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Abstract Studies suggest a possible association between Epstein-Barr virus (EBV) infection and bladder cancer (BCa) risk, though this remains unclear. Secreted frizzled-related protein (sFRP) is also linked to BCa, with some DNA viruses potentially regulating its expression. This study used Mendelian randomization (MR) and colocalization analysis to explore the causal relationship between EBV infection, BCa risk, and the mediating role of sFRP. We first performed a two-sample MR study to assess the causal relationship between 5 EBV-related antibodies (AEB-IgG, EA-D, EBNA-1, VCA-p18, ZEBRA) and BCa using the Finnish Consortium’s R11 dataset, validated with R10. Reverse MR analysis followed. For significant results, multivariable MR (MVMR) was applied to adjust for confounding risk factors. A two-step MR explored the potential mediating role of 3 sFRPs (sFRP1, sFRP2, sFRP3) between positive exposures and BCa. Colocalization analysis were conducted for positive exposures, mediators, and BCa, with multiple sensitivity analyses confirming the robustness of the results. The two-sample Mendelian randomization study found that EBNA-1 (OR = 1.15, 95% CI: 1.01–1.30; p = 0.039) and VCA-p18 (OR = 1.36, 95% CI: 1.13–1.64; p = 0.001) may increase BCa risk, with only VCA-p18 (P_fdr = 0.006) showing a significant effect after False Discovery Rate (FDR) correction. The Finnish Consortium R10 replication study yielded similar results, and reverse MR analysis did not suggest reverse causality. After MVMR adjusted for relevant confounders, VCA-p18 (OR = 1.40, 95% CI: 1.13–1.74; p = 0.002) still significantly increased BCa risk. Two-step MR identified sFRP2 as a mediator, with VCA-p18 down-regulating sFRP2 expression to elevate BCa risk. Colocalization analysis suggested a shared causal variant (nearby gene HLA-DQA1) between VCA-p18 and BCa (PPH4 = 65.44%). Multiple sensitivity analyses confirmed the robustness of the results. Our study suggests that EBV infection (VCA-p18 antibody) may increase the risk of BCa by lowering sFRP2 levels. Additionally, EBNA-1 antibodies may also contribute to an elevated risk of BCa. We hope these findings will provide new insights for future research on the association between EBV and BCa.

Abstract Background: Previous observational studies have suggested a potential association between Epstein-Barr virus (EBV) infection and the development of multiple myeloma (MM), but this relationship is not clear. Therefore, we conducted a systematic Mendelian randomization (MR) analysis to investigate the causal relationship between EBV infection and the risk of MM, while exploring the possible mediating role of immune cells in this association. Methods: The study first conducted a two-sample MR analysis using the MM R11 dataset from the FinnGen Consortium to evaluate the causal relationship between five EBV infection-related antibodies (AEB-IgG, EA-D, EBNA-1, VCA-p18, and ZEBRA) and MM, with validation in the MM R10 dataset. A reverse MR analysis was then performed. For significant results, multivariable MR (MVMR) was used to adjust for the effects of confounding risk factors. Next, a two-step MR mediation analysis was applied to investigate the potential mediating role of 731 immune cell types between positive exposure and MM. Multiple sensitivity analyses were conducted to assess the robustness of the findings. Results: A two-sample MR study found that EBNA-1 antibodies (OR = 1.36, 95% CI: 1.06–1.73; P = 0.015) were associated with an increased risk of MM, with similar results observed in the FinnGen Consortium R10 replication study. Although the association did not remain statistically significant after false discovery rate (FDR) adjustment (P_fdr = 0.075), further adjustment for relevant confounders using multivariable MR (MVMR) demonstrated that EBNA-1 antibodies (OR = 1.33, 95% CI: 1.01–1.75; P = 0.041) were still significantly associated with an increased risk of MM. Reverse MR analysis indicated no causal effect of MM on EBV-related antibodies. A two-sample MR analysis involving 731 immune cell phenotypes identified 27 potential mediating cell types. Ultimately, two-step MR confirmed that HLA-DR on myeloid dendritic cells (HLA-DR⁺ mDC) serves as a mediating factor, with EBNA-1 antibodies downregulating HLA-DR⁺ mDC, thereby increasing MM risk. Multiple sensitivity analyses supported the robustness of these findings. Conclusion: The findings of this study suggest that EBNA-1 antibodies may increase the risk of MM by downregulating HLA-DR⁺ mDC. This indicates that chronic EBV infection may contribute to an elevated risk of MM. We hope these results provide new insights for future research on the prevention and treatment of MM.

Introduction: Glioblastoma (GB) is the most aggressive glial tumor of the brain with a dismal prognosis. Studies conducted during the last two decades highlighted neurotropic viruses as a risk factors involved in development of glioblastoma. Authors present an immunohistological study conducted in a single center on sixty-three archive paraffin-embedded samples of GB. Patients and methods: The tissues were tested using immunohistochemistry in a homogenous group of sixty-three glioblastoma paraffin-embedded tissues for the presence of Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and herpes simplex virus type 1 (HSV-1). Results: Three species of herpes viruses were tested: HSV-1, Epstein-Barr virus (EBV) and Cytomegalovirus using the standard automatized immunohistochemistry. According to the IRS score, there were six samples of HSV-1 regarded as IRS 2 and five IRS 1 samples of the same virus. EBV and CMV were negative. Conclusion: The result of our study identified HSV-1 as the most prominent neurotropic virus among population surgically treated of GB. Further studies are necessary to confirm its possible oncomodulatory role.

Abstract Background Recent biomedical research has shown the unusual, multisystem effects of coronavirus disease 2019 in humans. One specific sequela of a primary severe acute respiratory syndrome coronavirus 2 infection is the reactivation of latent viruses in various tissues, such as Epstein–Barr virus. Epstein–Barr virus has been identified in many inflammatory gastrointestinal lesions, such as microscopic gastritides and colitides. One subtype of these diseases is collagenous disease. “Long COVID” may be related to the reactivation of these latent viruses, and the following case describes a patient who developed vague symptoms consistent with “long COVID.” Case presentation A non-Hispanic white male in his 50s, with previous collagenous gastritis and colitis, developed a 10-kg weight loss and diffuse leg cramps over 3 months. The patient had coronavirus disease 2019 about 3 months prior to presentation. He had iron deficiency and tested positive for human immunodeficiency virus antibody. His heterophile antibody was also positive. Confirmatory testing for human immunodeficiency virus was negative, and his Epstein–Barr virus antibody panel was positive for early antigen immunoglobulin G. His Epstein–Barr virus viral load was undetectable. Minimal improvement was achieved with a 4-week course of oral budesonide, and upper endoscopy showed diffuse gastritis. He is now improving with proton pump inhibitor therapy and ferrous sulfate supplementation. Conclusion This case report explores outpatient management of microscopic gastritides and colitides. The evidence around coronavirus disease 2019 causing reactivation of Epstein–Barr virus, and Epstein–Barr virus’ presence in chronic gastrointestinal inflammatory lesions, is discussed. Practice recommendations include corticosteroid and acid-suppression therapy for patients suspected of having a recurrence of inflammatory lesions.

Abstract The Epstein–Barr virus (EBV) is widespread and has been related to a variety of malignancies as well as infectious mononucleosis. Despite the lack of a vaccination, antiviral medications offer some therapy alternatives. The EBV BZLF1 gene significantly impacts viral replication and infection severity. The current study performed computer-assisted techniques to analyses the potential drug candidates against Epstein–Barr virus toxin Zta [Human gamma-herpesvirus 4 (Epstein–Barr virus)] from phytochemicals derived natural inhibitors. Various bioinformatics methods were employed to predict and analyze the toxin protein structure obtained from NCBI, and its secondary and tertiary structures were predicted using PSIPRED and the AlphaFold. ProtParam was used to assess physiochemical characteristics. Natural inhibitors were found in the literature and PubChem, tested with PyRx, and performed blind docking by using CB-Dock, then the top selected drug candidate from natural inhibitors was analyzed for possible drug development applications using preADMET, Molinspiration, and MD simulations. Density functional Theory analysis was executed to predict the transition energies and the reactivity. Imperatorin was the best candidate for developing the drug against toxin protein Zta coded by the BZLF1 gene because it exhibited the lowest binding energy (− 6.3 kcal/mol) during natural inhibitor screening. Imperatorin’s compliance with Lipinski’s Rule of 5 and favorable pharmacokinetics make it an ideal therapeutic agent against EBV. Since vaccines and medications are crucial for treating infectious diseases and cancer, computational approaches seem promising and less costly to design and discover potential drug candidates and vaccines with the help of in silico methods but further in vitro research is required for experimental validation.

Abstract Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies.

Abstract Background and objective The DNA load of EBV may play a part in CLL pathogenesis and prognosis. The objective of this cross-sectional study was to examine the prognostic value of EBV viral load in CLL patients in comparison with other common laboratory prognostic factors. Materials and methods Whole blood and sera from forty untreated CLL patients were collected. Next, DNA was extracted from total white blood cells (WBC), and TaqMan real-time PCR was performed to determine the EBV-DNA load by amplifying a specific fragment in the BNRF1 gene. In addition, parameters such as complete blood counts (CBC) and lactate dehydrogenase (LDH) were determined using an automated clinical laboratory analyzer. Results Twenty-one patients (52.5%) were positive for EBV by real-time PCR analysis (ranged 20 to 30000 copies/µL). The difference in LDH mean levels between EBV positive and negative patients was marginally significant (P = 0.05). Furthermore, platelet (PLT) count (P = 0.03) and CD5+/CD19+ count (P = 0.04), between EBV positive and negative subgroups, were substantially different. In addition, individuals with a severe form of illness, as defined by an increase in LDH, a decrease in PLT, and an 11q deletion, had considerably higher EBV-DNA copy numbers (the ranges of viral loads were 9966.66 ± 20033 in the severe form vs. 137.13 ± 245.41 in the mild form). Conclusion The EBV-DNA load could be used as a prognostic factor in the initial examination of CLL patients to better characterize the disease outcome and prognosis.

Abstract Non-alcoholic fatty liver disease (NAFLD) is a major global health concern, with its prevalence increasing steadily. While plasma proteins have been implicated in NAFLD, establishing causal relationships has been challenging due to confounding factors in observational studies. This study aims to explore the causal relationships between plasma proteins and NAFLD using Mendelian randomization (MR) analysis. We utilized genome-wide association study (GWAS) data from multiple sources to conduct MR analyses. Plasma protein data were obtained from the deCODE open database, and NAFLD data were sourced from the Finnish genetic sample collection (FinnGen). We performed MR analysis to identify plasma proteins causally related to NAFLD and explored the potential mediation effect of antibody-immune responses. Our MR analysis identified three plasma proteins—KNG1, MICB, and PKD2—with significant causal relationships to NAFLD. Mediation analysis further revealed that KNG1 negatively mediated the risk of NAFLD through Epstein-Barr virus EA-D antibody levels, while MICB and PKD2 positively mediated NAFLD risk through the same antibody levels. This study provides novel genetic evidence of causal relationships between specific plasma proteins and NAFLD risk. Measuring the levels of KNG1, MICB, PKD2, and Epstein-Barr virus EA-D antibody levels in patients may help clinicians assess NAFLD risk more accurately. Further clinical research is warranted to validate these findings and explore their potential therapeutic implications.

Abstract Purpose Glial fibrillary acidic protein astrocytopathy (GFAP-A) pathogenesis remains uncertain, with potential viral involvement. More clinical cases are needed to deepen our understanding of this disease, along with the exploration of more effective treatment options to provide clinicians with additional choices. Methods We report a severe case of GFAP-A secondary to EBV infection, characterized predominantly by central respiratory failure. Additionally, we conducted a literature review summarizing the characteristics of GFAP-IgG-positive patients associated with EBV infection. Results Among the 13 patients identified, fever (92.3%) and headache (84.6%) were the most common initial symptoms, while urinary dysfunction was universally present in all patients. Over half of the patients with altered consciousness required endotracheal intubation (7/11, 63.6%), with only one individual experiencing complete resolution without any residual sequela. Only two patients (16.7%) displayed the classic feature of periventricular enhancement on neuroimaging, whereas T2-FLAIR hyperintensities were more prevalent. All patients tested positive for GFAP-IgG in CSF, and 91.7% (11/12) had detectable serum GFAP-IgG antibodies. Three patients (23.1%) achieved full recovery solely through antiviral therapy. In patients receiving various immunotherapies, 60% (6/10) still had residual sequelae. Conclusion EBV infection may contribute to the pathogenesis of GFAP-A. GFAP antibody testing is recommended for diagnostic evaluation in cases of central nervous system viral infections presenting with respiratory insufficiency. For severe GFAP-A patients, Protein A immunoadsorption (Protein A IA).

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome marked by excessive immune activation. It can be triggered by various factors, including infections, malignancies, and autoimmune diseases, making the diagnosis challenging due to its overlap with other severe conditions. Case reports: We discuss two intensive care unit (ICU) cases illustrating the diverse manifestations of HLH and the critical importance of early recognition and treatment. The first case involves natural killer-cell leukaemia, and the second, a suspected viral trigger. Both highlight the necessity of a multidisciplinary approach in diagnosis and management, emphasizing the complexity of HLH in ICU settings. Conclusions: High mortality rates, particularly in malignancy-associated HLH, underscore the importance of tailored treatment strategies based on the underlying aetiology.

Introduction: Castleman disease (CD) is a rare lymphoproliferative disorder having a variegated clinical presentation. Diagnosis of the idiopathic HIV- and HHV8-negative multicentric CD (iMCD) subtype poses a challenge given its non-specific clinical manifestations. iMCD presents as diffuse lymphadenopathy with inflammatory manifestations, primarily driven by interleukin-6 (IL-6). Treatment includes suppressing the inflammation by targeting IL-6 with monoclonal antibodies such as siltuximab and, in severe cases, immuno-chemotherapy to control B- and plasma-cell activation. Case description: A previously healthy 43-year-old male presented to the emergency department with fever, night sweats, anasarca, anaemia, thrombocytopenia and acute renal insufficiency. Extensive blood and imaging workup was initiated. Several diagnoses were entertained including viral infections (comprising COVID-19), haemophagocytic lymphohistiocytosis, lymphoma and autoimmune conditions. Initial axillary lymph node biopsy was not diagnostics. A positron emission tomography (PET) scan showed diffuse and symmetrical cervical and hilar/mediastinal lymphadenopathies. A mediastinal lymph node biopsy was then performed and indicated iMCD. The patient was treated with high-dose steroids and siltuximab. An Epstein-Barr virus (EBV) PCR was positive, and rituximab was added to the treatment. The patient recovered and felt well after two months. Conclusions: Non-specific symptoms, non-diagnostic first biopsy and iMCD resemblance to haemophagocytic lymphohistiocytosis further complicated the diagnosis. A PET scan allowed the best selection of a lymph node to be biopsied. Anti-IL6 is the recommended treatment; however, we are lacking information on the duration of siltuximab, and the long-term toxicity and immunosuppressive effect of this treatment. The contribution of EBV reactivation in the development and treatment of iMCD needs further investigation.

Background: Dental caries is a multifactorial disease that can affect human teeth, and viruses play a hidden role in forming caries cavities and dental plaque. Objectives: This study attempted to assess the detection of the role of some viruses such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus type1 (HSV-1), and human papillomavirus (HPV) using the ELISA technique to detect the presence of viral antigens from three samples (dentine caries, necrotic pulp, and saliva) and to assess the relation between the presence of viruses and gender and age. Materials and Methods: From March 2022 to October 2022, samples were collected from 90 patients which were divided into three age groups, such as >20 years, 21–40 years, and ˂41 years, at the Dental Teaching Hospital of the University of Mosul. These patients represented both genders (45 men and 45 women). Results: The results indicated that the prevalence of HSV-1 was 66.6%, CMV was 68.8%, EBV was 86.6%, and HPV was 16.0% out of 90. The percentages of these viruses HSV-1, CMV, and EBV were higher in females than in males at 60.2%, 58.1%, and 43.4%, respectively, especially in the age group 21–40 years, with dominant of HSV-1 at 50%. Many studies focus on the role of bacteria in different types of dental caries, while the hidden role of viruses is excluded. Viruses play an important role in forming dental biofilm, and failed therapy may be due to viral infection. Conclusion: This study concludes that viruses in this study were detected in higher numbers in dentine caries, necrotic pulp, and saliva by ELISA technique, except human papillomavirus 16, which did not give any result.

An 18-year-old previously healthy Filipino male presented with abdominal pain, vomiting, dyspnoea and fever. Initial investigations revealed severe hepatosplenomegaly, pancytopaenia, elevated liver enzymes, coagulopathy and extremely high ferritin levels. Bone marrow biopsy confirmed an abnormal CD8+ T-cell population with haemophagocytosis. Extensive workup was performed, and he was ultimately diagnosed with haemophagocytic lymphohistiocytosis (HLH) secondary to Epstein-Barr virus-positive T-cell lymphoma of childhood (EBV-TCL), a rare and aggressive malignancy. Despite the initiation of modified dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide (SMILE) chemotherapy along with high-dose glucocorticoids, the patient did not respond to the treatment and expired. This case underscores the critical importance of early recognition and prompt intervention in EBV-TCL-associated HLH which is a unique condition and a rare entity. The diagnosis of this entity can be particularly challenging, given its rapid progression and high mortality rate. Therefore, timely diagnosis and the initiation of appropriate therapy are essential for improving patient outcomes. General medicine providers play a key role in identifying warning signs to avoid delays in treatment initiation.

Background: Timely identification of the etiology of transaminitis is critical in informing subsequent management as strategies can vary from supportive care to urgent transplant assessment. This is especially important in returning travelers as there may be multiple causes of injury that need to be addressed. Case report: We present a case of severe transaminitis secondary to non-hepatitis viral co-infections. A 28-year-old south Asian male returning traveler presented with an acute liver injury (aspartate aminotransferase/alanine aminotransaminase levels of >4000 IU/l) and marked jaundice. A thorough and expanded work-up of acute hepatitis was negative aside from positive mononucleosis spot testing and positive dengue fever serologies. This atypical presentation of mononucleosis and dengue fever was managed conservatively, and the patient was discharged with outpatient follow-up after an eight-day admission. Conclusions: Usually, non-hepatitis viruses typically do not present with severe transaminitis or hyperbilirubinemia. These viruses, such as infectious mononucleosis and dengue fever, may work synergistically to cause an elevated inflammatory response, resulting in severe transaminitis in returning travelers. In the absence of a classic clinical presentation, clinicians should be aware of co-infections in returning travelers and test for them based on a thorough history and physical examination.

Objective To analyze their molecular characteristics of microsatellite instability (MSI) by sequencing colorectal cancer patients in Sichuan region. Methods Next generation sequencing (NGS) was used to test 14 239 colon cancer patients from 2017 to 2022 in the Third People's Hospital of Chengdu for single nucleotide variation (SNV), insertion-deletion (InDel), copy number variation (CNV), fusion, MSI, tumor mutational burden (TMB), and Epstein-Barr virus (EBV). The clinical and molecular characteristics of highly microsatellite unstable (MSI-H) patients (MSI-H group, n=1 018) and microsatellite stable (MSS) patients (MSS group, n=13 221) were compared. Results The incidence rate of MSI in colorectal cancer was 7.15%, and detection rate of MSI varied in terms of age at diagnosis, tumour location and sample type. TMB was significantly higher in patients with MSI-H than in patients with microsatellite stable (MSS) (92.8 mutations/Mb vs 12.7 mutations/Mb, P＜0.05). EBV positivity in patients with colorectal cancer was 0.43%, but no patient with positive EBV was found in MSI-H. ERBB2, PIK3CA and BRAF all had significantly higher mutation frequencies in the MSI-H group, however, the positive rates of APC (51.26% vs 70.76%, χ2=168.823, P

Key Clinical Message Cholestatic hepatitis is a rare complication of Epstein–Barr virus infection and is often self‐limiting. Systemic signs, including viral prodrome and lymphadenopathy, can provide crucial diagnostic cues and avoid unnecessary invasive investigations or aggressive medical therapy unless indicated.

Abstract Background Novel biomarkers are required in gastric cancer (GC) treated by immunotherapy. Epstein-Barr virus (EBV) infection induces an immune-active tumor microenvironment, while its association with immunotherapy response is still controversial. Genes underlying EBV infection may determine the response heterogeneity of EBV + GC. Thus, we screened hub genes associated with EBV infection to predict the response to immunotherapy in GC. Methods Prognostic hub genes associated with EBV infection were screened using multi-omic data of GC. EBV + GC cells were established and confirmed by EBV-encoded small RNA in situ hybridization (EBER-ISH). Immunohistochemistry (IHC) staining of the hub genes was conducted in GC samples with EBER-ISH assay. Infiltrating immune cells were stained using immunofluorescence. Results CHAF1A was identified as a hub gene in EBV + GC, and its expression was an independent predictor of overall survival (OS). EBV infection up-regulated CHAF1A expression which also predicted EBV infection well. CHAF1A expression also predicted microsatellite instability (MSI) and a high tumor mutation burden (TMB). The combined score (CS) of CHAF1A expression with MSI or TMB further improved prognostic stratification. CHAF1A IHC score positively correlated with the infiltration of NK cells and macrophages M1. CHAF1A expression alone could predict the immunotherapy response, but its CS with EBV infection, MSI, TMB, or PD-L1 expression showed better effects and improved response stratification based on current biomarkers. Conclusions CHAF1A could be a novel biomarker for immunotherapy of GC, with the potential to improve the efficacy of existing biomarkers.

Epstein–Barr virus (EBV), also known as human herpesvirus 4, is a member of the herpes virus family. EBV is a widespread virus and causes infectious mononucleosis, which manifests with symptoms such as fever, fatigue, lymphadenopathy, splenomegaly, and hepatomegaly. Additionally, EBV is associated with different lymphocyte-associated non-malignant, premalignant, and malignant diseases. So far, no effective treatment or therapeutic drug is known for EBV-induced infections and diseases. This study investigated natural compounds that inhibit EBV glycoprotein L (gL) and block EBV fusion in host cells. We utilised computational approaches, including molecular docking, in silico ADMET analysis, and molecular dynamics simulation. We docked 628 natural compounds against gL and identified the four best compounds based on binding scores and pharmacokinetic properties. These four compounds, with PubChem CIDs 4835509 (CHx-HHPD-Ac), 2870247 (Cyh-GlcNAc), 21206004 (Hep-HHPD-Ac), and 51066638 (Und-GlcNAc), showed several interactions with EBV gL. However, molecular dynamics simulations indicated that the protein–ligand complexes of CID: 4835509 (CHx-HHPD-Ac) and CID: 2870247 (Cyh-GlcNAc) are more stable than those of the other two compounds. Therefore, CIDs 4835509 and 2870247 (Cyh-GlcNAc) may be potent natural inhibitors of EBV infection. These findings can open a new way for effective drug design against EBV and its associated infections and diseases.

Abstract Introduction Methotrexate induces lymphoproliferative disorders on rare occasions; however, its pathogenesis remains unknown. A clinical diagnosis based on imaging studies alone is often difficult. Case presentation A 57-year-old Japanese woman was referred to our department for the evaluation of multiple lung and hepatic nodules that developed during methotrexate treatment for rheumatoid arthritis. Since she had a history of nephrectomy for localized renal cell carcinoma, multiple lung and hepatic metastases were initially considered. However, pathological diagnosis of the lung nodules (needle biopsy) revealed methotrexate-associated polymorphic-type lymphoproliferative disorders. After methotrexate discontinuation, continuous smooth shrinkage of the lung and liver lymphoproliferative disorders was observed. Conclusion Methotrexate-associated lymphoproliferative disorders should be considered in the event of newly appearing neoplastic lesions, even during follow-up for renal cell carcinoma, if methotrexate is being administered.

In this study, we report a case of hydroa vacciniforme lymphoproliferative disorder (HVLPD). The patient, who was 21 years old at the time of initial consultation，suffering from recurrent papules, vesicular rashes, bleeding and black scabs on the neck, face and trunk. Serum EBV-DNA was significantly increased (2.88×107 copies/mL). The patient underwent skin biopsies twice within 2 years. The pathology of the first skin biopsy showed partial degeneration and loosening of the epidermal stratum spinosum, intraepidermal blister formation, partial epidermal detachment, and multifocal small abscesses seen in the blisters and stratum spinosum. Patchy infiltration of small lymphocytes, plasma cells, histiocytes, and eosinophils in the dermis, with no significant atypia of lymphocytes, EBER in situ hybridization was negative, which made it difficult to make a definitive diagnosis on pathology. The pathology of the second skin biopsy showed blisters visible within the patient's epidermis， and atypical lymphoid cells infiltrate around the hair follicles, sweat glands and blood vessels in the dermis. The immunohistochemical analysis indicated that lymphoid cells were positive for CD3, CD5, CD4, CD8, granzyme B and TIA-1, while CD56 and Perforin were negative, and the proliferation rate of Ki-67 was approximately 10%. EBER was positive by in situ hybridization consistent with clinicopathologic features of HVLPD. More than 1 year after receiving symptomatic treatment, the patient's rash worsened, with sometimes fever and left eyelid edema. The third skin biopsy performed in the other hospital showed that atypical lymphoid cells infiltrated the subcutaneous adipose tissue, and the proliferation rate of Ki-67 was 60%. The disease progressed to EBER-positive T-cell lymphoma. After 2 courses of chemotherapy with gemcitabine, cisplatin, dexamethasone and pegaspargase, the patient's edema subsided and the rash healed. This report demonstrates the clinical and pathologic features of the disease during its evolution and progression, with a view to enriching its diagnostic and therapeutic experience.

Abstract Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high propensity for lymphatic spread and distant metastasis. It is prominent as an endemic malignancy in Southern China and Southeast Asia regions. Studies on NPC pathogenesis mechanism in the past decades such as through Epstein Barr Virus (EBV) infection and oncogenic molecular aberrations have explored several potential targets for therapy and diagnosis. The EBV infection introduces oncoviral proteins that consequently hyperactivate many promitotic pathways and block cell-death inducers. EBV infection is so prevalent in NPC patients such that EBV serological tests were used to diagnose and screen NPC patients. On the other hand, as the downstream effectors of oncogenic mechanisms, the promitotic pathways can potentially be exploited therapeutically. With the apparent heterogeneity and distinct molecular aberrations of NPC tumor, the focus has turned into a more personalized treatment in NPC. Herein in this comprehensive review, we depict the current status of screening, diagnosis, treatment, and prevention in NPC. Subsequently, based on the limitations on those aspects, we look at their potential improvements in moving towards the path of precision medicine. The importance of recent advances on the key molecular aberration involved in pathogenesis of NPC for precision medicine progression has also been reported in the present review. Besides, the challenge and future outlook of NPC management will also be highlighted.

Objective(s): Targeting the lytic cycle of the Epstein-Barr virus (EBV) has been considered a new treatment strategy for malignancies caused by this virus. This study aimed to investigate the effect of Dendrosomal NanoCurcumin (DNC) to prevent cell transformation and inhibit the expression of viral lytic gene expression in the generation of lymphoblastoid cell line (LCL).Materials and Methods: Cell viability of LCLs and PBMCs was performed by MTT assay, and flow cytometry (Annexin/PI) was used for evaluation of apoptosis. CD markers on the surface of generated LCL (CD19) cells were examined for cell validation. The effect of DNC on transformation was evaluated by examining cell morphology and determining the expression level of lytic genes BZLF1, Zta, BHRF1, and BRLF1 of EBV using Real-time PCR. Student’s t-test was used for statistical analysis.Results: The MTT assay showed that DNC can inhibit the proliferation of LCL in a dose-dependent manner. The 50% cytotoxic concentration (CC50) of DNC and curcumin for LCL was determined 38.8 µg/ml and 75 µg/ml, respectively after 72 hr. Also, Real-time PCR data analysis showed that DNC in 30 µg/ml concentration significantly inhibited cell transformation in the LCL and significantly reduced viral lytic genes such as BZLF1, Zta, BHRF1, and BRLF1expression compared to control.Conclusion: Overall, these findings show that DNC reduces the expression of the viral lytic cycle genes and also the induction of cell apoptosis and finally prevents the generation of LCL.

Abstract Objectives Hashimoto’s thyroiditis (HT) is the most common cause of hypothyroidism. The exact mechanism initiating the development of HT is not yet clear. This study aimed to investigate the correlation between HT and the presence of Epstein-Barr virus (EBV) in a Sudanese population. Results EBV-LMP1 was detected in 11.1% of HT cases, which is consistent with previous studies. Studies have reported a wide range of frequencies indicating the presence of EBV in HT, and patients with autoimmune thyroiditis have increased titers of anti-EBV antibodies in their sera compared to healthy subjects. Intrathyroidal EBV-infected B cells may be responsible for the increased risk of development of B-cell lymphoma in the thyroid gland in patients with autoimmune thyroiditis. Our study suggests that regular follow-up is necessary for patients diagnosed with HT and are positive for EBV, as antiviral therapy is not applicable due to the risk of thyroid dysfunction. The study suggests an association between EBV and HT, but causation cannot be determined. The study also highlights the need for further research to determine the viral role and correlate it with the severity and progression of HT.

Key Clinical Message In patients with symptoms of viral infection and marked thickening of the gallbladder wall, it is important to suspect acalculous cholecystitis due to Epstein–Barr virus‐induced infectious mononucleosis. Abstract A 35‐year‐old Japanese man presented with fever, abdominal right upper quadrant pain, and liver dysfunction. Positive immunoglobulin M and ‐G antibodies and negative nuclear antigen for Epstein–Barr virus were observed. Abdominal ultrasonography revealed a markedly thickened gallbladder wall. Acalculous cholecystitis due to Epstein–Barr virus‐induced infectious mononucleosis was diagnosed.

Key Clinical Message Chronic active Epstein‐Barr virus (EBV) infection‐associated enteritis (CAEAE) in nonimmunodeficient individuals is rare. To report a case of CAEAE, relevant articles were searched through databases. The clinical manifestations, endoscopic findings, strategies of treatment, prognoses, and follow‐up results of CAEAE patients were analyzed. Including this report, seven citations in the literature provide descriptions of 27 cases of CAEAE. There were 21 males and six females, with a mean age of 40 years. The main clinical manifestations were fever (25/27), abdominal pain (14/27), diarrhea (16/27), hematochezia or bloody stools (13/27), and decreased hemoglobin and red blood cell counts in routine blood tests (14/27). Elevations in inflammatory markers, white blood cell (WBC) counts, and C‐reactive protein (CRP) were common. Coagulation was often abnormal. Histopathology confirmed EBV‐encoded small nuclear RNA (EBER) in the affected tissue via in situ hybridization. The average serum EBV DNA load was 6.3 × 10^5 copies/mL. All patients had varying degrees of intestinal ulcers endoscopically, and the ulcers and pathology were uncharacterized and misdiagnosed mostly as inflammatory bowel disease (IBD). The course of the disease was progressive and later complicated by intestinal bleeding, intestinal perforation, septic shock, and a high rate of emergency surgery. However, the conditions of the patients often did not improve after surgery, and some patients soon died due to reperforation or massive hematochezia. Hormone and antiviral treatment had no obvious effect. There was a significant difference in surgical and nonsurgical survival (p

Summary: Background: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignant epithelial tumor endemic to Southern China and Southeast Asia. While previous studies have revealed a low frequency of gene mutations in NPC, its epigenomic aberrations are not fully elucidated apart from DNA hypermethylation. Epigenomic rewiring and enhancer dysregulation, such as enhancer hijacking due to genomic structural changes or extrachromosomal DNA, drive cancer progression. Methods: We conducted Hi-C, 4C-seq, ChIP-seq, and RNA-seq analyses to comprehensively elucidate the epigenome and interactome of NPC using C666-1 EBV(+)-NPC cell lines, NP69T immortalized nasopharyngeal epithelial cells, clinical NPC biopsy samples, and in vitro EBV infection in HK1 and NPC-TW01 EBV(−) cell lines. Findings: In C666-1, the EBV genome significantly interacted with inactive B compartments of host cells; the significant association of EBV-interacting regions (EBVIRs) with B compartment was confirmed using clinical NPC and in vitro EBV infection model. EBVIRs in C666-1 showed significantly higher levels of active histone modifications compared with NP69T. Aberrant activation of EBVIRs after EBV infection was validated using in vitro EBV infection models. Within the EBVIR-overlapping topologically associating domains, 14 H3K4me3(+) genes were significantly upregulated in C666-1. Target genes of EBVIRs including PLA2G4A, PTGS2 and CITED2, interacted with the enhancers activated in EBVIRs and were highly expressed in NPC, and their knockdown significantly reduced cell proliferation. Interpretation: The EBV genome contributes to NPC tumorigenesis through “enhancer infestation” by interacting with the inactive B compartments of the host genome and aberrantly activating enhancers. Funding: The funds are listed in the Acknowledgements section.

Abstract Background and Aims Gastric cancer is a significant global issue with a high death rate. This malignancy could be associated with several viral agents such as EBV, CMV, HHV‐6, JCV, and BKV. Objective Evaluation of EBV, CMV, HHV‐6 ,and JCV, BKV frequency among gastric cancer patients. Methods In this cross‐sectional study, a total number of 60 gastric cancer specimens (32 male, 28 female) were retrieved from the pathology lab. Formalin‐fixed paraffin‐embedded tissue was used for molecular testing. DNA was extracted from samples, according to protocol, and used for PCR reaction. Polymerase chain reactions were used to assess CMV, EBV, HHV‐6, JCV, and BKV frequency. Results and Conclusion The mean age of the participants was 61 years and 53.3% (32) of the participants were Male. A total number of 5 samples (8.34%) were infected with viral agents. Four male gastric samples were infected with EBV (6.67%) and only one female sample contained the BKV genome (1.67%). Totally 8.34% of the samples were infected with EBV and BKV. The CMV, HHV‐6, and JCV genome was not detected in the samples. In conclusion, the presence of two viral agents including EBV and BKV among male and female samples respectively, and the genome of other viruses were not detected.

Objective To investigate the correlation between the serum level of 25-hydroxyvitamin D （25（OH）D） and liver function in children with infectious mononucleosis （IM）. Methods Ninety children with acute IM were enrolled into the IM group， and 40 healthy children who underwent physical examination during the same period were allocated into the control group. Serum level of 25（OH）D was determined by electrochemiluminescence and the viral load of Epstein-Barr virus DNA （EBV-DNA） in plasma was determined by quantitative fluorescent RT-PCR. Clinical data and serum 25（OH） D levels were compared between two groups. The correlation between 25（OH）D level and atypical lymphocytes， liver function parameters and plasma EBV-DNA in children with IM was analyzed. Results Serum 25（OH）D level in the IM group was significantly lower， whereas the 25（OH）D inadequacy rate was significantly higher than those in the control group （both P < 0.05）. Serum 25（OH）D level was negatively correlated with atypical lymphocytes in the IM group （P < 0.05）. The levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， glutamyl transpeptidase （GGT）， and adenosine deaminase （ADA） in IM children with serum 25（OH）D inadequacy were higher than those in their counterparts with adequate serum 25（OH）D （all P < 0.05）. No significant differences were found in total bilirubin （TBIL）， direct bilirubin （DBIL） and plasma EBV-DNA load between the adequate and inadequate subgroups （all P > 0.05）. In the IM group， serum 25（OH）D level was negatively correlated with ALT， GGT， and ADA （all P < 0.05）， whereas positively correlated with CHE （P < 0.05） and had no correlation with AST， TBIL or DBIL （all P > 0.05）. Conclusions Serum vitamin D insufficiency occurs in children with IM. Vitamin D may be involved in the incidence and development of the course of IM， which is probably associated with liver function impairment.

OBJECTIVE: To answer the question of whether viral infections such as Human papillomavirus (HPV) and Epstein-Barr virus (EBV) are involved in the occurrence of breast cancer or not. METHODOLOGY: In this case-control study, 50 paraffin-embedded breast samples (FFPE) and 50 non-cancerous FFPE samples were prepared from patients referred to Abadan hospitals from 2018 to 2021 to identify the genome of HPV and EBV by polymerase chain reaction (PCR). Data were analyzed using SPSS 15 with P-values of 0.05. Confirmed breast cancer biopsy samples with no medical history of chemotherapy and/or radiotherapy, the patient not being pregnant at the time of sampling, not using anti-cancer treatments, and not suffering from systemic inflammatory diseases such as rheumatoid arthritis. Patients of any age, with any breast cancer, and any size or stage of tumor were included without restrictions. RESULTS: Using PCR, HPV DNA was detected in 7/50 (14%) and 2/50(4%) of breast cancers and normal control, respectively. Moreover, 71.42% and 28.57% of HPV-infected persons in the patient's group were genotypes 16 and 18, respectively. All HPV-infected people in the control group were low-risk genotypes 26 and 53. Also, EBV DNA was found in 2/50 (4%) and 6/50 (12%) of breast cancers and control samples, respectively. Co-infection was not detected in samples. CONCLUSION: Although our study does not provide substantial Evidence about the role of viral infection in the progressiveness of breast tumors, significant studies have shown the critical role of these infections in the progression of breast tumors.

The article describes a rare clinical case of meningoencephalitis of Epstein-Barr viral (EBV) etiology in an immunocompetent patient. The purpose of the work was to acquaint practitioners with the problems of diagnosis and treatment of EBV-neuroinfection, features of the course and management of EBV-meningoencephalitis. The woman, 46 years old, was admitted to the intensive care unit with a diagnosis of mushroom poisoning. Based on clinical-laboratory-instrumental examinations the diagnosis of EBV-meningoencephalitis was made. EBV DNA was detected in the cerebrospinal fluid by polymerase chain reaction (PCR) and magnetic resonance imaging (MRI) of the brain showed focal changes in the left temporal-insular region with signs of leptomeningitis. Taking into account the specifics of this case, the authors of the article came to the following conclusions: EBV-meningoencephalitis can occur in people with normal immune status under conditions of psychological and physical stress; delayed diagnosis of meningoencephalitis at the onset of the disease in this case is associated with the prevalence of clinical manifestations of general brain syndrome, mistakenly regarded as symptoms of intoxication and dyspepsia due to food poisoning; meningoencephalitis of EBV-etiology is ac­companied by signs of convulsive, atactic, cognitive and mental syndromes; temporal-insular localization of focal brain changes may be characteristic for EBV-meningoencephalitis; treatment with acyclovir and glucocorticoids may have be­nefits; complicated vascular anamnesis, bed rest and glucocorticoid therapy predict an increased risk of venous thrombosis, which in this patient was realized as acute sural phlebothrombosis; according to MRI the resolution of leptomeningitis and focal brain changes with gliosis formation occurred 3 months after manifestation of the disease; the risk of the following neurological pathologies due to specific localization of gliosis should be considered and requires medical control.

Epstein-Barr virus (EBV) disease of central nervous system (CNS) in human immunodeficiency virus (HIV) patients is mostly associated with primary CNS lymphoma (PCNSL). In patients who cannot undergo biopsy and have typical clinical and radiographic findings, detection of EBV deoxyribonucleic acid in CSF may provide enough evidence to start treatment for PCNSL. Here, we described a case of EBV encephalitis presenting with fever, memory, and psycho-motor deficits in a patient with HIV infection and severe immunosuppression who started antiretroviral therapy (ART) one month earlier. Brain magnetic resonance imaging showed periventricular lesions with nodular enhancing pattern and restricted diffusion, and CSF was positive for EBV. Brain biopsy revealed inflammatory lesions and lymphoid infiltrate without signs of malignancy. After three months of ART, patient improved significantly and MRI showed a marked reduction of lesions. Two years later, patient’s condition remains stable. PCNSL is the leading diagnosis in HIV patients with CNS mass lesions and positive CSF for EBV. In the case described, starting treatment for PCNSL could have been considered if the patient could not undergo biopsy, or if there was no improvement under ART. However, EBV encephalitis can be a differential diagnosis in patients with compatible histopathology and clinical course.

Gastric cancer (GC) is a complex disease with various etiologies. While Helicobacter pylori infection is still one of the leading risk factors for GC, increasing evidence suggests a link between GC and other infective agents such as Epstein Bar Virus (EBV). EBV-associated gastric cancer (EBVaGC) is now recognized as a distinct subgroup of GC, and the complex interactions between the virus and gastric mucosa may influence its development. A recent integrative analysis of the genome and proteome of GC tissues by The Cancer Genome Atlas project has identified EBVaGC as a specific subtype characterized by PIK3CA and ARID1A mutations, extensive DNA hyper-methylation, and activation of immune signaling pathways. These molecular characteristics are markers of the unique molecular profile of this subset of GC and are potential targets for therapy. This review aims to provide an overview of the current knowledge on EBVaGC. It will focus on the epidemiology, clinic-pathological features, and genetic characteristics of EBVaGC. Additionally, it will discuss recent data indicating the potential use of EBV infection as a predictive biomarker of response to chemotherapy and immune checkpoint inhibitors. The review also delves into potential therapeutic approaches for EBVaGC, including targeted therapies and adoptive immunotherapy, highlighting the promising potential of EBV as a therapeutic target.

Abstract Background and Aims Gastric cancer (GC) is a common cancer type worldwide, and various factors can be involved in its occurrence. One of these factors is Epstein‐Barr virus (EBV) infection. In this regard, a systematic review and meta‐analysis was conducted to achieve a better understanding of the EBV prevalence in GC samples. Methods English databases were searched and studies that reported the prevalence and etiological factors of EBV related to GC from July 2007 to November 2022 were retrieved. The reported data were selected based on the inclusion and exclusion criteria. The pooled prevalence of EBV infection with 95% confidence intervals was calculated. Quality assessment, heterogeneity testing, and publication bias assessment were also performed. The literature search showed 953 studies, of which 87 studies met our inclusion criteria and were used for meta‐analysis. Results The pooled prevalence of EBV infection related to GC was estimated to be 9.5% (95% confidence interval [CI]: 8.2%−11%) in the general population. The prevalence of EBV infection related to GC by gender was 13.5% (95% CI: 11.1%−16.3%) in males and 7.6% (95% CI: 5.4%−10.6%) in females. No significant differences were observed in terms of geographical region. Out of the 87 studies included in the meta‐analysis, the most common diagnostic test was in situ hybridization (58 cases). Conclusions Altogether, the results indicated that EBV infection is one of the important factors in the development of GC. However, this does not necessarily mean that EBV infection directly causes GC since other factors may also be involved in the development of GC. Therefore, it is recommended to conduct extensive epidemiological studies on various aspects of the relationship between this virus and GC, which can provide valuable information for understanding the relationship between EBV and GC.

Key Clinical Message EBV infections rarely cause CNS involvement. For young adult patients with suspected CNS infection, bacterial and other common viral infections should be excluded first and treated empirically until proven otherwise. Challenges in diagnosing EBV‐associated CNS infection, emphasizing the role of CSF PCR in confirming the diagnosis.

Abstract Background and Aims Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). MS results from an inflammatory process leading to the loss of neural tissue and increased disability over time. The role of Epstein Barr Virus (EBV), as one of the most common global viruses, in MS development has been the subject of several studies. However, many related questions are still unanswered. This study aimed to review the connection between MS and EBV and provide a quick outline of MS prevention using EBV vaccination. Methods For this narrative review, an extensive literature search using specific terms was conducted across online databases, including PubMed/Medline, Scopus, Web of Science, and Google Scholar, to identify pertinent studies. Results Several studies proved that almost 100% of people with MS showed a history of EBV infection, and there was an association between high titers of EBV antibodies and an increased risk of MS development. Various hypotheses are proposed for how EBV may contribute to MS directly and indirectly: (1) Molecular Mimicry, (2) Mistaken Self, (3) Bystander Damage, and (4) Autoreactive B cells infected with EBV. Conclusion Given the infectious nature of EBV and its ability to elude the immune system, EBV emerges as a strong candidate for being the underlying cause of MS. The development of an EBV vaccine holds promise for preventing MS; however, overcoming the challenge of creating a safe and efficacious vaccine presents a significant obstacle.

Epstein-Barr virus is a rare ethology of the neurological infections, expressed as encephalitis, aseptic meningitis, Guillain-Barre syndrome or acute demyelinating encephalomyelitis. Most common cases were reported in children, while this infection is rarely described in immunocompetent adults. We present the case of an elderly immunocompetent patient with hypertension and hypothyroidism under treatment who has presented to the emergency department for unusual headache, confusion, sudden loss of consciousness with retrograde amnesia, suddenly onset for 2 hours associated with febrile respiratory symptoms. Traumatic neurological events, cerebral ischemia or metabolic encephalopathies were ruled out, while examination of the cerebrospinal fluid was positive for EpsteinBarr virus. The course of the meningoencephalitis was favourable, although an episode of diarrhoea with Clostridioides difficile with binary positive toxin A+B was notified. The primary infection or the reactivation of a previous infection, is a questionable mechanism of meningoencephalitis with Epstein-Barr virus in an old immunocompetent patient. According to the reported studies, the antiviral treatment with Acyclovir is controversial. The long-term prognosis of acute meningoencephalitis with Epstein-Barr virus is unpredictable and involves careful neurological and onco-haematological monitoring.

Introduction: The aim of this study was to estimate the prevalence of Epstein–Barr virus (EBV) infection among children presenting with acute cervical lymphadenopathy and describe the clinical characteristics of children with primary EBV-induced cervical lymphadenopathy. Materials and Methods: This was a prospective observational study in a tertiary care hospital. Results: Twenty-two children out of 127 patients evaluated had primary EBV infection among children presenting with acute cervical lymphadenopathy. The most common symptoms noted were fever (95.5%), loss of appetite (63%), and sore throat (45.5%). Posterior and anterior cervical lymph nodes (99.5% and 86.4%) were most commonly affected with a frequency of 2–6 nodes (mean of 3 nodes) and an average size of 2.4 cm (range: 2–6 cm). Maculopapular, nonpruritic rash was noted in 27.3% and Hoagland sign in 9.1% of cases. Hepatomegaly and clinical splenomegaly were noted in 81% and 59%, respectively, among EBV-positive patients. Conclusion: EBV primary infection is a common cause of acute cervical lymphadenopathy among Indian children with EBV responsible for approximately 17% of such clinical presentation. A high index of clinical suspicion and timely diagnosis of EBV in these children will be useful in limiting investigations and avoidable use of antibiotics by clinicians in such presentation.

Key Clinical Message Adult's Epstein–Barr virus‐associated hemophagocytic lymphohistiocytosis is a rare and life‐threatening condition characterized by atypical initial symptoms and rapid disease progression. To facilitate early diagnosis and prompt treatment, it is imperative to implement early multidisciplinary intervention and prioritize pathogen detection, as these measures significantly contribute to enhancing patient prognosis.

This study investigates the impact of Epstein–Barr virus (EBV) infection on children’s proteomes across different phases of the disease, utilising seventy-nine blood samples categorised into three groups: EBV-naive patients, acute infectious mononucleosis (IM) cases, and convalescents followed up for 12 months post-IM. The aim is to identify proteins influenced by EBV infection, shedding light on the chronic processes triggered by the virus. The results reveal thirty-nine proteins distinguishing between naive patients and those with IM, including actin, lumican, peroxiredoxin-2, fibulin-1, gelsolin, and alpha-2-macroglobulin, which are involved in immune responses, cell adhesion, and inflammation. Elevated oxidative stress markers like peroxiredoxin-2 in IM patients suggest potential links to EBV’s induction of reactive oxygen species. Increased levels of apolipoproteins A-I, A-IV, C-IV, and M during IM imply associations with viral infection, while complement system proteins (C1q, C1r, and C8 gamma chain) are also elevated, reflecting their role in the immune response and viral clearance. This study’s focus on children provides unique insights into EBV’s impact on young populations, emphasising proteomics’ role in uncovering protein associations and understanding the virus’s long-term consequences. However, specific relationships between identified proteins and EBV infection require further investigation.

Previous exposure to Epstein–Barr virus (EBV) is strongly associated with the development of multiple sclerosis (MS). By contrast, past cytomegalovirus (CMV) infection may have no association, or be negatively associated with MS. This study aimed to investigate the associations of herpesvirus infections with MS in an Italian population. Serum samples (n = 200) from Italian people with multiple sclerosis (PwMS) classified as the relapsing-and-remitting clinical phenotype and (n = 137) healthy controls (HCs) were obtained from the CRESM Biobank, Orbassano, Italy. Both PwMS and HCs samples were selected according to age group (20–39 years, and 40 or more years) and sex. EBV virus capsid antigen (VCA) IgG, EBV nucleic acid-1 antigen (EBNA-1) IgG, CMV IgG, herpes simplex virus (HSV) IgG, and varicella zoster virus (VZV) IgG testing was undertaken using commercial ELISAs. EBV VCA IgG and EBNA-1 IgG seroprevalences were 100% in PwMS and 93.4% and 92.4%, respectively, in HCs. EBV VCA IgG and EBNA-1 IgG levels were higher (p < 0.001) in PwMS compared with HCs. For PwMS, the EBNA-1 IgG levels decreased with age, particularly in females. The CMV IgG seroprevalence was 58.7% in PwMS and 62.9% in HCs. CMV IgG seroprevalence increased with age. The HSV IgG seroprevalence was 71.2% in PwMS and 70.8% in HCs. HSV IgG levels were lower (p = 0.0005) in PwMS compared with HCs. VZV IgG seroprevalence was 97.5% in PwMS and 98.5% in HCs. In the population studied, several herpesvirus infections markers may have been influenced by the age and sex of the groups studied. The lack of a negative association of MS with CMV infection, and the observation of lower levels of HSV IgG in PwMS compared with HCs are findings worthy of further investigation.

Abstract Background and objective Acute dacryocystitis is an atypical and rare manifestation of pediatric mononucleosis still widely underdiagnosed in clinical practice. We report this rare condition and describe challenges in its diagnosis and treatment on the basis of a presented case. Case presentation A 6-year-old Caucasian girl without any ophthalmic history was admitted for right preseptal cellulitis requiring intravenous antibiotic therapy. During hospitalization, she developed a fluctuating lump in the nasolacrimal region which resembled an abscess, both clinically and radiologically. There was no spontaneous purulent discharge. Serology was positive for acute mononucleosis and Epstein–Barr virus-related dacryocystitis was diagnosed. Following multidisciplinary discussion, she was treated conservatively with digital lacrimal sac massages and intravenous antibiotic therapy with an excellent outcome. Discussion This rare form of Epstein–Barr virus is poorly documented in the literature, and thus barely known. As initial symptoms are nonspecific (rhinitis, fever, eyelid edema and erythema lack of purulent discharge, and moderate bilateral cervical lymphadenopathy), diagnosis is often difficult. Nevertheless, differentiating between dacryocystitis and abscess is crucial to select the appropriate treatment and avoid unnecessary, potentially harmful surgery. Conservative management of dacryocystitis appears to be the gold standard of treatment. Conclusion Acute dacryocystitis in children free of ophthalmic history should raise suspicion of primary Epstein–Barr virus infection. With conservative treatment, prognosis appears to be excellent; therefore, surgery should be avoided as much as possible.

Epstein-Barr virus (EBV) belongs to the family of herpesviruses (herpes type 4) and is one of the most common and highly contagious. During the pandemic of a new coronavirus disease, it was found that in patients previously infected with EBV, COVID-19 can cause its reactivation, which is often manifested by the clinic of acute hepatitis. The article presents a clinical case of the development of acute hepatitis in a patient with mixed infection with EBV and SARS-CoV-2 in combination with allergic toxic reaction while taking sulfasalazine prescribed for spondyloarthritis. A feature of this case was the development of severe hepatitis of mixed genesis with a favorable outcome. The importance of adherence to drug monitoring rules for newly prescribed drugs for COVID-19 was emphasized. In severe cases of the disease, the possibility of mixed infection should be taken into account.

Key Clinical Message When treating patients with EBV encephalitis, the possibility of XLP should be considered. Once the diagnosis of XLP is made, aggressive treatment such as rituximab, and other immunosuppressive agents are desired for rapid transition to HSCT.

Key Clinical Message Consider the differential of Epstein–Barr virus (EBV) reactivation in pregnant women who develop progressive meningoencephalitis and transverse myelitis. EBV nucleic acid amplification should be considered in immunosuppressed patients. Abstract A 32‐year‐old G10P6M3K22 pregnant female presented to a regional hospital with progressive severe neurological and behavioral deficits. Magnetic resonance revealed cervical transverse myelitis. Lumbar puncture confirmed Epstein–Barr virus (EBV) DNA on a background of IgG‐positive EBV serology. A diagnosis of EBV reactivation‐related meningoencephalitis with transverse myelitis in pregnancy was concluded.

Abstract Background Use of kinase inhibitors such as dasatinib and imatinib might increase the risk of opportunistic infections, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. However, the effect of sorafenib on EBV and CMV infections remains unclear. The aim of this study was to investigate the effect of sorafenib maintenance post-transplantation on the incidence and mortality of EBV and CMV infections in patients with FLT3-ITD acute myeloid leukemia. Methods This was a follow-up of our randomized controlled trial undertaken at seven hospitals in China. The primary endpoint was EBV and CMV infections within 3 years post-transplantation. Secondary endpoints included the cumulative incidences of relapse, non-relapse mortality (NRM), overall survival (OS), leukemia-free survival (LFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) at 3 years. Results Two hundred two patients were assigned to sorafenib maintenance (n=100) or non-maintenance (control, n=102). Median extended follow-up post-transplantation was 36.8 (range, 2.5–67.1) months. The 3-year cumulative incidences of EBV-DNAemia and EBV-associated diseases were 24.0% (95% CI: 16.1–32.8%) and 5.0% (1.8–10.6%) in the sorafenib group, and 24.5% (16.6–33.2%) and 5.9% (2.4–11.6%) in the control group (P=0.937; P=0.771). The 3-year cumulative incidences of CMV-DNAemia and CMV-associated diseases were 56.0% (45.6–65.1%) and 8.0% (3.7–14.4%) in the sorafenib group, and 52.9% (42.7–62.1%) and 8.8% (4.3–15.3%) in the control group (P=0.997; P=0.826). The 3-year cumulative mortality of EBV- and CMV-associated diseases was 0.0% (0.0–0.0%) and 2.0% (0.4–6.4%) in the sorafenib group, and 1.0% (0.1–4.8%) and 2.0% (0.4–6.3%) in the control group (P=0.322, P=0.980). The 3-year cumulative incidences of relapse, NRM, OS, LFS, and GRFS were 13.0%, 11.1%, 79.0%, 75.9%, and 65.8% in the sorafenib group and 34.8%, 12.7%, 61.4%, 52.5%, and 46.6% in the control group, respectively (P0.05). Conclusions Sorafenib maintenance post-transplantation does not increase the incidence and mortality of EBV and CMV infections, demonstrating a favorable safety profile. Trial registration ClinicalTrials.gov Identifier: NCT02474290 . Registered on June 14, 2015

Schmincke described lymphoepithelioma as an undifferentiated carcinoma with abundant lymphoid stroma in the nasopharynx. Tumors with a similar histomorphology in extrapharyngeal areas have been referred to as lymphoepithelioma-like carcinoma (LELC). The association of an Ebstein-Barr virus (EBV) infection with lymphoepithelioma is well established in the nasopharynx but not so well at the extrapharyngeal sites. Only four cases of LELC have been reported in the gall bladder, of which all were negative for the EBV. This paper reports the first case of an EBV-associated mixed gall bladder carcinoma exhibiting a distinct phenotype of LELC and adenocarcinoma with mucinous differentiation. The EBV was confirmed by the strong granular membranous and cytoplasmic expression of LMP-1 (latent membrane protein-1) on immunohistochemistry and nuclear EBER RNA on chromogen in-situ hybridization in the tumor. This is the first case of LELC positive for EBV in the gall bladder. LELC has a more favorable prognosis than conventional adenocarcinoma or squamous cell carcinoma, irrespective of the site. Although a higher T stage and nodal metastasis were exceptional in the present case in contrast to the previous cases, the EBV-associated lymphocytic response might limit the disease spread and confer better overall survival and prognosis in these patients. Nevertheless, more prospective studies with a larger cohort will be needed to understand the pathogenesis, biological behavior, and prognosis of this rare entity.

Abstract Background Viruses must adapt to the environment of their host cells to establish infection and persist. Diverse mammalian cells, including virus-infected cells, release extracellular vesicles such as exosomes containing proteins and miRNAs, and use these vesicles to mediate intercellular communication. However, the roles of exosomes in viral infection remain unclear. Results We screened viral proteins to identify those responsible for the exosome-mediated enhancement of Epstein–Barr virus (EBV) infection. We identified BGLF2 protein encapsulated in exosomes, which were released by EBV-infected cells. BGLF2 protein is a tegument protein that exists in the space between the envelope and nucleocapsid, and it is released into the cytoplasm shortly after infection. BGLF2 protein-containing exosomes enhanced viral gene expression and repressed innate immunity, thereby supporting the EBV infection. Conclusions The EBV tegument protein BGLF2 is encapsulated in exosomes and released by infected cells to facilitate the establishment of EBV infection. These findings suggest that tegument proteins support viral infection not only between the envelope and nucleocapsid, as well as in extraviral particles such as exosomes. Graphical abstract Video abstract

Background Infectious mononucleosis (IM) is a common viral infection that typically presents with fever, pharyngitis and cervical lymphadenopathy. Our aim was to identify the different pathogens causing IM in children admitted to our hospital and to analyze the differences in features of infection with different organisms. Methods We retrospectively analyzed the data of children aged 0–17 years admitted to Wuhan Children’s Hospital during 2013–2022 with IM. We compared symptoms, physical findings, blood counts, and serum biomarkers between patients with IM due to Epstein–Barr virus (EBV) and IM due to other pathogens. Results Among 1480 enrolled children, 1253 (84.66%) had EBV infection, 806 (54.46%) had M. pneumoniae infection, 796 (53.78%) had cytomegalovirus infection, 159 (10.74%) had parvovirus infection, 38 (2.57%) had influenza virus infection, and 25 (1.69%) had adenovirus infection. Receiver operating characteristic curves were used to determine the area under the curve for alanine transaminase (ALT), aspartate transaminase (AST), Alkaline phosphatase (ALP), total bilirubin (TBil), indirect bilirubin (IBil) levels to assess liver damage, and for creatine kinase (CK), CK-MB, and lactate dehydrogenase (LDH) levels to assess myocardial damage. The optimal cutoff values of these biomarkers were then determined. In multivariate analysis, elevated ALT, AST, ALP, TBil, and IBil were independently associated with liver damage, and age

Acute acalculous cholecystitis (AAC) is a rare disease, particularly in children. The clinical and laboratory presentation of AAC is variable. The diagnosis is based on radiological criteria. AAC is an atypical and rare complication of Epstein-Barr virus (EBV) infection, therefore we present a girl with AAC and cholestasis due to EBV primary infection. Conservative treatment and careful monitoring was followed by clinical, radiological and laboratory improvement, and finally complete recovery. Our aim was to highlight the importance of recognizing AAC as a differential diagnosis in children with abdominal pain and/or acute cholestasis.

Abstract. The study of the role of Epstein-Barr viral infection in the occurrence of various pathological conditions in humans is of great importance. This is due to the significant epidemiological role, since upon reaching the age of majority, more than 90% of people are infected of Epstein-Barr virus. The steady increase in the number of diseases caused by Epstein-Barr virus both among adults and children, which is associated with its specific tropism for immunocompetent cells, lifelong persistence and latent course necessitates a comprehensive study and development of effective treatment methods. Purpose of the work: to assess clinical and immunological parameters in order to identify a protracted course and predict unfavorable outcomes in patients with infectious mononucleosis caused by the Epstein-Barr virus. Materials and methods: To achieve this purpose, 60 patients with infectious mononucleosis were examined, among them 38 women (63.3%), 22 men (36.7%). The average age of the patients was 24.3±4.3 years. The material for the study was the patient's serum obtained in the dynamics of the disease. The complex of examination of patients with Infectious mononucleosis included clinical and biochemical methods, enzyme-linked immunosorbent assay, polymerase chain reaction method, immunogram. The research results were processed by the method of variation and correlation statistics using the Statistica 10.0 for Windows program. Results. The analysis of the obtained results made it possible to establish that in patients with infectious mononucleosis, changes were revealed in the system of cellular and humoral immunity and its multidirectionality. The progressive nature of changes in immune parameters indicates the formation of a secondary cellular immune imbalance, activation of the humoral link, a change in the balance of immunoregulatory mediators towards Th2 cells. In the acute period, statistically significant violations of the cellular link of immunity were established, which were characterized by an increase in the number of cells with killer activity: mature T-lymphocytes (CD3+), cytotoxic T-suppressor cells (CD8+), cells expressing the activation marker CD25+ (IL-2 receptor ) and increased Th1/Th2. Conclusions. Thus, changes in the cellular and humoral links of immunity in a favorable course of myocardial infarction are characterized by activation of the cellular and humoral links of immunity, which is manifested by an increase in the content of lymphocytes in the peripheral blood with the [CD3+; CD4+; CD8+; CD16+; CD20+], Th1 cells, IgA and IgM; (p