痰6种基因标记可预测控制不良哮喘的未来恶化
2019/02/19
摘要
背景：预测哮喘未来恶化频率的诊断工具需要改进。6种痰基因表达的生物标记物（6GS-包括CLC、CPA3、DNASE1L3、ALPL、CXCR2、IL1B）可用来预测稳定期哮喘患者的炎症和治疗反应表型。最近研究证实，阿奇霉素（AZM）在未控制的中重度哮喘中的附加治疗显著降低了哮喘急性加重频率（AMAZES临床试验）。
目标：测试6GS是否能预测AMAZES临床试验人群未来的恶化和炎症表型。探讨AZM治疗对6GS表达及预后的影响。
方法：142名患者（73名安慰剂治疗，69名AZM治疗）在基线和治疗48周后对痰标本6GS基因标记物行qPCR检测。对基线测量值进行logistic回归、ROC和AUC分析，并在探索性分析中，将6GS的预测值与传统生物标志物对恶化和炎症表型的预测值进行比较。
结果：6GS显著预测了所有未来的恶化表型。6GS的计算AUC值显著高于外周血嗜酸性粒细胞计数、痰中性粒细胞计数和痰嗜酸性粒细胞和中性粒细胞联合计数的AUC值。6GS AUC的数值也高于但不显著高于FeNO和痰嗜酸性粒细胞计数的AUC值。AZM治疗既没有改变6GS的表达，也没有改变6GS对未来加重表型的预测能力。6GS是哮喘人群气道炎症表型的重要预测因子。
结论：我们证明痰基因可预测未来哮喘恶化的表型，在识别哮喘频繁恶化的患者方面具有最大的生物标志物性能。AZM治疗没有改变6GS的表达或生物标志物的性能，提示AZM的治疗作用独立于6GS相关的炎症途径。
A sputum 6 gene signature predicts future exacerbations of poorly controlled asthma.
Fricker M, Gibson PG, Powell H, Simpson JL, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ, Marks GB, Baraket M, Baines KJ.
Abstract
BACKGROUND: Improved diagnostic tools for predicting future exacerbation frequency in asthma are required. A sputum gene expression signature of 6 biomarkers (6GS - including CLC, CPA3, DNASE1L3, ALPL, CXCR2, IL1B) predicts inflammatory and treatment response phenotypes in stable asthma. We recently demonstrated that azithromycin (AZM) add-on treatment in uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial).
OBJECTIVES: To test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES. To test the impact of AZM therapy on 6GS expression and prognostic capacity.
METHODS: 142 patients (73 placebo-treated, 69 AZM-treated) had sputum stored for qPCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression, ROC and AUC were performed on baseline measures, and in an exploratory analysis the predictive value of 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes.
RESULTS: The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for 6GS were significantly higher than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts and combined sputum eosinophils and neutrophil counts. 6GS AUCs were also were numerically, but not significantly, higher than FeNO and sputum eosinophil counts. AZM treatment neither altered the 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population.
CONCLUSION: We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.
背景：预测哮喘未来恶化频率的诊断工具需要改进。6种痰基因表达的生物标记物（6GS-包括CLC、CPA3、DNASE1L3、ALPL、CXCR2、IL1B）可用来预测稳定期哮喘患者的炎症和治疗反应表型。最近研究证实，阿奇霉素（AZM）在未控制的中重度哮喘中的附加治疗显著降低了哮喘急性加重频率（AMAZES临床试验）。
目标：测试6GS是否能预测AMAZES临床试验人群未来的恶化和炎症表型。探讨AZM治疗对6GS表达及预后的影响。
方法：142名患者（73名安慰剂治疗，69名AZM治疗）在基线和治疗48周后对痰标本6GS基因标记物行qPCR检测。对基线测量值进行logistic回归、ROC和AUC分析，并在探索性分析中，将6GS的预测值与传统生物标志物对恶化和炎症表型的预测值进行比较。
结果：6GS显著预测了所有未来的恶化表型。6GS的计算AUC值显著高于外周血嗜酸性粒细胞计数、痰中性粒细胞计数和痰嗜酸性粒细胞和中性粒细胞联合计数的AUC值。6GS AUC的数值也高于但不显著高于FeNO和痰嗜酸性粒细胞计数的AUC值。AZM治疗既没有改变6GS的表达，也没有改变6GS对未来加重表型的预测能力。6GS是哮喘人群气道炎症表型的重要预测因子。
结论：我们证明痰基因可预测未来哮喘恶化的表型，在识别哮喘频繁恶化的患者方面具有最大的生物标志物性能。AZM治疗没有改变6GS的表达或生物标志物的性能，提示AZM的治疗作用独立于6GS相关的炎症途径。
(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. 2019 Jan 22. pii: S0091-6749(19)30090-9. doi: 10.1016/j.jaci.2018.12.1020.)
(J Allergy Clin Immunol. 2019 Jan 22. pii: S0091-6749(19)30090-9. doi: 10.1016/j.jaci.2018.12.1020.)
A sputum 6 gene signature predicts future exacerbations of poorly controlled asthma.
Fricker M, Gibson PG, Powell H, Simpson JL, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ, Marks GB, Baraket M, Baines KJ.
Abstract
BACKGROUND: Improved diagnostic tools for predicting future exacerbation frequency in asthma are required. A sputum gene expression signature of 6 biomarkers (6GS - including CLC, CPA3, DNASE1L3, ALPL, CXCR2, IL1B) predicts inflammatory and treatment response phenotypes in stable asthma. We recently demonstrated that azithromycin (AZM) add-on treatment in uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial).
OBJECTIVES: To test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES. To test the impact of AZM therapy on 6GS expression and prognostic capacity.
METHODS: 142 patients (73 placebo-treated, 69 AZM-treated) had sputum stored for qPCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression, ROC and AUC were performed on baseline measures, and in an exploratory analysis the predictive value of 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes.
RESULTS: The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for 6GS were significantly higher than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts and combined sputum eosinophils and neutrophil counts. 6GS AUCs were also were numerically, but not significantly, higher than FeNO and sputum eosinophil counts. AZM treatment neither altered the 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population.
CONCLUSION: We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.
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合并哮喘和/或过敏性鼻炎儿童的肺功能表现：PEF25-75%与标准测量方法的比较
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儿童鼻上皮，特应性和特应性哮喘中的DNA甲基化：一项全基因组研究
