Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Lung Transplant Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Lung Transplant Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Am J Transplant. 2023 Oct;23(10):1590-1602. doi: 10.1016/j.ajt.2023.06.014. Epub 2023 Jun 29.
Idiopathic pulmonary fibrosis lung transplant recipients (IPF-LTRs) are enriched for short telomere length (TL) and telomere gene rare variants. A subset of patients with nontransplant short-TL are at increased risk for bone marrow (BM) dysfunction. We hypothesized that IPF-LTRs with short-TL and/or rare variants would be at increased risk for posttransplant hematologic complications. Data were extracted from a retrospective cohort of 72 IPF-LTRs and 72 age-matched non-IPF-LTR controls. Genetic assessment was done using whole genome sequencing or targeted sequence panel. TL was measured using flow cytometry and fluorescence in-situ hybridization (FlowFISH) and TelSeq software. The majority of the IPF-LTR cohort had short-TL, and 26% of IPF-LTRs had rare variants. Compared to non-IPF controls, short-TL IPF-LTRs were more likely to have immunosuppression agents discontinued due to cytopenias (P = .0375), and BM dysfunction requiring BM biopsy was more prevalent (29% vs 4%, P = .0003). IPF-LTRs with short-TL and rare variants had increased requirements for transfusion and growth factor support. Multivariable logistic regression demonstrated that short-TL, rare variants, and lower pretransplant platelet counts were associated with BM dysfunction. Pretransplant TL measurement and genetic testing for rare telomere gene variants identified IPF-LTRs at increased risk for hematologic complications. Our findings support stratification for telomere-mediated pulmonary fibrosis in lung transplant candidates.
特发性肺纤维化肺移植受者(IPF-LTRs)的端粒长度(TL)较短且端粒基因稀有变异丰富。一部分端粒较短的非移植患者骨髓(BM)功能障碍风险增加。我们假设短端粒和/或稀有变异的 IPF-LTR 发生移植后血液学并发症的风险增加。数据从 72 例 IPF-LTR 和 72 例年龄匹配的非 IPF-LTR 对照的回顾性队列中提取。使用全基因组测序或靶向序列面板进行遗传评估。使用流式细胞术和荧光原位杂交(FlowFISH)和 TelSeq 软件测量 TL。大多数 IPF-LTR 队列的端粒长度较短,26%的 IPF-LTR 存在稀有变异。与非 IPF 对照组相比,端粒较短的 IPF-LTR 因细胞减少而更有可能停用免疫抑制剂(P=.0375),并且需要进行骨髓活检的 BM 功能障碍更为常见(29%对 4%,P=.0003)。端粒较短的 IPF-LTR 更需要输血和生长因子支持。多变量逻辑回归表明,短端粒、稀有变异和较低的移植前血小板计数与 BM 功能障碍相关。移植前 TL 测量和稀有端粒基因变异的遗传检测确定了发生血液学并发症风险增加的 IPF-LTR。我们的研究结果支持对肺移植候选者的端粒介导的肺纤维化进行分层。