Active Epstein-Barr Virus Infection Research Articles

Characterization of anti-EBNA-1 antibodies and exploration of their molecular mimicry potential in an EBV-infected Sjögren's syndrome patient

There is a potential link between autoimmune diseases and Epstein-Barr virus (EBV) infections, with EBV playing a substantial role in the onset of Sjögren's syndrome (SjS). Some EBV proteins could mimic host self-antigens post-infection, leading to molecular mimicry. This similarity may cause the immune system to attack its tissues mistakenly. Among the various proteins associated with EBV, nuclear antigen 1 (EBNA-1) is essential for the latent replication of infected cells and is prevalent in all EBV-related diseases. In the study, single-chain variable fragment (scFv) antibodies targeting EBNA-1 were isolated using phage display technology from a primary SjS patient who also had a chronic active EBV infection. The specific clones were enriched after panning, and the binding activity of selected scFvs targeting EBNA-1 was confirmed. Sequence analysis indicated that the scFvs exhibiting positive signals could be grouped into five clones, all of which used homologous heavy chain V regions derived from germline Vh4-39, and two types of light chain V regions stemming from germline Vλ1-44 and Vλ3-15. These scFvs were found to exhibit a high degree of somatic mutations, likely indicative of antigen selection. Of the scFvs, P1-3 demonstrated the strongest binding affinity to EBNA-1, exhibiting a determined value of 7.3 x 10-8 M, and showed cross-reactivity to the SjS associated La/SSB self-antigen. The experimental results combined with AlphaFold 3 predictions revealed a potential epitope for scFv P1-3 binding to EBNA-1. Additionally, scFv P1-3 could also cross-bind to the modeled structure of La/SSB. We inferred a possible structural correlation between EBNA-1 and La/SSB involving an X2AX6PG epitope motif. This research contributes to our understanding of the structural basis of the interactions between antibodies and EBNA-1, shedding light on the VH and VL gene usage of anti-EBNA-1 antibodies in EBV-infected SjS patients and the potential origins of autoantibodies.

Chronic active Epstein–Barr Virus infection in a teenage girl with suspect autoimmune Hepatitis

BackgroundThe pathogenesis of chronic active Epstein–Barr virus (EBV) disease (CAEBV) is complex, involving infection, inflammation, and in some cases malignancy. EBV reactivates in some patients, who develop a chronic disease with infectious mononucleosis-like symptoms. On occasion, it might be confused with autoimmune hepatitis (AIH), based on the similar symptoms and elevated liver enzymes. We aimed to describe a similar case to remind reader of this disease.Case Presentation: A 14-year-old girl was diagnosed with AIH based on biopsy and biomarker findings 1 year prior to admission and initially presented with elevated liver enzymes, portal hypertension, and parenchymal liver disease. Despite steroid administration, her condition fluctuated, and she was admitted to the hospital several times. She underwent a renal biopsy because of massive ascites, hypoalbuminemia, and increased renal echogenicity. An evaluation for impaired liver function showed positivity for EBV IgM, IgG, and early antigen (EBEA) antibodies. A PCR-based assay showed 5265 copies/mL of EBV DNA in peripheral blood. Epstein–Barr encoding region (EBER) in situ hybridization revealed abundant positive cells. Immunohistochemistry for CD56 also showed abundant positive cells, and CAEBV was diagnosed on this basis. Chemotherapy, hematopoietic stem cell transplantation (HSCT), and liver transplantation were proposed but her family refused.ConclusionsCAEBV should be considered when diagnosing AIH or in cases of treatment-refractory AIH.

Resistance mechanisms and potential therapeutic strategies in relapsed or refractory natural killer/T cell lymphoma.

Natural killer/T cell lymphoma (NKTCL) is a malignant tumor originating from NK or T cells, characterized by its highly aggressive and heterogeneous nature. NKTCL is predominantly associated with Epstein-Barr virus infection, disproportionately affecting Asian and Latin American populations. Owing to the application of asparaginase and immunotherapy, clinical outcomes have improved significantly. However, for patients in whom first-line treatment fails, the prognosis is exceedingly poor. Overexpression of multidrug resistance genes, abnormal signaling pathways, epigenetic modifications and active Epstein-Barr virus infection may be responsible for resistance. This review summarized the mechanisms of resistance for NKTCL and proposed potential therapeutic approaches.

Enhancing diagnostic precision in EBV-related HLH: a multifaceted approach using 18F-FDG PET/CT and nomogram integration

BackgroundThe hyperinflammatory condition and lymphoproliferation due to Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) affect the detection of lymphomas by 18F-FDG PET/CT. We aimed to improve the diagnostic capabilities of 18F-FDG PET/CT by combining laboratory parameters.MethodsThis retrospective study involved 46 patients diagnosed with EBV-positive HLH, who underwent 18F-FDG PET/CT before beginning chemotherapy within a 4-year timeframe. These patients were categorized into two groups: EBV-associated HLH (EBV-HLH) (n = 31) and EBV-positive lymphoma-associated HLH (EBV + LA-HLH) (n = 15). We employed multivariable logistic regression and regression tree analysis to develop diagnostic models and assessed their efficacy in diagnosis and prognosis.ResultsA nomogram combining the SUVmax ratio, copies of plasma EBV-DNA, and IFN-γ reached 100% sensitivity and 81.8% specificity, with an AUC of 0.926 (95%CI, 0.779–0.988). Importantly, this nomogram also demonstrated predictive power for mortality in EBV-HLH patients, with a hazard ratio of 4.2 (95%CI, 1.1–16.5). The high-risk EBV-HLH patients identified by the nomogram had a similarly unfavorable prognosis as patients with lymphoma.ConclusionsThe study found that while 18F-FDG PET/CT alone has limitations in differentiating between lymphoma and EBV-HLH in patients with active EBV infection, the integration of a nomogram significantly improves the diagnostic accuracy and also exhibits a strong association with prognostic outcomes.

Safety of teplizumab in patients with high-risk for diabetes mellitus type 1: A systematic review.

The incidence of diabetes mellitus type 1 (DM1) has been rising worldwide because of improvements in diagnostic techniques and improved access to care in countries with lower socioeconomic status. A new anti-CD4 antibody, Tep-lizumab, has been shown to delay the progression of DM1 and is the only medication approved for this indication. However, more information is needed about the safety profile of this drug. To identify the odds ratios (OR) of systems-based adverse effects for Teplizumab when compared to Placebo. An extensive systematic review was conducted from the inception of the medication until December 31, 2023. All clinical trials and studies that evaluated Teplizumab vs placebo were included in the initial review. The study protocol was designed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines guidelines and was registered in PROSPERO (ID: CRD42024496169). Crude OR were generated using RevMan Software version 5.4. After screening and review, 5 studies were selected to determine the risk of adverse effects of teplizumab compared to placebo. A total of 561 patients were included in the study population. Total adverse effects and system-based adverse effects were studied and reported. We determined that patients receiving Teplizumab had a higher risk of developing gastrointestinal (GI) (OR = 1.60, 95%CI: 1.01-2.52, P = 0.04), dermatological (OR = 6.33, 95%CI: 4.05-9.88, P < 0.00001) and hematological adverse effects (OR = 19.03, 95%CI: 11.09-32.66, P < 0.00001). These patients were also significantly likely to have active Epstein-Barr Virus infection (OR = 3.16, 95%CI: 1.51-6.64, P < 0.002). While our data showed that patients receiving Teplizumab did have a higher incidence of total adverse effects vs placebo, this finding did not reach statistical significance (OR = 2.25, 95%CI: 0.80-6.29, P = 0.12). Our systematic review suggests that Teplizumab patients are at risk for significant adverse effects, primarily related to GI, dermatological, and hematological systems. The total adverse effect data is limited as study populations are small. More studies should be conducted on this medication to better inform the target population of potential adverse effects.

Quantitatively assessed blood leukocyte Epstein–Barr virus in adult HIV-infected patients

Coinfection with the human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV) represents a current biomedical problem. The purpose of the study was to evaluate blood leukocyte EBV detection rate and viral load in adult HIV-infected patients. Materials and methods. There were examined blood leukocytes collected from 138 HIV(+) and 68 HIV(–) individuals aged 20–69 years. Statistical analysis was carried out differentiated according to the stages of HIV infection, the CD4+ T-lymphocyte count, and adherence to antiretroviral therapy. Results. It was shown that EBV DNA was detected significantly more often in HIV(+) vs HIV(–) individuals (70.3±3.9% and 48.5±6.1%, p = 0.008), with EBV viral load comprising 18 [5; 139] versus 2 [1; 3] copies/105 cells (р 0.001), respectively. It has been shown that the group of HIV(+) patients is heterogeneous in the frequency of EBV detection and viral load, with the peak EBV frequency (86.7±6.2%) and DNA (121 [34; 252] copies/105 cells) level observed in “naive” patients with severe immunodeficiency. Among “experienced” patients receiving therapy, the relative risk of detecting EBV DNA with low treatment adherence was significantly higher compared to those who developed high adherence (р 0.05). When the HIV viral load reached undetectable level, EBV DNA concentration was significantly lower where HIV RNA was detectable (1 [0; 8] versus 15 [1; 162] copies/105 cells, р 0.001). Detection of EBV DNA is associated with higher HIV viral load level and lower CD4+ T-lymphocyte count compared to patients with undetected EBV DNA. A relationship has been established between the CD4+ T-lymphocyte count in HIV(+) patients and the likelihood of active EBV infection. A threshold cut-off of 200 cells/μl was determined. CD4+ T-lymphocyte count 200 cells/μl vs ≥ 200 cells/μl (р 0.001) is associated with a 3.3-fold higher risk of detecting active EBV infection. Conclusion. It is necessary to continue interdisciplinary research to improve early diagnostics of EBV-associated diseases in HIV-infected individuals.

Investigation of atypical serological profiles for Epstein-Barr virus (EBV)

BackgroundCommercial immunoassays that detect IgG and IgM directed toward VCA and IgG EBNA are used in combination to assess EBV immune status. However, this strategy does not always confirm/exclude recent/past EBV infection or absence of immunity. ObjectivesThe aim of our study was to perform complementary investigations on samples with atypical EBV serological profiles, in order to identify the clinical situation they correspond to. Study designEBV serology was performed using EBV VCA IgM/IgG and EBNA IgG LXL® DiaSorin assay. Complementary investigations included ELISA IgM VCA, immunoblots, CMV IgM/IgG and CMV IgG avidity, and EBV PCR. ResultsIn our study, 12810 EBV serological results were analyzed, and 3580 atypical profiles were detected (28 %). Among these latter, isolated VCA IgG represented 42.9 %, the three positive markers accounted for 29.1 %, isolated EBNA IgG represented 18.5 %, isolated VCA IgM accounted for 6.4 % and positive VCA IgM & positive EBNA IgG represented 3.1 %. VCA IgG detected alone were specific in 100 % cases and EBNA IgG detected alone were specific in 91.7 % cases. VCA IgM detected alone were false positive or due to a cross reaction with CMV in 52.8 % cases. The pattern positive VCA IgM and positive EBNA IgG correspond to a false positive in VCA IgM, EBNA IgG or both in 83.4 % cases. Positive EBV VCA IgM/IgG and EBNA IgG were unreliable to detect active EBV infection in 66.7 % cases. DiscussionAtypical EBV serological profiles may correspond to several clinical situations and complementary investigations allow to determine the immune status in more than 98.5 % cases.

Primary Active Epstein-Barr Virus Infection Coexisting with Immune Thrombocytopenia in Children-A Rare Trigger Factor of Immun Thrombocytopenia: Two Case Reports

Immune thrombocytopenia (ITP) is a reason of thrombocytopenia that is characterized by isolated thrombocytopenia in childhood. Epstein barr virus infection (EBV) is a mildly and uncomplicated ailment that might be a trigger factor for ITP. Here, we discuss two cases with ITP secondary Epstein barr virus infection.

Targeting Epstein-Barr virus in multiple sclerosis: when and how?

Epidemiological evidence implicates Epstein-Barr virus (EBV) as the cause of multiple sclerosis (MS). However, its biological role in the pathogenesis of MS is uncertain. The article provides an overview of the role of EBV in the pathogenesis of MS and makes a case for targeting EBV as a treatment strategy for MS. EBV potentially triggers autoimmunity via molecular mimicry or immune dysregulation. Another hypothesis, supported by immunological and virological data, indicates that active EBV infection via latent-lytic infection cycling within the central nervous system or periphery drives MS disease activity. This supports testing small molecule anti-EBV agents targeting both latent and lytic infection, central nervous system-penetrant B-cell therapies and EBV-targeted immunotherapies in MS. Immunotherapies may include EBV-specific cytotoxic or chimeric antigen receptors T-cells, therapeutic EBV vaccines and immune reconstitution therapies to boost endogenous EBV-targeted cytotoxic T-cell responses. EBV is the probable cause of MS and is likely to be driving MS disease activity via latent-lytic infection cycling. There is evidence that all licensed MS disease-modifying therapies target EBV, and there is a compelling case for testing other anti-EBV strategies as potential treatments for MS.

Ultra-low doses of microARNs restore a strong immune response in patients with Chronic Active Epstein-Barr Virus infection (CAEBV)

Chronic active Epstein-Barr Virus infection (CAEBV) is an abnormal response of the immune system to EBV infection, characterized by the absence of anti-EBNA (EBV Nuclear Antigens) IgG and associated with chronic fatigue and several immune related diseases. We present here an innovative therapeutic approach of CAEBV based on the use of ultra-low doses of non-coding RNAs (ncRNAs) involved in the host-virus interaction. We performed a retrospective study on 26 patients treated with our remedy. All the patients expect one developed positive EBNA IgG within eighteen months of starting treatment. Among the 25 cases that seroconverted, 75% report a significant improvement of their symptoms, especial of chronic fatigue. This study gives the proof of the efficiency of ultra-low doses of ncRNAs in restoring a strong immune response against EBV. More generally, this therapeutic approach can potentially be used in almost all pathologies.

Differentiating Between Epstein-Barr Virus-positive Lymphoid Neoplasm Relapse and Post-transplant Lymphoproliferative Disorder After Sex-mismatched Hematopoietic Stem Cell Transplantation.

After allogeneic hematopoietic stem cell transplantation (HSCT), accurate differentiation between donor-derived post-transplant lymphoproliferative disorder (PTLD) and relapse of recipient-derived lymphoproliferative disorder (LPD) is crucial for determining treatment. Conventional diagnostic approaches for PTLD include histopathological examination, flow cytometry, and chimerism analysis of bulk tumor tissue. However, these methods are inconclusive in cases in which the primary disease is an Epstein-Barr virus (EBV)-positive LPD and is of the same lineage as that of the post-HSCT LPD tumor cells. Particularly, in cases where the number of tumor cells in the tissue is low, it is difficult to determine the origin of tumor cells. In this study, we developed a new method to simultaneously detect signals using sex chromosome fluorescence in situ hybridization, immunofluorescence staining, and EBV-encoded small RNA in situ hybridization on a single section of formalin-fixed paraffin-embedded histopathological specimen. The utility of the method was validated using specimens from 6 cases of EBV-positive LPD after sex-mismatched HSCT that were previously difficult to diagnose, including Hodgkin lymphoma-like PTLD that developed after HSCT for Hodgkin lymphoma and recurrence of chronic active EBV infection. This method successfully preserved the histologic structure after staining and allowed accurate determination of tumor cell origin and lineage at the single-cell level, providing a definitive diagnosis in all cases. This method provides a powerful tool for the diagnosis of LPDs after sex-mismatched HSCT.

Cytokine Storm Syndromes Associated with Epstein-Barr Virus.

Epstein-Barr virus (EBV) is a ubiquitous and predominantly B cell tropic virus. One of the most common viruses to infect humans, EBV, is best known as the causative agent of infectious mononucleosis (IM). Although most people experience asymptomatic infection, EBV is a potent immune stimulus and as such it elicits robust proliferation and activation of the B-lymphocytes it infects as well as the immune cells that respond to infection. In certain individuals, such as those with inherited or acquired defects affecting the immune system, failure to properly control EBV leads to the accumulation of EBV-infected B cells and EBV-reactive immune cells, which together contribute to the development of often life-threatening cytokine storm syndromes (CSS). Here, we review the normal immune response to EBV and discuss several CSS associated with EBV, such as chronic active EBV infection, hemophagocytic lymphohistiocytosis, and post-transplant lymphoproliferative disorder. Given the critical role for cytokines in driving inflammation and contributing to disease pathogenesis, we also discuss how targeting specific cytokines provides a rational and potentially less toxic treatment for EBV-driven CSS.

Haploidentical Transplantation with Post-Transplant Cyclophosphamide Versus Single Cord Blood Transplantation for Adults with Relapsed/Refractory Malignant Lymphoma

Introduction Although the treatment of malignant lymphoma has diversified with the advent of chimeric antigen receptor T-cell therapy and other novel agents, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative treatment for some patients with relapsed/refractory malignant lymphoma (R/R ML). R/R ML eligible for allo-HSCT often requires urgent transplantation, making human leukocyte antigen (HLA)-haploidentical transplantation with post-transplant cyclophosphamide (PTCY-haplo) or cord blood transplantation (CBT) a promising option when HLA-matched donors are unavailable. PTCY-haplo has recently been reported to achieve similar or better clinical outcomes than CBT for other hematological malignancies, though data regarding R/R ML are insufficient. Therefore, this study compares PTCY-haplo and CBT for patients with R/R ML using the Transplant Registry Unified Management Program 2 (TRUMP2) in Japan. Methods This study included adult patients with R/R ML registered with TRUMP2 who underwent PTCY-haplo and CBT for their first allo-HSCT between January 2013 and December 2021. In this study, R/R ML included mature B-, T-, and NK-cell neoplasms, as defined in the World Health Organization's 2017 classification. Patients undergoing allo-HSCT for Hodgkin's lymphoma, aggressive NK-cell leukemia, chronic active Epstein-Barr virus (EBV) infection, systemic EBV-positive T-cell lymphoma of childhood, or adult T-cell leukemia/lymphoma were excluded. The primary endpoint was 3-year overall survival (OS). A Cox proportional hazard regression model for OS was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) in the multivariate analysis. The following factors were included in the multivariate model: donor type, age, sex, performance status, Hematopoietic Cell Transplantation-specific Comorbidity Index score, disease status at allo-HSCT, conditioning regimen, cytomegalovirus seropositivity, and disease linage. The secondary endpoints were 3-year progression-free survival (PFS), 3-year graft versus host disease (GVHD)/relapse-free survival (GRFS), 3-year cumulative incidence of relapse and non-relapse mortality (NRM), 28-day cumulative incidence of neutrophil engraftment, 100-day cumulative incidence of platelet engraftment, 100-day cumulative incidence of grade II-IV and grade III-IV acute GVHD, and 3-year cumulative incidence of any and extensive chronic GVHD. Results A total of 1093 patients, including 223 who underwent PTCY-haplo and 870 who underwent CBT, were included in the study. The median age was 54 years (interquartile range, 44-61 years), and 616 (56%) patients had B-cell lymphoma. The PTCY-haplo group included older patients, more patients who were positive for cytomegalovirus antibodies in recipients or donors, and more patients who received a reduced-intensity conditioning regimen. The 3-year OS was 49% (95% CI: 41-56%) in the PTCY-haplo group and 42% (95% CI: 38-45%) in the CBT group (P=0.090). The adjusted HR was 0.88 (95% CI: 0.70-1.09, P=0.20). The PTCY-haplo group had comparable 3-year PFS, 3-year GRFS, 3-year relapse rates, and 3-year NRM as the CBT group. The PTCY-haplo group had higher neutrophil engraftment at 28 days (92.8% [95%CI: 88.5-95.6%] vs 81.6% [95%CI: 78.9-84.0%], P&amp;lt;0.001) and platelet engraftment at 100 days (77.6% [95%CI: 71.5-82.5%] vs 71.0% [95%CI: 67.9-73.9%], P&amp;lt;0.001); similar grade II-IV acute GVHD at 100 days and 3-year cumulative incidences of chronic GVHD and extensive chronic GVHD; and lower grade III-IV acute GVHD at 100 days (7.17% [95%CI: 4.27-11.1%] vs 13.6% [95%CI 11.5-16.0], P=0.01). Conclusion In this population, PTCY-haplo and CBT result in similar 3-year OS after allo-HSCT. Faster engraftment and less severe acute GVHD were noted in the PTCY-haplo group.

Clinical Characteristics of Peripheral Lymphocyte Subtypes in Chronic Active Epstein-Barr Virus Infection.

We aimed to analyze the clinical characteristics of peripheral Epstein-Barr virus (EBV)-infected lymphocyte subtypes in children with chronic active EBV infection (CAEBV). The levels of peripheral EBV infection of CD4+ T cells, CD8+ T cells, and CD56+ natural killer (NK) cells were determined by flow cytometry and quantitative polymerase chain reaction (qPCR) in patients with CAEBV from July 2017 to July 2022. In total, 112 children with CAEBV were evaluated. Of these, CD4+ type, CD8+ type, and CD56+ type were defined in 44, 21, and 47 patients, respectively. Patients with CD8+ T-cell type had a significantly higher frequency of rash, while hepatomegaly was more common in patients with CD4+ T-cell type. Generally, patients with CD8+ T-cell type had the lowest overall survival rate (P = .017). Patients treated with chemotherapy and hematopoietic stem cell transplantation (HSCT) had a better prognosis (P = .001). In multivariate analysis, rash, hemophagocytic lymphohistiocytosis, CD8+ T-cell type, and no decrease of plasma EBV-DNA after treatment were independent indicators of poor prognosis (P = .002, .024, .022, and .012, respectively). In children with CAEBV, rash was more frequent in patients with CD8+ T-cell type, whereas patients with CD4+ T-cell type were more likely to develop hepatomegaly. Patients with CD8+ T-cell type had a poor prognosis despite receiving chemotherapy or further HSCT.

Sintilimab treatment for chronic active Epstein–Barr virus infection and Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis in children

BackgroundChronic active Epstein–Barr virus infection (CAEBV) and Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) are rare but life-threatening progressive diseases triggered by EBV infection. Glucocorticoid/immunosuppressants treatment is temporarily effective; however, most patients relapse and/or progress. Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy; however, there are risks of transplantation-associated complications. Currently there is no standard treatment for CAEBV and EBV-HLH. Programmed death protein 1 (PD-1) inhibitors have achieved a high response in many EBV-related diseases. Sintilimab (a recombinant human IgG4 monoclonal antibody against PD-1) disrupts the interaction between PD-1 and its ligand, leading to T cell reinvigoration.MethodsA retrospective analysis was performed on three children with CAEBV or EBV-HLH in the Children’s Hospital of Soochow University between 12 December 2020 and 28 November 2022. The efficacy of sintilimab was evaluated.ResultsThree patients, including two males and one female, were analyzed. Among them, two children were diagnosed with CAEBV with intermittent fever for more than four years, and one child was diagnosed with EBV-HLH. After sintilimab treatment and a mean follow-up of 17.1 months (range 10.0–23.3 months), patients 1 and 3 achieved a complete clinical response and patient 2 achieved a partial clinical response. All three children showed a > 50% decrease in EBV-DNA load in both blood and plasma. EBV-DNA copies in sorted T, B, and NK cells were also markedly decreased after sintilimab treatment.ConclusionOur data supported the efficacy of PD-1 targeted therapy in certain patients with CAEBV and EBV-HLH, and suggested that sintilimab could provide a cure for these diseases, without HSCT. More prospective studies and longer follow-up are needed to confirm these conclusions.

Updated guidelines for chronic active Epstein-Barr virus disease.

Chronic active Epstein-Barr virus disease (CAEBV), formerly named chronic active Epstein-Barr virus infection, is characterized by systemic inflammation and clonal proliferation of Epstein-Barr virus (EBV)-infected T or NK cells. As CAEBV is a potentially life-threatening illness, appropriate diagnosis and therapeutic interventions are necessary for favorable clinical outcomes. Substantial evidence regarding the pathogenesis and treatment of CAEBV has been accumulated since previous guidelines for the diagnosis of CAEBV were proposed. To reflect this evidence, we updated the guidelines for the diagnosis and treatment of CAEBV to improve clinical management of the disease. The details of the updated guidelines are presented in this report. Diagnosis of CAEBV now requires confirmation of a high copy number of EBV genome and EBV-infected T or NK cells. An EBV DNA load ≥ 10,000IU/mL in whole blood is proposed as the diagnostic cutoff value for CAEBV in this updated guideline. A standard treatment approach for CAEBV has not been established, and hematopoietic stem cell transplantation (HSCT) is considered the only curative treatment. Chemotherapy can be administered to control disease activity before HSCT.

Proteomic Analysis of Pediatric Hemophagocytic Lymphohistiocytosis: a Comparative Study with Healthy Controls, Sepsis, Critical Ill, and Active Epstein-Barr virus Infection to Identify Altered Pathways and Candidate Biomarkers

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive activation of the immune system, along with uncontrolled proliferation of activated macrophages and lymphocytes. The clinical features of HLH often overlap with the clinical features of other severe inflammatory conditions such as sepsis, hindering accurate and timely diagnosis. In this study, we performed a data-independent acquisition mass spectrometry-based plasma proteomic analysis of 33 pediatric patients with HLH compared with four control groups: 39 healthy children, 43 children with sepsis, 39 children hospitalized in the pediatric intensive care unit without confirmed infections, and 21 children with acute Epstein-Barr virus infection. Proteomic comparisons between the HLH group and each of the control groups showed that HLH was characterized by alterations in complement and coagulation cascades, neutrophil extracellular trap formation, and platelet activation pathways. We identified eight differentially expressed proteins in patients with HLH, including plastin-2 (LCP1), vascular cell adhesion protein 1, fibrinogen beta chain, fibrinogen gamma chain, serum amyloid A-4 protein, extracellular matrix protein 1, apolipoprotein A-I, and albumin. LCP1 emerged as a candidate diagnostic marker for HLH with an area under the curve (AUC) of 0.97 in the original cohort and an AUC of 0.90 (sensitivity = 0.83 and specificity = 1.0) in the validation cohort. Complement C1q subcomponent subunit B was associated with disease severity in patients with HLH. Based on comparisons with multiple control groups, this study provides a proteomic profile and candidate biomarkers of HLH, offering researchers novel information to improve the understanding of this condition.

The Impact of Co-Infections for Human Gammaherpesvirus Infection and Associated Pathologies.

The two oncogenic human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause significant disease burden, particularly in immunosuppressed individuals. Both viruses display latent and lytic phases of their life cycle with different outcomes for their associated pathologies. The high prevalence of infectious diseases in Sub-Saharan Africa (SSA), particularly HIV/AIDS, tuberculosis, malaria, and more recently, COVID-19, as well as their associated inflammatory responses, could potentially impact either virus' infectious course. However, acute or lytically active EBV and/or KSHV infections often present with symptoms mimicking these predominant diseases leading to misdiagnosis or underdiagnosis of oncogenic herpesvirus-associated pathologies. EBV and/or KSHV infections are generally acquired early in life and remain latent until lytic reactivation is triggered by various stimuli. This review summarizes known associations between infectious agents prevalent in SSA and underlying EBV and/or KSHV infection. While presenting an overview of both viruses' biphasic life cycles, this review aims to highlight the importance of co-infections in the correct identification of risk factors for and diagnoses of EBV- and/or KSHV-associated pathologies, particularly in SSA, where both oncogenic herpesviruses as well as other infectious agents are highly pervasive and can lead to substantial morbidity and mortality.

T cell-mediated immunity during Epstein-Barr virus infections in children.

Epstein-Barr virus (EBV) infection is extremely common worldwide, with approximately 90% of adults testing positive for EBV antibodies. Human are susceptible to EBV infection, and primary EBV infection typically occurs early in life. EBV infection can cause infectious mononucleosis (IM) as well as some severe non-neoplastic diseases, such as chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which can have a heavy disease burden. After primary EBV infection, individuals develop robust EBV-specific T cell immune responses, with EBV-specific CD8+ and part of CD4+ T cells functioning as cytotoxic T cells, defending against virus. Different proteins expressed during EBV's lytic replication and latent proliferation can cause varying degrees of cellular immune responses. Strong T cell immunity plays a key role in controlling infection by decreasing viral load and eliminating infected cells. However, the virus persists as latent infection in EBV healthy carriers even with robust T cell immune response. When reactivated, it undergoes lytic replication and then transmits virions to a new host. Currently, the relationship between the pathogenesis of lymphoproliferative diseases and the adaptive immune system is still not fully clarified and needs to be explored in the future. Investigating the T cell immune responses evoked by EBV and utilizing this knowledge to design promising prophylactic vaccines are urgent issues for future research due to the importance of T cell immunity.

Bioinformatics analysis to screen the key genes in pediatric Chronic Active Epstein-Barr Virus Infection.

Chronic active EBV infection (CAEBV) is associated with poor prognosis and high mortality. We performed bioinformatics analysis to screen out key genes associated with CAEBV. Weighted gene co-expression network analysis (WGCNA) was used to identify the gene module which was most correlated with pediatric CAEBV. Furthermore, the differentially expressed genes (DEGs) between pediatric acute infectious mononucleosis (AIM) and pediatric CAEBV were investigated. Least absolute shrinkage and selection operator (LASSO) and random forest then were performed to identify the key variables associated with pediatric CAEBV. We also explored the correlation between these hub genes with EBV infection related pathway and immune cell abundance. Compared with pediatric AIM, 1561 DEGs were up-regulated in pediatric CAEBV, and these genes were mainly enriched in inflammatory response and inflammation-related pathways. WGCNA analysis showed that genes in blue module were mostly related to pediatric CAEBV. Genes in the blue module and DEGs are intersected to get 174 genes and these genes are also enriched in inflammatory response-related pathways. The key CAEBV-related genes were selected from these 174 genes by applying the random Forest and LASSO algorithm, resulting in TPST1, TNFSF8 and RAB3GAP1. These three genes showed good diagnostic performance in distinguishing pediatric CAEBV from pediatric AIM. Furthermore, Cibersort and GSEA analysis indicated that these three genes were positively correlated with myeloid cell enrichment and persistent EBV infection pathway, respectively. Our finding systematically analyzed the difference between AIM and CAEBV and identified TPST1, TNFSF8 and RAB3GAP1 were the key genes in the development of CAEBV.