Erik Verschuuren

The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update

Mandeep R. Mehra, MD (Chair), Charles E. Canter, MD, Margaret M. Hannan, MD, Marc J. Semigran, MD, Patricia A. Uber, PharmD, David A. Baran, MD, Lara Danziger-Isakov, MD, MPH, James K. Kirklin, MD, Richard Kirk, MD, Sudhir S. Kushwaha, MD, Lars H. Lund, MD, PhD, Luciano Potena, MD, PhD, Heather J. Ross, MD, David O. Taylor, MD, Erik A.M. Verschuuren, MD, PhD, Andreas Zuckermann, MD and on behalf of the International Society for Heart Lung Transplantation (ISHLT) Infectious Diseases, Pediatric and Heart Failure and Transplantation Councils

Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD)

Post‐transplant lymphoproliferative disorders (PTLD) are a life‐threatening complication following solid organ transplantation. Treatment with rituximab, a humanized anti‐CD20 monoclonal antibody, has proved to be a promising approach and shown a low toxicity profile. Between February 1999 and April 2002, we conducted a multicentre phase II trial investigating rituximab as single agent in 17 patients with PTLD. Transplanted organs were heart (n = 5), kidney (n = 4), lung (n = 4) and liver (n = 4). Patients were treated with four weekly doses of 375 mg/m2 of rituximab. The mean follow‐up time is 24.2 months. Histology was distributed in 10 diffuse large cell‐, 2 marginal zone‐, 1 Burkitt‐like lymphoma, 1 Hodgkin‐like PTLD and 3 polymorphic lymphoproliferations. Therapy was well tolerated and no severe adverse events were observed. The mean overall survival period is 37.0 months with 11 patients still living. In total, 9 patients (52.9%) achieved a complete remission, with a mean duration of 17.8 months. Partial remission was observed in 1 patient, minor remission in 2 patients, no change in 3 patients and 1 patient experienced progressive disease. Two patients relapsed, at intervals 3 and 5 months after obtaining complete remission. Rituximab proved to be well tolerated and effective in the treatment of PTLD.

Treatment of posttransplant lymphoproliferative disease with rituximab: the remission, the relapse, and the complication.

BACKGROUND Rituximab, a humanized anti-CD20 monoclonal antibody, is a promising new tool for the treatment of posttransplant lymphoproliferative disease (PTLD), especially for patients transplanted with rejection prone transplants of vital organs, such as patients after lung transplantation. Thus far, no major complications have been described. We treated three lung transplant recipients with Rituximab because of PTLD. METHODS Patients were treated with four weekly doses of 375 mg/m2 of Rituximab. Epstein-Barr virus (EBV) DNA was monitored with quantitative-competitive polymerase chain reaction and circulating B cells with flow cytometry. RESULTS Treatment with Rituximab resulted in a complete remission in all patients without signs of or progression of bronchiolitis obliterans syndrome. Patient 1 relapsed after 2 months with a partly CD20-negative PTLD but is in stable remission after radiotherapy. Patient 2 is in complete remission 16 months after treatment, but patient 3 developed a hypogammaglobulinemia and died of invasive aspergillosis after 6 months. EBV DNA was detectable in the blood samples of patients 2 and 3 before treatment with Rituximab and became negative instantly after Rituximab. In all three patients, B cells are absent in the peripheral blood 7 months (at death), 16 months, and 16 months after treatment with Rituximab. Antiproliferating agents, such as mycophenolate mofetil (MMF), might prolong B-cell depletion. CONCLUSIONS Rituximab was effective for the treatment of PTLD without progression of transplant dysfunction in our patients. Complications were a partly CD20-negative relapse of PTLD and a hypogammaglobulinemia. Attention should be paid to immunoglobulin G (IgG) levels, especially in patients treated with antiproliferating agents such as MMF.

Presentation and early detection of post-transplant lymphoproliferative disorder after solid organ transplantation

Post‐transplant lymphoproliferative disorder (PTLD) is a serious and still frequently observed complication of solid organ transplantation. Despite the recent introduction of anti B‐cell monoclonal antibody therapy (rituximab) for treatment of PTLD, mortality rates remain high. Because PTLD often presents in a nonspecific way in clinically unsuspected patients, it is a major challenge to diagnose PTLD at an early stage. Epstein–Barr virus (EBV)‐DNA load monitoring is a promising tool for the identification of patients at risk for PTLD development. However, there are some limitations of this method, and not all patients at risk for PTLD can be identified by EBV‐DNA measurements alone. Therefore, it is of major importance to recognize early clinical signs and symptoms of PTLD. In this review, risk factors for PTLD development, disease presentation, and methods for early detection will be discussed. Special attention is given to allograft and digestive tract localization and the relation with time of onset of PTLD. The value and pitfalls of EBV‐DNA load monitoring are discussed. In addition, because fluorodeoxyglucose (FDG)‐positron emission tomography (PET) has shown to be a powerful tool for staging and response evaluation of malignant lymphoma, the role of FDG‐PET for early diagnosis and staging of PTLD is addressed.

Variable EBV DNA Load Distributions and Heterogeneous EBV mRNA Expression Patterns in the Circulation of Solid Organ versus Stem Cell Transplant Recipients

Epstein-Barr virus (EBV) driven post-transplant lymphoproliferative disease (PTLD) is a heterogeneous and potentially life-threatening condition. Early identification of aberrant EBV activity may prevent progression to B-cell lymphoma. We measured EBV DNA load and RNA profiles in plasma and cellular blood compartments of stem cell transplant (SCT; n = 5), solid organ transplant recipients (SOT; n = 15), and SOT having chronic elevated EBV-DNA load (n = 12). In SCT, EBV DNA was heterogeneously distributed, either in plasma or leukocytes or both. In SOT, EBV DNA load was always cell associated, predominantly in B cells, but occasionally in T cells (CD4 and CD8) or monocytes. All SCT with cell-associated EBV DNA showed BARTs and EBNA1 expression, while LMP1 and LMP2 mRNA was found in 1 and 3 cases, respectively. In SOT, expression of BARTs was detected in all leukocyte samples. LMP2 and EBNA1 mRNA was found in 5/15 and 2/15, respectively, but LMP1 mRNA in only 1, coinciding with severe PTLD and high EBV DNA. Conclusion: EBV DNA is differently distributed between white cells and plasma in SOT versus SCT. EBV RNA profiling in blood is feasible and may have added value for understanding pathogenic virus activity in patients with elevated EBV-DNA.

Role of Epstein-Barr virus DNA load monitoring in prevention and early detection of post-transplant lymphoproliferative disease

Posttransplant lymphoproliferative disease (PTLD) is a severe and life-threatening complication after stem cell or solid-organ transplantation, virtually always associated with presence of Epstein-Barr virus (EBV) in the proliferating cells. PTLD is probably caused by the iatrogenically impaired T-cell response allowing outgrowth of EBV-positive B-cells. Quantitative EBV DNA load monitoring is a minimally invasive technique increasingly recognized as a valuable tool in posttransplant patient management. In this review, we focus on the clinical utility of EBV DNA load monitoring in the peripheral blood of transplant recipients using PCR and we discuss the currently most-widely used techniques and their value and limitations in predicting and diagnosing PTLD. Options for EBV DNA load-guided pre-emptive therapy and application of monitoring EBV DNA load dynamics in the prediction of clinical response after therapy are described. Origins of elevated EBV DNA loads in immunosuppressed patients and recent insights in the EBV life cycle in the immuncompromised host are discussed. Finally, a standardization of methodology, clinical specimen type, and cut-off values is proposed. This is essential for comparisons between different institutes and more adequate patient management.

Epstein-Barr virus-DNA load monitoring late after lung transplantation: A surrogate marker of the degree of immunosuppression and a safe guide to reduce immunosuppression

Background. Posttransplant lymphoproliferative disease (PTLD) is a serious complication after lung transplantation and its relation with Epstein-Barr virus (EBV) is well recognized. It has been postulated that preemptive reduction of immunosuppression guided by EBV-DNA load may lead to a significantly lower incidence of PTLD, because of the reconstitution of T-cell control. In this report, we describe the feasibility of this approach in terms of safety with regard to the risk of acute as well as chronic allograft rejection in 75 lung transplant recipients transplanted between 1990 and 2001 and followed for this study from June 1, 2001 until January 1, 2006. Methods. From all patients visiting our outpatient clinic, EBV-DNA load was measured at least twice a year during the study period. In patients with positive results, measurements were repeated every two to four weeks. EBV reactivation was defined as two consecutive EBV-DNA load measurements with a rising trend; with the last measurement exceeding 10.000 copies/mL under stable immunosuppression. In such case, immunosuppression was reduced. Results. EBV reactivation was observed in 26/75 patients (35%). One (1.5%) of these patients developed PTLD during the study period. Acute rejection, acceleration of chronic allograft rejection, or worse survival were not observed after reduction of immunosuppression. Conclusions. Preemptive reduction of immunosuppression after lung transplantation guided by EBV-DNA load appears to be a safe approach for the prevention of PTLD in lung transplant recipients late after transplantation.

Early onset post-transplant lymphoproliferative disease is associated with allograft localization.

Abstract:  Post‐transplant lymphoproliferative disease (PTLD) is a major complication after solid organ transplantation. We analyzed incidence, patient characteristics, clinical presentation, and prognostic factors for treatment outcome and survival of PTLD patients transplanted at our center. Records from adult kidney and lung transplant recipients, transplanted between January 1985 and December 2002 with a histologically confirmed diagnosis of PTLD, were retrieved. Histology was reviewed and prognostic factors for treatment outcome were evaluated by multivariable analysis. Of 1354 kidney and 206 lung transplants, PTLD was diagnosed in 40 transplant recipients (2.6%). Lung transplant recipients had a significantly higher incidence of PTLD (8.3%) than kidney transplant recipients (1.7%). Sites of presentation were highly heterogeneous. Notably, PTLD localized in the allograft occurred significantly earlier after transplantation than PTLD localized outside the allograft (p = 0.001). This was true for lung (p = 0.006) as well as for kidney transplant recipients (p = 0.03). In multivariable Cox regression, performance status (p = 0.01) and advanced stage (p = 0.04) were factors negatively predictive for response to first‐line treatment. Only performance status remained as negative predictive factor for survival (p = 0.002) and freedom from tumor progression (p = 0.01). In conclusion, the allograft is significantly more often involved as primary site of PTLD presentation during the first post‐transplant year. This may have clinical consequences and give new insights in pathogenesis of PTLD. Performance status and stage are important risk factors for outcome of PTLD.

Lung Transplantation from Nonheparinized Category III Non-Heart-Beating Donors. A Single-Centre Report

Background. Despite the increasing use of extended lung donors, the shortage of lung donors remains. Usage of non-heart-beating (NHB) lung donors contributes to fight this shortage. We describe our experience in 21 consecutive adult lung transplantations using nonheparinized category III NHB donors and standard flush preservation. Methods. From January 2005 to December 2008, we collected donor and recipient data of all NHB category III lung transplantations performed in our center. For comparison, we also collected the data of all heart-beating (HB) lung transplantations in the same period. We focused on data describing the donor, the donor procedure, the recipients primary graft dysfunction, survival, rejection episodes, and the lung graft function. Results. Twenty-one NHB and 77 HB lung transplantations were performed. Circulation arrest occurred after 14 (4–62) min and warm ischemia time was 30 (19–44) min. Occurrence of primary graft dysfunction, acute rejection episodes, development of bronchiolitis obliterans syndrome was equal to the HB cohort as was the 2 years survival of 95% in the NHB group compared with 86% in the HB group. Lung graft function during the first 2 years tended to be better preserved in the NHB group. Conclusion. Category III NHB lung donation is a good alternative in addition to HB lung donation. Using nonheparinized category III NHB donors and standard ante- and retrograde, flush perfusion resulted in good lung graft function and survival. NHB donation offers a great opportunity to reduce the burden of donor lung shortage.

Lung Transplantation for Cystic Fibrosis

Lung transplantation is a complex, high-risk, potentially life-saving therapy for the end-stage lung disease of cystic fibrosis (CF). The decision to pursue transplantation involves comparing the likelihood of survival with and without transplantation as well as assessing the effect of wait-listing and transplantation on the patients quality of life. Although recent population-based analyses of the US lung allocation system for the CF population have raised controversies about the survival benefits of transplantation, studies from the United Kingdom and Canada have suggested a definite survival advantage for those receiving transplants. In response to these and other controversies, leaders in transplantation and CF met together in Lansdowne, Virginia, to consider the state of the art in lung transplantation for CF in an international context, focusing on advances in surgical technique, measurement of outcomes, use of prognostic criteria, variations in local control over listing, and prioritization among the United States, Canada, the United Kingdom, and The Netherlands, patient adherence before and after transplantation and other issues in the broader context of lung transplantation. Finally, the conference members carefully considered how efforts to improve outcomes for lung transplantation for CF lung disease might best be studied. This Roundtable seeks to communicate the substance of our discussions.