1个月至13岁哮喘患儿气道阻塞和支气管反应：一项前瞻性出生队列研究
2019/08/27
摘要
背景：在过去二十年间，肥胖儿童与青少年的数量已经翻了一倍多。根据儿童期肥胖增长的这一趋势，超重哮喘儿童的数量将有惊人的增加。
目的：研究表明，哮喘患儿的早期生活中存在气道阻塞和支气管反应性增加，这对气道炎症导致肺功能下降的理论提出了挑战。需要进一步的研究来探讨低肺功能和支气管高反应性是否是增加气道炎症和哮喘症状发生风险的固有特征，进而能够及时建立初级预防措施。
方法和结果：本我们调查了来着哥本哈根儿童哮喘前瞻性研究（COPSAC2000）出生队列（母亲为哮喘患者）的411名儿童中的367名（89％）。评估包括1个月时的肺活量测定和支气管对乙酰甲胆碱反应性， 3岁时的体积描记法肺功能和支气管可逆性，4岁时的干燥冷空气过度通气，以及7岁时的运动激发。COPSAC儿科医生诊断和治疗哮喘的依据是症状、吸入皮质类固醇反应和停药后复发等标准化方法。采用重复测量混合模型分析1个月至13岁的患有或未患有哮喘的儿童的肺功能轨迹。在13岁前，儿童患哮喘人数为97（27％），未患哮喘人数为270（73％）。诊断时的中位年龄为2.0岁（IQR 1.2-5.7），中位缓解年龄为6.2岁（IQR 4.2-7.8）。患有哮喘的儿童较未患哮喘儿童肺功能降低（z评分差异，用力呼气量，-0.31 [95％CI -0.47; -0.15]，p <0.001），气道阻力增加（z评分差异，特定气道阻力， +0.40 [95％CI +0.24; +0.56]，p <0.001），支气管可逆性增加（第一秒用力呼气量变化[ΔFEV1]，+ 3％[95％CI + 2％; +4] ％]，p <0.001），对乙酰甲胆碱的反应性增加（激发剂量的z-得分差异，-0.40 [95％CI -0.58; -0.22]，p <0.001），干燥冷空气激发时的用力呼气量减少（ΔFEV1 ，-4％[95％CI -7％; -1％]，p <0.01），运动后用力呼气量减少（ΔFEV1，-4％[95％CI -7％; -1％]，p = 0.02）。症状出现前均存在气道阻塞和支气管高反应性，与疾病持续时间无关，并未随着症状缓解而改善。这些发现可能存在队列的高风险性质（所有母亲都诊断为哮喘）、中等研究规模和有限的种族差异性等限制。
结论：在1个月至13岁的某些时候患有哮喘的儿童在出现症状之前有气道阻塞和支气管高反应性，哮喘症状持续时间未增加，缓解期也未缩短。这表明气道阻塞和支气管高反应性是自出生后儿童哮喘的稳定特征，这意味着疾病症状可能部分源自这些特征，而不是疾病本身引起的。
Airway obstruction and bronchial reactivity from age 1 month until 13 years in children with asthma: A prospective birth cohort study.
Hallas HW, Chawes BL, Rasmussen MA, Arianto L, Stokholm J, Bønnelykke K, Bisgaard H.
Abstract
BACKGROUND:Studies have shown that airway obstruction and increased bronchial reactivity are present in early life in children developing asthma, which challenges the dogma that airway inflammation leads to low lung function. Further studies are needed to explore whether low lung function and bronchial hyperreactivity are inherent traits increasing the risk of developing airway inflammation and asthmatic symptoms in order to establish timely primary preventive initiatives.
METHODS AND FINDINGS:We investigated 367 (89%) of the 411 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort born to mothers with asthma, who were assessed by spirometry and bronchial reactivity to methacholine from age 1 month, plethysmography and bronchial reversibility from age 3 years, cold dry air hyperventilation from age 4 years, and exercise challenge at age 7 years. The COPSAC pediatricians diagnosed and treated asthma based on symptom load, response to inhaled corticosteroid, and relapse after treatment withdrawal according to a standardized algorithm. Repeated measures mixed models were applied to analyze lung function trajectories in children with asthma ever or never at age 1 month to 13 years. The number of children ever versus never developing asthma in their first 13 years of life was 97 (27%) versus 270 (73%), respectively. Median age at diagnosis was 2.0 years (IQR 1.2-5.7), and median remission age was 6.2 years (IQR 4.2-7.8). Children with versus without asthma had reduced lung function (z-score difference, forced expiratory volume, -0.31 [95% CI -0.47; -0.15], p < 0.001), increased airway resistance (z-score difference, specific airway resistance, +0.40 [95% CI +0.24; +0.56], p < 0.001), increased bronchial reversibility (difference in change in forced expiratory volume in the first second [ΔFEV1], +3% [95% CI +2%; +4%], p < 0.001), increased reactivity to methacholine (z-score difference for provocative dose, -0.40 [95% CI -0.58; -0.22], p < 0.001), decreased forced expiratory volume at cold dry air challenge (ΔFEV1, -4% [95% CI -7%; -1%], p < 0.01), and decreased forced expiratory volume after exercise (ΔFEV1, -4% [95% CI -7%; -1%], p = 0.02). Both airway obstruction and bronchial hyperreactivity were present before symptom debut, independent of disease duration, and did not improve with symptom remission. The generalizability of these findings may be limited by the high-risk nature of the cohort (all mothers had a diagnosis of asthma), the modest study size, and limited ethnic variation.
CONCLUSIONS:Children with asthma at some point at age 1 month to 13 years had airway obstruction and bronchial hyperreactivity before symptom debut, which did not worsen with increased asthma symptom duration or attenuate with remission. This suggests that airway obstruction and bronchial hyperreactivity are stable traits of childhood asthma since neonatal life, implying that symptomatic disease may in part be a consequence of these traits but not their cause.
背景：在过去二十年间，肥胖儿童与青少年的数量已经翻了一倍多。根据儿童期肥胖增长的这一趋势，超重哮喘儿童的数量将有惊人的增加。
目的：研究表明，哮喘患儿的早期生活中存在气道阻塞和支气管反应性增加，这对气道炎症导致肺功能下降的理论提出了挑战。需要进一步的研究来探讨低肺功能和支气管高反应性是否是增加气道炎症和哮喘症状发生风险的固有特征，进而能够及时建立初级预防措施。
方法和结果：本我们调查了来着哥本哈根儿童哮喘前瞻性研究（COPSAC2000）出生队列（母亲为哮喘患者）的411名儿童中的367名（89％）。评估包括1个月时的肺活量测定和支气管对乙酰甲胆碱反应性， 3岁时的体积描记法肺功能和支气管可逆性，4岁时的干燥冷空气过度通气，以及7岁时的运动激发。COPSAC儿科医生诊断和治疗哮喘的依据是症状、吸入皮质类固醇反应和停药后复发等标准化方法。采用重复测量混合模型分析1个月至13岁的患有或未患有哮喘的儿童的肺功能轨迹。在13岁前，儿童患哮喘人数为97（27％），未患哮喘人数为270（73％）。诊断时的中位年龄为2.0岁（IQR 1.2-5.7），中位缓解年龄为6.2岁（IQR 4.2-7.8）。患有哮喘的儿童较未患哮喘儿童肺功能降低（z评分差异，用力呼气量，-0.31 [95％CI -0.47; -0.15]，p <0.001），气道阻力增加（z评分差异，特定气道阻力， +0.40 [95％CI +0.24; +0.56]，p <0.001），支气管可逆性增加（第一秒用力呼气量变化[ΔFEV1]，+ 3％[95％CI + 2％; +4] ％]，p <0.001），对乙酰甲胆碱的反应性增加（激发剂量的z-得分差异，-0.40 [95％CI -0.58; -0.22]，p <0.001），干燥冷空气激发时的用力呼气量减少（ΔFEV1 ，-4％[95％CI -7％; -1％]，p <0.01），运动后用力呼气量减少（ΔFEV1，-4％[95％CI -7％; -1％]，p = 0.02）。症状出现前均存在气道阻塞和支气管高反应性，与疾病持续时间无关，并未随着症状缓解而改善。这些发现可能存在队列的高风险性质（所有母亲都诊断为哮喘）、中等研究规模和有限的种族差异性等限制。
结论：在1个月至13岁的某些时候患有哮喘的儿童在出现症状之前有气道阻塞和支气管高反应性，哮喘症状持续时间未增加，缓解期也未缩短。这表明气道阻塞和支气管高反应性是自出生后儿童哮喘的稳定特征，这意味着疾病症状可能部分源自这些特征，而不是疾病本身引起的。
(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)
(PLoS Med. 2019 Jan 8;16(1):e1002722. doi: 10.1371/journal.pmed.1002722.)
(PLoS Med. 2019 Jan 8;16(1):e1002722. doi: 10.1371/journal.pmed.1002722.)
Airway obstruction and bronchial reactivity from age 1 month until 13 years in children with asthma: A prospective birth cohort study.
Hallas HW, Chawes BL, Rasmussen MA, Arianto L, Stokholm J, Bønnelykke K, Bisgaard H.
Abstract
BACKGROUND:Studies have shown that airway obstruction and increased bronchial reactivity are present in early life in children developing asthma, which challenges the dogma that airway inflammation leads to low lung function. Further studies are needed to explore whether low lung function and bronchial hyperreactivity are inherent traits increasing the risk of developing airway inflammation and asthmatic symptoms in order to establish timely primary preventive initiatives.
METHODS AND FINDINGS:We investigated 367 (89%) of the 411 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort born to mothers with asthma, who were assessed by spirometry and bronchial reactivity to methacholine from age 1 month, plethysmography and bronchial reversibility from age 3 years, cold dry air hyperventilation from age 4 years, and exercise challenge at age 7 years. The COPSAC pediatricians diagnosed and treated asthma based on symptom load, response to inhaled corticosteroid, and relapse after treatment withdrawal according to a standardized algorithm. Repeated measures mixed models were applied to analyze lung function trajectories in children with asthma ever or never at age 1 month to 13 years. The number of children ever versus never developing asthma in their first 13 years of life was 97 (27%) versus 270 (73%), respectively. Median age at diagnosis was 2.0 years (IQR 1.2-5.7), and median remission age was 6.2 years (IQR 4.2-7.8). Children with versus without asthma had reduced lung function (z-score difference, forced expiratory volume, -0.31 [95% CI -0.47; -0.15], p < 0.001), increased airway resistance (z-score difference, specific airway resistance, +0.40 [95% CI +0.24; +0.56], p < 0.001), increased bronchial reversibility (difference in change in forced expiratory volume in the first second [ΔFEV1], +3% [95% CI +2%; +4%], p < 0.001), increased reactivity to methacholine (z-score difference for provocative dose, -0.40 [95% CI -0.58; -0.22], p < 0.001), decreased forced expiratory volume at cold dry air challenge (ΔFEV1, -4% [95% CI -7%; -1%], p < 0.01), and decreased forced expiratory volume after exercise (ΔFEV1, -4% [95% CI -7%; -1%], p = 0.02). Both airway obstruction and bronchial hyperreactivity were present before symptom debut, independent of disease duration, and did not improve with symptom remission. The generalizability of these findings may be limited by the high-risk nature of the cohort (all mothers had a diagnosis of asthma), the modest study size, and limited ethnic variation.
CONCLUSIONS:Children with asthma at some point at age 1 month to 13 years had airway obstruction and bronchial hyperreactivity before symptom debut, which did not worsen with increased asthma symptom duration or attenuate with remission. This suggests that airway obstruction and bronchial hyperreactivity are stable traits of childhood asthma since neonatal life, implying that symptomatic disease may in part be a consequence of these traits but not their cause.
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未控制的重度口服糖皮质激素依赖型哮喘患者中与强的松龙相关的2型生物标志物和细胞因子的变化：一项开放性干预研究
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抑郁状态与哮喘及鼻炎控制不佳有关：一项基于人群的调查研究
