Newell K A, Alonso E M, Whitington P F, Bruce D S, Millis J M, Piper J B, Woodle E S, Kelly S M, Koeppen H, Hart J, Rubin C M, Thistlethwaite J R
Department of Surgery, University of Chicago, Illinois 60637, USA.
Transplantation. 1996 Aug 15;62(3):370-5. doi: 10.1097/00007890-199608150-00012.
The incidence, risk factors, and outcome of posttransplant lymphoproliferative disease (PTLD) were examined for 298 children undergoing liver transplantation. The overall incidence of PTLD was 8.4% (25 of 298). Intensity of immunosuppression was found to be a major risk factor for the development of PTLD. Cyclosporine and tacrolimus when used as primary immunosuppression were associated with the development of PTLD in 4.3% and 6.6% of cases (P=NS). OKT3 and tacrolimus, when used as rescue therapy for steroid-resistant rejection, were associated with a comparable increase in the risk of developing PTLD (10.9% and 11.1%, P=NS). Patients requiring both OKT3 and tacrolimus to treat refractory rejection were at significantly increased risk for PTLD (28.1% vs. 4.3% or 6.6%, P<0.0001). PTLD was more common in patients who received transplants for Langerhans cell histiocytosis relative to other indications for transplantation (66% vs. 8.4%, P=0.0005). The data also support an association between primary Epstein-Barr virus (EBV) infections following transplantation and the development of PTLD. While only three patients were EBV seropositive before transplantation (14%), 19 patients were EBV seropositive at the time of diagnosis of PTLD (90%), confirming a high incidence of primary EBV infections in patients with PTLD (21 patients had both pre- and posttransplant EBV serologies). In this series, PTLD was associated with a mortality rate of 60%, and 12 of the 15 patients who died had persistent tumor at the time of death. Five of the 13 patients rendered disease-free developed ductopenic rejection. Of the four with severe liver dysfunction, two have undergone successful retransplantation and are alive without evidence of PTLD. In conclusion, intense immunosuppression using OKT3 and tacrolimus as rescue agents was associated with a significant increase in the incidence of PTLD. Primary EBV infection after transplantation further accentuated this risk. Independent of these risk factors, patients with Langerhans cell histiocytosis were at significantly increased risk for PTLD. The identification of high-risk patients should allow the development of protocols to screen patients for primary EBV infections and early indications of PTLD, as well as the institution of preemptive antiviral and antitumor therapies.
对298例接受肝移植的儿童进行了移植后淋巴组织增生性疾病（PTLD）的发病率、危险因素及转归情况的研究。PTLD的总体发病率为8.4%（298例中的25例）。免疫抑制强度被发现是PTLD发生的主要危险因素。环孢素和他克莫司作为初始免疫抑制药物使用时，PTLD的发生率分别为4.3%和6.6%（P值无统计学差异）。OKT3和他克莫司作为对激素抵抗性排斥反应的挽救治疗药物使用时，发生PTLD的风险有类似程度的增加（分别为10.9%和11.1%，P值无统计学差异）。需要同时使用OKT3和他克莫司治疗难治性排斥反应的患者发生PTLD的风险显著增加（28.1% 对比4.3%或6.6%，P<0.0001）。相对于其他移植适应证，接受移植治疗朗格汉斯细胞组织细胞增多症的患者中PTLD更为常见（66%对比8.4%，P=0.0005）。数据还支持移植后原发性EB病毒（EBV）感染与PTLD发生之间存在关联。虽然移植前仅有3例患者EBV血清学检测呈阳性（14%），但在诊断PTLD时19例患者EBV血清学检测呈阳性（90%），证实PTLD患者中原发性EBV感染的发生率很高（21例患者有移植前和移植后EBV血清学检测结果）。在本系列研究中，PTLD的死亡率为60%，15例死亡患者中有12例在死亡时肿瘤持续存在。13例疾病缓解的患者中有5例发生了胆管缺如性排斥反应。4例有严重肝功能障碍的患者中，2例已成功接受再次移植且存活，无PTLD证据。总之，使用OKT3和他克莫司作为挽救药物进行强化免疫抑制与PTLD发生率的显著增加相关。移植后原发性EBV感染进一步加重了这种风险。独立于这些危险因素之外，朗格汉斯细胞组织细胞增多症患者发生PTLD的风险显著增加。识别高危患者应有助于制定方案，对患者进行原发性EBV感染筛查及PTLD的早期指征筛查，以及实施预防性抗病毒和抗肿瘤治疗。
