tacrolimus and Lymphoproliferative-Disorders

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

Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a kidney transplant to lose the function of their transplanted kidney necessitating return to dialysis is chronic kidney transplant scarring. Immunosuppressant drugs have side effects that increase risks of cardiovascular disease, cancer and chronic kidney transplant scarring. Belatacept may provide sufficient immunosuppression while avoiding unwanted side effects of other immunosuppressant drugs. However, high rates of post-transplant lymphoproliferative disease (PTLD) have been reported when belatacept is used in particular kidney transplant recipients at high dosage.. 1) Compare the relative efficacy of belatacept versus any other primary immunosuppression regimen for preventing acute rejection, maintaining kidney transplant function, and preventing death. 2) Compare the incidence of several adverse events: PTLD; other malignancies; chronic transplant kidney scarring (IF/TA); infections; change in blood pressure, lipid and blood sugar control. 3) Assess any variation in effects by study, intervention and recipient characteristics, including: differences in pre-transplant Epstein Barr virus serostatus; belatacept dosage; and donor-category (living, standard criteria deceased, or extended criteria deceased).. We searched the Cochrane Renal Group's Specialised Register to 1 September 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.. Randomised controlled trials (RCT) that compared belatacept versus any other immunosuppression regimen in kidney transplant recipients were eligible for inclusion.. Two authors independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI).  Subgroup analyses and univariate meta-regression were used to investigate potential heterogeneity.. We included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients).Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better graft function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m², 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m², 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes after transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients.Risk of PTLD was similar in belatacept and CNI-treated recipients (4 studies, 1516 recipients: RR 2.79, 95% CI 0.61 to 12.66) and was no different among recipients who received different belatacept dosages (high versus low dosage: ratio of risk ratios (RRR) 1.06, 95% CI 0.11 to 9.80, test of difference = 0.96) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant (seronegative versus seropositive; RRR 1.49, 95% CI 0.15 to 14.76, test for difference = 0.73).Th. There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss and death, but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important side effects (particularly PTLD) remain poorly reported and so the relative benefits and harms of using belatacept remain unclear. Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear. Longer-term, fully reported and published studies comparing belatacept versus tacrolimus are needed to help clinicians decide which patients might benefit most from using belatacept.

Topics: Abatacept; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Prednisone; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

A 43-year-old male renal transplant recipient, who received a living related renal transplant 7 years ago and had been maintained with tacrolimus, mycophenolate mofetil (MMF), and prednisolone, was admitted to our hospital complaining of headache and nausea. MRI showed a large mass in the right hemisphere with ring-enhancement indicating brain abscess, tumor or lymphoma. Open biopsy was performed and pathological examination demonstrated diffuse proliferation of polymorphic cells, positive for CD20, bcl-2, EBER, and LMP-1. Based on these findings, primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) was diagnosed. MMF was discontinued and tacrolimus was tapered. After 2 weeks, MRI showed regression of the tumor size and after 9 months, the tumor had disappeared. Though many reports have shown the severity of PCNS-PTLD, and recommend aggressive treatments such as chemotherapy and/or radiotherapy, our case shows that reduction of immunosuppressant alone with close observation could be a choice of treatment.

Topics: Adult; Brain Diseases; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Prednisolone; Remission Induction; Tacrolimus

Knowledge of the significance of post-transplant lymphoproliferative disorders (PTLD) that occur "very late" or more 10 years after renal transplantation is limited. thus, we analysed and compared characteristics and prognosis of the disease in renal transplant patients with very late onset PTLD vs. early- and late-onset PTLD.. Retrospective study of data obtained from comprehensive search of medical literature. We searched for available data using the Pubmed and Google scholar search engines for reports of lymphoproliferative disorders occurring in renal transplant patients by disease presentation time.. We analyzed data from 27 studies that included 303 patients with lymphoproliferative disorders after renal transplantation. Renal graft recipients with very late onset PTLD were significantly less likely to be under mycophenolate mofetil (MMF)- and/or tacrolimus (FK-506) (vs. azathioprine) -based immunosuppression (P=.035) and less likely to have a history of antibody induction immunosuppression (P<.001). Compared to "early onset" disease, "very late" onset PTLD is more likely to develop in older patients (P=.032). Survival analysis did not show any difference in outcome (P=.5). no organ involvement priority was found for this patient group (P>.1 for all).. Older renal transplant patients are at increased risk for development of very late onset PTLD, and should be strictly followed. further multi-institutional prospective studies are needed to confirm our results.

Topics: Graft vs Host Disease; Health Surveys; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors

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

Patient survival time following renal and other solid organ transplantation has been increasing recently, in part due to modern immunosuppressive regimens. However, the probability of malignant tumor formation is also increasing proportionally to survival time, as a side effect of long-term immunosuppression. The primary factor of increased tumor risk is the deficient antitumoral and antiviral function of the immune system. The frequency of posttransplantation tumors is 2 to 4-fold compared to the non-transplanted population, and the distribution of tumor types is also different. The most frequent tumor types--skin cancer, lymphoma, Kaposi's sarcoma, oral cancer, anogenital tumors, etc.--are often associated with oncogenic viruses. Treatment options and the prognosis of posttransplant tumors are worse than in the normal population. The increasing frequency of posttransplantation tumors is an important factor determining the long-term fate of transplant patients. The reduction of carcinogenic agents, the early diagnosis and treatment of tumors and precancerous conditions, low dose immunosuppression and the usage of immunosuppressive agents with an oncologically favorable, anti-proliferative effect will help reduce the risk of posttransplant tumor formation.

Topics: Adrenal Cortex Hormones; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Muromonab-CD3; Neoplasms; Prognosis; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus

Topics: Administration, Topical; Adult; Adverse Drug Reaction Reporting Systems; Allergy and Immunology; Attitude of Health Personnel; Attitude to Health; Causality; Child; Dermatitis, Atopic; Drug Labeling; Fear; Humans; Lymphoma; Lymphoproliferative Disorders; Neoplasms; Patient Acceptance of Health Care; Patients; Physicians; Quality of Life; Skin Neoplasms; Societies, Medical; Tacrolimus

As newer immunosuppressive regimens have steadily reduced the incidence of acute rejection and have extended the life expectancy of allograft recipients, posttransplant malignancy has become an important cause of mortality. In fact, it is expected that cancer will surpass cardiovascular complications as the leading cause of death in transplant patients within the next 2 decades. An understanding of the underlying pathobiology and how to minimize cancer risks in transplant recipients are essential. The etiology of posttransplant malignancy is believed to be multifactorial and likely involves impaired immunosurveillance of neoplastic cells as well as depressed antiviral immune activity with a number of common posttransplant malignancies being viral-related. Although calcineurin inhibitors and azathioprine have been linked with posttransplant malignancies, newer agents such as mycophenolate mofetil and sirolimus have not and indeed may have antitumor properties. Long-term data are needed to determine if the use of these agents will ultimately lower the mortality due to malignancy for transplant recipients.

Topics: Azathioprine; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Cyclosporine; Hepatitis, Viral, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Neoplasms; Sirolimus; Skin Neoplasms; Tacrolimus; Transplantation Immunology; Transplantation, Homologous

Topics: Child; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Tacrolimus

Substitution of cyclosporin with tacrolimus should be considered for paediatric liver transplant recipients with cyclosporin-associated complications such as hypertension, gum hyperplasia, hirsutism, gynaecomastia and growth retardation, as well as recurrent or refractory acute rejection, chronic duct injury or chronic rejection. Continued experience with well tolerated drug administration and careful monitoring during drug substitution has limited drug toxicity associated with tacrolimus to a level comparable to or less than that associated with cyclosporin. Successful outcome with long term graft salvage has been reported in up to 80% of patients converted to tacrolimus because of acute rejection and 50% of patients converted because of chronic rejection. Nearly all children converted because of cyclosporin-related complications have a successful outcome. Additional benefits of conversion to tacrolimus include improvement in growth and resolution of hypertension, hirsutism and cushingoid facies. Complete corticosteroid withdrawal is possible in up to 78% of children post-conversion. Long term outcome in these patients may be optimised by conversion to tacrolimus at an early stage of acute or chronic transplant rejection in order to minimise the cumulative amount of immunosuppression. Avoidance of cyclosporin-related toxicity and minimisation of corticosteroid therapy may further improve patient compliance to drug therapy.

Topics: Child; Cyclosporine; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Tacrolimus

This review covers the new immunosuppressive drugs that have appeared in the past 5 years. It begins with the newest formulation (Neoral, Sandoz Pharmaceuticals, East Hanover, NJ, USA) of the clinically "mature" drug cyclosporin A and then reviews the literature on tacrolimus, sirolimus, and mycophenolate mofetil. In each case, the emphasis is on the evolution of experience with the drug and on the questions that the drug poses for pediatricians considering the risk-benefit ratio of the drug in children.

Topics: Child; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Sirolimus; Tacrolimus

Topics: Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Survival Rate; Tacrolimus

Credit for the first pediatric heart transplant is given to Kantrowitz and colleagues who, in 1967, transplanted the heart of an anencephalic infant into a 3-week-old with tricuspid atresia (1). Although the infant only survived a few hours after surgery, this pioneering procedure emphasized the technical feasibility of heart transplantation in childhood. Over the next decade, enthusiasm for heart transplantation declined in both adults and children, as it became apparent that the therapeutic armamentarium for controlling acute allograft rejection was inadequate for achieving graft and patient survival. Towards the end of the 1970s, several advances led to renewed interest in human heart transplantation. These included topical cooling of the donor heart to protect the myocardium from ischemia (and enabling distant procurement), the technique and interpretation of endomyocardial biopsy for the diagnosis of allograft rejection (2) and, most importantly, the introduction of cyclosporine into human clinical trials (3). Cyclosporine was the first oral agent specifically to inhibit T lymphocytes, the principal mediators of allograft rejection. The favorable impact on survival of adult heart transplant recipients was immediately apparent (4) and led to renewed interest in pediatric heart transplantation. The pediatric heart transplant program at the University of Pittsburgh commenced in 1982, drawing on the experience of the adult program which had begun two years earlier. It rapidly became apparent that children present unique problems for the transplant physician and surgeon. This review draws on many of the lessons learned in our program over the last 15 years and reviews some of the prospects for the future of pediatric thoracic organ transplantation.

Topics: Child; Contraindications; Graft Rejection; Heart Diseases; Heart Transplantation; Hospitals, University; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lymphoproliferative Disorders; Patient Selection; Pennsylvania; Postoperative Complications; Survival Analysis; Tacrolimus; Tissue Donors

Since cyclosporine (CsA) was introduced into clinical practice in late 1983 to prevent rejection in transplant patients, there has been an almost explosive growth in the number and types of transplants and the number of transplant centers, an increase in the life expectancy of the transplanted organ, and substantial decreases in rates of acute rejection and life-threatening infections. Despite these successes, major improvements in immunosuppressive therapy are needed, especially a reduction in toxic side effects and a rigorous definition of the relation between drug concentration and clinical effects. Such improvements may be achievable with the incorporation of new drugs such as tacrolimus and mycophenolate mofetil into immunosuppression protocols and the development of rigorously defined therapeutic drug-monitoring programs.

Topics: Cyclosporine; Drug Monitoring; Humans; Immunosuppressive Agents; Kidney Diseases; Lymphoproliferative Disorders; Organ Transplantation; Tacrolimus

Posttransplantation lymphoproliferative disorder (PTLD) is a well-described complication of the systemic immunosuppression required for successful organ transplantation. Lesions of PTLD often occur in the region of the head and neck and require otolaryngologic evaluations. Although the majority of reported cases of PTLD are associated with cyclosporine immunosuppression, recently, PTLD has been described in patients treated solely with the newer systemic immunosuppressive agent tacrolimus (FK 506). As an introduction to tacrolimus and to PTLD as one of its complications, a case of PTLD presenting as airway obstruction in a child treated solely with tacrolimus immunosuppression is described. In addition, a review of tacrolimus and PTLD in patients under tacrolimus immunosuppression is presented to familiarize the otolaryngologist with this important new immunosuppressive agent and a potential complication of its use.

Topics: Female; Humans; Immunoglobulin Light Chains; Infant; Liver Transplantation; Lymphoproliferative Disorders; Tacrolimus

In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss.. 36-month follow-up of the intention-to-treat population.. CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m. At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89).. Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed.. Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy.. Exploratory post hoc analysis with a small sample size.. Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.

Topics: Abatacept; Adult; Calcineurin Inhibitors; Cyclosporine; Drug Substitution; Female; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Infections; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mortality; Neoplasms; Tacrolimus; Treatment Outcome

This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42–48%) versus tacrolimus groups (15–38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15–34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.

Topics: Abatacept; Adult; Aged; Drug Administration Schedule; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunoconjugates; Immunosuppression Therapy; Immunosuppressive Agents; Leukoencephalopathies; Liver Failure; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Recurrence; Tacrolimus; Treatment Outcome

Several interventions can cure posttransplant lymphoproliferative disease (PTLD); a sequential approach is usual, starting with reduction in immunosuppressives (RI). The efficacy of RI remains poorly defined, particularly in adults. We assessed an algorithm starting with a defined course of RI in all patients, escalating to interferon (IFN) alpha2b, and finally to chemotherapy, in a prospective multicenter phase II study of adult solid organ transplant recipients. The design predated rituximab.. Reduction in immunosuppressives: cyclosporine or tacrolimus reduction by 50% for 2 weeks; a further 50% reduction for 1 week if not in complete remission (CR). Intravenous acyclovir was given for the duration of all RI. Patients with less than CR, or any rejection, resumed immunosuppressives and proceeded to IFN 3 MIU/m(2)/day for up to 3 months; if less than CR, ProMACE-CytaBOM chemotherapy.. Twenty patients were registered over 60 months; 16 patients with biopsy-proven PTLD were eligible (13 heart, 3 kidney recipients). Median age was 47 (24-75) years. Reduction in immunosuppressives resulted in only 1 of 16 partial responses (12.5%), no CR. Progressive disease occurred in 8 of 16 (50%) and 6 of 16 (38%) experienced rejection. Only 1 of 13 (7%) patients achieved durable CR with IFN. Seven eligible patients received ProMACE-CytaBOM chemotherapy, five of seven (67%) achieving CR, four of five durable beyond 2 years.. Reduction in immunosuppressives produced no CR, progressive disease and rejection were frequent; response to IFN was rare. A strong case can be made for adding rituximab to RI as initial therapy. Chemotherapy resulted in 57% durable CR, data that are relevant for the up to two thirds of PTLD patients who are refractory to rituximab.

Topics: Acyclovir; Adult; Aged; Antineoplastic Agents; Cyclosporine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Postoperative Complications; Recombinant Proteins; Remission Induction; Tacrolimus

Pediatric renal transplant recipients were enrolled in a multicenter, randomized, double-blind trial of steroid withdrawal. Subjects received basiliximab, calcineurin inhibitor, sirolimus and steroids. Of 274 subjects enrolled, 19 (6.9%) subjects developed posttransplant lymphoproliferative disorder (PTLD). The relative hazard (RH) for PTLD was 5.3-fold higher in children aged < or =5 versus those >12 years (p = 0.0017). EBV seronegative subjects had a 4.7-fold higher RH compared to EBV positive subjects (p = 0.02). Among EBV donor+/recipient- (D+/R-) subjects, the RH increased by 6.1-fold (p = 0.0001). In a multivariate model, risk factors included recipient age < or =5 years (RH 3.2, 95% CI: 1.1-9.6, p = 0.034) and EBV D+/R- status (RH 7.7, 95% CI: 1.6-35.9, p = 0.010). Of 19 patients with PTLD, 17 are alive with functioning grafts and 2 lost their grafts, 1 of whom subsequently died of recurrent PTLD. This 'robust' immunosuppression protocol was associated with low rejection rates but an unacceptably high incidence of PTLD. The combination of basiliximab, calcineurin inhibitor, sirolimus and steroids resulted in over-immunosuppression in a high-risk pediatric population and we do not recommend its use. Future studies must include routine viral monitoring to permit early identification of viral activity and a protocol driven reduction of immunosuppression aimed at avoiding complications.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Child; Child, Preschool; Cyclosporine; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Lymphoproliferative Disorders; Male; Multivariate Analysis; Postoperative Complications; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

Clinical and preclinical data indicate that tumor necrosis factor (TNF)-alpha is an important mediator of acute graft-versus-host disease (aGVHD) after allogeneic bone marrow transplantation. We completed a study using etanercept, a fusion protein capable of neutralizing TNF-alpha, for the initial treatment of aGVHD. Etanercept (25 mg subcutaneously) was administered twice weekly for 16 doses, along with methylprednisolone (2 mg/kg) and tacrolimus for biopsy-proven aGVHD. Twenty patients with a median age of 47 years (range, 8-63 years) were enrolled. Fourteen patients with grade II aGVHD (11 family donors and 3 unrelated donors) and 6 patients with grade III aGVHD (3 family donors and 3 unrelated donors) were treated. Twelve patients completed 16 doses of therapy, and 8 received 5 to 15 doses. Reasons for not completing all doses of etanercept included progression of aGVHD (n = 4), relapsed leukemia (n = 2), progression of pulmonary and central nervous system lesions (n = 1), and perforated duodenal ulcer (n = 1). Fifteen (75%) of 20 patients had complete resolution of aGVHD within 4 weeks of therapy. Increasing levels of soluble TNF receptor 1 plasma concentration during the first 4 weeks of therapy indicated progression of aGVHD in 5 patients. In contrast, for 15 responding patients, soluble TNF receptor 1 plasma concentration levels returned to baseline. These data demonstrate the feasibility of using cytokine blockade in the early treatment of aGVHD.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Bone Marrow Transplantation; Child; Drug Therapy, Combination; Etanercept; Female; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Methylprednisolone; Middle Aged; Pilot Projects; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Tacrolimus; Transplantation, Homologous; Tumor Necrosis Factor-alpha

The recent U.S. multicenter randomized trial of FK506 versus cyclosporine (CsA) demonstrated equivalent patient and graft survival in patients treated with FK506 and statistically fewer rejection episodes in the first year posttransplant.. To determine if more effective posttransplant immunosuppression was associated with an increased risk of cytomegalovirus (CMV) or posttransplant lymphoproliferative disease (PTLD), we examined the incidence of these two opportunistic infections during 3 years of follow-up.. CMV infection occurred in 40 (19.5%) FK506 and 40 (19.3%) CsA-treated patients. The incidence of CMV disease was 9.3% in FK506 and 6.8% in CsA-treated recipients; the most common site of CMV disease was the gastrointestinal tract. A multivariate analysis of several risk factors demonstrated that a CMV- recipient of a CMV+ donor was at greatest risk for CMV infection. The incidence of posttransplant lymphoproliferative disease was equal in the two treatment arms: six CsA- and five FK506-treated recipients.. The results of this study suggest that the superior efficacy of FK506 in the prevention of acute rejection was not associated with an increased risk of CMV or posttransplant lymphoproliferative disease compared with CsA.

Topics: Cyclosporine; Cytomegalovirus Infections; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Multivariate Analysis; Opportunistic Infections; Postoperative Complications; Tacrolimus

Lymphoproliferative disorders (LPDs) are a serious side effect of immunosuppression after liver transplantation, and the introduction on the market of a new immunosuppressive drug has been associated with an increased risk of these disorders. To compare the effect of cyclosporine A (CSA) and FK506 in a clinical setting, the incidence of monoclonal or oligoclonal gammopathies known to often precede the appearance of LPDs was evaluated. A total of 88 adult patients was analyzed, 46 were prospectively randomized to CSA and 42 to FK506 for immunosuppression. None of these patients had gammopathy before transplantation. All the patients were tested for immunoglobulin abnormalities five to nine times during a period of 1 year and then two to four times per year thereafter from December 1990 until March 1997. The same incidence of serum immunoglobulin (Ig) abnormalities was observed in both groups (13%) with a mean delay of appearance of 11.1 +/- 5.9 versus 7.6 +/- 3.6 months for CSA and FK506, respectively (P > .05). In each group, the gammopathies were transient in 3 patients and persisted in 2. The class of Ig involved was IgG, and a monoclonal component was documented in 2 patients treated with CSA and in 3 patients with FK506. One patient treated with FK506 developed an LPD localized to the lymph nodes 8 months after the occurrence of serum protein abnormalities. The lymphoproliferative lesions subsequently disappeared with the reduction of immunosuppression. In this study, an immunosuppressive regimen of FK506 has not shown an increased incidence of lymphoproliferation compared with CSA in adult liver transplant patients.

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Cyclosporine; Female; Humans; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Paraproteinemias; Tacrolimus

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provide

Topics: Acute Disease; Adult; Cyclosporine; Cytomegalovirus Infections; Drug Resistance; Evaluation Studies as Topic; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Tacrolimus; Treatment Outcome

Under FK506-based immunosuppression, 13 abdominal multivisceral transplantations were performed in 6 children and 7 adults. Of the 13 recipients, 7 (53.8%) are alive and well with functioning grafts after 9 to 31 months. Six recipients died: three from PTLD, one from rejection, one from sepsis, and one from respiratory failure. In addition to rejection, postoperative complications occurring in more than isolated cases included PTLD (n = 6), abdominal abscess formation (n = 5), pancreatitis (n = 3), and ampullary dysfunction (n = 2). In addition, infection by enteric microorganisms was common during the early postoperative period. Currently, all 7 survivors are on an oral diet and have normal liver function. Two recipients (one insulin-dependent) require antidiabetes treatment, in one case following distal pancreatectomy and in the other after two episodes of pancreatic rejection. Thus, abdominal multivisceral transplantation is a difficult but feasible operation that demands complex and prolonged posttransplantation management. It is not yet ready for application and awaits a better strategy of immune modulation.

Topics: Abdomen; Adult; Child; Child, Preschool; Digestive System Surgical Procedures; Graft Rejection; Humans; Infant; Intestines; Lymphoproliferative Disorders; Middle Aged; Survival Analysis; Tacrolimus; Viscera

Topics: Adolescent; Bilirubin; Child; Child, Preschool; Cyclosporine; Female; Graft Survival; Humans; Hyperkalemia; Immunosuppression Therapy; Infant; Infections; Liver Transplantation; Lymphoproliferative Disorders; Male; Safety; Tacrolimus

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Cyclosporine; Follow-Up Studies; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Infant; Intestine, Small; Liver Transplantation; Lung Transplantation; Lymphoproliferative Disorders; Prednisone; Survival Analysis; Tacrolimus

Posttransplant lymphoproliferative diseases are a rare but important cause of morbidity and mortality secondary to immunosuppression after solid-organ or bone marrow transplant. Generally, posttransplant lymphoproliferative diseases develop in the first 2 years after transplant, when immunosuppressive therapy is the most intense. Change or reduction in immunosup - pressive treatment is an option for treatment of posttransplant lymphoproliferative diseases. We evaluated the treatment of a patient with posttransplant lymphoproliferative disease after liver transplant. A 64-year-old man underwent liver transplant from a living donor (the patient's son) in 2011 to treat hepatocellular cancer secondary to chronic hepatitis B. Tacrolimus and mycophenolate mofetil were used for immunosuppression through 9 years after liver transplant. In the abdominal computed tomography performed in response to abdominal pain during follow-up in March 2019, multiple solid lesions were observed. A liver biopsy revealed posttransplant lymphoproliferative disease with diffuse large B-cell lymphoma. Fluorine-18 positron emission tomography/computed tomography imaging of the patient showed no pathology in favor of primary lymphoproliferative disease. Mycophenolate mofetil and tacrolimus treatment was changed to everolimus. In the follow-up dynamic magnetic resonance imaging examination that was performed at 3 months after treatment change, we observed that the lesion at liver segment 6 had regressed to 30 mm and several lesions with similar features were observed in the right lobe of the liver. Additional liver biopsy results were compatible with complete remission. The patient's clinical symptoms had fully regressed at 18 months after the diagnosis of PTLD, at the time of this writing. Ongoing radiological and clinical follow-up has shown complete remission. Change from calcineurin treatment to treatment with an inhibitor of the mechanistic target of rapamycin may be an essential and new option for treatment of posttransplant lymphoproliferative disease after liver transplant.

Topics: Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

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

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a troublesome problem in patients receiving MTX for rheumatoid arthritis (RA). However, its incidence, prognosis, and risk factors remain unclear. In this retrospective study, we evaluated the actual incidence, prognostic impact, and risk factors of MTX-LPD. Of the 986 patients with RA treated with MTX, 90 patients experienced 95 new malignancies (NMs), with LPD as the most frequent in 26 patients. The cumulative LPD incidences were 1.3% and 4.7% at 5 and 10 years after MTX initiation, respectively. Among the 24 patients who discontinued MTX after developing LPD, 15 showed sustained regression, without difference in overall survival between patients with LPD and without NM. Inflammatory markers and absolute lymphocyte counts were not useful for early LPD development detection, but most of the patients with LPD had persistently elevated erythrocyte sedimentation ratios. Regarding concomitant drugs, tacrolimus increased the risk only if patients were not receiving biological disease-modifying antirheumatic drugs (bDMARDs). bDMARDs did not increase the risk for any of the drugs or the number of classes used. The number of LPD cases was lower in patients with IL-6A even after a long period after MTX, although with no statistically significant difference. Thus, approximately 1 in 20 patients with RA developed MTX-LPD over the 10 years of MTX treatment, but it did not affect the survival of patients with RA. Tacrolimus increased the risk of developing LPD for certain patients and should be used with caution.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Lymphoproliferative Disorders; Methotrexate; Retrospective Studies; Tacrolimus

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

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

Topics: Airway Obstruction; Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Medical Illustration; Postoperative Complications; Tacrolimus

Posttransplant lymphoproliferative disorder (PTLD) is a serious disease that usually occurs after solid organ transplant and stem cell transplant. Posttransplant lymphoproliferative disorder often involves the head and neck, but it is rare to present as a nasal deformity. Here, we describe a case of external nasal enlargement resulting from PTLD.. A 40-year-old man presented with an enlarged external nose half a year ago. The nasal ala thickened, and the external nose was gradually enlarged, accompanied by bilateral nasal obstructions. A biopsy was taken under endoscopy procedure, and the result suggested a diagnosis of PTLD.. Posttransplant lymphoproliferative disorder usually appears in lymphoid tissues that form Waldeyer's rings or cervical lymph nodes in the head and neck. The early involvement of other head and neck subpoints is considered rare. This case is the first report of PTLD presenting as an external nasal deformity. The symptoms and clinical manifestations of PTLD in otorhinolaryngology are usually diverse and nonspecific but are early symptoms in the clinical course of PTLD.

Topics: Adult; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Magnetic Resonance Imaging; Male; Nose; Tacrolimus

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 71-year-old woman being treated with methotrexate (MTX) and tacrolimus (TAC) for rheumatoid arthritis (RA) was admitted to our hospital and underwent surgery for gastric perforation and peritonitis. An endoscopic examination six days post-surgery showed an extensive ulcer in the stomach, and a biopsy revealed diffused large B-cell lymphoma. We diagnosed her with immunodeficiency-associated lymphoproliferative disorder (LPD) and discontinued the MTX and TAC. She underwent gastrectomy due to stenosis approximately two months after the first operation, but the histopathological findings of lymphoma had disappeared. LPD should be considered as a potential cause of gastric perforation during RA treatment.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biopsy; Female; Humans; Iatrogenic Disease; Lymphoproliferative Disorders; Methotrexate; Peptic Ulcer Perforation; Tacrolimus

A case of primary cutaneous post liver transplant lymphoproliferative disorder (PTLD) mimicking squamous cell carcinoma-in-situ is presented.. Lesions mimicking SCC-in-situ were confirmed to be PTLD on histopathology and immunohistochemistry. Immunosuppression was gradually reduced and the lesions were successfully treated with 50 gray (Gy) in 25 fractions of radiotherapy.. There was no recurrence of lesions at 3 months follow-up.. Radiotherapy is an effective form of cutaneous directed treatment for localized PTLD.

Topics: Aged; Antibiotics, Antineoplastic; B-Lymphocytes; Carcinoma, Squamous Cell; Follow-Up Studies; Gamma Rays; Humans; Immunohistochemistry; Liver Cirrhosis, Biliary; Liver Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized and potentially fatal complication of cardiac transplantation that commonly involves the gastrointestinal tract. Herein, we report a case of life-threatening gastrointestinal bleeding from recurrent terminal ileac ulcers mimicking PTLD in a heart recipient treated with everolimus (EVL). A 40-year-old man underwent heart transplantation for dilated cardiomyopathy 3 years prior to the current admission and was treated with tacrolimus and EVL. He was admitted to a local hospital because of fever, abdominal pain, and diarrhea. His symptoms persisted and, 3 weeks later, hematochezia occurred; thus, he was transferred to our hospital. As computed tomography and

Topics: Adult; Diagnosis, Differential; Everolimus; Graft Rejection; Heart Transplantation; Humans; Ileal Diseases; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Tacrolimus; Ulcer

Heart transplantation has been an option for children in Sweden since 1989. As our unit faced an increased rate of post-transplant lymphoproliferative disorder, the objective of the study was to identify possible risk factors.. This is a retrospective study of all children aged 0-18 years who underwent heart transplantation in Gothenburg from 1989 to 2014.. A total of 71 children underwent heart transplantation. The overall incidence of post-transplant lymphoproliferative disorder was 14% (10/71); however, 17% (6/36) of those undergoing transplantation after 2007 developed lymphoma, compared with only 10% (4/35) of transplantation cases before 2007 (p=0.85). The mean age at transplantation was 9 years (0-17). The mean post-transplant follow-up time was 5.5 years (0.5-21.9) in the group that developed post-transplant lymphoproliferative disorder, compared with 10.2 years (0.02-25.2) in those who did not. In our study group, risk factors for post-transplant lymphoproliferative disorder were surgically palliated CHD (p=0.0005), sternotomy during infancy (p⩽0.0001), hypoplastic left ventricle (p=0.0001), number of surgical events (p=0.0022), mismatch concerning Epstein-Barr virus infection - that is, a positive donor-negative recipient (p⩽0.0001) - and immunosuppressive treatment with tacrolimus compared with ciclosporine (p=0.028). Discussion This study has three major findings. First, post-transplant lymphoproliferative disorder only developed in subjects born with CHD. Second, the vast majority (9/10) of the subjects developing the disorder had undergone sternotomy as infants. Third, the number of surgical events correlated with a higher risk for developing post-transplant lymphoproliferative disorder.

Topics: Adolescent; Child; Child, Preschool; Female; Heart Defects, Congenital; Heart Transplantation; Heart Ventricles; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Lymphoma; Lymphoproliferative Disorders; Male; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sternotomy; Sweden; Tacrolimus

We present a 13-year-old girl with Jessner lymphocytic infiltrate of the skin, who has suffered from the disease since the age of 9 years. It is a rare disease in childhood, and we highlight the clinical features and therapeutic response of tacrolimus.

Topics: Adolescent; Biopsy; Diagnosis, Differential; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Discoid; Lymphocytes; Lymphoproliferative Disorders; Rare Diseases; Skin; Tacrolimus

Topics: Anemia, Hemolytic, Autoimmune; Disease Management; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Middle Aged; Salvage Therapy; Sirolimus; Tacrolimus; Transplantation, Homologous; Waldenstrom Macroglobulinemia

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

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

Post-transplant lymphoproliferative disorders of T-cell origin are quite uncommon, and the vast majority represent neoplasms of mature, post-thymic T- or natural killer cells. Here, we report a rare case of T-cell acute lymphoblastic leukaemia (T-ALL), which occurred in an 18-year-old man who had undergone three liver transplants, initially for biliary atresia and subsequently for graft failure due to chronic rejection. He had received immunosuppression with cyclosporine and tacrolimus, as well as short-term treatment with OKT3. The T-ALL occurred 16 years after the first liver transplant. This case highlights the challenge for classifying rare neoplasms occurring in recipients of solid organ transplants that are currently not recognized to lie within the spectrum of post-transplant lymphoproliferative disorders. Given the long interval between the liver transplants and the development of T-ALL, a coincidental occurrence of the leukaemia cannot be ruled out. However, the potential roles of immunosuppressive therapy and other co-morbid conditions of the individual as possible risk factors for the pathogenesis of T-ALL are discussed.

Topics: Adolescent; Biliary Atresia; Causality; Clone Cells; Comorbidity; Cyclosporine; Diagnosis, Differential; Disease Susceptibility; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Radiation-Induced; Liver Transplantation; Lymphoproliferative Disorders; Male; Muromonab-CD3; Postoperative Complications; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Radiography; Remission Induction; Reoperation; Tacrolimus; Time Factors

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

Post-transplant lymphoproliferative disorder (PTLD) contributes to morbidity and mortality after transplantation. We examined the effect of immunosuppressive regimen on the risk of developing PTLD after pediatric heart transplantation.. The 324 pediatric heart transplant patients at 2 children's hospitals were retrospectively reviewed for the primary outcome of PTLD development. Patient demographics, rejection frequency, serum cyclosporine and tacrolimus levels, induction therapy, donor and recipient Epstein-Barr virus, and cytomegalovirus serologic status were reviewed and comparisons made between immunosuppressive regimens. Comparisons were also made between transplantation in the early (1984-1995) and late (1996-2008) eras to help account for changes in clinical protocols that occurred during the study period.. PTLD developed in 33 (10%), of whom 109 (34%) were treated with tacrolimus. PTLD developed in 15% of those treated with tacrolimus compared with 8% of patients treated solely with cyclosporine. Tacrolimus use was a significant predictor of PTLD, with a hazard ratio [HR] of 4.04 (95% confidence interval [CI], 2.03-8.02; p = 0.0001). Neither Epstein-Barr virus, cytomegalovirus donor/recipient status, nor gender predicted PTLD development. Younger age at transplant, higher rejection frequency, and induction therapy predicted PTLD development by univariate analysis. Multivariate modeling demonstrated that tacrolimus use (HR, 7.03; 95% CI, 2.87-17.2; p < 0.001) remained an independent predictor of PTLD, when controlling for age, era of transplantation, induction therapy, and rejection frequency.. This study suggests the use of tacrolimus after pediatric heart transplantation is independently associated with an increased risk of PTLD compared with cyclosporine alone.

Topics: Child; Cyclosporine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

The aim of this study is to clarify the association between hepatitis C virus (HCV) infection and post-transplant lymphoproliferative disease (PTLD) in the liver allograft.. Of the 933 adults who underwent liver transplantation (LT) between 1990 and 2005, 10 patients developed PTLD. Seven of the 10 patients that were HCV(+) (group 1) were compared with three HCV-negative recipients (group 2).. The mean time between LT and PTLD was 24.5 months. There were no differences between in Epstein-Barr virus antibody status or tumor lymphocyte subsets. In five of the seven HCV-positive recipients who developed PTLD, PTLD recurred preferentially in the liver allograft, whereas none of the three HCV-negative patients who developed PTLD did so in the liver (71.4 vs. 0%, respectively, P=0.038). In all five patients with graft PTLD, HCV recurred within 12 months followed by PTLD. There were significant differences between groups 1 and 2 in mean lymphocyte infiltrate scores (6.0±2.1 vs. 2.0±0.7, P=0.037), fibrosis stage (2.4±0.5 vs. 0.7±0.5, P=0.029), and frequency of lymphoid follicles in portal areas (33.6±14.8% vs. 1.1±2.3%, P=0.0002).. When PTLD occurs in patients with HCV recurrence after LT, it does so preferentially in the liver allograft.

Topics: Adolescent; Aged; Antibodies, Viral; Azathioprine; Cohort Studies; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Hepatitis C; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Steroids; Tacrolimus

PTLD is a very severe, life threatening complication after organ transplantation. A 17 years old female patient with kidney transplanted (KTx) 7th months ago on immunosuppression therapy: Tacrolimus (TAC), Cell Cept (MMF), Encorton (Enc) was described. She was admitted to the hospital due to: fever, abdominal pain, diarrhea and enlarged cervical and inguinal lymph nodes on palpation. Histopathological diagnosis revealed monomorphic PTLD; diffuse large B cell lymphoma, immunoblastic. Treatment of PTLD was started immediatly after the final diagnosis. MMF was stopped, dose of TAC was reduced (blood level 3-4 ng/ ml), Enc were continued. Anti-CD20 antibodies (Rituximab) were administered. After 7 days of treatment the patient developed signs of diffuse peritonitis. In the course of surgery, perforation in six sites of the small intestine and sigmoid colon were discovered. The Hartman's surgery was performed (sigmoidectomy) with formation of temporary sigmoideostomy. Resected parts of intestine and sigmoid colon were infiltrated by immnunoblasts and revealed diffuse necrosis - the same process was seen in lymph nodes. After the wounds healed, Rituksymab was continued (8 doses) and chemotherapy was started - CHOP - 6 cycles every month. Eight months after surgery, full remission was obtained, TAC was change to rapamycine (RAP) and closure of sigmoideostomy was performed. At present, almost 10 years after first symptoms of PTLD, the patient remains in full remission of the disease.

Topics: Adolescent; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Remission Induction; Rituximab; Sigmoidoscopy; Sirolimus; Tacrolimus

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

Liver transplantation (OLT) in children has seen significant improvements in recent years. Long-term immunosuppressive strategies have focused on avoiding the risks of long-term immunosuppression, particularly nephrotoxicity, de novo malignancy and late infections. Since its introduction in renal transplantation in 1999, sirolimus (SRL) has been used by an increasing number of liver transplant centers. The aim of this study was to review the experience using SRL in pediatric liver transplant recipients at a single center.. Between 1989 and 2006, 318 children underwent OLT including 13 who were converted to SRL therapy because of tacrolimus-related side effects. The indications were posttransplant lymphoproliferative disease (PTLD; n = 11), nephrotoxicity (n = 1), and de novo autoimmune hepatitis (n = 1). One patient with PTLD previously concurrently displayed chronic rejection. SRL dosages ranged between 0.4 and 5 mg/d. The median duration of follow-up was 18 months.. PTLD recurred in 1 patient. There were no episodes of acute rejection. One child developed hyperlipidemia that resolved with diet and medication.. Conversion from tacrolimus to SRL in selected pediatric liver transplant recipients is safe. Children with PTLD may benefit from immunosuppression with SRL after liver transplantation.

Topics: Adolescent; Cadaver; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Living Donors; Lymphoproliferative Disorders; Male; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Tissue Donors

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

Composite tissue allotransplantation may have different immunosuppressive requirements and manifest different complications compared with solid organ transplantation. We developed a non-human primate facial composite tissue allotransplantation model to investigate strategies to achieve prolonged graft survival and immunologic responses unique to these allografts.. Composite facial subunits consisting of skin, muscle, and bone were heterotopically transplanted to mixed lymphocyte reaction-mismatched Cynomolgus macaques. Tacrolimus monotherapy was administered via continuous intravenous infusion for 28 days then tapered to daily intramuscular doses.. Five of the six animals treated with tacrolimus monotherapy demonstrated rejection-free graft survival up to 177 days (mean, 113 days). All animals with prolonged graft survival developed posttransplant lymphoproliferative disorders (PTLD). Three animals converted to rapamycin after 28 days of rejection of their allografts, but did not develop PTLD. Genotypic analysis of PTLD tumors demonstrated donor origin in three of the five analyzed by short-tandem repeats. Sustained alloantibodies were detected in rejecting grafts and absent in nonrejecting grafts.. Tacrolimus monotherapy provided prolonged rejection-free survival of composite facial allografts in a non-human primate model but was associated with the development of a high frequency of donor-derived PTLD tumors. The transplantation of a large volume of vascularized bone marrow in composite tissue allografts may be a risk factor for PTLD development.

Topics: Animals; Bone Marrow Transplantation; Disease Models, Animal; Facial Transplantation; Graft Rejection; Graft Survival; Immunosuppressive Agents; Infusions, Intravenous; Isoantibodies; Lymphocyte Culture Test, Mixed; Lymphoproliferative Disorders; Macaca fascicularis; Magnetic Resonance Imaging; Male; Risk Factors; Sirolimus; Tacrolimus; Time Factors; Transplantation, Homologous

Malignancies are a serious long-term complication among liver transplant recipients, with an overall incidence of 4.5%-15%. Posttransplantation lymphoproliferative disease (PTLD) is one of the leading causes of late death. Its development is related to complex interactions between immunosuppressive drugs and environmental agents. The aim of this study was to analyze risk factors for PTLD and survival after orthotopic liver transplantation (OLT) compared with solid tumors.. We undertook a retrospective review of the clinical histories of adult patients who underwent OLT between July 1986 and February 2001, and who had been followed until 2005. This study comprised 528 adult recipients who survived more than 2 months after OLT. We excluded pediatric, partial-organ, and multiorgan recipients.. No differences were observed concerning gender, viral etiology of hepatitis, calcineurin inhibitor regimen, or steroid maintenance period. Treated acute rejection episodes accounted for 53.3% of patients who developed PTLD compared with 47.3% in the control group (P = .787). Patients with solid tumors were older at the time of diagnosis than those with PTLD (57.5 +/- 8.13 years vs 48.8 +/- 13.9; P = .002). The overall mortality rate for PTLD was 55.5%, which did not differ significantly from solid tumors.. PTLD develops in younger patients after OLT. Various immunosuppressive regimens do not seem to influence the incidence of PTLD or other solid tumors.

Topics: Adult; Carcinoma, Squamous Cell; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Transplantation; Lymphoproliferative Disorders; Male; Retrospective Studies; Risk Factors; Skin Neoplasms; Survival Analysis; Survivors; Tacrolimus

Topics: Adult; Antiviral Agents; Colonic Neoplasms; Cyclosporine; Esophageal Neoplasms; Female; Ganciclovir; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Lymphoproliferative Disorders; Middle Aged; Pharyngeal Neoplasms; Survival Analysis; Tacrolimus; Time Factors

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

Pediatric heart transplantation is entering its third decade, allowing for the first time an analysis of a large group of true long-term survivors, specifically children who have survived > or =10 years post-transplantation.. Fifty-two patients < or =18 years, who had undergone heart transplantation at Stanford between August 1974 and June 1993 and survived > or =10 years, were retrospectively reviewed.. Forty (77%) patients are currently alive. Thirteen survived >15 years and 5 >20 years (the longest being 26 years). Actuarial survival was 79.4% at 14 years and 53.1% at 20 years. Cardiomyopathy was the reason for transplantation in 71% and congenital heart disease (CHD) in 29%. At last evaluation, 71% were on a cyclosporine-based regimen and 23% a tacrolimus-based regimen; 33% were steroid-free. Twenty-seven percent were totally free from treatable rejection, 44% developed serious infections, 69% were receiving anti-hypertensives, and 8% required renal transplantation. Neoplasms occurred in 23%, graft coronary artery disease (CAD) in 31%, and 15% required re-transplantation. Of the 12 deaths, CAD was the most common cause (n = 4), followed by non-specific late graft failure (n = 3), infection (n = 2), rejection (n = 1), non-lymphoid cancer (n = 1) and lymphoid cancer (n = 1). Physical rehabilitation and return to normal lifestyle has been nearly 100%.. Heart transplantation in pediatric patients is compatible with true long-term survival with a growing cohort of children approaching their second and third decades. The gradual constant-phase decrease in survival noted in earlier studies appears to be continuing. Rejection and infection are low but persistent risks after the first years. Graft CAD and non-specific late graft dysfunction are the leading causes of death after 10 years. Rehabilitation is excellent.

Topics: Actuarial Analysis; Adolescent; Bacterial Infections; Cardiomyopathies; Child; Child, Preschool; Coronary Artery Disease; Cyclosporine; Female; Graft Rejection; Heart Defects, Congenital; Heart Transplantation; Humans; Immunosuppressive Agents; Infant; Lymphoproliferative Disorders; Male; Reoperation; Retrospective Studies; Survival Analysis; Survivors; Tacrolimus

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

Tumor lysis syndrome usually occurs after Initiation of chemotherapy or radiation therapy in cancer patients with a moderate to high tumor burden. To our knowledge, the occurrence of this syndrome after discontinuation or reduction of an immunosuppressive regimen has not been reported in the literature. We describe a patient who had undergone lung transplantation and who was receiving immunosuppression and experienced an episode of acute pancreatitis. During the course of the work-up, the patient was found to have a B-cell lymphoma (posttransplantation lymphoproliferative disease). His tacrolimus dosage was decreased, and azathioprine was discontinued. The patient subsequently developed tumor lysis syndrome. Other than the decrease in immunosuppression, we found no other factor that could have accounted for this syndrome.

Topics: Aged; Azathioprine; Fatal Outcome; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Substance Withdrawal Syndrome; Tacrolimus; Tumor Lysis Syndrome

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

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

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

The use of antilymphocyte antibodies for induction therapy or for treatment for rejection has been associated with an increased risk of posttransplant lymphoproliferative disorder (PTLD). The authors investigated the incidence of PTLD after monoclonal antilymphocyte, polyclonal antilymphocyte, interleukin (IL)-2 receptor antibody, or no induction therapy in primary kidney transplant recipients.. A multivariate Cox analysis of 38,519 primary kidney transplants from January 1, 1997, to December 31, 2000, was performed to compare the incidence of PTLD, graft survival, and patient survival among the induction groups.. The actual incidence of PTLD was 0.85% in 2,713 recipients with monoclonal, 0.81% in 4,343 with polyclonal, 0.50% in 7,800 with IL-2, and 0.51% in 23,663 recipients with no induction therapy (P=0.02). The Cox model indicated that as compared with no induction, the increased risk of PTLD was 72% with monoclonal (P=0.03), 29% with polyclonal (P=0.27), and 14% with IL-2 induction (P=0.52). IL-2 receptor antibody was associated with a 17% reduced risk of graft loss (P=0.002) and a 21% reduced risk of mortality (P=0.005) compared with no induction. Monoclonal and polyclonal induction therapies were not associated with a reduced risk of graft loss or mortality. Mycophenolate mofetil discharge maintenance immunosuppression was associated with a significantly reduced risk of PTLD and graft loss compared with azathioprine.. Among induction therapies, IL-2 receptor antibody induction was associated with the smallest risk of PTLD and improved graft and patient survival. Monoclonal or polyclonal induction was not associated with improved graft or patient survival, and monoclonal induction was associated with an increased risk of PTLD.

Topics: Adolescent; Adult; Antilymphocyte Serum; Child; Cyclosporine; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Interleukin-2; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Survival Analysis; Tacrolimus

Topics: Adolescent; Age Distribution; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Female; Humans; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Liver Diseases; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome

Tacrolimus (FK506) and mycophenolate mofetil (MMF) have been reported to increase PTLD risk. The NAPRTCS registry database now has several years of data on FK506 and MMF use in pediatric kidney transplantation. We analyzed the data registry to determine if the risk of PTLD was enhanced by the use of MMF or tacrolimus in initial immunosuppression. Data on day 30 therapy in the PTLD group were compared to corresponding data in patients who did not develop PTLD. Data were analyzed using SAS software and a log-rank test for significance. As of October 2000, there were 108 cases of PTLD in 6720 total transplants(1.60%). The use of MMF at day 30 was not a significant risk factor (0. 78% PTLD rate vs. 1.78% in cohort, RR = 1.05, p = 0.89). The relationship of FK506 with PTLD was linked to transplant era, 1987-95 or 1996-2000. In the earlier era, use of FK506 at day 30 was associated with PTLD (seen in 7/15 patients given FK506, RR = 47.7, p < 0.001). However, in the more recent era, there was no such significant association (seen in 3/313 patients given FK506, RR = 1.28, p = 0.692). There have been no cases of PTLD in 197 patients who received both FK506 and MMF at day 30. We conclude that FK506 and MMF use are not currently associated with increased risk of PTLD in pediatric kidney transplants.

Topics: Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Multicenter Studies as Topic; Mycophenolic Acid; 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

Success of pediatric liver transplantation has improved significantly. Most posttransplant deaths occur early and are related to surgical complications or recipient status at the time of transplantation. The causes of mortality beyond the first year have not been well described.. Three hundred twenty-six pediatric liver transplants were performed between November 1989 and April 1998 using tacrolimus-based immunosuppression. Patients were followed until March 2002. Mean follow-up was 9.2+/-2.4 years.. At 1 year, 279 patients (85.5%) were alive. In the subsequent 12.5 years, 10 of the remaining children died (3.58%) at a mean interval of 3.68+/-1.69 years after transplant. The mean age at transplant was 5.62+/-6.3 years. Six patients had infections as a major contributor to mortality, including two patients with posttransplant lymphoproliferative disorder (PTLD) and one patient that died after retransplantation for hepatitis. Two patients had recurrent malignancy. Other deaths were attributable to chronic rejection, liver failure after being lost to follow-up, and complications of cystic fibrosis.. Pediatric liver transplantation using tacrolimus-based immunosuppression has demonstrated excellent success, with 1- and 10-year survival rates of 85.5% and 82.9%, respectively. Late mortality after pediatric liver transplantation overall remains low, with a rate of 0.32% per year. The most common cause of death was infection (60%), including PTLD-related disease (20%). However, in the recent cohort of patients who underwent transplantation after September 1995, there were no fatal cases of Epstein-Barr virus or PTLD or late mortality thus far, suggesting a benefit from improved infectious disease surveillance using currently available modalities. Mortality from chronic rejection and noncompliance under tacrolimus has been exceedingly rare.

Topics: Cause of Death; Child; Child, Preschool; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infant; Infections; Liver Failure; Liver Neoplasms; Liver Transplantation; Lymphoproliferative Disorders; Male; Tacrolimus

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

Anetoderma is circumscribed atrophy of the skin due to a localized deficiency in elastic tissue. It can follow inflammatory skin diseases of several types, and occasionally is present in the skin around neoplasms. There are a few reports of anetoderma in the lesional skin of cutaneous lymphoma. We report on two patients who presented with multiple lesions of anetoderma and who later proved to have low-grade cutaneous B-cell lymphomas. One patient (Patient 1) is a 39-year-old man and the other patient is a 26-year-old woman who is a renal transplant recipient (Patient 2). Some biopsy specimens from the anetodermic skin of Patient 1 appeared to show an urticarial reaction, although plasma cells were present. A large nodule showed lymphoid follicles surrounded by plasmacytoid lymphocytes, with loss of elastic tissue in the adjacent dermis. The plasmacytoid cells stained overwhelmingly for lambda light chain, and staining of the urticarial lesions from this patient also showed a marked majority of lambda positive cells. Immunoglobulin heavy chain gene (IgH) rearrangements showed a dominant clonal pattern in the nodular lesion. We classified the disease in Patient 1 as marginal zone lymphoma and the disease in Patient 2 as a post-transplant lymphoproliferative disorder. Because of the intimate association of anetoderma and cutaneous B-cell lymphoproliferative disorders in these two patients, it seems possible that anetoderma could result from either a local effect of the neoplastic cells or associated inflammatory cells, especially neutrophils as in Case 1. The infiltrates of Case 1 had many interstitial neutrophils and only a few clonal plasmacytoid lymphocytes, indicating that this presentation of B-cell lymphoma can be a diagnostic pitfall. Given these two cases and similar ones in the literature, biopsy of lesional skin in anetoderma should be performed to ensure that lymphomatous infiltrates are not present. Even if plasma cells are sparse, studies to detect clonality are appropriate. Cutaneous B-cell lymphoma can be added to the list of associations of elastolysis and cutaneous lymphoma, which includes granulomatous slack skin (T-cell lymphoma) and cutis laxa (myeloma).

Topics: Adult; Atrophy; Cutis Laxa; Cyclosporine; DNA; Elastic Tissue; Female; Fluorescein-5-isothiocyanate; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunohistochemistry; In Situ Hybridization; Kidney Transplantation; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Polymerase Chain Reaction; RNA, Viral; Skin Neoplasms; Tacrolimus

The inhibitors of cyclin-dependent kinase (CDK) 4 (INK4) bind CDK4/6 to prevent their association with D-cyclins and G(1) cell cycle initiation and progression. We report here that among the seven CDK inhibitors, p18(INK4c) played an important role in modulating TCR-mediated T cell proliferation. Loss of p18(INK4c) in T cells led to hyperproliferation in response to CD3 stimulation. p18(INK4c)-null mice developed lymphoproliferative disorder and T cell lymphomas. Expression of IL-2, IL-2R-alpha, and the major G(1) cell cycle regulatory proteins was not altered in p18-null T cells. Both FK506 and rapamycin efficiently inhibited proliferation of p18-null T cells. In activated T cells, p18(INK4c) remained constant, and preferentially associated with and inhibited CDK6 but not CDK4. We propose that p18(INK4c) sets an inhibitory threshold in T cells and one function of CD28 costimulation is to counteract the p18(INK4c) inhibitory activity on CDK6-cyclin D complexes. The p18(INK4c) protein may provide a novel target to modulate T cell immunity.

Topics: Animals; CD28 Antigens; CD3 Complex; CDC2-CDC28 Kinases; Cell Cycle; Cell Cycle Proteins; Cell Division; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor p18; Cyclin-Dependent Kinases; Cytokines; Enzyme Inhibitors; G1 Phase; Immunosuppressive Agents; Lymphocyte Activation; Lymphoma, T-Cell; Lymphoproliferative Disorders; Mice; Mice, Knockout; Mice, SCID; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Receptors, Antigen, T-Cell; Sirolimus; T-Lymphocyte Subsets; Tacrolimus; Tumor Suppressor Proteins

While the overall incidence of post-transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients has been reported to be 4-11%, the long-term risk of PTLD associated with primary tacrolimus therapy is unknown. Therefore, in order to determine the incidence and long-term risk of PTLD, the present study examined 131 pediatric recipients who underwent liver transplantation (LTx) between October 1989 and December 1991 and received primary tacrolimus therapy. This cohort of children was evaluated over an extended time-period (until December 31 1996) with a mean follow-up of 6.3 yr. Actuarial Kaplan-Meier analysis was utilized to determine the risk of PTLD over time. The overall incidence of PTLD was 13% (17/131) with an average age of 4.3 +/- 0.75 yr at diagnosis. Pretransplant Epstein-Barr virus (EBV) serologies were negative in 82%, positive in 12%, and not available in 6% of the patients. The median time to diagnosis of PTLD post-Tx was 11.9 months (mean 16.4 +/- 3.9, range 1.7-63.0 months). Mean tacrolimus dose and plasma trough level (as evaluated by enzyme-linked immunosorbent assay [ELISA]) at the time of diagnosis was 0.32 +/- 0.06 mg/kg/day and 1.3 +/- 0.3 ng/mL, respectively. The cumulative long-term risk of PTLD was found to increase over time: 3% at 6 months, 8% at 1 yr, 12% at 2 yr, 14% at 3 yr, and 15% at 4 and 5 yr. Mortality from PTLD was 12% (two of 17 patients). Primary tacrolimus use in pediatric LTx has a long-term risk of PTLD approaching 15%, with the majority of episodes (78%) occurring in the first 2 yr, suggesting that intense EBV surveillance should occur early post-transplantation.

Topics: Adolescent; Child; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; 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

Topics: Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Nephrotic Syndrome; Postoperative Complications; Tacrolimus

Topics: Adolescent; Adult; Antibodies, Viral; Antigens, Viral; Child; Child, Preschool; Cyclosporine; Female; Herpesvirus 4, Human; Humans; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Monitoring, Physiologic; Postoperative Complications; Tacrolimus

Posttransplant lymphoproliferative disease (PTLD) is a serious complication associated with the use of chronic immunosuppression for solid organ transplantation. This study represents a retrospective analysis of UCLA's experience with PTLD in all pediatric liver transplant recipients between 1984-1997. We assessed the clinical presentation, risk factors, incidence density, immunological characteristics, management, and outcome of patients who developed PTLD when receiving either primary cyclosporin A (CsA) or tacrolimus.. A total of 251 children received primary CsA therapy of which 70 required OKT3 for steroid resistant rejection and 29 required tacrolimus rescue for OKT3 resistance and/or chronic rejection. One hundred forty one children received tacrolimus as primary therapy. Sixty patients who survived for less than 6 months after transplantation were excluded from the study.. The total incidence density (ID) rate of PTLD was 1.8+/-0.4 per 100 patient-years (30/392). The overall ID rate of PTLD in the CsA group was 0.93+/-0.2 per 100 patient-years (15/251). Within this group of primary CsA-treated patients, the ID rate of PTLD was 0.49+/-0.1 without OKT3 or tacrolimus, 0.67+/-0.2 with OKT3, and 6.42+/-1.1 with tacrolimus rescue. The overall PTLD ID rate in the primary tacrolimus-treated patients was 4.86+/-1.2 per 100 person-years (15/141). There was a 5-fold increase in the ID rate of PTLD in the primary tacrolimus group when compared to the comparable, primary CsA group (P<0.001). The mean time to PTLD was 5-fold longer (49.7+/-20.7 months) in the CsA group when compared to the CsA/tacrolimus rescue group (9.8+/-3 months, P<0.05) or the tacrolimus primary group (12.6+/-5.1 months, P<0.05). Five patients had monoclonal disease in the CsA group, but only one in the tacrolimus group (P<0.05). Clinical presentations with enlarged lymph nodes, fevers, malaise, anorexia, weight loss, hypoalbuminemia, and gastrointestinal blood loss were common. Mortality was 20%, three patients died in each group.. The use of primary tacrolimus therapy was associated with a significant 5-fold higher rate of PTLD when compared to those treated with primary cyclosporine. Early diagnosis, decrease and/or discontinuation of potent immunosuppressive agents may contribute to decrease morbidity and mortality of this entity.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Cyclosporine; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Infant; Liver Transplantation; Lymphoproliferative Disorders; Muromonab-CD3; Retrospective Studies; Risk Factors; Tacrolimus

The aim of this study is to evaluate the effects of RAPA conversion in patients undergoing cyclosporine (CsA) or tacrolimus (Tac) toxicity.. Twenty renal transplant recipients were switched to fixed dose rapamycin (RAPA) (5 mg/day) 0 to 204 months posttransplant. Drug monitoring was not initially used to adjust doses. The indications for switch were chronic CsA or Tac nephrotoxicity (12), acute CsA or Tac toxicity (3), severe facial dysmorphism (2), posttransplant lymphoproliferative disorder (PTLD) in remission (2), and hepatotoxicity in 1. Follow-up is 7 to 24 months.. In the 12 patients switched because of chronic nephrotoxicity there was a significant decrease in serum creatinine [233+/-34 to 210+/-56 micromol/liter (P<0.05) at 6 months]. Facial dysmorphism improved in two patients. No relapse of PTLD was observed. Five patients developed pneumonia (two Pneumocystis carinii pneumonia, one infectious mononucleosis with polyclonal PTLD lung infiltrate) and two had bronchiolitis obliterans. There were no deaths. RAPA was discontinued in four patients, because of pneumonia in two, PTLD in one, and oral aphtous ulcers in one. RAPA levels were high (>15 ng/ml) in 7 of 13 (54%) patients.. RAPA conversion provides adequate immunosuppression to enable CsA withdrawal. However, when converting patients to RAPA drug levels should be monitored to avoid over-immunosuppression and adequate antiviral and Pneumocystis carinii pneumonia prophylaxis should be given.

Topics: Adult; Blood Pressure; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Pneumonia; Sirolimus; Tacrolimus

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

Topics: Algorithms; Antigens, Viral; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Tacrolimus

Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Disease Progression; Female; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Lymphoma, B-Cell; Lymphoproliferative Disorders; Tacrolimus

Newer surgical techniques and immunosuppressive therapies have resulted in paediatric liver transplantation being available for most children with end-stage liver disease and has resulted in a greater than 80% 5-year survival rate. The most common indications for paediatric liver transplantation are biliary atresia (43%), metabolic disease (13%) and acute hepatic necrosis (11%). For approximately 75% of children with acute hepatic failure, the cause is unknown. Timing of liver transplantation not only affects survival rate, but may influence neurodevelopmental outcome. Fortunately, numerous types of donors, such as reduced-sized, living related or unrelated and blood-type mismatched, have reduced the mortality of children who are waiting for liver transplantation. However, the mortality and morbidity before and after liver transplantation remain high for children who have fulminant hepatic failure or are less than 5 months of age at the time of transplantation. The principle medical complications after liver transplantation are rejection and infection. Although use of newer immunosuppressive regimens has reduced the rate of rejection, Epstein-Barr virus infection with associated lymphoproliferative disorder remains the principle cause for morbidity and mortality after the initial 3 months post-liver transplant.

Topics: Adolescent; Adult; Age Factors; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Hepatic Encephalopathy; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Tacrolimus

B cell lymphoproliferative disorders (LPD) and liver rejection are major lethal complications after hepatic transplantation. Reduction in immunosuppression is the treatment for the former, but is a risk factor for the latter.. Here, we report three consecutive children with monoclonal LPD complicating orthotopic liver transplantation. All of them were treated with brief (<4 months) but intensive chemotherapy.. These three patients have remained in complete remission for LPD for 18 months to more than 3 years. Aggressive antimicrobial prophylaxis was successful in preventing life-threatening infections. The patient who received the highest cumulative doses of chemotherapy may have also developed relative immune tolerance to the allograft.. High-dose-intensity chemotherapy may be effective in the treatment of monoclonal LPD, as well as in the induction of immune tolerance for the prevention of allograft rejection and LPD recurrence.

Topics: Acyclovir; Antiviral Agents; Female; Graft Rejection; Humans; Immune Tolerance; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Remission Induction; Tacrolimus; Time Factors

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

Between March 27, 1989 and December 31, 1997, 1316 kidney transplantations alone were performed under tacrolimus-based immunosuppression at our center. Posttransplant lymphoproliferative disorders (PTLD) developed in 25 (1.9%) cases; the incidence in adults was 1.2% (15/1217), whereas in pediatric patients it was 10.1% (10/99; P<.0001). PTLD was diagnosed 21.0+/-22.5 months after transplantation, 25.0+/-24.7 months in adults and 14.4+/-18.2 months in pediatric patients. Of the 4 adult cases in whom both the donor and recipient Epstein Barr virus (EBV) serologies were known, 2 (50%) were seropositive donor --> seronegative recipient. Of 7 pediatric cases in whom both the donor and recipient EBV serologies were known, 6 (86%) were EBV seropositive donor --> seronegative recipient. Acute rejection was observed before the diagnosis of PTLD in 8 (53%) of 15 adults and 3 (30%) of 10 pediatric patients. Initial treatment of PTLD included a marked decrease or cessation of immunosuppression with concomitant ganciclovir therapy; two adults and two pediatric patients required chemotherapy. With a mean follow-up of 24.9+/-30.1 months after transplantation, the 1- and 5-year actuarial patient and graft survival rates in adults were 93% and 86%, and 80% and 60%, respectively. Two adults died, 3.7 and 46.2 months after transplantation, of complications related to PTLD, and 10 (including the 2 deaths) lost their allograft 3.7-84.7 months after transplantation. In children, the 1- and 5-year actuarial patient and graft survival rates were 100% and 100%, and 100% and 89%, respectively. No child died; one child lost his allograft 41.3 months after transplantation. One child had presumed recurrent PTLD that responded to discontinuation of tacrolimus and reinitiation of antiviral therapy. The mean serum creatinine level in adults was 2.5+/-1.2 mg/dl, and in children, it was 1.3+/-0.6 mg/ dl. Under tacrolimus-based immunosuppression, PTLD is less common after renal transplantation in adults than in children, but PTLD in children is associated with more favorable outcomes than in adults.

Topics: Adolescent; Adult; Age Distribution; Aged; Antibodies, Viral; Antiviral Agents; Child; Child, Preschool; Ganciclovir; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Middle Aged; Postoperative Complications; Survival Analysis; Tacrolimus; Tissue Donors

Topics: Child, Preschool; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Liver Transplantation; Living Donors; Lymphoproliferative Disorders; Postoperative Complications; RNA, Viral; Tacrolimus

Epstein-Barr virus (EBV) infection in association with immunosuppressive drugs used for solid organ transplantation can produce a spectrum of illnesses. Forty-one children who ranged in age from 6 months to 18.5 years received small intestinal transplants alone or in combination with other organs while undergoing primary tacrolimus (FK506) immunosuppression between July 1990 and June 1995. We reviewed hematoxylin and eosin-stained sections from all biopsy, surgical, and autopsy material from these children to determine the incidence and morphology of EBV-associated disease. Nuclear staining with in situ hybridization for EBV early RNA transcript (EBER) using the EBER-1 probe confirmed the presence of EBV. The EBV lymphoproliferations were graded as 1 to 4 according to histopathology and EBV quantitation determined in the area of greatest positivity. Twenty-one patients (51%) had EBV documented histologically on one or more occasions; only 8 (38%) are alive; 5 of these had the highest grade of 2. Posttransplant lymphoproliferative disease (PTLD) developed in 13 patients. Three of 10 patients (30%) with grade 3 lesions (polymorphous PTLD) are alive with intermittent evidence of EBV infection; 6 died with PTLD. Monomorphic PTLD (grade 4) was the cause of death in the three additional patients. Thirteen of 20 patients (65%) with no histologic evidence of EBV are alive. The incidence of EBV infection in pediatric small intestinal transplant recipients is higher than reported for any other solid organ cohort. With the aid of frequent EBER staining we were able to diagnose EBV infections in 51% of 41 patients; PTLD (grade 3 or 4) developed in 32% of these children. Low-grade EBV infections often preceded the development of PTLD and were identified in gastrointestinal biopsy samples from patients with concurrent PTLD; however, results of gastrointestinal biopsy samples may be negative for EBV in some patients with PTLD and, thus, underestimate systemic EBV-associated lymphoproliferations. Rejection and EBV infection can occur simultaneously, therefore, attention to low-grade infection may be useful to patient management.

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Cyclophosphamide; Female; Graft Rejection; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Intestine, Small; Lymphoproliferative Disorders; Male; Tacrolimus; Transplantation, Homologous; Tumor Virus Infections

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Humans; Hyperglycemia; Immunosuppressive Agents; Infant; Lymphoproliferative Disorders; Male; Medical Records; Prednisone; Retrospective Studies; Tacrolimus

Topics: Child; Child, Preschool; Drug Administration Schedule; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Methylprednisolone; Muromonab-CD3; Mycophenolic Acid; Postoperative Complications; Prednisone; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

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

Langerhans cell histiocytosis (LCH) is an unusual indication for orthotopic liver transplantation in children. Data from limited case reports suggest that orthotopic liver transplantation for LCH is associated with excellent survival rates and a low incidence of disease recurrence. However, in our experience, children who have transplantation for LCH appeared to experience a high incidence of refractory rejection and posttransplant lymphoproliferative disease (PTLD).. Data from 398 liver transplants performed in 298 children younger than 16 years of age were reviewed to determine the presence of risk factors for PTLD in patients with LCH and other causes of liver failure.. The incidence of PTLD was significantly higher in children who received transplants for LCH compared with all indications (p < 0.001) and specific indications that were associated with the development of PTLD (p < 0.002). Among patients in whom PTLD developed, there was no significant difference in the incidence of primary Epstein-Barr virus infections in patients who receive transplantation for LCH (4/4, 100%) versus all other indications (12/14, 86%). Children who had transplantation for LCH were older than those who had transplantation for other indications (LCH median age 3.1 years, other indications 1 year). The incidence of rejection, especially refractory rejection, was greater in patients who had transplantation for LCH (100% and 50%, respectively) compared with those who had transplantation for other indications (70% and 10%, p < 0.02 for refractory rejection).. Patients who had transplantation for liver disease related to LCH experienced a 67% long-term survival (median follow up 5.8 years, range 2.1 to 7.5 years). Recurrent LCH occurred in only 33% of patients and was easily managed. However, PTLD developed in two thirds of these patients, perhaps in part because of the high incidence of refractory rejection. This series therefore demonstrates an association between a primary disease process and the development of PTLD. Although the data indicate that children with LCH-induced liver failure benefit from transplantation, special care must be exercised in screening for and preemptive treatment of PTLD.

Topics: Adolescent; Age Factors; Antiviral Agents; Azathioprine; Child; Child, Preschool; Cyclosporine; Follow-Up Studies; Ganciclovir; Glucocorticoids; Graft Rejection; Herpesviridae Infections; Herpesvirus 4, Human; Histiocytosis, Langerhans-Cell; Humans; Immunosuppressive Agents; Incidence; Liver Failure; Liver Transplantation; Lymphoproliferative Disorders; Methylprednisolone; Muromonab-CD3; Prednisone; Recurrence; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus; Tumor Virus Infections

Posttransplant lymphoproliferative disease (PTLD) is a life-threatening condition the incidence of which in pediatric solid organ transplantation may be related to the immunosuppressive load. It has been suggested that tacrolimus, a new and potent immunosuppressor, causes an increased incidence of this syndrome.. The incidence, early signs, and risk factors for lymphoproliferative disease were reviewed in a cohort of 89 pediatric liver transplant recipients treated with tacrolimus.. Eighteen patients (20%) developed a PTLD-16 concomitant to a primary Epstein-Barr virus (EBV) infection and 2 with previous immunity against EBV. Three additional patients had preliminary signs of PTLD concomitant to primary EBV infection, but did not develop individualized lymphoid masses. Six patients died (6.7% of all tacrolimus-treated patients). Mean tacrolimus blood level during the 3 months preceding EBV infection reached 11.8+/-1.8 ng/ml in PTLD patients versus 9.4+/-3.4 ng/ml in non-PTLD patients (0.05

Topics: Child; Child, Preschool; Female; Graft Rejection; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Risk Factors; Tacrolimus; Time Factors; Tumor Virus Infections

Tacrolimus (formerly known as FK506) is a macrolide immunosuppressant that has been used to prevent rejection of solid organ allografts. Acute hemolytic anemia is one of the side effects associated with tacrolimus therapy, and two mechanisms have been described to account for acute hemolytic anemia in patients receiving tacrolimus: drug-induced hemolysis and alloimmune hemolysis resulting from donor lymphocytes derived from the allograft (passenger lymphocyte syndrome). We report a case of a liver transplant recipient who developed fatal autoimmune hemolytic anemia while under treatment with tacrolimus for allograft rejection, and in whom postmortem examination revealed a clinically unsuspected posttransplant lymphoproliferative disorder. This case implicates autoimmune hemolytic anemia as a novel mechanism of acute hemolysis in patients treated with tacrolimus and further suggests that acute hemolytic anemia in this group of patients may herald an occult lymphoproliferative disorder.

Topics: Anemia, Hemolytic, Autoimmune; Child; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Tacrolimus

FK-506 is an immunosuppressive agent used mainly to prevent allograft rejection in organ transplant patients. Recently, it has been applied as a treatment for patients with autoimmune disorders. An entity called posttransplant lymphoproliferative disorder (PTLD) is a well-recognized result of immunosuppression in transplant patients receiving long-term immunosuppression. This disorder is a complication of treatment with FK-506 in 0.7 to 1.6% of transplant patients and is usually of B-cell origin. A majority of patients have serologic evidence of EBV infection. We report a case of a patient receiving long-term FK-506 therapy for multiple sclerosis who developed lymphoproliferative disorder involving the cervix. We will discuss the possible role of FK-506 initiation of this tumor.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Multiple Sclerosis; Tacrolimus; Uterine Cervical Diseases

The incidence, risk factors, and outcome of posttransplant lymphoproliferative disease (PTLD) were examined for 298 children undergoing liver transplantation. The overall incidence of PTLD was 8.4% (25 of 298). Intensity of immunosuppression was found to be a major risk factor for the development of PTLD. Cyclosporine and tacrolimus when used as primary immunosuppression were associated with the development of PTLD in 4.3% and 6.6% of cases (P=NS). OKT3 and tacrolimus, when used as rescue therapy for steroid-resistant rejection, were associated with a comparable increase in the risk of developing PTLD (10.9% and 11.1%, P=NS). Patients requiring both OKT3 and tacrolimus to treat refractory rejection were at significantly increased risk for PTLD (28.1% vs. 4.3% or 6.6%, P<0.0001). PTLD was more common in patients who received transplants for Langerhans cell histiocytosis relative to other indications for transplantation (66% vs. 8.4%, P=0.0005). The data also support an association between primary Epstein-Barr virus (EBV) infections following transplantation and the development of PTLD. While only three patients were EBV seropositive before transplantation (14%), 19 patients were EBV seropositive at the time of diagnosis of PTLD (90%), confirming a high incidence of primary EBV infections in patients with PTLD (21 patients had both pre- and posttransplant EBV serologies). In this series, PTLD was associated with a mortality rate of 60%, and 12 of the 15 patients who died had persistent tumor at the time of death. Five of the 13 patients rendered disease-free developed ductopenic rejection. Of the four with severe liver dysfunction, two have undergone successful retransplantation and are alive without evidence of PTLD. In conclusion, intense immunosuppression using OKT3 and tacrolimus as rescue agents was associated with a significant increase in the incidence of PTLD. Primary EBV infection after transplantation further accentuated this risk. Independent of these risk factors, patients with Langerhans cell histiocytosis were at significantly increased risk for PTLD. The identification of high-risk patients should allow the development of protocols to screen patients for primary EBV infections and early indications of PTLD, as well as the institution of preemptive antiviral and antitumor therapies.

Topics: Adolescent; Child; Child, Preschool; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Muromonab-CD3; Postoperative Complications; Reoperation; Risk Factors; Salvage Therapy; Survival Analysis; Tacrolimus; Treatment Outcome; Tumor Virus Infections

The incidence of Epstein-Barr virus (EBV) infection and lymphoproliferative disorder (LPD) was determined in a pediatric liver transplant population consisting of 51 children treated with FK506 and 91 treated with cyclosporine. The incidence of symptomatic EBV infection was 21.9% (23 of 105 cases) in children < 5 yr old and 10.8% (4 of 37 cases) in children 5 to 17 yr old as compared with 2.7% (9 of 323 cases) in adults (P < 0.0001). In the under 5 yr old group on cyclosporine, the incidences of EBV infection and LPD were 9 of 68 (13.2%) and 2 of 68 children, (2.9%), respectively. In contrast, in children under 5 yr old group on FK506, the incidences of EBV infection and LPD in the FK506 group were 14 of 37 (37.8%) and 7 of 37 children (18.9%), respectively. The difference between these two groups was statistically significant (P < 0.02). There were no cases of LPD in the 5-17 yr-old children on either cyclosporine (n = 23) or FK506 (n = 14). The incidence of EBV infections in the 5 to 17 yr age group, 17.4% on cyclosporine and 0% on FK506, was less than for the younger children on FK506 (37.8%). A total of 39% (9 of 23) of children under 5 yr old who had symptomatic EBV infections developed LPD, and 44% (4 of 9) with LPD died. The higher incidence of EBV infections and LPD in the younger children treated with FK506 was probably related to a greater intensity of immunosuppression for patients on FK506 than those on cyclosporine.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Cyclosporine; Graft Rejection; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Liver Transplantation; Lymphoproliferative Disorders; Opportunistic Infections; Retrospective Studies; Tacrolimus; Tumor Virus Infections

We studied rejection, allograft function and side effects, such as hypertension, renal dysfunction and hypercholesterolemia, in seven patients switched from cyclosporine-based triple-drug immunosuppression to FK 506.. A subset of pediatric heart transplant recipients treated with triple-drug immunosuppression consisting of cyclosporine, azathioprine and prednisone experience either persistent rejection when attempts are made to taper corticosteroids or morbidity from cyclosporine and corticosteroids. Experience with the new immunosuppressive agent FK 506 has demonstrated its effectiveness as a single agent in heart transplant recipients, and anecdotal evidence has shown that side effects such as hypertension and hypercholesterolemia may be lower.. Seven patients whom we deemed corticosteroid dependent were switched to FK 506-based therapy. Allograft function, episodes of rejection, need for corticosteroids and incidence of side effects from FK 506 were monitored. The switch to FK 506 was performed using an established protocol. Follow-up time has ranged from 15 to 41 months. Serial right heart catheterizations and endomyocardial biopsies were performed after each reduction of corticosteroid dosing.. Catheterization data showed no significant change in pulmonary wedge pressure, mean right atrial pressure or cardiac index, indicating no decline in allograft function. Serial echocardiographic variables of allograft function were also stable. At present, all seven patients are free of the corticosteroid portion of their immune suppression. There have been only two episodes of significant acute rejection requiring treatment with intravenous corticosteroids. Antihypertensive medications have been discontinued in five of six patients previously treated with these drugs. Plasma cholesterol, low density lipoprotein and triglyceride levels were decreased, and renal function was stable.. Preliminary studies suggest that FK 506 may be an alternative immunosuppressive agent for pediatric and adolescent patients experiencing ongoing rejection or significant morbidity from cyclosporine and corticosteroids and in those patients dependent on corticosteroids for immune suppression.

Topics: Adolescent; Adult; Antihypertensive Agents; Azathioprine; Cardiac Catheterization; Child; Cyclosporine; Drug Therapy, Combination; Echocardiography; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Hyperlipidemias; Hypertension; Immunosuppression Therapy; Kidney Diseases; Lymphoproliferative Disorders; Prednisone; Tacrolimus; Time Factors

Topics: Adolescent; Age Factors; Child; Child, Preschool; Cytomegalovirus Infections; Graft Rejection; Graft Survival; Humans; Infant; Kidney Transplantation; Lymphoproliferative Disorders; Pennsylvania; Survival Rate; Tacrolimus; Time Factors; Tissue Donors; Treatment Outcome

Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Female; Follow-Up Studies; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Incidence; Infant; Intestines; Lymphoproliferative Disorders; Male; Retrospective Studies; Tacrolimus; Time Factors

Topics: Animals; Death; Epithelium; Graft Rejection; Graft Survival; Hyperplasia; Immunosuppression Therapy; Intestinal Mucosa; Intestine, Small; Lymphoproliferative Disorders; Swine; Tacrolimus

During the past 14 years, 746 hearts have been transplanted at the University of Pittsburgh. Immunosuppression has evolved from a CsA-based protocol with or without lympholytic prophylaxis to a tacrolimus-based protocol. Tacrolimus offers comparable survival to the conventional immunosuppression but is associated with lesser side effects and lower recurrent rejection. It also serves as an effective rescue agent for intractable rejection in patients receiving CsA-based immunosuppression. However, the shortage of donors, chronic rejection, and the morbidity associated with chronic use of nonspecific immunosuppression remain the major limitations in clinical transplantation. Currently, research at the University of Pittsburgh focuses on the induction of donor-specific transplantation tolerance in order to eliminate the morbidity associated with nonspecific immunosuppression and on left ventricular-assist devices as a bridge and/or an alternative to cardiac transplantation.

Topics: Actuarial Analysis; Adolescent; Adult; Aged; Cause of Death; Child; Child, Preschool; Demography; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Infant, Newborn; Kidney Diseases; Lymphoproliferative Disorders; Male; Middle Aged; Patient Selection; Pennsylvania; Retrospective Studies; Survival Rate; Tacrolimus

The application of lung transplantation to the pediatric population was a natural extension of the success realized in our adult transplantation program, which began in 1982. Twenty pediatric patients (age range 3 to 18 years) have had heart-lung (n = 11), double lung (n = 8), and single lung (n = 1) transplantation procedures. The causes of end-stage lung disease were primary pulmonary hypertension (n = 7), congenital heart disease (n = 5), cystic fibrosis (n = 4), pulmonary arteriovenous malformation (n = 2), graft-versus-host disease (n = 1), and desquamative interstitial pneumonitis (n = 1). Four (20%) patients had thoracic surgical procedures before the transplantation operation. The survival was 80% at a mean follow-up of 2 years. Immunosuppressive drugs included cyclosporine (n = 9) or FK 506 (n = 11) based therapy with azathioprine and steroids. Children were followed up by means of spirometry, transbronchial biopsy, and primed lymphocyte testing of bronchoalveolar lavage fluid. The mean number of treated episodes of rejection was 1.4 at 30 days, 0.5 at 30 to 90 days, and 1.4 at more than 90 days, and the first treated rejection episode occurred on average 28 days after the operation. Obliterative bronchiolitis developed in four (25%) of 16 patients surviving more than 100 days. Results of pulmonary function tests have remained good in almost all recipients. The greatest infectious risk was that of cytomegalovirus: one death and one case of pneumonia. Posttransplantation lymphoproliferative disease was diagnosed in two (12.5%) patients; both recovered. The most common complications were hypertension (25%) and postoperative bleeding (15%). Early results indicate that lung transplantation is a most promising therapy for children with severe vascular and parenchymal lung disease.

Topics: Adolescent; Child; Child, Preschool; Female; Follow-Up Studies; Graft Rejection; Heart-Lung Transplantation; Humans; Length of Stay; Lung Transplantation; Lymphoproliferative Disorders; Spirometry; Surgical Wound Infection; Survival Rate; Tacrolimus; Tissue Preservation

The decade from 1982 through 1992 witnessed tremendous growth in pediatric cardiac transplantation. At Children's Hospital of Pittsburgh 66 cardiac transplants were performed during this period (age range 7 hours to 18 years). The cause of cardiomyopathy was congenital (n = 30), cardiomyopathy (n = 29), myocarditis (n = 2), doxorubicin toxicity (n = 2), ischemic (n = 1), valvular (n = 1), and cardiac angiosarcoma (n = 1). Nine children (14%) required mechanical circulatory support before transplantation: extracorporeal membrane oxygenation (n = 8) and Novacor left ventricular assist system (n = 1) (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.). The mean follow-up time was 2 years (range 4 months to 8 years). The overall survival in the group was 67%. In children with congenital heart disease (> 6 months of age) the perioperative (30 day) mortality was 66% before mid-1988 (n = 10) and 0% since mid-1988 (n = 11). The late mortality (> 30 days) in children with cardiomyopathy transplanted prior to mid-1988 was 66% (n = 14) and 7% since mid-1988 (n = 15). Since mid-1988 1- and 3-year survival was 82% in children with congenital heart disease and 90% in children with cardiomyopathy. Twenty-six children have had FK 506 as their primary immunosuppressive therapy since November 1989. Survival in this group was 82% at 1 and 3 years. The actuarial freedom from grade 3A rejection in the FK group was 60% at 3 and 6 months after transplantation versus 20% and 12%, respectively, in the 15 children operated on before the advent of FK 506, who were treated with cyclosporine-based triple-drug therapy (p < 0.001, Mantel-Cox and Breslow). Twenty of 24 children (83%) in the FK 506 group are receiving no steroids. The prevalence of posttransplantation hypertension was 4% in the FK 506 group versus 70% in the cyclosporine group (p < 0.001, Fisher). Renal toxicity in children treated with FK 506 has been mild. Additionally, eight children have been switched to FK 506 because of refractory rejection and drug toxicity. FK 506 has not produced hirsutism, gingival hyperplasia, or abnormal facial bone growth. The absence of these debilitating side effects, together with the observed immune advantage and steroid-sparing effects of FK 506, hold tremendous promise for the young patient facing cardiac transplantation and a future wedded to immunosuppression.

Topics: Adolescent; Cardiomyopathies; Child; Child, Preschool; Cyclosporine; Extracorporeal Membrane Oxygenation; Female; Graft Rejection; Heart Defects, Congenital; Heart Transplantation; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Infections; Kidney; Lymphoproliferative Disorders; Male; Postoperative Complications; Tacrolimus

Topics: Anti-Bacterial Agents; Humans; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Tacrolimus

Topics: Anti-Bacterial Agents; Cyclosporins; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lymphoproliferative Disorders; Organ Transplantation; Tacrolimus

Topics: Acyclovir; Adult; Child; Female; Humans; Immunosuppression Therapy; Liver Transplantation; Lymphoproliferative Disorders; Male; Retrospective Studies; Tacrolimus; Treatment Outcome