通过肺灌洗成分聚类分析确定的新型学龄前难治性喘息表型
2021/05/26
摘要
背景：学龄前儿童难治性喘息往往需要非计划的急性护理。目前的指南建议用吸入糖皮质激素（ICS）治疗持续性喘息。针对结构异常和特定炎症模式的替代治疗可能更有效。
目的：应用肺灌洗（BAL）变量的无监督分析来确定学龄前儿童难治性喘息的集群。
方法：155名儿童≤ 6岁儿童接受支气管镜检查，用支气管肺泡灌洗液评估气道结构、炎症标志物和病原体。
结果：该模型在48例验证样本中重复性好，分类准确率达86%。第1组（n=60）有早发性喘息，85%伴有结构异常，多为气管软化，总IgE低，BAL为寡细胞型。第2组（n=42）有迟发性喘息，胃食管反流患病率最高，有少量特应性反应，2/3的BAL载脂巨噬细胞增多。簇3（n=46）有中度发作的喘息，总IgE低，2/3有BAL病毒转录物，主要是人鼻病毒（HRV），伴有BAL中性粒细胞升高。第4组（n=7）年龄较大，总IgE高，血液嗜酸性粒细胞增多，BAL为嗜酸性粒细胞和中性粒细胞混合型。
结论：ICS难治性反复喘息的学龄前儿童包括四组：气道软化、胃食管反流、慢性HRV支气管肺泡炎和高2型炎症。研究结果支持有创性支气管镜检查诊断难治性喘息的原因，并开发针对学龄前儿童气道软化、HRV感染和BAL中性粒细胞的新疗法。
Novel Treatment-Refractory Preschool Wheeze Phenotypes Identified by Cluster Analysis of Lung Lavage Constituents
W Gerald Teague, Monica G Lawrence, Sanford Williams, Andrea S Garrod, Deborah Froh, Stephen V Early, William Brand, Jeremy P Middleton, Michael V Mendoza, Kerry A Hollis, Kristin Wavell, Peter W Heymann, John W Steinke, Larry Borish
Abstract
Background: Preschool children with treatment-refractory wheeze often require unscheduled acute care. Current guidelines advise treatment of persistent wheeze with inhaled corticosteroids (ICS). Alternative treatments targeting structural abnormalities and specific inflammatory patterns could be more effective.
Objective: To apply unsupervised analysis of lung lavage (BAL) variables to identify clusters of preschool children with treatment-refractory wheeze.
Methods: 155 children ≤ 6 years of age underwent bronchoscopy with BAL for evaluation of airway structure, inflammatory markers, and pathogens. Variables were screened with factor analysis, sorted into clusters by Ward's method, membership was confirmed by discriminant analysis.
RESULTS: The model was repeatable in a 48 case validation sample and accurately classified 86% of cases. Cluster 1 (n=60) had early-onset wheeze, 85% with structural abnormalities, mostly tracheamalacia, with low total IgE and agranulocytic BAL. Cluster 2 (n=42) had later-onset wheeze, the highest prevalence of gastroesophageal reflux, little atopy, and 2/3 had increased BAL lipid-laden macrophages. Cluster 3 (n=46) had mid-onset wheeze, low total IgE, and 2/3 had BAL viral transcripts, predominately human rhinovirus (HRV), with BAL neutrophilia. Cluster 4 (n=7) was older, with high total IgE, blood eosinophilia, and mixed BAL eosinophils and neutrophils.
Conclusion: Preschool children with recurrent wheeze refractory to ICS treatment include four clusters: airway malacia, gastroesophageal reflux, indolent HRV bronchoalveolitis, and type-2high inflammation. The results support the risk and cost of invasive bronchoscopy to diagnose causes of treatment-refractory wheeze and develop novel therapies targeting airway malacia, HRV infection, and BAL neutrophilia in preschool children.
背景：学龄前儿童难治性喘息往往需要非计划的急性护理。目前的指南建议用吸入糖皮质激素（ICS）治疗持续性喘息。针对结构异常和特定炎症模式的替代治疗可能更有效。
目的：应用肺灌洗（BAL）变量的无监督分析来确定学龄前儿童难治性喘息的集群。
方法：155名儿童≤ 6岁儿童接受支气管镜检查，用支气管肺泡灌洗液评估气道结构、炎症标志物和病原体。
结果：该模型在48例验证样本中重复性好，分类准确率达86%。第1组（n=60）有早发性喘息，85%伴有结构异常，多为气管软化，总IgE低，BAL为寡细胞型。第2组（n=42）有迟发性喘息，胃食管反流患病率最高，有少量特应性反应，2/3的BAL载脂巨噬细胞增多。簇3（n=46）有中度发作的喘息，总IgE低，2/3有BAL病毒转录物，主要是人鼻病毒（HRV），伴有BAL中性粒细胞升高。第4组（n=7）年龄较大，总IgE高，血液嗜酸性粒细胞增多，BAL为嗜酸性粒细胞和中性粒细胞混合型。
结论：ICS难治性反复喘息的学龄前儿童包括四组：气道软化、胃食管反流、慢性HRV支气管肺泡炎和高2型炎症。研究结果支持有创性支气管镜检查诊断难治性喘息的原因，并开发针对学龄前儿童气道软化、HRV感染和BAL中性粒细胞的新疗法。
（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）
（J Allergy Clin Immunol Pract. 2021 Apr 24;S2213-2198(21)00465-7. doi: 10.1016/j.jaip.2021.03.059.）
（J Allergy Clin Immunol Pract. 2021 Apr 24;S2213-2198(21)00465-7. doi: 10.1016/j.jaip.2021.03.059.）
Novel Treatment-Refractory Preschool Wheeze Phenotypes Identified by Cluster Analysis of Lung Lavage Constituents
W Gerald Teague, Monica G Lawrence, Sanford Williams, Andrea S Garrod, Deborah Froh, Stephen V Early, William Brand, Jeremy P Middleton, Michael V Mendoza, Kerry A Hollis, Kristin Wavell, Peter W Heymann, John W Steinke, Larry Borish
Abstract
Background: Preschool children with treatment-refractory wheeze often require unscheduled acute care. Current guidelines advise treatment of persistent wheeze with inhaled corticosteroids (ICS). Alternative treatments targeting structural abnormalities and specific inflammatory patterns could be more effective.
Objective: To apply unsupervised analysis of lung lavage (BAL) variables to identify clusters of preschool children with treatment-refractory wheeze.
Methods: 155 children ≤ 6 years of age underwent bronchoscopy with BAL for evaluation of airway structure, inflammatory markers, and pathogens. Variables were screened with factor analysis, sorted into clusters by Ward's method, membership was confirmed by discriminant analysis.
RESULTS: The model was repeatable in a 48 case validation sample and accurately classified 86% of cases. Cluster 1 (n=60) had early-onset wheeze, 85% with structural abnormalities, mostly tracheamalacia, with low total IgE and agranulocytic BAL. Cluster 2 (n=42) had later-onset wheeze, the highest prevalence of gastroesophageal reflux, little atopy, and 2/3 had increased BAL lipid-laden macrophages. Cluster 3 (n=46) had mid-onset wheeze, low total IgE, and 2/3 had BAL viral transcripts, predominately human rhinovirus (HRV), with BAL neutrophilia. Cluster 4 (n=7) was older, with high total IgE, blood eosinophilia, and mixed BAL eosinophils and neutrophils.
Conclusion: Preschool children with recurrent wheeze refractory to ICS treatment include four clusters: airway malacia, gastroesophageal reflux, indolent HRV bronchoalveolitis, and type-2high inflammation. The results support the risk and cost of invasive bronchoscopy to diagnose causes of treatment-refractory wheeze and develop novel therapies targeting airway malacia, HRV infection, and BAL neutrophilia in preschool children.
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低呼出气一氧化氮水平排除了疑似哮喘吸入糖皮质激素的短期获益：一项随机安慰剂对照试验
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