P276 Reactivation of Epstein–Barr virus and cytomegalovirus behaves differently in pathophysiology of ulcerative colitis

Abstract Background Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) are members of the herpesvirus family. CMV reactivation is often complicated with ulcerative colitis (UC) and is known as one of exacerbation factors. However, the association between EBV reactivation and pathophysiology of UC is still unclear. Methods This study enrolled 116 active UC patients who received colonoscopy between January 2005 and January 2019 in Kyoto University Hospital. 244 biopsy specimens were obtained from inflamed colonic mucosa to assess EVB and CMV reactivation. Viral loads of EBV and CMV in inflamed mucosa were measured by real-time PCR assay. The reactivation of those viruses was defined as DNA quantity more than 10 copies/μg DNA. Clinical severity was assessed by Lichtiger index and defined as follow: 4–8 as mild, 9–12 as moderate, and more than 12 as severe. Endoscopic severity was assessed by Mayo endoscopic score. We examined the correlation between the positivity of each viral reactivation and patients’ characteristics or prognosis of UC. Results (1) Median age, Lichtiger score and Mayo endoscopic score at the time to assess the viral reactivations were 36 years-old, 8, and 3, respectively. (2) EBV and CMV reactivation were observed in 127 samples (52.0%) and 73 samples (29.9%), respectively. There was no correlation between EBV and CMV viral load (correlation coefficient 0.19), although a significant correlation between those viral reactivations was observed in active colonic mucosa of UC patients (p = 0.002). (3) The proportion of EBV reactivation was higher in both clinically and endoscopically severe UC patients compared with those with mild activity. On the other hands, there was no association between CMV reactivation and clinical or endoscopic severity. (4) Multivariate analysis indicated risk factors for EBV reactivation as receiving anti-TNF-α antibodies (odds ratio [OR] 4.2) or calcineurin inhibitors (OR 3.5), and CMV reactivation (OR 2.1), respectively. (5) Multivariate analysis also indicated risks for CMV reactivation as steroid-refractory (OR 4.7) and EBV reactivation (OR 2.0). (6) EBV and CMV reactivation did not affect clinical outcomes including the requirement of colectomy or intensification of immunosuppressive treatments and the incidence of colitis-associated cancer, dysplasia and lymphoproliferative disease. Conclusion Reactivation of EBV or CMV may behave differently in pathophysiology of UC. Further studies are required to clarify the role of EBV reactivation on colonic inflammation in UC patients.

Download Full-text

Pre-Emptive Use of Rituximab in Epstein-Barr Virus Reactivation: Incidence, Predictive Factors, Monitoring, and Outcomes

Blood ◽

10.1182/blood-2020-141596 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-31

Author(s):

Apostolia Papalexandri ◽

Eleni Gavriilaki ◽

Anna Vardi ◽

Eirini Baldoumi ◽

Christos Demosthenous ◽

...

Keyword(s):

Multivariate Analysis ◽

Viral Load ◽

Epstein Barr Virus ◽

Chronic Gvhd ◽

Molecular Monitoring ◽

Post Transplantation ◽

Barr Virus ◽

Ebv Infection ◽

Ebv Reactivation ◽

Epstein Barr

Introduction: Reactivation of Epstein-Barr virus (EBV) is common in allogeneic hematopoietic cell transplantation (HCT). EBV infection leads to post-transplantation lymphoproliferative disease (PTLD), a life-threatening complication in this setting. Frequent molecular monitoring of viral load, especially in high risk patients and pre-emptive use of Rituximab has improved the outcome of EBV infection. However, the expansion of alternative transplants, leads to higher incidence and effective measures are warranted. Methods: We have retrospectively studied the clinical characteristics of EBV reactivation in consecutive patients that underwent HCT between 2007-2019, when pre-emptive administration of Rituximab was a standard of care in our Unit and possible correlations were sought. EBV reactivation was considered when viral load >8500 viral genomic copies (VGC)/ml in whole blood was documented during regular molecular monitoring with RQ-PCR. Patients received treatment with Rituximab, at a scheme according to physician's decision. We considered undetectable levels as resolution of infection. Patients with PTLD proven by lymph node biopsy were treated as previously described by our group. Results: Among 546 HCT recipients, EBV reactivation was detected in 100 patients, that suffered from hematologic malignancy (98) or aplastic anemia (2) and received grafts from matched sibling (23), unrelated (70) or haploidentical donors (12). Haploidentical donors were significantly higher in patients with EBV reactivation compared to our transplant population (12% versus 6%, p<0.001). Eighty-eight patients received myeloablative and 12/100 reduced intensity conditioning. Overall, EBV reactivation was detected at median 65 (20-2970) post-transplant days (median load: 26100, range 8690-2670000 VGC/ml). Rituximab was administered in 74 patients at median 4 (3-158) days post EBV reactivation. Most patients (63/74) received one cycle of Rituximab until undetectable EBV load. Rituximab cycles (median 1, range 0-3) were not associated with outcomes. Relapse of EBV reactivation was noted in 13/100 patients, with greater incidence among patients with later resolution of infection (27 vs 14 days in non relapsed, p<0.01). Late onset neutropenia related to Rituximab was noted in 16/74 patients and significantly correlated with increased EBV loads. Significantly higher viral loads were also noticed among patients who received ATG (44550 vs 20000 VGC/ml) or had haploidentical donors (60800 vs 22750 VGC/ml). Multivariate analysis confirmed that all above factors were independently associated to increased viral load. CMV concurrent reactivation was noted in 47 patients. Patients that received preemptive anti-CMV treatment presented with significantly delayed resolution of EBV infection, probably corresponding to greater immunosuppression. Five patients (two with haploidentical and three with unrelated donors) presented PTLD at 41 days post transplantation. ROC curve analysis identified a cut off of 67150 VGC/ml that predicts PLTD with 80% sensitivity and specificity (green line in Figure). Relapse free survival (RFS), overall survival (OS) and treatment-related mortality (TRM) in the entire cohort were similar regardless the EBV viral load or PTLD [4-year RFS 32.2%, 4-year OS 48.1% in a median follow up 29 months (4-216)]. ATG and chronic GVHD were independently associated with OS in the multivariate analysis (p<0.001, p<0.05 respectively). Similarly, ATG, chronic GVHD and age at transplant were independently associated to higher TRM in multivariate analysis (HR: 0.1, 1.16, 1.03, 95%CI: 0.15-0.5, 0.008-1.16, 1.007-1.05, respectively p<0.05). A trend for higher TRM was also noted among patients with EBV loads higher than 50000VGC/ml. Conclusion: Our study indicates that regular monitoring and use of preemptive therapy is an effective strategy for prevention of EBV related complications. RFS and OS were not associated to severity of EBV reactivation. A useful cut off of EBV load for PTLD prevention was identified (67150 VGC/ml, specificity and sensitivity: 80%). However, expanding use of alternative transplants warrants a more effective treatment strategy. In this setting, use of specific antiviral cytotoxic cell lines could enhance viral specific cell mediated immunity and provide a better outcome in immunocompromised HCT recipients. Disclosures Gavriilaki: Omeros Pharmaceuticals: Consultancy.

Download Full-text

P187 Differential distribution of Epstein-Barr virus and Cytomegalovirus in colonic mucosa in patients with active ulcerative colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjx002.312 ◽

2017 ◽

Vol 11 (suppl_1) ◽

pp. S171-S172

Author(s):

S. Yamada ◽

M. Matsuura ◽

Y. Honzawa ◽

M. Okabe ◽

Y. Koshikawa ◽

...

Keyword(s):

Ulcerative Colitis ◽

Epstein Barr Virus ◽

Colonic Mucosa ◽

Active Ulcerative Colitis ◽

Differential Distribution ◽

Barr Virus ◽

Epstein Barr

Download Full-text

Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

Journal of Virology ◽

10.1128/jvi.01410-15 ◽

2015 ◽

Vol 90 (2) ◽

pp. 1129-1138 ◽

Cited By ~ 28

Author(s):

XueQiao Liu ◽

Jeffrey I. Cohen

Keyword(s):

Protein Kinase ◽

Signaling Pathways ◽

Epstein Barr Virus ◽

Virus Production ◽

Mitogen Activated Protein Kinase ◽

Tegument Protein ◽

Barr Virus ◽

Ebv Reactivation ◽

Mitogen Activated Protein ◽

Epstein Barr

ABSTRACTEpstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus associated with both B cell and epithelial cell malignancies. EBV infection of B cells triggers activation of several signaling pathways that are critical for cell survival, virus latency, and growth transformation. To identify EBV proteins important for regulating cell signaling, we used a proteomic approach to screen viral proteins for AP-1 and NF-κB promoter activity in AP-1– and NF-κB–luciferase reporter assays. We found that EBV BGLF2 activated AP-1 but not NF-κB reporter activity. Expression of EBV BGLF2 in cells activated p38 and c-Jun N-terminal kinase (JNK), both of which are important for mitogen-activated protein kinase (MAPK) signaling. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of BGLF2 to activate JNK and p38. Expression of BGLF2 enhanced BZLF1 expression in latently EBV-infected lymphoblastoid cell lines, and knockdown of BGLF2 reduced EBV reactivation induced by IgG cross-linking. Expression of BGLF2 induced BZLF1 expression and virus production in EBV-infected gastric carcinoma cells. BGLF2 enhanced BZLF1 expression and EBV production by activating p38; chemical inhibition of p38 and MAPK/ERK kinases 1 and 2 (MEK1/2) reduced expression of BZLF1 and virus production induced by BGLF2. In summary, the EBV tegument protein BGLF2, which is delivered to the cell at the onset of virus infection, activates the AP-1 pathway and enhances EBV reactivation and virus production.IMPORTANCEEpstein-Barr virus (EBV) is associated with both B cell and epithelial cell malignancies, and the virus activates multiple signaling pathways important for its persistence in latently infected cells. We identified a viral tegument protein, BGLF2, which activates members of the mitogen-activated protein kinase signaling pathway. Expression of BGLF2 increased expression of EBV BZLF1, which activates a switch from latent to lytic virus infection, and increased production of EBV. Inhibition of BGFL2 expression or inhibition of p38/MAPK, which is activated by BGLF2, reduced virus reactivation from latency. These results indicate that a viral tegument protein which is delivered to cells upon infection activates signaling pathways to enhance virus production and facilitate virus reactivation from latency.

Download Full-text

Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients

Blood ◽

10.1182/blood-2003-12-4197 ◽

2004 ◽

Vol 104 (1) ◽

pp. 243-249 ◽

Cited By ~ 208

Author(s):

Wing-Yan Au ◽

Annie Pang ◽

Carolyn Choy ◽

Chor-Sang Chim ◽

Yok-Lam Kwong

Keyword(s):

Multivariate Analysis ◽

Natural Killer ◽

Epstein Barr Virus ◽

Nk Cell ◽

Disease Stage ◽

Tumor Biomarker ◽

Barr Virus ◽

Ebv Dna ◽

Epstein Barr ◽

Immunocompetent Patients

Abstract In Epstein-Barr-virus (EBV)–positive lymphomas in immunocompetent patients, release of EBV DNA from tumor cells into the plasma might be useful for disease monitoring and prognostication. To test this hypothesis, we quantified serially plasma EBV DNA by quantitative polymerase chain reaction in 39 cases of EBV-positive (natural killer [NK] cell, n = 23; T cell, n = 8; B cell, n = 4; Hodgkin, n = 4) lymphomas. As control, EBV DNA was undetectable in 34 cases of EBV-negative lymphomas at diagnosis and during chemotherapy. In all cases of EBV-positive lymphomas, EBV DNA was detectable (105-1010 copies/mL) at diagnosis. It paralleled the clinical course, with EBV DNA becoming undetectable at remission and remaining elevated in refractory disease. On multivariate analysis, high-presentation EBV DNA (> 7.3 × 107 copies/mL) was significantly associated with an inferior overall survival (OS). Subgroup analysis of NK cell lymphomas, the largest cohort in this study, showed that presentation EBV DNA was correlated with disease stage and lactate dehydrogenase. On multivariate analysis, high-presentation EBV DNA (> 6.1 × 107 copies/mL) was significantly associated with an inferior disease-free survival. During treatment, patients with EBV DNA that showed further increases or failed to become undetectable had significantly inferior OS. In EBV-positive lymphomas, plasma EBV DNA is valuable as a tumor biomarker and for prognostication.

Download Full-text

A Case of Ulcerative Colitis Following Acute Hepatitis Induced by Epstein-Barr Virus Infection

Korean Journal of Gastroenterology ◽

10.4166/kjg.2016.68.2.104 ◽

2016 ◽

Vol 68 (2) ◽

pp. 104 ◽

Cited By ~ 3

Author(s):

Seung Hyun Oh ◽

Chan Ran You ◽

Eun Ok Kim ◽

Si Hyun Bae ◽

Jong Young Choi ◽

...

Keyword(s):

Ulcerative Colitis ◽

Virus Infection ◽

Acute Hepatitis ◽

Epstein Barr Virus ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Epstein Barr ◽

Barr Virus Infection

Download Full-text

Cytolytic Epstein-Barr Virus Reactivation Therapy for EBV-Associated Gastric Carcinoma

Clinical Oncology and Research ◽

10.31487/j.cor.2020.07.08 ◽

2020 ◽

pp. 1-10

Author(s):

Jaap M. Middeldorp ◽

Zlata Novalić ◽

Sandra A.W.M. Verkuijlen ◽

Astrid E. Greijer ◽

Jaap M. Middeldorp

Keyword(s):

Gastric Carcinoma ◽

Mouse Model ◽

Cell Lines ◽

Epstein Barr Virus ◽

Drug Combinations ◽

Model Systems ◽

Virus Reactivation ◽

Barr Virus ◽

Ebv Reactivation ◽

Epstein Barr

Background: Epstein-Barr virus associated gastric carcinoma (EBVaGC) is considered a distinct GC disease entity, with the virus persisting in a latent phase. Treatment with Epirubicin, Capecitabine and Cisplatin (ECC combination) showed survival benefit in patients with GC in clinical trials (MAGIC study and CRITICS study) when compared to chemotherapy with Capecitabine and Cisplatin (GCb/Cis). Current treatment protocols for GC do not consider virus involvement. Methods: In this study, we tested a CytoLytic Virus Activation (CLVA) strategy consisting of the ECC combination or GCb/Cis together with the HDAC inhibitor Valproic acid (VPA) to define whether EBV reactivation and subsequent antiviral treatment with Ganciclovir (GCV) could be used as virus-targeted therapy for EBVaGC. Drug combinations with VPA and GCV were evaluated in multiple cell lines and in an EBVaGC mouse model based on human naturally EBV-infected SNU-719 cells. Results: EBV reactivation was demonstrated by lytic mRNA transcripts and proteins in treated cells, and the virus-reactivating capacity of different CLVA drug combinations was compared in C666.1, AGS-BX1 and SNU-719 cell lines. In an EBVaGC mouse model, GCb/Cis with VPA and GCV strongly reduced tumor volume and showed the highest potential for EBV-reactivation. Upon a single round of CLVA treatment, EBV DNA levels in circulation decreased, and loss of EBV-positive cells in treated tumors was observed. In vivo EBV-reactivation was revealed by the presence of lytic gene transcripts and proteins in tumor tissues 6 days after treatment. Conclusion: In EBVaGC model systems, CLVA treatment showed a more potent virus reactivation and killing of tumor cells when compared to standard chemotherapy alone, suggesting that addition of VPA plus GCV to the ECC or GCb/Cis combination should be considered in future clinical studies.

Download Full-text

Clinical characteristics and outcomes of critically ill patients with acute COVID-19 with Epstein-Barr virus reactivation

BMC Infectious Diseases ◽

10.1186/s12879-021-06638-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yun Xie ◽

Song Cao ◽

Hui Dong ◽

Hui Lv ◽

Xiaolei Teng ◽

...

Keyword(s):

Epstein Barr Virus ◽

Mortality Rates ◽

Virus Reactivation ◽

Barr Virus ◽

Ebv Reactivation ◽

Imaging Characteristics ◽

Single Center Study ◽

Significant Difference ◽

Epstein Barr ◽

Epstein Barr Virus Reactivation

Abstract Background Our goal is to further elucidate the clinical condition and prognosis of patients with severe acute COVID-19 with EBV reactivation. Method This is a retrospective single-center study of COVID-19 patients admitted to the intensive care unit of Wuhan No. 3 Hospital (January 31 to March 27, 2020). According to whether Epstein-Barr virus reactivation was detected, the patients were divided into an EBV group and a Non-EBV group. Baseline data were collected including epidemiological, larithmics, clinical and imaging characteristics, and laboratory examination data. Results Of the 128 patients with COVID-19, 17 (13.3%) were infected with Epstein-Barr virus reactivation. In the symptoms,the rate of tachypnoea in the EBV group was apparently higher than that in the Non-EBV group. In lab tests, the lymphocyte and albumin of EBV group decreased more significantly than Non-EBV group, and the D-dimer and serum calcium of EBV group was higher than Non-EBV group. Regarding the infection index, CRP of EBV group was apparently above the Non-EBV group, and no significant difference was found in procalcitonin of the two groups. The incidence of respiratory failure, ARDS, and hypoproteinaemia of EBV group had more incidence than Non-EBV group. The 28-day and 14-day mortality rates of EBV group was significantly higher than that of Non-EBV group. Conclusions In the COVID-19 patients, patients with EBV reactivation had higher 28-day and 14-day mortality rates and received more immuno-supportive treatment than patients of Non-EBV group.

Download Full-text

An Absence of Epstein–Barr Virus Reactivation and Associations with Disease Activity in People with Multiple Sclerosis Undergoing Therapeutic Hookworm Vaccination

Vaccines ◽

10.3390/vaccines8030487 ◽

2020 ◽

Vol 8 (3) ◽

pp. 487

Author(s):

Peter A. C. Maple ◽

Bruno Gran ◽

Radu Tanasescu ◽

David I. Pritchard ◽

Cris S. Constantinescu

Keyword(s):

Multiple Sclerosis ◽

Disease Activity ◽

Epstein Barr Virus ◽

Nuclear Antigen ◽

Virus Reactivation ◽

Serum Samples ◽

Barr Virus ◽

Ebv Infection ◽

Ebv Reactivation ◽

Epstein Barr

Background: Epstein–Barr virus (EBV) infection is strongly associated with multiple sclerosis (MS). Helminth infection can downregulate antiviral immune responses, potentially protecting against MS, but with a theoretical risk for reactivating latent EBV infection. Objective: To investigate parameters of EBV infection and their relationship with disease activity in people with MS (PwMS) therapeutically vaccinated with Necator americanus (hookworm). Methods: Sequential serum samples from 51 PwMS; 26 therapeutically infected (25 larvae) with N. americanus and 25 controls were tested for EBV virus capsid antigen (VCA) IgG and IgM, EBV nuclear antigen-1 (EBNA-1) IgG, and EBV early antigen (EA) IgG. Disease activity was assessed by periodic MRI. Significance was set at p < 0.05. Results: All PwMS were EBV VCA IgG and EBNA-1 IgG positive, and 35.2% were EBV EA IgG positive. EBV antibody levels were generally stable, and EBV reactivation in PwMS was not demonstrated by significant increases in IgG titre over 12 months. Disease activity was most frequent in PwMS possessing high levels of EBV VCA IgG (>600 units/mL) or EBNA-1 IgG (>150 units/mL); however, there was no association with hookworm treatment. Interpretation: Therapeutic hookworm vaccination was not associated with EBV reactivation. Multiple sclerosis disease activity was associated with high levels of EBV VCA IgG or EBNA-1 IgG.

Download Full-text

Airway Obstruction in Children with Infectious Mononucleosis

Ear Nose & Throat Journal ◽

10.1177/014556139507400909 ◽

1995 ◽

Vol 74 (9) ◽

pp. 630-638 ◽

Cited By ~ 21

Author(s):

Daniel L. Wohl ◽

Jon E. Isaacson

Keyword(s):

Airway Obstruction ◽

Infectious Mononucleosis ◽

Epstein Barr Virus ◽

Upper Airway ◽

Upper Airway Obstruction ◽

Clinical Severity ◽

Prolonged Intubation ◽

Barr Virus ◽

Inflammatory Edema ◽

Epstein Barr

Epstein-Barr Virus (EBV) infection generally has a benign clinical course. Upper airway obstruction is a known complication requiring the otolaryngologist's attention. EBV is usually associated with adolescence but has been increasingly documented in younger children. We review 36 pediatric admissions for infectious mononucleosis over a 12-year period at our institution, 11 of which required consultation for airway obstruction. Airway management was based on clinical severity and ranged from monitored observation, with or without nasopharyngeal stenting, to prolonged intubation or emergent tonsilloadenoidectomy. A rare case of a four-year-old with near total upper airway obstruction secondary to panpharyngeal and transglottic inflammatory edema prompted this review and is reported. The otolaryngologist must recognize the potential severity of EBV-related airway compromise and be prepared to manage it.

Download Full-text