探索哮喘小气道功能障碍的相关性和程度(ATLANTIS)：一项前瞻性队列研究的基线数据
2019/04/19
摘要
背景：小气道功能障碍（SAD）在哮喘中是公认的，但其在哮喘严重程度和控制中的作用尚不清楚。本研究旨在评估哪些生物标记物、生理测试和影像标志物组合最能评估哮喘患者中SAD的存在和程度。
方法：在一项多国前瞻性队列研究（小气道参与哮喘评估[ATLANTIS]研究）的基线评估中，我们从9个国家（巴西、中国、德国、意大利、西班牙、荷兰、英国、美国和加拿大）的29个中心的全科医师、胸科医师数据库和广告中招募了患有及不患有哮喘（定义为全球哮喘倡议哮喘严重程度1-5级）的参与者。所有受试者年龄在18-65岁之间，哮喘患者在6个多月前接受了由胸科医生确认的哮喘临床诊断。这种诊断需要在基线或过去5年的客观证据的支持，这些证据可能是：气道对乙酰胆碱的高反应性，在用有或无垫片的定量吸入器予400μg沙丁胺醇治疗后气道可逆性阳性（30分钟内FEV1变化≥12%且≥200 ml），以及峰值呼气流量超过20%（在7天内测量），或记录在一个周期（如4周）的维持性抗哮喘治疗后的可逆性。纳入标准还要求患者在基线时有8周以上的稳定剂量的哮喘药物规律治疗（包括所谓的急救药物β2激动剂）中有稳定期哮喘，并且一生中吸烟最多10包年。对照组参与者通过广告招募；这些参与者年龄在18-65岁，没有与哮喘或慢性阻塞性肺病相适应的呼吸道症状，肺活量测定正常，气道反应性正常，吸烟最多10包年。我们对所有参与者进行了肺活量测定、体积描记测定、脉冲振荡法测定、重复呼吸氮气冲洗法测定、CT（在选定的参与者中）和哮喘控制、哮喘相关生命质量（仅在哮喘参与者中）和健康状况的问卷调查。我们在哮喘患者中应用结构方程模型来评估所有生理和CT变量对SAD的贡献，由此定义临床SAD和CT SAD评分。然后我们采用基于模型的聚类分析将哮喘患者分为SAD组，并通过SAD评分和SAD组比较了过去一年中哮喘的严重程度、控制和医疗保健使用情况。本试验在clinicaltrials.gov注册，编号NCT02123667。
结果：在2014年6月30日至2017年3月3日期间，我们招募并评估了773名哮喘患者和99名对照参与者。通过结构方程模型分析，所有生理指标都有助于临床SAD模型的建立。SAD在哮喘中的患病率取决于所采用的测量方法；我们发现与肺泡气道通气异质性（Sacin）相关的SAD患病率最低，这一结果由重复呼吸氮气冲洗决定，反映了大部分周边、肺泡前或腺泡气道的通气异质性。脉冲振荡法和肺活量测定法是评估中小型气道功能障碍的两种方法，其结果对SAD评分的贡献最大，且两组之间存在差异。临床SAD组1（n=452）受试者的SAD较第2组轻，与对照组受试者的重复呼吸氮气冲洗法结果相当。临床SAD组2（n=312）的受试者与组1相比，有异常的生理SAD结果，特别是他们的脉冲振荡和肺活量测量，组2的受试者也比组1有更严重的哮喘（哮喘控制、治疗、恶化和生活质量）。2组的临床SAD评分高于1组（表明SAD更严重），我们发现这些评分与哮喘控制、严重程度和恶化有关。我们发现临床SAD和CT SAD评分之间没有相关性。
解释：SAD是哮喘的一个复杂而沉默的特征，很可能直接或间接地被组合生理测试所捕获，如肺活量测定、体积描记、脉冲振荡和重复呼吸氮气冲洗。SAD存在于所有严重程度哮喘患者中，但在重度哮喘中尤其普遍。利用脉冲振荡法和肺活量测定法将SAD分为两组（较轻组和较重组），这两种方法易于使用，因为它与GINA严重程度、哮喘控制、生活质量和病情加重有关。
Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study.
Postma DS, Brightling C, Baldi S, Van den Berge M, Fabbri LM, Gagnatelli A, Papi A, Van der Molen T, Rabe KF, Siddiqui S, Singh D, Nicolini G, Kraft M; ATLANTIS study group.
Abstract
BACKGROUND: Small airways dysfunction (SAD) is well recognised in asthma, yet its role in the severity and control of asthma is unclear. This study aimed to assess which combination of biomarkers, physiological tests, and imaging markers best measure the presence and extent of SAD in patients with asthma.
METHODS: In this baseline assessment of a multinational prospective cohort study (the Assessment of Small Airways Involvement in Asthma [ATLANTIS] study), we recruited participants with and without asthma (defined as Global Initiative for Asthma severity stages 1-5) from general practices, the databases of chest physicians, and advertisements at 29 centres across nine countries (Brazil, China, Germany, Italy, Spain, the Netherlands, the UK, the USA, and Canada). All participants were aged 18-65 years, and participants with asthma had received a clinical diagnosis of asthma more than 6 months ago that had been confirmed by a chest physician. This diagnosis required support by objective evidence at baseline or during the past 5 years, which could be: positive airway hyperresponsiveness to methacholine, positive reversibility (a change in FEV1 ≥12% and ≥200 mL within 30 min) after treatment with 400 μg of salbutamol in a metered-dose inhaler with or without a spacer, variability in peak expiratory flow of more than 20% (measured over 7 days), or documented reversibility after a cycle (eg, 4 weeks) of maintenance anti-asthma treatment. The inclusion criteria also required that patients had stable asthma on any previous regular asthma treatment (including so-called rescue β2-agonists alone) at a stable dose for more than 8 weeks before baseline and had smoked for a maximum of 10 pack-years in their lifetime. Control group participants were recruited by advertisements; these participants were aged 18-65 years, had no respiratory symptoms compatible with asthma or chronic obstructive pulmonary disease, normal spirometry, and normal airways responsiveness, and had smoked for a maximum of 10 pack-years. We assessed all participants with spirometry, body plethysmography, impulse oscillometry, multiple breath nitrogen washout, CT (in selected participants), and questionnaires about asthma control, asthma-related quality of life (both in participants with asthma only), and health status. We applied structural equation modelling in participants with asthma to assess the contribution of all physiological and CT variables to SAD, from which we defined clinical SAD and CT SAD scores. We then classified patients with asthma into SAD groups with model-based clustering, and we compared asthma severity, control, and health-care use during the past year by SAD score and by SAD group. This trial is registered with ClinicalTrials.gov, number NCT02123667.
FINDINGS: Between June 30, 2014, and March 3, 2017, we recruited and evaluated 773 participants with asthma and 99 control participants. All physiological measures contributed to the clinical SAD model with the structural equation modelling analysis. The prevalence of SAD in asthma was dependent on the measure used; we found the lowest prevalence of SAD associated with acinar airway ventilation heterogeneity (Sacin), an outcome determined by multiple breath nitrogen washout that reflects ventilation heterogeneity in the most peripheral, pre-acinar or acinar airways. Impulse oscillometry and spirometry results, which were used to assess dysfunction of small-sized to mid-sized airways, contributed most to the clinical SAD score and differed between the two SAD groups. Participants in clinical SAD group 1 (n=452) had milder SAD than group 2 and comparable multiple breath nitrogen washout Sacin to control participants. Participants in clinical SAD group 2 (n=312) had abnormal physiological SAD results relative to group 1, particularly their impulse oscillometry and spirometry measurements, and group 2 participants also had more severe asthma (with regard to asthma control, treatments, exacerbations, and quality of life) than group 1. Clinical SAD scores were higher (indicating more severe SAD) in group 2 than group 1, and we found that these scores were related to asthma control, severity, and exacerbations. We found no correlation between clinical SAD and CT SAD scores.
INTERPRETATION: SAD is a complex and silent signature of asthma that is likely to be directly or indirectly captured by combinations of physiological tests, such as spirometry, body plethysmography, impulse oscillometry, and multiple breath nitrogen washout. SAD is present across patients with all severities of asthma, but it is particularly prevalent in severe disease. The clinical classification of SAD into two groups (a milder and a more severe group) by use of impulse oscillometry and spirometry, which are easy to use, is meaningful given its association with GINA severity stages, asthma control, quality of life, and exacerbations.
FUNDING: Chiesi Farmaceutici SpA.
背景：小气道功能障碍（SAD）在哮喘中是公认的，但其在哮喘严重程度和控制中的作用尚不清楚。本研究旨在评估哪些生物标记物、生理测试和影像标志物组合最能评估哮喘患者中SAD的存在和程度。
方法：在一项多国前瞻性队列研究（小气道参与哮喘评估[ATLANTIS]研究）的基线评估中，我们从9个国家（巴西、中国、德国、意大利、西班牙、荷兰、英国、美国和加拿大）的29个中心的全科医师、胸科医师数据库和广告中招募了患有及不患有哮喘（定义为全球哮喘倡议哮喘严重程度1-5级）的参与者。所有受试者年龄在18-65岁之间，哮喘患者在6个多月前接受了由胸科医生确认的哮喘临床诊断。这种诊断需要在基线或过去5年的客观证据的支持，这些证据可能是：气道对乙酰胆碱的高反应性，在用有或无垫片的定量吸入器予400μg沙丁胺醇治疗后气道可逆性阳性（30分钟内FEV1变化≥12%且≥200 ml），以及峰值呼气流量超过20%（在7天内测量），或记录在一个周期（如4周）的维持性抗哮喘治疗后的可逆性。纳入标准还要求患者在基线时有8周以上的稳定剂量的哮喘药物规律治疗（包括所谓的急救药物β2激动剂）中有稳定期哮喘，并且一生中吸烟最多10包年。对照组参与者通过广告招募；这些参与者年龄在18-65岁，没有与哮喘或慢性阻塞性肺病相适应的呼吸道症状，肺活量测定正常，气道反应性正常，吸烟最多10包年。我们对所有参与者进行了肺活量测定、体积描记测定、脉冲振荡法测定、重复呼吸氮气冲洗法测定、CT（在选定的参与者中）和哮喘控制、哮喘相关生命质量（仅在哮喘参与者中）和健康状况的问卷调查。我们在哮喘患者中应用结构方程模型来评估所有生理和CT变量对SAD的贡献，由此定义临床SAD和CT SAD评分。然后我们采用基于模型的聚类分析将哮喘患者分为SAD组，并通过SAD评分和SAD组比较了过去一年中哮喘的严重程度、控制和医疗保健使用情况。本试验在clinicaltrials.gov注册，编号NCT02123667。
结果：在2014年6月30日至2017年3月3日期间，我们招募并评估了773名哮喘患者和99名对照参与者。通过结构方程模型分析，所有生理指标都有助于临床SAD模型的建立。SAD在哮喘中的患病率取决于所采用的测量方法；我们发现与肺泡气道通气异质性（Sacin）相关的SAD患病率最低，这一结果由重复呼吸氮气冲洗决定，反映了大部分周边、肺泡前或腺泡气道的通气异质性。脉冲振荡法和肺活量测定法是评估中小型气道功能障碍的两种方法，其结果对SAD评分的贡献最大，且两组之间存在差异。临床SAD组1（n=452）受试者的SAD较第2组轻，与对照组受试者的重复呼吸氮气冲洗法结果相当。临床SAD组2（n=312）的受试者与组1相比，有异常的生理SAD结果，特别是他们的脉冲振荡和肺活量测量，组2的受试者也比组1有更严重的哮喘（哮喘控制、治疗、恶化和生活质量）。2组的临床SAD评分高于1组（表明SAD更严重），我们发现这些评分与哮喘控制、严重程度和恶化有关。我们发现临床SAD和CT SAD评分之间没有相关性。
解释：SAD是哮喘的一个复杂而沉默的特征，很可能直接或间接地被组合生理测试所捕获，如肺活量测定、体积描记、脉冲振荡和重复呼吸氮气冲洗。SAD存在于所有严重程度哮喘患者中，但在重度哮喘中尤其普遍。利用脉冲振荡法和肺活量测定法将SAD分为两组（较轻组和较重组），这两种方法易于使用，因为它与GINA严重程度、哮喘控制、生活质量和病情加重有关。
(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. 2019 Mar 12.pii:S2213-2600(19)30049-9.doi:10.1016/S2213-2600(19)30049-9.)
(Lancet Respir Med. 2019 Mar 12.pii:S2213-2600(19)30049-9.doi:10.1016/S2213-2600(19)30049-9.)
Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study.
Postma DS, Brightling C, Baldi S, Van den Berge M, Fabbri LM, Gagnatelli A, Papi A, Van der Molen T, Rabe KF, Siddiqui S, Singh D, Nicolini G, Kraft M; ATLANTIS study group.
Abstract
BACKGROUND: Small airways dysfunction (SAD) is well recognised in asthma, yet its role in the severity and control of asthma is unclear. This study aimed to assess which combination of biomarkers, physiological tests, and imaging markers best measure the presence and extent of SAD in patients with asthma.
METHODS: In this baseline assessment of a multinational prospective cohort study (the Assessment of Small Airways Involvement in Asthma [ATLANTIS] study), we recruited participants with and without asthma (defined as Global Initiative for Asthma severity stages 1-5) from general practices, the databases of chest physicians, and advertisements at 29 centres across nine countries (Brazil, China, Germany, Italy, Spain, the Netherlands, the UK, the USA, and Canada). All participants were aged 18-65 years, and participants with asthma had received a clinical diagnosis of asthma more than 6 months ago that had been confirmed by a chest physician. This diagnosis required support by objective evidence at baseline or during the past 5 years, which could be: positive airway hyperresponsiveness to methacholine, positive reversibility (a change in FEV1 ≥12% and ≥200 mL within 30 min) after treatment with 400 μg of salbutamol in a metered-dose inhaler with or without a spacer, variability in peak expiratory flow of more than 20% (measured over 7 days), or documented reversibility after a cycle (eg, 4 weeks) of maintenance anti-asthma treatment. The inclusion criteria also required that patients had stable asthma on any previous regular asthma treatment (including so-called rescue β2-agonists alone) at a stable dose for more than 8 weeks before baseline and had smoked for a maximum of 10 pack-years in their lifetime. Control group participants were recruited by advertisements; these participants were aged 18-65 years, had no respiratory symptoms compatible with asthma or chronic obstructive pulmonary disease, normal spirometry, and normal airways responsiveness, and had smoked for a maximum of 10 pack-years. We assessed all participants with spirometry, body plethysmography, impulse oscillometry, multiple breath nitrogen washout, CT (in selected participants), and questionnaires about asthma control, asthma-related quality of life (both in participants with asthma only), and health status. We applied structural equation modelling in participants with asthma to assess the contribution of all physiological and CT variables to SAD, from which we defined clinical SAD and CT SAD scores. We then classified patients with asthma into SAD groups with model-based clustering, and we compared asthma severity, control, and health-care use during the past year by SAD score and by SAD group. This trial is registered with ClinicalTrials.gov, number NCT02123667.
FINDINGS: Between June 30, 2014, and March 3, 2017, we recruited and evaluated 773 participants with asthma and 99 control participants. All physiological measures contributed to the clinical SAD model with the structural equation modelling analysis. The prevalence of SAD in asthma was dependent on the measure used; we found the lowest prevalence of SAD associated with acinar airway ventilation heterogeneity (Sacin), an outcome determined by multiple breath nitrogen washout that reflects ventilation heterogeneity in the most peripheral, pre-acinar or acinar airways. Impulse oscillometry and spirometry results, which were used to assess dysfunction of small-sized to mid-sized airways, contributed most to the clinical SAD score and differed between the two SAD groups. Participants in clinical SAD group 1 (n=452) had milder SAD than group 2 and comparable multiple breath nitrogen washout Sacin to control participants. Participants in clinical SAD group 2 (n=312) had abnormal physiological SAD results relative to group 1, particularly their impulse oscillometry and spirometry measurements, and group 2 participants also had more severe asthma (with regard to asthma control, treatments, exacerbations, and quality of life) than group 1. Clinical SAD scores were higher (indicating more severe SAD) in group 2 than group 1, and we found that these scores were related to asthma control, severity, and exacerbations. We found no correlation between clinical SAD and CT SAD scores.
INTERPRETATION: SAD is a complex and silent signature of asthma that is likely to be directly or indirectly captured by combinations of physiological tests, such as spirometry, body plethysmography, impulse oscillometry, and multiple breath nitrogen washout. SAD is present across patients with all severities of asthma, but it is particularly prevalent in severe disease. The clinical classification of SAD into two groups (a milder and a more severe group) by use of impulse oscillometry and spirometry, which are easy to use, is meaningful given its association with GINA severity stages, asthma control, quality of life, and exacerbations.
FUNDING: Chiesi Farmaceutici SpA.
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呼出气挥发性有机化合物能够区分中性粒细胞性哮喘和嗜酸性粒细胞性哮喘
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