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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2015  |  Volume : 26  |  Issue : 2  |  Page : 232-237
A meta-analysis of potential relationship between Epstein-Barr-Encoded-RNA (EBER) and onset time of post-transplant lymphoproliferative disorders


1 Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Atherosclerosis Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
3 Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran

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Date of Web Publication3-Mar-2015
 

   Abstract 

Epstein-Barr virus (EBV) encodes two non-polyadenylated RNAs termed EBV-encoded RNAs (EBERs). In this study, we tried to find series in which data of EBER and onset time of post-transplant lymphoproliferative disorder (PTLD) for patients have been documented to conduct a meta-analysis. A comprehensive search of the literature was performed by Pubmed and Google scholar to find reports indicating test results for EBER and PTLD onset in transplant patients. PTLD was considered "early onset" when it develops within the first post-transplant year. Finally, 265 patients from 15 studies have been included in the meta-analysis. The overall meta-analysis also showed a significant relation between EBER test positivity and early-onset PTLD development [relative risk (RR): 1.36; 95% CI: 1.16-1.59; P <0.001]. The i2 index was 49.8%. Our study suggests that PTLD lesions with positive EBER test are more likely to develop within the early post-transplant period. Since early-onset PTLD is supposed to have better prognosis, having a positive EBER test might not be a bad news. However, for having a precise conclusion, prospective studies are needed to be conducted.

How to cite this article:
Khedmat H, Karbasi-Afshar R, Agah S, Ghamar-Chehreh ME, Amini M. A meta-analysis of potential relationship between Epstein-Barr-Encoded-RNA (EBER) and onset time of post-transplant lymphoproliferative disorders. Saudi J Kidney Dis Transpl 2015;26:232-7

How to cite this URL:
Khedmat H, Karbasi-Afshar R, Agah S, Ghamar-Chehreh ME, Amini M. A meta-analysis of potential relationship between Epstein-Barr-Encoded-RNA (EBER) and onset time of post-transplant lymphoproliferative disorders. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2019 Dec 8];26:232-7. Available from: http://www.sjkdt.org/text.asp?2015/26/2/232/152398

   Introduction Top


Post-transplant lymphoproliferative disorder (PTLD) is usually referred to a wide spectrum of abnormal lymphatic proliferations, which have become clinically more relevant, especially in the recent two decades due to the substantial advancements in transplantation medicine and development of highly potent immunosuppressive agents for preventing or treating rejection episodes. [1] Besides the immunosuppression employed, the Epstein-Barr virus (EBV) has also been shown to have a major causative effect on the development of PTLD as it has been detected in up to 90% of PTLD lesion cells. [2],[3]

EBV is an opportunistic pathogen that substantially affects the prognosis of immunocompromised patients. [4] In vitro, EBV infects resting B cells and transforms them into proliferating blasts, which results in unregulated polyclonal expansion of latently infected lymphoblasts. [5],[6] In the absence of an appropriate EBV-specific cytotoxic T-cell response, probably caused by the administration of immunosuppression after transplantation, the transformed cells increase the risk of neoplasm development in these patients. PTLD is one of the malignancies shown by overwhelming evidence to be related with EBV infection. Because transplant recipients usually receive aggressive immunosuppressive medication to prevent rejection episodes and graft loss, they are at substantial risk for PTLD.

EBV encodes two non-polyadenylated RNAs termed EBV-encoded RNAs (EBERs). EBER1 and EBER2 are the most abundant viral transcripts in EBV-infected cells. [7],[8] EBERs have recently received higher attention because newer evidence suggests the possibility that they could be involved in oncogenesis. In the transplant era, due to the overall limited number of PTLD occurrence in single centers, there is an extreme level of data scarcity on the subject. In this study, we garnered available series in which data of EBER and onset time of PTLD for patients have been documented and conducted a meta-analysis.


   Materials and Methods Top


Search strategy

A comprehensive search of the literature was performed by Pubmed and Google scholar to find reports indicating test results for EBER and PTLD onset in transplant patients. PTLD was considered early onset when it started within the first year post-transplantation. Keywords used for this purpose included: PTLD, early onset, late onset, EBER, EBV encoded RNA or a combination of them. Because the found studies were not originally designed as case-control studies, we extracted data of patients of each study and included patients with a positive result for EBER in their PTLD lesions as the case group and those with a negative one as the controls. Only the studies with patients in both groups were included. From 28 studies, finally, data from 15 published studies [9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23] were included in the meta-analysis. Overall, 265 transplant recipients representing PTLD were included in the meta-analysis. [Table 1] summarizes data used from each study with regard to the study groups.
Table 1: characteristics of the included studies.

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   Statistical Analyses Top


Softwares used for data analyses were SPSS v. 13.0 (SPSS CORP., Chicago, IL, USA) and Stata v. 9.0 (Stata Corp, Texas, TX, USA). All statistical tests were performed at the 0.05 significance level.


   Results Top


Patients

Data of overall 265 transplant recipients developing lymphoproliferative disorders after transplantation were entered into the analysis. There were 162 (69%) male and 74 (31%) female patients (29 unreported). Mean age at diagnosis of PTLD was 35 ± 22 years. The mean interval between transplantation and the diagnosis of PTLD was 50 ± 50 months, whereas the follow-up time after diagnosis of PTLD was 25± 32 months. Characteristics of the patients of each included study have been summarized in [Table 1].

Meta-analysis

In the analysis, none of the included studies showed a significant positive association between having a positive EBER test and having a late-onset PTLD. Although most of the studies had a tendency toward a higher rate of EBER positivity and early-onset PTLD, in 13 of them, the 95% confidence interval (CI) crossed the neutral (1) line and significance level was only achieved in two of the included reports (IDs 2 and 6); also, the overall metaanalysis also showed a significant relation between EBER test positivity and early-onset PTLD development [relative risk (RR): 1.36; 95% CI: 1.16-1.59; P <0.001)] [Figure 1]. The i2 index was 49.8%, suggestive of a moderate to high heterogeneity. When the analysis has been repeated by removing single studies from the pooled data, the outcome saved its significance level, suggestive of no major effect from a single large study to put a significant deviation on the overall pooled analysis.
Figure 1: Meta-analysis of post-transplant lymphoproliferative disorder patients with a positive Epstein-Barr-encoded RNA test result; the Forest plot of the meta-analysis that includes all the participants from the 15 included reports.

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   Discussion Top


Infectious diseases are among the key players that adversely affect the lives of people of different subpopulations all around the world, but their significant role would become more prominent in patients with impaired immune systems. In the context of transplant, patients are extremely vulnerable to the effects of infectious agents, and infection is one of the major factors producing morbidity and mortality in this patient population. [24],[25] EBV is one of the most investigated infections in transplant patients, which is supposed to have a causative role in their post-transplant period. [26] Moreover, it has been suggested that this infection can affect mortality of transplant patients developing PTLD. [27] On the other hand, it has been suggested that EBV-positive patients are significantly more likely to develop early-onset PTLD (than late onset) compared with EBV-negative transplant recipients. [28]

EBERs are the most common viral transcripts found in EBV-infected cells and have been found within the PTLD lesions of several patients in different series. [29] EBER positivity result is also an important issue in conducting therapeutic interventions such as changes in immunosuppression, rituximab therapy and chemotherapy. [30] In pediatric organ transplant patients, EBER positivity has been associated with immunohistochemical changes in ton-sils. [31] In a previous review article, we showed that EBER positivity was able to predict the histopathology and prognosis of PTLD in transplant recipients. [32] In the current study, we performed a meta-analysis of 15 studies in which the authors have reported PTLD cases with positive and negative EBER tests to identify whether this test can predict the neoplasm onset time.

This study showed that EBER-positive PTLD lesions are significantly more likely to develop in transplant recipients who represent the disease within the first post-transplant year. However, our findings should be considered with caution as the heterogeneity in our meta-analysis was not limited (about 50%) and also because of the overall limited number of the included subjects. Moreover, data of the patients from the included studies were not derived from prospective case-control studies.

In conclusion, our study suggests that PTLD lesions with positive a EBER test are more likely to develop within the early post-transplant period. Because early-onset PTLDs are supposed to have better prognosis, having a positive EBER test might not be bad news. For having a precise conclusion, prospective studies have to be conducted.

 
   References Top

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Khedmat H, Taheri S. CD20 antigen expression by lymphoproliferative disorders after kidney transplant is independently associated with a poor outcome: PTLD Int survey. Exp Clin Transplant 2012;10:325-31.  Back to cited text no. 1
    
2.
Yang J, Tao Q, Flinn IW, et al. Characterization of Epstein-Barr virus-infected B cells in patients with posttransplantation lymphoproliferative disease: Disappearance after rituxmab therapy does not predict clinical response. Blood 2000;96:4055-63.  Back to cited text no. 2
    
3.
Young L, Alfieri C, Hennessy K, et al. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med 1989;321:1080-5.  Back to cited text no. 3
    
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Preiksaitis JK, Cockfield SM. Epstein-Barr virus and lymphoproliferative disorders after transplantation. In: Bowden RA, Ljungman P, Paya CV, eds. Transplant infections. Philadelphia: Lippincott-Raven Publishers; 1998. p. 245-63.  Back to cited text no. 4
    
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Diehl V, Henle G, Henle W, Kohn G. Demonstration of a herpes group virus in cultures of peripheral leukocytes from patients with infectious mononucleosis. J Virol 1968; 2:663-9.  Back to cited text no. 5
    
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Pope JH, Horne MK, Scott W. Transformation of foetal human leukocytes in vitro by filtrates of a human leukaemic cell line containing herpes-like virus. Int J Cancer 1968;3:857-66.  Back to cited text no. 6
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Lerner MR, Andrews NC, Miller G, Steitz JA. Two small RNAs encoded by Epstein-Barr virus and complexed with protein are precipitated by antibodies from patients with systemic lupus erythematosus. Proc Natl Acad Sci USA 1981;78:805-9.  Back to cited text no. 7
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8.
Rymo L. Identification of transcribed regions of Epstein-Barr virus DNA in Burkitt lymphoma-derived cells. J Virol 1979;32:8-18.  Back to cited text no. 8
[PUBMED]    
9.
Duvoux C, Pageaux GP, Vanlemmens C, et al. Risk factors for lymphoproliferative disorders after liver transplantation in adults: An analysis or 480 patients. Transplantation 2002; 74:1103-9.  Back to cited text no. 9
    
10.
Lucioni M, Ippoliti G, Campana C, et al. EBV positive primary cutaneous CD30+ large T-cell lymphoma in a heart transplanted patient: Case report. Am J Transplant 2004;4:1915-20.  Back to cited text no. 10
    
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Muti G, Cantoni S, Oreste P, et al. Post-transplant lympoproliferative disorders: Improved outcome after clinico-pathologically tailored treatment. Haematologica 2002;87:67-77.  Back to cited text no. 11
    
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Vakiani E, Basso K, Klein U, et al. Genetic and phenotypic analysis of B-cell posttransplant lymphoproliferative disorders provides insights into disease biology. Hematol Oncol 2008;26:199-211.  Back to cited text no. 12
    
13.
Capello D, Cerri M, Muti G, et al. Molecular histogenesis of posttransplantation lymphoproliferative disorders. Blood 2003;102:3775-85.  Back to cited text no. 13
    
14.
Djokic M, Le Beau MM, Swinnen LJ, et al. Post-transplant lymphoproliferative disorder subtypes correlate with different recurring chromosomal abnormalities. Genes Chromosomes Cancer 2006;45:313-8.  Back to cited text no. 14
    
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Collins MH, Montone KT, Leahey AM, et al. Post-transplant lymphoproliferative disease in children. Pediatr Transplant 2001;5:250-7.  Back to cited text no. 16
    
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Vilchez RA, Jauregui MP, Hsi ED, NovoaTakara L, Chang CC. Simian virus 40 in post-transplant lymphoproliferative disorders. Hum Pathol 2006;37:1130-6.  Back to cited text no. 17
    
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Abe T, Ichimaru N, Kokado Y, et al. Post-transplant lymphoproliferative disorder following renal transplantation: A single-center experience over 40 years. Int J Urol 2010; 17:48-54.  Back to cited text no. 18
    
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Sun X, Peterson LC, Gong Y, Traynor AE, Nelson BP. Post-transplant plasma cell myeloma and polymorphic lymphoproliferative disorder with monoclonal serum protein occurring in solid organ transplant recipients. Mod Pathol 2004;17:389-94.  Back to cited text no. 19
    
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Berg LC, Copenhaver CM, Morrison VA, et al. B-cell lymphoproliferative disorders in solid-organ transplant patients: Detection of Epstein-Barr virus by in situ hybridization. Hum Pathol 1992;23:159-63.  Back to cited text no. 20
    
21.
Chen W, Huang Q, Zuppan CW, et al. Complete absence of KSHV/HHV-8 in posttransplant lymphoproliferative disorders: An immunohistochemical and molecular study of 52 cases. Am J Clin Pathol 2009;131:632-9.  Back to cited text no. 21
    
22.
Johnson LR, Nalesnik MA, Swerdlow SH. Impact of Epstein-Barr virus in monomorphic B-cell posttransplant lymphoproliferative disorders: A histogenetic study. Am J Surg Pathol 2006;30:1604-12.  Back to cited text no. 22
    
23.
Ifthikharuddin JJ, Mieles LA, Rosenblatt JD, Ryan CK, Sahasrabudhe DM. CD-20 expression in post-transplant lymphoproliferative disorders: Treatment with rituximab. Am J Hematol 2000;65:171-3.  Back to cited text no. 23
    
24.
Nichols WG, Guthrie KA, Corey L, Boeckh M. Influenza infections after hematopoietic stem cell transplantation: Risk factors, mortality, and the effect of antiviral therapy. Clin Infect Dis 2004;39:1300-6.  Back to cited text no. 24
    
25.
Khedmat H, Taheri S. Hepatitis C virus infection can affect lymphoproliferative disorders only as a cofactor for Epstein-Barr virus in liver transplant recipients: PTLD.Int survey. Exp Clin Transplant 2012;10:141-7.  Back to cited text no. 25
    
26.
Yagi T, Ishikawa J, Aono N, et al. Epstein-Barr virus-associated post-transplant lymphoproliferative disorders after allogeneic peripheral blood stem cell transplantation for Hodgkin-like adult T-cell leukemia/lymphoma. Int J Hematol 2012;95:214-6.  Back to cited text no. 26
    
27.
Khedmat H, Alavian S, Taheri S. Significance of Epstein-Barr virus infection in the outcome of renal transplant patients with lymphoproliferative disorders. Ann Transplant 2010;15: 40-4.  Back to cited text no. 27
    
28.
Izadi M, Taheri S. Features, predictors and prognosis of lymphoproliferative disorders post-liver transplantation regarding disease presentation time: Report from the PTLD.Int. survey. Ann Transplant 2011;16:39-47.  Back to cited text no. 28
    
29.
Randhawa PS, Jaffe R, Demetris AJ, et al. Expression of Epstein-Barr virus-encoded small RNA (by the EBER-1 gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease. N Engl J Med 1992;327:1710-4.  Back to cited text no. 29
    
30.
Tsai DE, Nearey M, Hardy CL, et al. Use of EBV PCR for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients. Am J Transplant 2002;2:946-54.  Back to cited text no. 30
    
31.
Shapiro NL, Tang CG, Bhattacharyya N. Association between Epstein-Barr virus serocon-version and immunohistochemical changes in tonsils of pediatric solid organ transplant recipients. Laryngoscope 2011;121:1718-25.  Back to cited text no. 31
    
32.
Izadi M, Taheri S. Significance of in situ hybridization results for EBV-encoded RNA in post-transplantation lymphoproliferative disorder setting: Report from the PTLD Int. Survey. Ann Transplant 2010;15:102-9.  Back to cited text no. 32
    

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Correspondence Address:
Dr. Reza Karbasi-Afshar
Atherosclerosis Research Center, Baqiyatallah University of Medical Sciences, Tehran
Iran
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DOI: 10.4103/1319-2442.152398

PMID: 25758868

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