Epstein-Barr Virus Infection In Childhood Research Articles

Gene–environment interactions: Epstein–Barr virus infection and risk of pediatric-onset multiple sclerosis

Background and Objective: Prior Epstein–Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother’s education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). Results: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). Conclusion: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.

Childhood Epstein-Barr Virus infection and subsequent risk of psychotic experiences in adolescence: A population-based prospective serological study

BackgroundSeveral studies suggest a link between early-life infection and adult schizophrenia. Cross-sectional studies have reported: (1) increased prevalence of Epstein-Barr Virus (EBV), a member of the Herpesviridae family in schizophrenia; (2) a possible role of Herpes simplex virus in cognitive dysfunction in schizophrenia and healthy controls. We report a longitudinal serological study of early-life EBV infection, childhood IQ, and subsequent risk of psychotic experiences (PE) in adolescence. MethodsSerum antibodies to EBV (anti-VCA IgG) were measured in 530 participants from the ALSPAC cohort at age 4years. Assessments for IQ at age 9 and PE at age 13 were attended by 401 and 366 of these individuals, respectively. Logistic regression calculated odds ratio (OR) for PE in EBV-exposed, compared with unexposed group. Mean IQ scores were compared between these groups; effect of IQ on the EBV–PE association was examined. Potential confounders included age, gender, ethnicity, social class, household crowding, and concurrent depression and anxiety. ResultsAbout 25% of the sample was exposed to EBV at age 4. EBV exposure was associated with subsequent risk of definite PE in adolescence; OR 5.37 (95% CI 1.71–16.87), which remained significant after confounding adjustment. EBV-exposed individuals compared with unexposed performed worse on all IQ measures; mean difference in full-scale IQ 4.15 (95% CI 0.44–7.87); however, this was explained by socio-demographic differences. The EBV–PE association was not explained by IQ. ConclusionsEarly-life exposure to EBV is associated with PE in adolescence, consistent with a role of infection/immune dysfunction in the aetiology of psychosis.

The changing epidemiology of infectious mononucleosis?

Infectious mononucleosis is an acute and self-limited infection of the lymphatic system caused in over 90% of cases by a primary infection with Epstein-Barr virus (EBV), a member of the herpes virus group [1]. Infection during childhood is usually subclinical, whereas infection of adults results in infectious mononucleosis in 30± 75% of cases and can prove severe [2,3]. EBV infection in childhood is associated with low socioeconomic status, poor hygiene and crowding so that improved housing and decreasing family sizes may have resulted in a change in the epidemiology of EBV and therefore infectious mononucleosis [4,5]. To investigate this possibility we reviewed historical data of general practitioner (GP) consultations and hospitalisations in England and Wales over thirty years. Data on age-specific consultation rates for infectious mononucleosis in England and Wales were obtained from the Royal College of General Practitioners (RCGP) sentinel surveillance reports [6]. The surveillance programme is based on clinical diagnoses and uses a sample of practitioners throughout England and Wales which currently covers a population of over 600,000. Data for the calendar years 1989±1998 were extracted from the Hospitalisation Episode Statistics (HES, Department of Health) database that records every inpatient admission to National Health Service hospitals in England. Cases of infectious mononucleosis were identified using the International Classification Disease Codes 075* (ICD-9 up until 1995) and B27* (ICD-10 from 1996 onwards). The ICD-9 code 075* did not distinguish between different viral causes of infectious mononucleosis. For consistency, from 1996 onwards the ICD-10 code B27* was used which included infectious mononucleosis from EBV, cytomegalovirus (CMV), other viral causes and unspecified types. However, in practice

Life course epidemiology and infectious diseases

There has been a traditional view that divided epidemiology into infectious and chronic diseases. Since we now know that at least 15% of cancers worldwide are caused by infections, 1 that infections frequently have a natural history lasting decades and that the same epidemiological methods can be applied to both infectious and non-infectious diseases, this view can be considered purely historical. However, the nature of infectious diseases has implications for the application of epidemiological approaches including the specific example of life course epidemiology. Whilst the definition of this is still debated, it clearly refers to the way in which influences at different stages of life affect and modify risks of disease. Life course epidemiology particularly focuses on disease in adult life and so that is what we discuss here. We are not going to consider childhood or adolescent diseases. In addition it recognizes two types of influence on risk: (1) a simple accumulation of risks and (2) ‘programming’. 2 The latter is the way in which an influence modifies a biological system so that it responds differently to subsequent exposures. The epidemiological paradigm for this has been David Barker’s hypothesis that intra-uterine nutrition determines physiological responses in the cardiovascular system. 3 When we come to talk about infections we have to deal with a few semantics. Susceptibility means that the subject is vulnerable to infection if they are exposed. Infants may not be susceptible because of transferred immunity from their mother. Many, but not all, infections result in a loss of susceptibility due to immune memory. Exposure is traditionally used to define exposure to the infectious agent. We will use it in that context here and use the term ‘influence’ for non-agent exposures. There is a critical difference between infection and disease. The proportion of individuals infected who develop disease varies from 0% (as with infection with the hepatitis G virus) to virtually 100% (with measles and the human immunodeficiency virus [HIV]) depending on the infection. However, for many infections the relationship is strongly dependent on the age at which infection occurs—an obvious entree for life course epidemiology. Thus Epstein-Barr virus infection in childhood hardly causes any symptoms whereas in adolescence it results in glandular fever. Severity and rate of disease progression are also influenced by age at infection. Hepatitis A becomes an increasingly severe disease the older the subject. We return to this point below. Finally, we use the term ‘reactivation’ for persistent infections that produce disease after a prolonged period of latency following a first disease episode. Varicella zoster virus remains latent for years following chickenpox until around a fifth of infected people develop shingles. The simple model in Figure 1 shows how influences may affect various stages of the process. This emphasises proximate biological factors. Clearly there are more distal factors that may be more easily measured. For example, exposure to the infectious agent is highly dependent on behaviour—mixing patterns with other young children may determine exposure to childhood infections and sexual activity modulates risk of sexually transmitted infections. The timing from susceptibility to disability, death or recovery is incredibly variable. With many infections that do not persist, symptoms of disease occur, if they are going to, within days—at most months—after initial infection. Agents, such as hepatitis B and C viruses, that persist and replicate within the body may not lead to disease (in this case primary liver cancer) until 50 years after infection. Once infectious disease is recognized the natural history is as variable as that of non-communicable diseases. The reasons for all this variation are the influences at each stage.

Brain-Stem Encephalitis Caused by Epstein-Barr Virus

A case of brain-stem encephalitis with strong serologic evidence of acute Epstein-Barr virus infection is described. Recovery was rapid without treatment, but mild neurologic sequelae were seen at 6-month follow-up. Epstein-Barr virus infection in childhood may be asymptomatic and heterophil antibody negative. Encephalitis is an unusual but well-recognized complication of Epstein-Barr virus infection, but localized brain-stem involvement, to our knowledge, has not been previously described.

A Study on Hematological and Immunological Disorders in 2 Cases with Chronic Active Epstein-Barr Virus Infection in Childhood

A Study on Hematological and Immunological Disorders in 2 Cases with Chronic Active Epstein-Barr Virus Infection in Childhood

Aspects of Epstein-Barr virus infection in childhood.

Antibodies to Epstein-Barr (EB) virus capsid antigen and EB virus complement fixing antibodies were estimated in sera from 23 children and 27 young adults with infectious mononucleosis, and in 79 control patients. Complement fixing antibodies, but not those to virus capsid antigen, were much lower in patients tested during acute infectious mononucleosis than in controls. It is suggested that this disparity could form the basis of a diagnostic test. Anomalous results, in which the EB virus antibody pattern suggested active infection though heterophile antibodies and/or abnormal white blood cells were absent, were observed in sera from patients of all ages but the majority were aged 5 years or less. The proportion of sera with EB virus antibodies increased throughout childhood, suggesting that infection with this virus is relatively frequent in this age group and may often be unrecognized.