基于T2炎症梯度分层的重症哮喘生物治疗反应性：一项数据驱动的生物标志物聚类研究
2026/02/06
背景：对于2型（T2）炎症生物标志物水平较低的哮喘表型，目前认知尚不充分。
目的：旨在探讨重度哮喘的表型特征，并比较不同T2炎症参与度梯度的哮喘患者接受生物制剂治疗后的预后差异。
方法：本研究为一项基于注册登记系统的队列研究，纳入了来自 24 个国家的数据。在启动生物制剂治疗前，对生物标志物（血嗜酸性粒细胞计数 [BEC]、呼出气一氧化氮 [FeNO] 及 IgE）的分布进行了定量分析。采用五组分高斯有限混合模型进行聚类识别及表型特征描述。比较了各聚类组间及不同类别生物制剂在起始治疗前1年与治疗后 1年间的哮喘预后及医疗资源利用情况的变化。
结果：在 3,675 例哮喘患者中，依据T2炎症水平识别出5个生物标志物聚类：聚类 A（T2 参与度最低，16.4%）、聚类 B（20.4%）、聚类 C（22.9%）、聚类 D（30.3%）以及 聚类 E（T2 参与度最高，10.0%）。多因素分析显示，在5种聚类组中，生物制剂的使用均与预后改善均相关，且T2炎症参与度较高，疗效更佳。与聚类A相比，聚类C患者的第1秒用力呼气容积（FEV1）改善显著更高（差异为 0.16 L [95% CI: 0.08, 0.25]； P < 0.001）。与聚类A相比，其余各聚类组哮喘未控制的优势比（OR）均约0.6。总体而言，相较于聚类A，抗 IL-5/5 R单抗（而非抗 IgE 或抗 IL-4Rα 单抗）在所有其他聚类组中均显示出更低的急性加重率，以及更显著的肺功能改善和哮喘控制水平提升。
结论：靶向T2通路的生物制剂对低T2参与度哮喘患者有一定治疗价值，但疗效相对有限，提示该人群亟需更有效的治疗策略。未来研究需致力于在T2谱系低端识别可供生物制剂精准干预的特定致病通路。
关键词：血嗜酸性粒细胞计数；贝那利珠单抗；度普利尤单抗；有效性；呼出气一氧化氮；免疫球蛋白 E；美泊利珠单抗；奥马珠单抗；真实世界研究；瑞利珠单抗
Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma: A Data-Driven Biomarker Clustering Approach
Abstract
Background: Asthma with low levels of type 2 (T2) biomarkers is poorly understood.
Objective: To characterize severe asthma phenotypes and compare changes in asthma outcomes from pre- to postbiologic treatment along a gradient of T2 involvement.
Methods: This was a registry-based cohort study including data from 24 countries. Biomarker distribution (blood eosinophil count, fractional exhaled nitric oxide, and IgE) was quantified before biologic initiation. Clusters were identified using a 5-component Gaussian finite mixture model and phenotypically characterized. Changes in asthma and health care utilization outcomes between 1-year pre- and postbiologic initiation were compared between clusters and by biologic class.
Results: Among 3675 patients, 5 biomarker clusters were identified along a gradient of T2 involvement: cluster A with the lowest T2 involvement (16.4%), cluster B (20.4%), cluster C (22.9%), cluster D (30.3%), and cluster E with the highest T2 involvement (10.0%). In multivariable analysis, biologic use was associated with improved outcomes in all clusters but tended to be better at the higher end of the T2 spectrum. For example, patients in cluster C had a significantly greater increase in forced expiratory volume in 1 second compared with cluster A (difference 0.16 L [95% confidence interval: 0.08, 0.25]; P < .001). The odds of uncontrolled asthma were approximately 0.6 for all clusters compared with cluster A. Overall, exacerbation rates were lower, and greater improvements in lung function and asthma control were noted for anti-IL-5/5 receptor (R) (but not anti-IgE or anti-IL-4Rα) for all clusters compared with cluster A.
Conclusion: T2-targeting biologics have utility in the management of asthma with low T2 involvement, but more effective therapies are needed. Further research is warranted to identify specific pathogenic pathways at the lower end of the T2 spectrum that can be effectively targeted by biologics.
Keywords: BEC; Benralizumab; Dupilumab; Effectiveness; FeNO; IgE; Mepolizumab; Omalizumab; Real-life; Reslizumab.
目的：旨在探讨重度哮喘的表型特征，并比较不同T2炎症参与度梯度的哮喘患者接受生物制剂治疗后的预后差异。
方法：本研究为一项基于注册登记系统的队列研究，纳入了来自 24 个国家的数据。在启动生物制剂治疗前，对生物标志物（血嗜酸性粒细胞计数 [BEC]、呼出气一氧化氮 [FeNO] 及 IgE）的分布进行了定量分析。采用五组分高斯有限混合模型进行聚类识别及表型特征描述。比较了各聚类组间及不同类别生物制剂在起始治疗前1年与治疗后 1年间的哮喘预后及医疗资源利用情况的变化。
结果：在 3,675 例哮喘患者中，依据T2炎症水平识别出5个生物标志物聚类：聚类 A（T2 参与度最低，16.4%）、聚类 B（20.4%）、聚类 C（22.9%）、聚类 D（30.3%）以及 聚类 E（T2 参与度最高，10.0%）。多因素分析显示，在5种聚类组中，生物制剂的使用均与预后改善均相关，且T2炎症参与度较高，疗效更佳。与聚类A相比，聚类C患者的第1秒用力呼气容积（FEV1）改善显著更高（差异为 0.16 L [95% CI: 0.08, 0.25]； P < 0.001）。与聚类A相比，其余各聚类组哮喘未控制的优势比（OR）均约0.6。总体而言，相较于聚类A，抗 IL-5/5 R单抗（而非抗 IgE 或抗 IL-4Rα 单抗）在所有其他聚类组中均显示出更低的急性加重率，以及更显著的肺功能改善和哮喘控制水平提升。
结论：靶向T2通路的生物制剂对低T2参与度哮喘患者有一定治疗价值，但疗效相对有限，提示该人群亟需更有效的治疗策略。未来研究需致力于在T2谱系低端识别可供生物制剂精准干预的特定致病通路。
关键词：血嗜酸性粒细胞计数；贝那利珠单抗；度普利尤单抗；有效性；呼出气一氧化氮；免疫球蛋白 E；美泊利珠单抗；奥马珠单抗；真实世界研究；瑞利珠单抗
（南方医科大学南方医院 胡玉玲 龚钊乾 赵海金）
（Wang E, Henley W, Larenas-Linnemann D, et al. Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma: A Data-Driven Biomarker Clustering Approach. J Allergy Clin Immunol Pract. 2025;13(12):3296-3315. doi:10.1016/j.jaip.2025.08.021）
Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma: A Data-Driven Biomarker Clustering Approach
Abstract
Background: Asthma with low levels of type 2 (T2) biomarkers is poorly understood.
Objective: To characterize severe asthma phenotypes and compare changes in asthma outcomes from pre- to postbiologic treatment along a gradient of T2 involvement.
Methods: This was a registry-based cohort study including data from 24 countries. Biomarker distribution (blood eosinophil count, fractional exhaled nitric oxide, and IgE) was quantified before biologic initiation. Clusters were identified using a 5-component Gaussian finite mixture model and phenotypically characterized. Changes in asthma and health care utilization outcomes between 1-year pre- and postbiologic initiation were compared between clusters and by biologic class.
Results: Among 3675 patients, 5 biomarker clusters were identified along a gradient of T2 involvement: cluster A with the lowest T2 involvement (16.4%), cluster B (20.4%), cluster C (22.9%), cluster D (30.3%), and cluster E with the highest T2 involvement (10.0%). In multivariable analysis, biologic use was associated with improved outcomes in all clusters but tended to be better at the higher end of the T2 spectrum. For example, patients in cluster C had a significantly greater increase in forced expiratory volume in 1 second compared with cluster A (difference 0.16 L [95% confidence interval: 0.08, 0.25]; P < .001). The odds of uncontrolled asthma were approximately 0.6 for all clusters compared with cluster A. Overall, exacerbation rates were lower, and greater improvements in lung function and asthma control were noted for anti-IL-5/5 receptor (R) (but not anti-IgE or anti-IL-4Rα) for all clusters compared with cluster A.
Conclusion: T2-targeting biologics have utility in the management of asthma with low T2 involvement, but more effective therapies are needed. Further research is warranted to identify specific pathogenic pathways at the lower end of the T2 spectrum that can be effectively targeted by biologics.
Keywords: BEC; Benralizumab; Dupilumab; Effectiveness; FeNO; IgE; Mepolizumab; Omalizumab; Real-life; Reslizumab.
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慢性鼻窦炎对成人哮喘患者长期临床预后的影响
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重度哮喘急性加重期间无创正压通气使用与临床结局的相关性：基于倾向评分匹配的队列研究
