Keller Michael B, Lin Allison Y, Jang Moon Kyoo, Kong Hyesik, Charya Ananth, Berry Gerald J, Marboe Charles C, Ponor Ileana L, Aryal Shambhu, Orens Jonathan B, Shah Pali D, Nathan Steven D, Tian Xin, Agbor-Enoh Sean
Division of Pulmonary, Critical Care & Sleep Medicine, University of Maryland Medical Center, Baltimore, MD.
Division of Pulmonary & Critical Care Medicine, Baltimore VA Medical Center, Baltimore, MD.
Transplant Direct. 2025 Jun 27;11(7):e1828. doi: 10.1097/TXD.0000000000001828. eCollection 2025 Jul.
Despite treatment of major risk factors such as acute rejection (AR) and organizing pneumonia (OP) in lung transplant recipients, chronic lung allograft dysfunction (CLAD) still develops at high rates, suggesting that traditional methods of assessing response to treatment and resolution remain inadequate. It is unknown whether the degree of molecular allograft injury after treatment of AR/OP modulates the risk of CLAD and death.
To evaluate the association of molecular allograft injury after AR/OP with the incidence of CLAD/death, we conducted a multicenter prospective cohort study that included 93 patients who underwent lung transplantation between 2015 and 2022. The degree of molecular allograft injury after AR/OP was quantified by the mean area under the curve of longitudinal measures of plasma donor-derived cell-free DNA (dd-cfDNA).
Over a median follow-up of 5 y, patients who developed CLAD/death had persistently higher levels of dd-cfDNA in the months after AR/OP. In multivariable Cox regression analysis adjusting for patient and transplant risk factors, mean dd-cfDNA levels after AR/OP were independently associated with an increased risk of CLAD/death (adjusted hazard ratio, 2.84; 95% confidence interval, 1.67-4.83; < 0.001) and remained consistent when accounting for changes in pulmonary function after AR/OP events (hazard ratio, 2.62; 95% confidence interval, 1.53-4.47; < 0.001).
The degree of allograft injury on the molecular level after AR/OP events in lung transplant recipients is associated with the risk of developing CLAD or death. This study demonstrates the potential of dd-cfDNA for improving risk stratification and monitoring the resolution and treatment responses of lung allograft injury.
尽管对肺移植受者的主要风险因素如急性排斥反应（AR）和机化性肺炎（OP）进行了治疗，但慢性肺移植功能障碍（CLAD）的发生率仍然很高，这表明传统的评估治疗反应和病情缓解的方法仍然不足。AR/OP治疗后分子水平的同种异体移植损伤程度是否会调节CLAD和死亡风险尚不清楚。
为了评估AR/OP后分子水平的同种异体移植损伤与CLAD/死亡发生率之间的关联，我们进行了一项多中心前瞻性队列研究，纳入了2015年至2022年间接受肺移植的93例患者。AR/OP后分子水平的同种异体移植损伤程度通过血浆供体来源的游离DNA（dd-cfDNA）纵向测量曲线下的平均面积进行量化。
在中位随访5年期间，发生CLAD/死亡的患者在AR/OP后的数月中dd-cfDNA水平持续较高。在对患者和移植风险因素进行调整的多变量Cox回归分析中，AR/OP后的平均dd-cfDNA水平与CLAD/死亡风险增加独立相关（调整后的风险比为2.84；95%置信区间为1.67-4.83；P<0.001），并且在考虑AR/OP事件后肺功能变化时保持一致（风险比为2.62；95%置信区间为1.53-4.47；P<0.001）。
肺移植受者AR/OP事件后分子水平的同种异体移植损伤程度与发生CLAD或死亡的风险相关。本研究证明了dd-cfDNA在改善风险分层以及监测肺同种异体移植损伤的缓解和治疗反应方面的潜力。
