小气道功能障碍作为严重嗜酸性粒细胞性哮喘生物治疗临床反应的预测指标和标志物：一项纵向观察性研究
2020/11/17
摘要
背景：在严重的嗜酸性粒细胞性哮喘中，已证明抗T2生物疗法可有效减少急性加重和口服类固醇的每日剂量。尽管临床效果显著，但通常在气流受限方面仅有中等程度的改善，这表明其他肺功能指标（如小气道功能障碍（SAD））可能会更好地反应临床治疗效果。我们旨在研究小气道功能的措施是否可以预测并与抗T2治疗的临床反应相关。
方法：我们研究了先前纳入德国前瞻性纵向全年龄哮喘队列（ALLIANCE）的患者数据，该队列招募了所有严重程度等级和炎性表型的哮喘患者。这项分析的选择标准是接受抗T2生物药物治疗的患有严重嗜酸性粒细胞性哮喘的成年患者。哮喘控制通过哮喘控制测试（ACT）和严重加重次数进行评估。小气道功能通过脉冲示波法（IOS）得出的阻力的频率依赖性（FDR，R5-20）和强制肺活量的25％至75％（FEF25-75）之间的平均强制呼气流量来评估。我们还研究了空气潴留（RV和RV / TLC），血液嗜酸性粒细胞和FeNO。将患者分为有反应者和部分或无反应者。临床反应被定义为严重急性发作和每日口服类固醇剂量至少减少50％，同时ACT评分至少增加3分。与其他临床变量（如血液嗜酸性粒细胞）相比，我们使用接收者操作特征（ROC）研究了FDR预测临床反应的能力。我们使用线性回归研究了FDR量度与临床反应之间的相关性，以ACT评分和加重次数表示。
结果：包括20例患者（平均年龄59±9岁;女性60％;平均体重指数（BMI）为27.6±5.4 kg/m2;平均绝对血嗜酸性粒细胞为570±389/μl;严重加重的平均次数为12个月在开始生物治疗之前，5.0±3;平均预测FEV1，76±21％;平均预测FDR，224±140％;平均泼尼松龙日剂量，6.4±4.9 mg;平均ACT评分，15±5）。与部分或无应答者相比，应答者的基线FDR明显更高，但FEV1，FEF25-75，RV和RV / TLC相似。ROC分析表明，在所有测试的临床指标（FeNO，FEV1，FDR，血液嗜酸性粒细胞）中，FDR和血液嗜酸性粒细胞的结合对临床反应的预测能力最佳，AUC为85％[67-100％]，（CI = 0.95，p = 0.01）。线性回归表明，与FEV1和ACT得分（R2 = 0.25，p = 0.013）相比，FDR和ACT得分（R2 = 0.42，p = 0.001）改善之间的关联更好。同样，我们观察到FDR改善与急性发作减少之间的更好关联（R2 = 0.41，p=0.001）比FEV1（R2 = 0.20，p = 0.025）更好。
结论：我们的数据表明，严重的SAD可能代表嗜酸性哮喘的独特表型，在抗T2生物疗法下可显着改善。除血液嗜酸性粒细胞计数外，小气道功能的测量可能对选择符合抗T2生物治疗资格的合适患者有用。
Small airway dysfunction as predictor and marker for clinical response to biological therapy in severe eosinophilic asthma: a longitudinal observational study
Mustafa Abdo, Henrik Watz , Vera Veith , et al.
Abstract
BACKGROUND: Anti-T2 biological therapies have proven to effectively reduce acute exacerbations and daily doses of oral steroids in severe eosinophilic asthma. Despite the remarkable clinical efficacy, there are usually only moderate improvements in airflow limitation, suggesting that other measures of lung function like small airway dysfunction (SAD) might better reflect the clinical response. We aimed to investigate if measures of small airway function would predict and correlate with the clinical response to anti-T2 therapy.
METHODS: We studied data of patients who were previously included in the German prospective longitudinal All Age Asthma Cohort (ALLIANCE) that recruits asthma patients of all severity grades and inflammatory phenotypes. The selection criteria for this analysis were adult patients with severe eosinophilic asthma under treatment with anti-T2 biological agents. Asthma control was assessed by asthma control test (ACT) and number of severe exacerbations. Small airway function was assessed by the frequency dependence of resistance (FDR, R5-20)) derived from impulse oscillometry (IOS) and the mean forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75). We also studied air trapping (RV and RV/TLC), blood eosinophils and FeNO. Patients were classified into responders and partial or non-responders. Clinical response was defined as at least 50% reduction in annualized severe exacerbations and daily oral steroid doses accompanied with a minimum increase of 3 points in the ACT score. We used a Receiver Operator Characteristic (ROC) to study the capacity of FDR in predicting clinical response compared to other clinical variable like blood eosinophils. We studied the correlation between FDR measures and clinical response, represented by the ACT score and number of exacerbations, using linear regressions.
RESULTS:20 patients were included (mean age, 59±9 years; 60% female; mean body mass index (BMI), 27.6±5.4 kg/ m2 ; mean absolute blood eosinophils, 570±389/µl; mean number of severe exacerbations 12 months prior to initiating the biological therapy, 5.0±3; mean predicted FEV1, 76±21%; mean predicted FDR, 224±140%; mean daily prednisolone dose, 6.4±4.9 mg; mean ACT score, 15±5). Responders had significantly higher baseline FDR compared to partial or non-responders but similar FEV1, FEF25–75, RV and RV/TLC. ROC analysis showed that the combination of FDR and blood eosinophils had the best predictive capacity of the clinical response among all tested clinical markers (FeNO, FEV1, FDR, blood eosinophils) with an AUC of 85% [67–100%], (CI=0.95, p=0.01). Linear regressions indicated better associations between improvements in FDR and ACT score (R2=0.42, p=0.001) than with FEV1 and ACT score (R2=0.25, p=0.013). Likewise, we observed better associations between improvements in FDR and reduction of exacerbations (R2=0.41, p=0.001) than with FEV1 (R2=0.20, p=0.025).
CONCLUSION: Our data suggest that severe SAD may represent a distinct phenotype of eosinophilic asthma that substantially improves under anti-T2 biological therapy. Measures of small airway function might be useful in selecting appropriate patients qualifying for anti-T2 biological therapy in addition to blood eosinophil count.
背景：在严重的嗜酸性粒细胞性哮喘中，已证明抗T2生物疗法可有效减少急性加重和口服类固醇的每日剂量。尽管临床效果显著，但通常在气流受限方面仅有中等程度的改善，这表明其他肺功能指标（如小气道功能障碍（SAD））可能会更好地反应临床治疗效果。我们旨在研究小气道功能的措施是否可以预测并与抗T2治疗的临床反应相关。
方法：我们研究了先前纳入德国前瞻性纵向全年龄哮喘队列（ALLIANCE）的患者数据，该队列招募了所有严重程度等级和炎性表型的哮喘患者。这项分析的选择标准是接受抗T2生物药物治疗的患有严重嗜酸性粒细胞性哮喘的成年患者。哮喘控制通过哮喘控制测试（ACT）和严重加重次数进行评估。小气道功能通过脉冲示波法（IOS）得出的阻力的频率依赖性（FDR，R5-20）和强制肺活量的25％至75％（FEF25-75）之间的平均强制呼气流量来评估。我们还研究了空气潴留（RV和RV / TLC），血液嗜酸性粒细胞和FeNO。将患者分为有反应者和部分或无反应者。临床反应被定义为严重急性发作和每日口服类固醇剂量至少减少50％，同时ACT评分至少增加3分。与其他临床变量（如血液嗜酸性粒细胞）相比，我们使用接收者操作特征（ROC）研究了FDR预测临床反应的能力。我们使用线性回归研究了FDR量度与临床反应之间的相关性，以ACT评分和加重次数表示。
结果：包括20例患者（平均年龄59±9岁;女性60％;平均体重指数（BMI）为27.6±5.4 kg/m2;平均绝对血嗜酸性粒细胞为570±389/μl;严重加重的平均次数为12个月在开始生物治疗之前，5.0±3;平均预测FEV1，76±21％;平均预测FDR，224±140％;平均泼尼松龙日剂量，6.4±4.9 mg;平均ACT评分，15±5）。与部分或无应答者相比，应答者的基线FDR明显更高，但FEV1，FEF25-75，RV和RV / TLC相似。ROC分析表明，在所有测试的临床指标（FeNO，FEV1，FDR，血液嗜酸性粒细胞）中，FDR和血液嗜酸性粒细胞的结合对临床反应的预测能力最佳，AUC为85％[67-100％]，（CI = 0.95，p = 0.01）。线性回归表明，与FEV1和ACT得分（R2 = 0.25，p = 0.013）相比，FDR和ACT得分（R2 = 0.42，p = 0.001）改善之间的关联更好。同样，我们观察到FDR改善与急性发作减少之间的更好关联（R2 = 0.41，p=0.001）比FEV1（R2 = 0.20，p = 0.025）更好。
结论：我们的数据表明，严重的SAD可能代表嗜酸性哮喘的独特表型，在抗T2生物疗法下可显着改善。除血液嗜酸性粒细胞计数外，小气道功能的测量可能对选择符合抗T2生物治疗资格的合适患者有用。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Respir Res. 2020,21:278）
（Respir Res. 2020,21:278）
Small airway dysfunction as predictor and marker for clinical response to biological therapy in severe eosinophilic asthma: a longitudinal observational study
Mustafa Abdo, Henrik Watz , Vera Veith , et al.
Abstract
BACKGROUND: Anti-T2 biological therapies have proven to effectively reduce acute exacerbations and daily doses of oral steroids in severe eosinophilic asthma. Despite the remarkable clinical efficacy, there are usually only moderate improvements in airflow limitation, suggesting that other measures of lung function like small airway dysfunction (SAD) might better reflect the clinical response. We aimed to investigate if measures of small airway function would predict and correlate with the clinical response to anti-T2 therapy.
METHODS: We studied data of patients who were previously included in the German prospective longitudinal All Age Asthma Cohort (ALLIANCE) that recruits asthma patients of all severity grades and inflammatory phenotypes. The selection criteria for this analysis were adult patients with severe eosinophilic asthma under treatment with anti-T2 biological agents. Asthma control was assessed by asthma control test (ACT) and number of severe exacerbations. Small airway function was assessed by the frequency dependence of resistance (FDR, R5-20)) derived from impulse oscillometry (IOS) and the mean forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75). We also studied air trapping (RV and RV/TLC), blood eosinophils and FeNO. Patients were classified into responders and partial or non-responders. Clinical response was defined as at least 50% reduction in annualized severe exacerbations and daily oral steroid doses accompanied with a minimum increase of 3 points in the ACT score. We used a Receiver Operator Characteristic (ROC) to study the capacity of FDR in predicting clinical response compared to other clinical variable like blood eosinophils. We studied the correlation between FDR measures and clinical response, represented by the ACT score and number of exacerbations, using linear regressions.
RESULTS:20 patients were included (mean age, 59±9 years; 60% female; mean body mass index (BMI), 27.6±5.4 kg/ m2 ; mean absolute blood eosinophils, 570±389/µl; mean number of severe exacerbations 12 months prior to initiating the biological therapy, 5.0±3; mean predicted FEV1, 76±21%; mean predicted FDR, 224±140%; mean daily prednisolone dose, 6.4±4.9 mg; mean ACT score, 15±5). Responders had significantly higher baseline FDR compared to partial or non-responders but similar FEV1, FEF25–75, RV and RV/TLC. ROC analysis showed that the combination of FDR and blood eosinophils had the best predictive capacity of the clinical response among all tested clinical markers (FeNO, FEV1, FDR, blood eosinophils) with an AUC of 85% [67–100%], (CI=0.95, p=0.01). Linear regressions indicated better associations between improvements in FDR and ACT score (R2=0.42, p=0.001) than with FEV1 and ACT score (R2=0.25, p=0.013). Likewise, we observed better associations between improvements in FDR and reduction of exacerbations (R2=0.41, p=0.001) than with FEV1 (R2=0.20, p=0.025).
CONCLUSION: Our data suggest that severe SAD may represent a distinct phenotype of eosinophilic asthma that substantially improves under anti-T2 biological therapy. Measures of small airway function might be useful in selecting appropriate patients qualifying for anti-T2 biological therapy in addition to blood eosinophil count.
上一篇：
青少年和成人哮喘管理：国家哮喘教育和预防计划2020年哮喘指南更新
下一篇：
CASCADE:一项2期随机、双盲、安慰剂对照、平行组试验，评估tezepelumab对未控制哮喘患者气道炎症的影响
