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.

中文翻译：

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小气道刷基因表达可预测慢性肺同种异体移植物功能障碍和死亡率。


背景 慢性肺同种异体移植物功能障碍 （CLAD） 限制了肺移植后的生存率，但通过传统方法诊断前会发生严重的肺损伤。我们假设小气道基因表达模式可以在肺活量诊断之前识别 CLAD 风险并预测随后的移植失败。方法 在来自 45 例 CLAD 病例的 156 个小气道刷和 37 例具有 >1 年稳定肺功能的时间匹配对照的衍生队列中，评估来自 4 个排斥相关转录本集的候选基因与 CLAD 或移植物失败的关联。排除了与 CLAD 和移植失败时间无关的候选基因，产生了气道炎症 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） 和死亡或移植失败的竞争风险。结果 32 个候选基因与 CLAD 和移植失败相关，包括 AI2 评分，分为 3 个亚组分。AI2 评分在CLAD开始前、CLAD 后早期和晚期以及验证队列 （AUC 0.69-0.88） 中识别了 CLAD。AI2 评分与 CLAD 的相关性与阳性微生物学、 CLAD 分期或 CLAD 亚型无关。然而，与 CLAD 最相关的转录本从 CLAD 发病开始随着时间的推移而演变。AI2 评分预测了两个队列的移植失败时间和无再移植生存期 （p ≤ 0.03）。结论 该气道炎症基因评分与 CLAD 发展、移植物失败和死亡相关。未来定义气道炎症分子异质性的研究可能会导致内型靶向治疗。