Jennifer Carnahan

Chromosomal Integration of Human Herpesvirus 6 Is the Major Mode of Congenital Human Herpesvirus 6 Infection

OBJECTIVE. We examined the frequency and characteristics of chromosomally integrated human herpesvirus 6 among congenitally infected children. METHODS. Infants with and without congenital human herpesvirus 6 infection were prospectively monitored. Cord blood mononuclear cell, peripheral blood mononuclear cell, saliva, urine, and hair follicle samples were examined for human herpesvirus 6 DNA. Human herpesvirus 6 RNA, serum antibody, and chromosomally integrated human herpesvirus 6 levels were also assessed. RESULTS. Among 85 infants, 43 had congenital infections and 42 had postnatal infections. Most congenital infections (86%) resulted from chromosomally integrated human herpesvirus 6; 6 infants (14%) had transplacental infections. Children with chromosomally integrated human herpesvirus 6 had high viral loads in all sites (mean: 5–6 log10 genomic copies per μg of cellular DNA); among children with transplacental infection or postnatal infection, human herpesvirus 6 DNA was absent in hair samples and inconsistent in other samples, and viral loads were significantly lower. One parent of each child with chromosomally integrated human herpesvirus 6 who had parental hair samples tested had hair containing human herpesvirus 6 DNA. Variant A caused 32% of chromosomally integrated human herpesvirus 6 infections, compared with 2% of postnatal infections. Replicating human herpesvirus 6 was detected only among chromosomally integrated human herpesvirus 6 samples (8% of cord blood mononuclear cells and peripheral blood mononuclear cells). Cord blood human herpesvirus 6 antibody levels were similar among children with chromosomally integrated human herpesvirus 6, transplacental infection, and postnatal infection and between children with maternal and paternal chromosomally integrated human herpesvirus 6 transmission. CONCLUSIONS. Human herpesvirus 6 congenital infection results primarily from chromosomally integrated virus which is passed through the germ-line. Infants with chromosomally integrated human herpesvirus 6 had high viral loads in all specimens, produced human herpesvirus 6 antibody, and mRNA. The clinical relevance needs study as 1 of 116 newborns may have chromosomally integrated human herpesvirus 6 blood specimens.

Characteristics and Acquisition of Human Herpesvirus (HHV)–7 Infections in Relation to Infection with HHV-6

Although both human herpesvirus (HHV) 6 and HHV-7 infections are ubiquitous during childhood, few acute HHV-7 infections are identified. It is unknown whether HHV-7 viremia indicates primary infection, as with HHV-6, or reactivation, and if these differ clinically. We studied, in otherwise healthy children < or =10 years old, HHV-7 and HHV-6 infections and their interaction by serologic assessment, viral isolation, and polymerase chain reaction. In children < or =24 months of age, HHV-7 infections occurred less often than HHV-6 infections (P< or =.002). Of 2806 samples from 2365 children < or =10 years old, 30 (1%) showed evidence of HHV-7 viremia; 23 (77%) of these were primary and 7 (23%) were reactivated HHV-7 infections. Four (13%) showed concurrent HHV-6 viremia, 2 associated with primary HHV-7 infections. The clinical manifestations of primary and reactivated HHV-7 infections were similar, except that seizures occurred more frequently in reactivated infections. These findings, previously unrecognized in otherwise healthy children, suggest that HHV-7 viremia could represent primary or reactivated infection and may be affected by the interaction between HHV-6 and HHV-7.

Prenatal Maternal Anxiety Predicts Reduced Adaptive Immunity in Infants

Prenatal anxiety has been linked with altered immune function in offspring in animal studies, but the relevance for human health is unknown. We examined prenatal maternal anxiety as a predictor of adaptive immunity in infants at 2 and 6 months of age as part of a prospective longitudinal study. The humoral immune response to hepatitis B vaccine was assessed at 2 months (n=80) and 6 months (n=76) of age. Prenatal anxiety predicted lower hepatitis B antibody titers at 6 months of age independent of obstetric and socio-demographic covariates; the effects were limited to those infants who had not completed the 3-dose vaccine series (for transformed titer values, r=-.36, p<.05). Cell-mediated immune responses at 2 (n=56) and 6 (n=54) months of age were examined by ELISpot assays for interferon(IFN)-γ, interleukin(IL)-2, and IL-4 responder cell frequencies to three antigens: hepatitis B surface antigen, tetanus toxoid, and phytohaemagglutinin (PHA). Prenatal maternal anxiety was associated with reduced IFN-γ and increased IL-4 responder cell frequencies at 6 months of age, independent of obstetric and socio-demographic covariates. No effect of prenatal anxiety was found on adaptive immunity at 2 months of age. The findings provide the first demonstration in humans that prenatal anxiety alters adaptive immunity in the infant.

Diagnostic assays for active infection with human herpesvirus 6 (HHV-6)

BACKGROUND Human herpesvirus 6 (HHV-6) causes ubiquitous infection in early childhood with lifelong latency or persistence. Reactivation of HHV-6 has been associated with multiple diseases including encephalitis. Chromosomal integration of HHV-6 also occurs. Previous studies have suggested that the detection of HHV-6 DNA in plasma is an accurate marker of active viral replication. OBJECTIVE We sought to determine whether PCR assays on plasma could correctly differentiate between primary HHV-6 infection, chromosomal integration of HHV-6 and latent HHV-6 infection. STUDY DESIGN We performed qualitative PCR, real-time quantitative PCR (RQ-PCR), and reverse-transcriptase PCR (RT-PCR) assays on samples of peripheral and cord blood mononuclear cells, as well as plasma, from groups of subjects with well defined HHV-6 infection, including subjects with chromosomally integrated HHV-6. RESULTS AND CONCLUSIONS The detection of HHV-6 DNA in plasma was 92% sensitive compared to viral isolation for the identification of primary infection with HHV-6. All plasma samples from infants with chromosomally integrated HHV-6 had HHV-6 DNA detectable in plasma while only 5.6% were positive by RT-PCR. The specificity of plasma PCR for active replication of HHV-6 was 84% compared to viral culture while the specificity of RT-PCR was 98%. Our results demonstrate that qualitative or quantitative PCR of plasma is insufficient to distinguish between active viral replication and chromosomal integration with HHV-6. We found a higher specificity of RT-PCR performed on PBMC samples compared to PCR or RQ-PCR performed on plasma when evaluating samples for active HHV-6 replication.

Early Developmental Outcomes of Children With Congenital HHV-6 Infection

OBJECTIVE: The goal of this study was to determine if congenital human herpesvirus-6 (HHV-6) infection influences early neurodevelopment. METHODS: We enrolled 57 newborns with HHV-6 congenital infection and 242 control newborns without congenital infection into a prospective, double-blind study with 4 visits between 4 and 30 months of age. Assessments included the Fagan Test of Infant Intelligence, the Visual Expectation Paradigm, and the Mental Development Index (MDI) of the Bayley Scales of Infant Development II. Newborn audiology screening and follow-up audiology examinations were completed at 12 to 24 months. RESULTS: No differences were noted in baseline characteristics between infants with HHV-6 congenital infection and control infants. No clinical syndrome due to congenital infection with HHV-6 was evident at birth. No differences were identified on the Fagan Test of Infant Intelligence or the Visual Expectation Paradigm between the two groups. In 39 infants with HHV-6 congenital infection, the mean ± SD Bayley Scale of Infant Development II MDI score was 103.4 ± 8.9 at 12 months of age. The matched control infants had a mean score of 105.4 ± 12.4. After controlling for covariates, HHV-6 congenital infection was associated with lower scores on the Bayley Scale of Infant Development II MDI at 12 months of age (mean difference: 4.3 [95% confidence interval: 0.4 to 8.1]; P = .03) compared with infants without HHV-6 congenital infection. CONCLUSIONS: Congenital HHV-6 infection may have a detrimental effect on neurodevelopment at 12 months of age and requires further study given that congenital infection with HHV-6 is present in ∼1 in every 101 births.

Observed Parent-Child Relationship Quality Predicts Antibody Response to Vaccination in Children

BACKGROUND Quality of the parent-child relationship is a robust predictor of behavioral and emotional health for children and adolescents; the application to physical health is less clear. METHODS We investigated the links between observed parent-child relationship quality in an interaction task and antibody response to meningococcal conjugate vaccine in a longitudinal study of 164 ambulatory 10-11 year-old children; additional analyses examine associations with cortisol reactivity, BMI, and somatic illness. RESULTS Observed Negative/Conflict behavior in the interaction task predicted a less robust antibody response to meningococcal serotype C vaccine in the child over a 6 month-period, after controlling for socio-economic and other covariates. Observer rated interaction conflict also predicted increased cortisol reactivity following the interaction task and higher BMI, but these factors did not account for the link between relationship quality and antibody response. CONCLUSIONS The results begin to document the degree to which a major source of child stress exposure, parent-child relationship conflict, is associated with altered immune system development in children, and may constitute an important public health consideration.

Depressive symptoms and immune response to meningococcal conjugate vaccine in early adolescence.

Research findings in psychoneuroimmunology document reliable, bidirectional linkages among psychological processes, the nervous system, and the immune system. However, available data are based almost entirely on animal and adult human studies; the application to children and adolescents is uncertain. We capitalized on the experimental leverage provided by a routine vaccination to examine the link between mood symptoms and the immune response to a vaccine challenge in early adolescence. One hundred twenty-six 11-year-olds for whom vaccine response data were available were assessed at prevaccination and 4 weeks, 3 months, and 6 months following vaccination; self-report ratings of depression and anxiety as well as measures of psychosocial and somatic risk were assessed prior to vaccine response. Analyses indicated that childrens internalizing mood symptoms were associated with elevated and persistently higher antibody responses, with evidence extending to two of the four serogroups. The associations remained after controlling for multiple possible confounders (social class, body mass index, sleep, psychosocial risk, and pubertal status). The observed enhanced vaccine response associated with depressive and anxious symptoms in early adolescence may reflect an important developmental difference in immune system-brain interplay between adults and children, and it underscores the need for further developmental studies of psychoneuroimmunology.

Immune and neuroendocrine correlates of temperament in infancy

There is now a clear focus on incorporating, and integrating, multiple levels of analysis in developmental science. The current study adds to research in this area by including markers of the immune and neuroendocrine systems in a longitudinal study of temperament in infants. Observational and parent-reported ratings of infant temperament, serum markers of the innate immune system, and cortisol reactivity from repeated salivary collections were examined in a sample of 123 infants who were assessed at 6 months and again when they were, on average, 17 months old. Blood from venipuncture was collected for analyses of nine select innate immune cytokines; salivary cortisol collected prior to and 15 min and 30 min following a physical exam including blood draw was used as an index of neuroendocrine functioning. Analyses indicated fairly minimal significant associations between biological markers and temperament at 6 months. However, by 17 months of age, we found reliable and nonoverlapping associations between observed fearful temperament and biological markers of the immune and neuroendocrine systems. The findings provide some of the earliest evidence of robust biological correlates of fear behavior with the immune system, and identify possible immune and neuroendocrine mechanisms for understanding the origins of behavioral development.