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

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Abstract

Background

Several 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.

Methods

Serum antibodies to EBV (anti-VCA IgG) were measured in 530 participants from the ALSPAC cohort at age 4 years. 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.

Results

About 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.

Conclusions

Early-life exposure to EBV is associated with PE in adolescence, consistent with a role of infection/immune dysfunction in the aetiology of psychosis.

Introduction

A role for viral infection in the pathogenesis of schizophrenia was proposed nearly a century ago (Menninger, 1926). Recent longitudinal studies have linked serologically determined prenatal maternal infection with Herpes Simplex Virus type 2 (HSV-2) (Buka et al., 2001a, Buka et al., 2008, Mortensen et al., 2010), influenza (Brown et al., 2004a), or cytomegalovirus (CMV) (Blomstrom et al., 2012) with the risk of schizophrenia in adult offspring in some but not all cohorts (Brown et al., 2006, Mortensen et al., 2007); for a systematic review see Khandaker et al. (2013). Viral infection of the CNS during childhood has also been associated with the risk of adult psychotic illness (Rantakallio et al., 1997, Dalman et al., 2008, Khandaker et al., 2012). Epstein-Barr Virus (EBV) is a member of the Herpesviridae family, and is potentially neurotropic (Schmutzhard, 2001). However, studies of EBV and psychiatric risk are limited. Two cross-sectional studies have reported increased sero-prevalence of EBV in psychiatric disorders (Gotlieb-Stematsky et al., 1981) including schizophrenia (Delisi et al., 1986). Recently, an association between EBV sero-positivity and self-reported psychotic experiences (PE) in adolescents has also been reported (Wang et al., 2011). However, longitudinal studies of EBV and subsequent risk of psychotic outcomes are lacking.

Early-life PE may be important antecedents of adult schizophrenia. Population-based birth cohort studies have reported a substantially increased risk of adult psychotic illness among individuals reporting PE during childhood/adolescence (Poulton et al., 2000, Zammit et al., 2013). Early-life PE are also associated with a number of risk factors for schizophrenia (Horwood et al., 2008, Thomas et al., 2009, Zammit et al., 2009). Thus, it has been suggested that studying these experiences may help to elucidate the pathophysiology of adult psychotic disorders (Kelleher and Cannon, 2011, Murray and Jones, 2012). The neurodevelopmental hypothesis of schizophrenia posits abnormal brain development as a cause of this illness (Murray and Lewis, 1987, Weinberger, 1987). Identification of a linear relationship between IQ deficit in the premorbid period and future risk of schizophrenia is a key piece of evidence underpinning a developmental aspect to the disorder (Jones et al., 1994, David et al., 1997, Khandaker et al., 2011). IQ deficit is present in different stages of schizophrenia and is one of the most important predictors of functional outcome (Gold et al., 2002). Longitudinal studies have also found cognitive deficits in children who report PE subsequently in childhood/adolescence (Horwood et al., 2008, Polanczyk et al., 2010, Niarchou et al., 2013).

Early-life infection is a plausible candidate for neurodevelopmental insult. Therefore, it possible that infection leads to IQ deficit, which in turn increase subsequent risk of psychotic outcomes. Such an explanatory model would view IQ deficit as a risk mediator. This is consistent with the evidence linking exposure to HSV-1 with cognitive dysfunction both in schizophrenia (Dickerson et al., 2003) and healthy individuals (Watson et al., 2012). Alternatively, IQ deficit may arise from the interplay between infection and psychosis risk. This is in line with a previous study reporting lower childhood verbal IQ in prenatal maternal influenza-exposed cases of adult schizophrenia, compared with the unexposed cases (Ellman et al., 2009). Therefore, studies of early-life infection, subsequent IQ, and PE may help to elucidate the underlying pathways to schizophrenia or cognitive dysfunctions that are integral parts of the disorder. To our knowledge, no general population longitudinal study has examined whether childhood neurocognitive deficit associated with early-life infection mediate the risk of subsequent PE.

Using data from the general population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, we report associations between serologically confirmed exposure to EBV at age 4 years, IQ at age 9 years, and risk of PE at age 13 years. We predicted that EBV exposure would be associated with subsequent PE, and IQ deficit would explain this association.

Section snippets

Sample selection

The ALSPAC birth cohort comprises 14,062 live births from pregnant women resident in the county of Avon, a geographically defined region in the southwest of England, with expected dates of delivery between April 1991 and December 1992 (www.bristol.ac.uk/alspac/). Parents have completed regular postal questionnaires about all aspects of their child's health and development from birth. Since age 7, the children have attended an annual assessment clinic during which they participate in a range of

Results

Out of 530 children assessed, 134 (25.3%) were seropositive to EBV at age 4 years. There was no significant difference in socio-demographic characteristics between those exposed and unexposed to EBV (Table 1).

Discussion

Findings from this population-based longitudinal study suggest that serologically confirmed EBV infection in early childhood, as measured by the presence of anti-VCA IgG in serum is associated with definite PE in adolescence. This is independent of a number of potential socio-demographic confounders as well as household crowding, concurrent depression and anxiety. To our knowledge, this is the first longitudinal study linking exposure to EBV with subsequent risk of psychotic outcomes. Thus, the

Role of funding source

This study was funded through a doctoral clinical research training fellowship awarded to Golam Khandaker from the Wellcome Trust (PhD Programme Clinicians, Cambridge Institute of Medical Research, grant number 094790/Z/10/Z). Dr Zammit holds a Clinician Scientist Award from the National Assembly for Wales. Professor Jones is supported by the Wellcome Trust (095844/Z/11/Z & 088869/Z/09/Z), and NIHR (RP-PG-0606-1335), which also supports Dr Stochl. The UK Medical Research Council (Grant ref:

Contributors

GMK designed the study, analysed data and wrote the first draft. JS contributed to data analysis and revision of the draft. SZ contributed to data collection, analysis, and revision of the draft. GL and PBJ contributed to study design, analysis, revision, and provided overall supervision for the study.

Conflict of interest

None of the authors has any conflicts of interest to declare. Professor Peter Jones is a co-inventor on patent PCT/GB2005/003279 (methods for assessing psychotic disorders), and received research support from GlaxoSmithKline 2006–2010. He directs the National Institute for Health Research Collaborations for Leadership in Applied Health Research and Care for Cambridgeshire and Peterborough (CLAHRC-CP) of which this work forms part.

Acknowledgement

We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, including interviewers, computer and laboratory technicians, clerical workers, research scientists, statisticians, volunteers, managers, receptionists and nurses.

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