Dynamic monitoring of plasma Epstein-Barr Virus DNA load can predict the occurrence of lymphoproliferative disorders after haploidentical hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To determine the optimal cutoff value of Epstein-Barr virus (EBV) DNA load that can assist in the diagnosis of post-transplant lymphoproliferative disease (PTLD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) . Methods: The data of patients with EBV infection after haplo-HSCT from January to December 2016 were retrospectively analyzed. Through constructing the receiver operating characteristic (ROC) curve and calculating the Youden index to determine the cutoff value of EBV-DNA load and its duration of diagnostic significance for PTLD. Results: A total of 94 patients were included, of whom 20 (21.3% ) developed PTLD, with a median onset time of 56 (40-309) d after transplantation. The median EBV value at the time of diagnosis of PTLD was 70,400 (1,710-1,370,000) copies/ml, and the median duration of EBV viremia was 23.5 (4-490) d. Binary logistic regression was used to analyze the peak EBV-DNA load (the EBV-DNA load at the time of diagnosis in the PTLD group) and duration of EBV viremia between the PTLD and non-PTLD groups. The results showed that the difference between the two groups was statistically significant (P=0.018 and P=0.001) . The ROC curve was constructed to calculate the Youden index, and it was concluded that the EBV-DNA load ≥ 41 850 copies/ml after allogeneic hematopoietic stem cell transplantation had diagnostic significance for PTLD (AUC=0.847) , and the sensitivity and specificity were 0.611 and 0.932, respectively. The duration of EBV viremia of ≥20.5 d had diagnostic significance for PTLD (AUC=0.833) , with a sensitivity and specificity of 0.778 and 0.795, respectively. Conclusion: Dynamic monitoring of EBV load in high-risk patients with PTLD after haplo-HSCT and attention to its duration have important clinical significance, which can help clinically predict the occurrence of PTLD in advance and take early intervention measures.

Progress in diagnosis and treatment of Epstein-Barr virus associated lymphoproliferative disease after solid organ transplantation in children / 国际儿科学杂志

Post transplant lymphoproliferative disease(PTLD)is one of the most serious malignant complication in children after solid organ transplantation.Immunosuppression after transplantation and Epstein-Barr virus infection are the two main reasons for the onset of PTLD.The diagnosis of the disease depends on pathology, which includes early lesions, monomorphic PTLD, polymorphic PTLD and Hodgkin′s lymphoma PTLD.The treatment includes reduction in immunosuppression, rituximab, chemotherapy, radiotherapy and surgery, etc.The selection of chemotherapy mainly depends on pathology.The advance in the management of PTLD will be reviewed in the manuscript.

Post-Transplant Lymphoproliferative Diseases in Pediatric Kidney Allograft Recipients with Epstein-Barr Virus Viremia

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is one of the major complications of organ transplantation, especially in children with Epstein-Barr virus (EBV) viremia (EV). We performed a retrospective study to evaluate risk factors for PTLD in children with EV. METHODS: Among 199 pediatric kidney transplantation (KT) recipients at our center from January 2001 to October 2015, records of those with EBV viral loads of > 1,000 copies/mL and/or PTLD were reviewed. RESULTS: Diagnosis of PTLD was made in seven patients (PTLD group), and 39 patients had EV only (EV only group). The median time from KT to EV and PTLD diagnosis was 6.7 (range 0.4–47.8) months and 8.2 (range, 2.8–98.9) months, respectively. There were no significant differences between the groups in terms of sex, age at transplantation, donor type, EBV viral load, or EV-free duration after KT. Higher tacrolimus level before EV (hazard ratio, 44.5; P = 0.003) was an independent risk factor for PTLD in multivariate Cox regression analysis. Six patients with a high EBV load (median 171,639 copies/mL) were treated with preemptive rituximab (RTX) therapy, resulting in transient reduction of EBV load. None of these patients developed PTLD (median follow-up 51.5 months); however, two had neutropenia and two developed infection requiring hospital admission. CONCLUSION: In pediatric KT recipients, higher tacrolimus levels were associated with a higher incidence of PTLD. Conversely, those who received preemptive RTX for EV did not develop PTLD.

Recent advances in the risk factors, diagnosis and management of Epstein-Barr virus post-transplant lymphoproliferative disease / Avances recientes en los factores de riesgo, diagnóstico y tratamiento de la enfermedad linfoproliferativa post trasplante con infección por virus de Epstein-Barr

Fifty years after the first reports of Epstein-Barr virus (EBV)-associated endemic Burkitt's lymphoma, EBV has emerged as the third most prevalent oncogenic virus worldwide. EBV infection is associated with various malignancies including Hodgkin and non-Hodgkin lymphoma, NK/T-cell lymphoma and nasopharyngeal carcinoma. Despite the highly specific immunologic control in the immunocompetent host, EBV can cause severe complications in the immunocompromised host (namely, post-transplant lymphoproliferative disease). This is particularly a problem in patients with delayed immune reconstitution post-hematopoietic stem cell transplant or solid organ transplant. Despite advances in diagnostic techniques and treatment algorithms allowing earlier identification and treatment of patients at highest risk, mortality rates remain as high as 90% if not treated early. The cornerstones of treatment include reduction in immunosuppression and in vivo B cell depletion with an anti-CD20 monoclonal antibody. However, these treatment modalities are not always feasible due to graft rejection, emergence of graft vs. host disease, and toxicity. Newer treatment modalities include the use of adoptive T cell therapy, which has shown promising results in various EBV-related malignancies. In this article we will review recent advances in risk factors, diagnosis and management of EBV-associated malignancies, particularly post-transplant lymphoproliferative disease. We will also discuss new and innovative treatment options including adoptive T cell therapy as well as management of special situations such as chronic active EBV and EBV-associated hemophagocytic lymphohistiocytosis.

A cincuenta años de los primeros reportes de asociación del linfoma de Burkitt con el virus de Epstein-Barr (VEB), el VEB ha emergido como el tercer virus de tipo oncogénico con mayor prevalencia a escala mundial. La infección por VEB se asocia con diversas neoplasias, incluyendo el linfoma de Hodgkin y el no Hodgkin, linfoma de células T/NK y carcinoma nasofaríngeo. A pesar del control inmunológico altamente específico en el huésped inmunocompetente, el VEB puede ocasionar complicaciones severas en el huésped inmunocomprometido (es decir, la enfermedad linfoproliferativa post-trasplante). Esto es un problema particularmente en pacientes en quienes se retrasa la reconstitución de la inmunidad después de un trasplante de células madre hematopoyéticas o un trasplante de órganos sólidos. A pesar de los avances en las técnicas de diagnóstico y los algoritmos de tratamiento que permiten la identificación temprana y el tratamiento de pacientes de alto riesgo, las tasas mortalidad siguen siendo muy altas (del 90%) si no se recibe tratamiento temprano. La piedra angular del tratamiento incluye la disminución de la inmunosupresión y la depleción de células B in vivo con un anticuerpo monoclonal anti-CD20. Sin embargo, estas modalidades de tratamiento no son siempre posibles debido al rechazo del injerto, la enfermedad de injerto contra huésped y la toxicidad. Nuevas modalidades de tratamiento incluyen el uso de la terapia adoptiva de células T, que ha mostrado resultados promisorios en diversas neoplasias relacionadas con el VEB. En este artículo se revisan los avances más recientes en cuanto a los factores de riesgo, diagnóstico y tratamiento de las neoplasias asociadas con VEB, particularmente la enfermedad linfoproliferativa post-trasplante. También se discuten los tratamientos más recientes e innovadores, que incluyen la terapia adoptiva de células T así como el manejo de situaciones especiales, como la infección crónica activa de VEB y la linfohistiocitosis hemafagocítica asociada con VEB.

Pediatric Liver Transplantation

Pediatric liver transplantation has evolved into a definite and effective therapeutic modality for various liver diseases in the pediatric patient. During the last 25 years, liver transplant outcomes in Korea have reached international standards and Korea has become the leader in living-donor liver transplantation. This review will present the cumulative outcomes of pediatric liver transplantation performed in Korea and will focus on other issues of interest involving pediatric liver transplant recipients, especially in the field of immunosuppression and post-transplant lymphoproliferative disease.

Profilaxis de enfermedad por virus de Epstein Barr en niños y adultos receptores de trasplante de órganos sólidos y de precursores hematopoyéticos / Prophylaxis against Epstein Barr disease in pediatric and adult patients undergoing solid organ and hematopoietic stem cells transplantation

Post transplant lymphoproliferative disease (PTLD) associated with EBV infection is one of the most life-threatening complications in SOT and HSCT. Risk factors for infection or reactivation of EBV in SOT are the use of greater immunosuppression, seronegative receptor and CMV infection. In HSCT, the risk factors are related to type of transplant, HLA disparity, the greater immunosuppression, T-cell depletion and severe GVHD. There is no scientific evidence to support the use of specific therapy for prophylaxis of EBV infection. Prophylaxis recommendations focus on avoid exposure of transplant recipients to sources of virus, through hygiene practices such as hand washing (A3), avoid sharing utensils (B3) and avoid contact with potentially infected secretions (respiratory or saliva) (A2). For PTLD prevention, the recommendation is regular EBV viral load monitoring by rtPCR. In SOT with logarithmic rising of EBV loads, it is recommended to reduce immunosuppression and periodically perform exams to diagnose PTLD. In HSCT, it is recommended to reduce immunosuppression whenever possible, and use rituximab according to speciic protocol. Acyclovir or gancyclovir have not proven to be of any eficacy in PTLD prophylaxis in SOT (C3) or HSCT (D2), so their administration as preemptive therapy is no recommended.

El síndrome linfoproliferativo (SLP) asociado a VEB constituye una grave complicación en TOS y en TPH. Los factores de riesgo de infección o reactivación de VEB en TOS son el uso de mayor inmunosupresión, la seronegatividad del receptor previa al trasplante y la infección por CMV. En TPH se consideran factores de riesgo el tipo de trasplante, disparidad HLA, mayor inmunosupresión, depleción linfocitaria y enfermedad injerto contra hospedero (EICH) grave. No hay evidencia cientíica que apoye el uso de medidas especíicas de proilaxis en prevención de infección por VEB. Se recomienda evitar la exposición a fuentes del virus de los candidatos a trasplantes a través de prácticas de higiene tales como lavado de manos (A3), evitar el compartir utensilios (B3) y evitar el contacto con potenciales secreciones infectadas (respiratorias o saliva) (A2). Para la prevención de SLP, se recomienda un esquema de monitoreo periódico de carga viral de VEB por RPC-TR. En el caso de TOS con cargas de VEB en ascenso logarítmico, se recomienda disminuir inmuno-supresión y buscar activa y periódicamente la aparición de SLP. En TPH, se recomienda, en lo posible, disminuir la inmunosupresión y se reserva el uso de rituximab para casos especíicos según protocolo. El uso de aciclovir o ganciclovir no han demostrado constituir medidas profilácticas efectivas en TOS (C3) ni en TPH (D2), no siendo recomendada su administración en esquemas de terapia anticipada.

Post-transplant Lymphoproliferative Disorder Arising from Renal Allograft Parenchyma: A Case Report

Post-transplant lymphoproliferative disorder (PTLD) is a rare but serious complication that occurs in patients undergoing kidney transplantation. PTLD usually manifests as a renal hilar mass comprised of histologically B-lymphocytes. We report our experience of managing a patient with PTLD arising from renal parenchyma. Ultrasonographic and MR imaging features of this unusual PTLD suggested differentiated renal cell carcinoma arising from the renal allograft.

Two Cases of Post Transplant Lymphoproliferative Disorder in Lung Transplant Recipients

Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after solid organ transplantation. The incidence of PTLD is greater among heart (2~13%), lung (12%) and heart/lung (5~9%) transplant recipients than among liver (2%), renal (1~3%) and bone marrow (1~2%) transplants recipients. The difference in the incidence of PTLD may be partly attributed to the higher dose of immunosuppressant therapy used for heart and lung transplantation. The Epstein-Barr virus (EBV) infection status of the donor and recipient before a transplant, and high dose of immunosuppressive drugs are considered major risk factors. Recently, 2 cases of PTLD in a single lung and a heart-lung transplantation recipient were encountered. Both patients presented with multiple pulmonary nodules in the transplanted lung, which developed 6 months and 2 years after the transplantation, respectively. Following a transthoracic lung biopsy for diagnostic confirmation, one patient underwent chemotherapy for PTLD and the other conservative care for an accompanying viral infection. Both patients showed rapid clinical deterioration, without response to treatment, and then rapidly succumbed. Herein, our experiences are reported, with a review of the literature.