan D. Jackson, Satria P. Sajuthi, Elmar Pruesse, Camille M. Moore, Jamie L. Everman, Cydney Rios, Monica Tang, Marc Gauthier, Sally E. Wenzel, Eugene R. Bleecker, Mario Castro, Suzy Comhair, Serpil C. Erzurum, Annette T. Hastie, Wendy C. Moore, Elliot Israel, Bruce D. Levy, Loren C. Denlinger, Nizar N. Jarjour, Mats W. Johansson, David T. Mauger, Brenda R. Phillips, Kaharu Sumino, Prescott G. Woodruff, Michael C. Peters, Max A. Seibold
Abstract
Abstract Rationale Corticosteroid-responsive type 2 (T2) inflammation underlies the T2-high asthma endotype. However, we hypothesized that type 1 (T1) inflammation, possibly related to viral infection, may also influence corticosteroid response. Objectives To determine the frequency and within-patient variability of T1-high, T2-high, and T1/T2-high asthma endotypes and whether virally influenced T1-high disease influences corticosteroid response in asthma. Methods Patients in SARP-3 (Severe Asthma Research Program-3) had sputum collected at baseline, after intramuscular (triamcinolone acetonide) corticosteroid treatment, and at 1- and 3-year follow-ups. Sputum cell RNA was used for whole-transcriptome gene network and viral metagenomic analyses. We then profiled patients as highly expressing T1 and/or T2 gene networks and established the influence of these endotypes on corticosteroid responsiveness and the likelihood of viral transcript detection in the airways. Measurements and Main Results We found that 22% and 35% of patients with asthma highly expressed T1 and T2 network genes, respectively, and that 8.5% highly expressed both networks. Asthma severity outcomes were worse in T2-high compared with T1-high asthma and most severe in the T1-high/T2-high subgroup. Corticosteroid treatment strongly suppressed T2 but poorly suppressed T1 gene expression, and corticosteroid-associated improvements in FEV1 occurred only in patients with T1-low/T2-high disease and not in patients with T1-high/T2-high disease. Viral metagenomic analyses uncovered that 24% of asthma sputum samples tested positive for a respiratory virus, and high viral carriage was associated with 14-fold increased risk of T1-high disease. Conclusions Airway T1 immune responses are relatively common in asthma, are largely corticosteroid resistant, and are associated with subclinical viral infection.