Abstract：
BACKGROUND: Chronic lung allograft dysfunction (CLAD) limits survival following lung transplant, but substantial lung damage occurs before diagnosis by traditional methods. We hypothesized that small airway gene expression patterns could identify CLAD risk before spirometric diagnosis and predict subsequent graft failure.
METHODS: Candidate genes from 4 rejection-associated transcript sets were assessed for associations with CLAD or graft failure in a derivation cohort of 156 small airway brushes from 45 CLAD cases and 37 time-matched controls with >1-year stable lung function. Candidate genes not associated with CLAD and time to graft failure were excluded, yielding the Airway Inflammation 2 (AI2) gene set. Area under the receiver operating curve (AUC) for CLAD and competing risks of death or graft failure were assessed in an independent validation cohort of 37 CLAD cases and 37 controls.
RESULTS: Thirty-two candidate genes were associated with CLAD and graft failure, comprising the AI2 score, which clustered into 3 subcomponents. The AI2 score identified CLAD before its onset, in early and late post-CLAD brushes, as well as in the validation cohort (AUC 0.69-0.88). The AI2 score association with CLAD was independent of positive microbiology, CLAD stage, or CLAD subtype. However, transcripts most associated with CLAD evolved over time from CLAD onset. The AI2 score predicted time to graft failure and retransplant-free survival in both cohorts (p ≤ 0.03).
CONCLUSIONS: This airway inflammation gene score is associated with CLAD development, graft failure, and death. Future studies defining the molecular heterogeneity of airway inflammation could lead to endotype-targeted therapies.
METHODS: Candidate genes from 4 rejection-associated transcript sets were assessed for associations with CLAD or graft failure in a derivation cohort of 156 small airway brushes from 45 CLAD cases and 37 time-matched controls with >1-year stable lung function. Candidate genes not associated with CLAD and time to graft failure were excluded, yielding the Airway Inflammation 2 (AI2) gene set. Area under the receiver operating curve (AUC) for CLAD and competing risks of death or graft failure were assessed in an independent validation cohort of 37 CLAD cases and 37 controls.
RESULTS: Thirty-two candidate genes were associated with CLAD and graft failure, comprising the AI2 score, which clustered into 3 subcomponents. The AI2 score identified CLAD before its onset, in early and late post-CLAD brushes, as well as in the validation cohort (AUC 0.69-0.88). The AI2 score association with CLAD was independent of positive microbiology, CLAD stage, or CLAD subtype. However, transcripts most associated with CLAD evolved over time from CLAD onset. The AI2 score predicted time to graft failure and retransplant-free survival in both cohorts (p ≤ 0.03).
CONCLUSIONS: This airway inflammation gene score is associated with CLAD development, graft failure, and death. Future studies defining the molecular heterogeneity of airway inflammation could lead to endotype-targeted therapies.
摘要：
背景：慢性肺移植功能障碍（CLAD）限制了肺移植后的存活，但是在通过传统方法诊断之前会发生实质性的肺损伤。我们假设小气道基因表达模式可以在肺活量测定诊断之前识别CLAD风险并预测随后的移植物失败。
方法：在来自45例CLAD病例和37例时间匹配的对照组的156个小气道刷的衍生队列中，评估了来自4个排斥相关转录组的候选基因与CLAD或移植物失败的相关性。排除与CLAD和移植失败时间无关的候选基因，产生气道炎症2（AI2）基因集。在37例CLAD病例和37例对照的独立验证队列中评估了CLAD的受试者工作曲线下面积（AUC）和死亡或移植物失败的竞争风险。
结果：32个候选基因与CLAD和移植物失败有关，包括AI2分数，分为3个子组件。AI2评分在发病前确定了CLAD，在早期和晚期后CLAD画笔中，以及验证队列（AUC0.69-0.88）。AI2评分与CLAD的相关性独立于阳性微生物学，CLAD阶段，或CLAD子类型。然而,与CLAD最相关的转录本从CLAD开始随着时间的推移而演变。AI2评分预测了两个队列中移植物失败和无再移植存活的时间（p≤0.03）。
结论：该气道炎症基因评分与CLAD发展相关，移植失败，和死亡。定义气道炎症的分子异质性的未来研究可能会导致内生型靶向治疗。
方法：在来自45例CLAD病例和37例时间匹配的对照组的156个小气道刷的衍生队列中，评估了来自4个排斥相关转录组的候选基因与CLAD或移植物失败的相关性。排除与CLAD和移植失败时间无关的候选基因，产生气道炎症2（AI2）基因集。在37例CLAD病例和37例对照的独立验证队列中评估了CLAD的受试者工作曲线下面积（AUC）和死亡或移植物失败的竞争风险。
结果：32个候选基因与CLAD和移植物失败有关，包括AI2分数，分为3个子组件。AI2评分在发病前确定了CLAD，在早期和晚期后CLAD画笔中，以及验证队列（AUC0.69-0.88）。AI2评分与CLAD的相关性独立于阳性微生物学，CLAD阶段，或CLAD子类型。然而,与CLAD最相关的转录本从CLAD开始随着时间的推移而演变。AI2评分预测了两个队列中移植物失败和无再移植存活的时间（p≤0.03）。
结论：该气道炎症基因评分与CLAD发展相关，移植失败，和死亡。定义气道炎症的分子异质性的未来研究可能会导致内生型靶向治疗。
