美泊利单抗治疗后残留发作的城市儿童哮喘的炎症途径分析：一项随机临床试验的二次分析
2025/08/01
摘要
背景：虽然针对2型（T2）炎症的生物疗法降低了T2炎症哮喘儿童的急性发作率，但仍有急性发作发生，其潜在分子机制尚不清楚。
目的：本研究对一项比较美泊利单抗与安慰剂疗效的临床试验进行分析，旨在通过表征城市嗜酸性哮喘儿童的呼吸系统疾病，确定与哮喘急性发作相关的多种不同分子机制。
方法：本研究是针对基于免疫治疗预防和维持治疗哮喘急性加重机制的研究：一项系统方法2期（MUPPITS-2）双盲、安慰剂对照、平行组、随机临床试验的二次分析。原试验比较了美泊利珠单抗与安慰剂在美国9个低收入城市中心哮喘易发作儿童中的治疗效果。数据分析于2022年9月至2025年4月进行。参与者随机分配接受美泊利珠单抗单抗（6-11岁：40mg；12-17岁：100mg）或匹配的安慰剂，每4周皮下注射一次，持续52周。本研究主要通过对急性呼吸系统疾病发作期间获得的鼻样本进行RNA测序并进行转录组模块分析。本研究对上呼吸道转录特征、呼吸系统疾病临床结局和肺功能之间的相关性进行分析。
结果：本研究在参与MUPPITS-2试验的290名参与者中，从176起急性呼吸系统疾病事件中抽样108名受试者（中位[IQR]年龄，10.0[9.0-13.0]岁；48例[44%]女性）。导致哮喘加重的疾病事件中，与接受安慰剂的儿童相比，接受美泊利珠单抗的儿童表现出与T2炎症相关的嗜酸性粒细胞相关模块表达降低（log2倍数变化[FC]估计值为-0.60；误发现率[FDR]<0.05），但与上皮和巨噬细胞炎症途径相关的基因模块表达增加（log2 FC估计值为0.22-0.85；FDR<0.005）。与非急性发作期相比，两组在急性发作期均表现出粘液分泌增加和细胞应激反应通路表达增加。美泊利珠单抗组非呼吸道病毒相关急性发作表现为上皮炎症途径上调，而巨噬细胞途径对病毒诱发急性发作有特异性作用。本研究证明，三个不同的半正交炎症轴是两组急性发作中大多数异质性的基础。
结论：本研究结果表明，与上皮细胞和巨噬细胞相关的多种替代炎症途径，以及粘液高分泌，是接受美珠单抗治疗儿童残留急性发作的机制。此外，多个不同炎症轴可独立诱发哮喘发作。
Inflammatory Pathways in Residual Asthma Exacerbations Among Mepolizumab-Treated Urban Children: A Secondary Analysis of a Randomized Clinical Trial.
Altman MC, Janczyk T, Murphy RC, Jayavelu ND, Calatroni A, Kattan M, Gill MA, Stokes J, Liu AH, Khurana Hershey GK, Sherenian M, Kumar R, Robison RG, Gruchalla RS, O'Connor GT, Zoratti EM, Teach SJ, Lynch SV, Dill-McFarland KA, Becker PM, Togias A, Gern JE, Bacharier LB, Busse WW, Jackson DJ; Inner City Asthma Consortium and Childhood Asthma in Urban Settings Network.
Abstract
BACKGROUND:
While biologic therapies targeting type 2 (T2) inflammation reduce acute exacerbation rates in children with asthma and T2 inflammation, exacerbations still occur, and the underlying molecular mechanisms are poorly defined.
OBJECTIVES:
To identify multiple distinct molecular mechanisms implicated in asthma exacerbations by characterizing respiratory illnesses among urban children with eosinophilic asthma enrolled in a clinical trial comparing treatment with mepolizumab vs placebo.
METHODS:
This is a secondary analysis of the Mechanisms Underlying Asthma Exacerbations Prevented and Persistent With Immune-Based Therapy: A Systems Approach Phase 2 (MUPPITS-2) double-blind, placebo-controlled, parallel-group, randomized clinical trial comparing treatment with mepolizumab vs placebo among children with exacerbation-prone asthma in low-income urban centers in 9 US cities. Data analysis was performed from September 2022 to April 2025. Participants were randomized to receive either mepolizumab (aged 6-11 years: 40 mg; aged 12-17 years: 100 mg) or matching placebo by subcutaneous injection once every 4 weeks for 52 weeks. The primary measurement was a transcriptomic modular analysis by RNA sequencing of nasal samples obtained during acute respiratory illnesses. Associations among upper airway transcriptional signatures, the clinical outcome of respiratory illnesses, and pulmonary functions were investigated.
RESULTS:
Of the 290 participants enrolled in the MUPPITS-2 trial, 108 participants (median [IQR] age, 10.0 [9.0-13.0] years; 48 [44%] female) were sampled during 176 acute respiratory illness events. During illness events resulting in asthma exacerbations, children receiving mepolizumab demonstrated decreased expression of an eosinophil-associated module associated with T2 inflammation (log2 fold change [FC] estimate, -0.60; false discovery rate [FDR] < .05) but increased expression of gene modules associated with epithelial and macrophage inflammatory pathways relative to children receiving placebo (log2 FC estimates, 0.22-0.85; FDR < .05). Both groups showed higher expression of mucus secretion and cellular stress response pathways during exacerbations relative to nonexacerbation illnesses. The mepolizumab group demonstrated upregulation of epithelial inflammatory pathways in exacerbations irrespective of a respiratory virus, while macrophage pathways contributed specifically to viral exacerbations. Three distinct, semiorthogonal inflammatory axes were shown to underlie the majority of the heterogeneity among exacerbations in the 2 groups.
CONCLUSION:
The study's findings implicate multiple alternative inflammatory pathways associated with the epithelium and macrophages, as well as mucus hypersecretion, as mechanisms of residual acute exacerbations in children receiving mepolizumab. Further, they indicate that multiple distinct inflammatory axes can independently contribute to asthma exacerbations.
背景：虽然针对2型（T2）炎症的生物疗法降低了T2炎症哮喘儿童的急性发作率，但仍有急性发作发生，其潜在分子机制尚不清楚。
目的：本研究对一项比较美泊利单抗与安慰剂疗效的临床试验进行分析，旨在通过表征城市嗜酸性哮喘儿童的呼吸系统疾病，确定与哮喘急性发作相关的多种不同分子机制。
方法：本研究是针对基于免疫治疗预防和维持治疗哮喘急性加重机制的研究：一项系统方法2期（MUPPITS-2）双盲、安慰剂对照、平行组、随机临床试验的二次分析。原试验比较了美泊利珠单抗与安慰剂在美国9个低收入城市中心哮喘易发作儿童中的治疗效果。数据分析于2022年9月至2025年4月进行。参与者随机分配接受美泊利珠单抗单抗（6-11岁：40mg；12-17岁：100mg）或匹配的安慰剂，每4周皮下注射一次，持续52周。本研究主要通过对急性呼吸系统疾病发作期间获得的鼻样本进行RNA测序并进行转录组模块分析。本研究对上呼吸道转录特征、呼吸系统疾病临床结局和肺功能之间的相关性进行分析。
结果：本研究在参与MUPPITS-2试验的290名参与者中，从176起急性呼吸系统疾病事件中抽样108名受试者（中位[IQR]年龄，10.0[9.0-13.0]岁；48例[44%]女性）。导致哮喘加重的疾病事件中，与接受安慰剂的儿童相比，接受美泊利珠单抗的儿童表现出与T2炎症相关的嗜酸性粒细胞相关模块表达降低（log2倍数变化[FC]估计值为-0.60；误发现率[FDR]<0.05），但与上皮和巨噬细胞炎症途径相关的基因模块表达增加（log2 FC估计值为0.22-0.85；FDR<0.005）。与非急性发作期相比，两组在急性发作期均表现出粘液分泌增加和细胞应激反应通路表达增加。美泊利珠单抗组非呼吸道病毒相关急性发作表现为上皮炎症途径上调，而巨噬细胞途径对病毒诱发急性发作有特异性作用。本研究证明，三个不同的半正交炎症轴是两组急性发作中大多数异质性的基础。
结论：本研究结果表明，与上皮细胞和巨噬细胞相关的多种替代炎症途径，以及粘液高分泌，是接受美珠单抗治疗儿童残留急性发作的机制。此外，多个不同炎症轴可独立诱发哮喘发作。
（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）
（JAMA Pediatr. 2025 Jul 14:e252044. doi: 10.1001/jamapediatrics.2025.2044.）
Inflammatory Pathways in Residual Asthma Exacerbations Among Mepolizumab-Treated Urban Children: A Secondary Analysis of a Randomized Clinical Trial.
Altman MC, Janczyk T, Murphy RC, Jayavelu ND, Calatroni A, Kattan M, Gill MA, Stokes J, Liu AH, Khurana Hershey GK, Sherenian M, Kumar R, Robison RG, Gruchalla RS, O'Connor GT, Zoratti EM, Teach SJ, Lynch SV, Dill-McFarland KA, Becker PM, Togias A, Gern JE, Bacharier LB, Busse WW, Jackson DJ; Inner City Asthma Consortium and Childhood Asthma in Urban Settings Network.
Abstract
BACKGROUND:
While biologic therapies targeting type 2 (T2) inflammation reduce acute exacerbation rates in children with asthma and T2 inflammation, exacerbations still occur, and the underlying molecular mechanisms are poorly defined.
OBJECTIVES:
To identify multiple distinct molecular mechanisms implicated in asthma exacerbations by characterizing respiratory illnesses among urban children with eosinophilic asthma enrolled in a clinical trial comparing treatment with mepolizumab vs placebo.
METHODS:
This is a secondary analysis of the Mechanisms Underlying Asthma Exacerbations Prevented and Persistent With Immune-Based Therapy: A Systems Approach Phase 2 (MUPPITS-2) double-blind, placebo-controlled, parallel-group, randomized clinical trial comparing treatment with mepolizumab vs placebo among children with exacerbation-prone asthma in low-income urban centers in 9 US cities. Data analysis was performed from September 2022 to April 2025. Participants were randomized to receive either mepolizumab (aged 6-11 years: 40 mg; aged 12-17 years: 100 mg) or matching placebo by subcutaneous injection once every 4 weeks for 52 weeks. The primary measurement was a transcriptomic modular analysis by RNA sequencing of nasal samples obtained during acute respiratory illnesses. Associations among upper airway transcriptional signatures, the clinical outcome of respiratory illnesses, and pulmonary functions were investigated.
RESULTS:
Of the 290 participants enrolled in the MUPPITS-2 trial, 108 participants (median [IQR] age, 10.0 [9.0-13.0] years; 48 [44%] female) were sampled during 176 acute respiratory illness events. During illness events resulting in asthma exacerbations, children receiving mepolizumab demonstrated decreased expression of an eosinophil-associated module associated with T2 inflammation (log2 fold change [FC] estimate, -0.60; false discovery rate [FDR] < .05) but increased expression of gene modules associated with epithelial and macrophage inflammatory pathways relative to children receiving placebo (log2 FC estimates, 0.22-0.85; FDR < .05). Both groups showed higher expression of mucus secretion and cellular stress response pathways during exacerbations relative to nonexacerbation illnesses. The mepolizumab group demonstrated upregulation of epithelial inflammatory pathways in exacerbations irrespective of a respiratory virus, while macrophage pathways contributed specifically to viral exacerbations. Three distinct, semiorthogonal inflammatory axes were shown to underlie the majority of the heterogeneity among exacerbations in the 2 groups.
CONCLUSION:
The study's findings implicate multiple alternative inflammatory pathways associated with the epithelium and macrophages, as well as mucus hypersecretion, as mechanisms of residual acute exacerbations in children receiving mepolizumab. Further, they indicate that multiple distinct inflammatory axes can independently contribute to asthma exacerbations.
上一篇：
没有了
下一篇：
美泊利单抗对伴或不伴慢性鼻-鼻窦炎伴鼻息肉的重症哮喘患者的疗效：真实世界汇总分析
