哮喘持续气流限制表型的预测因子和相关性：ATLANTIS研究的事后分析
2022/08/19
摘要
背景：持续性气流受限（PAL）发生在一部分哮喘患者中。既往关于哮喘PAL的研究包括相对较小的人群，主要限于重症哮喘，或者没有包括纵向数据。这项事后分析的目的是调查纳入ATLANTIS研究的哮喘患者PAL的决定因素，临床意义和结果。。
方法：在ATLANTIS研究的事后分析中，我们评估了PAL在整个哮喘严重程度范围内的患病率，临床特征和影响。研究人群包括18-65岁的患者，他们在入选前至少6个月被诊断为哮喘。我们将PAL定义为支气管扩张剂后FEV1/用力肺活量（FVC）低于招募时的正常下限。哮喘严重程度是根据全球哮喘倡议定义的。我们使用Mann-Whitney U检验，t检验或χ2检验来分析有和没有PAL的患者之间基线特征的差异。Logistic回归用于PAL和基线数据之间关联的多变量分析。使用Cox回归分析与PAL相关的急性发作风险，并使用线性混合效应模型分析患有PAL的患者与没有PAL的患者的FEV1随时间的变化。结果在U-BIOPRED队列中验证。
结果：2014年6月30日至2017年3月3日期间，773名患者参加了ATLANTIS研究，其中760名（98%）有支气管扩张剂后FEV1/FVC数据。在纳入数据的患者中，平均年龄为44岁（SD 13），760名有441名女性（58%），578名（76%）从不吸烟者，248名（33%）存在PAL。PAL不仅存在于重症哮喘患者中，而且存在于133例GINA步骤1患者中的21例（16%）和83例GINA步骤2中的24例（29%）。PAL与基线年龄较大（PAL组46岁，非PAL组43岁），哮喘持续时间较长（24岁vs 12岁），男性（51% vs 38%）独立相关，血液嗜酸性粒细胞计数较高（中位数0·27×109细胞/L vs 0·20×109细胞/L），小气道功能障碍更多，随访1年更多急性发作。PAL，年龄和嗜酸性粒细胞炎症之间的关联在U-BIOPRED队列中得到验证，而与性别，哮喘持续时间和急性发作风险的关联未得到验证。
解释：PAL不仅存在于重症哮喘中，而且存在于相当比例的轻度患者。在轻度哮喘患者中，PAL与嗜酸性粒细胞炎症和更高的急性发作风险相关。我们的研究结果很重要，因为他们建议对轻度哮喘和PAL患者应考虑增加治疗强度。
Predictors and associations of the persistent airflow limitation phenotype in asthma: a post-hoc analysis of the ATLANTIS study
Tessa M Kole, Elise Vanden Berghe, Monica Kraft, Judith M Vonk, Martijn C Nawijn, Salman Siddiqui, Kai Sun, Leonardo M Fabbri, Klaus F Rabe, Kian Fan Chung, Gabriele Nicolini, Alberto Papi, Chris Brightling, Dave Singh, Thys van der Molen, Sven-Erik Dahlén, Alvar Agusti, Rosa Faner, Jadwiga A Wedzicha, Gavin C Donaldson, Ian M Adcock, Lies Lahousse, Huib A M Kerstjens, Maarten van den Berge, ATLANTIS; U-BIOPRED; CADSET investigators
Abstract
Background：Persistent airflow limitation (PAL) occurs in a subset of patients with asthma. Previous studies on PAL in asthma have included relatively small populations, mostly restricted to severe asthma, or have no included longitudinal data. The aim of this post-hoc analysis was to investigate the determinants, clinical implications, and outcome of PAL in patients with asthma who were included in the ATLANTIS study.
Methods：In this post-hoc analysis of the ATLANTIS study, we assessed the prevalence, clinical characteristics, and implications of PAL across the full range of asthma severity. The study population included patients aged 18-65 years who had been diagnosed with asthma at least 6 months before inclusion. We defined PAL as a post-bronchodilator FEV1/forced vital capacity (FVC) of less than the lower limit of normal at recruitment. Asthma severity was defined according to the Global Initiative for Asthma. We used Mann-Whitney U test, t test, or χ2 test to analyse differences in baseline characteristics between patients with and without PAL. Logistic regression was used for multivariable analysis of the associations between PAL and baseline data. Cox regression was used to analyse risk of exacerbation in relation to PAL, and a linear mixed-effects model was used to analyse change in FEV1 over time in patients with versus patients without PAL. Results were validated in the U-BIOPRED cohort.
Findings：Between June 30, 2014 and March 3, 2017, 773 patients were enrolled in the ATLANTIS study of whom 760 (98%) had post-bronchodilator FEV1/FVC data available. Of the included patients with available data, mean age was 44 years (SD 13), 441 (58%) of 760 were women, 578 (76%) were never-smokers, and 248 (33%) had PAL. PAL was not only present in patients with severe asthma, but also in 21 (16%) of 133 patients with GINA step 1 and 24 (29%) of 83 patients with GINA step 2. PAL was independently associated with older age at baseline (46 years in PAL group vs 43 years in non-PAL group), longer duration of asthma (24 years vs 12 years), male sex (51% vs 38%), higher blood eosinophil counts (median 0·27 × 109 cells per L vs 0·20 × 109 cells per L), more small airway dysfunction, and more exacerbations during 1 year of follow-up. Associations between PAL, age, and eosinophilic inflammation were validated in the U-BIOPRED cohort, whereas associations with sex, duration of asthma, and risk of exacerbations were not validated.
Interpretation：PAL is not only present in severe disease, but also in a considerable proportion of patients with milder disease. In patients with mild asthma, PAL is associated with eosinophilic inflammation and a higher risk of exacerbations. Our findings are important because they suggest that increasing treatment intensity should be considered in patients with milder asthma and PAL.
背景：持续性气流受限（PAL）发生在一部分哮喘患者中。既往关于哮喘PAL的研究包括相对较小的人群，主要限于重症哮喘，或者没有包括纵向数据。这项事后分析的目的是调查纳入ATLANTIS研究的哮喘患者PAL的决定因素，临床意义和结果。。
方法：在ATLANTIS研究的事后分析中，我们评估了PAL在整个哮喘严重程度范围内的患病率，临床特征和影响。研究人群包括18-65岁的患者，他们在入选前至少6个月被诊断为哮喘。我们将PAL定义为支气管扩张剂后FEV1/用力肺活量（FVC）低于招募时的正常下限。哮喘严重程度是根据全球哮喘倡议定义的。我们使用Mann-Whitney U检验，t检验或χ2检验来分析有和没有PAL的患者之间基线特征的差异。Logistic回归用于PAL和基线数据之间关联的多变量分析。使用Cox回归分析与PAL相关的急性发作风险，并使用线性混合效应模型分析患有PAL的患者与没有PAL的患者的FEV1随时间的变化。结果在U-BIOPRED队列中验证。
结果：2014年6月30日至2017年3月3日期间，773名患者参加了ATLANTIS研究，其中760名（98%）有支气管扩张剂后FEV1/FVC数据。在纳入数据的患者中，平均年龄为44岁（SD 13），760名有441名女性（58%），578名（76%）从不吸烟者，248名（33%）存在PAL。PAL不仅存在于重症哮喘患者中，而且存在于133例GINA步骤1患者中的21例（16%）和83例GINA步骤2中的24例（29%）。PAL与基线年龄较大（PAL组46岁，非PAL组43岁），哮喘持续时间较长（24岁vs 12岁），男性（51% vs 38%）独立相关，血液嗜酸性粒细胞计数较高（中位数0·27×109细胞/L vs 0·20×109细胞/L），小气道功能障碍更多，随访1年更多急性发作。PAL，年龄和嗜酸性粒细胞炎症之间的关联在U-BIOPRED队列中得到验证，而与性别，哮喘持续时间和急性发作风险的关联未得到验证。
解释：PAL不仅存在于重症哮喘中，而且存在于相当比例的轻度患者。在轻度哮喘患者中，PAL与嗜酸性粒细胞炎症和更高的急性发作风险相关。我们的研究结果很重要，因为他们建议对轻度哮喘和PAL患者应考虑增加治疗强度。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Lancet Respir Med. 2022 Jul 27;S2213-2600(22)00185-0. doi: 10.1016/S2213-2600(22)00185-0. Online ahead of print.)
(Lancet Respir Med. 2022 Jul 27;S2213-2600(22)00185-0. doi: 10.1016/S2213-2600(22)00185-0. Online ahead of print.)
Predictors and associations of the persistent airflow limitation phenotype in asthma: a post-hoc analysis of the ATLANTIS study
Tessa M Kole, Elise Vanden Berghe, Monica Kraft, Judith M Vonk, Martijn C Nawijn, Salman Siddiqui, Kai Sun, Leonardo M Fabbri, Klaus F Rabe, Kian Fan Chung, Gabriele Nicolini, Alberto Papi, Chris Brightling, Dave Singh, Thys van der Molen, Sven-Erik Dahlén, Alvar Agusti, Rosa Faner, Jadwiga A Wedzicha, Gavin C Donaldson, Ian M Adcock, Lies Lahousse, Huib A M Kerstjens, Maarten van den Berge, ATLANTIS; U-BIOPRED; CADSET investigators
Abstract
Background：Persistent airflow limitation (PAL) occurs in a subset of patients with asthma. Previous studies on PAL in asthma have included relatively small populations, mostly restricted to severe asthma, or have no included longitudinal data. The aim of this post-hoc analysis was to investigate the determinants, clinical implications, and outcome of PAL in patients with asthma who were included in the ATLANTIS study.
Methods：In this post-hoc analysis of the ATLANTIS study, we assessed the prevalence, clinical characteristics, and implications of PAL across the full range of asthma severity. The study population included patients aged 18-65 years who had been diagnosed with asthma at least 6 months before inclusion. We defined PAL as a post-bronchodilator FEV1/forced vital capacity (FVC) of less than the lower limit of normal at recruitment. Asthma severity was defined according to the Global Initiative for Asthma. We used Mann-Whitney U test, t test, or χ2 test to analyse differences in baseline characteristics between patients with and without PAL. Logistic regression was used for multivariable analysis of the associations between PAL and baseline data. Cox regression was used to analyse risk of exacerbation in relation to PAL, and a linear mixed-effects model was used to analyse change in FEV1 over time in patients with versus patients without PAL. Results were validated in the U-BIOPRED cohort.
Findings：Between June 30, 2014 and March 3, 2017, 773 patients were enrolled in the ATLANTIS study of whom 760 (98%) had post-bronchodilator FEV1/FVC data available. Of the included patients with available data, mean age was 44 years (SD 13), 441 (58%) of 760 were women, 578 (76%) were never-smokers, and 248 (33%) had PAL. PAL was not only present in patients with severe asthma, but also in 21 (16%) of 133 patients with GINA step 1 and 24 (29%) of 83 patients with GINA step 2. PAL was independently associated with older age at baseline (46 years in PAL group vs 43 years in non-PAL group), longer duration of asthma (24 years vs 12 years), male sex (51% vs 38%), higher blood eosinophil counts (median 0·27 × 109 cells per L vs 0·20 × 109 cells per L), more small airway dysfunction, and more exacerbations during 1 year of follow-up. Associations between PAL, age, and eosinophilic inflammation were validated in the U-BIOPRED cohort, whereas associations with sex, duration of asthma, and risk of exacerbations were not validated.
Interpretation：PAL is not only present in severe disease, but also in a considerable proportion of patients with milder disease. In patients with mild asthma, PAL is associated with eosinophilic inflammation and a higher risk of exacerbations. Our findings are important because they suggest that increasing treatment intensity should be considered in patients with milder asthma and PAL.
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哮喘恶化与肺功能下降有关：一项基于人群的纵向研究
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重症哮喘的生物学特性与气道重塑
