The effect of immunosuppression on posttransplant lymphoproliferative disease in pediatric liver transplant patients

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Epstein-Barr virus DNA in serum after liver transplantation — surveillance of viral activity during treatment with different immunosuppressive agents

In immunocompromised HIV-infected and transplanted patients, there is a risk of developing Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD) and lymphomas. EBV has previously been detected by the polymerase chain reaction (PCR) in cerebrospinal fluid from all AIDS patients with EBV-associated cerebral lymphomas. We therefore thought it would be of interest to determine whether transplant patients with extracerebral EBV-associated LPD have detectable EBV genomes in serum. Nested PCR (nPCR) showed that 58% (18/31) of liver transplant (LTX) patients had EBV DNA in 17% (21/125) of serum samples obtained within the first 3 months after LTX. In 39% (7/18) of the patients, the first EBV nPCR-positive sample was found within 2 weeks post-LTX. Basic immunosuppression with cyclosporin A or FK506 did not seem to influence the frequency of detectable EBV genomes in serum. In contrast, positive EBV nPCR correlated to secondary OKT3 treatment for severe acute rejection (P=0.009). EBV-associated malignant lymphoma developed in three patients 2–6 months post-LTX. In all of them, EBV DNA was amplifiable within 12–14 days after LTX. The EBV antibody titers were not directly related to detectable EBV DNA in serum. We conclude that monitoring of LTX patients receiving increased immunosuppression by nPCR for EBV DNA in serum may help in the early identification of those at risk of developing EBV-associated LPD.     

Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se?

BACKGROUND: An association between posttransplant lymphoproliferative disorder (PTLD) and cyclosporine A (CsA) and OKT3 has often been postulated on the basis of retrospective studies, although a randomized study with PTLD as the endpoint will probably never be performed. Because focus on PTLD coincided with the use of these drugs, a bias could be suspected. METHODS: In a retrospective, nonrandomized study, we reevaluated all lymphoma-like lesions arising in kidney-transplant patients grafted at our center during 1969 to 1998 and observed up to 2002. Case pathology was reviewed, and an association with Epstein-Barr virus (EBV) infection (and latency pattern) was assessed. RESULTS: We did not find any significant difference in the incidence of PTLDs when comparing the prednisolone/azathioprine, and CsA eras (P=0.89), the periods before or after OKT3 (P=0.61), and those before or after antilymphocyte globulin (ALG) (P=0.22). Occurrence time was shorter in the CsA (P=0.059), OKT3 (P=0.007), and ALG (P=0.007) eras. In the OKT3 era, 182 patients received, and 224 did not receive, OKT3; after the same observation time, there had been eight and five PTLDs, respectively (P=0.34). The use of mycophenolate mofetil (MMF) was associated with a reduction in the number of PTLDs (P=0.01). EBV was detected in 16 of 21 (76%) cases. CONCLUSIONS: We found no evidence to implicate any one drug regime preferentially in the development of PTLDs. The risk of developing PTLD seems to be a result of the whole transplantation process, which includes the antigenicity of the foreign graft, the immunosuppression resulting in inadequate cytotoxic T-cell activity, and the result of EBV infection. An important minority of cases are EBV negative.     

CMV, EBV, HHV6, and HHV7 infections after intestinal transplantation without specific antiviral prophylaxis

PURPOSE: To analyze the incidence and relevance of viral infections after intestinal transplantation (ITx) without specific antiviral prophylaxis. METHODS: Eleven patients (median age 34 years; range 26 to 58 years) who underwent ITx received no CMV/EBV prophylaxis but rather preemptive treatment. Viral monitoring for CMV or EBV polymerase chain reactions (PCR) in peripheral blood and graft biopsies, for HHV6-, and HHV7-PCR; for adeno-/rotavirus antigen and serology was performed based on clinical indications. RESULTS: Median time under risk was 19 months (range 2 to 39). CMV: The donor (D)-to-recipient (R) status prior to ITx was: D+/R+ (4); D+/R- (3); D-/R- (2); D-/R+ (2). Eight patients showed no positive CMV-PCR. Three episodes of tissue invasive CMV disease occurred in two patients. There were two asymptomatic CMV infections but no episodes of CMV disease. None of the R(-) recipients developed CMV infection or enteritis irrespective of the donor status. EBV: Four patients experienced six episodes of transient significant EBV-viremia. Two patients developed EBV enteritis concurrently with CMV enteritis during acute rejection. There were no PTLD. CMV and EBV enteritis only occurred during or immediately after steroid and OKT3 therapy. None of the patients developed significant HHV6 and HHV7 infection or viremia. There was one episode of adeno- and rotavirus enteritis. CONCLUSIONS: Despite witholding specific antiviral prophylaxis against CMV and EBV, we observed no such infections in 60% to 80% of patients. Donor-recipient matching regarding CMV was not predictive for the occurrence of CMV-related complications. HHV6 and HHV7 have not contributed to posttransplant morbidity.     

Prospective longitudinal analysis of quantitative Epstein-Barr virus polymerase chain reaction in pediatric liver transplant recipients

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) remains a significant cause of morbidity and mortality in pediatric liver transplant recipients. Epstein-Barr Virus (EBV) mismatch associated with more prevalent use of split-liver, reduced size, and living-related transplants has increased the risk of primary EBV infection and subsequent PTLD. Early identification of EBV viremia may reduce the risk of PTLD, because it allows for early adjustment of immunosuppression and antiviral therapy. METHODS: EBV viral load was measured monthly by quantitative competitive polymerase chain reactions in three pediatric liver transplant recipients. RESULTS: Onset of EBV viremia was documented in one recipient. Established EBV viremia was followed in the other two recipients (one with chronic rejection and one with PTLD) who were initially tested once monitoring was initiated in our program. CONCLUSIONS: EBV quantitative competitive polymerase chain reactions may represent a promising way to follow EBV viral load and potentially prevent the development of PTLD.     

Postural hand tremor before and following liver transplantation and immunosuppression with cyclosporine or tacrolimus in patients without clinical signs of hepatic encephalopathy

OBJECTIVE: To assess tremor characteristics and severity in patients with severe liver disease without hepatic encephalopathy and following orthotopic liver transplantation (LTX) and immunosuppression (IS) with cyclosporin A (CsA) or tacrolimus (FK 506). METHODS: A total of 35 consecutive patients were included into the prospective study and serum levels of CsA (n = 29) or FK 506 (n = 6) were monitored following LTX. Tremor characteristics and severity were assessed by two-blinded raters before and following LTX. In addition, accelerometric recordings were taken before and after LTX, and compared with 16 normal controls without tremor and without clinical signs of hepatic encephalopathy or liver disease. Accelerometry was performed while sitting in a comfortable chair with the forearms supported and included rest and postural condition with and without weight load (500 g) on each hand. Kolmogorov-Smirnov test, paired t-test and t-test for independent samples were used for statistical analysis. RESULTS: The clinical rating revealed no rest but a mild postural hand tremor before LTX with a significant increase following LTX (p < 0.001). After LTX the mean score of postural tremor was significantly (p < 0.05) higher in patients with plasma levels of >850 ng CsA/ml compared with patients with lower levels. Patients and normal controls showed comparable mean peak frequencies of rest and postural hand tremor. The mean amplitude of postural hand tremor was significantly higher in patients before and after LTX compared with controls. In the majority of patients (89%) and controls (88%), the dominant tremor frequency decreased significantly (>1.5 Hz) when applying a weight load on each hand. CONCLUSION: The present study is the first to describe hand tremor characteristics in patients with severe liver disease without clinical signs of hepatic encephalopathy and in patients following LTX and IS. Compared with normal controls the patients showed a significant postural hand tremor prior and post-LTX and an increase of mean tremor amplitude following LTX and CsA/FK 506 treatment. The decrease of the dominant tremor frequency with weight load and an increase of tremor amplitude with higher plasma levels of CsA are both indicative of an enhanced physiological or toxic tremor.     

Significance of serial real-time PCR monitoring of EBV genome load in living donor liver transplantation

BACKGROUND: Quantitative analysis of the Epstein-Barr virus (EBV) genome has been recently reported to be helpful for early identification of EBV viremia which could reduce the risk of post-transplantation lymphoproliferative disorder (PTLD). AIM: To demonstrate the significance of serial monitoring of EBV genome load by real-time quantitative polymerase chain reaction (PCR) after living donor liver transplantation. METHODS: From March 1999 to April 2000, the EBV genome load in peripheral blood mononuclear cells (PBMNC) was measured serially in a total of 15 recipients of living donor liver transplantation (LDLT) who had a symptomatic EBV infection. RESULTS: In 15 patients, the mean values of the highest EBV DNA levels from the patients who had fever, URS, diarrhea, ascites, lymphadenopathy and PTLD were 36 232, 16 040, 15 968, 2485, 336 858 and 60 486 copies/microg DNA, respectively. Patients were treated by reduction or discontinuation of immunosuppressives and/or antiviral agents. The EBV DNA levels decreased in all these patients following the recovery from their symptoms. We encountered two cases of PTLD during this study period. One of them was referred to us after the onset of PTLD and one had been undergoing aggressive immunosuppression treatment for severe rejection. Both were successfully treated. CONCLUSIONS: Serial quantitative analysis of the EBV genome load by means of real-time PCR are thought to be useful for preventing PTLD through adjustment of the immunosuppression level in response to the viral genome load following symptomatic EBV infection.     

Use of mycophenolate mofetil as rescue therapy after pediatric liver transplantation

BACKGROUND: Mycophenolate mofetil (MMF) has been increasingly used after liver transplantation (LT) in adults. We report our preliminary experience with MMF as rescue therapy after pediatric LT. METHODS: A total of 19 children received MMF for 21 indications. Median age at LT was 30 months (range 7-149). The median initial oral dose of MMF was 23 mg/kg/day (range 12-43) orally. Median follow-up after initiation of MMF therapy was 642 days (range 229-1606). RESULTS: 1) Efficacy: MMF was indicated for rejection or insufficient immunosuppression in 16 cases, with normalization of both liver function tests and liver histology in 10 (62%). MMF was successfully used in one patient with post-LT immmune hepatitis and one patient with corticodependence. In three patients with renal function impairment, MMF allowed reduction of cyclosporine A or tacrolimus blood levels, without subsequent rejection. 2) Tolerance: Six patients (32%) experienced eight side effects, mainly gastrointestinal and hematological, which resolved after cessation of MMF in five cases and dose reduction in three. One case of posttransplant lymphoproliferative disease (PTLD) occurred under MMF therapy (5.2%). Four patients had EBV primary infection, while under MMF therapy, without subsequent PTLD. Three patients had CMV primary infection, and five CMV reactivation, under MMF therapy. Seven remained asymptomatic, and one presented with CMV enteritis. CONCLUSIONS: These preliminary results suggest that MMF is an effective and safe immunosuppressant in pediatric LT recipients. Its use is hampered by frequent gastrointestinal and hematological side-effects. MMF does not seem to increase the risk of PTLD nor CMV disease.     

Current induction immunosuppression and post-heart transplant lymphoproliferative disorders

BACKGROUND: The use of high-dose OKT3 has been reported to be associated with a high incidence of posttransplant lymphoproliferative disorders (PTLD) in heart transplantation (HTx) recipients. The incidence and characteristics of PTLD with current induction protocols remain largely unknown. The aim of our study was to analyze the incidence and characteristics of PTLD in a large series of HTx recipients treated with low-dose OKT3 induction. METHODS: From 1984 to 2002, a retrospective review of diagnosis, treatment, and evolution of PTLD cases was performed on the 560 patients who underwent HTx in our center. RESULTS: The incidence of PTLD was 1% (6/560). The disease occurred early after HTx in two cases and between 13 and 121 months in the other four. Molecular studies showed evidence of Epstein-Barr virus (EBV) infection in four patients. B-cell proliferation was observed in five cases, and T-cell proliferation in the other one. Various therapies were employed for each patient. Ganciclovir and reduction in immunosuppression were the most common measures. Interestingly, OKT3 was used as a specific anti-T-cell proliferation agent with some success in the one case of T-cell PTLD. Complete remission was achieved in just two patients, whereas the other four (67%) died, mostly due to other conditions. CONCLUSIONS: The use of low-dose OKT3 as induction therapy did not increase the incidence of PTLD in our series. Late appearance of disease prevailed among our patients. Despite a multidisciplinary approach to therapy, including the use of OKT3 against T-cell proliferation, the mortality rate was high (67%).     

Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3.

A prospective study to investigate risk factors for CMV disease was conducted in 94 renal transplant recipients. CMV disease was defined as either unexplained fever for greater than 3 days with viremia or unexplained fever for greater than 3 days with isolation of CMV from the urine or throat wash and at least one of the following: leukopenia, elevated serum alanine aminotransferase, or biopsy-proved invasive tissue infection of the lung or gastrointestinal tract. Fifty-three patients received immunosuppressive regimens consisting of prednisone and cyclosporine, with or without azathioprine. The remaining 41 patients were treated with these agents plus OKT3 (21 received OKT3 to treat rejection, 20 received OKT3 prophylactically). Thirty-seven patients were at minimal risk of CMV disease (donor and recipient seronegative for CMV); 12 patients were at risk of primary disease (donor seropositive, recipient seronegative), and 45 were at risk of reactivation disease (recipient seropositive at the time of transplantation). The incidences of CMV disease in the 3 groups were 0%, 58%, and 36%, respectively. Although the incidence of CMV disease in patients at risk of primary disease was not influenced by the immunosuppressive regimen, immunosuppression had a profound effect on the occurrence of CMV disease in CMV-seropositive transplant recipients. The incidence of CMV disease in those receiving OKT3 was 59%; but only 21% in those who did not receive OKT3. OKT3 increased the risk of CMV disease five-fold (odds ratio 5.2 (95% confidence limits 1.4-17.5)). In the CMV-seropositive patient, OKT3 was also the most important predictor of CMV disease by multivariate analysis (P less than 0.002). A pilot study of preemptive therapy with ganciclovir (2.5 mg/kg daily during OKT3 therapy) in 17 patients decreased the incidence of CMV disease without appreciable toxicity.     

Longitudinal analysis of Epstein-Barr viral load in plasma and peripheral blood mononuclear cells of transplanted patients by real-time polymerase chain reaction

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a significant cause of morbidity and mortality in transplant recipients and is caused by iatrogenic suppression of T cell function. Elevations in the Epstein-Barr viral (EBV) load in plasma (>1000 EBV copies/100 microL plasma) or peripheral blood mononuclear cells (PBMC) (>5000 EBV copies/microg PBMC DNA) as determined by real-time quantitative polymerase chain reaction (RQ-PCR) have been shown to be sensitive indicators for the development of PTLD in patients. METHODS: The diagnostic value of frequent monitoring of EB viral load in peripheral blood from 46 patients after heart transplantation was investigated compared with 21 healthy controls in a prospective longitudinal study. EB viral load was detected in PBMC and plasma using real-time quantitative (RQ)- polymerase chain reaction (PCR)-based assays and compared with serological parameters of EBV infection or with the occurrence of CMV reactivations. RESULTS: EB viral load was significantly increased in PBMC and in plasma from transplanted patients compared with healthy controls. Regarding levels and fluctuations of EB viral load in PBMC, patients were grouped in three distinct categories with high, intermediate, or low EB viral load. Although in one patient without PTLD, the EB viral load exceeded the threshold value for PTLD of 5000 EBV copies/microg PBMC DNA, all patients had an EB viral load in plasma of less than 1000 EBV copies/100 microL plasma. No correlation was found between the level of EB viral load and serological parameters of EBV reactivations in patients or in healthy control individuals. EBV and cytomegalovirus reactivations occurred independently in the majority of patients. CONCLUSIONS: EB viral load measurements in plasma and PBMC of patients using RQ-PCR are superior to serology and are a powerful tool for monitoring transplanted patients.     

肝移植受者移植后淋巴组织增生性疾病的单中心诊疗经验

目的  总结肝移植受者移植后淋巴组织增生性疾病（PTLD）的发病情况和诊疗经验。方法  回顾性分析734例肝移植受者的临床资料,收集肝移植受者中PTLD的发病情况、临床症状、实验室数据及影像学资料;分析PTLD受者的病理学结果与治疗方式;分析PTLD受者的预后情况。结果  肝移植受者PTLD发生率为2.2%（16/734）, 中位术后发病时间为8（3, 46）个月。PTLD的临床表现主要为发热、淋巴结肿大,部分出现贫血、肝脾肿大、肝功能异常和消化系统症状等。16例PTLD受者中,1例他克莫司血药浓度异常升高;6例转氨酶升高;14例爱泼斯坦-巴尔病毒（EBV）DNA载量升高;5例巨细胞病毒（CMV）DNA载量升高。13例受者正电子发射计算机体层显像仪（PET/CT）检查提示相关肿大淋巴结¹⁸F-氟代脱氧葡萄糖代谢增高;2例受者颈部及腹部CT检查提示相应区域多发淋巴结肿大;1例受者仅超声提示淋巴结肿大。16例PTLD受者均行病理学检查, 其中13例受者原位杂交结果提示EBV编码的小RNA（EBER）阳性。降低免疫抑制剂水平是PTLD受者的基础治疗方案,根据不同病理类型的PTLD可联合利妥昔单抗靶向治疗及化学药物治疗;针对肿大淋巴结,给予手术及放射治疗。1例受者因PTLD治疗致移植肝衰竭死亡。结论  肝移植术后免疫抑制剂的使用可增加PTLD的患病风险,PTLD在儿童肝移植受者中发生率高于成人,尽早诊断和合理治疗可极大地改善PTLD受者的预后。     

Clinical and virologic outcomes in high‐risk adult Epstein‐Barr virus mismatched organ transplant recipients

Epstein‐Barr virus (EBV) D+/R? organ transplant recipients are a high‐risk group for developing post‐transplant lymphoproliferative disease (PTLD). Little data are available for prevention in the adult EBV mismatched population. We conducted a retrospective study of EBV D+/R? organ transplants performed during 2002‐2014. Of the 153 patients identified, 82.4% patients received antiviral prophylaxis with valganciclovir for a median of 4.5 months (range: 0.8‐22 months) and 36.6% underwent viral load monitoring in the first post‐transplant year. EBV viremia developed in 67.2% monitored patients. In viremic patients, immunosuppression was reduced in 20/37(54.1%) in response to viremia and 17/37 (45.9%) received therapeutic dose valganciclovir. In patients with EBV viremia who received valganciclovir and/or had a reduction in immunosuppression and had sufficient viral load time points (n=31), 28 (90.3%) had a significant decline in viral load at day 14 (median log decline 0.49 (0.24‐0.64), P<.001) and at day 30 (0.87 (0.52‐1.21), P<.001). PTLD developed in 27 (15%) patients (biopsy proven=25, possible=2) at median 8 months (range: 2.4‐130) post‐transplant with the majority (81.5%) within the first year. In multivariate analysis, viral load monitoring and use of mycophenolate were associated with a lower incidence of PTLD. Antiviral prophylaxis was not associated with a lower risk of PTLD, but viral load monitoring and use of mycophenolate mofetil were protective.     

Transplantation of solid organ recipients shedding Epstein‐Barr virus DNA pre‐transplant: A prospective study

Epstein‐Barr virus (EBV) poses a significant threat to patient and graft survival post‐transplant. We hypothesized that recipients who shed EBV at transplant had less immunologic control of the virus and hence were more likely to have active EBV infection and disease post‐transplant. To test this hypothesis, we conducted a 5‐year prospective study in primary solid organ transplant recipients. We measured EBV DNA in oral washes and blood samples by quantitative PCR before transplant and periodically thereafter for up to 4 years. Pre‐transplant samples were available from 98 subjects. EBV DNA was detected pre‐transplant in 32 of 95 (34%) and 5 of 93 subjects (5%) in oral wash and blood, respectively. Recipients with and without detectable pre‐transplant EBV DNA were not significantly different demographically and had no significant difference in patient and graft survival (P = .6 for both comparisons) or post‐transplant EBV viremia‐free survival (P = .8). There were no cases of EBV‐related disease or post‐transplant lymphoproliferative disorder (PTLD) in any of the patients with detectable EBV DNA pre‐transplant. In conclusion, detectable EBV DNA pre‐transplant was not associated with differences in patient/graft survival, post‐transplant EBV viremia, or EBV‐related diseases including PTLD.     

Response of elevated Epstein-Barr virus DNA levels to therapeutic changes in pediatric liver transplant patients: 56-month follow up and outcome

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a serious complications after liver transplantation. Epstein-Barr virus (EBV) load measured by quantitative competitive polymerase chain reaction (PCR) has been used as an early marker for the development of PTLD and a guide for initiating preemptive therapy. The aim of this study is to report the results of EBV DNA PCR screening in a transplant population and to examine the risk factors for developing elevated EBV DNA PCR and the effect of interventions for reducing EBV DNA levels. METHODS: Medical records of 44 children who underwent liver transplantation and EBV DNA PCR screening during a 3-year period were reviewed, and the patients were prospectively followed up for another 2 years. Eleven patients who developed elevated EBV DNA PCR levels, defined as >/=40 genomes/105 peripheral blood lymphocytes (PBL) in pretransplant EBV-seronegative patients and >/=200 genomes/105 PBL in pretransplant-seropositive patients, were treated. The initial intervention was reduction of immunosuppression and initiation of anti-viral therapy in all patients, with administration of cytomegalovirus immunoglobulin (CMV-IgG) in two patients. CMV-IgG was then given to five of the patients who did not respond to the initial intervention. RESULTS: The initial intervention resulted in the reduction of EBV DNA PCR levels to below threshold values in 4 of 11 patients. Five patients who did not respond to the initial interventions were subsequently given intravenous CMV-IgG. The EBV DNA PCR level fell in all five of these patients during the course of treatment with CMV-IgG, with a significant reduction (to threshold levels or by two dilutions) in four of the five patients. No episodes of graft rejection were observed. CONCLUSION: Eleven patients (25%) developed elevated EBV DNA PCR after liver transplantation. There were no identifiable risk factors for developing elevated EBV DNA PCR. A combination of reducing immunosuppression, adding antiviral agents, and initiating CMV-IgG resulted in a significant reduction of EBV DNA levels in nine (82%) patients during the follow-up period.     

Epstein–Barr virus reactivation in allogeneic stem cell transplantation is highly related to cytomegalovirus reactivation

Monitoring of Epstein–Barr virus (EBV) load and pre‐emptive rituximab is an appropriate approach to prevent post‐transplant lymphoproliferative disease (PTLD) occurring after hematopoietic stem cell transplantation (HSCT). This pre‐emptive approach, based on EBV‐DNA monitoring through a quantitative polymerase chain reaction, was applied to 101 consecutive patients who underwent allo HSCT at our Institute (median age 50). A single infusion of rituximab was administered to 11 of 16 patients who were at high risk for progression to PTLD, defined as a DNA value >10 000 copies/mL. All patients cleared EBV DNAemia, without any recurrences. Main factors significantly associated with high risk for PTLD were as follows: (i) unrelated vs. sibling (26% vs. 7%; p = 0.011); (ii) T‐cell depletion (29% vs. 6%; p = 0.001); (iii) graft versus host disease (GVHD; 30% vs. 7%; p = 0.002); and (iv) cytomegalovirus (CMV) reactivation (29% vs. 4%; p = 0.001). Multivariate analysis showed that CMV reactivation was the only independent variable associated with EBV reactivation. We conclude that: (i) a single infusion of rituximab is able to prevent the risk of progression into EBV‐related PTLD; and (ii) CMV reactivation is strongly associated with EBV reactivation; therefore, an intensive EBV monitoring strategy could be advisable only in case of CMV reactivation.     

Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus

AIMS: 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. RESULTS: 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). CONCLUSIONS: SRL and reduced-dose TAC may achieve adequate immunosuppression without compromising renal function or enhancing EBV viremia significantly.     

The long-term outcome of OKT3 compared with cyclosporine prophylaxis after liver transplantation

We report the long-term follow-up (greater than 1 year) of 46 patients (12 pediatric) randomized to receive OKT3 for the first 14 days after OLT with low-dose steroids compared with 39 patients (8 pediatric) who received cyclosporine, steroids, and azathioprine. The mean period of follow-up for survivors was 648 +/- 261 days for the OKT3 group and 682 +/- 216 days for the cyclosporine group. Of the OKT3 patients, 46% were rejection-free in the first month compared with 31% of CsA-treated patients (P = NS). Rejection occurred after 1 month in 21% of the OKT3 group patients compared with 19% of the CsA group patients. One patient in each group developed vanishing bile duct syndrome. Eight patients in the OKT3 group and 13 in the CsA group experienced steroid-resistant rejection and required OKT3 rescue. In the 8 patients in whom OKT3 was reused, 4 had a positive ELISA after prophylaxis, and in 6, CD3-positive cells were greater than 10% during OKT3 reuse. Five patients resolved the episode. Of patients receiving OKT3 prophylaxis, 39% developed anti-OKT3 antibodies. In the OKT3 group 83% of patients and in the CsA group 75% currently have normal liver function. There was no difference in serum creatinine for either adult or pediatric recipients at 12 months in the two groups. Eight episodes (2 CMV) of severe infection occurred after 1 month in the OKT3 group compared to 11 (4 CMV) in the CsA group. Graft survival, 63% for the OKT3 group and 73% for the CsA group, and patient survival, 67% for the OKT3 group and 84% for the CsA group, were not significantly different in the two groups. We recommend reserving the use of OKT3 for resistant rejection or when cyclosporine is contraindicated, as we can show no long-term benefit from its routine prophylactic use.     

Effect of early EBV and/or CMV viremia on graft function and acute cellular rejection in pediatric liver transplantation

Indolfi G, Heaton N, Smith M, Mieli‐Vergani G, Zuckerman M. Effect of early EBV and/or CMV viremia on graft function and acute cellular rejection in pediatric liver transplantation.
Clin Transplant 2012: 26: E55–E61.
© 2011 John Wiley & Sons A/S. Abstract: Background: The clinical impact of Epstein–Barr virus (EBV) and cytomegalovirus (CMV) infections in the early post‐transplantation period are poorly documented. We investigated the prevalence and timing of EBV and CMV infections during the first 21 d post‐transplantation in relation to graft function and acute cellular rejection in a large cohort of pediatric liver transplantation recipients. Patients and methods: Clinical, biochemical, virological, and histopathological data of 62 consecutive children who received a liver transplant were reviewed retrospectively. Results: Seventeen patients (27%) developed EBV and 11 (18%) CMV viremia (mean interval from surgery: 7.6 d, SD 3.6 and 8.7 d, SD 6.4, respectively). EBV and CMV viremia were more common as a consequence of reactivation than of primary infection. EBV viremic recipients had more often abnormal bilirubin levels [p = 0.01; OR 5.8: 95% CI 1.3–25.5]. Acute rejection was diagnosed in 20 recipients (32.3%). No correlation was found between rejection and EBV and CMV serology before transplantation and viremia after transplantation (mean interval between the diagnosis of rejection and the detection of EBV DNA and CMV DNA: one d, SD 4.4 and five d, SD 9.2, respectively). Conclusion: EBV and CMV viremia occur at a very early‐stage post‐transplantation and do not appear to affect the short‐term outcome of the transplant.