血嗜酸性粒细胞和部分呼出气一氧化氮可作为儿童哮喘预后和疗效预测的生物标志物
2024/03/26
摘要
背景：血嗜酸性粒细胞和部分呼出气一氧化氮（Feno）是青少年和成人哮喘急性加重的预后生物标志物，可预测患者肺功能对度普利尤单抗的反应。
目的：本研究旨在评估哮喘儿童基线血嗜酸性粒细胞、Feno与度普利尤单抗疗效之间的关系。
方法：本研究将6至11岁患有未控制中重度哮喘的儿童（n=408）随机分组，按体重每2周接受一次100或200mg度普利尤单抗或等体积安慰剂治疗，持续52周。根据Feno（<20ppb vs≥20ppb）和血嗜酸性粒细胞计数（<150、≥150至<300、≥300至<500和≥500个细胞/μL）的基线水平，评估第12周的年急性加重率（AER）降低情况和支气管扩张前第一秒用力呼吸容积占预计值的百分比（ppFEV1）最小二乘平均变化值。通过生物标志物阈值和连续终点的样条模型定义的人群中进行象限分析，以评估与Feno和嗜酸性粒细胞计数的关系。相互作用测试评估了Feno和血嗜酸性粒细胞作为预测标志物的独立作用。
结果：在基线生物标志物水平较高的亚组中，急性加重风险和AER降低幅度增加。象限分析显示，度普利尤单抗对Feno或嗜酸性粒细胞计数升高的患者一定临床疗效。相互作用测试表明，血嗜酸性粒细胞计数或Feno独立增加值可作为预测性生物标志物。
结论：在患有未控制的中重度哮喘儿童中，血嗜酸性粒细胞计数和Feno是临床相关性生物标志物，可用于识别有哮喘急性加重风险的儿童，以及对度普利尤单抗临床治疗有效的儿童。
Blood eosinophils and fractional exhaled nitric oxide are prognostic and predictive biomarkers in childhood asthma.
Bacharier LB, Pavord ID, Maspero JF, Jackson DJ, Fiocchi AG, Mao X, Jacob-Nara JA, Deniz Y, Laws E, Mannent LP, Amin N, Akinlade B, Staudinger HW, Lederer DJ, Hardin M.
Abstract
BACKGROUND:Blood eosinophils and fractional exhaled nitric oxide (Feno) are prognostic biomarkers for exacerbations and predict lung function responses to dupilumab in adolescents and adults with asthma.
OBJECTIVE：We evaluated the relationship between baseline blood eosinophils and Feno and response to dupilumab in children with asthma.
METHODS:Children aged 6 to 11 years with uncontrolled moderate-to-severe asthma (n = 408) were randomized to receive dupilumab 100/200 mg by body weight or volume-matched placebo every 2 weeks for 52 weeks. Annualized exacerbation rate (AER) reduction and least squares mean change in prebronchodilator percent predicted forced expiratory volume in 1 second (ppFEV1) at week 12 were assessed according to cutoff baseline levels for Feno (<20 ppb vs ≥20 ppb) and blood eosinophil count (<150, ≥150 to <300, ≥300 to <500, and ≥500 cells/μL). Quadrant analyses in populations defined by biomarker thresholds and spline models across continuous end points assessed the relationship with Feno and eosinophil count. Interaction testing evaluated the independent roles of Feno and blood eosinophils as predictive markers.
RESULTS:Exacerbation risk and magnitude of AER reduction increased in subgroups with higher baseline biomarker levels. Quadrant analyses revealed that disease of patients with either elevated Feno or eosinophil counts demonstrated a clinical response to dupilumab. Interaction testing indicated blood eosinophil counts or Feno independently added value as predictive biomarkers.
CONCLUSION:In children with uncontrolled moderate-to-severe asthma, blood eosinophil counts and Feno are clinically relevant biomarkers to identify those at risk for asthma exacerbations, as well as those with disease with clinical response to dupilumab.
背景：血嗜酸性粒细胞和部分呼出气一氧化氮（Feno）是青少年和成人哮喘急性加重的预后生物标志物，可预测患者肺功能对度普利尤单抗的反应。
目的：本研究旨在评估哮喘儿童基线血嗜酸性粒细胞、Feno与度普利尤单抗疗效之间的关系。
方法：本研究将6至11岁患有未控制中重度哮喘的儿童（n=408）随机分组，按体重每2周接受一次100或200mg度普利尤单抗或等体积安慰剂治疗，持续52周。根据Feno（<20ppb vs≥20ppb）和血嗜酸性粒细胞计数（<150、≥150至<300、≥300至<500和≥500个细胞/μL）的基线水平，评估第12周的年急性加重率（AER）降低情况和支气管扩张前第一秒用力呼吸容积占预计值的百分比（ppFEV1）最小二乘平均变化值。通过生物标志物阈值和连续终点的样条模型定义的人群中进行象限分析，以评估与Feno和嗜酸性粒细胞计数的关系。相互作用测试评估了Feno和血嗜酸性粒细胞作为预测标志物的独立作用。
结果：在基线生物标志物水平较高的亚组中，急性加重风险和AER降低幅度增加。象限分析显示，度普利尤单抗对Feno或嗜酸性粒细胞计数升高的患者一定临床疗效。相互作用测试表明，血嗜酸性粒细胞计数或Feno独立增加值可作为预测性生物标志物。
结论：在患有未控制的中重度哮喘儿童中，血嗜酸性粒细胞计数和Feno是临床相关性生物标志物，可用于识别有哮喘急性加重风险的儿童，以及对度普利尤单抗临床治疗有效的儿童。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2024 Jan 23:S0091-6749(24)00043-5. doi: 10.1016/j.jaci.2023.09.044.)
(J Allergy Clin Immunol. 2024 Jan 23:S0091-6749(24)00043-5. doi: 10.1016/j.jaci.2023.09.044.)
Blood eosinophils and fractional exhaled nitric oxide are prognostic and predictive biomarkers in childhood asthma.
Bacharier LB, Pavord ID, Maspero JF, Jackson DJ, Fiocchi AG, Mao X, Jacob-Nara JA, Deniz Y, Laws E, Mannent LP, Amin N, Akinlade B, Staudinger HW, Lederer DJ, Hardin M.
Abstract
BACKGROUND:Blood eosinophils and fractional exhaled nitric oxide (Feno) are prognostic biomarkers for exacerbations and predict lung function responses to dupilumab in adolescents and adults with asthma.
OBJECTIVE：We evaluated the relationship between baseline blood eosinophils and Feno and response to dupilumab in children with asthma.
METHODS:Children aged 6 to 11 years with uncontrolled moderate-to-severe asthma (n = 408) were randomized to receive dupilumab 100/200 mg by body weight or volume-matched placebo every 2 weeks for 52 weeks. Annualized exacerbation rate (AER) reduction and least squares mean change in prebronchodilator percent predicted forced expiratory volume in 1 second (ppFEV1) at week 12 were assessed according to cutoff baseline levels for Feno (<20 ppb vs ≥20 ppb) and blood eosinophil count (<150, ≥150 to <300, ≥300 to <500, and ≥500 cells/μL). Quadrant analyses in populations defined by biomarker thresholds and spline models across continuous end points assessed the relationship with Feno and eosinophil count. Interaction testing evaluated the independent roles of Feno and blood eosinophils as predictive markers.
RESULTS:Exacerbation risk and magnitude of AER reduction increased in subgroups with higher baseline biomarker levels. Quadrant analyses revealed that disease of patients with either elevated Feno or eosinophil counts demonstrated a clinical response to dupilumab. Interaction testing indicated blood eosinophil counts or Feno independently added value as predictive biomarkers.
CONCLUSION:In children with uncontrolled moderate-to-severe asthma, blood eosinophil counts and Feno are clinically relevant biomarkers to identify those at risk for asthma exacerbations, as well as those with disease with clinical response to dupilumab.
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Benralizumab在重度嗜酸性粒细胞性哮喘中根据先前生物制剂使用情况和关键临床亚组的应用：XALOC-1的真实世界
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