小气道功能障碍与哮喘控制良好（ATLANTIS）患者急性发作风险关系的评估：一项观察性研究
2025/12/30
摘要
背景：最近研究表明，尽管有基于指南的标准治疗，但超过50%的成人哮喘控制仍不足。小气道往往被低估为气道阻塞和炎症的主要部位。这可能与缺乏对脉冲振荡法等现有工具的评估有关，因此治疗不足可能是控制不足的原因。小气道功能障碍在哮喘控制良好的成年人中很常见，可能是未来恶化风险的重要生物标志物。
目的：本研究旨在探明哮喘控制良好的患者是否存在小气道功能障碍，如果是，这是否是该人群未来病情恶化的危险因素。
方法：2014年6月30日至2017年3月3日，小气道在哮喘中作用的观察性评估（ATLANTIS）研究共纳入了来自9个国家29个初级和专科诊所的773名18-65岁哮喘患者。根据气道高反应性、支气管舒张剂可逆性或呼气峰流速变异性的证据，患者需要在纳入前至少6个月被诊断为哮喘。患者需处于哮喘稳定期，定义为在基线访视前8周无哮喘加重，并定期接受恒定剂量的哮喘治疗。本研究分析包括哮喘控制良好的患者，定义为基线时哮喘控制问卷（ACQ-6）得分低于0.75。根据脉冲振荡参数预测值的偏差，小气道功能障碍被定义为R5-R20（5 Hz电阻减去20 Hz电阻）和AX（电抗面积）的Z值大于1.645，X5（5 Hz电抗）的Z值小于-1.645，并进一步分析探索严重小气道功能障碍（Z评分为3或-3）。ATLANTIS已在ClinicalTrials.gov注册，注册号为NCT02123667。
结果：在773名患者中，772名患者接受了ACQ-6评估。在这些患者中，384名（50%）被归类为哮喘控制良好。对于存在小气道功能障碍的患者，304名有R5-R20脉冲振荡数据的患者中有108名（36%[95%CI 30-41]），261名有AX数据的患者有89名（34%[28-42]），303名有X5数据的患者中共有79名（26%[21-31]）。在多变量分析中，本研究发现R5-R20定义的小气道功能障碍与未来急性发作的风险增加有关，与年龄、性别、吸烟状况、全球哮喘倡议第4-5步、既往急性发作、预测FEV1的百分比、残余体积与总肺容量的比率和外周血嗜酸性粒细胞计数无关（风险比[HR]2.26[95%CI 1.05-4.85]；p=0.038），而AX（2.07[0.91-4.70]；p=0.082）和X5（0.86[0.33-2.21]；p=0.75）与急性发作无关。对于严重的小气道疾病，R5-R20（HR 2.80[95%CI 1.26-6.26]；p=0.012）和AX（2.51[1.04-6.04]；p=0.041）都成为未来恶化的独立预测因素，而X5仍然不显著（0.99[0.29-3.32]；p=0.98）。
结论：本研究阐明了一个被低估的特征，即证明小气道功能障碍是成人控制良好哮喘未来恶化的常见、敏感、早期独立风险生物标志物。
Assessment of the role of small airway dysfunction in relation to exacerbation risk in patients with well controlled asthma (ATLANTIS): an observational study.
Galant SP, Kuks PJM, Kole TM, Kraft M, Siddiqui S, Fabbri LM, Beghé B, Rabe KF, Papi A, Brightling CE, Singh D, Kocks JWH, Franzini L, Vonk JM, Kerstjens HAM, Heijink IH, Pouwels SD, Slebos DJ, van den Berge M.
Abstract
BACKGROUND:Recent surveys suggest that asthma remains inadequately controlled in more than 50% of adults with asthma despite guideline-based standard therapy. Small airways are often under-recognised as major sites of airway obstruction and inflammation. This might be related to lack of assessment with current tools such as impulse oscillometry, and thus under-treatment might explain inadequate control. Small airway dysfunction, which is common in adults with well controlled asthma, might represent an important biomarker of future risk of exacerbations.
OBJECTIVES:We aimed to investigate whether small airway dysfunction is present in patients with well controlled asthma and, if so, whether it is a risk factor for future exacerbations in this population.
METHODS:The observational Assessment of Small Airways Involvement in Asthma (ATLANTIS) study included 773 extensively characterised patients with asthma aged 18-65 years from 29 primary and specialty clinics in nine countries from June 30, 2014, to March 3, 2017. Patients were required to be diagnosed with asthma at least 6 months before inclusion based on evidence of airway hyper-responsiveness, bronchodilator reversibility, or peak expiratory flow variability. Patients were required to have stable asthma, defined as no asthma exacerbations and regular asthma treatment at a consistent dose for 8 weeks before baseline visits. The current analysis included patients with well controlled asthma, defined as an Asthma Control Questionnaire (ACQ-6) score of less than 0.75 at baseline. Small airway dysfunction was defined, based on deviation from predicted values of impulse oscillometry parameters, as a Z score of more than 1.645 for R5-R20 (resistance at 5 Hz minus resistance at 20 Hz) and AX (area of reactance) and a Z score of less than -1.645 for X5 (reactance at 5 Hz), with additional analyses exploring severe small airway dysfunction (Z score of 3 or -3). ATLANTIS is registered with ClinicalTrials.gov, NCT02123667.
RESULTS:Of 773 patients, ACQ-6 assessments were available for 772 patients. Among these patients, 384 (50%) were classified as having well controlled asthma, and small airway dysfunction was present in 108 (36% [95% CI 30-41]) of 304 patients with impulse oscillometry data available for R5-R20, 89 (34% [28-42]) of 261 patients with data for AX, and 79 (26% [21-31]) of 303 patients with data for X5. In the multivariable analysis, we found that R5-R20-defined small airway dysfunction was associated with increased risk of future exacerbations, independent of age, sex, smoking status, Global Initiative for Asthma steps 4-5, previous exacerbations, percentage of predicted FEV1, ratio of residual volume to total lung capacity, and peripheral blood eosinophil count (hazard ratio [HR] 2.26 [95% CI 1.05-4.85]; p=0.038), whereas AX (2.07 [0.91-4.70]; p=0.082) and X5 (0.86 [0.33-2.21]; p=0.75) were not associated with exacerbations. For severe small airway disease, both R5-R20 (HR 2.80 [95% CI 1.26-6.26]; p=0.012) and AX (2.51 [1.04-6.04]; p=0.041) became independent predictors of future exacerbations, whereas X5 remained non-significant (0.99 [0.29-3.32]; p=0.98).
CONCLUSION: We have addressed an undervalued trait by showing that small airway dysfunction is a common, sensitive, early independent risk biomarker for future exacerbations in adults with well controlled asthma.
背景：最近研究表明，尽管有基于指南的标准治疗，但超过50%的成人哮喘控制仍不足。小气道往往被低估为气道阻塞和炎症的主要部位。这可能与缺乏对脉冲振荡法等现有工具的评估有关，因此治疗不足可能是控制不足的原因。小气道功能障碍在哮喘控制良好的成年人中很常见，可能是未来恶化风险的重要生物标志物。
目的：本研究旨在探明哮喘控制良好的患者是否存在小气道功能障碍，如果是，这是否是该人群未来病情恶化的危险因素。
方法：2014年6月30日至2017年3月3日，小气道在哮喘中作用的观察性评估（ATLANTIS）研究共纳入了来自9个国家29个初级和专科诊所的773名18-65岁哮喘患者。根据气道高反应性、支气管舒张剂可逆性或呼气峰流速变异性的证据，患者需要在纳入前至少6个月被诊断为哮喘。患者需处于哮喘稳定期，定义为在基线访视前8周无哮喘加重，并定期接受恒定剂量的哮喘治疗。本研究分析包括哮喘控制良好的患者，定义为基线时哮喘控制问卷（ACQ-6）得分低于0.75。根据脉冲振荡参数预测值的偏差，小气道功能障碍被定义为R5-R20（5 Hz电阻减去20 Hz电阻）和AX（电抗面积）的Z值大于1.645，X5（5 Hz电抗）的Z值小于-1.645，并进一步分析探索严重小气道功能障碍（Z评分为3或-3）。ATLANTIS已在ClinicalTrials.gov注册，注册号为NCT02123667。
结果：在773名患者中，772名患者接受了ACQ-6评估。在这些患者中，384名（50%）被归类为哮喘控制良好。对于存在小气道功能障碍的患者，304名有R5-R20脉冲振荡数据的患者中有108名（36%[95%CI 30-41]），261名有AX数据的患者有89名（34%[28-42]），303名有X5数据的患者中共有79名（26%[21-31]）。在多变量分析中，本研究发现R5-R20定义的小气道功能障碍与未来急性发作的风险增加有关，与年龄、性别、吸烟状况、全球哮喘倡议第4-5步、既往急性发作、预测FEV1的百分比、残余体积与总肺容量的比率和外周血嗜酸性粒细胞计数无关（风险比[HR]2.26[95%CI 1.05-4.85]；p=0.038），而AX（2.07[0.91-4.70]；p=0.082）和X5（0.86[0.33-2.21]；p=0.75）与急性发作无关。对于严重的小气道疾病，R5-R20（HR 2.80[95%CI 1.26-6.26]；p=0.012）和AX（2.51[1.04-6.04]；p=0.041）都成为未来恶化的独立预测因素，而X5仍然不显著（0.99[0.29-3.32]；p=0.98）。
结论：本研究阐明了一个被低估的特征，即证明小气道功能障碍是成人控制良好哮喘未来恶化的常见、敏感、早期独立风险生物标志物。
（中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校）
（Lancet Respir Med. 2025 Nov;13(11):990-1000. doi: 10.1016/S2213-2600(25)00283-8.）
（Lancet Respir Med. 2025 Nov;13(11):990-1000. doi: 10.1016/S2213-2600(25)00283-8.）
Assessment of the role of small airway dysfunction in relation to exacerbation risk in patients with well controlled asthma (ATLANTIS): an observational study.
Galant SP, Kuks PJM, Kole TM, Kraft M, Siddiqui S, Fabbri LM, Beghé B, Rabe KF, Papi A, Brightling CE, Singh D, Kocks JWH, Franzini L, Vonk JM, Kerstjens HAM, Heijink IH, Pouwels SD, Slebos DJ, van den Berge M.
Abstract
BACKGROUND:Recent surveys suggest that asthma remains inadequately controlled in more than 50% of adults with asthma despite guideline-based standard therapy. Small airways are often under-recognised as major sites of airway obstruction and inflammation. This might be related to lack of assessment with current tools such as impulse oscillometry, and thus under-treatment might explain inadequate control. Small airway dysfunction, which is common in adults with well controlled asthma, might represent an important biomarker of future risk of exacerbations.
OBJECTIVES:We aimed to investigate whether small airway dysfunction is present in patients with well controlled asthma and, if so, whether it is a risk factor for future exacerbations in this population.
METHODS:The observational Assessment of Small Airways Involvement in Asthma (ATLANTIS) study included 773 extensively characterised patients with asthma aged 18-65 years from 29 primary and specialty clinics in nine countries from June 30, 2014, to March 3, 2017. Patients were required to be diagnosed with asthma at least 6 months before inclusion based on evidence of airway hyper-responsiveness, bronchodilator reversibility, or peak expiratory flow variability. Patients were required to have stable asthma, defined as no asthma exacerbations and regular asthma treatment at a consistent dose for 8 weeks before baseline visits. The current analysis included patients with well controlled asthma, defined as an Asthma Control Questionnaire (ACQ-6) score of less than 0.75 at baseline. Small airway dysfunction was defined, based on deviation from predicted values of impulse oscillometry parameters, as a Z score of more than 1.645 for R5-R20 (resistance at 5 Hz minus resistance at 20 Hz) and AX (area of reactance) and a Z score of less than -1.645 for X5 (reactance at 5 Hz), with additional analyses exploring severe small airway dysfunction (Z score of 3 or -3). ATLANTIS is registered with ClinicalTrials.gov, NCT02123667.
RESULTS:Of 773 patients, ACQ-6 assessments were available for 772 patients. Among these patients, 384 (50%) were classified as having well controlled asthma, and small airway dysfunction was present in 108 (36% [95% CI 30-41]) of 304 patients with impulse oscillometry data available for R5-R20, 89 (34% [28-42]) of 261 patients with data for AX, and 79 (26% [21-31]) of 303 patients with data for X5. In the multivariable analysis, we found that R5-R20-defined small airway dysfunction was associated with increased risk of future exacerbations, independent of age, sex, smoking status, Global Initiative for Asthma steps 4-5, previous exacerbations, percentage of predicted FEV1, ratio of residual volume to total lung capacity, and peripheral blood eosinophil count (hazard ratio [HR] 2.26 [95% CI 1.05-4.85]; p=0.038), whereas AX (2.07 [0.91-4.70]; p=0.082) and X5 (0.86 [0.33-2.21]; p=0.75) were not associated with exacerbations. For severe small airway disease, both R5-R20 (HR 2.80 [95% CI 1.26-6.26]; p=0.012) and AX (2.51 [1.04-6.04]; p=0.041) became independent predictors of future exacerbations, whereas X5 remained non-significant (0.99 [0.29-3.32]; p=0.98).
CONCLUSION: We have addressed an undervalued trait by showing that small airway dysfunction is a common, sensitive, early independent risk biomarker for future exacerbations in adults with well controlled asthma.
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