Role of hepatitis C virus in lymphoproliferative disorders after liver transplantation.

It has been suggested that hepatitis C virus (HCV) infection could be associated with B-cell clonal expansion. The aim of this study was to analyze the relationship between lymphoproliferative disorders and HCV infection in liver transplant recipients. We studied 157 patients receiving a liver transplant between January 1989 and May 1997 with a follow-up longer than 3 months. The incidence of posttransplant lymphoproliferative disorders (PTLDs) was analyzed with reference to the indication for liver transplantation, the induction and maintenance immunosuppression, the incidence of acute rejection episodes, and Epstein-Barr virus (EBV) infection. Six PTLDs occurred after a median posttransplant follow-up of 7 months (3.8%). Four of the 6 PTLDs occurred among the 38 patients transplanted for HCV-related cirrhosis, and 2 PTLDs occurred in the 119 patients receiving a liver transplant for non-HCV liver diseases (10.5% vs. 1.7%, respectively; P =.03). The 4-year probability of PTLD was significantly higher in patients receiving a liver transplant for HCV-related cirrhosis than non-HCV liver diseases (12.3% vs. 2.2%, respectively; P =.015). Patients receiving a liver transplant for HCV-related cirrhosis were more likely to receive antithymocyte globulins (ATG). However, in patients treated with ATG, the 4-year probability of PTLD was higher among those patients receiving a liver transplant for HCV-related cirrhosis than for non-HCV liver diseases (27.1% vs. 6.4%, respectively; P =.08). EBV gene products were detected in tumor tissues in 3 of 4 patients with HCV-associated PTLD. Our data suggest that, in addition to EBV infection, 2 mutually nonexclusive factors, i.e., the use of ATG and HCV infection, could play a role in the occurrence of PTLD after a liver transplant for HCV-related cirrhosis.     

Identifying the patient at risk for post-transplant lymphoproliferative disorder

Abstract: Post-transplant lymphoproliferative disorders (PTLD) are a recognized complication of the immunosuppression required to prevent allograft rejection, occurring in 1–20% of recipients of solid organ transplants. Several factors greatly increase the risk of developing PTLD early post-transplant in any individual recipient. Epstein–Barr virus (EBV) infection is critical in the pathogenesis of the majority of these cases. Pre-transplant EBV seronegativity increases the incidence of PTLD 10- to 75-fold over that of EBV-seropositive recipients. Other risk factors include very young recipient age, cytomegalovirus infection or mismatching (donor positive–recipient negative), aggressive immunosuppression with conventional biologic agents, and the type of organ transplanted. In contrast, the risk of developing PTLD late in the post-transplant course does not appear to be influenced by the type of immunosuppressive agents employed, but rather by the duration of any immunosuppression. The role of EBV in late PTLD is also less certain, as a greater proportion of lesions are not associated with evidence of EBV infection. As the understanding of these risk factors has expanded, opportunities exist to target those populations at highest risk for the development of PTLD for aggressive monitoring and pre-emptive or prophylactic therapy. It is hoped that implementation of such strategies will render early PTLD a preventable complication of transplantation.     

Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication

Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorders (PTLDs) are a well-recognized complication of immunosuppression in solid organ transplant recipients. The reported therapeutic approaches are frequently complicated by rejection, toxicity, and other infectious pathologies, and overall mortality in patients with unresponsive PTLD remains high. Thus, low-toxicity treatment options or, preferably, some form of prophylactic/preemptive intervention are warranted to improve PTLD outcome in this setting. We assessed whether transfer of EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from the peripheral blood of allograft recipients receiving immunosuppression could increase EBV-specific killing in vivo without augmenting the probability of graft rejection. Autologous EBV-specific CTLs were generated for 23 patients who were identified as being at risk of developing PTLD through the finding of elevated EBV DNA load. Of the 23 patients, 7 received 1 to 5 infusions of EBV-specific CTLs. CTL transfer was well tolerated, and none of the patients showed any evidence of rejection. An increase of the EBV-specific cytotoxicity was observed after infusion, notwithstanding continuation of immunosuppressive therapy. EBV DNA levels had a 1.5- to 3-log decrease in 5 patients, whereas in the other 2 graft recipients CTL transfer had no apparent stable effect on EBV load. Our data suggest that the infusion of autologous EBV-specific CTLs obtained from peripheral blood mononuclear cells recovered at the time of viral reactivation is able to augment virus-specific immune response and to reduce viral load in organ transplant recipients. This approach may, therefore, be safely used as prophylaxis of EBV-related lymphoproliferative disorders in these patients, following a strategy of preemptive therapy guided by EBV DNA levels.     

Posttransplant Lymphoproliferative Disease in Liver Transplant Patients

Posttransplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Many posttransplant lymphomas develop from the uncontrolled proliferation of Epstein–Barr virus (EBV)-infected B-cells, whereas EBV-negative PTLDs were increasingly recognized within the past decade. Major risk factors for the development of PTLDs after liver transplantation are immunosuppressive therapy and the type of underlying disease: viral hepatitis, autoimmune liver disease, or alcoholic liver cirrhosis contribute to an increased risk for PTLD. Therapeutic regimens include reduction of immunosuppression, the anti-CD20 antibody rituximab, and chemotherapy, as well as new approaches using interferon-α and anti-interleukin-6 antibodies. Despite the different therapeutic regimens, mortality from PTLD remains high. Therefore, it is of major importance to identify patients at risk at an early stage of the disease. In this review, risk factors for PTLD development after liver transplantation, clinical presentation, diagnosis, and therapy are discussed.     

Hepatitis C virus infection and risk of posttransplantation lymphoproliferative disorder among solid organ transplant recipients

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. Hepatitis C virus (HCV) infection has been linked to increased risk of lymphoma among immunocompetent individuals. We therefore investigated the association between HCV infection and PTLD in a retrospective cohort study of all individuals in the United States who received their first solid organ transplant from 1994 to 2005 (N = 210 763) using Scientific Registry of Transplant Recipients data. During follow-up, 1630 patients with PTLD were diagnosed. HCV prevalence at transplantation was 11.3%. HCV infection did not increase PTLD risk in the total cohort (Cox regression model, hazard ratio [HR] = 0.84; 95% confidence interval [CI] 0.68-1.05), even after adjustment for type of organ transplanted, indication for transplantation, degree of HLA mismatch, donor type, or use of immunosuppression medications. Additional analyses also revealed no association by PTLD subtype (defined by site, pathology, cell type, and tumor Epstein-Barr virus [EBV] status). HCV infection did increase PTLD risk among the 2.8% of patients (N = 5959) who were not reported to have received immunosuppression maintenance medications prior to hospital discharge (HR = 3.09; 95% CI, 1.14-8.42; P interaction = .007). Our findings suggest that HCV is not a major risk factor for PTLD, which is consistent with the model in which an intact immune system is necessary for development of HCV-related lymphoproliferation.     

A low incidence of posttransplant lymphoproliferative disorder in 109 lung transplant recipients

STUDY OBJECTIVES: The incidence of posttransplant lymphoproliferative disorder (PTLD) has been reported to range from 6.4 to 20% in lung transplant (LT) recipients. Postulated contributing factors include Epstein-Barr virus (EBV) infection and the use of immunosuppression, particularly muromonab-CD3 (OKT3)(Orthoclone OKT-3; Ortho Biotech; Raritan, NJ). We sought to examine these PTLD risk factors in 109 LT recipients at our institution who survived > 1 month. DESIGN: Retrospective review of EBV serology of all LT recipients at our institution. Our standard transplant protocol includes OKT3 for induction and refractory rejection, as well as lifelong acyclovir for herpes prophylaxis. We do not perform EBV donor-recipient matching. SETTING: A university-based LT center. RESULTS: We found that 5 of 109 patients were serologically negative for EBV prior to lung transplantation, and all of these patients converted following lung transplantation. The mean time to conversion was 151 days (range, 11 to 365 days). One fatal case of PTLD was documented in an EBV seroconverter (one of five patients) 12 weeks status posttransplantation for lymphangioleiomyomatosis. One nonfatal extrathoracic PTLD was documented in a seropositive patient (1 of 104 patients) 33 months posttransplantation. CONCLUSIONS: We conclude the following: (1) PTLD in LT recipients may have a lower incidence (2 of 109 patients; 1.8%) than previously reported, despite an aggressive immunosuppressive regimen; and (2) the incidence of PTLD is higher in patients with primary EBV infection (20% vs 1%).     

Post renal transplantation human herpesvirus 8-associated lymphoproliferative disorder and Kaposi's sarcoma

Post-transplantation lymphoproliferative disorders (PTLDs) and Kaposi's sarcoma (KS) are immunosuppression-related tumours developing in solid organ transplant patients. Although the Epstein-Barr virus (EBV) is detected in the majority of the PTLDs during the first year after transplantation, the proportion of EBV-negative PTLDs has increased in recent years. We report a case of a 17-year-old man who developed severe immune haemolytic anaemia, KS and human herpesvirus 8 (HHV-8)-associated, polymorphic-type PTLD 9 months after allogeneic renal transplantation from his HHV-8-seropositive father. It is suggested that: (i) HHV-8 may be associated with EBV-negative, polymorphous-type PTLD occurring less than 1 year after transplantation, and (ii) PTLD may be listed among other tumours, including KS, Castleman's disease and primary effusion lymphoma (PEL), that are related to HHV-8 infection.     

Epstein-Barr-Virus-Infektion nach pädiatrischer Nierentransplantation

Due to its mild cytopathic effects, Epstein-Barr virus (EBV) rarely causes severe clinical symptoms in immunocompetent hosts. While infants often remain asymptomatic during EBV infections, young immunocompetent adolescents and adults typically develop signs of infectious mononucleosis. Also, immunocompromised pediatric renal transplant recipients exhibit mostly mild acute EBV-related clinical symptoms. However, immunosuppressive therapy after pediatric renal transplantation may lead to an uncontrolled malignant proliferation of EBV infected B cells, due to the lack of T cell-specific regulation, and thus to post-transplant lymphoproliferative disease (PTLD). Pediatric patients bear an increased risk of PTLD, as they are often EBV seronegative at the time of transplantation and develop EBV primary infection after receiving an EBV positive kidney. The EBV-specific serology and EBV viral load constitute insufficient surrogate markers for the risk assessment of PTLD. An uncritical reduction of immunosuppressive therapy, based solely on the presence of a high, persistent EBV load, may put patients at risk of transplant rejection and subsequent graft failure and should therefore be avoided. Treatment of PTLD comprises reduction of immunosuppression, administration of rituximab in cases of CD20 antigen expression and possibly chemotherapy. The 5-year survival rate after PTLD amounts to approximately 61–87%, with involvement of the bone marrow and/or central nervous system being a risk factor for poor survival. An EBV vaccine is currently not available. An antiviral chemoprophylaxis with (val-)ganciclovir, however, reduces the incidence of EBV primary infection in patients with a high-risk seroconstellation (donor EBV positive, recipient EBV negative) and, hence, potentially the rate of PTLD.     

Post-transplantation lymphoproliferation in patients with intensive immunosuppression

Organ allograft recipients are at higher risk for malignancies development. This risk is known to be different in different types of tumours. Skin cancers and lymphoproliferative disorders have been described to be ones the most frequent (comprising 15-25% of all malignancies). Here, we present the case of expansive formation localized near the renal allograft in patient, whose native kidneys failed as a consequence of long-term cyclosporine A therapy after orthotopic heart transplantation. The maintenance immunosuppression consisted of combination of cyclosporine A, mycophenolate mofetil and steroids. The expansion offside of transplanted kidney was detected by routine ultrasound examination. After indifferent neurological symptoms, sepsis, and then multiorgan failure occured. Shortly after acute surgery patient died. Autopsy and histopathology showed lymphoproliferative disorder--mo- nomorphic type of posttransplant lymphoproliferative disorder (PTLD). Occurence of PTLD in organ transplantation is discussed.     

Dynamic EBV gene loads in renal, hepatic, and cardiothoracic transplant recipients as determined by real-time PCR light cycler

BACKGROUND: Epstein-Barr virus (EBV) is recognised as one of the causative agents for most cases of post-transplant lymphoproliferative disease (PTLD). Elevated levels of EBV DNA are known to be associated with the onset of PTLD, but little information is available regarding how EBV loads change with time in asymptomatic transplant recipients following transplantation. Our aims were to study the trend of EBV loads in renal (RTx), hepatic, and cardiothoracic transplant recipients and to compare their EBV loads with other healthy and patient controls. METHODS: A prospective study was performed using a real-time TaqMan polymerase chain reaction technique to measure EBV DNA loads from three types of organ transplant recipients and haemodialysis patients (HD). Their results were then compared with those from the healthy controls (HC); monospot test negative (MN-) and infectious mononucleosis positive (IM+) patients; patients who were previously treated for PTLD (pPTLD); those who were currently diagnosed to have PTLD (PTLD+); and patients who had a stable renal, hepatic, or cardiothoracic graft for more than a year. RESULTS: Post-transplant EBV loads were significantly higher than the pre-transplant levels. Asymptomatic transplant recipients were differentiated from the PTLD+group at 600 genome copies of EBV/mug DNA, and from IM+group at 100 genome copies. Both HC and MN- groups had significantly lower EBV loads than the three transplant groups. The dynamic change of EBV loads in RTx was greater in the first post-transplant month when compared with the HD group. All transplant recipients had transient rises of EBV loads whereas EBV load continued to rise in one suspected PTLD patient. CONCLUSIONS: Asymptomatic transplant recipients had higher baseline post-transplant EBV levels than the non-transplant and MN- groups. The rising post-transplant EBV load in these transplant recipients did not seem to be sustained for longer than 2 weeks. However, in a PTLD+patient the rising EBV load continued over a period of 4 weeks. Hence, the dynamic pattern of EBV loads is more important than absolute EBV DNA measurements alone in identifying those who might go on to develop PTLD.     

Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is an uncommon but potentially fatal complication of immunosuppression in solid-organ transplant recipients. A semiquantitative DNA polymerase chain reaction assay was developed to amplify a unique 269-bp region of the EBNA-1 gene in peripheral blood lymphocytes (PBL) using the primers described by Telenti et al (J Clin Microbiol 28:2187, 1990). Serial samples were studied from 23 transplant recipients, 12 of whom were diagnosed with PTLD. The majority of transplant recipients who were EBV seropositive at the time of transplant surgery and who did not develop PTLD (5 of 7, 71%) exhibited less than a 10-fold increase in the levels of EBV-infected PBL over the 0.1 to 5 EBV genomes/10(6) PBL observed in immunocompetent EBV seropositive controls. Transplant recipients who were seronegative at the time of transplantation and who underwent a primary EBV infection but did not develop PTLD exhibited a reduced capacity to control viremia because the levels of EBV-infected PBL were up to 400 times greater than the 1.0 to 50 EBV genomes/10(6) PBL observed in individuals undergoing acute infectious mononucleosis (Rocci et al: N Engl J Med 296:132, 1977). However, all transplant recipients who developed PTLD exhibited a marked elevation of EBV-infected PBL independent of their serologic state at the time of transplantation. Six of the 10 transplant recipients with PTLD exhibited > or = 300,000 EBV genomes/10(5) PBL, two exhibited 10,000 to 50,000 EBV-infected genomes/10(5) PBL, and one each exhibited 2,500 and 500 EBV genomes/10(5) PBL. However, the latter two samples were obtained 4 to 5 weeks after the diagnosis of PTLD and may reflect a decrease in viral load resulting from immunomodulation. Marked decreases in the levels of EBV nuclear antigen-1 (EBNA-1), EBNA-2, and EBNA-LP antibodies correlated with the increase in EBV-infected PBL. Hence, a quantitative difference in circulating EBV viral load and EBNA antibody levels is evident between transplant recipients with and without PTLD and may be useful as a noninvasive prognostic marker with which to monitor and/or predict the development of PTLD.     

Activation and adoptive transfer of Epstein–Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease

The treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (PTLD) in EBV seronegative solid organ transplant recipients who acquire their EBV infection after engraftment poses a considerable challenge because of underlying immunosuppression that inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. We have developed a protocol for activating autologous EBV-specific CTL lines from these patients and show their potential use for immunotherapy against PTLD in solid organ transplant patients. Peripheral blood mononuclear cells from a panel of solid organ transplant recipients with and without active PTLD were used to assess EBV-specific memory CTL responses. The activation protocol involved cocultivation of peripheral blood mononuclear cells with an autologous lymphoblastoid cell line under conditions that favored expansion of virus-specific CTL and hindered the proliferation of allospecific T cells. These CTL consistently showed (i) strong EBV-specificity, including reactivity through defined epitopes in spite of concurrent immunosuppressive therapy, and (ii) no alloreactivity toward donor alloantigens. More importantly, adoptive transfer of these autologous CTLs into a single patient with active PTLD was coincident with a very significant regression of the PTLD. These results demonstrate that a potent EBV-specific memory response can be expanded from solid organ recipients who have acquired their primary EBV infection under high levels of immunosuppressive therapy and that these T cells may have therapeutic potential against PTLD.     

The biology of Epstein–Barr virus in post-transplant lymphoproliferative disease

Post-transplant lymphoproliferative disease (PTLD) is a B cell proliferative disorder that is associated with Epstein–Barr virus (EBV), an ubiquitous herpesvirus. EBV-seronegative organ transplant recipients are at highest risk. EBV infection in PTLD lesions exists in a latent rather than lytic state, making tumor regression in response to antiviral agents unlikely. Viral latency proteins drive proliferation of T cells but also allow T cells to target PTLD lesions for destruction. Augmentation of the cellular immune response via the infusion of EBV-specific cytotoxic T cells has yielded promising results in the prevention and treatment of PTLD in bone marrow transplant recipients. Efforts to extend this strategy to solid organ transplant recipients are ongoing. Editor’s comment: The spectrum of post-transplant lymphoproliferative disease includes both B- and T-cell malignancies. While the vast majority are EBV-associated, there is a growing subset without obvious EBV markers. Given the present state of the art, which is summarized in this paper, we are incapable of stratifying patients in terms of prognosis or the likelihood of clinical response to reduction in immune suppression or to chemotherapy. The goal for multicenter trials must include the development of uniform definitions for the clinical and virologic manifestations of PTLD, as well as further attempts to define the natural history of this group of diseases. Jay A. Fishman, M.D.     

Slc11a1 (formerly Nramp1) polymorphisms and susceptibility to post-transplant lymphoproliferative disease following pediatric liver transplantation

BACKGROUND: Polymorphisms of the solute carrier family 11 member 1 (Slc11a1) gene have previously been associated with susceptibility to infectious disease, anti-tumor defenses, and autoimmune diseases. We postulated that polymorphisms of the gene may also be associated with susceptibility to post-transplant lymphoproliferative disease (PTLD), a disease thought to be related to an impaired immune response to Epstein-Barr virus (EBV) in immunosuppressed patients. METHODS: Whole blood samples were obtained from 45 pediatric patients who underwent liver transplantation. Polymerase chain reaction (PCR) was used to amplify a 3' region of the gene that includes an exon 15 single-nucleotide substitution (referred to as D543N) and a 4-bp deletion polymorphism (referred to as 3'-UTR). PCR products were digested using AvaII and FokI restriction enzymes for the D543N and 3'-UTR polymorphisms, respectively. PTLD disease status and EBV virus serum titers of all patients were obtained from hospital records. RESULTS: Six of the 45 pediatric transplant recipients developed PTLD. An association was found between 3'-UTR polymorphisms of Slc11a1 and incidence of PTLD after liver transplantation (P = 0.005). In addition, post-transplant serum EBV titers were higher (P = 0.009) for recipients with certain Slc11a1 polymorphisms. No association was found between the D543N polymorphism and incidence of PTLD. CONCLUSION: 3'-UTR polymorphisms of the Slc11a1 gene appear to be associated with susceptibility to PTLD and the immune response to EBV in pediatric liver transplant recipients. Genotyping of pediatric patients undergoing liver transplantation may enable early identification of patients at high risk for developing high EBV titers and/or PTLD.     

Successful treatment of posttransplantation lymphoproliferative disorder (PTLD) following renal allografting is associated with sustained CD8(+) T-cell restoration

Posttransplantation lymphoproliferative disorder (PTLD) is a life-threatening Epstein-Barr virus (EBV)-associated B-cell malignancy occurring in 1% to 2% of renal transplantation patients. Host- and PTLD-related factors determining the likelihood of tumor response following reduction of immune suppression (IS) and antiviral therapy remain largely unknown. Standard therapy for PTLD is not well established. Eleven consecutive renal transplantation patients who developed EBV-positive PTLD 8 to 94 months after allografting were uniformly treated with acyclovir and IS reduction. All PTLDs were EBV-positive diffuse large B-cell lymphomas. Ten patients (91%) obtained a durable complete response (CR), and 9 (82%) have remained in continuous CR with a median follow-up of 29 months. Five patients (45%) lost their allograft. Of these, 4 patients had PTLD affecting the transplanted kidney. Peripheral blood CD8(+) T cells increased significantly (P =.0078) from baseline in 8 responders available for analysis. One of 2 patients whose absolute CD8(+) T-cell count subsequently dropped to baseline after IS reduction relapsed. The expanded CD8(+) T cells from 2 responders specifically recognized an immunodominant peptide from the EBV lytic gene BZLF-1. Another lytic EBV gene, thymidine kinase, was expressed in all 8 PTLDs tested. IS reduction and antiviral therapy for PTLD after renal transplantation is a highly successful therapeutic combination, but the risk of graft rejection is significant, particularly in patients with PTLD involving the renal allograft. A sustained expansion of CD8(+) T cells and a cellular immune response to EBV lytic antigens may be important for PTLD clearance in renal transplantation patients.     

Variability in Epstein-Barr virus serological markers in adult kidney transplant recipients

Epstein-Barr virus (EBV) infection is associated with the development of post-transplant lymphoproliferative disorders (PTLD). However, the clinical relevance and criteria for EBV serological reactivation in EBV-seropositive transplant recipients is unclear. EBV-specific antibodies: viral capsid immunoglobulm G [IgG (VCA)], nuclear antigen (EBNA) IgG, immunoglobulin M [IgM (VCA)] and early antigen IgG (EA) were prospectively analyzed in 71 adult kidney transplant recipients, before starting immunosuppression, when they were uraemic, and after transplantation. A total of 351 serum samples were tested. Relevance of different EBV reactivation-related variables were analyzed using the chi-square test. In 37 of 71 (52.1%) patients IgM (VCA) or IgG (EA) were detected when they were uraemic. EBV reactivation occurred in 25 of 71 (35.2%) patients, with clinical symptoms (fever, leukopenia, kidney function impairment, and increase in transaminases) in nine cases. One of 71 patients developed a PTLD, without detection of serologically EBV reactivation, but with an increase in EBV viral load. Absence of mycophenolate mofetil, that inhibits lymphocyte proliferation and antibody production, in immunosuppression was statistically significantly associated with EBV reactivation (p = 0.015). Serological diagnosis of EBV reactivation should be based on strict criteria (IgM (VCA) seroconversion, four-fold increase in IgM (VCA) or IgG (EA), or four-fold decrease in IgG (EBNA) titers and on analysis of serial samples. Some EBV-seropositive patients at high risk of developing PTLD could benefit from this diagnostic methodology.     

Early gastric post-transplantation lymphoproliferative disorder and H pylori detection after kidney transplantation: a case report and review of the literature.

The incidence of post-transplantation lymphoproliferative disorder (PTLD) in the adult renal transplant population ranges from 0.7% to 4%. The majority of cases involve a single site and arise, on average, seven months after transplantation. Histopathology usually reveals B-cell proliferative disease and has been standardized into its own classification. Treatment modalities consist of decreased immunosuppression, eradication of Epstein-Barr virus, surgical resection, systemic chemotherapy and monoclonal antibody therapy; however, mortality remains high, typically with a short survival time. In patients who have undergone renal transplantation, approximately 10% of those with PTLDs present with gastrointestinal symptomatology and disease. Reported sites include the stomach, and small and large bowel. Very few cases of Helicobacter pylori or mucosal-associated lymphoid tissue have been described in association with PTLD. In the era of cyclosporine immunosuppression, the incidence of PTLD affecting the gastrointestinal tract may be increasing in comparison with the incidence seen with the use of older immunosuppression regimens. A case of antral PTLD and H pylori infection occurring three months after renal transplantation is presented, and the natural history and management of gastric PTLD are reviewed.     

Identification of early antigen BZLF1/ZEBRA protein of Epstein-Barr virus can predict the effectiveness of antiviral treatment in patients with post-transplant lymphoproliferative disease

Epstein-Barr virus (EBV)-associated B-cell lymphoproliferations may arise in solid organ transplant recipients. In these patients, an insufficient control of EBV-infected B cells commonly occurs. Antiviral treatment against EBV may represent a causal, relatively low-toxic treatment option. Treatment with foscarnet, an inhibitor of viral-DNA polymerase, in three patients with EBV-associated post-transplant lymphoproliferative disease (PTLD) after heart (n = 2) and heart/kidney transplantation (n = 1), who did not respond to, or were not eligible for reduction of immunosuppression, resulted in complete remission (48+, 27 and 15 months respectively). Response of PTLD to antiviral treatment correlated with the expression of lytic phase antigen BZLF1/ZEBRA protein, an early antigen of lytic EBV-activity, in the biopsied PTLD specimens.     

Prevalence, incidence and correlates of HHV-8/KSHV infection and Kaposi's sarcoma in renal and liver transplant recipients.

BACKGROUND: To determine whether the incidence of HHV-8/KSHV infection and the risk of developing KS among organ transplant recipients differ by type of organ transplanted, we calculated the rate of HHV-8/KSHV seroconversion and the risk of developing KS among renal and liver transplant recipients. METHODS: The study population consisted of renal and liver transplant recipients recruited in two transplant centres in Rome, Italy. Both pre-transplant and post-transplant serum samples were available for all participants. The prevalence of HHV-8/KSHV infection before transplantation was calculated. To determine risk factors for infection, we calculated ORs and 95% CI. Seroconversion rates (i.e. attack rates) after transplantation were also calculated. Differences in attack rates were calculated using a binomial test for proportions. RESULTS: Of the 130 participants, 21 (16.1%) were HHV-8/KSHV-positive before transplantation. Women were more likely to be infected than men, whereas no difference was observed by type of organ transplanted. Of the 109 initially negative individuals, 13 (11.9%) developed anti-HHV-8/KSHV antibodies after transplantation. The incidence of HHV-8/KSHV infection tended to be higher among liver transplant recipients. Four renal transplant recipients and none of the liver transplant recipients developed KS after transplantation. The risk of KS was higher among recipients who were already HHV-8/KSHV-positive before transplantation. CONCLUSIONS: HHV-8/KSHV seroconversion rates appear to be higher among liver transplant recipients, compared to renal transplant recipients. However, renal transplant recipients tend to have a higher risk of KS. HHV-8/KSHV reactivation appears to play a greater role on the risk of KS than incident infections.     

Thoracic presentations of posttransplant lymphoproliferative disorders

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) are rare complications following transplantation. Although organ-specific cases have been reported, primary presentation in the thoracic cavity has not been fully characterized. METHODS: Eleven cases of PTLD with a primary thoracic presentation were identified among 3,085 solid-organ transplant patients and 1,662 bone marrow transplant patients from 1990 to 2001. RESULTS: There were eight men and three women with a mean age of 49 years. Transplanted organs included lungs (three patients), kidneys (three patients), kidney/pancreas (two patients), allogeneic bone marrow (two patients), and heart (one patient). The time to presentation ranged from 1 to 97 months (median time, 8 months). Six patients developed PTLD within 1 year of undergoing transplantation. Pretransplant serology for Epstein-Barr virus (EBV) and cytomegalovirus was negative in 80% and 78% of cases, respectively. Radiographic evaluation revealed mediastinal adenopathy in 45% of patients, and pulmonary parenchymal lesions in 55%. Fifty-five percent of patients also had extrathoracic involvement. Diagnosis was achieved by CT-guided transthoracic needle biopsy in eight patients, and by open biopsy in three patients. Pathologic analysis revealed monomorphic PTLD (ie, diffuse large B-cell lymphoma) in seven patients, polymorphic PTLD in two patients, anaplastic large cell lymphoma in one patient, and Hodgkin lymphoma in one patient. Eighty-four percent of the specimens evaluated for EBV were determined to be positive by in situ hybridization and/or immunohistochemistry. All patients were initially treated with a reduction in immunosuppression therapy, and six patients (55%) received adjuvant chemotherapy. The overall mortality rate was 64%. Four patients died from complications of PTLD (kidney, two patients; heart, one patient; bone marrow, one patient), and three patients (all lung transplant recipients) died from rejection or infectious complications. The median interval from diagnosis to death was 13 months (range, 1 to 42 months). CONCLUSIONS: Thoracic PTLD can occur in any transplant patient and must be regarded as a potentially fatal complication in the immunosuppressed patient. Heart and lung allograft recipients have the worst prognosis because of the mortality that accompanies rejection with subtherapeutic immunosuppression therapy. Earlier diagnosis and improvements in immunosuppression and chemotherapy may improve survival for these inherently high-risk patients.