哮喘病程较长与重症哮喘中非T2型痰液生物标志物升高及T2型炎症降低相关
2026/07/31
摘要
背景：较长的哮喘病程可预测接受T2型生物制剂治疗的重症哮喘患者难以达到缓解，但其潜在机制尚不明确。本研究旨在探讨哮喘病程与炎症生物标志物之间的关联，这可能有助于解释生物制剂疗效的个体差异。
方法：我们分析了U-BIOPRED研究中重症哮喘成人患者的横断面数据。哮喘病程定义为从确诊至入组时的年数。在血液及痰液中检测T2型及非T2型生物标志物。在PRISM队列（生物制剂初始治疗者的验证队列）中进行相同的检测。采用多变量回归模型，校正年龄、性别、种族、体质指数（BMI）、吸烟史及口服糖皮质激素剂量。在PRISM队列中探索与病程相关的生物标志物与12个月生物制剂治疗缓解之间的关系。
结果：在U-BIOPRED研究（n=411）中，哮喘病程中位数为23年（四分位距[IQR] 12-38年）。较长的病程与较高的非T2型生物标志物水平相关，包括痰液CXCL9（β=0.024，95%置信区间[CI] 0.011-0.038）、痰液白细胞介素-6（IL-6）（β=0.024，95% CI 0.011-0.037）及痰液中性粒细胞计数（β=0.009，95% CI 0.001-0.017）；而与较低的T2型生物标志物水平相关，包括血浆骨膜蛋白（β=-0.006，95% CI -0.009至-0.003）、嗜酸性粒细胞（血液：β=-0.002，95% CI -0.003至-0.001；痰液：β=-0.023，95% CI -0.035至-0.011）、痰液嗜酸粒细胞衍化神经毒素（EDN）（β=-0.032，95% CI -0.049至-0.014）及呼出气一氧化氮（FeNO）（β=-0.006，95% CI -0.010至-0.001）。PRISM队列（n=474）证实了上述关联。在接受抗IL-4Rα治疗且哮喘病程≥20年的患者中，较高的痰液CXCL9水平与较低的缓解率相关（β=-1.73，95% CI -3.180至-0.276）。
结论：较长的哮喘病程与气道非T2型炎症升高及全身和气道T2型炎症降低相关。这一发现强调了气道生物标志物检测的重要性，并提示为实现长期哮喘患者的缓解，可能需要联合应用T2型及非T2型靶向治疗策略。
Longer Asthma Duration Is Associated With Elevated Non-T2 Sputum Biomarkers and Reduced T2 Inflammation in Severe Asthma.
Freda, Yang; Sujin, Seo;
Abstract
BACKGROUND: Longer asthma duration predicts non-remission in Type-2 (T2) biologic-treated severe asthma, but underlying mechanisms remain unclear. We investigated associations between asthma duration and inflammatory biomarkers that may explain differential biologic response.
METHODS: We analysed cross-sectional data from adults with severe asthma in U-BIOPRED. Asthma duration was defined as years from diagnosis to study entry. T2 and non-T2 biomarkers were measured in blood and sputum. Identical assays were performed in PRISM, a validation cohort of biologic-initiators. Multivariable regression models adjusted for age, sex, ethnicity, BMI, smoking and oral corticosteroid dose. Associations between duration-related biomarkers and 12-month biologic remission were explored in PRISM.
RESULTS: In U-BIOPRED (n = 411), median asthma duration was 23 years (IQR 12-38). Longer duration was associated with higher non-T2 biomarkers including sputum CXCL9 (β = 0.024, 95% CI 0.011-0.038), sputum IL-6 (β = 0.024, 95% CI 0.011-0.037) and sputum neutrophils (β = 0.009, 95% CI 0.001-0.017), but lower T2 biomarkers including plasma periostin (β = -0.006, 95% CI -0.009 to -0.003), eosinophils (blood: β = -0.002, 95% CI -0.003 to -0.001; sputum: β = -0.023, 95% CI -0.035 to -0.011), sputum EDN (β = -0.032, 95% CI -0.049 to -0.014) and FeNO (β = -0.006, 95% CI -0.010 to -0.001). PRISM (n = 474) confirmed these associations. Higher sputum CXCL9 was associated with reduced remission in anti-IL-4Rα-treated patients with asthma duration ≥ 20 years (β = -1.73, 95% CI -3.180 to -0.276).
CONCLUSION: Longer asthma duration was associated with elevated airway non-T2 inflammation and reduced systemic and airway T2 inflammation. This highlights the importance of airway biomarker sampling and suggests combined T2 and non-T2 therapeutic strategies may be needed to achieve remission in long-standing asthma. BACKGROUND: Biologics targeting type 2 cytokines can inhibit airway inflammation and improve lung function in moderate-to-severe asthma; however, their impact on airway mucosal inflammatory cells is unclear.
背景：较长的哮喘病程可预测接受T2型生物制剂治疗的重症哮喘患者难以达到缓解，但其潜在机制尚不明确。本研究旨在探讨哮喘病程与炎症生物标志物之间的关联，这可能有助于解释生物制剂疗效的个体差异。
方法：我们分析了U-BIOPRED研究中重症哮喘成人患者的横断面数据。哮喘病程定义为从确诊至入组时的年数。在血液及痰液中检测T2型及非T2型生物标志物。在PRISM队列（生物制剂初始治疗者的验证队列）中进行相同的检测。采用多变量回归模型，校正年龄、性别、种族、体质指数（BMI）、吸烟史及口服糖皮质激素剂量。在PRISM队列中探索与病程相关的生物标志物与12个月生物制剂治疗缓解之间的关系。
结果：在U-BIOPRED研究（n=411）中，哮喘病程中位数为23年（四分位距[IQR] 12-38年）。较长的病程与较高的非T2型生物标志物水平相关，包括痰液CXCL9（β=0.024，95%置信区间[CI] 0.011-0.038）、痰液白细胞介素-6（IL-6）（β=0.024，95% CI 0.011-0.037）及痰液中性粒细胞计数（β=0.009，95% CI 0.001-0.017）；而与较低的T2型生物标志物水平相关，包括血浆骨膜蛋白（β=-0.006，95% CI -0.009至-0.003）、嗜酸性粒细胞（血液：β=-0.002，95% CI -0.003至-0.001；痰液：β=-0.023，95% CI -0.035至-0.011）、痰液嗜酸粒细胞衍化神经毒素（EDN）（β=-0.032，95% CI -0.049至-0.014）及呼出气一氧化氮（FeNO）（β=-0.006，95% CI -0.010至-0.001）。PRISM队列（n=474）证实了上述关联。在接受抗IL-4Rα治疗且哮喘病程≥20年的患者中，较高的痰液CXCL9水平与较低的缓解率相关（β=-1.73，95% CI -3.180至-0.276）。
结论：较长的哮喘病程与气道非T2型炎症升高及全身和气道T2型炎症降低相关。这一发现强调了气道生物标志物检测的重要性，并提示为实现长期哮喘患者的缓解，可能需要联合应用T2型及非T2型靶向治疗策略。
（中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校）
（Allergy 2026 Jul 9;(0) DOI：10.1111/all.70436. IF: 8.706）
（Allergy 2026 Jul 9;(0) DOI：10.1111/all.70436. IF: 8.706）
Longer Asthma Duration Is Associated With Elevated Non-T2 Sputum Biomarkers and Reduced T2 Inflammation in Severe Asthma.
Freda, Yang; Sujin, Seo;
Abstract
BACKGROUND: Longer asthma duration predicts non-remission in Type-2 (T2) biologic-treated severe asthma, but underlying mechanisms remain unclear. We investigated associations between asthma duration and inflammatory biomarkers that may explain differential biologic response.
METHODS: We analysed cross-sectional data from adults with severe asthma in U-BIOPRED. Asthma duration was defined as years from diagnosis to study entry. T2 and non-T2 biomarkers were measured in blood and sputum. Identical assays were performed in PRISM, a validation cohort of biologic-initiators. Multivariable regression models adjusted for age, sex, ethnicity, BMI, smoking and oral corticosteroid dose. Associations between duration-related biomarkers and 12-month biologic remission were explored in PRISM.
RESULTS: In U-BIOPRED (n = 411), median asthma duration was 23 years (IQR 12-38). Longer duration was associated with higher non-T2 biomarkers including sputum CXCL9 (β = 0.024, 95% CI 0.011-0.038), sputum IL-6 (β = 0.024, 95% CI 0.011-0.037) and sputum neutrophils (β = 0.009, 95% CI 0.001-0.017), but lower T2 biomarkers including plasma periostin (β = -0.006, 95% CI -0.009 to -0.003), eosinophils (blood: β = -0.002, 95% CI -0.003 to -0.001; sputum: β = -0.023, 95% CI -0.035 to -0.011), sputum EDN (β = -0.032, 95% CI -0.049 to -0.014) and FeNO (β = -0.006, 95% CI -0.010 to -0.001). PRISM (n = 474) confirmed these associations. Higher sputum CXCL9 was associated with reduced remission in anti-IL-4Rα-treated patients with asthma duration ≥ 20 years (β = -1.73, 95% CI -3.180 to -0.276).
CONCLUSION: Longer asthma duration was associated with elevated airway non-T2 inflammation and reduced systemic and airway T2 inflammation. This highlights the importance of airway biomarker sampling and suggests combined T2 and non-T2 therapeutic strategies may be needed to achieve remission in long-standing asthma. BACKGROUND: Biologics targeting type 2 cytokines can inhibit airway inflammation and improve lung function in moderate-to-severe asthma; however, their impact on airway mucosal inflammatory cells is unclear.
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