哮喘发作的炎症和临床危险因素（ORACLE2）：对22个随机试验对照组的患者水平荟萃分析

IF 38.7 1区医学 Q1 CRITICAL CARE MEDICINE

Lancet Respiratory Medicine Pub Date : 2025-04-08 DOI:10.1016/s2213-2600(25)00037-2

Fleur L Meulmeester, Samuel Mailhot-Larouche, Carlos Celis-Preciado, Samuel Lemaire-Paquette, Sanjay Ramakrishnan, Michael E Wechsler, Guy Brusselle, Jonathan Corren, Jo Hardy, Sarah E Diver, Christopher E Brightling, Mario Castro, Nicola A Hanania, David J Jackson, Neil Martin, Annette Laugerud, Emilio Santoro, Chris Compton, Megan E Hardin, Cecile T J Holweg, Simon Couillard

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引用次数: 0

摘要

背景：严重哮喘发作的临床危险因素已经确定，但其增量预后价值尚不清楚。此外，2型炎症（一种常见的、可治疗的过程）的增量贡献尚不确定。我们的目的是量化基线特征和2型炎症生物标志物的预后价值，特别是血液嗜酸性粒细胞计数和呼气一氧化氮分数（FeNO），以预测哮喘发作。在这项随机对照试验（RCTs）的系统评价和荟萃分析中，牛津哮喘发作风险量表2 (ORACLE2)，我们检索了MEDLINE从1993年1月1日至2021年4月1日，研究固定治疗方案对至少6个月的哮喘发作率的影响，包括基线血嗜酸性粒细胞计数和FeNO。符合条件的参与者是12岁或以上的哮喘患者（任何严重程度），他们被随机分配到随机对照试验的对照组。相关试验由两个独立的审稿人（SC和IDP）手动检索和审查。与五位审稿人讨论了分歧。研究作者要求提供用于meta分析的个体患者数据（IPD）。我们调查了对照组参与者至少6个月的严重哮喘发作率（≥3天的全身皮质类固醇）和基线血嗜酸性粒细胞计数和FeNO对预后的影响。通过校正了关键变量（包括血嗜酸性粒细胞计数和FeNO）的负二项模型，得出了95% ci的哮喘年发作率的比率（rr），并探讨了这些2型炎症生物标志物之间的相互作用。使用GRADE评估证据的确定性。采用一致性统计量（C-statistic）量化纳入研究的异质性和生态偏倚的可能性。本研究注册号为PROSPERO， CRD42021245337。研究结果：我们确定了976项可能符合条件的研究。在自动筛选之后，我们人工审查了219篇全文文章。其中，包括23项随机对照试验的19篇出版物入选。6513例（女性4140例，占64%）；2370[36%]男；纳入22项rct进行数据分析。6513例患者中有5972例（92%）患有中度至重度哮喘。在5482人-年随访期间发生4615次哮喘发作（年化率0.84 /人-年）。较高的血嗜酸性粒细胞计数或FeNO与哮喘发作风险升高相关(每增加10倍，血嗜酸性粒细胞计数的RR为1.48 [95% CI为1.30 - 1.68]，FeNO的RR为1.44 [95% CI为1.26 - 1.65]；高确定性的证据)。其他预后因素为发作史（是vs否，RR为1.94[1.61 - 2·32]）；疾病严重程度（重度vs中度，RR为1.57 [1.22 - 2.03]）；FEV1预测百分比(FEV1%；每降低10%，RR为1.11 [1.08 - 1.15])；哮喘控制问卷（ACQ-5）评分；每增加0.5，RR为1.10[1.07 - 1.13])。高血嗜酸性粒细胞计数和FeNO合并比单独的任何预后因素的风险更大。支气管扩张剂可逆性与严重哮喘发作风险降低相关（每增加10%，RR为0.93[0.90 - 0.96]），降低的风险主要在0% - 25%之间。关于纳入研究的异质性，c统计量范围为0.58 ~ 0.95，表明研究之间患者和疾病特征存在较大差异。在每个试验的单变量荟萃分析中，我们发现研究之间的相关性存在显著的异质性，I2统计量范围为0.56至0.97。血液嗜酸性粒细胞计数、FeNO、哮喘发作史、疾病严重程度、低肺功能（低FEV1%）和症状（ACQ-5评分）是哮喘发作的关键预测因子。相反，我们发现适度的支气管扩张剂可逆性与风险降低相关。这些来自高质量多国随机对照试验的结果支持将嗜酸性粒细胞和FeNO纳入临床风险分层，以有针对性地降低风险。应探索更加个性化的临床决策模式。英国国家卫生与保健研究所牛津生物医学研究中心；青海肺病协会；quassei - san研究基金会；组织-空气-交叉-呼吸器- son网络；缝合Astma strijding；莱顿大学基金；和医学科学院

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Inflammatory and clinical risk factors for asthma attacks (ORACLE2): a patient-level meta-analysis of control groups of 22 randomised trials

Background

Clinical risk factors for severe asthma attacks have been identified, but their incremental prognostic values are unclear. Additionally, the incremental contribution of type 2 inflammation, a common, treatable process, is undetermined. We aimed to quantify the prognostic value of baseline characteristics and type 2 inflammatory biomarkers, specifically blood eosinophil count and fractional exhaled nitric oxide (FeNO), to predict asthma attacks.

Methods

In this systematic review and meta-analysis of randomised controlled trials (RCTs), Oxford Asthma Attack Risk Scale 2 (ORACLE2), we searched MEDLINE from Jan 1, 1993, to April 1, 2021, for trials investigating fixed treatment regimen effects on asthma attack rates for at least 6 months with baseline blood eosinophil count and FeNO. Eligible participants were aged 12 years or older with asthma (any severity) who had been randomly assigned to the control group of an RCT. Relevant trials were manually retrieved and reviewed by two independent reviewers (SC and IDP). Disagreements were discussed with five reviewers. Individual patient data (IPD) for meta-analysis were requested from study authors. We investigated the rate of severe asthma attacks (≥3 days of systemic corticosteroids) for at least 6 months and prognostic effects of baseline blood eosinophil count and FeNO in control group participants. Rate ratios (RRs) with 95% CIs were derived for annualised asthma attack rates from negative binomial models adjusted for key variables, including blood eosinophil count and FeNO, and interactions between these type 2 inflammatory biomarkers were explored. Certainty of evidence was assessed using GRADE. The heterogeneity of the included studies and potential for ecological bias were quantified by the concordance statistic (C-statistic). This study was registered with PROSPERO, CRD42021245337.

Findings

We identified 976 potentially eligible studies. After automated screening, we manually reviewed 219 full-text articles. Of these, 19 publications comprising 23 RCTs were eligible. 6513 participants (4140 [64%] female; 2370 [36%] male; three missing) spanning 22 RCTs were included for data analysis. 5972 (92%) of 6513 patients had moderate-to-severe asthma. 4615 asthma attacks occurred during 5482 person-years of follow-up (annualised rate 0·84 per person-year). Higher blood eosinophil count or FeNO was linked to higher asthma attack risk (per 10-fold increase, RR 1·48 [95% CI 1·30–1·68] for blood eosinophil count and 1·44 [1·26–1·65] for FeNO; high-certainty evidence). Other prognostic factors were attack history (yes vs no, RR 1·94 [1·61–2·32]); disease severity (severe vs moderate, RR 1·57 [1·22–2·03]); FEV₁ percentage predicted (FEV₁%; per 10% decrease, RR 1·11 [1·08–1·15]); and 5-item Asthma Control Questionnaire score (ACQ-5; per 0·5 increase, RR 1·10 [1·07–1·13]). High blood eosinophil count and FeNO combined were associated with greater risk than either prognostic factor separately. Bronchodilator reversibility was associated with lower risk of severe asthma attacks (per 10% increase, RR 0·93 [0·90–0·96]), with the reduction observed primarily between 0% and 25%. Regarding heterogeneity of the included studies, the C-statistic ranged from 0·58 to 0·95, indicating major differences in patient and disease characteristics between studies. In the univariable meta-analysis per trial, we found substantial heterogeneity in associations between studies, with I² statistics ranging from 0·56 to 0·97.

Interpretation

Blood eosinophil count, FeNO, asthma attack history, disease severity, low lung function (low FEV₁%), and symptoms (ACQ-5 score) are key predictors of asthma attacks. Conversely, we found that moderate bronchodilator reversibility was associated with reduced risk. These findings from high-quality multinational RCTs support incorporation of blood eosinophils and FeNO into clinical risk stratification for targeted risk reduction. More individualised clinical decision-making models should be explored.

Funding

National Institute of Health and Care Research Oxford Biomedical Research Centre; Association pulmonaire du Québec; Fonds de recherche du Québec—Santé; Québec Air-Intersectorialité-Respiratoire-Son network; Stichting Astma Bestrijding; Leiden University Fund; and Academy of Medical Sciences

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来源期刊

Lancet Respiratory Medicine RESPIRATORY SYSTEM-RESPIRATORY SYSTEM

CiteScore

87.10

自引率

0.70%

发文量

572

期刊介绍： The Lancet Respiratory Medicine is a renowned journal specializing in respiratory medicine and critical care. Our publication features original research that aims to advocate for change or shed light on clinical practices in the field. Additionally, we provide informative reviews on various topics related to respiratory medicine and critical care, ensuring a comprehensive coverage of the subject. The journal covers a wide range of topics including but not limited to asthma, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), tobacco control, intensive care medicine, lung cancer, cystic fibrosis, pneumonia, sarcoidosis, sepsis, mesothelioma, sleep medicine, thoracic and reconstructive surgery, tuberculosis, palliative medicine, influenza, pulmonary hypertension, pulmonary vascular disease, and respiratory infections. By encompassing such a broad spectrum of subjects, we strive to address the diverse needs and interests of our readership.