Development Of Post-transplant Lymphoproliferative Disease Research Articles

Identifying predictive factors for posttransplant lymphoproliferative disease in pediatric solid organ transplant recipients with Epstein-Barr virus viremia.

Epstein-Barr virus (EBV) viremia (EV) in pediatric solid organ transplant (SOT) recipients is a significant risk factor for posttransplant lymphoproliferative disease (PTLD) but not all patients with EV develop PTLD. We identify predictive factors for PTLD in patients with EV. We conducted a retrospective chart review of all pediatric SOT recipients (0 to 21 y) at a single institution between 2001 and 2009. A total of 350 pediatric patients received a SOT and 90 (25.7%) developed EV. Of EV patients, 28 (31%) developed PTLD. The median age at transplant was 11.5 months in the PTLD group and 21.5 months in the EV-only group (P=0.003). Twenty-three (37%) EV-only patients had immunosuppression increased before EV, compared with 28 (100%) of PTLD patients (P<0.001). The median peak EBV level was 3212 EBV copies/10 lymphocytes for EV-only and 8392.5 EBV copies/10 lymphocytes for PTLD (P=0.005). All patients who developed PTLD had ≥1 clinical symptoms. Younger age at transplant, increased immunosuppression before EV, higher peak EBV level, and presence of clinical symptoms have predictive value in the development of PTLD in SOT patients with EV.

Determination of EBV serostatus prior to kidney transplantation: Comparison of VIDAS®, LIAISON® and immunofluorescence assays

Immunosuppression following solid organ transplantation reduces T cell-mediated immune control of Epstein–Barr Virus (EBV), which may then drive development of post-transplant lymphoproliferative disease. Serology plays a key role in determination of risk of outgrowth of such lesions following transplantation.The study compared the VIDAS® (bioMérieux) and LIAISON® (DiaSorin) enzyme immunoassays (EIAs) and immunofluorescence assays (IFA; MBL-Bion) in the kidney transplantation setting. Sera from 100 live kidney donors [51 males; age range 20–82 years (mean 51.2 years)] and 100 cadaveric kidney recipients [70 males; age range 17–77 years (mean 51.0 years)] were tested. Overall proportional agreement ranged from 96% to 100% for VIDAS® and LIAISON®. Sensitivity ranged from 91% to 100% and 92% to 100% for VIDAS®/IFA and LIAISON®/IFA, respectively.The VIDAS® and LIAISON® approaches gave similar results. Such automated random access EIAs are well suited to busy clinical virology laboratories and rapid determination of donor and recipient EBV serostatus prior to transplantation.

Ultra-early onset post-transplantation Lymphoproliferative disease

Post-transplant lymphoproliferative disease (PTLD) can present as early as days to as late as several decades after transplantation. This study, however, tries to research PTLD characteristics including histopathological and clinical features, predictors and prognosis of the disease when occurring within the first month post-transplantation. We conducted a comprehensive search for the available data using the Pubmed and Google scholar search engines for reports indicating presentation time in PTLD patients. Data from 25 previously published studies were included in the analysis. Finally, we found 355 recipients of organs presenting with "ultra-early onset PTLD." Transplant recipients with ultra-early onset PTLD were significantly more likely to have kidney allografts (P = 0.032). Transplant recipients with ultra-early onset PTLD were comparable to their counterparts in the control group in their demographics, histopathological findings and survival. Patients with ultra-early onset PTLD were significantly more likely to receive induction therapy (100% vs. 49%, respectively; P = 0.013). Pancreas transplant recipients were at a significantly higher risk for development of ultra-early onset PTLD (20% vs. 1%, respectively; P <0.001). Our findings emphasize the importance of immunosuppression potency as well as the type of allograft transplanted on the incidence of PTLD in the early stages after transplantation. However, we found no histopathological or outcome disparities for patients with ultra-early PTLD compared with controls. Further prospective studies with more comparable approaches to the patients are needed to confirm our findings.

Posttransplant Lymphoproliferative Disease after Pediatric Solid Organ Transplantation

Patients after solid organ transplantation (SOT) carry a substantially increased risk to develop malignant lymphomas. This is in part due to the immunosuppression required to maintain the function of the organ graft. Depending on the transplanted organ, up to 15% of pediatric transplant recipients acquire posttransplant lymphoproliferative disease (PTLD), and eventually 20% of those succumb to the disease. Early diagnosis of PTLD is often hampered by the unspecific symptoms and the difficult differential diagnosis, which includes atypical infections as well as graft rejection. Treatment of PTLD is limited by the high vulnerability towards antineoplastic chemotherapy in transplanted children. However, new treatment strategies and especially the introduction of the monoclonal anti-CD20 antibody rituximab have dramatically improved outcomes of PTLD. This review discusses risk factors for the development of PTLD in children, summarizes current approaches to therapy, and gives an outlook on developing new treatment modalities like targeted therapy with virus-specific T cells. Finally, monitoring strategies are evaluated.

A 16-Year Multi-Institutional Study of the Role of Age and EBV Status on PTLD Incidence Among Pediatric Heart Transplant Recipients

The objective was to determine the incidence and hazard for posttransplant lymphoproliferative disease (PTLD) in a study of 3170 pediatric primary heart transplants between 1993 and 2009 at 35 institutions in the Pediatric Heart Transplant Study. 147 of 151 reported malignancy events were classified as PTLD. Overall freedom from PTLD was 98.5% at 1 year, 94% at 5 years and 90% at 10 years. Freedom from PTLD was lowest in children (ages 1 to < 10 years) versus infants (<1 year) and adolescents (10 to < 18 years) with children at highest risk for PTLD with a relative risk of 2.4 compared to infants and 1.7 compared to adolescents. Positive donor EBV status was a strong risk factor for PTLD in the seronegative recipient, but risk magnitude was dependent on recipient age at the time of transplantation. Nearly 25% of EBV seronegative recipients of EBV+ donors at ages 4-7 at transplantation developed some form of PTLD. The overall risk for PTLD declined in the most recent transplant era (2001-2009, p = 0.003). These findings indicate that EBV status and the age of the recipient at the time of transplantation are important variables in the development of PTLD in the pediatric heart transplant recipient.

Pre-Emptive Rituximab for the Prevention of EBV-Related PTLD in Umbilical Cord Blood Transplantion Patients

Abstract 3031 Objective:We observed a high rate of Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disease (PTLD) in our umbilical cord blood transplantation (UCBT) patients. We retrospectively analyzed all UBCTs performed at our institution in order to 1) define risk factors for the development of PTLD and 2) assess whether pre-emptive therapy with rituximab (RTX) altered the incidence and outcomes of PTLD in patients with EBV viremia. Patients and Methods:One hundred twenty-seven patients underwent UCBTs, with primarily double cord units, between March 2003 and April 2010. EBV viral loads were monitored by quantitative PCR. Viremia was defined as any detectable level of EBV DNA in peripheral blood. EBV events included all cases of isolated viremia, sustained viremia (≥ 2 positive viral loads on two separate dates), or biopsy/autopsy proven PTLD. One to four weekly doses of RTX (375mg/m2) were given pre-emptively to prevent PTLD in patients with sustained viremia. The frequency of monitoring, the decision to treat with RTX and the duration of treatment were at the clinician’s discretion. Fisher’s exact test and Cox modeling were used to evaluate the effect of clinical variables on the probability of developing PTLD. Results:Cohort Characteristics: Ninety-nine of 127 patients (77%) underwent reduced-intensity conditioning (RIC) transplantion. Eighty-five (86%) of those who received RIC transplants were conditioned with fludarabine, melphalan and anti-thymocyte globulin (ATG). Seventy-nine of the 99 patients (80%) who underwent RIC transplantation received ATG doses at 6mg/kg or greater.PTLD rate and risk factors: Thirty-three patients (26%) had an EBV event. 9 patients (7%) had isolated viremia. No patient with isolated viremia was treated with RTX and none developed PTLD. 11 patients developed sustained viremia but not PTLD. Thirteen patients (10%) had biopsy-proven PTLD, a one-year cumulative probability of 12% (95% CI, 0.08–0.15). All patients who developed PTLD underwent RIC transplant and received at least 6mg/kg of ATG. ATG use was found to be a statistically significant risk factor for PTLD (p = 0.02) yet ATG use was not associated with decreased survival. Age, primary disease, degree of HLA match, graft-versus-host disease (GVHD) and type of GVHD prophylaxis were not identified as PTLD risk factors.Effect of pre-emptive rituximab: 14 patients developed sustained viremia and did not have clinical evidence of PTLD at the time viremia was detected (12%). Twelve of these patients were treated pre-emptively with RTX. EBV DNA became undetectable in 9 of 12 (67%) of these patients, none of whom developed PTLD. EBV viremia resolved in 1 patient without RTX; this patient did not develop PTLD. One patient died of other causes before RTX could be given. Viremia initially cleared in one patient who later progressed to PTLD but achieved complete remission after treatment with virus-specific cytotoxic T-lymphocytes (CTL). Viremia did not resolve in 2 patients, both of whom developed PTLD. Despite treatment with virus-specific CTL both died of PTLD.The adjusted hazard ratio (HR) for the development of PTLD among patients with sustained viremia was 230 (95% CI, 29–1856); the adjusted HR of pre-emptive rituximab was 0.24 (95% CI, 0.07 – 0.9). Conclusions:ATG doses of 6mg/kg or greater were associated with PTLD in the UBCT population. Isolated EBV viremia was not a risk factor for the development of PTLD. Sustained EBV viremia conferred considerable risk. This risk of developing PTLD in patients with sustained viremia was reduced when RTX was given as pre-emptive therapy in this cohort. Further studies to better define the optimal duration of RTX therapy are needed. Prophylactic immune reconstitution with closely HLA-matched virus-specific CTL may also be an alternative option in this high-risk population. Disclosures:No relevant conflicts of interest to declare.

Risk factors for post‐transplant lymphoproliferative disease in patients with cystic fibrosis

The objective of this study was to retrospectively analyze risk factors associated with post-transplant lymphoproliferative disease (PTLD) in a cohort of 112 lung transplant recipients with cystic fibrosis (CF). Prior to transplantation, patients were tested for Epstein-Barr virus (EBV), human herpesvirus (HHV types 1, 2, 3, 6, and 8), herpes zoster virus, and cytomegalovirus (CMV) serologies. PTLD diagnosis was established based on increased EBV viral charge plus clinical/radiographic findings and confirmed by biopsy. Negative EBV and HHV serologies at the time of lung transplantation (LTx) were significant risk factors associated with development of PTLD in patients with CF in the univariate logistic regression analysis (p < 0.05) and also in the multivariate analysis (odds ratio of 77.5 and 12.5, respectively). CMV serology, CMV mismatch, acute rejection in the first three months following LTx, HLA-A3 antigen expression, and female gender did not affect PTLD. Our study confirmed the presence of a strong association between negative EBV serology at the time of LTx and PTLD and suggested an independent effect of negative HHV serology on PTLD.

Clinical characteristics, outcome and the role of viral load in nontransplant patients with Epstein--Barr viraemia

Epstein--Barr virus (EBV) is important in the development of post-transplant lymphoproliferative disease in allogeneic stem cell and solid organ transplant recipients. We have studied the clinical significance of EBV DNAaemia among nontransplant patients in a tertiary referral hospital. We retrospectively reviewed the medical records for main diagnosis, outcome, immunosuppressive/cytotoxic chemotherapy and other opportunistic infections of the patients who were found -positive in quantitative real-time PCR assay for EBV (EBV-qPCR) between the years 2000 and 2007. Allogeneic stem cell and solid organ transplant recipients were excluded, and all patients in nonsurgical adult wards were included. Altogether, 62 patients had at least one plasma sample -positive with an EBV-qPCR. Fifteen were immunocompetent, most had primary EBV infection, and the outcome was good. On the other hand, 36 had malignant disease, seven had HIV infection and seven had immunosuppressive conditions of an other aetiology. All but one of the malignancies were of lymphoid origin, and most of these patients had a history of multiple cytotoxic treatments. Immunosuppressed patients had higher viral loads. EBV viraemia is associated with severe immunosuppression and lymphoid malignancies.

Liver transplanted patients with preoperative autoimmune hepatitis and immunological disorders are at increased risk for Post-Transplant Lymphoproliferative Disease (PTLD)

Background Long term immunosuppression and therapy of acute rejections result in a 20–120-fold increased risk to develop Non Hodgkin lymphoma (NHL). Since immunosuppressive therapy and immunological disorders are major risk factors for the development of NHL in the non-transplant population we aimed to analyze risk factors for PTLD in our cohort of liver transplanted (LT) patients. Methods We analyzed retrospectively 431 patients liver transplanted between 1998 and 2008. Results PTLD was diagnosed in eleven of 431 patients (2.6%). PTLD, especially late PTLD, was significantly more frequent in patients who received steroids before LT (Kaplan–Meier: p < 0.001). Moreover PTLD in immunocompromised patients with preoperative steroid treatment occurred at a significantly younger age (49.5 ± 4.7 years) compared to patients without steroids (60.6 ± 5.1 years; p = 0.006). Multivariate analysis revealed pretransplant steroid treatment and liver transplantation for autoimmune hepatitis as main risk factors for the development of PTLD after liver transplantation ( p < 0.001). Conclusion Liver transplanted patients who received steroids before LT due to immunological disorders and patients with autoimmune hepatitis seem to be at particular high risk to develop PTLD. Prospective cohort studies including immunoepidemiologic investigations of abnormalities of cellular, humoral and innate immunity should be carried out to identify predictive factors and patients at risk.

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Tumour necrosis factor gene polymorphism: a predictive factor for the development of post-transplant lymphoproliferative disease

Background:Epstein–Barr virus-positive post-transplant lymphoproliferative disease (PTLD) is a potentially lethal complication of iatrogenic immunosupression after transplantation. Predicting the development of PTLD allowing early and effective intervention is therefore of importance. Polymorphisms within cytokine genes are implicated in susceptibility to, and progression of, disease however the published data are often conflicting. We undertook investigation of polymorphic alleles within cytokine genes in PTLD and non-PTLD transplant cohorts to determine risk factors for disease.Methods:SSP-PCR was used to analyse single nucleotide polymorphism within tumour necrosis factor (TNF)-α, interleukin- 1, -6, -10 and lymphotoxin-α genes. The TNF-α levels were measured by standard enzyme-linked immuno-absorbant assay.Results:We show an association between variant alleles within the TNF-α promoter (−1031C (P=0.005)); −863A (P=0.0001) and TNF receptor I promoter regions (−201T (P=0.02)); −1135C (P=0.03) with the development of PTLD. We also show an association with TNF-α promoter haplotypes with haplotype-3 significantly increased (P=0.0001) and haplotype-1 decreased (P=0.02) in PTLD patients compared to transplant controls. Furthermore, we show a significant increase (P=0.02) in the level of TNF-α in PTLD patient plasma (range 0–97.97 pg ml−1) compared to transplant controls (0–8.147 pg ml−1), with the highest levels found in individuals carrying the variant alleles.Conclusion:We suggest that genetic variation within TNF-α loci and the level of plasma cytokine could be used as a predictive risk factor for the development of PTLD.

Hepatitis B virus reactivation is a risk factor for development of post‐transplant lymphoproliferative disease after liver transplantation

Post-transplant lymphoproliferative disease (PTLD) is believed to be associated with immunosuppressive regimens, underlying diseases and lymphotropic viral infections after organ transplantation. Hepatitis B virus (HBV) has been identified as a risk factor for non-Hodgkin's lymphoma, but no association between HBV and PTLD has been shown. In this study, we reviewed a series of 203 consecutive patients who underwent liver transplantation (LTx) for benign liver disease in our center. The patients comprised 144 patients with hepatitis B and 59 contemporary patients without hepatitis B. After LTx, 36 of the 144 patients with hepatitis B experienced HBV reactivation, while the remaining 108 patients did not. There was no difference in the incidences of PTLD between patients with and without hepatitis B (p = 0.497). Overall, four patients (11.1%) with HBV reactivation developed PTLD, compared to only one patient (0.9%) without HBV reactivation (p = 0.007). The relative odds for developing PTLD in patients with HBV reactivation were 17.5. No differences were observed for the follow-up periods, immunosuppressive regimens and rejection episodes (p > 0.05 for all). These data suggest that PTLD may be more prevalent in patients who experience HBV reactivation after liver transplantation. HBV reactivation may be a risk factor for development of PTLD.

Epstein‐Barr Virus–related Optic Neuritis as a Precursor to the Development of Posttransplant Lymphoproliferative Disease

Epstein‐Barr Virus–related Optic Neuritis as a Precursor to the Development of Posttransplant Lymphoproliferative Disease

Preemptive Management of Epstein-Barr Virus Reactivation After Hematopoietic Stem-Cell Transplantation

Epstein-Barr virus (EBV) reactivation after hematopoietic stem-cell transplantation can lead to posttransplant lymphoproliferative disease (PTLD), which carries a high mortality rate. Among therapeutic and prophylactic options being developed, B-cell depletion with monoclonal antibodies is encouraging. Because viral load after transplantation is correlated with PTLD occurrence, we developed a preemptive attitude based on polymerase chain reaction (PCR)-guided rituximab administration. We monitored 115 transplant patients with a quantitative PCR for EBV DNA performed on whole-blood samples. Criteria for treatment initiation were a single PCR above 40,000 DNA genome copies per milliliter (gCop/mL) or two rising values above 10,000 gCop/mL. Weekly rituximab infusion at the dose of 375 mg/m was administered until negative PCR results were available. We evaluated the incidence of EBV reactivation and PTLD development. Nineteen patients (16.5%) met the criteria for treatment. Incidence of reactivation was the same in high-risk and standard-risk patients (12 vs. 7, P=0.38). One patient developed PTLD after discontinuation of therapy due to a serious adverse event. No other serious adverse events were noticed. Viral load disappeared after a median of three cycles of therapy, and weekly monitoring allowed prompt intervention. No PTLD-related death was observed, all-cause mortality in the treated population was 68%. Our PCR-guided and rituximab-based preemptive approach to avoid PTLD after allogeneic hematopoietic stem-cell transplantation is feasible but probably overtreated patients. Prospective trials are strongly needed, they should use uniform PCR techniques and consider higher threshold values for treatment initiation.

633: Lack of Relationship between Immunosuppression and Epstein-Barr Viral Load/Lymphoproliferative Disease in Pediatric Heart Transplant Recipients

Post-transplant lymphoproliferative disease (PTLD) is a severe complication in pediatric heart transplant (HT) recipients. An high EBV load in the blood of transplant patients may be a significant risk factor for the development of PTLD and reduction of calcineurin inhibitor has been suggested as a treatment option. This study was performed to obtain information about the impact of immunosuppressive medication on the EBV load in pediatric HT patients.

Epstein–Barr virus, rapamycin, and host immune responses

To summarize recent advances that contribute to our understanding of the pathobiology of Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD), the host immune response to virally infected B cells, and the molecular basis for the effects of mammalian target of rapamycin inhibitors on EBV+ B-cell lymphomas. Cytogenetic and genomic analyses support the concept that the underlying biology of EBV-associated PTLD is complex. Transplant recipients can generate and maintain significant populations of EBV-specific CD8+ memory T cells but the function of these cells may be impaired. EBV invokes multiple strategies to subvert and evade the host immune response. The phosphoinositide-3 kinase/Akt/mammalian target of rapamycin signal transduction pathway is a nexus for growth and survival signals in PTLD-associated EBV+ B-cell lymphomas. Multiple factors influence the development of EBV-associated PTLD including the host immune response to EBV, virally induced effects on the infected cell and the host immune system, and the type and intensity of immunosuppression.

Expression of CD20 but Not EBV Is Associated with Significantly Improved Overall (OS) and Event Free Survival (EFS) in Children with Post Transplant Lymphoproliferative Disease (PTLD) Following Solid Organ Transplantation (SOT).

The risk of developing post transplant lymphoproliferative disease (PTLD) following solid organ transplantation (SOT) in children is in large part dependent on the specific organ transplanted and the degree of immune suppression post SOT (Webber et al Lancet 2006; Dharnidharka et al Transplantation 2001; Newell et al Transplantation 1996). However, the importance of expression of CD20 and/or Epstein-Barr virus (EBV) as prognostic factors for development and survival of pediatric PTLD after SOT in young patients are poorly understood. We previously demonstrated the safety and efficacy of cyclophosphamide, prednisone and rituximab (CPR) in CD20+ PTLD (Orjuela/Cairo, CCR 2005). We now report on our experience in children, adolescents and young adults with PTLD following SOT treated at a single institution from 1990–2008 and on the prognostic significance of expression of CD20 and EBV in this population. 45 SOT pts (28 heart, 11 liver, 6 kidney) were diagnosed with PTLD (53.3 % female) at a mean onset of 45±43 months (mo) post primary SOT (4–153). Three patients had multiple SOT. Age at diagnosis of PTLD ranged from14 to 287 mo with mean 118 (SD=77) mo. EBV and CD20 status were evaluated in all evaluable tumor sites. CD20 status was categorized as positive when all tumor sites expressed CD20 (by IHC) and negative when only some or no tumor sites expressed CD20. EBV status was categorized as positive when any tumor sites were EBV positive (by ISH), and negative when no tumor sites were EBV positive. Of 40 evaluable tumors (11 monomorphic, 19 polymorphic, 5 early lesions, 2 T-cell lymphomas, and 3 rarer types (2 HD, 1 multiple myeloma like), 32 (80%) had detectable EBV, while 28 (70%) were classified as CD20 positive. EBV expression was unrelated to age at SOT. Those patients whose PTLD expressed CD20 and/or EBV had shorter time interval between last SOT and the onset of PTLD (CD20 positive vs negative (mean±SD): 28±31 mo vs 64±44 mo, p<0.01, EBV positive vs negative: 29±24 vs 77±59 mos, p<0.02, Wilcoxon test). After controlling for the age at last SOT in the regression model for the time interval between last SOT and PTLD, expression of either CD20 or EBV was significantly associated with the shorter length of the interval. All patients had immunosuppression reduced, followed by chemo-and immunotherapy as needed. Patients with CD20 positive PTLD had a higher 5-year overall and PTLD related EFS than those patients whose PTLD was CD20 negative (92 vs 56%, p=0.02; 84 vs 29%, p<0.001, Chi-square test). The survival curve for EFS differed by CD20 status, log rank test, p<0.01 (Figure one). Organ transplant type and morphology subtype were unrelated to OS or EFS. There was no significant difference in OS or EFS based on EBV expression. In summary, expression of CD20 and/or EBV in young patients with PTLD post SOT are both important predictors of the length of time that elapses between SOT and development of PTLD. CD20 positive PTLD is associated with significantly improved 5-year OS and EFS for PTLD in young SOT patients. Patients with CD20 negative PTLD appear to have lower 5-year survival and EFS suggesting a need for alternative treatment strategies. [Display omitted]

Post-transplantation Lymphoproliferative Disease

Elevation in Epstein-Barr virus (EBV) circulating DNA has been proposed as a marker for development of post-transplant lymphoproliferative disease (PTLD), but few published data exist in the study of lung-transplant recipients. To determine if elevated EBV DNA levels, in combination with other risk factors, were predictive of PTLD. We conducted a retrospective, single-center study examining all lung transplant recipients (n = 296) and EBV DNA levels (n = 612) using real-time TaqMan polymerase chain reaction. There were 13 cases of PTLD overall, of which 5 occurred in the era of EBV DNA monitoring. EBV DNA levels were distributed differently among seropositive and seronegative patients, with the latter having higher values (P < 0.0001). Among the cohort of pretransplantation seropositive patients, there was one diagnosed with PTLD. The EBV DNA level in this patient was elevated at the time of PTLD diagnosis (sensitivity = 100%, specificity = 100% for PTLD). Among the cohort of pretransplantation seronegative patients, there were four with a diagnosis of PTLD. In all four patients, the EBV DNA level was detectable (sensitivity = 100%, specificity = 24%), but in only two was it elevated (sensitivity = 50%, specificity = 22%). HLA-A3 expression in the recipient and/or donor conferred additional risk for PTLD among the seronegative patients (P = 0.026 to 0.003). No other PTLD risk factor was found. EBV DNA levels are a useful but imperfect predictor of PTLD in patients with lung transplants. Pretransplant EBV status affected the results of the assay and should be considered when interpreting test results. HLA-A3 was strongly linked to PTLD and may be a novel marker of PTLD risk.

Persistent detection of Epstein-Barr virus DNA after pediatric liver transplantation: Unclear risks and uncertain responses

Persistent detection of Epstein-Barr virus DNA after pediatric liver transplantation: Unclear risks and uncertain responses

Epstein-Barr virus load in whole blood is associated with immunosuppression, but not with post-transplant lymphoproliferative disease in stable adult heart transplant patients

Development of Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a serious complication following heart transplantation (HTX). This study investigates EBV DNA load in adult heart transplant recipients, its association with immunosuppression, and its potential as a marker for development of PTLD. EBV DNA load was measured prospectively by quantitative real-time polymerase chain reaction (PCR) in 172 stable HTX patients. Sixty-seven patients (39.0% of total) had a positive EBV PCR at initial examination [median 4.9 (range 1.1-16.9) years post-HTX]. In follow-up testing of 67 positive patients 6 months later, 36 patients continued to have a positive EBV PCR. Overall incidence of EBV DNA was significantly associated with calcineurin inihibitors, azathioprine medication, and with the absence of mycophenolate mofetil (MMF) treatment. In patients with positive EBV DNA levels at initial examination and negative levels at retesting, cyclosporine A levels were found to be significantly higher at initial examination (148.4 +/- 70.2 vs. 119.6 +/- 53.5 ng/ml, P < 0.05). Three patients (1.7%, 3/172) were diagnosed with PTLD during the course of the study (mean follow up 4.0 years). EBV DNA viral load determination does not appear to be useful for risk prediction or early diagnosis of PTLD in adults after HTX, but an association of EBV DNA load with qualitative and quantitative immunosuppression is demonstrated.