Fahy John V, Jackson Nathan D, Sajuthi Satria P, Pruesse Elmar, Moore Camille M, Everman Jamie L, Rios Cydney, Tang Monica, Gauthier Marc, Wenzel Sally E, Bleecker Eugene R, Castro Mario, Comhair Suzy A, Erzurum Serpil C, Hastie Annette T, Moore Wendy, Israel Elliot, Levy Bruce D, Denlinger Loren, Jarjour Nizar N, Johansson Mats W, Mauger David T, Phillips Brenda R, Sumino Kaharu, Woodruff Prescott G, Peters Michael C, Seibold Max A
Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California.
Center for Genes, Environment, and Health and.
Am J Respir Crit Care Med. 2025 Feb;211(2):194-204. doi: 10.1164/rccm.202402-0403OC.
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. 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. 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. 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 FEV 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. Airway T1 immune responses are relatively common in asthma, are largely corticosteroid resistant, and are associated with subclinical viral infection.
皮质类固醇反应性2型（T2）炎症是T2高哮喘内型的基础。然而，我们推测1型（T1）炎症，可能与病毒感染有关，也可能影响皮质类固醇反应。以确定T1高、T2高和T1/T2高哮喘内型的频率及患者内变异性，以及病毒影响的T1高疾病是否会影响哮喘患者的皮质类固醇反应。重度哮喘研究项目3（SARP-3）中的患者在基线、肌肉注射（曲安奈德）皮质类固醇治疗后以及1年和3年随访时采集痰液。痰液细胞RNA用于全转录组基因网络和病毒宏基因组分析。然后，我们将患者描述为高表达T1和/或T2基因网络，并确定这些内型对皮质类固醇反应性的影响以及气道中病毒转录本检测的可能性。我们发现，分别有22%和35%的哮喘患者高表达T1和T2网络基因，8.5%的患者高表达这两个网络。与T1高哮喘相比，T2高哮喘的严重程度结局更差，而在T1高/T2高亚组中最为严重。皮质类固醇治疗强烈抑制T2但对T1基因表达抑制不佳，且皮质类固醇相关的第一秒用力呼气容积（FEV）改善仅发生在T1低/T2高疾病患者中，而在T1高/T2高疾病患者中未出现。病毒宏基因组分析发现，24%的哮喘痰液样本呼吸道病毒检测呈阳性，高病毒携带与T1高疾病风险增加14倍相关。气道T1免疫反应在哮喘中相对常见，在很大程度上对皮质类固醇耐药，且与亚临床病毒感染相关。
