Use Of Antilymphocyte Antibodies Research Articles

Lymphoproliferative disorders after renal transplantation along 2 decades: a large longitudinal study of 21.546 recipients

IntroductionPost transplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid proliferations in recipients of solid organs which seem to be related to Epstein Barr Virus (EBV). The use of antilymphocyte antibodies, EBV seronegativity in the recipient,acute rejection and CMV infection have been identified as classical risk factors. Material y methodsWe have studied in a retrospective observational study, the incidence of PTLD in a period of 22 years, its relationship with EBV, presence of classical risk factors and outcome in 21546 simple adult renal transplant recipients from cadaveric and living donors, transplanted in 21 hospitals from 1990 to 2009. ResultsA total of 275 recipients developed PTLD (1,2%),195 males (70,9%), 80 females (29,1%) aged 59.2 (p25 44.7 p75 68)years. Two hundred forty-five (89.0%) were 1st transplant recipients and 269 (97,8%) from cadaveric donors. EBV in the tissue was reported in 94 out of the 155 studied recipients (60.6%) and 86.0% of the proliferations were due to B lymphocytes. PTLD median appearance after transplant were 42.months (p25, 75, 12, 77, 5). One hundred eighty-eight recipients out of 275 patients (68.3%) had any classical risk factor and the use of antilymphocyte antibodies was the most frequent.During the follow-up, 172 patients died (62,5%) and 103 (37,5%) had a complete remission. The main cause of death was PTLD progression (n = 91, 52,9%), followed by sepsis (n = 24, 13,9%). The follow-up period post-transplant of the recipients was between 3 and 22 years.The incidence was 0,14% during the first year post-trasplant and 0.98% the cumulative incidence at 10 years.Patient survival after diagnosis was 51%, 44% and 39% after 1, 2 and 5 years, respectively. Finally, overall graft survival was 48%, 39% and 33% at the same periods. ConclusionPTLD has a low incidence in renal transplant recipients. Most of the proliferations are due to B lymphocytes and seem to have a close relationship with EBV. PTLD can develop in the absence of classical risk factors. The prognosis is poor, mainly due to PTLD progression, but the survivors can even maintain their grafts.

631P A meta-analysis of the outcome of post-transplant lymphoproliferative disorder in adult patients after hematopoietic stem cell transplant

Post-transplant lymphoproliferative disorder is a fatal complication that can occur early after solid organ or hematopoietic stem cell transplantation (HSCT). It represents a spectrum of Epstein Barr virus (EBV)-related clinical diseases, from benign mononucleosis like illness to malignancies like non-Hodgkin's lymphoma. Some of the established risk factors for PTLD are HLA mismatching, T-cell depletion, and the use of anti-lymphocyte antibodies as conditioning or immunosuppression for the treatment of graft-versus-host disease.

Enfermedad linfoproliferativa difusa postrasplante renal: estudio longitudinal de 21.546 receptores durante 2 décadas en España

IntroductionPosttransplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid proliferations in recipients of solid organs which seem to be related to Epstein-Barr virus. The use of antilymphocyte antibodies, Epstein-Barr virus seronegativity in the recipient, acute rejection and CMV infection have been identified as classical risk factors. Material and methodsWe have studied, in a retrospective observational study, the incidence of PTLD in a period of 22 years, its relationship with Epstein-Barr virus, presence of classical risk factors and outcome in 21,546 simple adult renal transplant recipients from cadaveric and living donors, transplanted in 21 hospitals from 1990 to 2009. ResultsA total of 275 recipients developed PTLD (1.2%), 195 males (70.9%), 80 females (29.1%), aged 59.2 (p25 44.7; p75 68) years. Two hundred forty-five (89.0%) were first transplant recipients and 269 (97.8%) from cadaveric donors. Epstein-Barr virus in the tissue was reported in 94 out of the 155 studied recipients (60.6%) and 86.0% of the proliferations were due to B lymphocytes. PTLD median appearance after transplant were 42 (p25 12; p75 77.5) months. One hundred eighty-eight recipients out of 275 patients (68.3%) had any classical risk factor and the use of antilymphocyte antibodies was the most frequent. During the follow-up, 172 patients died (62.5%) and 103 (37.5%) had a complete remission. The main cause of death was PTLD progression (n=91, 52,9%), followed by sepsis (n=24, 13.9%). The follow-up period post-transplant of the recipients was between 3 and 22 years.The incidence was 0.14% during the first year post-trasplant and 0.98% the cumulative incidence at 10 years.Patient survival after diagnosis was 51, 44 and 39% after one, 2 and 5 years, respectively. Finally, overall graft survival was 48, 39 and 33% at the same periods. ConclusionPTLD has a low incidence in renal transplant recipients. Most of the proliferations are due to B lymphocytes and seem to have a close relationship with Epstein-Barr virus. PTLD can develop in the absence of classical risk factors. The prognosis is poor, mainly due to PTLD progression, but the survivors can even maintain their grafts.

Tuberculosis and Transplantation.

Mycobacterium tuberculosis is a major opportunistic pathogen in transplant recipients. Compared to that in the general population, the frequency of tuberculosis (TB) is 10 to 40 times higher in hematopoietic stem cell transplant (HSCT) recipients and 20 to 74 times higher in solid-organ transplant (SOT) recipients. Transplant recipients with TB are also more likely to develop disseminated disease, have longer time to definitive diagnosis, require more invasive diagnostic procedures, and experience greater anti-TB treatment-related toxicity than the general population. Specific risk factors for TB in SOT recipients include previous exposure to M. tuberculosis (positive tuberculin skin tests and/or residual TB lesions in pretransplant chest X ray) and the intensity of immunosuppression (use of antilymphocyte antibodies, type of basal immunosuppression, and intensification of immunosuppressive therapy for allograft rejection). Risk factors in HSCT recipients are allogeneic transplantation from an unrelated donor; chronic graft-versus-host disease treated with corticosteroids; unrelated or mismatched allograft; pretransplant conditioning using total body irradiation, busulfan, or cyclophosphamide; and type and stage of primary hematological disorder. Transplant recipients with evidence of prior exposure to M. tuberculosis should receive treatment appropriate for latent TB infection. Optimal management of active TB disease is particularly challenging due to significant drug interactions between the anti-TB agents and the immunosuppressive therapy. In this chapter, we address the epidemiology, clinical presentation, diagnostic considerations, and management strategies for TB in SOT and HSCT recipients.

Invasive Fungal Disease in Renal Transplant Recipients at a Brazilian Center: Local Epidemiology Matters.

Invasive fungal disease (IFD) is an important complication after solid organ transplantation (SOT). A marked geographic variation in the epidemiology of IFD after kidney transplantation (KT) has been suggested by the results of previous studies. Nevertheless, data from Latin American centers are scarce. This study sought to describe the epidemiology of IFD at a Brazilian KT center. This study was a retrospective single-center cohort study that included patients who underwent KT between 1998 and 2009 and were followed up until July 2015. Cases of simultaneous kidney-pancreas transplantation were excluded. The primary study outcome was the occurrence of proven or probable IFD. Among 908 KT recipients, 44 cases of IFD occurred in 42 patients (4.6%). Cryptococcus spp. infection, diagnosed in 16 cases (36.3%), was the leading cause of IFD, followed by histoplasmosis in 10 cases (22.7%) and invasive candidiasis in 10 (22.7%). Sporotrichosis, mucormycosis, invasive aspergillosis, pulmonary Cladophialophora sp. infection, trichosporonosis and Saccharomyces cerevisiae fungemia occurred in 1 recipient each (2.3%). Two additional (4.5%) cases of unspecified mold infections were identified by histopathological analysis. Most cases of IFD (67%) occurred later than 6 months after transplantation. Previous use of antilymphocyte antibodies (P= .008) and corticosteroid pulse therapy (P< .001) were more frequent among cases of IFD occurring within the first 6 months after transplantation. The epidemiology of IFD in this Brazilian cohort was characterized by a large predominance of late infections and a high proportion of cases of cryptococcosis and histoplasmosis. These results highlight the considerable geographic variability of IFD epidemiology after KT.

INVASIVE FUNGAL INFECTIONS AFTER ADULT SMALL BOWEL TRANSPLANTATION: RISK FACTORS AND EFFICACY OF PROPHYLACTIC THERAPY

P831 Aims: Intestinal transplant recipients are at high risk for invasive fungal infections because of the breach of intestinal mucosa rich in fungal flora due to preservation injury and/or rejection and the chronic need for a relatively heavy post-transplant immunosuppression. Methods: Using a computerized database, we reviewed the medical records of all adult small bowel recipients that were transplanted between May 1990 and February 2002. Invasive fungal infection was defined as positive fungal blood, tissue and deep wound cultures and/or histopathologic fungal identification on tissue samples or autopsy materials. Relevant clinical data including pre-transplant TPN duration, CMV infection, hemodialysis and use of antifungal prophylaxis were gathered and correlated with the presence or absence of invasive fungal infection using Fisher’s exact test. Results: Fifty-nine episodes of invasive fungal infections were identified in 43 (44.8%) out of 96 intestinal recipients. Of these, 47 (80%) were candidiasis, 6 (10 %) were aspergillosis, 3(5%) were dematiaceous fungi, 1 (1.7%) was cryptococcosis, 1 (1.7%) was coccidiomycosis and 2 (3%) were infections by other fungi. CMV disease and hemodialysis were associated with increased risk of invasive fungal infection with a p value of 0.05 and 0.06, respectively. The use of high-dose prophylactic liposomal amphotericin B was protective against function infection, compared to no prophylaxis (p=0.003), and conventional low dose amphotericin B (p=0.014). Age, operative time, ICU stay, use of anti-lymphocyte antibodies, and duration of TPN prior to transplant were not significant risk factors. Conclusions: Invasive fungal infections are common among small bowel transplant recipients. However, the recent use of a high-dose liposomal amphotericin B has been effective as a prophylactic therapy with significant reduction in the incidence of such a serious morbidity and it’s associated mortality.

Cytomegalovirus Prophylaxis and Graft Outcome in Solid Organ Transplantation: A Collaborative Transplant Study Report

We investigated relationships between cytomegalovirus (CMV) seropairing and CMV prophylaxis on graft outcome in recipients of solid organ transplants. Transplants carried out from 1985 to 2002 and reported to the Collaborative Transplant Study were analyzed. In cadaver kidney recipients, CMV prophylaxis was significantly associated with improved graft survival only in the seronegative-recipient/seropositive-donor combination (at 3 years: 79.4% with prophylaxis vs. 73.5% without prophylaxis; RR 0.80, p < 0.0001). Among patients who had a functioning graft at 1 year, significantly fewer patients who received CMV prophylaxis received rejection treatment in the preceding year (26.3%), compared with patients who did not receive prophylaxis (32.4%) (p = 0.0001), suggesting an inhibitory effect of CMV prophylaxis on acute rejection. Significant improvements in graft survival after CMV prophylaxis were found also in CMV-negative recipients of CMV-positive heart, and lung or heart-lung transplants, but not liver transplants. The age of the recipient had a differential effect on graft and patient survival after CMV prophylaxis. Use of antilymphocyte antibodies or mycophenolate mofetil was not associated with an enhanced CMV effect on graft outcome. These results may contribute to a better understanding of the influence of pretransplant CMV serology on the effect of CMV prophylaxis.

Prophylaxis of cytomegalovirus primary infection with short-term ganciclovir theraphy

CYTOMEGALOVIRUS (CMV) remains one of the most important pathogens in kidney and other solid organ transplantation. It produces greater morbility nowadays rather than the significant mortality rates in the past. CMV not only produces direct damage due to the infection, but also indirect complications including excessive immunosuppression and augmented acute rejection as well as decreasing patient and allograft survivals and increasing economic costs. The most important risk factors for CMV infection are recipient CMV serologic status in relation to organ donor serology (D /R ), and the use of antilymphocyte antibodies either for induction or for acute rejection therapy. There are two major forms of CMV infection; prophylaxis by administration of antiviral drugs or gammaglobulins at the time of transplantation and for a variable period after transplantation, and preemptive therapy, namely giving antiviral drugs when there is evidence of the virus replication after kidney transplantation. We report our experience with a group of high risk patients (D /R ) who received low-dose and short-term gancyclovir prophylaxis.

Post-transplant lymphoproliferative disorder: a review.

Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of Epstein-Barr virus-related (EBV) clinical diseases, from a benign mononucleosis-like illness to a fulminant non-Hodgkin's lymphoma. In the setting of hematopoietic stem cell transplantation, PTLD is an often-fatal complication occurring relatively early after transplant. Risk factors for the development of PTLD are well established, and include HLA-mismatching, T-cell depletion, and the use of antilymphocyte antibodies as conditioning or treatment of graft-versus-host disease. Early recognition of PTLD is particularly important in the SCT setting, because PTLD in these patients tends to be rapidly progressive. Familiarity with the clinical features of PTLD and a heightened level of suspicion are critical for making the diagnosis. Surveillance techniques with EBV antibody titers and/or polymerase chain reaction (PCR) may have a role in some high-risk settings. Immune-based therapies such as monoclonal anti-B-cell antibodies, interferon-alpha, and EBV-specific donor T cells, either as treatment for PTLD or as prophylaxis in high-risk patients, represent promising new directions in the treatment of this disease.

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

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

Leukocyte response to thymoglobulin or Atgam for induction immunosuppression in a randomized, double-blind clinical trial in renal transplant recipients

EVENTS surrounding the renal transplant procedure and initial hospitalization are important determinants of long-term allograft function. The initial immunosuppressive regimen may have a significant impact on these events, but the optimal immunosuppressive strategy for renal transplant recipients is not known. “Induction immunosuppressive therapy” generally refers to the use of antilymphocyte antibodies at the time of transplant. The theoretical advantages are: (1) avoiding the use of cyclosporine in the immediate posttransplant period and thus avoid vasoconstriction and (2) blocking T-cell activation and/or other immune cell function at the time of transplant. These combined effects may improve early allograft function, delay or prevent rejection, and improve long-term allograft survival. Induction therapy, however, may be associated with increased risk for cytomegalovirus (CMV) disease, and posttransplant lymphoproliferative disease (PTLD). In a recent randomized, double-blinded, multicenter clinical trial, thymoglobulin (SangStat Medical Corporation, Menlo Park, Calif) was found to be more efficacious than Atgam (Pharmacia & Upjohn, Kalamazoo, Mich) for the treatment of rejection. It was felt that this benefit might be due to the more profound and longer duration of T-cell depletion seen with thymoglobulin than with Atgam. To further evaluate this phenomenon, we performed a randomized, double-blind clinical trial for the prevention of acute rejection (induction) and analyzed T-cell subsets, absolute lymphocytes, and total white blood cell counts during the induction period and for 1 year following transplantation.

Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials

Objective: To compare tacrolimus with cyclosporin for immunosuppression in renal transplantation.Design: Meta-analysis of randomised trials of two treatments after kidney transplantation.Identification: Four studies involving 1037 patients. Trials were included if...

Anti-lymphocyte antibodies late in the course of pediatric renal transplantation.

Beyond the immediate post-transplant period, physicians are often reluctant to use anti-lymphocyte preparations to treat episodes of acute renal functional deterioration attributable to acute rejection. This is due to the perception that such episodes are less likely to be reversible, and to concern regarding the potential adverse effects of anti-lymphocyte antibodies, including opportunistic infections, lymphoproliferative disorders, and the development of human anti-mouse antibodies. Records were reviewed for all 365 renal transplants performed in 267 patients at our center from 1971 to 1996. Anti-lymphocyte antibodies were used in an attempt to reverse 6 episodes of corticosteroid-resistant acute rejection in 5 children at a mean interval of 24.5 months following transplantation. The mean serum creatinine at initiation of therapy with the anti-lymphocyte agents was 2.9 mg/dl. Following treatment, the mean serum creatinine decreased to 1.3 mg/dl (P=0.03, Student's t-test). Two patients developed uncomplicated opportunistic infections after completion of anti-lymphocyte therapy; none have developed lymphoproliferative disorders or antibodies to OKT3. We conclude that in the correct clinical setting with corticosteroid-resistant acute rejection, the use of anti-lymphocyte antibodies should not be withheld solely on the basis of length of time since transplantation.

The effect of antilymphocyte induction therapy on renal allograft survival. A meta-analysis of individual patient-level data. Anti-Lymphocyte Antibody Induction Therapy Study Group.

Randomized, controlled trials have not shown that the perioperative use of antilymphocyte antibodies (induction therapy) improves survival of cadaveric kidney allografts. This study combined individual patient-level data from published trials to examine the effect of induction therapy on allograft survival. Randomized, controlled trials identified from MEDLINE. Published trials that compared adult recipients of cadaveric renal allografts who did and did not receive antilymphocyte antibodies in the perioperative period were selected if individual patient-level data were available. Individual patient-level data were collected for each of 628 study patients. Multivariable Cox proportional hazards regression was used to estimate the effect of induction therapy on allograft survival. The adjusted rate ratio for allograft failure with induction therapy compared with conventional therapy was 0.62 (95% CI, 0.43 to 0.90) (P = 0.012) over 2 years and 0.82 (CI, 0.62 to 1.09) (P = 0.17) over 5 years. The effect of induction therapy on allograft survival diminished over time; no benefit overall was seen after 2 years after transplantation (rate ratio, 1.13 [CI, 0.72 to 1.78]) (P > 0.2). Greater HLA-DR mismatch, delayed allograft function, diabetes mellitus in the recipient, African-American ethnicity of the recipient, and presensitization (panel-reactive antibody levels > or = 20%) were significantly associated with allograft failure at 5 years. Among high-risk patients, only those who were presensitized benefited from induction therapy at 2 years (rate ratio, 0.12 [CI, 0.03 to 0.44]) (P = 0.001). Results were similar at 5 years. Using individual-level data, this study showed a benefit of induction therapy at 2 years, particularly among presensitized patients. Although the benefit of this therapy subsequently waned, presensitized patients continued to have benefit at 5 years.

Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA.

Tuberculosis is unusual in transplant recipients. The incidence, clinical manifestations, and optimal treatment of this disease in this population has not been adequately defined. The present study was undertaken to assess the incidence, clinical features, and response to therapy of Mycobacterium tuberculosis infection in solid-organ transplant recipients. We evaluated retrospectively the incidence, clinical characteristics, diagnostic procedures, antituberculous treatment, clinical course, and factors influencing mortality in 51 solid-organ transplant recipients who developed tuberculosis after transplantation. We also reviewed the world literature on tuberculosis in solid-organ transplantation. The overall incidence of tuberculosis was 0.8%. The localization was pulmonary in 63% of the cases, disseminated in 25%, and extrapulmonary in 12%. Tuberculosis developed from 15 days to 13 years after surgery (mean, 23 months). In one third of the cases, diagnosis was not suspected initially, and in three cases, diagnosis was made at necropsy. Fever was the most frequent symptom, followed by constitutional symptoms, cough, respiratory insufficiency, and pleuritic pain. Fifteen patients (33%) developed hepatotoxicity during treatment; hepatotoxicity was severe in seven cases. Hepatotoxicity was higher in patients receiving four or more antituberculous drugs (50%) than in patients receiving three drugs (21%; P=0.03). Serum levels of cyclosporine decreased in the 26 patients under the simultaneous use of rifampin. Nine of them (35%) developed acute rejection, and five (56%) died, in comparison with 3 of 17 patients (18%) who did not develop rejection after the use of cyclosporine and rifampin (P=0.03). Although microbiological response was favorable in 94% of the 35 patients who completed 6 or more months of treatment, 16 other patients (31%) died before diagnosis or in the course of treatment. None of the patients treated for more than 9 months died as a consequence of tuberculosis, whereas the mortality rate was 33% among those treated for 6 to 9 months (P=0.03). Use of antilymphocyte antibodies or high doses of steroids for acute rejection before tuberculosis was associated with a higher mortality rate. M tuberculosis causes serious and potentially life-threatening disease in solid-organ transplant recipients. Treatment with at least three drugs during 9 months or more, avoiding the use of rifampin, appears to be appropriate.