Allograft Liver Biopsy in Patients With Epstein-Barr Virus???Associated Posttransplant Lymphoproliferative Disease

Division of Transplantation Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
American Journal of Surgical Pathology (Impact Factor: 5.15). 04/2001; 25(3):324-30. DOI: 10.1097/00000478-200103000-00006
Source: PubMed


Allograft liver biopsy specimens (n = 24) obtained in the clinical setting of primarily extrahepatic posttransplant lymphoproliferative disease (PTLD) were studied for histopathology, lymphocyte subsets, and Epstein-Barr virus (EBV)-encoded EBER RNA. Acute rejection was found in 20 (83.3%) of 24 biopsy specimens and graded as indeterminate in 7 (35%) of 20 (35%), mild in 3 (15%) of 20, and moderate in 10 (50%) of 20 cases. EBV hepatitis was the primary diagnosis in two biopsy specimens and a secondary finding in six others. Four biopsy specimens showed nonspecific reactive hepatitis, and five showed recurrence of primary liver disease. Immunoperoxidase staining showed primarily T cells. EBER RNA was detected in 14 (58.3%) of 24 biopsy specimens: 12 (60%) of 20 with and 2 (50%) of 4 without acute rejection. Antirejection therapy resulted in complete or partial response in 4 (36.3%) of 11 and 7 (63.7%) of 11 treated cases, respectively, despite the presence of EBV-infected cells in some tissues. Subsequent follow-up showed early or late chronic rejection in 6 (25%) of 24 patients. Gamma glutamyl transferase, a marker for early or late chronic rejection, was greater than five times the upper limit of normal in 9 (37.5%) of 24 patients. In conclusion, liver biopsy specimens in patients with PTLD show a spectrum of pathologic changes. Rejection may be treated even if EBV is concurrently present. Long-term graft is suboptimal, because low immunosuppression results in a tendency to develop chronic rejection.

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Available from: Michael Andrew Nalesnik, Jan 20, 2014
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    ABSTRACT: Background: Opportunistic viral infections can cause considerable morbidity and mortality in organ and stem cell transplanted (SCT) patients, mainly due to iatrogenic T cell dysfunction. Whereas in SCT patients, in general the immunosuppressive treatment can be discontinued after 6-12 months, for the majority of organ transplanted patients, the need for treatment is life-long. Aims: This thesis focuses on infections with cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus (AdV) and human herpes virus type 6 (HHV-6) in liver and stem cell transplanted children and on the value of quantitative viral DNA measurements. The aims were to (i) investigate the incidence and clinical picture of CMV and EBV infection the first year after liver transplantation and the usefulness of DNA quantification for identifying these infections, (ii) to compare serum and whole blood as material for the analyses and (iii) to describe infections with CMV, EBV, AdV and HHV-6 and their risk factors, identification and outcome in SCT patients during the first 6-12 months after transplantation. Methods: Serum samples, drawn the first year after transplantation from 18 liver transplanted children were retrospectively investigated for CMV DNA by a quantitative PCR from Roche (CA Monitor), and from 24 liver transplanted children for EBV DNA by real time TaqMan PCR. In the comparison of sample materials, clinical samples (10,641 for CMV and 2,855 for EBV) drawn mainly from transplant patients, were surveyed as regards to viral DNA levels in whole blood and serum. In the study of SCT children, serum samples from 47 consecutively transplanted children were retrospectively investigated with analysis of viral DNA by TaqMan PCR and related to risk factors in a multivariate analysis. Results: Any CMV marker was found in 83 % of the liver transplanted patients. Symptomatic infection was found in 22% and was associated with significantly higher CMV DNA levels (paper I). More than half of the liver transplanted patients in paper II were EBV naïve at transplantation, probably due to low median age, but 92 % had markers of EBV infection within 1 year. Symptomatic infection was found in 21%: 3 patients with post transplantation lymphoproliferative disease (PTLD) and 2 with hepatitis. In these 5 patients, the EBV DNA levels were significantly higher than in the patients with asymptomatic infection. In paper III, CMV DNA levels were only 0.2 log higher in WB as compared to serum, while EBV DNA levels were 1.5 log higher in WB than in serum. Out of 47 SCT children (paper IV), 47% developed CMV DNAaemia, 19% at levels > 10 4 Geq/mL, and 45% developed EBV DNAaemia, but only 6 % > 10 4 Geq/mL. CMV DNAaemia did not develop if neither donor nor recipient had CMV IgG. ATG and total body irradiation were independent risk factors for high CMV and EBV DNA levels. HHV-6 DNA and AdV DNA were each present in 28% of the SCT patients, in the majority in low or moderate levels. Three children died from CMV, EBV and AdV complications, representing 21 % of the total mortality after SCT, and all these 3 cases were retrospectively found to have very high viral DNA levels in serum. Conclusion: Quantification of viral DNA levels contributes to a better basis of understanding of post transplant viral infections, and is critical for taking the right actions in terms of balancing immunosuppression and antiviral measures. As sample material, serum and whole blood seemed equally useful for CMV, while for EBV whole blood was more sensitive but less specific.
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    ABSTRACT: Post-transplant lymphoproliferative disease (PTLD) is one of the major causes of morbidity and mortality in transplantation patients. A primary Epstein–Barr virus (EBV) infection is a major risk factor for developing PTLD. The aim of this study was to determine circulating EBV DNA after liver transplantation in pediatric patients in relation to primary EBV infection and development of PTLD. EBV serology was performed before transplantation. Every 4 weeks after transplantation a competitive quantitative polymerase chain reaction (PCR) assay for EBV nuclear antigen-1 was performed in 13 patients. Patients were followed for development of a PTLD. Before transplantation four patients were EBV seropositive and nine patients were EBV seronegative. In one of the four patients who were EBV seropositive before transplantation, EBV DNA became detectable after transplantation, with a peak load of 3600 copies/mL. None of these four patients developed a PTLD. Eight of the nine patients who were EBV seronegative before transplantation developed positive EBV DNA samples. EBV DNA was first detected at a mean of 64 days after transplantation (range 38–89). The mean peak EBV DNA load was 79,700 copies/mL (3600–446,000). Two of these patients developed PTLD, but they could not be identified based on prior or concomitant EBV PCR results. Conclusions: In pediatric liver transplantation EBV DNA load is higher in patients with a primary infection than in patients who were EBV seropositive before transplantation. The EBV PCR cannot be used to identify individual patients who develop PTLD. However, elevated EBV DNA load can be used to detect a group of patients at increased risk for PTLD.
    Full-text · Article · Feb 2004 · Transplant Infectious Disease

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