通过患者层面的荟萃分析和转化前瞻性研究表征、预测和预防哮喘发作的症状负担：一项患者层面的荟萃分析
2026/09/09
摘要
背景：哮喘症状常用于指导疾病评估和管理，但其预后和预测价值尚不明确。我们评估了由5项哮喘控制问卷（ACQ-5）测量的症状负担预测未来严重哮喘发作及对抗炎治疗反应的程度。
方法：我们对选定的不同严重程度的哮喘随机对照试验和转化观察队列研究进行了个体参与者数据荟萃分析。主要分析使用ORACLE2患者层面荟萃分析（n=6513），纳入22项随机对照试验中对照组参与者。基于数据可用性，纳入了评估靶向2型抗炎治疗的研究附加数据集，以深入了解ACQ-5与痰细胞计数或介质数据之间的关联。附加数据集包括DREAM静脉注射美泊利珠单抗组（n=461）；一个横断面严重哮喘队列（SA-OT，n=74）；以及两个急性哮喘队列（PRISMA，生物制剂初治，n=53；BOOST，抗白细胞介素-5治疗，n=60）。研究了基线ACQ-5评分与临床、生理和炎症特征、哮喘发作风险及抗炎治疗反应之间的关联。
结果：五个涵盖7161名不同参与者的数据集中，哮喘严重程度、肺功能、炎症特征、合并症和ACQ-5结果差异较大。高症状负担（ACQ-5评分>1.5）患者的比例范围为39%至100%。基线ACQ-5与哮喘的其他临床、生理或炎症特征之间没有一致的横断面关联。基线ACQ-5评分每增加0.5分，未来哮喘发作风险适度增加（调整后的率比[aRR] 1.09 [95% CI 1.06-1.12]；Δ R²=0.02 vs 无ACQ-5的多变量预测模型）。基线ACQ-5评分不影响DREAM研究中静脉注射美泊利珠单抗的相对和绝对发作风险降低。相反，高血嗜酸粒细胞计数和高呼气一氧化氮分数（FeNO）的患者具有最高的相对和绝对风险降低（2.81 vs 1.17次发作；aRR 0.38 [95% CI 0.25-0.57]）。在PRISMA和BOOST数据集中，ACQ-5与糖皮质激素治疗后肺功能变化无关。在各研究中，相对和绝对治疗效果与血嗜酸粒细胞计数和FeNO显示出一致的关联。
解释：在一项大型随机对照试验和转化前瞻性观察队列研究的患者层面荟萃分析中，我们发现症状负担与其他哮喘临床、生理或生物学特征的关联性较低，对严重发作的预测价值有限。相反，2型生物标志物更可靠地识别高风险患者和可能对治疗有反应的患者。哮喘中的症状可能需要结合背景进行解读，以指导抗炎治疗的升级。
Symptom burden to characterise, predict, and prevent asthma attacks: a patient-level meta-analysis of randomised trials and translational prospective studies
Simon Couillard, Fleur L Meulmeester, Pascal Charland, Samuel Lemaire-Paquette, Imran Howell, Carlos Celis-Preciado, Philippe Lachapelle, Liam G Heaney, Peter Bradding, Samuel Mailhot-Larouche, Sanjay Ramakrishnan, Michael E Wechsler, Guy Brusselle, Sarah E Diver, Christopher E Brightling, Mario Castro, Nicola A Hanania, David J Jackson, Neil Martin, Alison Moore, Peter Howarth, Megan E Hardin, Rebecca Gall, Cecile T J Holweg, Vennila Dharman, Richard W Beasley, Jacob K Sont, Ewout W Steyerberg, Ian D Pavord; Oxford Asthma Attack Risk Scale Meta-analysis (ORACLE2) Consortium
Abstract
Background: Asthma symptoms often guide disease assessment and management, but their prognostic and predictive value is unclear. We evaluated the extent to which symptom burden measured by the 5-item Asthma Control Questionnaire (ACQ-5) predicts future severe asthma attacks and response to anti-inflammatory therapy.
Methods: We conducted an individual participant data meta-analysis of selected randomised controlled trials and translational observational cohort studies of asthma of varying severity. Primary analyses used the ORACLE2 patient-level meta-analysis (n=6513) of control-group participants from 22 randomised controlled trials. Additional datasets from studies assessing type 2 targeting anti-inflammatory therapies were included on the basis of availability of data, to provide insight into the association between ACQ-5 and sputum cell counts or mediator data. Additional datasets were the DREAM intravenous mepolizumab group (n=461); a cross-sectional severe asthma cohort (SA-OT, n=74); and two acute asthma cohorts (PRISMA, biologic-naive, n=53; BOOST, anti-interleukin-5-treated, n=60). Associations between baseline ACQ-5 scores and clinical, physiological, and inflammatory profiles, asthma attack risk, and anti-inflammatory treatment responses were examined.
Findings: Across five datasets encompassing 7161 distinct participants, asthma severity, lung function, inflammatory profiles, comorbidities, and ACQ-5 results varied widely. The proportion of patients with high symptom burden (ACQ-5 score >1.5) ranged from 39% to 100%. Baseline ACQ-5 showed no consistent cross-sectional association with other clinical, physiological, or inflammatory asthma features. Each 0.5-point increase in baseline ACQ-5 score was associated with a modest increase in future asthma attack risk (adjusted rate ratio [aRR] 1.09 [95% CI 1.06-1.12]; Δ R2=0.02 vs multivariable prediction model without ACQ-5). Baseline ACQ-5 score did not alter relative and absolute attack risk reduction from intravenous mepolizumab in DREAM. By contrast, patients with high blood eosinophil counts and high fractional exhaled nitric oxide (FeNO) had the highest relative and absolute risk reduction (2.81 vs 1.17 attacks; aRR 0.38 [95% CI 0.25–0.57]). In the PRISMA and BOOST datasets, ACQ-5 was not associated with post-corticosteroid lung function change. Across studies, relative and absolute treatment effects showed consistent associations with blood eosinophil counts and FeNO.
Interpretation: In a large, individual patient-level meta-analysis of randomised controlled trials and translational prospective observational cohort studies, we observed little alignment of symptom burden with other clinical, physiological, or biological features of asthma and modest prognostic value for severe attacks. Conversely, type 2 biomarkers more reliably identified patients at high risk and those likely to respond to treatment. Symptoms might require contextual interpretation to guide anti-inflammatory escalation in asthma.
背景：哮喘症状常用于指导疾病评估和管理，但其预后和预测价值尚不明确。我们评估了由5项哮喘控制问卷（ACQ-5）测量的症状负担预测未来严重哮喘发作及对抗炎治疗反应的程度。
方法：我们对选定的不同严重程度的哮喘随机对照试验和转化观察队列研究进行了个体参与者数据荟萃分析。主要分析使用ORACLE2患者层面荟萃分析（n=6513），纳入22项随机对照试验中对照组参与者。基于数据可用性，纳入了评估靶向2型抗炎治疗的研究附加数据集，以深入了解ACQ-5与痰细胞计数或介质数据之间的关联。附加数据集包括DREAM静脉注射美泊利珠单抗组（n=461）；一个横断面严重哮喘队列（SA-OT，n=74）；以及两个急性哮喘队列（PRISMA，生物制剂初治，n=53；BOOST，抗白细胞介素-5治疗，n=60）。研究了基线ACQ-5评分与临床、生理和炎症特征、哮喘发作风险及抗炎治疗反应之间的关联。
结果：五个涵盖7161名不同参与者的数据集中，哮喘严重程度、肺功能、炎症特征、合并症和ACQ-5结果差异较大。高症状负担（ACQ-5评分>1.5）患者的比例范围为39%至100%。基线ACQ-5与哮喘的其他临床、生理或炎症特征之间没有一致的横断面关联。基线ACQ-5评分每增加0.5分，未来哮喘发作风险适度增加（调整后的率比[aRR] 1.09 [95% CI 1.06-1.12]；Δ R²=0.02 vs 无ACQ-5的多变量预测模型）。基线ACQ-5评分不影响DREAM研究中静脉注射美泊利珠单抗的相对和绝对发作风险降低。相反，高血嗜酸粒细胞计数和高呼气一氧化氮分数（FeNO）的患者具有最高的相对和绝对风险降低（2.81 vs 1.17次发作；aRR 0.38 [95% CI 0.25-0.57]）。在PRISMA和BOOST数据集中，ACQ-5与糖皮质激素治疗后肺功能变化无关。在各研究中，相对和绝对治疗效果与血嗜酸粒细胞计数和FeNO显示出一致的关联。
解释：在一项大型随机对照试验和转化前瞻性观察队列研究的患者层面荟萃分析中，我们发现症状负担与其他哮喘临床、生理或生物学特征的关联性较低，对严重发作的预测价值有限。相反，2型生物标志物更可靠地识别高风险患者和可能对治疗有反应的患者。哮喘中的症状可能需要结合背景进行解读，以指导抗炎治疗的升级。
（北京朝阳医院呼吸与危重症医学科 顾宪民 摘译 中日友好医院呼吸与危重症医学科 林江涛 审校）
（J Pediatr Health Care. Jan-Feb 2017;31(1):37-45. doi: 10.1016/j.pedhc.2016.01.005.）
（Lancet Respir Med. 2026 Aug 20:S2213-2600(26)00150-5.doi: 10.1016/S2213-2600(26)00150-5.）
（J Pediatr Health Care. Jan-Feb 2017;31(1):37-45. doi: 10.1016/j.pedhc.2016.01.005.）
（Lancet Respir Med. 2026 Aug 20:S2213-2600(26)00150-5.doi: 10.1016/S2213-2600(26)00150-5.）
Symptom burden to characterise, predict, and prevent asthma attacks: a patient-level meta-analysis of randomised trials and translational prospective studies
Simon Couillard, Fleur L Meulmeester, Pascal Charland, Samuel Lemaire-Paquette, Imran Howell, Carlos Celis-Preciado, Philippe Lachapelle, Liam G Heaney, Peter Bradding, Samuel Mailhot-Larouche, Sanjay Ramakrishnan, Michael E Wechsler, Guy Brusselle, Sarah E Diver, Christopher E Brightling, Mario Castro, Nicola A Hanania, David J Jackson, Neil Martin, Alison Moore, Peter Howarth, Megan E Hardin, Rebecca Gall, Cecile T J Holweg, Vennila Dharman, Richard W Beasley, Jacob K Sont, Ewout W Steyerberg, Ian D Pavord; Oxford Asthma Attack Risk Scale Meta-analysis (ORACLE2) Consortium
Abstract
Background: Asthma symptoms often guide disease assessment and management, but their prognostic and predictive value is unclear. We evaluated the extent to which symptom burden measured by the 5-item Asthma Control Questionnaire (ACQ-5) predicts future severe asthma attacks and response to anti-inflammatory therapy.
Methods: We conducted an individual participant data meta-analysis of selected randomised controlled trials and translational observational cohort studies of asthma of varying severity. Primary analyses used the ORACLE2 patient-level meta-analysis (n=6513) of control-group participants from 22 randomised controlled trials. Additional datasets from studies assessing type 2 targeting anti-inflammatory therapies were included on the basis of availability of data, to provide insight into the association between ACQ-5 and sputum cell counts or mediator data. Additional datasets were the DREAM intravenous mepolizumab group (n=461); a cross-sectional severe asthma cohort (SA-OT, n=74); and two acute asthma cohorts (PRISMA, biologic-naive, n=53; BOOST, anti-interleukin-5-treated, n=60). Associations between baseline ACQ-5 scores and clinical, physiological, and inflammatory profiles, asthma attack risk, and anti-inflammatory treatment responses were examined.
Findings: Across five datasets encompassing 7161 distinct participants, asthma severity, lung function, inflammatory profiles, comorbidities, and ACQ-5 results varied widely. The proportion of patients with high symptom burden (ACQ-5 score >1.5) ranged from 39% to 100%. Baseline ACQ-5 showed no consistent cross-sectional association with other clinical, physiological, or inflammatory asthma features. Each 0.5-point increase in baseline ACQ-5 score was associated with a modest increase in future asthma attack risk (adjusted rate ratio [aRR] 1.09 [95% CI 1.06-1.12]; Δ R2=0.02 vs multivariable prediction model without ACQ-5). Baseline ACQ-5 score did not alter relative and absolute attack risk reduction from intravenous mepolizumab in DREAM. By contrast, patients with high blood eosinophil counts and high fractional exhaled nitric oxide (FeNO) had the highest relative and absolute risk reduction (2.81 vs 1.17 attacks; aRR 0.38 [95% CI 0.25–0.57]). In the PRISMA and BOOST datasets, ACQ-5 was not associated with post-corticosteroid lung function change. Across studies, relative and absolute treatment effects showed consistent associations with blood eosinophil counts and FeNO.
Interpretation: In a large, individual patient-level meta-analysis of randomised controlled trials and translational prospective observational cohort studies, we observed little alignment of symptom burden with other clinical, physiological, or biological features of asthma and modest prognostic value for severe attacks. Conversely, type 2 biomarkers more reliably identified patients at high risk and those likely to respond to treatment. Symptoms might require contextual interpretation to guide anti-inflammatory escalation in asthma.
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