Primary Epstein-Barr Virus Infection Research Articles

Epstein Barr Virus Hepatitis-A Mild Clinical Symptom or a Threat?

The present study aimed to characterize pediatric patients diagnosed with hepatitis associated with primary Epstein-Barr Virus (EBV) infection. We described the changes in liver aminotransferases activity during the disease, and we analyzed the results of abdominal ultrasonography. A retrospective study was performed by analyzing the medical records of 166 immunocompetent children diagnosed with primary EBV hepatitis hospitalized at the Department of Children's Infectious Diseases, Medical University of Warsaw, Regional Hospital of Infectious Diseases in Warsaw, between August 2017 and March 2023. Elevated alanine aminotransferase (ALT) activity was noted in the first three weeks of the disease. In 46.3% of patients, ALT values exceeded five times the upper limit of the laboratory norm in the first week of illness. Aspartate aminotransferase activity increased from the first to fourth week from the onset of symptoms and showed two peaks in the first and third weeks. The changes over time of mean AST activity demonstrated significance. Transient cholestatic liver disease was the predominant type of hepatic involvement in 10.8% of children; 66.6% of them were older than 15 years. Clinical and ultrasound criteria of acute acalculous cholecystitis (AAC) were met in three female patients over 16 years of age. Hepatitis associated with primary EBV infection is usually a mild and self-limiting condition. Significantly elevated values of liver enzymes with features of cholestatic liver disease may occur in patients with a more severe course of the infection.

Infectious Mononucleosis: A Case Report with Unusual Features and EBV Induced Hepatitis

Despite the fact that Epstein-Barr virus (EBV) infections are common, we continue to hear about new cases of the illness with bizarre and unique symptoms, which prompts the issue of how well we understand this disease. In developing countries, the average age at which an infection is contracted is rising. Other physical symptoms are less noticeable and liver involvement is more noticeable throughout these stages. To inform healthcare professionals of this change, an update on infectious mononucleosis (IM) variable manifestation is necessary. Although our patient didn't have many physical symptoms, blood testing revealed a typical picture of EBV-induced hepatitis. This instance is consistent with recent research suggesting that hepatic involvement is among the most noticeable symptoms in adults with primary EBV infection. Keywords: [Epstein-Barr virus, Infectious mononucleosis, Hepatitis]

Identification of ADA as a Biomarker for Atypical Epstein Barr Virus Infection in Children.

This study aims to explore the ability of adenosine deaminase (ADA) to discriminate atypical Epstein Barr virus (EBV) infection in children from acute febrile illness. All children admitted to the Children's Hospital of Soochow University between 2018 and 2019, who were acute febrile patients and subjected to the plasma EBV-DNA polymerase chain reaction (PCR) and indirect immunofluorescence (IIF) assay for EBV-specific antibodies assays. The diagnostic value of each detection index was compared by the area under the ROC curve. In children with atypical Epstein Barr virus infection, the sensitivity, specificity, positive predictive value, negative predictive value and Youden index were 62.87%, 100.00%,100.00%, 61.73% and 0.63 for EBV-DNA PCR assay, 80.84%, 100.00%, 100.00%, 75.76% and 0.81 for VCA-IgG avidity and 89.22%, 87.00%, 91.98%, 82.86% and 0.76 for ADA. VCA-IgG avidity (AUC=0.904, P<0.01) and ADA (AUC=0.881, P<0.01) assays had the great diagnostic efficiency. In addition, the sensitivity, specificity and AUC were 92.75%,91.43% and 0.921(95%CI: 0.856-0.985) for ADA in the course≤3 days group, respectively. ADA has a good diagnostic value in the early stage of atypical EBV infection, and is not affected by primary EBV infection and reactivation. SCHLüSSELWöRTER: Adenosine deaminase, Epstein -Barr virus, Biomarker, children.

Comparative Analysis of Primary and Reactivated EB Virus Infection Associated Hemophagocytic Lymphohistiocytosis

To compare the clinical characteristics of children with hemophagocytic lymphocytosis (HLH) associated with primary Epstein-Barr virus (EBV) infection and EBV reactivation, and explore the effects of different EBV infection status on the clinical indexes and prognosis of HLH. The clinical data of 51 children with EBV associated HLH treated in Henan Children's Hospital from June 2016 to June 2021 were collected. According to the detection results of plasma EBV antibody spectrum, they were divided into EBV primary infection-associated HLH group (18 cases) and EBV reactivation-associated HLH group (33 cases). The clinical features, laboratory indexes and prognosis of the two groups were analyzed and compared. There were no significant differences in age, gender, hepatomegaly, splenomegaly, lymphadenopathy, neutrophil count in peripheral blood, hemoglobin content, platelet count, plasma EBV-DNA load, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, albumin, fibrinogen, triglyceride, ferritin, hemophagocytosis in bone marrow, NK cell activity and sCD25 between the two groups(P>0.05). The central nervous system involvement and CD4/CD8 in EBV reactivation-associated HLH group were significantly higher than those in primary infection-associated HLH group, but the total bilirubin was significantly lower than that in primary infection-associated HLH group (P<0.05). After treatment according to HLH-2004 protocol, the remission rate, 5-year OS rate and 5-year EFS rate of patients in EBV reactivation-associated HLH group were significantly lower than those in EBV primary infection-associated HLH group (P<0.05). EBV reactivation-associated HLH is more likely to cause central nervous system involvement and the prognosis is worser than EBV primary infection-associated HLH, which requires intensive treatment.

Characteristics of plasma Epstein-Barr virus DNA in children with primary infection

Objective: To explore the characteristics of plasma Epstein-Barr virus (EBV) DNA in primary infection in pediatric cases. Methods: The laboratory and clinical data of 571 children diagnosed with EBV primary infection in Children's Hospital of Fudan University during September 1st, 2017 to September 30th, 2018 were retrospectively analyzed. According to the results of plasma EBV DNA, they were divided into positive group and negative group. According to the EBV DNA, they were devided into high plasma virol load group and low plasma virol load group. The Chi-square test, Wilcoxon rank sum test were used to compare the differences between groups. Results: Among the 571 children with EBV primary infection, 334 were males and 237 were females. The age of first diagnosis was 3.8 (2.2, 5.7) years. There were 255 cases in positive group and 316 cases in negative group. The percentage of cases with fever,hepatomegaly and (or) splenomegaly, elevated transaminase in the positive group were higher than those in the negative group (235 cases (92.2%) vs. 255 cases (80.7%), χ2=15.22, P<0.001; 169 cases (66.3%) vs. 85 cases (26.9%), χ2=96.80, P<0.001; and 144 cases (56.5%) vs. 120 cases (38.0%), χ2=18.27, P<0.001; respectively).In the positive group, 70 cases were followed up for 46 (27, 106) days, 68 cases (97.1%) turned negative within 28 days, with the exception of 2 cases (2.9%) developed chronic active EBV infection by follow-up revision.There were 218 cases in high plasma viral DNA copies group and 37 cases in low copies group. More cases presented with elevated transaminases in the high plasma viral DNA copies group than those in the low group (75.7% (28/37) vs. 56.0%(116/207), χ2=5.00, P=0.025).Both the positive rate of EBV DNA in peripheral blood leukocytes (84.2% (266/316) vs. 44.7% (255/571), χ2=76.26, P<0.001) and the copies of EBV DNA (7.0×107 (1.3×107, 3.0×108) vs. 3.1×106 (1.6×106, 6.1×106) copies /L, Z=15.23, P<0.001) were higher than that of plasma. Conclusions: In immunocompetent pediatric cases diagnosed as EBV primary infection, cases with positive plasma EBV DNA were prone to have fever, hepatomegaly and (or) splenomegaly, and elevated transaminase than those with negative plasma viral DNA. The plasma EBV DNA usually turns negative within 28 days after initial diagnosis.Most cases with high viral load in plasma showed elevated aminotransferase.

Global DNA Methylation Levels in Epstein-Barr-Virus-Positive Iraqi Patients with Acute Lymphoblastic Leukaemia

Acute lymphoblastic leukemia (ALL) is one of the commonest hematological malignancies affecting children and adults. Recent evidence suggests an involvement of Epstein-Barr virus (EBV) in ALL pathogenicity. Epigenetic aberration, especially altered DNA methylation marks, is a key event of cancer development. The present study aims to investigate how the ALL epimethylome reacts to viral infection through the assessment of the total 5-methylcytosine (5mC) levels in ALL patients, according to EBV infection. The 5mC global DNA methylation levels in 50 diagnosed ALL patients (age mean 26.23 yrs; age range 10-60 yrs) and 25 age-matched healthy controls were assessed using MethylFlash™ Methylated DNA Quantification Kit. Acute primary EBV infection in the studied subjects was detected by measuring Epstein-Barr Virus (EBNA-1) IgG levels using ELISA. The results showed a significant (P˂0.001) decrease in 5mC levels in ALL-EBV positive cases as compared to those who were negative for EBV infection (0.234±0.117 vs. 0.441±0.153, respectively). The reduction in the average 5mC level seemed to be negatively correlated with EBV viral load (r = -0.599, p= 0.001). Additionally, 5mC levels were able to distinguish between ALL main subtypes (B-ALL and T-ALL; derived from B or T lymphocytes), where T-ALL cases showed significantly (P=0.005) higher 5mC levels than those of B-ALL cases (0.587±0.070 vs. 0.180±0.092, respectively). Also significantly (P=0.04) lower 5mC levels were detected in Philadelphia chromosome-positive (Ph+) ALL cases than in those who were negative to this genetic abnormality (Ph- -ALL) (0.13±0.021 vs. 0.179±0.093, respectively). Overall, the findings of the present study suggest an involvement of EBV infection in ALL pathogenicity, with the potential of utilizing the differences in global DNA methylation levels in ALL patients' risk stratification.

Childhood infectious mononucleosis

Epstein-Barr virus (EBV) is a human herpesvirus that is ubiquitous in nature, and most of the world population is infected by it. Infectious Mononucleosis (IM) is the most common clinical syndrome caused by EBV. This study was conducted to valuate epidemiological and clinical features of Infectious Mononucleosis caused by EBV in children. In it were enrolled 107 children 0-14 years old hospitalized with the diagnosis of Infectious Mononucleosis. Children ranged from 8-months old to 12.5years old, median age was 4.74 years. Fever was the most prominent feature in 97% of cases followed by lymphadenitis and pharyngitis in 79% and 78% of cases. Hepatitis was found in 55% of children. Classic syndrome of Infectious Mononucleosis was more prevalent in older children. Conclusively the probability of developing Infectious Mononucleosis after primary EBV infection correlates with age, young children are often moderately ill, presenting with atypical or partial Infective Mononucleosis syndrome.

Claudin18.2 expression and clinicopathological features in cytology effusion specimens from gastric adenocarcinoma: Acomparative study with tissue specimens.

Zolbetuximab (IMAB362) is under investigation for treating advanced gastrointestinal tumors because it targets Claudin18.2 (CLDN18.2). CLDN18.2 is a promising molecule along with the presence of human epidermal growth factor receptor 2 in gastric cancer. This study evaluated cell block (CB) preparations of serous cavity effusions for the feasibility for CLDN18.2 protein expression and compared the results with those of biopsy or resection specimens. The association of CLDN18.2 expression in effusion samples and the clinicopathological features were also investigated. Cytological effusion specimens and matched surgical pathology biopsy or resection specimens of 43 gastric and gastroesophageal junctional cancer cases were stained for CLDN18.2 expression and quantified using immunohistochemistry based on the manufacturer's instructions. Positive staining was detected in 34 (79.1%) tissue and 27 (62.8%) effusion CB samples in this study. When "positivity" was defined as moderate-to-strong staining in ≥40% viable tumor cells, CLDN18.2 expression was observed in 24 (55.8%) tissue and 22 (51.2%) effusion CB samples. A cutoff of 40% for CLDN18.2 positivity was used to demonstrate high concordance (83.7%) between cytology CB and tissue specimens. The results showed that CLDN18.2 expression in effusion specimens correlated with tumor size (p=.021) but not with sex, age at diagnosis, primary tumor location, staging, Lauren phenotype, cytomorphologic features, or Epstein-Barr virus infection. Cytological effusions with or without CLDN18.2 expression did not significantly affect overall survival. This study's results show that serous body cavity effusions may be suitable for CLDN18.2 biomarker testing; however, discordant cases should be interpreted cautiously.

Epstein-Barr virus as a leading cause of multiple sclerosis: mechanisms and implications.

Epidemiological studies have provided compelling evidence that multiple sclerosis (MS) is a rare complication of infection with the Epstein-Barr virus (EBV), a herpesvirus that infects more than 90% of the global population. This link was long suspected because the risk of MS increases markedly after infectious mononucleosis (symptomatic primary EBV infection) and with high titres of antibodies to specific EBV antigens. However, it was not until 2022 that a longitudinal study demonstrated that MS risk is minimal in individuals who are not infected with EBV and that it increases over 30-fold following EBV infection. Over the past few years, a number of studies have provided clues on the underlying mechanisms, which might help us to develop more targeted treatments for MS. In this Review, we discuss the evidence linking EBV to the development of MS and the mechanisms by which the virus is thought to cause the disease. Furthermore, we discuss implications for the treatment and prevention of MS, including the use of antivirals and vaccines.

The influence of steroid therapy of complications of infectious mononucleosis on the course of Epstein-Barr virus hepatitis.

The purpose of the study was to characterize the differences in the course of Epstein-Barr virus (EBV) primary infection-induced hepatitis between patients treated with steroids due to complications of infectious mononucleosis (IM) and those not receiving such therapy. We analyzed the changes in the activity of liver enzymes and differences in abdominal ultrasound results. The study was based on reviewing the medical records of children hospitalized for primary EBV infection at the Department of Children's Infectious Diseases, Medical University of Warsaw, Regional Hospital of Infectious Diseases in Warsaw, between August 2017 and March 2023. The study population was divided into two groups: patients treated with steroids (Group 1) and children not receiving steroids (Group 2). Significant differences were obtained for alanine aminotransferase activity only in the first week of IM (205.34 ±115.40 vs. 288.82 ±170.16 IU/l for Group 1 and 2, respectively; p = 0.024), and for aspartate aminotransferase in the first (170.63 ±159.47 vs. 218.85 ±128.22 IU/l for Group 1 and 2, respectively; p = 0.009) and the third week (151.09 ±138.57 vs. 235.50 ±170.27 IU/l for Group 1 and 2, respectively; p = 0.016). The analysis of the results of laboratory tests for the diagnosis of cholestasis (γ-glutamyl transferase and total serum bilirubin concentrations with fractions) did not show significant differences between the groups. Our results indicated that the two cohorts of patients may differ in the course of hepatitis associated with primary EBV infection, especially at the beginning of the disease, when the laboratory features of hepatitis were less pronounced in children treated with steroids.

Razvoj produženog COVID-a kao posledice kompleksnog odnosa između Epštajn-Bar virusa i našeg imunskog sistema

Introduction: The pathophysiological development of long COVID (LC) is still insufficiently known. However, post infection fatigue syndromes were seen before, among other pathogens including Epstein-Barr virus (EBV). Considering EBV reservoir in COVID-19 patients, this review aims to present current knowledge related to EBV role in development of LC and with the potential diagnostic utility. EBV infection: Following the primary lytic infection of epithelial oropharyngeal and nasopharyngeal cells EBV establishes a very complex mechanism of lifelong survival in B cells. Latent infection with occasional viral reactivations constantly challenges the host's immune response. In individuals with immune imbalance including COVID-19, it could drive long-term consequences. EBV and COVID-19: The activity of EBV has been shown as the most prevalent human herpesvirus infection in COVID-19 population (41%). Correlation between lymphocytopenia-induced disability to remove the EBV, increases in EBV DNA viremia and COVID-19 complications have also been reported. EBV and long COVID: The positivity of EBV DNA during acute SARS-CoV-2 infection predicted the presence of symptoms up to 60 days after COVID-19. Association between EBV infection and symptoms such as brain fog, fatigue, arthralgia and skin rashes have been also described in post infection sequelae ME/CFS. Anti-EBV early antigen-diffuse (EA-D) IgG antibodies were detectable among two-thirds of respondents experiencing LC. Increases in anti-EBNA1 IgG levels analyzed months following COVID-19 onset in convalescent LC population could serve as a potential marker of EBV reactivation at the time of acute SARS-CoV-2 infection. Some authors also managed to show anti-EBV viral capsid antigen (VCA) IgM seropositivity in half of COVID-19 patients indicating of either coinfection or EBV reactivation. Conclusion: As a multisystemic illness, LC is without a defined spectrum of diagnostic and treatment options. Whereas EBV reactivation alone or together with other risk factors drives LC symptoms, further prospective studies involving different cohorts and tissue reservoirs are necessary to understand underlying biological mechanisms.

Descending Necrotizing Mediastinitis Caused by Streptococcus pyogenes in a Child with Primary Epstein–Barr Virus Infection

Descending necrotizing mediastinitis (DNM) is a severe, life-threatening disease with a high mortality rate resulting from sepsis or other complications. DNM can also be a rare and severe complication of Epstein-Barr virus (EBV) infection in adolescents and young adults but has never been reported in a pre-school child. A 4-year-old girl was admitted to our hospital with a 2-day history of fever and chest pain. Computed tomography (CT) revealed a right sided pleural effusion, fluid collection in the retropharyngeal and mediastinal areas, cervical lymphadenopathy, and marked hepatosplenomegaly. She was diagnosed with empyema, retropharyngeal abscess, and mediastinitis. To improve her dyspnea, a chest tube was inserted, and antibiotic treatment was initiated. Her condition improved temporarily, but on day 5 in our hospital, she developed a fever again. A repeat CT scan showed exacerbation of fluid retention in the retropharyngeal area and the mediastinum, for which she underwent drainage and debridement of necrotic tissue in the retropharynx and mediastinum. The presence of cervical lymphadenopathy and marked hepatosplenomegaly suggested the involvement of EBV. Serological tests for EBV revealed primary EBV infection at the time of the DNM onset. Finally, she was diagnosed with DNM following primary EBV infection. At follow-up 1 year later, she was doing well. The risk of DNM should be recognized in patients, even pre-school aged children, with primary EBV infection.

Ruxolitinib-induced reactivation of cytomegalovirus and Epstein-Barr virus in graft-versus-host disease

ObjectivesSteroid-refractory graft-versus-host disease (SR-GVHD) is a challenging complication of allogeneic hematopoietic stem cell transplantation, and leads to high morbidity and mortality rates. The orally administered, selective Janus-associated kinase 1/2 inhibitor ruxolitinib gives overall response rates (ORR) of more than 70 % in acute and chronic SR-GVHD. However, several studies have highlighted an elevated risk of cytomegalovirus (CMV) reactivation in patients with ruxolitinib-treated SR-GVHD. MethodsWe therefore analyzed risk of CMV and Epstein-Barr virus (EBV) primary infection or reactivation in 57 patients with ruxolitinib-treated GVHD, while taking account of the competing risk (CR) of death prior to the first reactivation. ResultsInitiation of ruxolitinib treatment was a significant adverse prognostic factor for the CR of first CMV reactivation (hazard ratio (HR)= 1.747, 95 % confidence interval (CI): 1.33–2.92, p < 0.0001) and first EBV reactivation (HR=2.657, 95 % CI: 1.82–3.87, p < 0.0001) during GVHD. In our cohort of ruxolitinib-treated patients, the ORR (48 % and 58 % for acute and chronic GVHD, respectively) and the toxicity profile (haematological adverse events in 29.8 % of the patients) were similar to the literature values. ConclusionGiven ruxolitinib’s efficacy in SR-GVHD, use of this drug should not be limited by the fear of viral reactivation; however, our present results emphasize the importance of monitoring the viral load.

ACUTE PRIMARY EPSTEIN-BARR VIRUS INFECTION IN 8-MONTH-OLD CHILD: CASE REPORT

This article highlights the difficulties in diagnosis and features of the course of acute primary Epstein-Barr virus infection in an infant. A clinical case of an 8-month-old child with this disease is presented. Primary infection with the Epstein-Barr virus in young children is often characterized by a subclinical course or may be asymptomatic. Peculiarities of acute primary Epstein-Barr virus infection in the child are manifested by purulent-necrotic angina, secondary thrombocytopenia, anaemia of the 1st degree (with minimal changes on the part of the lymph nodes, the absence of hepatosplenomegaly) under the dysfunction of the immune system (age-related immunodeficiency condition). The latter cause and the failure to obtain specific maternal antibodies with breast milk (the child is kept on artificial feeding) have resulted in the severe course of this disease. Immature adaptation mechanisms of the mucous membranes of children lead to the phenomena of dysbiosis in the form of an imbalance of different degrees of severity of the disease. The final diagnosis of the child is based on the isolation of Epstein-Barr virus DNA in the blood serum during the polymerase chain reaction. The child requires dynamic monitoring from a paediatrician and cardiologist that enables to select effective measures to manage the disease and to assess physical development.

Epstein–Barr virus-related dacryocystitis: a case report

Background and objectiveAcute 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 presentationA 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.DiscussionThis 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.ConclusionAcute 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.

PD-L1 is upregulated in CD163+ tonsillar macrophages from children undergoing EBV primary infection.

Epstein-Barr Virus (EBV) is a tumor associated virus that modulates not only the infected cells but also innate and adaptive immunity. Macrophages play a key role in tumor development and progression. Particularly, the M2 phenotype (CD163) with anti-inflammatory activity contributes to a favorable microenvironment for tumor development while the M1 (CD68) proinflammatory phenotype contributes to a restrictive one. In the context of pediatric EBV infection, little is known about macrophage contribution to PD-L1 expression, a molecule involved in immune exhaustion. We studied tonsils of primary infected (PI), healthy carriers (HC), reactivated (R), and not infected (NI) pediatric patients. Positive correlations were demonstrated for CD68+PD-L1+ in R and for CD163+PD-L1+ only in PI. Furthermore, CD163+PD-L1+ cell numbers were higher than PD-L1+CD68+ in PI patients. In addition, a positive correlation between PD-L1+CD163+ cells and LMP1 viral latent protein was observed in PI patients, and a positive correlation between PD-L1+CD68+ cells and BMRF1 lytic antigen was demonstrated. A positive correlation between TGF-β and PD-L1 expression was demonstrated in HC patients. Our findings indicate that EBV's lytic and latent antigens might be regulating macrophages' PD-L1 expression, particularly in PI patients, whereas, surprisingly, only TGF-β could be related to total PD-L1 upregulation. Given the relevance of macrophages and the PD-1/PD-L1 pathway in tumor progression and survival, more studies in early EBV infection could help to develop EBV-associated tumor therapies.

Siblings reduce multiple sclerosis risk by preventing delayed primary Epstein-Barr virus infection.

Epstein-Barr virus infection, and perhaps almost exclusively delayed Epstein-Barr virus infection, seems to be a prerequisite for the development of multiple sclerosis. Siblings provide protection against infectious mononucleosis by occasionally preventing delayed primary Epstein-Barr virus infection, with its associated high risk of infectious mononucleosis. Each additional sibling provides further protection according to the age difference between the index child and the sibling. The closer the siblings are in age, the higher the protection, with younger siblings being more protective against infectious mononucleosis than older siblings. If the hypothesis that delayed Epstein-Barr virus infection is necessary for the development of multiple sclerosis is true, then the relative risk of multiple sclerosis as a function of sibship constellation should mirror the relative risk of infectious mononucleosis as a function of sibship constellation. Such an indirect hypothesis test is necessitated by the fact that age at primary Epstein-Barr virus infection is unknown for practically all people who have not experienced infectious mononucleosis. In this retrospective cohort study using nationwide registers, we followed all Danes born during the period 1971-2018 (n = 2 576 011) from 1977 to 2018 for hospital contacts with an infectious mononucleosis diagnosis (n = 23 905) or a multiple sclerosis diagnosis (n = 4442), defining two different end points. Relative risks (hazard ratios) of each end point as a function of sibship constellation were obtained from stratified Cox regression analyses. The hazard ratios of interest for infectious mononucleosis and multiple sclerosis could be assumed to be identical (test for homogeneity P = 0.19), implying that having siblings, especially of younger age, may protect a person against multiple sclerosis through early exposure to the Epstein-Barr virus. Maximum protection per sibling was obtained by having a 0-2 years younger sibling, corresponding to a hazard ratio of 0.80, with a 95% confidence interval of 0.76-0.85. The corresponding hazard ratio from having an (0-2 years) older sibling was 0.91 (0.86-0.96). Our results suggest that it may be possible essentially to eradicate multiple sclerosis using an Epstein-Barr virus vaccine administered before the teenage years. Getting there would require both successful replication of our study findings and, if so, elucidation of why early Epstein-Barr virus infection does not usually trigger the immune mechanisms responsible for the association between delayed Epstein-Barr virus infection and multiple sclerosis risk.

Impact of Epstein-Barr virus infection in patients with inflammatory bowel disease.

A high prevalence of Epstein-Barr virus (EBV) infection in patients with inflammatory bowel disease (IBD) has been reported in many case reports and studies; thus, the association between EBV and IBD has gained increasing attention. Patients with IBD are at an increased risk of opportunistic EBV infection owing to the common use of immunomodulators. EBV infection in IBD patients can cause various complications, including superimposed viral colitis, which is associated with chronicity, exacerbation, and poor prognosis of refractory IBD, and can induce progression to lymphoproliferative disorders, such as EBV-positive mucocutaneous ulcer (EBVMCU), lymphomatoid granulomatosis (LYG), hemophagocytic lymphohistiocytosis (HLH) and diffuse large B-cell lymphoma (DLBCL). It has been suggested to screen for EBV before initiating immunosuppressive therapy and monitor the status of EBV infection in patients with IBD, especially those who are EBV-seronegative and have a risk of primary EBV infection. Clinicians should also be careful of misdiagnosing IBD and EBV-associated lymphoproliferative diseases due to similarities in both clinical symptoms and endoscopic manifestations. Withdrawal of immunosuppressants has been shown to be an effective strategy to achieve remission of disease at the time of EBV diagnosis, but antiviral therapy remains controversial. The present review aims to describe the characteristics of the complications caused by EBV infection and generalize the recent research progress on and challenges caused by EBV infection in IBD patients. The literature for writing this review was collected from 'PubMed' research engine. The keywords 'inflammatory bowel disease and Epstein-Barr virus' or 'ulcerative colitis and Epstein-Barr virus' or 'Crohn's disease and Epstein-Barr virus' were used to collect the literature and relevant papers were collected to help writing this review.

Host microRNAs are decreased in pediatric solid-organ transplant recipients during EBV+ Post-transplant Lymphoproliferative Disorder.

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. Predisposing factors include primary Epstein-Barr virus (EBV) infection, reactivation of EBV in recipient B cells, and decreased T cell immunity due to immunosuppression. In our previous studies EBV infection was demonstrated to markedly alter the expression of host B cell microRNA (miR). Specifically, miR-194 expression was uniquely suppressed in EBV+ B cell lines from PTLD patients and the 3’untranslated region of IL-10 was determined to be targeted by miR-194. Although EBV has been shown to regulate host miR expression in B cell lymphoma cell lines, the expression of miRs in the circulation of patients with EBV-associated PTLD has not been studied. The objective of this study was to determine if changes in miR expression are associated with EBV+ PTLD. In this study, we have shown that miR-194 is significantly decreased in EBV+PTLD tumors and that additional miRs, including miRs-17, 19 and 106a are also reduced in EBV+PTLD as compared to EBV-PTLD. We quantitated the levels of miRs-17, 19, 106a, 155, and 194 in the plasma and extracellular vesicles (EV; 50-70 nm as determined by nanoparticle tracking analysis) from pediatric recipients of solid organ transplants with EBV+ PTLD+ that were matched 1:2 with EBV+ PTLD- pediatric transplant recipients as part of the NIH-sponsored Clinical Trials in Organ Transplantation in Children, (CTOTC-06) study. Levels of miRs-17, 19, 106a, and 194 were reduced in the plasma and extracellular vesicles (EV) of EBV+ PTLD+ group compared to matched controls, with miRs-17 (p = 0.034; plasma), miRs-19 (p = 0.029; EV) and miR-106a (p = 0.007; plasma and EV) being significantly reduced. Similar levels of miR-155 were detected in the plasma and EV of all pediatric SOT recipients. Importantly, ~90% of the cell-free miR were contained within the EV supporting that EBV+ PTLD tumor miR are detected in the circulation and suggesting that EVs, containing miRs, may have the potential to target and regulate cells of the immune system. Further development of diagnostic, mechanistic and potential therapeutic uses of the miRs in PTLD is warranted.

Rapid antibody responses to Epstein-Barr virus correlate with reduced severity of primary infection.

We investigated Epstein-Barr virus (EBV) antibody kinetics in university freshmen who developed laboratory-documented primary EBV infection during prospective studies and correlated these kinetics with disease severity. EBV-naïve participants had blood collected periodically and sera tested for EBV-specific antibodies with line blot and enzyme immunoassays. The line blot assay contained EBNA-1, p18, p23, BZLF-1, p138, and p54 antigens; the enzyme immunoassay contained viral capsid antigen and EBNA-1. Severity of illness (SOI) was graded 0 (asymptomatic) to 6 (bedridden). Participants with maximum SOI scores 0-2 were compared with those whose maximum SOI scores were 3-6. Time to first antibody response was analyzed using the semi-parametric COX model. A total of 201 sera from 38 college students collected before, during, and after primary EBV infection were tested. Earlier antibody responses correlated with milder symptoms. This was most pronounced for late-developing antibodies. The median time to development of p18 IgG was significantly earlier among low-SOI participants (64 days) than high-SOI patients (119 days; P=0.0003).). Participants with mild disease developed EBNA-1 antibodies sooner than participants with more severe disease (125 days versus >270 days; P=0.017). Participants with mild disease also showed more rapid loss of antibodies against IgG EA p138 and p54 ≥12 weeks post-infection (P=0.012 and P=0.026, respectively). These data suggest that rapid antibody responses to EBV correlate with reduced severity of primary EBV infection.