University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Asthma Institute at the University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
Lancet Respir Med. 2021 Oct;9(10):1165-1173. doi: 10.1016/S2213-2600(21)00124-7. Epub 2021 Jun 25.
Fractional exhaled nitric oxide (FeNO) has potential as a prognostic biomarker in asthma, but its prognostic value among other recognised indicators is unclear. We assessed the added prognostic value of baseline FeNO to blood eosinophil count and prior severe asthma exacerbations for subsequent exacerbations.
In this post-hoc analysis of the 52-week, double-blind, phase 3 LIBERTY ASTHMA QUEST study, we identified 620 patients with moderate-to-severe asthma who were randomly assigned to placebo; had uncontrolled asthma with inhaled glucocorticoids plus up to two controllers; one or more exacerbations in the previous year; FEV percent predicted 40-80%; FEV reversibility of 12% or higher and 200 mL; Asthma Control Questionnaire (ACQ-5) score of 1·5 or higher; and complete data on baseline type 2 biomarkers (FeNO, eosinophils, and total IgE) with no baseline minimum requirement. Annualised severe exacerbation rate was assessed by baseline FeNO (<25 ppb, ≥25 to <50 ppb, ≥50 ppb; negative binomial model) and cross-classified by baseline blood eosinophils (<150 cells per μL, ≥150 to <300 cells per μL, ≥300 cells per μL) and prior exacerbations (one, two or more), all adjusted for baseline ACQ-5, postbronchodilator FEV, and other clinical characteristics. Post-hoc analyses were done in the intention-to-treat population. The LIBERTY ASTHMA QUEST STUDY is registered on ClinicalTrials.gov, NCT02414854, and is complete.
Patients with baseline FeNO of 50 ppb or higher (n=144) had a 1·54-times higher exacerbation rate than patients with FeNO of less than 25 ppb (n=291; relative risk 1·54 [95% CI 1·11-2·14]; p=0·0097). Patients with baseline FeNO of 25 to <50 ppb (n=185) had a 1·33-times higher exacerbation rate than patients with FeNO of less than 25 ppb (1·33 [0·99-1·78]; p=0·0572). Patients with baseline FeNO of 25 ppb or higher, a blood eosinophil count of 150 cells per μL or higher, and two or more prior exacerbations (n=157) had an exacerbation rate 3·62-times higher than patients with FeNO of less than 25 ppb, a blood eosinophil count of less than 150 cells per μL, and one prior exacerbation (n=116; 3·62 [1·67-7·81]; p=0·0011).
In uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations.
Sanofi and Regeneron Pharmaceuticals.
呼出气一氧化氮分数（FeNO）有可能成为哮喘的预后生物标志物，但在其他公认的指标中，其预后价值尚不清楚。我们评估了基线 FeNO 对血嗜酸性粒细胞计数和既往重度哮喘加重的预测价值，以预测随后的加重情况。
在这项为期 52 周、双盲、3 期 LIBERTY ASTHMA QUEST 研究的事后分析中，我们确定了 620 名中重度哮喘患者，他们被随机分配至安慰剂组；接受吸入性糖皮质激素加两种控制药物治疗，但哮喘仍未得到控制；过去一年中发生过一次或多次加重；预计用力呼气量（FEV）占预计值的 40%-80%；FEV 可逆性为 12%或更高且 200 毫升；哮喘控制问卷（ACQ-5）评分≥1.5 分；并且有基线 2 型生物标志物（FeNO、嗜酸性粒细胞和总 IgE）的完整数据，无基线最低要求。根据基线 FeNO（<25 ppb、≥25 至<50 ppb、≥50 ppb；二项式模型）和基线血嗜酸性粒细胞（<150 个/μL、≥150 至<300 个/μL、≥300 个/μL）和既往加重次数（一次、两次或更多次）进行年化重度加重率评估，并调整了基线 ACQ-5、支气管扩张剂后 FEV 和其他临床特征。事后分析在意向治疗人群中进行。LIBERTY ASTHMA QUEST 研究在 ClinicalTrials.gov 上注册，编号为 NCT02414854，现已完成。
基线 FeNO 为 50 ppb 或更高的患者（n=144）的加重率比 FeNO 低于 25 ppb 的患者（n=291）高 1.54 倍（相对风险 1.54 [95%CI 1.11-2.14]；p=0.0097）。基线 FeNO 为 25 至<50 ppb 的患者（n=185）的加重率比 FeNO 低于 25 ppb 的患者高 1.33 倍（1.33 [0.99-1.78]；p=0.0572）。基线 FeNO 为 25 ppb 或更高、血嗜酸性粒细胞计数为 150 个/μL 或更高且既往有两次或更多次加重的患者（n=157）的加重率比 FeNO 低于 25 ppb、血嗜酸性粒细胞计数低于 150 个/μL 且既往有一次加重的患者（n=116）高 3.62 倍（3.62 [1.67-7.81]；p=0.0011）。
在未得到控制的中重度哮喘中，较高的基线 FeNO 水平与重度哮喘加重的风险增加相关，尤其是与嗜酸性粒细胞计数升高和既往加重相关，支持 FeNO 作为预后生物标志物的附加价值。需要进一步的研究来证实 FeNO 作为哮喘加重的独立预测因子。
赛诺菲和再生元制药。
