Epstein-Barr Virus Antibody Levels Research Articles

Herpesvirus Antibody Response and Occurrence of Symptoms in Acute and Post-Acute COVID-19 Disease

Knowledge about the underlying causes of the individual occurrence of symptoms during acute COVID-19 disease and during the post-acute sequelae of COVID-19 is limited. In a German COVID-19 follow-up study, we assessed whether elevated antibody responses to herpesviruses were associated with symptom occurrence in acute COVID-19 disease (n = 96 participants) and during 20 months of follow-up (n = 62 participants). Serum samples were analyzed for their antibodies to herpes simplex virus (HSV)-1 and -2, Epstein–Barr virus (EBV), and Cytomegalovirus (CMV) using fluorescent bead-based multiplex serology. The association of herpesvirus antibodies with symptom occurrence (fatigue, fever, dyspnea, decrease in taste, concentration problems) was assessed using multivariate logistic regression models. High EBV antibody levels were significantly associated with a more than fourfold increased odds of experiencing fatigue during acute COVID-19 disease and during follow-up. High CMV antibody levels were significantly associated with a more than threefold increased odds of experiencing concentration problems and a decrease in taste during the follow-up. The HSV-1 and -2 antibody levels were not elevated in the individuals that experienced symptoms. In conclusion, our findings indicate that herpesvirus infections, specifically EBV and CMV infections, might play a role in symptom development during acute and post-acute COVID-19 disease. It remains to be elucidated whether the elevated EBV and CMV antibodies determined in our study are indicators of herpesvirus reactivation.

Genetics of immune response to Epstein-Barr virus: prospects for multiple sclerosis pathogenesis.

Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 (EBNA-1, truncated=aa[325-641], peptide=aa[385-420]) and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched controls. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 (OR=1.74, 95% CI=1.60-1.88) and EBNA-1, particularly the peptide (OR=3.13, 95% CI=2.93-3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to twelve times the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g., DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01, which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defense against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defense against EBV. Lastly, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility.

Antibodies to varicella-zoster virus and three other herpesviruses and survival in adults with glioma.

Lifetime exposure to the varicella-zoster virus (VZV) has been consistently inversely associated with glioma risk, however, the relationship of VZV with survival in adults with glioma has not been investigated. In this study, we analyzed the survival of adults with glioma in relation to their antibody measurements to 4 common herpes viral infections, including VZV, measured post-diagnosis. We analyzed IgG antibody measurements to VZV, cytomegalovirus (CMV), herpes simplex virus 1/2 (HSV), and Epstein-Barr virus (EBV) collected from 1378 adults with glioma diagnosed between 1991 and 2010. Blood was obtained a median of 3 months after surgery. Associations of patient IgG levels with overall survival were estimated using Cox models adjusted for age, sex, self-reported race, surgery type, dexamethasone usage at blood draw, and tumor grade. Models were stratified by recruitment series and meta-analyzed to account for time-dependent treatment effects. VZV antibody seropositivity was associated with improved survival outcomes in adults with glioma (Hazard ratio, HR = 0.70, 95% Confidence Interval 0.54-0.90, P = .006). Amongst cases who were seropositive for VZV antibodies, survival was significantly improved for those above the 25th percentile of continuous reactivity measurements versus those below (HR = 0.76, 0.66-0.88, P = .0003). Antibody seropositivity to EBV was separately associated with improved survival (HR = 0.71, 0.53-0.96, P = .028). Antibody positivity to 2 other common viruses (CMV, HSV) was not associated with altered survival. Low levels of VZV or EBV antibodies are associated with poorer survival outcomes for adults with glioma. Differential immune response rather than viral exposure may explain these findings.

Nasopharyngeal carcinoma patients from Norway show elevated Epstein-Barr virus IgA and IgG antibodies prior to diagnosis

BackgroundIgA antibodies against few Epstein-Barr virus (EBV) proteins are established serological markers for nasopharyngeal carcinoma (NPC). We recently validated a novel, comprehensive EBV marker panel and showed that IgA, but also IgG antibodies against multiple EBV proteins are highly sensitive and specific for EBV-positive NPC at diagnosis. However, data about these novel biomarkers as prospective markers for NPC are sparse. MethodsThis study included 30 incident NPC cases and 60 matched controls from the Norwegian Janus Serum Bank. For 21 NPCs, molecular EBV and human papillomavirus (HPV) status were assessed by EBER-ISH and HPV DNA/RNA testing by PCR, respectively. IgA and IgG serum antibodies against 17 EBV antigens were analyzed in prediagnostic sera of cases (median lead time 14 years) and controls using multiplex serology. Sensitivities were calculated using receiver operating characteristic analysis pre-specified to yield 90% specificity in the control group. From 10 cases, serial samples were available. ResultsQuantitative EBV antibody levels were significantly elevated among all cases (p < 0.05) for three IgA and six IgG antibodies. The highest sensitivities for defining 12 EBER-ISH-positive NPCs were observed for BGLF2 IgA (67%) and BGLF2 IgG (83%). Increased IgA and IgG antibody levels between the first and last draw before diagnosis were observed for EBER-ISH positive, but not for EBER-ISH negative NPCs. Among 21 molecularly analyzed NPCs, 4 EBER-ISH negative NPCs showed concomitant positivity to HPV type-specific DNA and RNA; 3 NPCs were HPV16 and 1 NPC was HPV18 positive. ConclusionBoth, EBV IgA and IgG antibody levels are significantly elevated many years before diagnosis of EBV-positive NPCs in Norway, an NPC low-incidence region. This study provides insights into one of the largest available prospective sample collections of NPCs in a non-endemic country.

Prognostic Value of Serum Epstein-Barr Virus Antibodies and Their Correlation with TNM Classification in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma.

PurposeThis study assessed the correlation between Epstein-Barr virus (EBV) biomarkers and the eighth American Joint Committee on Cancer staging system and the prognostic values of IgG antibodies against replication and transcription activator (Rta-IgG), IgA antibodies against Epstein-Barr nuclear antigen 1, and BamH1 Z transactivator (Zta-IgA) in locoregionally advanced nasopharyngeal carcinoma (NPC) patients.Materials and MethodsSerum EBV antibody levels were measured by enzyme-linked immunosorbent assay in 435 newly diagnosed stage III-IVA NPC patients administered intensity-modulated radiation therapy±chemotherapy. The primary endpoint was progression-free survival (PFS).ResultsRta-IgG and Zta-IgA levels were positively correlated with the N category and clinical stage. Patients with high Rta-IgG levels (> 29.07 U/mL) showed a significantly inferior prognosis as indicated by PFS (77% vs. 89.8%, p=0.004), distant metastasis–free survival (DMFS) (88.3% vs. 95.8%, p=0.021), and local recurrence-free survival (LRFS) (91.2% vs. 98.3%, p=0.009). High Rta-IgG levels were also significantly associated with inferior PFS and LRFS in multivariable analyses. In the low-level EBV DNA group (≤ 1,500 copies/mL), patients with high Rta-IgG levels had significantly inferior PFS and DMFS (both p < 0.05). However, in the high-level EBV DNA group, Rta-IgG levels were not significantly associated with PFS, DMFS, and LRFS. In the advanced T category (T3–4) subgroup, high Rta-IgG levels were also significantly associated with inferior PFS, DMFS, and LRFS (both p < 0.05).ConclusionRta-IgG and Zta-IgA levels were strongly correlated with the TNM classification. Rta-IgG level was a negative prognostic factor in locoregionally advanced NPC patients, especially those with advanced T category or low EBV DNA level.

An Absence of Epstein-Barr Virus Reactivation and Associations with Disease Activity in People with Multiple Sclerosis Undergoing Therapeutic Hookworm Vaccination.

Background: Epstein–Barr virus (EBV) infection is strongly associated with multiple sclerosis (MS). Helminth infection can downregulate antiviral immune responses, potentially protecting against MS, but with a theoretical risk for reactivating latent EBV infection. Objective: To investigate parameters of EBV infection and their relationship with disease activity in people with MS (PwMS) therapeutically vaccinated with Necator americanus (hookworm). Methods: Sequential serum samples from 51 PwMS; 26 therapeutically infected (25 larvae) with N. americanus and 25 controls were tested for EBV virus capsid antigen (VCA) IgG and IgM, EBV nuclear antigen-1 (EBNA-1) IgG, and EBV early antigen (EA) IgG. Disease activity was assessed by periodic MRI. Significance was set at p < 0.05. Results: All PwMS were EBV VCA IgG and EBNA-1 IgG positive, and 35.2% were EBV EA IgG positive. EBV antibody levels were generally stable, and EBV reactivation in PwMS was not demonstrated by significant increases in IgG titre over 12 months. Disease activity was most frequent in PwMS possessing high levels of EBV VCA IgG (>600 units/mL) or EBNA-1 IgG (>150 units/mL); however, there was no association with hookworm treatment. Interpretation: Therapeutic hookworm vaccination was not associated with EBV reactivation. Multiple sclerosis disease activity was associated with high levels of EBV VCA IgG or EBNA-1 IgG.

Efficacy of Chemiluminescence Immunoassays on VCA-IgA and EBNA1-IgA Antibodies of Epstein-Barr Virus in Diagnosing Nasopharyngeal Carcinoma.

Background: IgA antibodies against Epstein-Barr virus (EBV) capsid antigen (VCA) and nuclear antigen 1 (EBNA1) have been proposed to facilitate the diagnosis and early detection of nasopharyngeal carcinoma (NPC) in high-incidence regions. However, while new methodologies and new platforms for the detection of VCA-IgA and EBNA1-IgA have become available, proper interassay simultaneous comparisons have not been carried out. The study was to compare the performance of the chemiluminescent immunoassays (CLIA) and enzyme-linked immunosorbent assay (ELISA) for VCA-IgA and EBNA1-IgA antibodies, and to evaluate the levels of EBV antibodies in healthy population from different areas of China.Methods: CLIA and ELISA for VCA-IgA and EBNA1-IgA were performed in NPC and healthy populations from high-incidence areas of NPC in South China (N=555), medium-incidence areas of NPC in Central China (N=318) and low-incidence areas of NPC in North China (N=379), and the results were compared and analyzed.Results: (1) The highest sensitivity in total, early and advanced NPC were 91.5% (CLIA for VCA-IgA), 86.4% (CLIA and ELISA-2 for EBNA1-IgA) and 93.6% (CLIA for VCA-IgA). However, the specificity of EBV-IgA measured by CLIA was relatively lower than ELISA. The top three seromarkers with the largest AUC was CLIA for VCA-IgA (AUC: 0.929, 95% CI: 0.905-0.953), ELISA-2 for EBNA1-IgA (AUC: 0.922, 95% CI: 0.896-0.947) and CLIA for EBNA1-IgA (AUC:0.919, 95% CI: 0.893-0.945), respectively. The positive and negative coincidence rates of the two EBNA1-IgA kits were 69.5% and 91.9%, respectively. However, the coincidence rates of VCA-IgA were relatively low. CLIA kits had good repeatability between different laboratories. (2) The positive rates of EBV-IgA antibodies were relatively high in high-incidence areas of NPC (P < 0.017), while there was no significant difference in the antibody positive rates between medium-incidence areas and low-incidence areas of NPC (P > 0.05).Conclusions: The performance of EBV-IgA antibodies measured by CLIA has good repeatability, higher sensitivity and similar specificity. The higher EBV-IgA positive rate in healthy subjects by CLIA raises concern about its suitability for NPC-risk screening and requires further analysis.

Associations between environmental factors and serological Epstein‐Barr virus antibodies in patients with nasopharyngeal carcinoma in South China

Epstein‐Barr virus (EBV) reactivation, reflected by aberrantly increased levels of various serological antibodies, has been suggested to be an early indicator of nasopharyngeal carcinoma (NPC) onset and progression. We have previously suggested that certain lifestyle and dietary factors were associated with elevated serological levels of the antibody against various EBV antigens namely VCA, Zta, EBNA1, and oral EBV DNA loads among healthy population. It remains unclear whether these potential environmental factors would also influence EBV serological antibodies in NPC patients. We conducted an epidemiological study to evaluate the associations between such environmental factors and EBV antibody levels among 1701 NPC patients in South China. Pretreatment serums were collected and examined for VCA‐IgA and EA‐IgA by immunoenzymatic assays and antienzyme rate (AER) of EBV DNase‐specific neutralizing antibody. We found that consumption of Canton‐style herbal tea was significantly correlated with increased serological antibody levels of VCA‐IgA and EA‐IgA, with adjusted ORs of 1.35 (95% CI: 1.03‐1.76) and 1.32 (95% CI: 1.01‐1.73), respectively, in the weekly intake frequency stratum, while not related to AER of EBV DNase‐specific neutralizing antibody. Smoking was found to be not only an apparent risk factor for higher antibody levels of AER in stage III‐IV patients (OR = 1.60, 95% CI: 1.11‐2.30), but also associated closely with NPC stage at diagnosis (OR = 2.17, 95% CI: 1.47‐3.22), with dose‐response effects. In conclusion, we found consumption of Canton‐style herbal tea and cigarette smoking were in positive associations with elevated EBV antibodies in NPC patients, which may be of public health significance for the primary prevention of EBV‐associated diseases especially NPC.

Higher EBV response is associated with more severe gray matter and lesion pathology in relapsing multiple sclerosis patients: A case-controlled magnetization transfer ratio study

Background: Epstein–Barr virus (EBV) infection has been associated with higher clinical activity and risk of multiple sclerosis (MS). Objective: To evaluate associations between EBV-specific humoral response and magnetization transfer ratio (MTR)-derived measure in MS patients and healthy controls (HCs). Methods: The study included 101 MS patients (69 relapsing-remitting multiple sclerosis (RRMS) and 32 secondary-progressive multiple sclerosis (SPMS)) and 41 HCs who underwent clinical, serological, and magnetic resonance imaging (MRI) investigations. MTR values of T1 or T2 lesion volume (LV), normal-appearing (NA) brain tissue (NABT), gray matter (NAGM), and white matter (NAWM) were obtained. Enzyme-linked immunosorbent assay was used to quantify EBV antibody levels. Partial correlations corrected for MRI strength were used, and Benjamini–Hochberg–adjusted p-values < 0.05 were considered significant. Results: MS patients had significantly higher anti-EBV nuclear antigen-1 (EBNA-1) titer when compared to HCs (107.9 U/mL vs 27.8 U/mL, p < 0.001). Within the MS group, higher serum anti-EBNA-1 titer was significantly correlated with lower T1-LV MTR (r = –0.287, p = 0.035). Within the RRMS group, higher serum anti-EBNA-1 titer was associated with T1-LV MTR (r = –0.524, p = 0.001) and NAGM MTR (r = –0.308, p = 0.043). These associations were not present in HCs or SPMS patients. Conclusion: Greater EBV humoral response is associated with lower GM MTR changes and focal destructive lesion pathology in RRMS patients.

ME/CFS, case definition, and serological response to Epstein-Barr virus. A systematic literature review

ABSTRACT Background: The levels of antibodies to Epstein–Barr virus (EBV) in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have been compared to healthy controls in many studies. However, the results are inconsistent. Purpose: The objective of this systematic literature review was to determine whether differences in EBV serology between ME/CFS patients and controls vary with the case definition that is used. Methods: MEDLINE, EMBASE, and earlier reviews were searched for studies in which the serum levels of antibodies to EBV-antigens in ME/CFS patients were compared with those in persons without ME/CFS. Results: 27 studies were identified. The levels of antibodies to EBV in ME/CFS patients differed from those in controls in 14 studies. The differences in EBV serology that were revealed, were almost exclusively signs that may indicate higher EBV activity in the patient group. The serological differences between patients and controls were seen in the 2 studies in which ME/CFS was defined using the Canadian criteria, in 5 of the 9 studies using the Holmes criteria, in 1 of the 2 studies using modified Holmes criteria, in 2 of the 6 studies using the Fukuda criteria, and in 4 of the 7 studies using less known criteria. The single study using the Oxford criteria, showed no difference between cases and controls. Conclusions: There seems to be increased EBV activity in subset(s) of ME/CFS patients. The data do not allow firm conclusions about EBV antibody levels varying with the illness case definition used.

O5.4. NATURAL CAUSE MORTALITY IN PERSONS WITH SCHIZOPHRENIA AND BIPOLAR DISORDER

BackgroundIt is now well established that persons with schizophrenia and with bipolar disorder have a reduced life expectancy but the reasons for this premature mortality are not known with certainty. The aim of the current investigation was to identify the determinants of natural-cause mortality in a cohort of individuals with schizophrenia or bipolar disorder. To our knowledge, our investigation is unique in studying patients who were assessed at baseline with an in-person clinical assessment and blood sample and then subsequently evaluated regarding their mortality status and cause of death.MethodsPersons with schizophrenia (n=789) and bipolar disorder (n=498), mean age of 38 (s.d. 12.6) years, underwent an in-person clinical assessment. They also had a blood sample drawn which was tested by enzyme immunoassay tests for IgG class antibodies to Herpes Simplex Virus type 1 (HSV-1), Cytomegalovirus (CMV), Epstein Barr Virus Nuclear Antigen (EBV), Human Herpesvirus Type 6 and Toxoplasma gondii. Participants were followed for a median observation period of 7.87 years (range 1 day – 16.9 years); the total number of person-years of observation was 10,859.3 person-years. Mortality was subsequently determined utilizing data from the US National Death Index.ResultsA total of 6.8% (87/1287) of persons died of natural causes. There were 70 deaths in the schizophrenia and 17 in the bipolar disorder participants. The mean age at death of those who died from natural causes was 56.7 years (range 19.4 – 79.1 years). The standardized mortality ratio (SMR), the age-adjusted ratio of the number of observed deaths in this study sample to that expected in the general population, was 2.57 (95% CI 1.24 – 4.75).Natural cause mortality was predicted in a multivariate model by baseline cigarette smoking (RR=6.29, 95% CI 1.41, 3.72, p=0.00076); divorced or widowed status (RR=1.90, CI 1.21, 2.99); reduced cognitive score (RR=0.73, CI 0.61, 0.87); receipt of antidepressant medication (RR=1.74, CI 1.12, 2.71); elevated levels of antibodies to Epstein Barr Virus (EBV) (RR=1.29, CI 1.01, 1.66); and a genitourinary (RR 1.82, CI 1.16, 2.86), respiratory (RR 1.82, CI 1.16, 2.86), or cardiac (RR 2.09, CI 1.33, 3.29) condition.Interaction models showed evidence of additive effects of smoking and both cardiac and respiratory condition. Compared to non-smokers without a cardiac condition, non-smokers with a cardiac condition had a more than threefold elevation of mortality risk (RR=3.76, 95% CI 1.47 – 9.63, p=0.0057) as did smokers without a cardiac condition (RR=3.63, 95% CI 1.49 – 8.85, p=0.0046), while the presence of both smoking and a cardiac condition increased mortality risk by more than six-fold (RR=6.75, 95% CI 2.84 – 16.0, p<0.0001). Compared to non-smokers without a respiratory condition, mortality risk more than doubled for non-smokers with a respiratory condition (RR=2.30, 95% CI 0.97 – 5.46, p=0.058), as well as for smokers without a respiratory condition (RR=2.37, 95% CI 1.31 – 4.28, p=0.0044), while the mortality risk more than quadrupled for smokers with a respiratory condition (RR=4.72, 95% CI 2.45 – 9.09, p<0.0001). There was not a significant interaction between smoking and elevated EBV antibody levels. There was a synergistic effect of antidepressant use and cardiac disease on mortality risk: participants with both risk factors had a more than threefold elevation of mortality risk compared to persons with neither risk factor (RR=3.10, 95% CI 1.71 – 5.63, p=0.0002).DiscussionMultiple factors contribute to the excess mortality of persons with schizophrenia and bipolar disorder, but cigarette smoking is a major preventative cause. The delivery of smoking cessation treatments should be a high priority.

The Relationship Between Environmental Factors and the Profile of Epstein-Barr Virus Antibodies in the Lytic and Latent Infection Periods in Healthy Populations from Endemic and Non-Endemic Nasopharyngeal Carcinoma Areas in China

Our previous study found that smoking was associated with an elevated level of the antibody against VCA in the Epstein-Barr virus (EBV) lytic phase, which was an important predictive marker of the risk of nasopharyngeal carcinoma (NPC). It remained unknown whether environmental factors were associated with the levels of other EBV antibodies, such as Zta-IgA, EA-IgA, EBNA1-IgA, and LMP1-IgA, in the lytic and latent infection periods. We aimed to investigate the possible environmental inducers that could affect EBV antibody levels in two independent healthy male populations from endemic NPC areas in South China (N=1498) and non-endemic NPC areas in North China (N=1961). We performed ELISA and immunoenzymatic assays to test the levels of antibodies specific to the EBV antigens. The seropositive rates of antibodies against the antigens expressed in both the EBV latent and lytic infection periods, namely, LMP1-IgA, EBNA1-IgA, and Zta-IgA, in endemic areas (28.65%, 5.43% and 14.49%, respectively) were significantly higher than those in non-endemic areas (14.43%, 1.07% and 6.32%, respectively). Smoking was associated with higher seropositivity for EBNA1-IgA (OR=1.47, 95% CI=1.12–1.93) and Zta-IgA (OR=1.28, 95% CI=0.99–1.66), with dose-response effects, while not associated with the levels of LMP1-IgA. In conclusion, smoking was an important environmental factor, which associated with increased levels of EBNA1-IgA, and Zta-IgA.

Epstein-Barr virus antibodies in serum and DNA load in saliva are not associated with radiological or clinical disease activity in patients with early multiple sclerosis.

ObjectiveTo investigate the association of Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) and viral capsid antigen (VCA) immunoglobulin (Ig)G antibodies in serum as well as EBV DNA load in saliva with radiological and clinical disease activity in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS).MethodsEBNA-1 and VCA immunoglobulin (Ig)G antibodies were determined in serum of 100 patients with CIS/early RRMS and 60 healthy controls. EBV DNA load was measured in saliva of 48 patients and 50 controls. Patients underwent clinical assessment with the Expanded Disability Status Scale (EDSS) and 3 Tesla magnetic resonance imaging at baseline and after a median of 20 months of follow-up (n = 63 for MRI, n = 71 for EDSS). The association of EBV parameters with occurrence of a second relapse, indicating conversion to clinically definite MS (CDMS), was evaluated over a median of 35 months of follow-up after the first clinical event (n = 89).ResultsEBNA-1 IgG antibody frequency (p = 0.00005) and EBNA-1 and VCA IgG antibody levels (p<0.0001 for both) were higher in patients than in controls. EBV DNA load in saliva did not differ between groups. Neither EBV antibody levels nor DNA load in saliva were associated with baseline or follow-up number or volume of T2-weighted (T2w) or contrast enhancing lesions, number of Barkhof criteria or the EDSS, or with the number of new T2w lesions, T2w lesion volume change or EDSS change on follow-up. Likewise, levels of EBV IgG antibodies in serum and DNA load in saliva were not associated with conversion to CDMS.ConclusionsWhile these findings confirm the association of EBV infection with early MS, neither EBNA-1 nor VCA IgG antibodies in serum nor EBV DNA load in saliva were associated with radiological or clinical disease activity in patients with CIS/early RRMS. These data are compatible with the concept that EBV may be a trigger for MS acting very early during the development of the disease.

Physical activity, sedentary behaviors, and Epstein-Barr virus antibodies in young adults

This study aimed to elucidate the associations between physical activity, sedentary behaviors, and Epstein-Barr virus (EBV) antibody levels (as an indirect marker of cell-mediated immunity, CMI). This study made use of a 14-year longitudinal study with a representative sample of adolescents in the US. A total of 3361 participants (42.1% male) aged 11 to 21years at baseline who completed Wave I (1994–1995), Wave III (2001−2002), and Wave IV (2008) surveys of the National Longitudinal Study of Adolescent Health (Add Health) were analyzed. Physical activity and sedentary behaviors at Waves I and III were assessed using interviewer-administered questionnaire. EBV viral capsid antigen (VCA) IgG antibody levels at Wave IV were analyzed from dried blood spot assays. Adjusted for confounders, among males, one additional day spent per week on strenuous sports at Wave III were associated with a decrease of 4.09AU/ml in EBV antibody levels (p=0.012), while one additional hour spent per week viewing videos at Wave I was associated with an increase of 0.83AU/ml in EBV antibody levels (p=0.026). Among females, one additional day spent per week on individual sports at Wave III were associated with a decrease of 4.63AU/ml in EBV antibody levels (p=0.014), while sedentary behaviors were not associated with EBV antibody levels. To conclude, physical activity and sedentary behaviors were associated with CMI among males and physical activity was associated with CMI among females.

Vitamin D, HLA-DRB1 and Epstein-Barr virus antibody levels in a prospective cohort of multiple sclerosis patients.

Our objective was to study the association between serum levels of anti Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibody and 25-hydroxyvitamin D (25(OH)D) in a prospective cohort of patients with relapsing-remitting multiple sclerosis. The study comprised 90 patients with relapsing-remitting multiple sclerosis, all participants in a randomized clinical trial of ω-3 fatty acids (the OFAMS study). Repeated, paired measurements of serum 25(OH)D and serum EBNA-1 immunoglobulin G (IgG) levels were obtained at baseline and every 6 months for 24 months. The association between serum EBNA-1 IgG and serum 25(OH)D levels was analysed using generalized linear models for hierarchical data. There was a significant variation in EBNA-1 IgG antibody level between sampling months (Fdf 11 = 1.8, P = 0.043, one-way anova). There was a negative association between EBNA-1 IgG and 25(OH)D [B = -0.230, 95% confidence interval (CI) (-0.440, -0.023), P = 0.030] and a positive association between EBNA-1 IgG and HLA-DRB1*15 positive status [B = 94.7, 95% CI (2.423, 186.9), P = 0.044]. The association between 25(OH)D and EBNA-1 IgG remained significant after adjusting for the patient's age, gender, HLA-DRB1*15, retinol levels and interferon β-1a treatment. Our study demonstrates monthly differences in EBNA-1 IgG levels and an association between EBNA-1 IgG, 25(OH)D levels and HLA-DRB1*15. These results indicate that EBNA-1 IgG serum levels are affected by genetic and environmental factors that also modulate multiple sclerosis risk.

Epstein-Barr virus and risk of non-Hodgkin lymphoma in the cancer prevention study-II and a meta-analysis of serologic studies

Epstein-Barr virus (EBV) causes rare, malignant lymphomas. The role of EBV in other non-Hodgkin lymphomas (NHLs) remains unclear, but mildly reduced immune function could lead to reactivation of EBV and subsequent NHL. We examined the association between prospectively-collected plasma EBV antibodies and NHL risk in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort and conducted a meta-analysis of our and published results. The CPS-II study included 225 NHL cases and 2:1 matched controls. No associations were observed between EBV serostatus or antibody levels and risk of NHL overall. However, when including only the three most common types of NHL (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma), high compared to low early antigen (EA-D) diffuse and BZLF1-encoded replication activator antibodies were associated with approximately 60% higher risk of NHL. Odds ratios (ORs) for EBV nuclear antigen-1 and viral capsid antigen (VCA)-p18 were elevated but not statistically significant. In the meta-analysis, both EA (summary OR = 1.52, 95% confidence interval (CI): 1.16-2.00) and VCA (summary OR = 1.20, 95% CI: 1.00-1.44) were positively associated with NHL risk. These results suggest EBV may be associated with a wider spectrum of NHL subtypes, but further study is needed to confirm and fully understand these associations.

Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis

Background: Previous reports indicate an association between Epstein-Barr virus (EBV) antibody levels and multiple sclerosis (MS) disease activity, but the results have been conflicting. Objectives: The objective of this paper is to study if EBV antibody levels reflect MRI disease activity in MS and examine the potential for EBV antibody levels as biomarkers for treatment response. Methods: A total of 87 MS patients were followed for two years prior to and during interferon beta (IFNB) treatment, with MRI examinations and serum measurement of IgM and IgG antibodies to viral capsid antigen (VCA), EBV nuclear antigen 1 (EBNA-1) and early antigen (EA). Associations between EBV antibody levels and MRI activity were assessed by a logistic regression model. Results: Higher anti-EBNA-1 IgG levels were associated with increased MRI activity, OR = 2.95 (95% CI 1.07–8.10; p = 0.036) for combined unique activity (CUA; the sum of T1Gd+ lesions and new or enlarging T2 lesions). Although most patients were anti-VCA IgM negative, there was an inverse association, OR = 0.32 (95% CI 0.12–0.84; p = 0.021) with CUA during IFNB treatment. Conclusions: This study supports an association between anti-EBNA-1 IgG levels and MS disease activity. We also found an inverse association with anti-VCA IgM levels during IFNB treatment not previously described, indicating anti-VCA IgM as a possible biomarker for IFNB treatment response.

Reply to Letter Re: Childhood adversity and cell-mediated immunity in young adulthood

Dear Editor and BBI readership, We appreciate the correspondence from Dowd and colleagues, which informed us and BBI readers that our study (Slopen et al., 2013) using data from the National Longitudinal Study of Adolescent Health (Add Health) included individuals who were Epstein Barr Virus (EBV) seronegative. We agree with Dowd and colleagues that (1) use of EBV antibodies as an indicator of stress-related reactivation of latent herpes virus applies only to seropositive individuals, and (2) studies of psychosocial stressors and reactivation of latent herpes virus should focus exclusively on seropositive individuals. In error, we assumed that seronegative individuals did not have valid entries for EBV antibody levels in the Add Health data; for this reason, all individuals with an EBV antibody value were eligible for inclusion (range: 18–1310 au/mL). As a result, as described by Dowd and colleagues, our findings reflect both risk for EBV seropositivity and antibody response to latent infection among seropositive individuals, which introduced error into our associations of interest. We appreciate that Dowd and colleagues have estimated a seronegative cut-off (i.e., the lowest 10% of continuous survey-weighted EBV antibody values), based on recent estimates from NHANES (Dowd et al., 2013). The criterion for establishing seropositivity varies depending on the assay used to measure EBV antibody titers. Notably, the EBV threshold value used by Dowd and colleagues for Add Health data is much higher than a previously-reported threshold (McDade et al., 2000), which exemplifies the importance of disseminating seropositivity threshold values at the time of data release for public-use or contractual datasets like Add Health. Although the seronegativity threshold for Add Health has not been officially released, we have prepared tables to estimate how our results change once EBV seronegative individuals (i.e., EBV antibody values in the bottom 10%) are excluded. Associations of socioeconomic position and child maltreatment with EBV antibody levels are attenuated once seronegative individuals are excluded, and several of the associations that were significant at p 10 occasions of sexual abuse had significantly higher EBV titers. Table 3A Regression coefficients for the relationship between adolescent socioeconomic context and log EBV antibody titers (au/mL) in young adulthood among individuals seropositive for EBV (N = 11886).a Table 4A Regression coefficients for the relationship between frequency of abuse and timing of 1st onset of abuse and log EBV antibody titers (au/mL) in young adulthood among individuals seropositive for EBV.a,b,c We thank the Editor for the opportunity to submit revised tables so that readers can observe how our results change once seronegative individuals are excluded. We have requested that these tables be linked to our original article.

Racial–ethnic differences in Epstein–Barr virus antibody titers among U.S. children and adolescents

PurposeTo examine racial–ethnic differences in Epstein–Barr virus (EBV) antibody levels among U.S. children and adolescents. Elevated titers among seropositive youth can indicate viral reactivation—an indirect measure of impaired cell-mediated immunity. MethodsData from the 2003–2010 National Health and Nutrition Examination Survey were analyzed using multivariable linear regression accounting for the complex survey design and potential confounders. The sample comprised 4663 black-African American, Mexican American, and white youth aged 6–17 years who were EBV seropositive. ResultsEBV antibody levels were significantly higher for black-African American youth compared with their white peers (b = 0.343, P < .0001). Gender-stratified models were consistent with the total sample except differences in EBV antibody levels were greater between black-African American and white males (b = 0.525, P < .0001) than between black-African American and white females (b = 0.169, P = .0185). Differences in EBV antibody levels between Mexican American and white youth were only marginally significant in the total and the gender-stratified samples. ConclusionsBlack–white differences in EBV antibody levels were found suggesting EBV reactivation and potential disparities in immune function among minority youth. Research on multilevel factors contributing to the disparities is needed, including potential health implications over the life course for minority youth.

Evaluation of reactive Epstein–Barr Virus (EBV) in Iranian patient with different subtypes of multiple sclerosis (MS)

ObjectivesEpstein-Barr virus has been recently associated with the onset of multiple sclerosis, yet understanding how it elicits autoimmunity remains elusive. We investigated the relation between Epstein-Barr virus reactivation and disease development in different subtypes of multiple sclerosis. MethodsIn the present research, we have determined the Epstein-Barr virus-DNA load by quantitative real-time polymerase chain reaction and Epstein-Barr virus antibody levels by EIA technique in both multiple sclerosis patients (n=78) and healthy controls (n=123). ResultsOur results demonstrated increased titer of both anti-Epstein-Barr virus-IgG and IgM antibodies in patients (91.02% vs 82.11% in controls, p<0.001 and 14.1% vs 4.06% in controls, p<0.001, respectively). Overall, Epstein-Barr virus reactivation was found in 68.75% of subtypes of multiple sclerosis, 4.54% of multiple sclerosis primary subtype, and in only 3.25% of healthy control subjects. Moreover, in samples of patients with disease relapse (exacerbation) cell free viral DNA was elevated in contrast to other patients (p<0.001). ConclusionsThese findings provide further support for the detrimental effects of Epstein-Barr virus in the reactivation of multiple sclerosis attacks.