tacrolimus and Epstein-Barr-Virus-Infections

A 58-year-old man with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5-DM) developed Epstein-Barr virus (EBV)-associated malignant lymphoma as other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) during the combined immunosuppressive therapy of high-dose prednisolone, tacrolimus, and intravenous cyclophosphamide for MDA5-DM. Serum EBV DNA was detected, and EBV-encoded small RNA was positive in the tissue sample of LPD, indicating that EBV reactivation contributed to the pathogenesis of LPD in our case. The patient underwent chemotherapy, including rituximab, promptly after discontinuation of tacrolimus and cyclophosphamide, resulting in complete remission of the malignant lymphoma, and MDA5-DM has not recurred with 3.5 mg/d of prednisolone monotherapy. We reviewed 19 cases of OIIA-LPD in patients with idiopathic inflammatory myopathies and herein report the first case of MDA5-DM complicated with OIIA-LPD. Among the 19 patients, 7 showed regression of LPD only following withdrawal of immunosuppressants, 9 took chemotherapy for LPD, and 5 died. It should be noted that patients with MDA5-DM-associated rapidly progressive interstitial lung disease could develop OIIA-LPD because they receive aggressive immunosuppressive therapy.

Topics: Cyclophosphamide; Dermatomyositis; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Iatrogenic Disease; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Middle Aged; Prednisolone; Tacrolimus

Severe anemia requiring multiple blood transfusions in the posttransplant period can trigger rejection. The evaluation of anemia among transplant recipients is a challenging task. Awareness should be continued for tacrolimus to manage pure red cell aplasia, but further evidence is needed to prove whether tacrolimus is a real cause of posttransplant anemia. Our case patient, a 66-year-old male patient with end-stage renal disease due to diabetic nephropathy, underwent a preemptive living donor renal transplant in September 2018. He had received a coronary artery bypass graft with transcatheter aortic valve implantation 3 years before renal transplant. Initially, he was maintained on prednisolone, mycophenolate mofetil, and tacrolimus after basiliximab induction. One month later, he presented with low cardiac output symptoms. His complete blood count showed normocytic normochromic anemia with reticulocytopenia (his hemoglobin level dropped from 112 to 69 g/L), which necessitated regular blood transfusions. His iron profile, serum folate, and vitamin B12 were within normal limits, and he had negative hemolytic and autoimmune screening tests. A bone marrow biopsy revealed acquired pure red cell aplasia, which was most likely drug induced as viral profiles were negative for parvovirus B19, cytomegalovirus, and Epstein-Barr virus. The patient was managed by discontinuing mycophenolate mofetil, and the steroid dose was increased up to 20 mg/day but without improvement. With tacrolimus then considered, 3 weeks after presentation, we replaced tacrolimus with cyclosporine. Complete blood count follow-up showed improvement without any need for further blood transfusions. After 1 month of cyclosporine maintenance, mycophenolate mofetil was resumed with a steady increase of hemoglobin up to 150 g/L and serum creatinine of 122 μmol/L. Pure red cell aplasia is a rare disorder among renal transplant recipients, which could be induced by maintenance tacrolimus therapy.

Topics: Aged; Anemia; Cyclosporine; Epstein-Barr Virus Infections; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Red-Cell Aplasia, Pure; Tacrolimus; Transplant Recipients; Treatment Outcome

The development of lymphomas and solid malignancies in association with immunosuppression is a well-documented occurrence in the medical literature. We report the case of a young man who developed progressive diffuse lymphadenopathy with associated extremely high levels of serum Epstein-Barr virus in the setting of chronic immunosuppressive treatment of glomerulonephritis. Excisional biopsy of a right inguinal node revealed a sclerosing process with the morphologic appearance of angioimmunoblastic T-cell lymphoma with a CD3(+), CD4(+) immunophenotype. In situ hybridization of Epstein-Barr virus-encoded RNA was positive. Molecular probe studies demonstrated a clonal T-cell population. Upon reduction of immunosuppression, the patient's lymphadenopathy and Epstein-Barr virus titer have resolved without recurrence over 2 years time. This case demonstrates that a benign Epstein-Barr virus-associated process can mimic angioimmunoblastic T-cell lymphoma and should be considered particularly in the setting of immunosuppression, emphasizing the need for close communication with the treating physician in the interpretation of lymph node biopsies.

Topics: Adolescent; Diagnosis, Differential; Epstein-Barr Virus Infections; Glomerulonephritis; Herpesvirus 4, Human; Humans; Immunoblastic Lymphadenopathy; Immunocompromised Host; Immunosuppressive Agents; Lymph Nodes; Lymphadenitis; Lymphoma, T-Cell; Male; Nephrotic Syndrome; Tacrolimus; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Diabetic Nephropathies; Disease Progression; Epstein-Barr Virus Infections; Fatal Outcome; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Lumbar Vertebrae; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Pancreas Transplantation; Plasmacytoma; Postoperative Complications; Prednisone; Reoperation; Rituximab; Spinal Neoplasms; Tacrolimus; Thalidomide

Belatacept is employed alongside calcineurin inhibitor (CNI) therapy to prevent graft rejection in kidney transplant patients who are Epstein-Barr virus (EBV) seropositive. Preliminary data suggested that rates of post-transplant lymphoproliferative disorder (PTLD) were higher in individuals treated with belatacept compared to CNI therapy alone.. The records of 354 adults who underwent kidney only transplantation from January 2015 through September 2021 at one medical center were evaluated. Patients underwent treatment with either low-doses of mycophenolate, tacrolimus and sirolimus (B. Non-belatacept (MMF, tacrolimus and sirolimus) and belatacept-based (MMF, tacrolimus and belatacept) regimens do not appear to pose any increased risk of early onset PTLD. Both cohorts benefited from low rates of rejection, malignancy, mortality and graft failure. Recipients will continue to be monitored as PTLD can manifest as a long-term complication.

Topics: Abatacept; Adult; Calcineurin Inhibitors; Epstein-Barr Virus Infections; Graft Rejection; Graft Survival; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Neoplasms; Sirolimus; Tacrolimus

A 36-year-old male was admitted to our hospital with diarrhea, weakness and loss of appetite over two months. He had received a liver transplant two years before and was taking immunosuppressors (everolimus, mycophenolate mofetil and tacrolimus). Initial laboratory tests showed iron-deficiency anemia (Hb 9.8 g/dl), lymphopenia and mild elevation in C-reactive protein (35 mg/l). Blood and stool cultures, and cytomegalovirus (CMV) quantitation in blood were all negative. Finally, the colonoscopy showed two rectal fimbriated ulcers close to the anal sphincter and multiple biopsies from the ulcer margins identified the presence of Epstein-Barr virus (EBV). All symptoms were completely resolved three weeks after immunosuppression was diminished. He underwent a follow-up colonoscopy, without any evidence of the former ulcers.

Topics: Adult; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver; Male; Tacrolimus; Ulcer

Patients after heart transplantation are at increased risk for malignancy secondary to immunosuppression and oncogenic viral infections. Most common among children is posttransplant lymphoproliferative disorder (PTLD), occurring in 5% to 10% of patients. We used a national database to examine the incidence and risk factors for posttransplant malignancy.. The United Network for Organ Sharing database was queried for pediatric (<18 years) heart transplant recipients from October 1987 through November 2019. Freedom from malignancy after transplant was assessed with Kaplan-Meier analysis. Cox regression was performed to generate hazard ratios (HRs) and 95% CIs for risk of malignancy development.. Of 8581 pediatric heart transplant recipients, malignancy developed in 8.1% over median follow-up time of 6.3 years, with PTLD compromising 86.4% of the diagnosed cancers. The incidence of PTLD development was 1.3% at 1 year and 4.5% at 5 years. Older age at the time of transplant was protective against the development of malignancy (HR, 0.98; 95% CI, 0.96-0.99; P < .001), whereas a history of previous malignancy (HR, 1.9; 95% CI, 1.2-3.0; P = .007) and Ebstein-Barr virus (EBV) recipient-donor mismatch (HR, 1.7; 95% CI, 1.3-2.2; P < .001) increased the risk. Induction therapy, used in 78.9% of the cohort, did not increase malignancy risk (P = .355) nor did use of maintenance tacrolimus (P = .912).. PTLD occurred after 7% of pediatric heart transplants, with risk increased by younger age and EBV mismatch, highlighting the importance of PTLD monitoring in EBV-seronegative recipients. Induction therapy, used in most of the pediatric heart transplants, does not seem to increase posttransplant malignancy nor does tacrolimus, the most commonly used calcineurin inhibitor.

Topics: Calcineurin Inhibitors; Child; Epstein-Barr Virus Infections; Heart Transplantation; Herpesvirus 4, Human; Humans; Induction Chemotherapy; Lymphoproliferative Disorders; Neoplasms; Risk Factors; Tacrolimus

There is a scarcity of long-term data on steroid-free immunosuppression using alemtuzumab in pediatric kidney transplantation (KTx). This study examines long-term outcomes with alemtuzumab without steroid maintenance therapy in pediatric KTx.. From July 2005 to June 2015, 71 pediatric KTx recipients received alemtuzumab without steroid maintenance. They were followed from 4.1 to 14.1 years post KTx.. Patient survival: One child expired with a functioning graft from post-transplant lymphoproliferative disorder (PTLD). Patient survival was 98.6%. Graft survival: Eighteen grafts were lost (16 from chronic rejection). Graft survival at 5 and 10 years was 92.3% and 61.3%, respectively. Rejection: Twenty-three (32.4%) patients were free from T-cell-mediated rejection (TCMR), 16 (22.5%) had >3 episodes. Sixteen (22.5%) were treated for antibody-mediated rejection (AMR). Infection: Twenty-three children developed Epstein-Barr virus (EBV), 5 developed cytomegalovirus (CMV), and 20 developed BK virus infection. Four (5.6%) developed PTLD. Twenty-two (31.0%) required treatment for neutropenia. Growth parameters: Mean height and weight increased by 0.56 and 0.69 SDS (standard deviation score), respectively. Body mass index increased by 5.1 kg/m. Alemtuzumab, without corticosteroid maintenance, offers 98.6% patient survival at 14 years with five and 10-year graft survival of 92.3% and 61.3%, respectively. TCMR and AMR requiring treatment were 67.4% and 22.5%, respectively. CMV, EBV, and BK viremia rates were 7.0%, 32.4%, and 28.2%, respectively. Thirty-one percent were treated for neutropenia; 5.6% developed PTLD. There were improvements in growth parameters and blood pressure.

Topics: Adolescent; Alemtuzumab; Child; Child, Preschool; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Kidney Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Tacrolimus

PTLD is a clinical condition with high mortality. Monitoring EBV replication can be a useful tool to avoid the development of PTLD.. This was a retrospective analysis of 428 pediatric patients who underwent liver transplantation between 1989 and 2016. The patients were divided into 2 groups (transplanted before 2006, when PCR-EBV was not monitored, and after 2006, when PCR-EBV monitoring was started). Patients with continuous PCR measurements for EBV were evaluated for the impact of a reduction in immunosuppression or a change in immunosuppressants on the number of viral copies. A logistic regression model was applied to evaluate factors related to PTLD.. The prevalence of PTLD was 4.2%. After monitoring patients with PCR for EBV levels, a predominance of the most severe, monomorphic form of lymphoproliferative disorder was observed (p = .009). The PTLD mortality was 5%. There was a change in the PCR level after tacrolimus reduction (p = .002) and after tacrolimus exchange for mTOR (p = .008). The number of EBV copies was significantly higher (p = .029) in patients who developed PTLD. In the multiple regression model, seropositivity for CMV was an independent protective factor for lymphoproliferative disorder (OR=0.09; 95% CI 0.02-0.42), reducing the chance of having PTLD adjusted by serology for EBV by 91%.. Monitoring the EBV viral load by PCR seems to prevent the emergence of milder forms of lymphoproliferative disorder. Pretransplant seropositivity for CMV is a protective factor for PTLD.

Topics: Child; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Liver Transplantation; Lymphoproliferative Disorders; Polymerase Chain Reaction; Protective Factors; Retrospective Studies; Tacrolimus; Viral Load

Maintenance with "everolimus + reduced dose tacrolimus" (Ev + Tac. CMV and EBV viremia rates were similar in Ev + Tac. CMV-Tc and EBV-Tc were similar in Ev + Tac

Topics: Epstein-Barr Virus Infections; Everolimus; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; T-Lymphocytes; Tacrolimus

The intrapatient variability (IPV) of tacrolimus (Tac) is associated with the long-term outcome of kidney transplantation. The CYP3A single-nucleotide polymorphism (SNP) may affect the IPV of Tac. We investigated the impact of IPV and genetic polymorphism in pediatric patients who received kidney transplantation.. A total of 202 pediatric renal transplant recipients from 2000 to 2016 were analyzed retrospectively. The IPV was calculated between 6 and 12 months after surgery. Among these patients, CYP3A5 polymorphism was analyzed in 67 patients.. The group with high IPV had a significantly higher rate of de novo donor-specific human leukocyte antigen antibodies (dnDSA) development (35.7% vs. 16.7%, p = .003). The high IPV group also had a higher incidence of T-cell-mediated rejection (TCMR; p < .001). The high IPV had no significant influence on Epstein-Barr virus, cytomegalovirus, and BK virus viremia but was associated with the incidence of posttransplant lymphoproliferative disorders (p = .003). Overall, the graft survival rate was inferior in the high IPV group (p < .001). The CYP3A5 SNPs did not significantly affect the IPV of Tac. In the CYP3A5 expressor group, however, the IPV was significantly associated with the TCMR-free survival rate (p < .001).. The IPV of Tac had a significant impact on dnDSA development, occurrence of acute TCMR, and graft failure in pediatric patients who received renal transplantation. CYP3A5 expressors with high IPV of Tac showed worse outcomes, while the CYP3A5 polymorphism had no impact on IPV of Tac.

Topics: Child; Cytochrome P-450 CYP3A; Epstein-Barr Virus Infections; Genotype; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Polymorphism, Single Nucleotide; Retrospective Studies; Tacrolimus

Post-transplant lymphoproliferative disorder is a life-threatening complication of immunosuppression following transplantation mediated by failure of T cells to control Epstein-Barr virus (EBV)-infected and transformed B cells. Typically, a modification or reduction of immunosuppression is recommended, but insufficiently defined thus far. In order to help delineate this, we characterized EBV-antigen-specific T cells and lymphoblastoid cell lines from healthy donors and in patients with a kidney transplant in the absence or presence of the standard immunosuppressants tacrolimus, cyclosporin A, prednisolone, rapamycin, and mycophenolic acid. Phenotypes of lymphoblastoid cell-lines and T cells, T cell-receptor-repertoire diversity, and T-cell reactivity upon co-culture with autologous lymphoblastoid cell lines were analyzed. Rapamycin and mycophenolic acid inhibited lymphoblastoid cell-line proliferation. T cells treated with prednisolone and rapamycin showed nearly normal cytokine production. Proliferation and the viability of T cells were decreased by mycophenolic acid, while tacrolimus and cyclosporin A were strong suppressors of T-cell function including their killing activity. Overall, our study provides a basis for the clinical decision for the modification and reduction of immunosuppression and adds information to the complex balance of maintaining anti-viral immunity while preventing acute rejection. Thus, an immunosuppressive regime based on mTOR inhibition and reduced or withdrawn calcineurin inhibitors could be a promising strategy for patients with increased risk of or manifested EBV-associated post-transplant lymphoproliferative disorder.

Topics: Calcineurin; Cyclosporine; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lymphoproliferative Disorders; MTOR Inhibitors; Mycophenolic Acid; Prednisolone; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

We report a case of donor-derived diffuse large B-cell lymphoma (DLBCL), which developed 5 years after stem cell transplantation from a human leukocyte antigen (HLA)-haploidentical donor for acute myeloid leukemia (AML). A 51-year-old male was diagnosed with AML with variant KMT2A translocation involving t(6;11)(q13;q23). After 12 cycles of azacitidine treatment, fluorescence in situ hybridization (FISH) for KMT2A split signal indicated that 94% of his bone marrow (BM) cells were positive. He underwent peripheral blood stem cell transplantation (PBSCT) from his HLA-haploidentical son. The preconditioning regimen consisted of fludarabine, busulfan, melphalan, and antithymocyte globulin (ATG). The graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and short-term methotrexate. On day 28, KMT2A FISH analysis indicated that he had achieved a complete response (CR). He continued to receive tacrolimus for the limited type of cutaneous chronic GVHD. Five years after the transplantation, positron emission tomography/computed tomography (PET/CT) showed an abdominal tumor. The tumor was diagnosed as DLBCL without Epstein-Barr virus. BM aspiration revealed the infiltration of lymphoma cells with t(8;14)(q24;q32). Chimerism analysis showed that both the peripheral blood (PB) and abdominal lymphoma cells were of donor origin. After 4 cycles of salvage chemotherapy, PET/CT showed that a CR had been achieved. He underwent a second PBSCT from an HLA-identical unrelated donor. The preconditioning regimen and GVHD prophylaxis were the same as those for the first PBSCT without ATG. The patient's PB revealed complete second donor-type chimerism, and the patient has maintained a CR since the second transplantation.

Topics: Antilymphocyte Serum; Azacitidine; Busulfan; Epstein-Barr Virus Infections; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; HLA Antigens; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myeloid, Acute; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methotrexate; Middle Aged; Positron Emission Tomography Computed Tomography; Tacrolimus; Transplantation Conditioning

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA-LPDs, including 36 with diffuse large B-cell lymphoma (DLBCL)-type and 19 with Hodgkin lymphoma (HL)-type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein-Barr virus positivity in DLBCL-type (P = 0·013). The 2-year overall survival and progression-free survival (PFS) at a median follow-up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2-year PFS was seen between patients with DLBCL-type and HL-type OIIA-LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour-derived DNA from 20 DLBCL-type OIIA-LPD samples, histone-lysine N-methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha-induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL-type OIIA-LPD. Cases with DLBCL-type OIIA-LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA-LPDs, especially DLBCL-types, showed favourable prognoses.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Histone-Lysine N-Methyltransferase; Hodgkin Disease; Humans; Iatrogenic Disease; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Kaplan-Meier Estimate; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Myeloid-Lymphoid Leukemia Protein; Prognosis; Progression-Free Survival; Proportional Hazards Models; Receptors, Tumor Necrosis Factor, Member 14; Retrospective Studies; Rheumatic Diseases; Tacrolimus; Tumor Necrosis Factor alpha-Induced Protein 3

To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs).. All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study.. During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred.. EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Topics: Age Factors; Anti-Allergic Agents; Biliary Atresia; Budesonide; Child; Child, Preschool; Cholestasis, Intrahepatic; Dermatitis, Atopic; Disease Progression; Drug Tapering; Enteritis; Enterocolitis; Eosinophilia; Eosinophilic Esophagitis; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Gastritis; Glucocorticoids; Graft Rejection; Humans; Hypersensitivity; Immunosuppressive Agents; Infant; Ketotifen; Liver Failure, Acute; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Viremia

Posttransplant lymphoproliferative disorder (PTLD) occurs in 1% to 3% of adult renal transplant recipients (RTRs). PTLD has a heterogeneous presentation and is often associated with Epstein-Barr virus (EBV) and immunosuppression. We present a descriptive case series of 16 RTRs who demonstrate a variety of PTLD manifestations. Fifty-six percent received rabbit antithymocyte globulin induction, and 37.5% received basiliximab. Maintenance immunosuppression included glucocorticoids, tacrolimus, and mycophenolate mofetil. Median time from transplantation to PTLD diagnosis was 96.5 months. PTLD involved a single site in 44% of RTRs and multiple sites in 56%. PTLD was localized to the gastrointestinal tract in 9 RTRs, in lymph nodes in 9, central nervous system in 4, bone marrow in 3, skin in 3, lungs in 2, perinephric space in 2, mediastinum in 1, and native kidney in 1. PTLD was EBV positive in 8 RTRs, monomorphic/monoclonal in 14, and of B-cell lineage in 13. Three RTRs had T-cell PTLD. Immunosuppressive agents, except glucocorticoids, were discontinued at diagnosis. Treatment was chemotherapy either alone (in 14 RTRs) or in combination with radiation. Complete remission was achieved in 62.5% of RTRs. Renal dysfunction developed in 62.5% of RTRs, and 4 received dialysis. The overall mortality rate was 62.5%, with median time of death 6.5 months after diagnosis. PTLD that was EBV negative and had T-cell involvement presented with aggressive disease and a higher mortality. Clinicians should be aware of the various PTLD manifestations. Early diagnosis and a multidisciplinary approach to treatment is crucial for improved patient outcomes.

Topics: Adult; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphoma; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Postoperative Complications; Renal Dialysis; Tacrolimus; Treatment Outcome

To examine and characterize post-transplant eosinophilic gastrointestinal disorders (PTEGID) and post-transplant lymphoproliferative disorder (PTLD) in pediatric liver transplant recipients.. This is a single center retrospective study of all liver transplant recipients aged 0-18 years from 1999 to 2019 who received tacrolimus as their primary immunosuppressant. Demographic data and clinical/laboratory data including PTEGID, PTLD, liver transplant types, Epstein-Barr virus status, and blood eosinophil count were reviewed. Analysis was done with logistic regression and Mann-Whitney U test.. Ninety-eight pediatric liver transplant recipients were included with median age at transplantation of 3.3 years (IQR: 1.1-9.3). The major indication for transplantation was biliary atresia, 51 (52%) cases. Eight (8%) children had PTLD and 14 (14%) had PTEGID. Receiving liver transplantation at an age of ≤1 year was associated with developing PTEGID (OR = 11.9, 95% CI = 3.5-45.6, p < 0.001). Additionally, eosinophilic count of ≥500/μL was associated with having PTLD (OR = 10.7, 95% CI = 1.8-206.0, p = 0.030) as well as having at least one liver rejection (OR = 2.8, 95% CI = 1.2-7.0, p = 0.024). The frequency of food-induced anaphylaxis significantly increased post-transplantation (p = 0.023).. PTEGID and PTLD are common in this cohort and are associated with certain risk factors that help screen children to improve recipient survival. Further studies are needed to evaluate the clinical benefits of these findings.

Topics: Child; Epstein-Barr Virus Infections; Gastrointestinal Diseases; Herpesvirus 4, Human; Humans; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Retrospective Studies; Tacrolimus

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication after organ transplantation frequently associated with the Epstein-Barr virus (EBV). Immunosuppressive treatment is thought to allow the expansion of EBV-infected B cells, which often express all eight oncogenic EBV latent proteins. Here, we assessed whether HLA-A2 transgenic humanized NSG mice treated with the immunosuppressant FK506 could be used to model EBV-PTLD. We found that FK506 treatment of EBV-infected mice led to an elevated viral burden, more frequent tumor formation and diminished EBV-induced T cell responses, indicative of reduced EBV-specific immune control. EBV latency III and lymphoproliferation-associated cellular transcripts were up-regulated in B cells from immunosuppressed animals, akin to the viral and host gene expression pattern found in EBV-PTLD. Utilizing an unbiased gene expression profiling approach, we identified genes differentially expressed in B cells of EBV-infected animals with and without FK506 treatment. Upon investigating the most promising candidates, we validated sCD30 as a marker of uncontrolled EBV proliferation in both humanized mice and in pediatric patients with EBV-PTLD. High levels of sCD30 have been previously associated with EBV-PTLD in patients. As such, we believe that humanized mice can indeed model aspects of EBV-PTLD development and may prove useful for the safety assessment of immunomodulatory therapies.

Topics: Animals; B-Lymphocytes; Disease Models, Animal; DNA, Viral; Epstein-Barr Virus Infections; Female; Gene Expression Profiling; Herpesvirus 4, Human; HLA-A2 Antigen; Humans; Immunocompromised Host; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred NOD; Mice, Transgenic; Organ Transplantation; Tacrolimus; Transcriptome; Viral Load

Duodenal ulcers are most often caused by Helicobacter pylori (HP) infection, followed by nonsteroidal anti-inflammatory drugs and hypoperfusion. Posttransplant lymphoproliferative disorder (PTLD) occurs in about 1-6.3% of patients with a heart transplant under immunosuppression therapy. Up to 25% of cases of PTLD have gastrointestinal involvement. Due to a wide spectrum of clinical symptoms and pathological entities, the diagnosis can be challenging. We report the case of a 55-year-old man 12 years after receiving a heart transplant being treated with immunosuppressive agents (tacrolimus) who presented with recurrent bleeding from peptic duodeni. Immunohistochemistry revealed a rare Epstein-Barr-virus-associated polymorphic PTLD. Rarely, PTLD can manifest only with isolated lesions of the duodenal bulb. The course was progressive, going from an incidental finding requiring transfusion anemia to a perforation within 1 month. Repeated endoscopic interventions were unsuccessful. After a surgical intervention the patient died in the course of multiple organ failure. Retrospectively, a reduction of immunosuppression in polymorphic PTLD would have been a treatment option.

Topics: Duodenal Ulcer; Epstein-Barr Virus Infections; Fatal Outcome; Heart Transplantation; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Middle Aged; Prognosis; Tacrolimus; Treatment Outcome

This study is aimed to investigate the risk factors and clinical characteristics of posttransplant lymphoproliferative disorder (PTLD) after conducting Epstein-Barr virus (EBV) viral load monitoring in pediatric liver transplant (LT) patients in Taiwan, where EBV infection is endemic.. From 2007 to 2013, pediatric LT recipients who underwent EBV viral load monitoring within 3 months after LT were recruited in this study. The impact of clinical parameters-including age at LT, sex, peak EBV viral load and immunosuppressant levels after LT-on the risk of PTLD were assessed.. A total 39 patients underwent LT at a median age of 1.3 years (range: 0.6-14.0 years), and 5 patients developed PTLD during follow-up. Cox's proportional-hazards model identified two predictors of PTLD: peak EBV viral load within 3 months of LT >4100 copies/μg peripheral blood mononuclear cells (PBMC) DNA and peak tacrolimus level within 3 months of LT >14.8 ng/mL (Hazard ratio = 17.14 and 11.54, P = 0.02 and 0.03, respectively). Kaplan-Meier survival analysis revealed significant higher cumulative incidence rates of PTLD (27.3% and 41.8% at 0.3 and 1.2 years after LT) in subjects with peak EBV viral load >4100 copies/μg PBMC DNA within 3 months after LT. (P = 0.001, log-rank test).. Close monitoring of EBV viral load within 3 months after LT is helpful to predict a high risk of PTLD. Tapering of immunosuppressants is suggested if the EBV viral load is >4100 copies/μg PBMC DNA in LT children.

Topics: Adolescent; Child; Child, Preschool; DNA, Viral; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Kaplan-Meier Estimate; Leukocytes, Mononuclear; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Proportional Hazards Models; Tacrolimus; Taiwan; Viral Load

A 27-year old caucasian male was diagnosed 2.7 years after kidney transplantation with Epstein-Barr virus (EBV)-associated smooth muscle tumors in liver and spleen. The reduction in immunosuppression and conversion from tacrolimus to sirolimus did not lead to a regression of the tumors. Additionally, the patient developed a cellular rejection of his renal allograft, which was successfully treated. A combined approach with stereotactic radiofrequency ablation (SRFA) and surgical resection was effective in the treatment of the tumors.

Topics: Adult; Epstein-Barr Virus Infections; Graft Rejection; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Liver; Male; Radiosurgery; Sirolimus; Smooth Muscle Tumor; Spleen; Tacrolimus; Treatment Outcome

Primary effusion lymphoma (PEL) is a rare type of extranodal lymphoma, typically of a B-cell origin, which presents as lymphomatous effusion with no nodal enlargement or tumor masses. The development PEL is universally associated with human herpes virus-8 (HHV-8) infection. Cases of HHV-8-negative primary lymphomatous effusion have recently been reported and referred to as HHV-8-unrelated PEL-like lymphoma. Some cases of this disease have been reported in iatrogenic immunocompromised patients. The mechanisms responsible for the inhibitory effects of the discontinuation of immunosuppressants other than methotrexate (MTX) against the disease, which have been demonstrated for MTX-associated lymphoproliferative disorders, have not yet been elucidated. We describe a case of PEL-like lymphoma that developed in the course of antisynthetase syndrome and was treated with tacrolimus. A single dose of systemic chemotherapy did not improve lymphomatous effusion, whereas the discontinuation of tacrolimus resulted in the long-term remission of this disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Epstein-Barr Virus Infections; Female; Herpesvirus 8, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; Lymphoma, Primary Effusion; Middle Aged; Myositis; Prednisolone; Tacrolimus; Treatment Outcome; Vincristine; Withholding Treatment

The aim of the present study was to describe the salivary shedding of human herpesviruses (HHV) in renal transplant recipients and to observe the oral manifestations in this group.. A prospective case-control study was conducted with a study group of 20 renal transplant recipients and a control group of 20 non-transplanted, immunocompetent individuals. Clinical examination evaluated the presence of drug-induced gingival overgrowth (DIGO), salivary flow, and caries. Stimulated saliva was collected from both groups, with HHV being detected by using real-time polymerase chain reaction.. The mean age of the study group was 45.90 ± 9.89 years, with 55% (11/20) being female, 60% (12/20) being Caucasian, 65% (13/20) having a deceased donor, and 70% (14/20) having used tacrolimus as the main immunosuppressive drug. Renal transplant recipients had shedding of more herpesviruses compared to the control group, with the exception of HHV-7. Statistical significance was found for herpes simplex virus-1 (HSV-1) (P = 0.017) and cytomegalovirus (P = 0.035). DIGO was observed in seven patients (35%), with 35% (7/20) presenting with decreased salivary flow and four (20%) reporting xerostomia.. Renal transplant recipients excreted herpesviruses more often than control individuals, especially HSV-1. Decreased salivary flow and xerostomia were more frequent in patients who used tacrolimus, whereas those who used cyclosporine had more cases of DIGO.

Topics: Brazil; Case-Control Studies; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Female; Herpes Simplex; Herpesviridae; Herpesviridae Infections; Herpesvirus 1, Human; Herpesvirus 4, Human; Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prevalence; Prospective Studies; Real-Time Polymerase Chain Reaction; Roseolovirus Infections; Saliva; Tacrolimus; Virus Shedding

Post-transplant lymphoproliferative disorder is a severe complication in solid organ transplant recipients, which is highly associated with Epstein-Barr virus infection in pediatric patients and occasionally presents as Burkitt- or Burkitt-like lymphoma. The mammalian target of rapamycin (mTOR) pathway has been described as a possible antitumor target whose inhibition may influence lymphoma development and proliferation after pediatric transplantation. We treated Epstein-Barr virus positive (Raji and Daudi) and negative (Ramos) human Burkitt lymphoma derived cells with mTOR inhibitor everolimus alone and in combination with clinically relevant immunosuppressive calcineurin inhibitors (tacrolimus or cyclosporin A). Cell proliferation, toxicity, and mitochondrial metabolic activity were analyzed. The effect on mTOR Complex 1 downstream targets p70 S6 kinase, eukaryotic initiation factor 4G, and S6 ribosomal protein activation was also investigated. We observed that treatment with everolimus alone significantly decreased Burkitt lymphoma cell proliferation and mitochondrial metabolic activity. Everolimus in combination with cyclosporin A had a stronger suppressive effect in Epstein-Barr virus negative but not in Epstein-Barr virus positive cells. In contrast, tacrolimus completely abolished the everolimus-mediated suppressive effects. Moreover, we showed a significant decrease in activation of mTOR Complex 1 downstream targets after treatment with everolimus that was attenuated when combined with tacrolimus, but not with cyclosporin A. For the first time we showed the competitive effect between everolimus and tacrolimus when used as combination therapy on Burkitt lymphoma derived cells. Thus, according to our in vitro data, the combination of calcineurin inhibitor cyclosporin A with everolimus is preferred to the combination of tacrolimus and everolimus.

Topics: Antineoplastic Agents; Burkitt Lymphoma; Calcineurin; Cell Proliferation; Cell Survival; Cyclosporine; Drug Therapy, Combination; Epstein-Barr Virus Infections; Everolimus; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Mitochondria; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Tacrolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Posttransplantation lymphoproliferative disorder (PTLD) in infants after liver transplantation is strongly associated with tacrolimus (Tac) administration and primary Epstein-Barr virus (EBV) transmission.. From 1991 to 2012, 32 survivors younger than 2 years who had undergone living-donor liver transplantation using Tac for primary immunosuppression were retrospectively investigated for changes in Tac trough levels before and at the onset of posttransplantation viral infection episodes.. Twenty-one recipients experienced 33 viral infection episodes associated with EBV-related PTLD (n = 5), symptomatic EBV infection without development of PTLD (n = 8), and other viral infections (n = 20). Although the average Tac trough levels during the 2 months before the onset of viral infection episodes were similar among the 33 episodes (9.0 ± 2.8 ng/mL), the Tac trough levels at the onset were significantly higher in the episodes with PTLD than in those with EBV infection without the development of PTLD and with other viral infections (19.2 ± 9.0 ng/mL vs. 9.3 ± 5.2 ng/mL and 10.6 ± 5.1 ng/mL, respectively) (P<0.05). Tacrolimus trough levels at the onset of PTLD were significantly higher during the 2 months before the onset (median, 1.83 times higher than average) compared with EBV infection (1.14 times higher) and other viral infections (1.06 times higher) (P<0.05). The Tac blood concentration-to-dose ratio at the onset of PTLD was more than twice as high as the average value during the 2 months before the onset.. Deteriorated Tac metabolism accompanied by a positive change in the blood EBV DNA load may enable us to predict the development of PTLD in liver-transplanted infants with viral infection.

Topics: Age Factors; Biomarkers; DNA, Viral; Drug Monitoring; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Living Donors; Lymphoproliferative Disorders; Male; Predictive Value of Tests; Retrospective Studies; Risk Factors; Tacrolimus; Viral Load

Epstein-Barr virus (EBV)-associated posttransplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), although effective in SCT, is less successful after SOT where lifelong immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin (CN) inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined whether or not FK506-resistant EBV-CTLs control EBV-driven tumor progression in the presence of immunosuppression in a xenogeneic mouse model. NOD/SCID/IL2rγ(null) mice bearing human B-cell lymphoma were injected with autologous CTLs transduced with either CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506, whereas eGFP-CTLs did not. CNA12-CTLs persisted longer, homed to the tumor, and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control-treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumors in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Drug Resistance; Epstein-Barr Virus Infections; Genetic Engineering; Genetic Therapy; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Immunotherapy, Adoptive; Lymphoma; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; T-Lymphocytes, Cytotoxic; Tacrolimus; Transduction, Genetic

To summarize the clinical characteristics, early diagnosis, comprehensive treatment and prognosis of 6 cases of children with post-transplantation lymphoproliferative disorder (PTLD) after liver transplantation.. Data of 6 cases with PTLD seen between January 2011 and December 2013 were retrospectively analyzed. The anti-rejection drug dose adjustments, the effect of rituximab, antiviral therapy and comprehensive treatment program after surgery were explored.. (1) The diagnosis of PTLD was confirmed by histologic findings. Six cases of PTLD including 3 males and 3 females were diagnosed as congenital biliary atresia and underwent split liver transplantation. The occurrence rate of PTLD was 2.9%. (2) The median time to the development of PTLD was less than 6 months. The initial symptom of PTLD in all patients was fever and clinical manifestations of PTLD were non-specific, depending on the involving organs. Five cases of PTLD developed gastrointestinal symptoms, including diarrhea, abdominal pain, and abdominal distension. One case developed respiratory symptoms, including cough and tachypnea. Three cases had lymph node involvement. In 2 cases pathophysiology involved polymorphic lymphocyte proliferation and in 4 cases B lymphocyte proliferation. (3) Two cases died, in whom EBV DNA was not detected and were diagnosed as PTLD by surgical pathology before death. Four survived cases had high EBV-DNA load and then were diagnosed as PTLD by biopsy pathology. (4) Of the 6 cases of PTLD, 2 cases died and 4 cases survived. The overall mortality was 33%. The dead cases were only treated with laparotomy because of intestinal obstruction or perforation and the survived cases were treated with tacrolimus at reduced doses or discontinuation and rituximab. In 2 cases antiviral therapy (acyclovir) was continued, including 1 cases of intestinal obstruction treated with surgical repair. All the survived patients were followed up for 4 months to 1 year and no evidence has been found.. EBV infection is the high risk factor for PTLD after liver transplantation. Close clinical surveillance of EBV DNA for pediatric liver transplantation was important for the early diagnosis of PTLD. Reducing doses of immunosuppressive agents and rituximab is the initial therapy for PTLD. A reduction in the dose of tacrolimus is suggested. Operation therapy can also play a role in the management of local complications.

Topics: Antiviral Agents; Biliary Atresia; DNA, Viral; Drug Therapy, Combination; Early Diagnosis; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Pediatrics; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus

PTLDs are a well-recognized and potentially fatal complication after intestinal transplantation. We analyzed the incidence, clinical features, and outcome in a 63 intestinal transplantation series performed in our unit between October 1999 and July 2011. Types of graft included ISB (n = 23), LSB (n = 20), and MV (n = 20). Patients were categorized into three groups of immunosuppression: I (n = 43) received basiliximab, tacrolimus, and steroids; II (n = 11) thymoglobulin and tacrolimus, and III (n = 9) alemtuzumab and tacrolimus. EBV status was serially assessed. All PTLD cases were biopsied to establish histopathological diagnosis. The incidence of PTLD was 14.2% (9/63). Median onset of PTLD after transplant was four months (range: 0.5-28), within first postoperative year in 6 (66.6%) patients. Fever was the most common symptom. Graft removal was needed in four patients (44%). The patient survival rate was 66.6% (6/9). We have not found any association between PTLD and immunosuppression regimen or transplant type. However, there was a statistical association with EBV active infection.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Child, Preschool; Epstein-Barr Virus Infections; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infant; Intestines; Lymphoproliferative Disorders; Male; Postoperative Complications; Postoperative Period; Recombinant Fusion Proteins; Retrospective Studies; Steroids; Tacrolimus; Transplantation; Treatment Outcome

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) remains a major cause of morbidity and mortality after hematopoietic stem cell (HSCT) or solid organ transplant (SOT). Strategies to reconstitute immunity by adoptive transfer of EBV-specific cytotoxic T lymphocyte (CTL) therapy while highly effective in the HSCT setting where immunosuppression can be withdrawn have been less successful in the SOT setting where continued immunosuppression therapy is necessary. Additionally, the complexity and time taken to generate EBV-CTLs for adoptive transfer limit the clinical applicability. We have developed a system for the rapid generation of EBV-CTLs resistant to immunosuppression based on selection of interferon-gamma (IFN-γ) secreting EBV-CTLs and retroviral transduction with a calcineurin B mutant. With this methodology, EBV-CTLs resistant to the calcineurin inhibitor Tacrolimus (TAC) can be produced in 14 days. These CTLs show high specificity for EBV with negligible alloreactivity in both proliferation and cytotoxicity assays and are able to proliferate and secrete IFN-γ in response to antigen stimulation in the presence of therapeutic doses of TAC. This strategy will substantially facilitate clinical application of this approach for the treatment of PTLD in SOT recipients.

Topics: Antigens; Calcineurin; Calcineurin Inhibitors; Cell Proliferation; Epstein-Barr Virus Infections; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Humans; Immunologic Memory; Immunosuppression Therapy; Immunotherapy, Adoptive; Interferon-gamma; Leukocytes, Mononuclear; Lymphoma; Mutation; Organ Transplantation; Phenotype; Postoperative Complications; Retroviridae; T-Lymphocytes; T-Lymphocytes, Cytotoxic; Tacrolimus

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Cisplatin; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Epstein-Barr Virus Infections; Etoposide; Female; Humans; Immunosuppressive Agents; Lymphoma, T-Cell, Peripheral; Melphalan; Methotrexate; Middle Aged; Nitrosourea Compounds; Pharyngitis; Prednisolone; Recurrence; Rituximab; Salvage Therapy; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vincristine; Whole-Body Irradiation

The association of immunosuppressive regimens (ISRs) with posttransplant lymphoproliferative disorder (PTLD) may be related with the Epstein-Barr virus (EBV) recipient serostatus.. We selected primary kidney transplant recipients from Organ Procurement Transplant Network/United Network for Organ Sharing database (2000-2009) who were discharged with a functioning graft and were receiving an ISR including an antiproliferative drug and a calcineurin inhibitor as follows: mycophenolate mofetil (MMF)/mycophenolate sodium+tacrolimus (TAC), MMF+cyclosporine A (CsA); mammalian target of rapamycin inhibitor (mTORi)+TAC; and mTORi+CsA. Adjusted risks of PTLD, rejection, death, and graft failure were examined in all recipients and compared between EBV+ and EBV- recipients.. Of 114,025 recipients, 754 developed PTLD (5-year incidence of 0.84%). Adjusted hazard ratio for PTLD was 4.39 (95% CI: 3.60-5.37) for EBV- versus EBV+ recipients; and 1.40 (95% CI: 1.03-1.90) for mTORi+TAC, 0.80 (95% CI: 0.65-0.99) for MMF+CsA, and 0.90 (95% CI: 0.57-1.42) for mTORi+CsA, versus MMF+TAC users. In EBV- recipients, hazard ratio for PTLD was 1.98 (95% CI: 1.28-3.07) for mTORi+TAC, 0.45 (95% CI: 0.28-0.72) for MMF+CsA, and 0.84 (95% CI: 0.39-1.80) for mTORi+CsA users versus MMF+TAC. No difference was seen in EBV+ recipient groups. Rejection rates were higher among MMF+CsA recipients in both EBV groups. Death and graft failure risk were increased in all EBV+ISR groups, while in EBV- these risks were only increased in mTORi+TAC group versus MMF+TAC.. In EBV- recipients, immunosuppression with mTORi+TAC was associated with increased risk of PTLD, death, and graft failure, while MMF+CsA use was associated with a trend to increased risk of rejection, lower PTLD risk, and similar risk for graft failure when compared with MMF+TAC.

Topics: Adolescent; Adult; Comorbidity; Cyclosporine; Drug Therapy, Combination; Epstein-Barr Virus Infections; Female; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Transplantation; Longitudinal Studies; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Transplantation; Young Adult

Topics: Arthritis, Juvenile; Child, Preschool; Epstein-Barr Virus Infections; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Prednisolone; Stomach Ulcer; Tacrolimus

EBV-associated PTLD is a serious complication of liver transplantation. We performed periodical molecular EBV monitoring in 140 consecutive pediatric patients who had living-related liver transplantation in the National Center for Child Health and Development, Tokyo. Sixty-three of the 140 patients showed elevation of EBV DNA level to >10(2) copies/μg DNA and were further examined immunologically by flow cytometry, and the dose of tacrolimus and/or cyclosporine A was adjusted according to the results. The decrease in CD4/CD8 ratio and the increase in the number of HLA-DR(+) CD8(+) cells were observed in parallel with the decrease in EBV DNA load and in the number of CD19(+) CD23(+) cells following the reduction in immunosuppressive drugs. Analysis with HLA tetramers in a patient demonstrated a dramatic increase in the number of CD8(+) T cells specific to the EBV latent protein LMP2 accompanying the decline of EBV DNA load, suggesting that T cells of this specificity were actually involved in the control of EBV infection. No clinically apparent PTLD has developed in the 140 recipients, suggesting that our program of EBV control by molecular EBV monitoring coupled with lymphocyte phenotype analyses is effective in controlling EBV infection in pediatric liver transplant recipients.

Topics: Adolescent; Adult; Antigens, CD19; CD8-Positive T-Lymphocytes; Child; Child, Preschool; Cyclosporine; DNA, Viral; Epstein-Barr Virus Infections; Flow Cytometry; Herpesvirus 4, Human; Humans; Infant; Infant, Newborn; Liver Failure; Liver Transplantation; Lymphocytes; Receptors, IgE; Tacrolimus; Viral Load; Viral Matrix Proteins

The objective of this study was to identify the incidence of posttransplantation lymphoproliferative disease (PTLD) among children within 1 year after liver transplantation.. This retrospective review analyzed information in medical charts of pediatric (younger than 18 years of age) recipients of liver transplants between September 2000 and December 2007.. Seventy-one patients underwent a liver transplantation and 7 (9.85%) developed PTLD. Among this group, 6 children were girls and 1 was a boy. The median age at transplantation was 35.14 months. Indications that led the children to have their transplantation were 1 case of hemangioendothelioma, 1 case of autoimmune hepatic cirrhosis, 1 case of alpha-1-antitrypsin deficiency, and 4 cases of biliary atresia. The most frequent symptoms were splenomegaly, diarrhea, and fever. The median time from the first symptoms to the initial treatment was 9.7 days. The standard treatment was withdrawal of immunosuppression and close observation of tacrolimus levels and liver function tests associated with antiviral drugs and chemotherapy. Four among 7 children died; 3 children recovered. All 3 children who recovered has presented at the transplantation center within 5 days of initiation of symptoms (P = .033896).. Despite its rarity, when it occurs, PTLD shows a high mortality rate. Therefore, it is necessary to have interdisciplinary work between the medical team that performs the transplantation and those promoting the primary care to diagnose the disease early and treat it effectively.

Topics: alpha 1-Antitrypsin Deficiency; Biliary Atresia; Child; Child, Preschool; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Splenomegaly; Tacrolimus

Post-transplantation lymphoproliferative disorder (PTLD) is a major cause of morbidity and mortality after pediatric heart transplantation.. Heart transplant recipients at The Hospital for Sick Children, Toronto, from 1990 to May 2008, were reviewed. Competing risk hazard analysis was used to model the natural history of the disease. Patients were matched for gender and duration of follow-up to identify potential covariates associated with increased risk of PTLD.. A total of 173 heart transplant recipients (42% <1 year old) were reviewed. Twenty-three developed PTLD at a median of 4 years post-transplantation. After transplantation, PTLD affected 9%, 15% and 28% at 3, 5 and 10 years, respectively. Freedom from death or PTLD recurrence was 72%, 58% and 50% at 1, 3 and 5 years, respectively, after PTLD diagnosis. Higher maximum Epstein-Barr viral (EBV) load (hazard ratio [HR]: 2.6, p = 0.004) and longer duration of induction therapy (HR: 1.7, p = 0.02) were associated with increased risks of PTLD. Higher cumulative cyclosporine doses over the first year post-transplantation were associated with increased risks of PTLD (HR: 1.2 per 1 mg/kg/day equivalent, p = 0.03), but higher tacrolimus doses were not (p = 0.38). Patients on cyclosporine at 6 months post-transplantation were at higher risk of PTLD than those on tacrolimus (HR: 5.2, p = 0.003). The use of anti-viral prophylaxis in patients with high EBV load may provide some protection (HR: 7.6 vs 15.4 with no anti-viral, p = 0.02).. PTLD is a major concern in pediatric heart transplant recipients and is associated with high morbidity/mortality. Exposure to EBV and higher intensity of immunosuppression seems to be associated with increased risk.

Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Cyclosporine; Dose-Response Relationship, Drug; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Heart Transplantation; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Lymphoproliferative Disorders; Male; Proportional Hazards Models; Recurrence; Risk Assessment; Tacrolimus; Time Factors; Viral Load; Young Adult

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation that has been linked to Epstein-Barr virus (EBV) infection. The aim of this article was to describe a single-center experience with the multiplicity of clinical presentations of PTLD. Among 350 liver transplantations performed in 303 children, 13 survivor children displayed a histological diagnosis of PTLD (13/242 survivors; 5.4%). The age at diagnosis ranged from 12 to 258 months (median, 47), and the time from transplantation ranged from 1 to 84 months (median, 13). Ten of these children (76.9%) were EBV-naïve prior to transplantation. Fever was present in all cases. The clinical signs at presentation were anemia (92.3%), diarrhea and vomiting (69.2%), recurrent upper airway infections (38.4%), Waldeyer ring lymphoid tissue hypertrophy (23.0%), abdominal mass lesions (30.7%), massive cervical and mediastinal adenopathy (15.3%), or gastrointestinal and respiratory symptoms (30.7%). One child developed fulminant hepatic allograft failure secondary to graft involvement by PTLD. Polymorphic PTLD was diagnosed in 6 patients; 7 had the diagnosis of lymphoma. Treatment consisted of stopping immunosuppression as well as starting intravenous gancyclovir and anti-CD20 monoclonal antibody therapy. The mortality rate was 53.8%. The clinical presentation of PTLD varied from fever of unknown origin to fulminant hepatic failure. The other symptoms that may be linked to the diagnosis of PTLD are pancytopenia, tonsil and adenoid hypertrophy, cervical or mediastinal lymph node enlargement, as well as abdominal masses. Despite numerous advances, the optimal treatment approach for PTLD is not completely known and the mortality rate is still high.

Topics: Biliary Atresia; Child; Child, Preschool; Colonic Neoplasms; Cyclosporine; Drug Therapy, Combination; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymph Nodes; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Postoperative Complications; Prednisone; Retrospective Studies; Survivors; Tacrolimus

We studied the incidence, risk factors, treatment, and outcomes of post-transplantation lymphoproliferative disorder (PTLD) that occurred at the University of Michigan since 1964.. We identified 7,040 patients who received solid organ transplantation (SOT) and post-transplantation immunosuppressive therapy. Seventy-eight patients developed PTLD.. Diffuse large B-cell lymphoma (n = 43), polymorphic PTLD (n = 10), Hodgkin's lymphoma (n = 7), Burkitts lymphoma (n = 6), plasmacytoma (n = 5), and mucosa-associated lymphoid tissue lymphoma (n = 3) were all over-represented in the SOT population compared with a population sample from the Surveillance, Epidemiology, and End Results (SEER) database; follicular lymphoma (n = 0) was underrepresented. Negative pretransplantation Epstein-Barr virus (EBV) serology was a risk factor for PTLD. Available histologic analysis of tumor tissue showed that 75% were CD20 positive and that 62% were EBV positive; EBV-positive tumors occurred sooner after SOT than EBV-negative tumors (mean, 29 v 66 months). Extralymphatic disease (79%), poor performance status (68%), elevated lactate dehydrogenase (LDH; 71%), and advanced stage (68%) disease were all common at the time of lymphoma diagnosis. Two thirds of patients had a complete response when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone-like chemotherapy (either with or without rituximab). Median overall survival in all patients with PTLD was 8.23 years (95% CI, 2.28 to 30.0 years).. EBV-naïve patients who receive a donor organ from an EBV-infected donor are in the highest-risk situation for PTLD development. Most of these lymphomas are CD20 positive. Follicular lymphoma is unusual. With treatment, survival of patients with PTLD was indistinguishable from that of the SEER population sample.

Topics: Adolescent; Adult; Aged; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunohistochemistry; Immunosuppressive Agents; In Situ Hybridization; Kaplan-Meier Estimate; Lymphoma; Lymphoproliferative Disorders; Male; Michigan; Middle Aged; Organ Transplantation; Risk Factors; RNA, Viral; Tacrolimus; Treatment Outcome; Viral Matrix Proteins

Epstein-Barr virus (EBV)-driven posttransplantation lymphoproliferative disease (PTLD) is a serious complication of immunosuppression after either stem cell transplantation (SCT) or solid organ transplantation (SOT). Adoptive transfer of EBV-specific cytotoxic T lymphocytes (EBV-CTLs) is an effective prophylaxis and treatment for PTLD after SCT, but not for PTLD after SOT when pharmacologic immunosuppression cannot be discontinued. We report the generation of calcineurin (CN) mutants that render EBV-CTL resistant to the immunosuppressants tacrolimus (FK506) and cyclosporin A (CsA): mutant CNa12 confers resistance to CsA but not FK506, and mutant CNa22 confers resistance to FK506 but not CsA, whereas mutant CNb30 renders CTLs resistant to both calcineurin inhibitors. Untransduced EBV-CTLs do not proliferate in the presence of FK506/CsA. However, EBV-CTLs transduced with a retroviral vector coding for these mutants retain the ability to both proliferate and secrete normal levels of interferon-gamma in the presence therapeutic levels of FK506 (CNa12), CsA (CNa22), or both (CNb30). The cytotoxicity and phenotype of EBV-CTL lines were unaffected by expression of these mutant CNs. This approach should allow effective immunotherapy with EBV-CTLs in the SOT setting without risking the graft by reduction in immunosuppression, and represents a generic approach to improving immunotherapy in the face of immunosuppression.

Topics: Adoptive Transfer; Calcineurin; Calcineurin Inhibitors; Cells, Cultured; Cyclophilin A; Cyclosporine; Cytotoxicity, Immunologic; Drug Resistance; Epstein-Barr Virus Infections; Genetic Vectors; Humans; Immunosuppressive Agents; Interferon-gamma; Jurkat Cells; Lymphoproliferative Disorders; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Organ Transplantation; Postoperative Complications; Protein Conformation; Protein Interaction Mapping; Recombinant Fusion Proteins; Retroviridae; T-Lymphocytes, Cytotoxic; Tacrolimus; Tacrolimus Binding Protein 1A

Transient hyperphosphatasemia was found in a 3-year-old male liver transplant recipient. The condition was associated with diarrheal disease due to the Epstein-Barr virus (EBV). Immunosuppression was tapered and valganciclovir prescribed for 3 months, after which the diarrhea resolved and the EBV polymerase chain reaction assays became negative. After 6 months, alkaline phosphatase levels normalized. Isolated elevation of alkaline phosphatase in conjunction with enteric infection is a rare condition. No further diagnostic or therapeutic interventions except treatment of the underlying infection are needed, as this has been shown to be a benign, transient condition.

Topics: Adult; Child, Preschool; Cholestasis; Enteritis; Epstein-Barr Virus Infections; Family; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Male; Phosphoric Monoester Hydrolases; Phosphorus Metabolism Disorders; Postoperative Complications; Tacrolimus; Treatment Outcome

EBV infection is one of major complications arising in pediatric patients who have undergone renal transplantation. A strong correlation between the grade of immunosuppression and the development of PTLD, one of the most severe EBV-associated diseases, has been recognized. In this study, we monitored the serologic profile in conjunction with peripheral blood EBV-DNA load of 32 children who underwent renal transplantation with tacrolimus as an immunosuppressant. Six patients were EBV-seronegative (EBV-) before the transplantation, and the mean DNA load in the EBV- group was significantly higher than that in the EBV-seropositive (EBV+) group. Seroconversion occurred in five of these patients in a mean period of 22 weeks after the transplantation. The EBV-DNA load in the EBV+ group was maintained at a low level for a year, whereas it increased rapidly to over 1 x 10(5) copies/mL in two patients in the EBV- group three to seven months after the transplantation, which corresponds to the timing of seroconversion, and one of them developed PTLD. These observations suggest that the close monitoring of the EBV-DNA load, along with longitudinal observation of seroconversion, is essential in pediatric renal transplantation, particularly for younger children who are more likely to be EVB-.

Topics: Child; DNA, Viral; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Lymphoproliferative Disorders; Male; Methylprednisolone; Mycophenolic Acid; Polymerase Chain Reaction; Tacrolimus; Viral Load

Posttransplant lymphoproliferative disorders (PTLDs) are an uncommon but important cause of morbidity and mortality in solid organ transplant recipients. They are often the result of Epstein-Barr virus (EBV)-induced proliferation of B-lymphocytes in the setting of immunosuppression.. We retrospectively analyzed four cases of PTLD after liver transplantation. In all patients immunosuppression was reduced and anti-CD20 monoclonal antibody (rituximab) was administered. In two of four patients, EBV viral load was positive in the peripheral blood, and gancyclovir was therefore also prescribed. Chemotherapy (CHOP) was used as a rescue in the event of treatment failure.. Even if no severe adverse events were observed during the treatment period, our treatment approach to PTLD was not effective, and only one patient out of four is still alive.. Well-designed clinical trials are necessary to evaluate the role of this combined approach in the treatment of PTLD in liver transplant recipients.

Topics: Aged; Antibodies; Antigens, CD20; Cyclosporine; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Viral Load

Topics: Antilymphocyte Serum; Brain Neoplasms; Cytomegalovirus Retinitis; Epstein-Barr Virus Infections; Female; Ganciclovir; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Postoperative Complications; Prednisolone; Radiography; RNA, Viral; Tacrolimus; Transplantation, Homologous

Intestinal transplantation has developed to become the standard of care for patients with irreversible intestinal failure who are not responding to total parenteral nutrition. Once considered experimental, it has taken time and much effort for the procedure to become a clinical reality, with final acceptance primarily because of the vastly improved outcomes. Advances and novel modifications in immunosuppression have been at the forefront of these improvements. The authors review their evolutionary experience with intestinal transplantation, particularly relating changes in immunosuppression protocols to improved outcomes.. From July 1990 to December 2003, 122 children received 129 intestinal containing allografts (70 liver/intestine, 42 isolated intestine, 17 multivisceral). Mean age was 5.3 +/- 5.2 years, and 55% were boys. Indications for transplantation were mostly short gut syndrome. The allografts were cadaveric, ABO identical (except one), with no immunomodulation. Bone marrow augmentation was used in 29% of the recipients since 1995. T-cell lymphoctytotoxic crossmatch was positive in 24% cases. Immunosuppression protocols can be divided into 3 categories: (i) maintenance tacrolimus and steroids (n = 52, 1990-1995, 1997-1998); (ii) addition of induction therapy with cyclophosphamide (n = 16, 1995-1997) then daclizumab (n = 24, 1998-2001). A third immunosuppressive agent was added in either group where increased immunosuppression was indicated; (iii) pretreatment/induction with antilymphocyte conditioning and steroid-free posttransplantation tacrolimus monotherapy (n = 37, 2002-2003). In this later group, if clinically stable at 60 to 90 days posttransplantation, and no recent rejection, the tacrolimus was weaned by decreasing frequency of dosing.. The overall Kaplan-Meier patient/graft survival was 81%/76% at 1 year, 62%/60% at 3 years, and 61%/51% at 5 years. Survival continues to improve, with 1-year patient/graft survival being 71%/62%, 77%/75%, and 100%/100% for groups (i), (ii), and (iii), respectively. Acute intestinal allograft rejection has decreased markedly in group (iii). The rate of infectious diseases, such as cytomegalovirus and Epstein-Barr virus, is lowest in group (iii). Graft-versus-host disease has not significantly increased with the latest protocol. Most importantly, the overall level of immunosuppression requirements has decreased markedly, with most patients in group (iii) being on monotherapy. Of these, most had their monotherapy weaned down to spaced doses, something never systematically attempted or achieved in pediatric intestinal transplantation.. Intestinal transplantation has progressed markedly over the last 13 years. Although there have been modifications in all aspects of the procedure, the story of intestinal transplantation has been the evolution of successful immunosuppression regimens. Our latest pretreatment/induction conditioning and posttransplantation monotherapy strategy improves graft acceptance and lowers subsequent immunosuppression dosing requirements. It is expected this will overcome many of the complications related to the previously high immunosuppression requirements. Minimization of immunosuppression with avoidance of steroid therapy offers profound long-term benefits, especially in the pediatric population. The patients still remain challenging and complex in every aspect; however, these advances offer significant hope to both patients and caregivers alike.

Topics: Adolescent; Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Child; Child, Preschool; Cyclophosphamide; Cytomegalovirus Infections; Daclizumab; Epstein-Barr Virus Infections; Female; Graft Rejection; Graft Survival; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Intestinal Diseases; Intestines; Male; Organ Transplantation; Survival Analysis; Tacrolimus; Transplantation Conditioning

The development of Epstein-Barr virus (EBV) associated lymphoproliferative disorder (PTLD) is related to EBV genome numbers in serum or plasma and B-cells, and the level of immunosuppression. EBV DNA viremia, defined as presence of EBV genomes in serum or plasma, is common in immunodeficiency. This survey of EBV viremia was performed by real-time polymerase chain reaction (PCR) on consecutive serum samples of 21 patients with acute (n = 3) or chronic liver disease (n = 18) during the first year after liver transplantation (LTX). Cytomegalovirus (CMV) DNA was analyzed with PCR in serum or leukocytes. The levels of EBV and CMV viremia were related to PTLD and the effect of different anti-rejection regimens. All patients were EBV-seropositive pre-LTX. In total, 24 of 152 (16%) samples from 10 of 21 (48%) individuals were EBV positive [five of 11 cyclosporin A (CsA); five of 10 tacrolimus treated cases]. EBV viremia was demonstrated in five of seven patients with OKT3 therapy. The number of EBV DNA positive samples was highest (26%) at 14 days after LTX. In the OKT3 treated groups, the medians of EBV DNA copy numbers were 1600/ml (range 230-7200) and 380/ml (range 120-860) in the CsA and tacrolimus patients, respectively (P < 0.02). One patient developed EBV lymphoma and another one EBV hepatitis 13 months and 24 days post-LTX, respectively. Both patients had received OKT3. Their EBV genome load was not significantly different from what was found in other patients. After ganciclovir therapy, EBV DNA was eradicated from serum in four of five patients for several months. EBV DNA load was not affected by CMV infection or disease. We conclude that presence of EBV in serum is a possible marker of an active infection and an early ganciclovir therapy may be beneficial. Quantification of EBV load offers the potential to implement pre-emptive interventions.

Topics: Adult; Antiviral Agents; Cytomegalovirus; DNA, Viral; Epstein-Barr Virus Infections; Female; Ganciclovir; Gene Dosage; Genome, Viral; Hepatitis, Viral, Human; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoma; Male; Middle Aged; Muromonab-CD3; Postoperative Period; Tacrolimus; Viral Load; Viremia

In pediatric solid organ transplantation, the Epstein-Barr virus (EBV)-related lymphoproliferative disorders (PTLD) still play a major role in post-transplant morbidity and mortality. The aim of the study was to determine the incidence of PTLD in pediatric patients with liver transplant who receive low-dose immunosuppression protocols.. All pediatric patients (n = 269) received a dual immunosuppression therapy consisting of cyclosporine A (initial trough levels, 170-200 microg/L; trough levels for maintenance immunosuppression after 1 year, 80-100 microg/L) and prednisolone (starting dose, 60 mg/m2). Steroids were reduced to 30 mg/m2 after 1 week, followed by a weekly tapering to 5 mg/m2. Seventy-seven of 269 patients were switched to tacrolimus therapy. The authors evaluated the significance of EBV-DNA monitoring by quantitative polymerase chain reaction in identifying patients at risk for PTLD.. Patient survival was 90.3%; graft survival was 85.9%. Eight patients lost their grafts because of chronic rejection. The incidence of PTLD was low (0.7%), although a significant EBV viral load was found in 42.4% of the patients. One third of the patients with a viral load of 3,000 genomes/10(5) cells or greater had clinical signs of EBV infection.. The authors conclude that low-dose immunosuppressive protocols significantly reduce the incidence of PTLD. In patients treated with that regimen, the monitoring of EBV viral load seems not to be helpful. It can be assumed that low-dose immunosuppression does not suppress EBV-specific cytotoxic CD8+ T cells, thus allowing the host to control EBV infection without the risk of PTLD. Our low-dose immunosuppression protocol did not increase the risk of chronic rejection.

Topics: Adolescent; Child; Child, Preschool; Cyclosporine; DNA, Viral; Epstein-Barr Virus Infections; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prednisolone; Retrospective Studies; Tacrolimus; Viral Load

Topics: Child; Drug Resistance; Eosinophilia; Epstein-Barr Virus Infections; Herpesviridae Infections; Herpesvirus 6, Human; Humans; Immunosuppressive Agents; Intestines; Male; Syndrome; Tacrolimus

Complement factor H (FH) deficiency is one of the causes of atypical hemolytic uremic syndrome (HUS). Most patients with FH deficiency associated HUS progress to end-stage renal disease despite plasma therapy. Moreover, the disease invariably recurs in the graft kidney and causes graft failure. We confirmed FH deficiency in a 30-month-old boy with recurrent HUS of 2 years duration, and attempted an auxiliary partial orthotopic liver transplantation (APOLT) to overcome the sustained intractable dependency on plasma therapy. APOLT restored the plasma FH level, without HUS recurrence, for 7 months. However, thereafter he suffered from serious infectious complications associated with immunosuppression and finally died 11 months after APOLT. In conclusion, although APOLT showed clinical and laboratory improvement for some period in this patient, the final fatal outcome suggests that liver transplantation should be cautiously applied to patients with HUS associated with FH deficiency.

Topics: Bacterial Infections; Blotting, Western; Child, Preschool; Complement Factor H; Epstein-Barr Virus Infections; Fatal Outcome; Hemolytic-Uremic Syndrome; Humans; Immunocompromised Host; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Lymphoproliferative Disorders; Male; Tacrolimus

Chronic active Epstein-Barr virus infection (CAEBV) is a heterogeneous EBV-related disorder, ranging from mild/moderate forms to rapidly lethal disorders. The lethal form of CAEBV is characterized by multiple organ failure, hemophagocytic syndrome, and development of lymphomas. Allogeneic stem cell transplantation is considered as the only potentially curative treatment for the lethal form of CAEBV, but it is not always desirable because of the high incidence of regimen-related toxicities. A 17-year-old female with CAEBV, who was refractory to conventional therapies and considered to be unable to receive a myeloablative regimen because of multiple organ dysfunction, underwent allogeneic nonmyeloablative stem cell transplantation (allo-NST) before developing a hematological malignancy. She has been well without any signs of CAEBV for 27 months after allo-NST, and we confirmed that specific cytotoxic T lymphocyte activity against EBV was reconstituted. This outcome suggests that allo-NST can control CAEBV by reconstituting the host immunity against EBV.

Topics: Adolescent; B-Lymphocytes; Cell Line, Transformed; Cell Transformation, Viral; Chronic Disease; Cyclosporine; DNA, Viral; Drug Resistance; Epstein-Barr Virus Infections; Etoposide; Female; Hepatitis, Viral, Human; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Multiple Organ Failure; Peripheral Blood Stem Cell Transplantation; T-Lymphocytes, Cytotoxic; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

Previous studies have suggested an increased risk of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder (EBV-PTLD) in patients receiving tacrolimus for immunosuppression. We hypothesized that after correction for confounding variables, immunosuppression with tacrolimus is not associated with an increased risk of EBV-PTLD.. Potential cases of EBV-PTLD, identified by chart review, were independently ascertained by three clinicians and defined using published criteria. Agreement in diagnosing EBV-PTLD was measured using Kappa coefficients. Unadjusted and adjusted relative risk estimates were determined using proportional hazards regression.. Twenty-three cases of EBV-PTLD were identified in 221 patients, a proportion of 10.4% (95% confidence interval [CI]: 6.4%-14.4%). Multivariable analysis revealed that immunosuppression with tacrolimus was associated with an increased risk of EBV-PTLD (relative risk 3.10: 95% CI: 1.21-7.92), as was age at transplantation as a continuous variable (parameter estimate -0.15, P=0.03). Kappa coefficients in diagnosing EBV-PTLD and subclassifying as neoplastic and non-neoplastic EBV-PTLD were 0.73 (95% CI: 0.54-0.93) and 0.54 (95% CI: 0.40-0.68), respectively. Patients with neoplastic PTLD demonstrated a lower probability of survival than patients with non-neoplastic PTLD and non-cases.. Immunosuppression with tacrolimus and young age at transplantation are associated with an increased risk of EBV-PTLD in children undergoing liver transplantation, although we cannot exclude detection bias as an explanation for this observed increase. Good agreement between observers can be achieved using previously published criteria for defining EBV-PTLD. Patients with neoplastic EBV-PTLD may have a worse prognosis, and thus identification of risk factors for the development of this subtype of the disorder may be more important.

Topics: Aging; Child; Child, Preschool; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Liver Transplantation; Lymphoproliferative Disorders; Male; Risk Factors; Tacrolimus

To prevent post-transplant lymphoproliferative disease (PTLD), the viral load must be diminished before the symptoms of Epstein-Barr virus (EBV) infection appear. Twenty-three consecutive liver transplant recipients were entered into our study to identify the characteristics of post-transplant EBV-infected patients and to clarify the correlation between the FK506 blood level and EBV load. After transplantation, EBV-DNA appeared more frequently in patients who had been seronegative before transplantation than in seropositive patients (10/13 versus 1/10; P=0.0014). As for rejection, resistance to steroid pulse therapy, and FK506 trough level, there were no significant differences between patients with and without EBV infection. In patients with primary EBV infection after transplantation, there was a strong correlation ( r=0.681) between the FK506 level and the viral load. In liver transplant recipients, especially in those seronegative for EBV, it is necessary to check the viral load by polymerase chain reaction (PCR) carefully after liver transplantation, before any symptom appears.

Topics: Adolescent; Child; Child, Preschool; DNA, Viral; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Polymerase Chain Reaction; Serologic Tests; Tacrolimus; Viral Load

We describe a renal transplant recipient, with overimmunosuppression induced by the interaction of tacrolimus and fluconazole, who developed two severe diseases produced by two different viruses of the herpes group (cytomegalovirus [CMV] disease and posttransplant lymphoproliferative [PTLD] disease EBV-related). Detection of Epstein-Barr virus (EBV) DNA in the blood preceded the histological diagnosis of PTLD. Both diseases improved after changes in the immunosuppressive regime and treatment with ganciclovir. Because CMV infection is a risk factor in developing PTLD, and the clinical and endoscopic manifestations of both diseases could be become confused, PTLD should be excluded in EBV seronegative patients that develop CMV disease. The detection of the EBV genome in blood could help in the early diagnosis of PTLD in these patients.

Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Fluconazole; Ganciclovir; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunosuppression Therapy; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Postoperative Complications; Tacrolimus

Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein-Barr virus (EBV) infection and a defect of EBV specific cellular immunity is supposed to be the basis of PTLD. However, EBV load is so far the only marker proposed to evaluate PTLD risk, and no study has investigated the role of specific anti-EBV T lymphocytes (EBV-TL).. We therefore prospectively measured the EBV-TL by enzyme-linked immunospot (elispot) assay, in correlation to EBV load by real-time quantitative PCR and lymphoproliferation occurrence in 45 liver transplanted children.. EBV load at the time of primary infection was high in all patients irrespective to subsequent emergence of PTLD. Seven patients developed PTLD, all of them following primary EBV infection. All seven had low EBV-TL (<2/mm3) associated with high viral load (>25,000 copies/microg DNA). Both parameters can be combined in a 100% positive predictive index. Healing from lymphoma was characterized by rapid EBV-TL increase concomitant to decreasing viral load. EBV-TL follow-up helped to adapt immunomodulation. No patient had PTLD whenever EBV-TL were above 2/mm3.. We conclude that high viral load is systematic in patients who underwent primary EBV infection and is indicative of the PTLD risk only if there is low concomitant cellular immune response. Healing from PTLD requires modulation of immunosuppression, and appearance of EBV-TL.

Topics: Adolescent; Child; Child, Preschool; DNA, Viral; Epstein-Barr Virus Infections; Follow-Up Studies; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Predictive Value of Tests; T-Lymphocytes; Tacrolimus; Viral Load

A case of intraocular posttransplant lymphoproliferative disorder (PTLD) is described in a 9-year-old female who underwent orthotopic liver transplantation at the age of 18 months. The prevalence of ophthalmic involvement in PTLD can be expected to rise with the increasing number of major organ transplantations, as well as improved survivorship. Children are particularly at risk for this posttransplant complication because they are usually seronegative for the Epstein-Barr virus (EBV) prior to transplant. Accurate diagnostic classification of PTLD to include confirmation of EBV infection carries significant therapeutic and prognostic implications.

Topics: Child; Diagnosis, Differential; DNA, Viral; Epstein-Barr Virus Infections; Eye Infections, Viral; Female; Graft Rejection; Granuloma; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Iris Diseases; Liver Transplantation; Lymphoproliferative Disorders; Tacrolimus; Uveitis

In immunodeficient hosts, Epstein-Barr virus (EBV) often induces extensive B-cell lymphoproliferative disease and lymphoma. Without effective in vitro immune surveillance, B cells infected by the virus readily form immortalized cell lines. In the regression assay, memory T cells inhibit the formation of foci of EBV-transformed B cells that follows recent in vitro infection by EBV. No one has yet addressed which T cell regulates the early proliferative phase of B cells newly infected by EBV. Using new quantitative methods, we analyzed T-cell surveillance of EBV-mediated B-cell proliferation. We found that CD4+ T cells play a significant role in limiting proliferation of newly infected, activated CD23+ B cells. In the absence of T cells, EBV-infected CD23+ B cells divided rapidly during the first 3 weeks after infection. Removal of CD4+ but not CD8+ T cells also abrogated immune control. Purified CD4+ T cells eliminated outgrowth when added to EBV-infected B cells. Thus, unlike the killing of EBV-infected lymphoblastoid cell lines, in which CD8+ cytolytic T cells play an essential role, prevention of early-phase EBV-induced B-cell proliferation requires CD4+ effector T cells.

Topics: Adult; B-Lymphocytes; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Division; Cell Size; Cells, Cultured; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Flow Cytometry; Herpesvirus 4, Human; Humans; Immunologic Memory; Lymphocyte Count; Receptors, IgE; Serology; T-Lymphocyte Subsets; Tacrolimus

The role of sirolimus (SRL) as a rescue agent (n=42) and as a component of primary immunosuppression (n=8) was evaluated in a mixed population of 50 transplanted children receiving tacrolimus (liver: 26, heart: 5, intestinal: 5, liver-intestine: 9, lung: 1, bone marrow: 1, liver-kidney: 1, multivisceral: 1). Rescue indications for tacrolimus (TAC) failure were recurrent acute rejection and acute rejection complicating withdrawal of immunosuppression in posttransplant lymphoproliferative disorder (PTLD). Rescue indications for TAC toxicity were nephrotoxicity, pancreatitis, seizures, hypertrophic cardiomyopathy, and graft-versus-host disease.. Mean age at rescue was 11.5 years and mean follow-up was 204 (range 18-800) days. As primary immunosuppression, SRL+TAC prevented early acute rejection in 7/8 children. The indication for rescue resolved in 33/42 children. In children with TAC toxicity, this was associated with decrease in TAC doses by 50%, significant improvements in renal function, and continuing decline in Epstein-Barr virus (EBV) viral load in PTLD patients. Serious adverse events led to discontinuation of SRL in 9/42 rescue patients, 3 of them also experienced acute rejection. Three additional children also experienced acute rejection on SRL therapy (overall incidence 6/50, 12%). Pharmacokinetic analysis in the first week of SRL administration suggested a short half-life (11.8+/-5.5 hr, n=21).. SRL and reduced-dose TAC may achieve adequate immunosuppression without compromising renal function or enhancing EBV viremia significantly.

Topics: Acute Disease; Adolescent; Adult; Child; Child, Preschool; Epstein-Barr Virus Infections; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Kidney; Lymphoproliferative Disorders; Recurrence; Sirolimus; Tacrolimus; Transplantation Immunology

Risk factors for the development of posttransplant lymphoproliferative disease (PTLD), a major cause of morbidity and mortality after pediatric liver transplantation, are primary Epstein-Barr virus (EBV) infection and intensity of immunosuppression. The authors assessed monitoring of EBV replication and preemptive immunosuppression reduction in pediatric liver transplant recipients.. The authors prospectively followed monthly EBV-quantitative competitive polymerase chain reaction to measure EBV replication in 23 patients who underwent liver transplant between July 1997 and November 1998. Preemptive immunosuppression reduction was instituted for significant EBV replication. Patients were followed up for at least 1 year and divided in two groups for analysis (group 1, pretransplant seronegative for EBV [13 patients]; group 2, seropositive for EBV [10 patients]).. In group 1, 9 of 13 patients had positive polymerase chain reaction results at a mean time of 22.4 weeks after transplantation. All but one of these patients were asymptomatic. In seven of nine patients, preemptive immunosuppression reduction was undertaken without development of PTLD or rejection. In two of nine patients, immunosuppression could not be continuously reduced, and both patients experienced low-grade and medically responsive PTLD. In no patient in group 2 did an EBV-positive viral load or PTLD develop.. Prospective longitudinal measurement of EBV by quantitative competitive polymerase chain reaction permits early detection of asymptomatic viral replication. Subsequent preemptive reduction of immunosuppression may prevent the progression to PTLD.

Topics: Adolescent; Adult; Child; Child, Preschool; Cohort Studies; Epstein-Barr Virus Infections; Fatal Outcome; Female; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Infant, Newborn; Lymphoproliferative Disorders; Male; Organ Transplantation; Polymerase Chain Reaction; Postoperative Complications; Prospective Studies; Risk Factors; Tacrolimus; Viral Load

In children undergoing renal transplantation, Epstein-Barr virus- (EBV) related disorders, including posttransplant lymphoproliferative disorder, constitute a major complication associated with tacrolimus-based immunosuppression. In this study, we reviewed the EBV complications in 81 children, all of whom had EBV serological studies before renal transplantation. We also highlight the data in a subgroup of 30 children transplanted more recently who were monitored sequentially for EBV symptoms and signs and with immunological studies, and in whom the donor EBV serology was also determined. During a mean follow-up time of 3.9+/-2.3 years, 19 children developed symptomatic Epstein-Barr virus (EBV*) infection. This consisted of the clinical syndrome of infectious mononucleosis in 7 children; in addition, 10 children developed posttransplant lymphoproliferative disorder (PTLD), which was histologically confirmed in 8, and 2 others developed malignant lymphoma. Recipient seronegativity (EBV-) and donor EBV seropositivity (EBV+) predicted a high probability for seroconversion (P=0.0072) and for developing PTLD or malignancy (P<0.01). In the subgroup of 30 children studied prospectively, seroconversion occurred in 15 of 19 seronegative recipients of EBV seropositive grafts at 6.6+/-2.6 months (mean+/-SD) after transplantation. Seven children developed symptomatic EBV infection (including three with PTLD) in association with seroconversion and a rise in EBV viral load in the peripheral blood, demonstrated by an EBV-specific polymerase chain reaction (EBV-PCR). Of 15 seroconverters, 7 who developed symptomatic infection had received EBV+ grafts; 8 others with EBV+ grafts seroconverted but did not become symptomatic. These two subgroups did not differ in age, rejection rate, antiviral prophylaxis, or level of immunosuppression. In the overall group of 81 children, only the two with malignant lymphoma who were managed with chemotherapy had substantial morbidity. The 10 individuals with PTLD received a regimen combining i.v. ganciclovir and CytoGam, and stopping or reducing the tacrolimus. Four children with associated marked tonsilar growth underwent tonsillectomy. All 19 individuals with EBV disorders resolved their symptoms and signs, and all have maintained good allograft function during a follow-up time of 3.0+/-2.5 years (mean+/-SD) after the development of symptomatic EBV infection, PTLD, or malignancy. We conclude that seronegative recipients of EBV+ grafts are

Topics: Adolescent; Child; Child, Preschool; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Prospective Studies; Tacrolimus

Posttransplant lymphoproliferative disease (PTLD) after pediatric liver transplantation has been associated with high mortality rates.. The present study examined 282 consecutive pediatric liver transplant recipients from October 1989 to June 1996 who received primary tacrolimus immunosuppression. The aim was to determine the incidence of PTLD, management strategies, and patient outcome.. The incidence of PTLD was 13% (361282) with a mean age of 5.5+/-0.7 years (range 0.6 to 15) at diagnosis. The average time from transplantation to PTLD was 10.1+/-2.1 months. Initial treatment of PTLD consisted of reduction (3 patients) or discontinuation (33 patients) of tacrolimus and initiation of antiviral therapy (intravenous ganciclovir, 14 patients; intravenous acyclovir, 22 patients; or both, 5 patients). Alpha-interferon was used in four patients (two successfully). One patient also received gamma-interferon, chemotherapy, and radiation for a central nervous system lesion. Chemotherapy was also used in one patient with Burkitt's, whereas one patient with a pulmonary lesion received additional radiation therapy. Three patients received supportive surgery for gastrointestinal involvement, and one patient had a splenectomy for hemolysis. Overall mortality was 22% (8/36) with 5 (14%) PTLD-related deaths (disseminated disease, 4 patients; bowel perforation, 1 patient). Of 31 survivors, 23 had acute rejection at a median time of 24 days after PTLD, with 2 patients developing chronic rejection. One patient required retransplantation. Present immunosuppression consists of tacrolimus monotherapy in 14 patients, tacrolimus/prednisone in 8 patients, and none in 6 patients.. In summary, PTLD can be successfully treated with reduction of immunosuppression and administration of antiviral agents in most patients. The management of rejection after PTLD requires reassessment of disease status and judicious reintroduction of immunosuppression therapy.

Topics: Adolescent; Antiviral Agents; Child; Child, Preschool; Cohort Studies; Epstein-Barr Virus Infections; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infant; Intestines; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Prednisone; Reoperation; Splenectomy; Survival Analysis; Tacrolimus; Treatment Outcome