Epstein-Barr virus (EBV) is usually acquired silently early in life and carried thereafter as an asymptomatic infection of the B lymphoid system. However, many circumstances disturb the delicate ...EBV-host balance and cause the virus to display its pathogenic potential. Thus, primary infection in adolescence can manifest as infectious mononucleosis (IM), as a fatal illness that magnifies the immunopathology of IM in boys with the X-linked lymphoproliferative disease trait, and as a chronic active disease leading to life-threatening hemophagocytosis in rare cases of T or natural killer (NK) cell infection. Patients with primary immunodeficiencies affecting the NK and/or T cell systems, as well as immunosuppressed transplant recipients, handle EBV infections poorly, and many are at increased risk of virus-driven B-lymphoproliferative disease. By contrast, a range of other EBV-positive malignancies of lymphoid or epithelial origin arise in individuals with seemingly intact immune systems through mechanisms that remain to be understood.
Primary Epstein-Barr virus infection Dunmire, Samantha K.; Verghese, Priya S.; Balfour, Henry H.
Journal of clinical virology,
20/May , Letnik:
102
Journal Article
Recenzirano
•Age-specific prevalence of EBV infection may be declining in developed countries.•Close personal contact and fomites implicated but not proven to transmit EBV.•Incubation period virologic and immune ...events inform a model of EBV infection.•Innate immune cells continue to emerge as important players in controlling EBV.
Epstein-Barr virus (EBV) infects about 90% of adults worldwide. It is the main cause of infectious mononucleosis, which is observed most frequently in adolescents. The disease can last several weeks and is characterized by lymphocytosis, sore throat, lymphadenopathy, and fatigue. Exposure to oral secretions during deep kissing has been identified as the major source for primary EBV infection in adolescents. Oral secretions are also thought to be the source for younger children through intimate intact or sharing food and eating utensils, although this has not been confirmed. Unlike most acute viral illnesses such as influenza, the incubation period of symptomatic primary EBV infection is unusually long, lasting about six weeks. Diagnosis is typically made by heterophile antibody tests and/or EBV-specific antibody tests. Long-term consequences may result from acquisition of the virus, including nasopharyngeal carcinoma and lymphomas. Nevertheless, there remains a surprising dearth of knowledge regarding the establishment of an immune response to persistent EBV infection, especially during the incubation period. This lack of knowledge has impaired our ability to develop an effective prophylactic EBV vaccine, despite various attempts. Our greatest challenges in EBV research are to develop a prophylactic vaccine and devise treatment strategies for persons already infected with EBV.
Epstein-Barr virus-related post-transplant lymphoproliferative disorders are recognized as a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell ...transplantation. To better define current understanding of post-transplant lymphoproliferative disorders in stem cell transplant patients, and to improve its diagnosis and management, a working group of the Sixth European Conference on Infections in Leukemia 2015 reviewed the literature, graded the available quality of evidence, and developed evidence-based recommendations for diagnosis, prevention, prophylaxis and therapy of post-transplant lymphoproliferative disorders exclusively in the stem cell transplant setting. The key elements in diagnosis include non-invasive and invasive methods. The former are based on quantitative viral load measurement and imaging with positron emission tomography; the latter with tissue biopsy for histopathology and detection of Epstein-Barr virus. The diagnosis of post-transplant lymphoproliferative disorder can be established on a proven or probable level. Therapeutic strategies include prophylaxis, preemptive therapy and targeted therapy. Rituximab, reduction of immunosuppression and Epstein-Barr virus-specific cytotoxic T-cell therapy are recommended as first-line therapy, whilst unselected donor lymphocyte infusions or chemotherapy are options as second-line therapy; other methods including antiviral drugs are discouraged.
Natural killer (NK)/T-cell lymphomas failing L-asparaginse regimens have no known salvage and are almost invariably fatal. Seven male patients with NK/T-cell lymphoma (median age, 49 years; range, ...31-68 years) for whom a median of 2 (range, 1-5) regimens (including l-asparaginase regimens and allogeneic hematopoietic stem-cell transplantation HSCT in 2 cases) failed were treated with the anti–programmed death 1 (PD1) antibody pembrolizumab. All patients responded, according to various clinical, radiologic (positron emission tomography), morphologic, and molecular (circulating Epstein-Barr virus EBV DNA) criteria. Two patients achieved complete response (CR) in all parameters. Three patients achieved clinical and radiologic CRs, with two having molecular remission (undetectable EBV DNA) but minimal EBV-encoded RNA-positive cells in lesions comprising predominantly CD3+CD4+ and CD3+CD8+ T cells (which ultimately disappeared, suggesting they represented pseudoprogression) and one having detectable EBV DNA despite morphologic CR. Two patients achieved partial response (PR). After a median of 7 (range, 2-13) cycles of pembrolizumab and a follow-up of a median of 6 (range, 2-10) months, all five CR patients were still in remission. The only adverse event was grade 2 skin graft-versus-host disease in one patient with previous allogeneic HSCT. Expression of the PD1 ligand was strong in 4 patients (3 achieving CR) and weak in 1 (achieving PR). PD1 blockade with pembrolizumab was a potent strategy for NK/T-cell lymphomas failing l-asparaginase regimens.
•NK/T-cell lymphomas failing L-asparaginse, generally fatal, showed a high CR rate to PD1 blockade with pembrolizumab.•Comprehensive clinical, radiologic, pathologic, and molecular assessments showed different patterns of CRs and PRs.
Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders ...the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.
Plasmablastic lymphoma (PBL) is a rare B-cell non-Hodgkin lymphoma often associated with Epstein-Barr virus (EBV) infection. To gain insight in this aggressive lymphoma subtype, the clinicopathologic ...characteristics of 25 unpublished single-center PBLs (2 in acquired immunodeficiency syndrome patients, 11 in immunocompetent individuals IC-PBL, 12 in transplant recipients PT-PBL) and of 277 reported PBLs were summarized. In the reported series, PBL patients were predominantly male (77%) with a median age at diagnosis of 46 years (range, 1.2 to 87 y). The majority of the biopsies (66%) was EBV positive. Extranodal presentation was most frequent (88%, of which 35% were oral, 18% gastrointestinal, 12% cutaneous). PBL was diagnosed in acquired immunodeficiency syndrome patients (50%), immunocompetent individuals (35%), and transplant recipients (14%). These subgroups differed in age at diagnosis (median41, 64, 47 y, respectively), primary localization (oral, oral, cutaneous, respectively), EBV positivity (75%, 50%, 67%, respectively), CD45 expression (31%, 33%, 70%, respectively), and C-MYC aberrations (78%, 44%, 38%, respectively). Ann Arbor stage I, EBV positivity, CD45 expression, and lack of C-MYC aberrations were associated with better outcome (P<0.05). Our series of IC-PBL and PT-PBL cases revealed differential expression of CD10 (0% vs. 42%, respectively), CD56 (22% vs. 42%, respectively), TP53 (67% vs. 8%, respectively), and BCL2 (88% vs. 25%, respectively). Gene expression analysis of 5 of our PT-PBLs revealed upregulation of DNMT3B, PTP4A3, and CD320 in EBV-positive PT-PBL and suggested a role for cancer/testis antigens. The results of this retrospective study suggest different pathogenic mechanisms of PBL in different immunologic settings and a potentially important impact of EBV and CD45 on prognosis.
Background. The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)—related posttransplant lymphoproliferative disorder (PTLD) ...after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting. Methods. A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease. Results. One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age ≥30 years, involvement of extra-lymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0–1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival. Conclusions. More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome.
Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these ...studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC - high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV.
The objective of this study was to detect the Epstein-Barr virus (EBV) coinfection in coronavirus disease 2019 (COVID-19). In this retrospective single-center study, we included 67 COVID-19 patients ...with onset time within 2 weeks in Renmin Hospital of Wuhan University from January 9 to February 29, 2020. Patients were divided into EBV/SARS-CoV-2 coinfection group and SARS-CoV-2 infection alone group according to the serological results of EBV, and the characteristics differences between the two groups were compared. The median age was 37 years, with 35 (52.2%) females. Among these COVID-19 patients, thirty-seven (55.2%) patients were seropositive for EBV viral capsid antigen (VCA) IgM antibody. EBV/SARS-CoV-2 coinfection patients had a 3.09-fold risk of having a fever symptom than SARS-CoV-2 infection alone patients (95% CI 1.11-8.56; P = 0.03). C-reactive protein (CRP) (P = 0.02) and the aspartate aminotransferase (AST) (P = 0.04) in EBV/SARS-CoV-2 coinfection patients were higher than that in SARS-CoV-2 infection alone patients. EBV/SARS-CoV-2 coinfection patients had a higher portion of corticosteroid use than the SARS-CoV-2 infection alone patients (P = 0.03). We find a high incidence of EBV coinfection in COVID-19 patients. EBV/SARS-CoV-2 coinfection was associated with fever and increased inflammation. EBV reactivation may associated with the severity of COVID-19.
PDF
