• 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 A Comhair, Serpil C Erzurum, Annette T Hastie, Wendy Moore, Elliot Israel, Bruce D Levy, Loren Denlinger, Nizar N Jarjour, Mats W Johansson, David T Mauger, Brenda R Phillips, Kaharu Sumino, Prescott G Woodruff, Michael C Peters, Max A Seibold, and National Heart, Lung, and Blood Institute Severe Asthma Research Program-3.
• University of California San Francisco, San Francisco, California, United States.
• Am. J. Respir. Crit. Care Med. 2024 Nov 27.

RationaleCorticosteroid-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.ObjectivesTo 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.MethodsPatients in the Severe Asthma Research Program (SARP)-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 likelihood of viral transcript detection in the airways.Measurements And Main ResultsWe found that 22% and 35% of asthma patients 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 to 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 T1-high/T2-high patients. 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.ConclusionsAirway type 1 immune responses are relatively common in asthma, are largely corticosteroid-resistant, and are associated with sub-clinical viral infection.

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