控制良好的哮喘降级治疗期间作为哮喘发作预测因子的2型气道炎症生物标志物：长效β受体激动剂降级研究（LASST）
2020/08/20
摘要
背景：控制良好的哮喘在降级治疗期间缺乏能够预测哮喘发作的生物标志物。
目的：评估基线2型气道炎症标志物和/或连续测量呼出一氧化氮（FeNO）能否预测降级治疗时的哮喘发作。
方法：本研究（长效β受体激动剂降级研究）为一项多中心、双盲、平行三臂的临床试验，比较了控制良好的哮喘的降级治疗策略。在亚组分析在，我们评估了是否基线变应性反应[由血清气源性致敏原筛查试验（Phadiatop）检测]、基线血清嗜酸性粒细胞过氧化物酶（EpX）及基线或随访中连续FeNO测量能够预测受试者哮喘发作的时间。我们分析了调整后模型中的关联性，包括分配到三个治疗组（ICS-LABA维持治疗、吸入性皮质类固醇激素（ICS）降级治疗或停用长效支气管扩张剂（LABA））的全部受试者。
结果：553名LASST受试者中，447名被随机分配到3个治疗组中的一个，并且至少测量了一个生物标志物。基线水平，较高水平的FeNO与较高水平的多重变应原IgE水平显著相关（P<0.001），但与血清EpX无关（P=0.742）。在所有参与者中，基线生物标志物的升高并不能预测更高的治疗失败风险。此外，以6周为间隔连续测量的FeNO水平表明，与低水平（<25 ppb）的受试者相比，中水平（25-50 ppb）和高水平（>50 ppb）的受试者没有明显增加后续治疗失败的可能性[危险比（95%置信区间）分别为1.03（0.59，1.78）和1.29（0.65，2.54）]。治疗组与基线生物标志物之间没有明显的相互作用。
结论：在哮喘控制良好的患者中，无论是2型气道炎症标志物基线水平还是连续FeNO测定都不是治疗失败的有力预测因子。
Biomarkers of type 2 airway inflammation as predictors of loss of asthma control during step-down therapy for well-controlled disease: The Long Acting Beta Agonist Step-down Study (LASST).
Sonali Bose, Christian Bime, Robert J Henderson, Kathryn V Blake, Mario Castro, Emily DiMango, Nicola A Hanania, Janet T Holbrook, Charles G Irvin, Monica Kraft, Stephen P Peters, Joan Reibman, Elizabeth A Sugar, Kaharu Sumino, Robert A Wise, Linda Rogers, American Lung Association Airways Clinical Research Centers
Abstract
BACKGROUND:Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking.
OBJECTIVE:To evaluate if baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (FeNO) predict loss of asthma control as therapy is stepped down.
METHODS:In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase (EpX), or baseline or serial FeNO measurements during follow-up, predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the three treatment groups (continuation of stable dose of combination ICS-LABA, step-down of inhaled corticosteroid (ICS), or discontinuation of long acting bronchodilator (LABA)).
RESULTS:Four hundred and forty-seven of the 553 LASST participants who were randomized to one of 3 treatment arms and had at least one biomarker measurement were included in this analysis. At baseline, higher levels of FeNO were significantly associated with greater levels of multi-allergen IgE levels (P<0.001), but not with serum EpX (p=0.742). Among all participants as a group, elevations in baseline biomarkers were not predictive of higher risk of treatment failure. In addition, FeNO levels measured serially at 6-week intervals, demonstrated that compared to participants with low levels (<25 ppb), those with intermediate (25-50 ppb) and high (>50 ppb) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios (95% confidence interval) 1.03 (0.59, 1.78) and 1.29 (0.65, 2.54), respectively. There were no significant interactions of treatment group and baseline biomarkers.
CONCLUSIONS:In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of FeNO are strong predictors of treatment failure.
背景：控制良好的哮喘在降级治疗期间缺乏能够预测哮喘发作的生物标志物。
目的：评估基线2型气道炎症标志物和/或连续测量呼出一氧化氮（FeNO）能否预测降级治疗时的哮喘发作。
方法：本研究（长效β受体激动剂降级研究）为一项多中心、双盲、平行三臂的临床试验，比较了控制良好的哮喘的降级治疗策略。在亚组分析在，我们评估了是否基线变应性反应[由血清气源性致敏原筛查试验（Phadiatop）检测]、基线血清嗜酸性粒细胞过氧化物酶（EpX）及基线或随访中连续FeNO测量能够预测受试者哮喘发作的时间。我们分析了调整后模型中的关联性，包括分配到三个治疗组（ICS-LABA维持治疗、吸入性皮质类固醇激素（ICS）降级治疗或停用长效支气管扩张剂（LABA））的全部受试者。
结果：553名LASST受试者中，447名被随机分配到3个治疗组中的一个，并且至少测量了一个生物标志物。基线水平，较高水平的FeNO与较高水平的多重变应原IgE水平显著相关（P<0.001），但与血清EpX无关（P=0.742）。在所有参与者中，基线生物标志物的升高并不能预测更高的治疗失败风险。此外，以6周为间隔连续测量的FeNO水平表明，与低水平（<25 ppb）的受试者相比，中水平（25-50 ppb）和高水平（>50 ppb）的受试者没有明显增加后续治疗失败的可能性[危险比（95%置信区间）分别为1.03（0.59，1.78）和1.29（0.65，2.54）]。治疗组与基线生物标志物之间没有明显的相互作用。
结论：在哮喘控制良好的患者中，无论是2型气道炎症标志物基线水平还是连续FeNO测定都不是治疗失败的有力预测因子。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Allergy Clin Immunol Pract. 2020 Jul 18;S2213-2198(20)30714-5. doi: 10.1016/j.jaip.2020.06.067.)
(J Allergy Clin Immunol Pract. 2020 Jul 18;S2213-2198(20)30714-5. doi: 10.1016/j.jaip.2020.06.067.)
Biomarkers of type 2 airway inflammation as predictors of loss of asthma control during step-down therapy for well-controlled disease: The Long Acting Beta Agonist Step-down Study (LASST).
Sonali Bose, Christian Bime, Robert J Henderson, Kathryn V Blake, Mario Castro, Emily DiMango, Nicola A Hanania, Janet T Holbrook, Charles G Irvin, Monica Kraft, Stephen P Peters, Joan Reibman, Elizabeth A Sugar, Kaharu Sumino, Robert A Wise, Linda Rogers, American Lung Association Airways Clinical Research Centers
Abstract
BACKGROUND:Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking.
OBJECTIVE:To evaluate if baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (FeNO) predict loss of asthma control as therapy is stepped down.
METHODS:In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase (EpX), or baseline or serial FeNO measurements during follow-up, predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the three treatment groups (continuation of stable dose of combination ICS-LABA, step-down of inhaled corticosteroid (ICS), or discontinuation of long acting bronchodilator (LABA)).
RESULTS:Four hundred and forty-seven of the 553 LASST participants who were randomized to one of 3 treatment arms and had at least one biomarker measurement were included in this analysis. At baseline, higher levels of FeNO were significantly associated with greater levels of multi-allergen IgE levels (P<0.001), but not with serum EpX (p=0.742). Among all participants as a group, elevations in baseline biomarkers were not predictive of higher risk of treatment failure. In addition, FeNO levels measured serially at 6-week intervals, demonstrated that compared to participants with low levels (<25 ppb), those with intermediate (25-50 ppb) and high (>50 ppb) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios (95% confidence interval) 1.03 (0.59, 1.78) and 1.29 (0.65, 2.54), respectively. There were no significant interactions of treatment group and baseline biomarkers.
CONCLUSIONS:In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of FeNO are strong predictors of treatment failure.
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