与病毒感染相关的1型免疫反应影响哮喘患者对皮质类固醇的治疗反应
2025/07/15
摘要
研究背景：皮质类固醇敏感的2型（T2）炎症反应是T2-high哮喘内型的病理基础。然而，我们假设1型（T1）炎症反应（可能与病毒感染相关）也可能影响皮质醇治疗反应。
研究目的：明确T1-high、T2-high及T1/T2-high哮喘内型的发生频率与患者个体内变异性，并探究病毒相关的T1-high内型是否影响哮喘患者对皮质类固醇的治疗反应。
研究方法：参与重症哮喘研究计划（SARP-3）的患者在基线期、肌肉注射（曲安奈德）皮质类固醇治疗后，以及1年和3年随访期接受痰液采集。通过痰细胞RNA进行全转录组基因网络分析和病毒宏基因组检测。我们对高表达T1和/或T2基因网络的患者进行分型，并评估这些内型对皮质类固醇治疗反应性及气道病毒转录本检出率的影响。
测量指标与主要结果：研究发现22%和35%的哮喘患者分别高表达T1和T2网络基因，8.5%的患者同时高表达两种网络基因。T2-high哮喘患者的严重程度结局较T1-high患者更差，而T1-high/T2-high亚组的病情最为严重。皮质类固醇治疗能显著抑制T2基因表达，但对T1基因的抑制作用较弱；仅T1-low/T2-high患者的FEV1在皮质类固醇治疗后改善，而T1-high/T2-high患者未见改善。病毒宏基因组分析显示24%的哮喘痰样本检出呼吸道病毒阳性，且高病毒载量的患者患T1-high哮喘的风险增加了14倍。
研究结论：气道1型免疫反应在哮喘中较为常见，对皮质类固醇治疗普遍不敏感，且与亚临床病毒感染相关。
Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma
Am J Respir Crit Care Med. 2025 Feb;211(2):194-204. doi: 10.1164/rccm.202402-0403OC.
Fahy JV, Jackson ND, Sajuthi SP, Pruesse E, Moore CM, Everman JL, Rios C, Tang M, Gauthier M, Wenzel SE, Bleecker ER, Castro M, Comhair SA, Erzurum SC, Hastie AT, Moore W, Israel E, Levy BD, Denlinger L, Jarjour NN, Johansson MW, Mauger DT, Phillips BR, Sumino K, Woodruff PG, Peters MC, Seibold MA.
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 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.
研究背景：皮质类固醇敏感的2型（T2）炎症反应是T2-high哮喘内型的病理基础。然而，我们假设1型（T1）炎症反应（可能与病毒感染相关）也可能影响皮质醇治疗反应。
研究目的：明确T1-high、T2-high及T1/T2-high哮喘内型的发生频率与患者个体内变异性，并探究病毒相关的T1-high内型是否影响哮喘患者对皮质类固醇的治疗反应。
研究方法：参与重症哮喘研究计划（SARP-3）的患者在基线期、肌肉注射（曲安奈德）皮质类固醇治疗后，以及1年和3年随访期接受痰液采集。通过痰细胞RNA进行全转录组基因网络分析和病毒宏基因组检测。我们对高表达T1和/或T2基因网络的患者进行分型，并评估这些内型对皮质类固醇治疗反应性及气道病毒转录本检出率的影响。
测量指标与主要结果：研究发现22%和35%的哮喘患者分别高表达T1和T2网络基因，8.5%的患者同时高表达两种网络基因。T2-high哮喘患者的严重程度结局较T1-high患者更差，而T1-high/T2-high亚组的病情最为严重。皮质类固醇治疗能显著抑制T2基因表达，但对T1基因的抑制作用较弱；仅T1-low/T2-high患者的FEV1在皮质类固醇治疗后改善，而T1-high/T2-high患者未见改善。病毒宏基因组分析显示24%的哮喘痰样本检出呼吸道病毒阳性，且高病毒载量的患者患T1-high哮喘的风险增加了14倍。
研究结论：气道1型免疫反应在哮喘中较为常见，对皮质类固醇治疗普遍不敏感，且与亚临床病毒感染相关。
（四川大学华西医院呼吸与危重症医学科 吴雯雯1 王霁1 王刚1 译）
（Am J Respir Crit Care Med. 2025 Feb;211(2):194-204. doi: 10.1164/rccm.202402-0403OC.）
Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma
Am J Respir Crit Care Med. 2025 Feb;211(2):194-204. doi: 10.1164/rccm.202402-0403OC.
Fahy JV, Jackson ND, Sajuthi SP, Pruesse E, Moore CM, Everman JL, Rios C, Tang M, Gauthier M, Wenzel SE, Bleecker ER, Castro M, Comhair SA, Erzurum SC, Hastie AT, Moore W, Israel E, Levy BD, Denlinger L, Jarjour NN, Johansson MW, Mauger DT, Phillips BR, Sumino K, Woodruff PG, Peters MC, Seibold MA.
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 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.
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难治性哮喘伴肥胖患者的一年体重管理计划：一项随机对照研究
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代谢型与未控制儿童哮喘、肠道微生物群和全身炎症相关性研究
