Onset Of Posttransplant Lymphoproliferative Disorder Research Articles

Influence of Posttransplant Lymphoproliferative Disorder on Survival in Children After Heart Transplantation.

The influence of posttransplant lymphoproliferative disorder (PTLD) on long-term survival in children after heart transplantation (HTx) is not well studied. The United Network for Organ Sharing database was queried from 1987 to 2013 for data on PTLD in relation to induction immunosuppression and recipient Epstein-Barr virus status in children (<18years of age) who underwent HTx. Of 6818 first-time pediatric heart transplants, 5169 had follow-up data on posttransplant malignancy, with 360 being diagnosed with PTLD. Univariate Cox analysis identified diminished survival after PTLD onset using a time-varying measure of PTLD (HR 2.208; 95% CI 1.812, 2.689; p<0.001), although Kaplan-Meier survival functions found no difference in survival between the group ever diagnosed with PTLD and the non-PTLD reference group (log-rank test: χ 1 (2) =0.02; p=0.928). A multivariate Cox model found a greater mortality hazard associated with the development of PTLD after adjusting for recipient EBV seronegativity and other covariates (HR 3.024; 95% CI 1.902, 4.808; p<0.001). Induction immunosuppression at time of HTx did not significantly influence posttransplant mortality. The development of PTLD adversely influenced long-term survival in children after HTx after adjusting for confounding variables.

A meta-analysis of potential relationship between Epstein-Barr-Encoded-RNA (EBER) and onset time of post-transplant lymphoproliferative disorders.

Epstein-Barr virus (EBV) encodes two non-polyadenylated RNAs termed EBV-encoded RNAs (EBERs). In this study, we tried to find series in which data of EBER and onset time of post-transplant lymphoproliferative disorder (PTLD) for patients have been documented to conduct a meta-analysis. A comprehensive search of the literature was performed by Pubmed and Google scholar to find reports indicating test results for EBER and PTLD onset in transplant patients. PTLD was considered "early onset" when it develops within the first post-transplant year. Finally, 265 patients from 15 studies have been included in the meta-analysis. The overall meta-analysis also showed a significant relation between EBER test positivity and early-onset PTLD development [relative risk (RR): 1.36; 95% CI: 1.16-1.59; P <0.001]. The i2 index was 49.8%. Our study suggests that PTLD lesions with positive EBER test are more likely to develop within the early post-transplant period. Since early-onset PTLD is supposed to have better prognosis, having a positive EBER test might not be a bad news. However, for having a precise conclusion, prospective studies are needed to be conducted.

Comparative analysis of post-transplant lymphoproliferative disorder after kidney transplantation versus hematopoietic stem cell transplantation

Post-transplant lymphoproliferative disorder (PTLD) is a major complication caused by immune-suppression after transplantation. Survival outcome is known to be poor and the characteristics are not fully understood because of its rare incidence. This single center retrospective study enrolled 41 adult PTLD patients after kidney-transplantation (KT, n = 28) and hematopoietic stem cell transplantation (HSCT, n = 13) from 1992 to 2012. We compared the characteristics and estimated the survival outcomes according to several factors [age-adjusted-IPI (aaIPI), pathologic subtype, viral status, extranodal manifestation] and added some significant parameters to aaIPI scoring system. Post-HSCT-PTLD patients were younger and showed earlier onset, and viral status was more frequently identified. Ten-year OS of the entire group was 44% but the 10-year OS was not significantly different between post-KT-PTLD and post-HSCT-PTLD (39% vs. 56%, P = 0.860). The time onset of PTLD and viral statuses were not meaningful, however, aaIPI, age > 50, extranodal manifestation and monomorphic subtype were predictive for OS. We used those factors for PTLD-specific scoring which showed intermediate-risk (HR = 7.1, P = 0.019) and high-risk (HR = 16.5, P = 0.001) presented worse OS compared to low-risk subgroup. Although the treatment strategies were heterogenous, this study showed comprehensive PTLD data between KT versus HSCT, and our PTLD-specific scoring might be validated by another larger studies.

Posttransplant Lymphoproliferative Disorder in Pediatric Patients

Transplantation of solid organs and hematopoietic stem cells is accompanied by profound disturbance of immune function mediated by immunosuppressive drugs or delayed immune reconstitution. Disturbed T cell control of Epstein-Barr virus (EBV)-infected B cells leads to posttransplant lymphoproliferative disorder (PTLD) in up to 10% of patients. Children are at a higher risk because they are more often EBV-naïve before transplantation. Patients with PTLD often present with unspecific symptoms (pain and organ/graft dysfunction). Depending on the onset of PTLD, manifestations vary between mainly nodal (late PTLD) and extranodal sites (early PTLD). Histology, immunohistology, EBER in situ hybridization and molecular pathology are required for diagnosis and subclassification of PTLD. The three major types are early lesions (resembling reactive proliferations in immunocompetent patients), polymorphic PTLD (proliferation of B and T cells with effacement of histoarchitecture) and monomorphic PTLD (presenting as malignant lymphomas, mainly high-grade B cell lymphomas). In a subfraction of cases, including monomorphic PTLD, reduction of immunosuppressive medication alone is sufficient to induce remission. Surgical debulking of tumor mass and anti-CD20-antibody treatment with or without chemotherapy (usually at lower dosages than in immunocompetent patients) constitute the basis of additional therapy.

The adolescent and liver transplantation

The outcome of liver transplantation is usually reported in terms of graft and patient survival, medical and surgical complications, and quality of life, but when it comes to transplanted adolescents such conventional parameters are unable to give a full account of their life with a new liver, and their transition from adolescence to adulthood is a time when they are particularly vulnerable. Adolescents with liver transplants have excellent survival rates, over 80% of them surviving more than 10 years. Graft loss is most often associated with complications such as chronic rejection, hepatic artery thrombosis, and biliary complications. Calcineurin inhibitors may have various side effects, including hypertension and nephrotoxicity. Liver-transplanted adolescents are also exposed to viral infections, among which Epstein-Barr virus is very common and associated with the onset of post-transplant lymphoproliferative disorders. Growth retardation may also be an issue in some liver transplant recipients. Future studies will determine the best way to assess the functional immune status of adolescents with a transplanted liver with a view to ensuring the best treatment to induce tolerance without the complications of excessive immunosuppression. Schooling may be disrupted due to adolescent transplant recipients' poor adherence. Non-adherence is associated with a poor medical outcome. Both physical and psychosocial functioning is reportedly lower among young liver transplant recipients than in the general population.

Posttransplant Lymphoproliferative Disorders of the Central Nervous System After Kidney Transplantation: Single Center Experience Over 40 Years -Two Case Reports-

Posttransplant lymphoproliferative disorder (PTLD) is one of the life-threatening complications of organ transplantation. PTLD sometimes involves the central nervous system (CNS), but the clinical characteristics are not well recognized. A total of 631 patients received kidney transplantation at Osaka University Hospital between March 1965 and December 2008. Two of the 631 patients (0.32%) developed CNS PTLD. A 40-year-old Japanese woman suffered onset of CNS PTLD 5 years after renal transplantation. After diagnosis based on histological examination by open biopsy, she obtained remission with dose increase of steroid and dose reduction of mycophenolate mofetil. She experienced relapse 20 months after first remission. She underwent second biopsy and the diagnosis was recurrent CNS PTLD. Further reduction of mycophenolate mofetil and increase of steroid led to second remission. The disease remained in complete remission at 60 months after first onset. A 61-year-old woman suffered onset of CNS PTLD 19 years after renal transplantation. After tumor removal, whole brain irradiation was performed. The disease remained in remission at 54 months after onset. Histological examination showed polymorphic-type PTLD in both cases. The first case of polymorphic CNS PTLD was successfully treated by modulation of immunosuppressants without radiation therapy even at recurrence. PTLD should be included in the differential diagnosis of brain tumors in recipients of solid organ transplantation, and histological subtype should be carefully identified to establish the correct treatment strategy.

Post‐transplant lymphoproliferative disorder following renal transplantation: A single‐center experience over 40 years

To investigate post-transplant lymphoproliferative disorder (PTLD) following renal transplantation at our institution. Medical records of 631 patients who underwent renal transplantation at Osaka University Hospital between March 1965 and December 2008 were reviewed. PTLD following renal transplantation was detected in 10 patients (five men, five women; mean age at transplantation, 38.5 years). Mean duration from renal transplantation to the onset of PTLD was 7.1 years (range, 5 months to 18 years, 9 months). Mean duration of observation was 3.9 years from the onset of PTLD. Immunosuppressant therapy comprised multidrug combination therapy, including cyclosporine in six patients and tacrolimus in four patients. In addition to a reduction in the immunosuppressant dose, which was performed in all patients, PTLD was treated with surgery in seven patients, radiotherapy in two patients, rituximab in five patients, and cytotoxic chemotherapy in four patients. A complete remission in eight patients and progressive disease in two were observed. At last follow up, seven patients were alive and five patients had functioning grafts. The incidence of PTLD following renal transplantation at our institution is 1.6% with onset occurring more than 5 years after transplantation in five patients. Consequently, with long-term renal graft survival now feasible, attention must be paid to detecting late-onset PTLD.

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Monitoring of Epstein-Barr virus load and killer T cells in pediatric renal transplant recipients

The aim of this study is to establish a monitoring method to prevent Epstein-Barr virus (EBV)-associated symptoms including post-transplant lymphoproliferative disorder (PTLD) that occur after pediatric renal transplantation. Circulating EBV loads were quantified by real-time PCR every 1 - 3 months after grafting in 22 pediatric recipients (13 EBV-seronegative [R(-)] and 9 EBV-seropositive [R(+)] recipients before grafting). The peripheral blood cell populations of non-specific activated killer cells (CD8+HLA-DR+ phenotype) in 13 R(-) recipients and EBV-specific cytotoxic T cells (CTLs) reactive with a tetramer expressing HLA-A24-restricted EBV-specific antigens in 8 of 13 R(-) recipients were determined by flow cytometry. EBV-associated symptoms including PTLD (2 cases) were found in 4 R(-) and none of the R(+) recipients. The maximum of EBV load in the R(-) group was significantly higher that in the R(+) group. In R(-) recipients, 4 symptomatic cases had significantly more EBV genome than asymptomatic cases. EBV-specific CTLs were detected in 6 of the 8 R(-) recipients, but these CTLs could not be detected in 1 of the 2 cases at onset of PTLD. The percentage of CD8+HLA-DR+ cells was significantly higher in asymptomatic recipients than in recipients with EBV-associated symptoms whose EBV loads were over 400 copies/microg DNA. Monitoring of killer T cells and EBV loads may allow assessment of the risk of EBV-associated symptoms, and high EBV loads and low EBV-specific and/or non-specific CTL responses may be predictive for development of EBV-associated symptoms such as PTLD.

A Case Report of Posttransplant Lymphoproliferative Disorders Successfully Treated with R-CHOP in Korea

Posttransplant lymphoproliferative disorder (PTLD) is a group of heterogeneous lymphoid diseases that cause serious complications after organ or stem cell transplantation. The onset of PTLD is mostly due to EBV infection-induced B-cell proliferation and a defect in cytotoxic T cell function that occurs with immunosuppression. The usual treatment strategy for PTLD is reduction or withdrawal of immuno- suppressive drugs with or without the administration of antiviral agents. Recently, various studies on the efficacy of rituximab or chemotherapy have been reported. We report two cases of rapidly progressing and complicated PTLDs after kidney transplantation that were successfully treated with a combination regimen consisting of rituximab, cyclophosphamide, adriamycin, vincristine and prednisolone (R-CHOP).

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.

Posttransplant Lymphoproliferative Disorders in Pediatric Solid Organ Recipients: A Multicenter Retrospective Analysis of Patients from 1990 to 2003.

Posttransplant lymphoproliferative disorders (PTLD) have been recognized as severe side effects of immunosuppressive therapy after organ transplantation. However, no standard diagnostic and therapeutic approaches have been defined. Furthermore, few interdisciplinary perspectives comparing patients with heart/liver/kidney transplants are available. Here, we present results of a multicenter, retrospective analysis of pediatric patients treated for PTLD in Germany and Switzerland from 1990 to 2003. Patients were recruited by surveys through the working groups of pediatric renal, liver, and heart/lung transplantation as well as from the registry of pediatric Non-Hodgkin's lymphomas (NHL-BFM). Inclusion criteria consisted of a history of solid organ transplantation, biopsy-proven diagnosis of PTLD, and age at onset of PTLD 18 years of less. Patient charts were analyzed for clinical course from transplant to onset of PTLD, virus serology, treatment regimen, and outcome. A total of 53 patients from 19 centers could be included, among them 25 renal graft recipients, 14 heart-, 11 liver-, and 1 lung transplant recipients as well as 2 patients after combined heart/lung transplantation. PTLD was diagnosed at a median time of 34 months [range 2 – 119 months] post organ transplantation. Histological evaluation based on the WHO classification showed 2 early lesion PTLD, 8 polymorphic PTLD, 26 high-grade B-cell lymphomas, 12 Burkitt-like lymphomas, 3 cases of Hodgkin's disease and 2 T-cell lymphomas. Cytogenetic analysis revealed translocations involving chromosome 8 in five patients with Burkitt-like lymphomas. EBV gene products were detected in 31 tumors by in situ hybridization or immunohistochemistry, while 13 tumors were EBV negative (no data available on 9 tumors). EBV serology was negative in 55% of patients at the time of organ transplantation. However, in 29 patients EBV primary infection/reactivation was documented after organ transplantation (median time to infection/reactivation 5.9 months). In all patients immunosuppressive therapy was reduced. Treatment and follow up data were available in 51 patients: six patients remained in complete remission without additional treatment, in one patient autologous EBV-specific T-cells were infused. 41 patients received monoclonal antibodies (anti-CD20; n=7), chemotherapy (n=28), or a combination thereof (n=5). Fifteen of 51 patients died of progressing PTLD (n=7; among them 3 patients in which treatment was refused), treatment-related mortality (n=7), or fatal graft failure (n=2). Mortality was higher in patients with Burkitt-like lymphomas (7 of 12 patients) compared to all other entities (8 of 39 patients; p=0.026). Patients with stage IV disease had an inferior outcome compared to patients with stage I-III disease (mortality 6 of 7 vs. 9 of 44 patients, p=0.002). Thus, pediatric PTLD is a heterogeneous disease often associated with fatal outcome. The PED-PTLD study group has initiated a prospective multicenter trial of standardized diagnosis and treatment of PTLD after solid organ transplantation in children.

The Outcome of Lymphoproliferative Disorder in Liver Transplant Recipients May Correlate with Age at Diagnosis and the Use of Chemotherapy: A Single Centre Report.

Post transplant lymphoproliferative disorder (PTLD) occurs with an incidence of 1.7–3.3% and 5.6–13% in adults and children respectively. Mortality remains high with rates of 40–70%; approximately double that of other high grade lymphoproliferative disorders. To date, no preventative or therapeutic regimen has been shown to have an overall survival advantage. We examined the clinical and histological features of 31 adults and children diagnosed with PTLD following liver transplantation in a single centre to determine which factors might influence clinical outcome. Patient records were reviewed from the database of cases at King's College Hospital from 1988–2005 including both children and adults. 60 cases were identified and in 31 cases, relevant data could be obtained. This gave an incidence of PTLD of 1.7% and 2.7% in adults and children respectively. 10 of the 31 cases were children. Most children had an original diagnosis of extra hepatic biliary atresia; the adults had a broad range of primary liver disease. At the time of diagnosis of PTLD, the mean age was 34 years (1.5–64). The mean onset of PTLD from the time of liver transplantation was 50 months (3–156). Approximately equal numbers of patients were on either 1, 2 or 3 forms of immunosuppression when diagnosed. 12 patients presented with extranodal disease and 13 with Stage 4 disease. In 18 patients the IPI could be assessed, with 14 having an IPI of 2 or more. The histological diagnosis in 20 patients was high grade B cell lymphoma, 1 high grade T cell, 1 TNK cell, 1 Hodgkins, 1 low grade B cell, 1 mixed cell, 1 B cell, 1 high grade, 1 plasmacytoid variant and in 3 cases the histological diagnosis was unknown. The tissue affected by lymphoproliferative disease was positive for EBV in 22 cases and 6 patients (all aged <15) were positive for EBV DNA in the serum at diagnosis. Only one adult was tested and found to be negative. All patients were treated with immunoreduction with 18 receiving chemotherapy. 14 patients also received antivirals. 6 patients were treated with immunoreduction alone. Cytotoxic T lymphocytes were used in 2 cases. Chemotherapy used included CHOP, CHOPR and Rituximab alone. 16 patients had a complete response, 2 a partial response and 9 no response. In 4 patients the outcome was unknown. The median follow up was 12.5 months (1–166). Overall survival was 40.36% with median survival at 1 year being 59%. Using univariate analysis, favourable outcome was associated with age <15 at diagnosis (p=0.04) and treatment with chemotherapy (p<0.01). Overall survival in those patients developing PTLD>1 year post transplant was 52.6% compared to 25% in those developing PTLD<1 year post transplant (p=0.28). 1 patient treated with immunoreduction alone survived. Longer term remissions appear to be achieved in younger patients, those who present later following liver transplantation and in whom chemotherapy is used. The amount of immunosuppression, EBV positivity of tissue and stage of disease at presentation do not appear to influence outcome. IPI scores are high in many patients although it remains unclear whether these are applicable to PTLD.

Rituximab treatment for posttransplant lymphoproliferative disorder (PTLD) induces complete remission of recurrent nephrotic syndrome

A 12-year-old Japanese boy who underwent kidney transplantation with a kidney from his mother developed severe proteinuria immediately after the operation. Because his original disease was nephrotic syndrome (focal segmental glomerulosclerosis, or FSGS) and electron microscopic examination of the renal biopsy showed foot process fusion, we diagnosed this as a recurrence of nephrotic syndrome to the transplanted kidney. Four months after the transplantation, posttransplant lymphoproliferative disorder (PTLD) developed, which was pathologically diagnosed as diffuse large B cell lymphoma. Treatment consisting of a reduction in immunosuppression resulted in improvement in PTLD a month after the start of treatment. However, relapse occurred 2 months after the first onset of PTLD, which we treated with rituximab (CD-20 monoclonal antibody 375 mg/m2) once weekly for a total of four doses. The PTLD resolved immediately after the rituximab treatment was started, and, interestingly, urinary protein levels also improved at the same time. Three years later, the boy shows no signs of PTLD, and no proteinuria has been detected. These findings suggest that rituximab may be an effective treatment for recurrence of nephrotic syndrome after transplantation and that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation.

Gastrointestinal Involvement of Posttransplant Lymphoproliferative Disorder in Lung Transplant Recipients: Report of a Case

Lymphoproliferative disorder is a well-recognized complication of lung transplantation. Risk factors include Epstein-Barr virus infection and immunosuppression. The gastrointestinal manifestations of post-transplant lymphoproliferative disorder in lung transplant recipients have not been fully characterized. Case presentation and 16 previously reported cases of post-transplant lymphoproliferative disorder with gastrointestinal involvement are reviewed. Patient ages ranged from 25 to 65 (median, 52) years. Median time from lung transplantation to onset of posttransplant lymphoproliferative disorder was 36 (range, 1-109) months; 35 percent of cases (6/17) occurred within 18 months; Eighty-eight percent of patients (15/17) had positive Epstein-Barr virus serology before transplantation. In five patients (29 percent), the posttransplant lymphoproliferative disorder also involved sites other than the gastrointestinal tract. The most common gastrointestinal site of posttransplant lymphoproliferative disorder was the colon, followed by the small intestine and stomach. Clinical features included abdominal pain, nausea, and bloody diarrhea. Diagnosis was based on typical pathologic changes on gastrointestinal tract biopsy obtained mainly by colonoscopy. Treatment included a reduction in the immunosuppressive regimen in 15 of 17 cases (88 percent) and surgical resection in 10 (59 percent). One patient was untreated. Seven of 16 patients (44 percent) responded to treatment and 9 patients died. Median time from onset of posttransplant lymphoproliferative disorder to death was 70 (range, 10-85) days. Posttransplant lymphoproliferative disorder with gastrointestinal involvement is a unique entity that should be considered in all Epstein-Barr-Virus-positive lung transplant recipients who present with abdominal symptoms. Although immunosuppressive modulation and resection can lead to remission, the risk of death is 50 percent.

Recipient Epstein Barr Virus (EBV) Seropositivity with IgG Antibodies Against Early Antigens (EA) Could Be a Predictive Marker for the Early Onset of Post Transplant Lymphoproliferative Disorders (PTLDs) after Allogeneic Non T Depleted Stem Cell Transplantation.

After allogeneic bone marrow (BM) or peripheral blood stem (PBSC)cells transplantation, the occurrence of PTLDs most frequently associated with EBV represent a serious clinical management problem. Identification of risk factors to allow preventive strategies could be useful. In this single center retrospective study from1999 to 2003, we analyzed the EBV virus load in the graft and the EBV serological pretransplant status from 21 recipients with a PTLD and 28 control allografted patients without PTLDs. All patients received a non T cells depleted stem cells transplantation from geno and matched unrelated identical donors for various hematological disorders. The median time from graft to he onset of PTLD was two months (range 1–8 months). All the PTLDs patients received ATG in the conditioning regimen and had an EBV real time-PCR (RT-PCR) highly positive at time of diagnostic.First, we assessed the EBV viral load in the infused cells by RT-PCR. In the PTLDs group, only 2 cases( one BM and one PBSC) contained infected EBV cells: 1,3x10e7 and 4,33x10e8 per 10e6 cells respectively. In the control group, we did not detect copies (the difference was not significant). The recipient pretransplant EBV infection status (median time: 15 days before transplant) was completed with serology anti-EA (IgA,IgG) and anti -VCA(IgA). Results are in the table 1. We found only a significant difference (p=0,00023) between the recipients with PTLDs and the control group for the early antigens positivity. Anti-EA are associated with a reactivation of EBV.In conclusion, the EBV viral load in the infused cells is not associated with the onset of PTLD. However, our findings suggest that the detection of IgG antibodies to EA antigens in the recipient pretransplant serology could be a predictive marker of the early onset of a PTLD.EBV recipient pre transplant statusanti-VCA IgGanti-VCA IgAanti-EBNA IgGanti-EA IgGanti-EA IgAPTLDs pts n=2121/21 (100%)0/21 (0%)21/21 (100%)12/21 (57%)#0/21 (0%)Control pts n=2828/28 (100%)0/28 (0%)28/28 (100%)2/28 (7%)#0/28 (0%)# p=0,00023

Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis of 480 patients.

Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication of organ transplantation that leads to death in more than 50% of cases. The aim of this work was to identify specific risk factors for lymphoproliferative disorders after liver transplantation in adults. A total of 480 consecutive patients who underwent transplantation between 1986 and 1997 were studied (323 men, 157 women; mean age: 49.8+/-10.4 years). Demographics, the indication for transplantation, the immunosuppressive regimens, the incidence of rejection episodes, and Epstein-Barr virus infection were analyzed. Univariate and multivariate analysis were used to identify factors predictive of PTLD. Sixteen cases of PTLD (3.3%) occurred at a median of 5.5 (range, 1-39) months after liver transplantation. All 16 cases occurred in patients with evidence of exposure to Epstein-Barr virus before transplantation. In multivariate analysis, the use of antilymphocyte antibodies (P=0.007, relative risk [RR]=4.2, 95% confidence interval [CI]=1.5-11.7), age older than 50 years (P=0.037, RR=3.5, 95% CI=0.95-13.0), liver transplantation for hepatitis C virus cirrhosis (P=0.015, RR=8.7, 95% CI=1-78.3), and liver transplantation for alcoholic cirrhosis (P=0.015, RR=9.6, 95% CI=1.2-77.2) were independently associated with the onset of PTLD. Liver transplantation for hepatitis C virus-related and alcoholic cirrhosis and age older than 50 years are three additional risk factors for lymphoproliferative disorder independent of the use of antilymphocyte antibodies. The use of antilymphocyte antibodies after liver transplantation should be avoided in these categories of patients, especially those older than 50 years.

Lymphoproliferative disorders in heart transplant recipients: role of hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection

Abstract Post-transplant lymphoproliferative disorders (PTLD) are a well known complication after orthotopic heart transplantation (OHT). Although Epstein-Barr virus (EBV) infection has long been implicated in the pathogenesis of such disorders, other factors may play a part. Because of its lymphotropic properties, hepatitis C virus (HCV) may induce clonal expansion of B-lymphocytes and lead to PTLD. The aim of this study was to evaluate the potential association between HCV and EBV infection and PTLD in OHT patients. The retrospective study considered 404 adult patients screened for HCV. EBV serology, histology, and molecular analysis on tissue biopsies were performed in the PTLD patients (10/404, 2.5%). HCV positivity was found in 36/404 (8.9 %) patients. The EBV genome was expressed on all neoplastic tissue samples analyzed. A higher proportion of HCV-positive patients developed PTLD than the HCV-negative cases (8 % vs 2%, P = 0.017). EBV has a demonstrated role in the onset of PTLD, but HCV infection probably has to be considered as well.

Lymphoproliferative disorders in heart transplant recipients: role of hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection.

Post-transplant lymphoproliferative disorders (PTLD) are a well known complication after orthotopic heart transplantation (OHT). Although Epstein-Barr virus (EBV) infection has long been implicated in the pathogenesis of such disorders, other factors may play a part. Because of its lymphotropic properties, hepatitis C virus (HCV) may induce clonal expansion of B-lymphocytes and lead to PTLD. The aim of this study was to evaluate the potential association between HCV and EBV infection and PTLD in OHT patients. The retrospective study considered 404 adult patients screened for HCV. EBV serology, histology, and molecular analysis on tissue biopsies were performed in the PTLD patients (10/404, 2.5%). HCV positivity was found in 36/404 (8.9%) patients. The EBV genome was expressed on all neoplastic tissue samples analyzed. A higher proportion of HCV-positive patients developed PTLD than the HCV-negative cases (8% vs 2%, P = 0.017). EBV has a demonstrated role in the onset of PTLD, but HCV infection probably has to be considered as well.

Rational management of posttransplant lymphoproliferative disorder in pediatric recipients

Background/Purpose: Posttransplant lymphoproliferative disorder (PTLD) is a potentially lethal complication in the pediatric transplant patient secondary to Epstein-Barr virus (EBV) infection and potent immunosuppression. PTLD may develop in up to 10% of pediatric transplant recipients with mortality rates up to 80%. The authors report their experience with the diagnosis and efficacy of aggressive sequential management of PTLD in five patients under age 5 years. Methods: A review of 75 pediatric liver transplant recipients on FK-506-based immunosuppression identified five biopsyproven cases of PTLD and one probable case (8%). The probable case was a teenager, 6 months posttransplant in Spain, with mediastinal masses. No treatment or diagnosis was sought, and the patient died. The other five cases were managed with sequential therapy on an “intent-to-treat” basis with initial withdrawal of immunosuppression. If the disease progressed, patients were treated with four courses of intravenous cyclophosphamide, vincristine, Adriamycin, and intrathecal methotrexate and ara-C. Results: Five children were anti-EBV titer negative at the time of transplant. Three of five received EBV-positive donor organs and two children received EBV-negative livers. Monoclonal PTLD developed between 2 and 31 months posttransplant (mean, 15.7 months). With onset of PTLD (four B cell lymphoma, one B cell leukemia) all patients had tapering or withdrawal of immunosuppression and initiation of high-dose acyclovir. Two of five patients had complete remission and resumed immunosuppression. Two patients progressed and required chemotherapy. One patient with initial response relapsed 4 months later with B cell leukemia and required chemotherapy. All five patients are alive 10 to 38 months postdiagnosis (mean, 29 months). Three patients had rejection requiring resumption of FK-506 therapy. Two patients are maintained on low-dose alternate-day prednisone and no FK-506. All patients have normal liver function. Central nervous system lymphoma developed in one child with significant neurological sequelae. Conclusions: PTLD can develop in pediatric liver transplant recipients. Early withdrawal of immunosuppression and aggressive chemotherapy enabled us to achieve 100% patient and graft survival.