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 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 RESULTS We 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. CONCLUSIONS Airway type 1 immune responses are relatively common in asthma, are largely corticosteroid-resistant, and are associated with sub-clinical viral infection.

中文翻译：

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与病毒感染相关的 1 型免疫反应会影响哮喘患者的皮质类固醇反应。


基本原理皮质类固醇反应性 2 型 （T2） 炎症是 T2 高哮喘内型的基础。然而，我们假设可能与病毒感染有关的 1 型 （T1） 炎症也可能影响皮质类固醇反应。目的 确定 T1 高、 T2 高和 T1/T2 高哮喘内型的频率和患者内部变异性，以及病毒影响的 T1 高疾病是否影响哮喘中的皮质类固醇反应。方法 严重哮喘研究计划 （SARP）-3 患者在基线、肌内注射 （曲安奈德） 皮质类固醇治疗后以及 1 年和 3 年随访时收集痰液。痰细胞 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和气道中病毒转录物检测可能性的影响。测量和主要结果我们发现 22% 和 35% 的哮喘患者分别高度表达 T1 和 T2 网络基因，8.5% 的患者高度表达这两个网络。与 T1 高哮喘相比，T2 高哮喘的哮喘严重程度结局更差，而 T1 高/T2 高亚组最严重。皮质类固醇治疗强烈抑制 T2 但抑制 T1 基因表达较差，皮质类固醇相关 FEV1 的改善仅发生在 T1 低/T2 高疾病患者中，而未发生在 T1 高/T2 高患者中。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，高病毒携带与患 T1 高疾病的风险增加 14 倍相关。 结论 1 型气道免疫反应在哮喘中相对常见，主要对皮质类固醇耐药，并与亚临床病毒感染相关。