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

Additionally, the incremental contribution of type 2 inflammation, a common, treatable process, is undetermined.

此外，2型炎症这一常见且可治疗过程的增量贡献尚未确定。

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.

我们旨在量化基线特征和2型炎症生物标志物（特别是血液嗜酸性粒细胞计数和呼出气一氧化氮分数（FeNO））的预后价值，以预测哮喘发作。

Methods

In this systematic reviewand meta-analysisof 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.

在这项系统评价和随机对照试验（RCTs）的荟萃分析中，我们使用牛津哮喘发作风险量表2（ORACLE2），从1993年1月1日至2021年4月1日，对MEDLINE进行了检索，以寻找研究固定治疗方案对至少6个月哮喘发作率影响的试验，并要求有基线血液嗜酸性粒细胞计数和FeNO数据。

Eligible participants were aged 12 years or older with asthma (any severity) who had been randomly assigned to the control group of an RCT.

符合条件的参与者年龄在12岁或以上，患有哮喘（任何严重程度），并已被随机分配到一项随机对照试验的对照组。

Relevant trials were manually retrieved and reviewed by two independent reviewers (SC and IDP).

相关试验由两位独立的评审员（SC和IDP）手动检索和审查。

Disagreements were discussed with five reviewers.

与五位评审员讨论了分歧意见。

Individual patient data (IPD) for meta-analysiswere requested from study authors.

向研究作者请求了用于荟萃分析的个别患者数据(IPD)。

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.

我们调查了对照组参与者在至少6个月内严重哮喘发作（≥3天全身性皮质类固醇）的发生率以及基线血液嗜酸性粒细胞计数和FeNO的预后影响。

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.

从调整了包括血液嗜酸性粒细胞计数和FeNO在内的关键变量的负二项模型中得出了哮喘发作的年化率比（RRs）及其95%置信区间（CIs），并探索了这些2型炎症生物标志物之间的相互作用。

Certainty of evidence was assessed using GRADE.

证据的确定性是通过GRADE方法进行评估的。

The heterogeneity of the included studies and potential for ecological bias were quantified by the concordance statistic (C-statistic).

纳入研究的异质性和潜在的生态偏差通过一致性统计量（C统计量）进行量化。

This study was registered with PROSPERO, CRD42021245337.

本研究已在PROSPERO注册，注册号为CRD42021245337。

Results

We identified 976 potentially eligible studies.

我们确定了976项可能符合条件的研究。

After automated screening, we manually reviewed 219 full-text articles.

经过自动化筛选后，我们手动审查了219篇全文文章。

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).

在这些文章中，有19篇包含23项随机对照试验(RCTs)符合入选标准。

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).

较高的血液嗜酸性粒细胞计数或FeNO与较高的哮喘发作风险相关（每增加10倍，血液嗜酸性粒细胞计数的风险比为1.48 [95% 置信区间 1.30-1.68]，FeNO的风险比为1.44 [1.26-1.65]；高确定性证据）。

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]).

其他预后因素包括发作史（是 vs 否，风险比为1.94 [1.61-2.32]）；疾病严重程度（严重 vs 中度，风险比为1.57 [1.22-2.03]）；FEV1百分比预测值（FEV1%；每减少10%，风险比为1.11 [1.08-1.15]）；以及5项哮喘控制问卷评分（ACQ-5；每增加0.5分，风险比为1.10 [1.07-1.13]）。

High blood eosinophil count and FeNO combined were associated with greater risk than either prognostic factor separately.

高血嗜酸性粒细胞计数与FeNO联合使用时，与单独使用任一预后因素相比，相关风险更大。

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%.

支气管扩张剂可逆性与严重哮喘发作的较低风险相关（每增加10%，相对风险 RR 0·93 [0·90-0·96]），主要观察到的降低风险在0%至25%之间。

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.

关于纳入研究的异质性，C统计量范围从0.58到0.95，表明研究之间患者和疾病特征存在显著差异。

In the univariable meta-analysisper trial, we found substantial heterogeneity in associations between studies, with I2 statistics ranging from 0·56 to 0·97.

在每项试验的单变量荟萃分析中，我们发现研究之间关联存在显著异质性，I2统计量范围从0.56到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.

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素。

Conversely, we found that moderate bronchodilator reversibility was associated with reduced risk.

相反，我们发现中度支气管舒张剂可逆性与降低的风险相关。

These findings from high-quality multinational RCTs support incorporation of blood eosinophils and FeNO into clinical risk stratification for targeted risk reduction.

这些来自高质量多国随机对照试验(RCTs)的发现支持将血液嗜酸性粒细胞和呼出气一氧化氮(FeNO)纳入临床风险分层，以实现针对性的风险降低。

More individualised clinical decision-making models should be explored.

应探索更多个性化的临床决策模型。

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.

国家卫生与护理研究牛津生物医学研究中心