A genome-wide integrative genomic study localizes genetic factors influencing antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA-1).

Infection with Epstein-Barr virus (EBV) is highly prevalent worldwide, and it has been associated with infectious mononucleosis and severe diseases including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal lymphoma, and lymphoproliferative disorders. Although EBV has been the focus of extensive research, much still remains unknown concerning what makes some individuals more sensitive to infection and to adverse outcomes as a result of infection. Here we use an integrative genomics approach in order to localize genetic factors influencing levels of Epstein Barr virus (EBV) nuclear antigen-1 (EBNA-1) IgG antibodies, as a measure of history of infection with this pathogen, in large Mexican American families. Genome-wide evidence of both significant linkage and association was obtained on chromosome 6 in the human leukocyte antigen (HLA) region and replicated in an independent Mexican American sample of large families (minimum p-value in combined analysis of both datasets is 1.4×10(-15) for SNPs rs477515 and rs2516049). Conditional association analyses indicate the presence of at least two separate loci within MHC class II, and along with lymphocyte expression data suggest genes HLA-DRB1 and HLA-DQB1 as the best candidates. The association signals are specific to EBV and are not found with IgG antibodies to 12 other pathogens examined, and therefore do not simply reveal a general HLA effect. We investigated whether SNPs significantly associated with diseases in which EBV is known or suspected to play a role (namely nasopharyngeal lymphoma, Hodgkin lymphoma, systemic lupus erythematosus, and multiple sclerosis) also show evidence of associated with EBNA-1 antibody levels, finding an overlap only for the HLA locus, but none elsewhere in the genome. The significance of this work is that a major locus related to EBV infection has been identified, which may ultimately reveal the underlying mechanisms by which the immune system regulates infection with this pathogen.

Oral acyclovir suppression and neurodevelopment after neonatal herpes.

BACKGROUND: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Neonatal herpes disease following maternal antenatal antiviral suppressive therapy: a multicenter case series.

OBJECTIVE: The goal was to describe herpes simplex virus (HSV) disease in neonates whose mothers received suppressive acyclovir therapy for HSV infection. STUDY DESIGN: A multicenter case series of 8 infants who developed neonatal HSV disease following maternal antiviral suppressive therapy during pregnancy. RESULTS: Eight infants were identified from New Jersey (5), Maine (1), New York (1), and Texas (1) between 2005 and 2009. All 6 mothers of infants infected with HSV who were screened prenatally for group B Streptococcus were positive; 1 mother was not tested and the other had bacterial vaginosis and genital human papillomavirus infection. Six mothers had a first clinical episode of genital HSV infection during this pregnancy; mothers with a prior history of genital HSV had no clinically recognized outbreak during the pregnancy. Perinatal transmission of HSV occurred in 7 infants (despite suppressive therapy until the day of delivery in 5 instances). Seven of 8 patients were born at term; 6 infants were male. In 7 of 8 cases, HSV was diagnosed by 8 days of age. Five infants had skin, eye, and mucous membrane disease, 2 had central nervous system disease (without and with disseminated disease), and one had intrauterine/disseminated disease. CONCLUSIONS: Although maternal antiviral suppressive therapy is an increasingly wide practice, physicians caring for neonates should be aware that suppressive therapy does not prevent neonatal HSV disease, which can have an atypical clinical presentation and drug resistance.

Genetic factors influence serological measures of common infections.

BACKGROUND/AIMS: Antibodies against infectious pathogens provide information on past or present exposure to infectious agents. While host genetic factors are known to affect the immune response, the influence of genetic factors on antibody levels to common infectious agents is largely unknown. Here we test whether antibody levels for 13 common infections are significantly heritable. METHODS: IgG antibodies to Chlamydophila pneumoniae, Helicobacter pylori, Toxoplasma gondii, adenovirus 36 (Ad36), hepatitis A virus, influenza A and B, cytomegalovirus, Epstein-Barr virus, herpes simplex virus (HSV)-1 and -2, human herpesvirus-6, and varicella zoster virus were determined for 1,227 Mexican Americans. Both quantitative and dichotomous (seropositive/seronegative) traits were analyzed. Influences of genetic and shared environmental factors were estimated using variance components pedigree analysis, and sharing of underlying genetic factors among traits was investigated using bivariate analyses. RESULTS: Serological phenotypes were significantly heritable for most pathogens (h(2) = 0.17-0.39), except for Ad36 and HSV-2. Shared environment was significant for several pathogens (c(2) = 0.10-0.32). The underlying genetic etiology appears to be largely different for most pathogens. CONCLUSIONS: Our results demonstrate, for the first time for many of these pathogens, that individual genetic differences of the human host contribute substantially to antibody levels to many common infectious agents, providing impetus for the identification of underlying genetic variants, which may be of clinical importance.

Novel Brain-Penetrating Oxime Acetylcholinesterase Reactivators Attenuate Organophosphate-Induced Neuropathology in the Rat Hippocampus.

Organophosphate (OP) anticholinesterases cause excess acetylcholine leading to seizures which, if prolonged, result in neuronal damage in the rodent brain. Novel substituted phenoxyalkyl pyridinium oximes have previously shown evidence of penetrating the rat blood-brain barrier (BBB) in in vivo tests with a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the active metabolite of the insecticide parathion, paraoxon (PXN), by reducing the time to cessation of seizure-like behaviors and accumulation of glial fibrillary acidic protein, whereas 2-PAM did not. The neuroprotective ability of our lead oximes (15, 20, and 55) was tested using NeuN, Nissl, and Fluoro-Jade B staining in the rat hippocampus. Following lethal-level subcutaneous challenge with NIMP or PXN, rats were intramuscularly administered a novel oxime or 2-PAM plus atropine and euthanized at 4 days. There were statistically significant increases in the median damage scores of the NeuN-stained NIMP, NIMP/2-PAM, and NIMP/Oxime 15 groups compared with the control whereas the scores of the NIMP/Oxime 20 and NIMP/Oxime 55 were not significantly different from the control. The same pattern of statistical significance was observed with PXN. Nissl staining provided a similar pattern, but without statistical differences. Fluoro-Jade B indicated neuroprotection from PXN with novel oximes but not with 2-PAM. The longer blood residence times of Oximes 20 and 55 compared with Oxime 15 might have contributed to their greater efficacy. These results suggest that novel oximes 20 and 55 were able to penetrate the BBB and attenuate neuronal damage after NIMP and PXN exposure, indicating potential broad-spectrum usefulness.

Genome-wide genetic investigation of serological measures of common infections.

Populations and individuals differ in susceptibility to infections because of a number of factors, including host genetic variation. We previously demonstrated that differences in antibody titer, which reflect infection history, are significantly heritable. Here we attempt to identify the genetic factors influencing variation in these serological phenotypes. Blood samples from >1300 Mexican Americans were quantified for IgG antibody level against 12 common infections, selected on the basis of their reported role in cardiovascular disease risk: Chlamydia pneumoniae; Helicobacter pylori; Toxoplasma gondii; cytomegalovirus; herpes simplex I virus; herpes simplex II virus; human herpesvirus 6 (HHV6); human herpesvirus 8 (HHV8); varicella zoster virus; hepatitis A virus (HAV); influenza A virus; and influenza B virus. Pathogen-specific quantitative antibody levels were analyzed, as were three measures of pathogen burden. Genome-wide linkage and joint linkage and association analyses were performed using ~1 million SNPs. Significant linkage (lod scores >3.0) was obtained for HHV6 (on chromosome 7), HHV8 (on chromosome 6), and HAV (on chromosome 13). SNP rs4812712 on chromosome 20 was significantly associated with C. pneumoniae (P=5.3 × 10(-8)). However, no genome-wide significant loci were obtained for the other investigated antibodies. We conclude that it is possible to localize host genetic factors influencing some of these antibody traits, but that further larger-scale investigations will be required to elucidate the genetic mechanisms contributing to variation in antibody levels.

Methicillin-resistant Staphylococcus aureus infection in the Texas prison system.

Recent reports indicate that correctional facility inmates may be at elevated risk for contracting methicillin-resistant Staphylococcus aureus (MRSA) infection because of overcrowding, poor hygiene, and high rates of diseases causing immunosuppression. The present study of 299,179 Texas inmates who were incarcerated between 1999-2001 indicated an incidence of 12 MRSA infections/1000 person-years. Inmates with circulatory disease, cardiovascular disease, diabetes, end-stage liver disease, end-stage renal disease, human immunodeficiency virus infection or acquired immunodeficiency syndrome, and skin diseases all exhibited elevated rates of MRSA infection.

Human herpesvirus 6 and cytomegalovirus infections in children with human immunodeficiency virus infection and cancer.

AIM: Measure the prevalence of human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) infections in children and adolescents with HIV infection and malignancy. METHODS: Semiquantitative polymerase chain reaction and serology were used to test for HHV-6 and CMV infections in 31 cases (HIV-infected children with cancer), 56 HIV controls (HIV-infected children without cancer) and 30 cancer controls (HIV-uninfected children with cancer). RESULTS: In cases, HIV controls and cancer controls, HHV-6 DNA was detected in 29, 39 and 34%, respectively, and CMV DNA was detected in 13, 4 and 7%, respectively. Four cases (13%) and no HIV controls or cancer controls harbored HHV-6 subtype A (P = 0.014). In cases, HIV controls and cancer controls, the prevalence of HHV-6 antibodies was 58, 68 and 93%, respectively, and the prevalence of CMV antibodies was 71, 48 and 70%, respectively. HHV-6 seroprevalence was lower in cases than in cancer controls (P = 0.002), even with adjustments for age and CD4 concentrations; however, HHV-6 infection rates (presence of HHV-6 DNA and/or HHV-6 antibodies) were similar in all groups. Stratification showed that CMV infection was more common in younger patients (ages < 8 years) without severe immune suppression (CD4 concentration >200 cells/microl) than in HIV controls (odds ration, 10.343; 95% confidence interval, 1.65, 121.57). Geometric mean titers of serum anti-CMV antibodies, but not anti-HHV-6 antibodies, were higher in cases (1:71) than in HIV controls (1:33) (P = 0.005). CONCLUSIONS: HHV-6 and CMV infections were common among children with HIV infection and cancer. CMV seropositivity also was associated with cancer in younger HIV-infected patients who did not have severe immune suppression. HHV-6A was detected only in HIV-infected children with cancer.

The association of neoplasms and HIV infection in the correctional setting.

HIV-associated immunosuppression has been linked to an increased risk of a number of cancers, including Kaposi sarcoma (KS), non-Hodgkin's lymphoma (NHL), and invasive cervical cancer. Because prison inmates constitute one of the highest HIV/AIDS prevalent populations in the US, understanding the link between HIV infection and cancer in the correctional setting holds particular public health relevance. The study population consisted of 336,668 Texas Department of Criminal Justice inmates who were incarcerated, for any duration, between 1 January 1999 and 31 December 2001. Inmates diagnosed with HIV infection exhibited elevated rates of KS, NHL, anal cancer, and Hodgkin's disease, after adjusting for age and race. The elevated rates of cancer among HIV-infected individuals, particularly prison inmates, may be mediated, in part, by high-risk behaviours. HIV-associated risk behaviours, including unsafe sexual practices, injection drug use, and prostitution may be associated with cancer-related risk behaviours, such as smoking, excessive alcohol consumption, and poor diet. It will be important for future investigators to examine the association between HIV infection and cancer risk with sufficiently large study cohorts and appropriate longitudinal designs.

Long-term changes in adiposity and glycemic control are associated with past adenovirus infection.

OBJECTIVE: Ad36, a human adenovirus, increases adiposity but improves glycemic control in animal models. Similarly, natural Ad36 infection is cross-sectionally associated with greater adiposity and better glycemic control in humans. This study compared longitudinal observations in indices of adiposity (BMI and body fat percentage) and glycemic control (fasting glucose and insulin) in Ad36-infected versus uninfected adults. RESEARCH DESIGN AND METHODS: Baseline sera from Hispanic men and women (n = 1,400) were screened post hoc for the presence of Ad36-specific antibodies. Indices of adiposity and glycemic control at baseline and at ~10 years past the baseline were compared between seropositive and seronegative subjects, with adjustment for age and sex. In addition to age and sex, indices of glycemic control were adjusted for baseline BMI and were analyzed only for nondiabetic subjects. RESULTS: Seropositive subjects (14.5%) had greater adiposity at baseline, compared with seronegative subjects. Longitudinally, seropositive subjects showed greater adiposity indices but lower fasting insulin levels. Subgroup analyses revealed that Ad36-seropositivity was associated with better baseline glycemic control and lower fasting insulin levels over time in the normal-weight group (BMI ≤25 kg/m(2)) and longitudinally, with greater adiposity in the overweight (BMI 25-30 kg/m(2)) and obese (BMI >30 kg/m(2)) men. Statistically, the differences between seropositive and seronegative individuals were modest in light of the multiple tests performed. CONCLUSIONS: This study strengthens the plausibility that in humans, Ad36 increases adiposity and attenuates deterioration of glycemic control. Panoptically, the study raises the possibility that certain infections may modulate obesity or diabetes risk. A comprehensive understanding of these under-recognized factors is needed to effectively combat such metabolic disorders.

Seroprevalence of 13 common pathogens in a rapidly growing U.S. minority population: Mexican Americans from San Antonio, TX.

BACKGROUND: Infection risks vary among individuals and between populations. Here we present information on the seroprevalence of 13 common infectious agents in a San Antonio-based sample of Mexican Americans. Mexican Americans represent the largest and most rapidly growing minority population in the U.S., and they are also considered a health disparities population. METHODS: We analyzed 1227 individuals for antibody titer to Chlamydophila pneumoniae, Helicobacter pylori, Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, herpes simplex virus-1, herpes simplex virus-2 (HSV-2), human herpesvirus-6 (HHV-6), varicella zoster virus (VZV), adenovirus-36, hepatitis A virus, and influenza A and B. Seroprevalence was examined as a function of sex, age, household income, and education. RESULTS: Seroprevalence estimates ranged from 9% for T. gondii to 92% for VZV, and were similar in both sexes except for HSV-2, which was more prevalent in women. Many pathogens exhibited a significant seroprevalence change over the examined age range (15-94 years), with 7 pathogens increasing and HHV-6 decreasing with age. Socioeconomic status significantly correlated with serostatus for some pathogens. CONCLUSIONS: Our findings demonstrate substantial seroprevalence rates of these common infections in this sample of Mexican Americans from San Antonio, Texas that suffers from high rates of chronic diseases including obesity and type-2 diabetes.

Safety of oseltamivir compared with the adamantanes in children less than 12 months of age.

BACKGROUND: When oseltamivir is administered in extremely high doses (500-1000 mg/kg) to young juvenile rats, central nervous system toxicity and death occurred in some animals. Mortality was not observed in older juvenile rats, suggesting a possible relationship between neurotoxicity and an immature blood-brain barrier. To assess potential neurologic adverse effects of oseltamivir use in infants, a retrospective chart review was performed in infants less than 12 months of age who received oseltamivir, amantadine, or rimantadine. METHODS: The primary objective was to describe the frequency of neurologic adverse events among children less than 12 months of age who received oseltamivir compared with those receiving adamantanes. Medical record databases, emergency department databases, and/or pharmacy records at 15 medical centers were searched to identify patients. RESULTS: Of the 180 infants identified as having received antiviral therapy, 115 (64%) received oseltamivir, 37 (20%) received amantadine, and 28 (16%) received rimantadine. The median dose of oseltamivir was 2.0 mg/kg/dose in 3- to 5-month-old and 2.2 mg/kg/dose in 9- to 12-month-old infants. The maximum dose administered was 7.0 mg/kg/dose. There were no statistically significant differences in the occurrence of adverse neurologic events during therapy among subjects treated with oseltamivir versus those treated with the adamantanes (P = 0.13). CONCLUSIONS: This is the largest report to date of oseltamivir use in children less than 12 months of age. Neurologic events were not more common with use of oseltamivir compared with that of the adamantanes. Dosing of oseltamivir was variable, illustrating the need for pharmacokinetic data in this younger population.

Performance of two commercial glycoprotein G-based enzyme immunoassays for detecting antibodies to herpes simplex viruses 1 and 2 in children and young adolescents.

In 61 patients 1 to 14 years of age, the Gull/Meridian enzyme-linked immunosorbent assay (ELISA) had a sensitivity of 100% for herpes simplex virus type 1 (HSV-1) and specificities of 74% for HSV-1 and 48% for HSV-2. In 128 similarly aged patients, the HerpeSelect ELISA (Focus Technologies) showed sensitivities of 80% for HSV-1 and 88% for HSV-2, and specificities of 97% for HSV-1 and 100% for HSV-2.

High prevalence of human herpesvirus 8 (HHV-8) infection in south Texas children.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus, is etiologically associated with Kaposi's sarcoma and other rare malignancies. HHV-8 infection is common in certain areas of Africa and Italy, but occurs in only 0-15% of populations in North America and Europe. The epidemiology and prevalence of HHV-8 infection among children in the United States has not been determined, but is assumed to be low based on limited studies. The objective of this study was to determine the seroprevalence and possible risk factors of HHV-8 infection in children living in south Texas. Questionnaire data were collected and HHV-8 serologic tests were performed from a consecutive, non-probability sample of 123 healthy children (ages 4-13 years) attending general pediatric clinics in south Texas. Serum was tested for HHV-8 antibodies by latent immunofluorescence assay and ORF65 enzyme-linked immunosorbent assay confirmed by immunoblot. HHV-8 prevalence and 95 percent confidence intervals were calculated using standard epidemiologic methods. Logistic regression was used to assess independent risk factors associated with HHV-8 seropositivity. The overall prevalence of HHV-8 infection was 26%. No statistically significant associations were exhibited between HHV-8 prevalence and the variables under study. The prevalence of HHV-8 infection among children in south Texas, particularly among those under the age of 12 years, indicates that non-sexual transmission of this virus is likely to occur among this population. Future investigations of larger study samples will be necessary to develop an understanding of specific routes and risk factors of HHV-8 transmission among children in south Texas.

The infectious disease profile of Texas prison inmates.

PURPOSE: Prison inmates present with higher rates of disease morbidity and mortality than the general population. The rates of certain infectious diseases such as hepatitis C, HIV/AIDS, and tuberculosis are reported to be particularly elevated in prison systems. Scarce information, however, exists on the overall infectious disease profile of inmate populations. The present study examined the prevalence of major infectious diseases in one of the nation's largest prison populations. METHODS: The study population consisted of 336,668 Texas Department of Criminal Justice (TDCJ) inmates who were incarcerated for any duration between January 1, 1999 and December 31, 2001. Information on medical conditions, sentencing factors, and sociodemographic factors was obtained from an institution-wide medical information system. RESULTS: Latent tuberculosis infection constituted the most prevalent infectious disease reported among inmates. This was followed in frequency by hepatitis C, HIV/AIDS, and syphilis. Prevalence estimates for most of the infectious diseases under study exhibited substantial differences across gender, age, and ethnicity. CONCLUSION: The present study shows that the prison population had prevalence rates that were substantially higher for latent TB, HIV/AIDS, and hepatitis C than those reported for the general population and some incarcerated populations. The rate of active TB among TDCJ inmates, however, was comparable to that of the general population and other incarcerated populations.

Risk factors for pediatric human immunodeficiency virus-related malignancy.

CONTEXT: Although cancers occur with increased frequency in children with human immunodeficiency virus (HIV) infection, the specific clinical, immunological, and viral risk factors for malignancy have not been identified. OBJECTIVE: To identify risk factors for malignancy among HIV-infected children. DESIGN, SETTING, AND PATIENTS: A multicenter case-control study of children with HIV at 26 institutions participating in the Pediatric Oncology Group. Forty-three case patients with a new malignancy and 74 control patients without a malignancy were matched based on the duration of their infection. Patients were enrolled between January 1992 and July 1998. MAIN OUTCOME MEASURES: Clinical and laboratory factors assessed as putative risk factors included demographic characteristics, HIV characteristics, prior antiretroviral treatment, and CD4 cell count. Coviral infections with Epstein-Barr virus (EBV), cytomegalovirus, and human herpesvirus 6 were assessed by semiquantitative polymerase chain reaction assays and serological testing. RESULTS: Case malignancy diagnoses included 28 non-Hodgkin lymphoma, 4 B-cell acute lymphoblastic leukemia, 1 Hodgkin disease, 8 leiomyosarcoma, 1 hepatoblastoma, and 1 schwannoma. Epstein-Barr virus viral load of more than 50 viral genome copies per 105 peripheral blood mononuclear cells was strongly associated with cancer risk but only for children with CD4 cell counts of at least 200/ microL (odds ratio [OR], 11.33; 95% confidence interval [CI], 2.09-65.66, P<.001). High EBV viral load was not associated with cancer for children with CD4 cell counts of less than 200/ microL (OR, 1.12; 95% CI, 0.13-9.62; P =.99). Zidovudine antiretroviral therapy did not confer a significant protective effect for either the high (OR, 0.81; 95% CI, 0.22-3.09; P =.77) or the low CD4 cell count groups (OR, 0.27; 95% CI, 0.04-1.46; P =.16). The route of HIV infection was not associated with increased cancer risk. CONCLUSIONS: Route of infection, demographic characteristics, and zidovudine use were not associated with the development of malignancy in HIV-infected children. High viral burden with EBV was associated with the development of malignancy in HIV-infected children although the effect was modified by CD4 cell count. The pathogenesis of HIV-related pediatric malignancies remains unclear and other contributing risk factors can be elucidated only through further study.