Epstein-Barr Virus and Posttransplant Lymphoproliferative Disorder in Solid Organ Transplantation

American Journal of TransplantationVolume 13, Issue s4 p. 107-120 Special ArticleFree Access Epstein-Barr Virus and Posttransplant Lymphoproliferative Disorder in Solid Organ Transplantation U. D. Allen, Corresponding Author U. D. Allen Departments of Pediatrics, and Health Policy, Management & Evaluation Research Institute, Hospital for Sick Children Division of Infectious Diseases, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada Corresponding author: Upton D. Allen, upton.allen@sickkids.caSearch for more papers by this authorJ. K. Preiksaitis, J. K. Preiksaitis Division of Infectious Diseases, Department of Medicine, University of Alberta, Alberta, CanadaSearch for more papers by this authorthe AST Infectious Diseases Community of Practice, the AST Infectious Diseases Community of PracticeSearch for more papers by this author U. D. Allen, Corresponding Author U. D. Allen Departments of Pediatrics, and Health Policy, Management & Evaluation Research Institute, Hospital for Sick Children Division of Infectious Diseases, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada Corresponding author: Upton D. Allen, upton.allen@sickkids.caSearch for more papers by this authorJ. K. Preiksaitis, J. K. Preiksaitis Division of Infectious Diseases, Department of Medicine, University of Alberta, Alberta, CanadaSearch for more papers by this authorthe AST Infectious Diseases Community of Practice, the AST Infectious Diseases Community of PracticeSearch for more papers by this author First published: 06 March 2013 https://doi.org/10.1111/ajt.12104Citations: 124AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abbreviations ACVBP chemotherapy (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone); ANZDATA, Australia and New Zealand Dialysis and Transplant Registry; ATP, adenosine triphosphate; BAL, bronchoalveolar lavage; CHOP, Cyclophosphamide, Hydroxydaunorubicin (also called doxorubicin or Adriamycin), Oncovin (vincristine), Prednisone or prednisolone; CMV, cytomegalovirus; CNS, central nervous system; CT, computerized tomography; CTL, cytotoxic T lymphocyte; EBV, Epstein-Barr virus; ECOG, Eastern Cooperative Oncology Group; HHV6, human herpesvirus type 6; HIV, human immunodeficiency virus; IL6, interleukin 6; IVIG, intravenous immune globulin; LDH, lactate dehydrogenase; PET, positron emission tomography; PNCL, primary central nervous system lymphoma; PTLD, posttransplant lymphoproliferative disorder; RSST, risk stratified sequential treatment; SRTR, Scientific Registry of Transplant Recipients Introduction Posttransplant lymphoproliferative disorder (PTLD) is recognized as potentially one of the most devastating complications of organ transplantation. The Epstein–Barr virus (EBV) genome is found in the majority (>90%) of B cell PTLD occurring early (within the first year) after solid organ transplantation The entity referred to as EBV-associated PTLD encompasses a wide spectrum of clinical conditions characterized by lymphoproliferation after transplantation, which may or may not be symptomatic. These syndromes range from uncomplicated infectious mononucleosis to true malignancies 1-3. Disease may be nodal or extranodal, localized, often in the allograft, or widely disseminated. PTLD may resemble a self-limited infection or be indistinguishable from non-Hodgkin's lymphoma. Lesions may be localized and progress slowly or the patient may present with a fulminant multisystem sepsis-like syndrome. EBV is known to play a major role in the development of PTLD 4. The pathogenesis of these disorders is complex, and related to EBV's ability to transform and immortalize B lymphocytes, sometimes combined with secondary genetic or epigenetic events that occur during uncontrolled proliferation. Host and viral genomics affecting the response to EBV infection, local environmental factors including chronic antigenic stimulation, and the presence of other infections may impact outcome. Immunomodulation caused directly by EBV viral proteins, the coordinated effects of viral and cellular miRNAs 5 and exogenous immunosuppressive drugs alter the proliferative response and survival of infected cells 6, 7 and the innate and adaptive immune responses, particularly the EBV-specific cytotoxic T lymphocyte (CTL) responses critical for controlling EBV infection. Although B cell transformation and PTLD are a result of latent EBV infection, lytic EBV infection appears to be extremely important during primary EBV infection prior to the development of the CTL response 8. For a patient experiencing EBV infection for the first time in the early posttransplant period, delay in development of the immune response theoretically would prolong the one-way self-amplifying circuit of naïve B cell infection, latency in memory cells and reactivation with infectious virus production. The resulting high virion peak results in massive infection of the B cell pool and perhaps other cells not normally infected (T cells, NK cells, memory B cells), thereby setting the stage for secondary events that lead to malignancy. Although the role of EBV in EBV-negative PTLD is uncertain, recent data support the hypothesis that over time, immune escape occurs in initially EBV-driven lymphoproliferation, with cellular mutations replacing the functions of EBV oncogenes 9. This document summarizes current recommendations and supporting data that guide the prevention, diagnosis and treatment of PTLD in the solid organ transplant recipient. The recent literature was reviewed, including recommendations for the diagnosis and management of PTLD that were published by notable groups (e.g. the British Transplantation Society [10, 11]). Although the focus is largely on PTLD, relevant aspects of non-PTLD EBV syndromes are addressed, as appropriate. Epidemiology Humans are the only known hosts of EBV. In immunocompetent individuals, this virus is transmitted in the community by exposure to infected body fluids such as saliva. Although infection may also be acquired in the community by the traditional routes of transmission seen in immunocompetent patients, for solid organ transplant recipients, EBV that is transmitted from the seropositive donor organ is an important source of infection. Transmission is also possible when nonleukoreduced blood products are used. In the least affluent nations, greater than 90% of individuals are EBV-seropositive before the age of 5 years 12. However, in more affluent developed nations, this level of seropositivity is not attained until the fourth decade of life. The diagnosis of PTLD requires tissue examination. In many settings tissue is not available or accessible. When laboratory evidence of EBV infection is present and other causes have been ruled out, investigators have used the term EBV “disease” to describe a number of clinical syndromes where EBV is believed to play a causative role. Although the highest rate of PTLD in the solid organ transplant setting is seen in the first year after transplant, recent analyses suggest that the incidence of early PTLD is decreasing 13, 14. However, cases occurring in the first year after transplant represent only one-fifth of the total cumulative 10-year post transplant PTLD burden 15. Analyses of both French and ANZDATA renal PTLD registries suggest a biphasic pattern of disease with a second peak occurring in years 7–10 after transplant after a period of reduced incidence in years 2–7. A significant proportion of late B cell PTLD is monomorphic and may be EBV-negative (∼20%), with the relative proportion of EBV-negative lesions increasing over time after transplant; NK or T cell PLTD (approximately 37% are EBV positive) may also occur late after transplant 16. As transplant patient survival improves, late and EBV-negative PTLD will represent an increasing proportion of cases seen in adult populations. Although historically the median time of onset of primary EBV infection after solid organ transplantation is 6 weeks and reactivation/infection events were most often observed in the 2–3-month period after transplantation, recent studies in patients monitored serially using EBV viral load, note later initial detection of EBV DNAemia at a median of 110 days 17 and a mean of 276 days 18. PTLD incidence is also dependent on the type of organ transplanted, which may reflect immunosuppressive regimens, lymphoid load in the allograft and chronic antigenic exposure when organs directly communicate with the environment 8. Small intestine transplant recipients are at the highest risk for development of PTLD (up to 32%), while recipients of pancreas, heart, lung and liver transplants are at moderate risk (3–12%). Renal transplant recipients are at relatively low risk (1–2%). Recently, Caillard also described a temporal sequence of sites of PTLD involvement in adult renal allograft recipients, with disease localized to the graft occurring within the first two years, CNS disease occurring between years 2 and 7 and gastrointestinal disease occurring between years 6 and 10 and becoming the predominant site of late disease 13. Although PTLD in solid organ transplant recipients is most often of recipient origin 19, PTLD limited to the graft occurring early after transplant is predominantly donor in origin 20. Risk Factors The risk factors for the development of early (<12 months after transplant) and late PTLD (>12 months after transplant) in solid organ transplant recipients are shown in Table 1 21-24. Analyses of risk factors for PTLD have used both smaller single center and larger registry datasets. Both approaches have limitations and often involve specific subsets of patients, adults versus children or specific allograft types. Many of the risk factors are interrelated and multivariate analysis is required to identify independent risk factors. Even using this approach, results are not always consistent 25. An overwhelming risk factor in most analyses is primary EBV infection, placing pediatric populations at higher risk of developing PTLD than their adult counterparts 14, 26. Surprisingly, in a recent Collaborative Transplant Study database analysis, pretransplant EBV seronegativity in liver transplant recipients, unlike other allograft types, was not associated with an increased risk of developing non-Hodgkin's lymphoma. However, a subsequent analysis of the SRTR data in the United States confirmed that being EBV seronegative was a risk factor for PTLD development even in liver transplant recipients (but less so than in kidney and heart transplant recipients) because of a higher baseline risk in seropositive liver transplant recipients 27. Individuals who are R+ are not devoid of PTLD risk, and account for up to 25% of PTLD cases in children 28. Intestinal transplant recipients who are EBV-seropositive remain at a high risk of PTLD. Although, PTLD rates increased after calcineurin inhibitors became the backbone of most immunosuppressive regimens in the 1990s, it is likely that the net state of immunosuppression, an entity difficult to measure, is a major risk factor. Attempts to quantify the risk associated with specific immunosuppressive agents used for induction or maintenance therapy have often led to inconsistent results 25, 29. Antilymphocyte globulins that result in selective T cell depletion, particularly when used in high dose or repetitive courses, have historically been associated with increased PTLD risk. Among the newer biologic agents, alemtuzumab does not seem to be associated with an increased PTLD risk. Very high rates of PTLD presenting predominantly as primary CNS lymphoma were observed in renal transplant patients who received belatacept and were EBV seronegative prior to transplant, leading to prohibition of the use of this agent in this subset of patients 30-32. The duration of immunosuppression and older recipient age are risk factors for late PTLD development. This highlights the need for studies to optimize minimization of long term immunosuppression in individual patients including the accommodation of immunosenescence associated with aging in patients surviving for long periods after transplant. Cytomegalovirus infection may contribute to the net state of immunosuppression and is known to be a risk factor for PTLD. Table 1. Risk Factors for PTLD in solid organ transplant recipients Early PTLD Primary EBV infection Type of organ transplanted OKT3 and polyclonal antilymphocyte antibodies Young recipient age (i.e. infants and young children) CMV mismatch or CMV disease Late PTLD Duration of immunosuppression Type of organ transplanted Older recipient age (i.e. adults) Contradictory/controversial evidence exists for the role of the following as risk factors for primary disease: Tacrolimus in pediatric recipients; HLA matching; certain cytokine gene polymorphisms; preexisting chronic immune stimulation; Hepatitis C infection; viral strain virulence (EBV1 vs. EBV-2 and LMP1 deletion mutants). Manifestations of Non-PTLD EBV Syndromes Although the most feared EBV-associated disease after transplantation is PTLD, patients may experience non-PTLD-related disease. The features of this might include the manifestations of infectious mononucleosis (fever, malaise, exudative pharyngitis, lymphadenopathy, hepatosplenomegaly and atypical lymphocytosis), specific organ diseases such as hepatitis, pneumonitis, gastrointestinal symptoms and hematological manifestations such as leucopenia, thrombocytopenia, hemolytic anemia and hemophagocytosis. Some of these manifestations may be identical to the features of PTLD (Table 2). EBV-associated posttransplant smooth muscle tumors can occur de novo or after PTLD at a median interval of 48 months after transplant and develop earlier in children than adults. They can be of donor or recipient origin, and appear in atypical sites such as solid organs. When involving multiple sites, disease is multifocal rather than metastatic in origin 33. HHV6 reactivation may theoretically be an indirect cofactor for PTLD due to the potential for interaction with CMV 34. Table 2. Presenting symptoms and signs in patients with lymphoproliferative disorder Symptoms/complaints Signs Swollen lymph glands Lymphadenopathy Weight loss Hepatosplenomegaly Fever or night sweats Subcutaneous nodules Sore throat Tonsillar enlargement Malaise and lethargy Tonsillar inflammation Chronic sinus congestion and discomfort Signs of bowel perforation Anorexia, nausea and vomiting Focal neurologic signs Abdominal pain Mass lesions Gastrointestinal bleeding Symptoms of bowel perforation Manifestations and Diagnosis of PTLD Clinical assessment Relevant clinical information includes, but is not limited to the following: EBV serostatus of transplant recipient and donor. CMV donor/recipient serostatus. Time from transplantation to PTLD diagnosis. Type of allograft. An adequate physical examination is required to detect the manifestations of PTLD, which may be quite nonspecific (Table 2). Given the predilection for the reticuloendothelial system to be involved, this clinical examination should include a meticulous assessment for lymphadenopathy and adenotonsillar hypertrophy. The general physical examination might elicit signs referable to the site(s) of organs affected by PTLD. Laboratory tests Blood tests (Non-EBV) Initial tests include a complete blood count with white blood cell differential. In the case of the latter, lymphopenia might suggest less overall CTL activity, which is essential in containing EBV-driven lymphoproliferation. In some patients with PTLD, there may be evidence of anemia, which is usually normochromic, normocytic, but may be hemolytic. In patients with gastrointestinal tract PTLD and occult bleeding over a prolonged period of time, there may be evidence of iron-deficiency anemia with hypochromia and microcytosis. The source of bleeding can be determined by performing additional testing, such as examination of the stools for occult blood. Thrombocytopenia has also been observed in non-PTLD EBV disease. Depending on the location of PTLD lesions, there may be evidence of disturbances in serum electrolytes, liver and renal function tests. Elevations in serum uric acid and lactate dehydrogenase may occur. Serum immunoglobulin levels may be elevated as part of an acute phase reaction. CMV infection status should be determined using CMV pp65 antigenemia assays, plasma or whole blood quantitative nucleic acid testing for CMV DNA as well as the examination of biopsy tissue for viral inclusions, CMV DNA or CMV antigens by immunohistochemistry. Other adjunctive tests that might predict PTLD risk have been investigated. Promising initial results have been obtained for biomarkers that include serum 1L-6 35, serum/plasma free light chains 36, serum sCD30 37, serum CXCL13 38 and host genetic polymorphisms particularly in cytokine genes 25 but require further validation. How these markers relate to each other and to EBV viral load in predicting PTLD risk should be the subject of future research. Blood tests (EBV-related) EBV serology In immunocompetent patients, primary EBV infection can be determined by measuring EBV antiviral capsid antigen IgM and IgG antibodies, antibodies to early antigen (EA) and Epstein–Barr nuclear antigen. Persistence of anti-EA antibodies has been shown to be more likely in PTLD patients 39 and patients who are known to be seropositive before transplantation may have falling anti-EBNA-1 titers in the setting of elevated EBV loads and the presence of PTLD 40. Serology is unreliable as a diagnostic tool for either PTLD or primary EBV infection in immunocompromised patients, due to delayed or absent humoral responses. Another important drawback is that if these patients are receiving blood products, the passive transfer of antibodies may render EBV IgG antibody assays difficult to interpret. The most important role of EBV serology in the setting of transplantation is the determination of pretransplant donor and recipient EBV serostatus for PTLD risk assessment. Detection of EBV nucleic acids or protein in tissue Documenting the presence of EBV-specific nucleic acids in tissues is of value in the diagnosis of EBV-associated PTLD. RNA in situ hybridization targeting EBV-encoded small nuclear RNA (EBER; Refs. 41, 42) is the preferred approach and is more sensitive for detecting EBV-infected cells than in situ hybridization directly targeting viral DNA because are at levels of higher in infected EBV latent or lytic antigens can also be in tissues by using antibodies and or 41, and used to document the presence of EBV these are less sensitive than in situ EBV DNA from tissue is less as it does not cellular or of EBV in lesions from that present in load determination The to and quantitative EBV viral load assays for diagnostic and disease In the Health the for EBV by the for and for of the wide of and in developed assays being used for EBV nucleic acid This should the significant and in both and quantitative viral load results the impact of the on result assays is result requires of assays between suggest that in most result and result over the range of the is in patients over time within individual using a single are and more than single gene and for EBV viral load have not been Although EBV viral load in whole blood and appears and of to cellular DNA does not in individual patients of whole blood is with to preferred type blood vs. and should be the focus of future studies blood or lymphocyte EBV viral load is more sensitive than plasma for detection of early EBV Although, EBV DNA in plasma as EBV viral load in whole blood the quantitative between EBV viral load in whole blood or versus plasma is of the and of quantitative EBV viral load for the diagnosis of early PTLD and EBV infection are limited populations have been the focus of many of these from studies targeting adult patients are limited In solid organ transplant recipients being serially the use of EBV viral load as a diagnostic (i.e. levels a specific quantitative being diagnostic of has for detecting PTLD but some cases of localized and PTLD. However, it has resulting in than but value low as and not greater than in these populations. When used in the diagnostic this would result in significant of patients for PTLD. of EBV viral load as a diagnostic tool using a single in patients presenting with symptoms signs with of recent or have not been in populations at high risk for PTLD. In seropositive adult transplant recipients presenting for with signs and symptoms with PTLD, high EBV viral load cases of EBV-negative PTLD and some cases of localized PTLD, but was specific for PTLD EBV viral load in plasma appears to the of the as a diagnostic tool for PTLD while not relative to in cellular blood data suggest that EBV viral load testing in other than that or may be Among pediatric lung and heart lung transplant patients in the lung is often the primary site of PTLD, high quantitative levels of EBV load in may be a more sensitive of PTLD than viral load assays However, EBV often at high levels were in of adult lung transplant recipients in the of PTLD from experience in patients, and quantitative EBV testing in is to in the diagnosis of CNS lymphoma However, further data the and of testing in and are required in to testing at these laboratory testing may the of high viral load as a of PTLD. The and most are assays measuring T cell or EBV-specific T cell responses Although data suggest that the and value of EBV viral load can be by using EBV-specific T cell and assays, these assays are complex, and difficult to in a diagnostic laboratory assays to and EBV-specific T cell using assays and T have as markers of PTLD risk when combined with viral load testing in pediatric transplant recipients but require further gene in blood as an adjunctive of PTLD risk has been and is the subject of research. pattern that is of PTLD or PTLD risk has been a total body to as part of the initial assessment of PTLD. the of tests largely on the location of lesions and the sequence of prior Many that a or be as part of the initial as the presence of central nervous system lesions will treatment and outcome. of the may to the of involvement or detect early that biopsy to PTLD. Depending on the location (e.g. CNS may be a more than due to with and more with lesions that are on may require for prior to of the may and small nodules that are not on the lesions may be with and This is in to other of including in the case of and where emission is to be a in the of PTLD additional data are on the known spectrum of PTLD may be more for response to therapy than for initial diagnosis. A major is that the of exposure is greater than that associated with the for PTLD diagnosis Although biopsy is biopsy is when larger are as in the case of allograft organ The tissue should be by a or with features of PTLD. should be in to that tissue is for diagnostic tests. is essential that conditions such as plasma cell and infectious mononucleosis be in the from potentially lesions, which The Society for has published a of PTLD the of the Health and is for use Table summarizes the features of this are present in the of PTLD. have a of the pathogenesis of PTLD with the of developing more and more Use of diagnostic tests as essential is if available In to and the detection of latent antigens as these tests are as to and therapy dependent markers (i.e. EBV studies genetic markers of antigen genes to versus recipient origin in situ hybridization or gene by to detect in genes or Table of posttransplant lymphoproliferative disorder (PTLD) Early lesions in the posttransplant setting may have the of or other but lymphoid Infectious PTLD PTLD to the lymphoma B cell B cell lymphoma lymphoma cell small B cell in transplant recipients are not the PTLD. T cell T cell T cell lymphoma small B cell in transplant recipients are not the PTLD.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.