Heterogeneity in association of remote herpesvirus infections and pediatric MS

Abstract

ObjectiveWhile prior Epstein–Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections.MethodsCases with pediatric‐onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses‐1 (HSV‐1) and ‐2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA‐DRB1:1501 status.ResultsA total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV‐viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5–12.0, P < 0.001). Seropositivity for HSV‐1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06–2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35–3.52, P < 0.001) and those negative for HLA‐DRB1*1501 (OR = 1.89, 95% CI 1.17–3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA‐DRB1*15:01 status.Interpretation EBV seropositivity is strongly associated with pediatric MS, as is HSV‐1 seropositivity in subjects negative for HLA‐DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

“…Herpes simples virus (HSV)-1 seropositivity was associated with pediatric MS cases negative for HLA-DRB1*15:01, highlighting the complex nature of viral exposure and genetic factors. Multivariate analysis in the same study revealed a reduction in the risk of developing MS associated with CMV infection and no influence on MS status associated with HSV-1 infection [91]. Taken together, a role for EBV in early MS is supported by convergent pediatric MS studies.…”

“…However, neither EBNA-1 nor viral capsid antigen (VCA) IgG antibodies in serum, nor EBV DNA load in saliva, were associated with radiological or clinical disease activity. EBV infection is strongly associated with pediatric MS [91][92][93][94]. Herpes simples virus (HSV)-1 seropositivity was associated with pediatric MS cases negative for HLA-DRB1*15:01, highlighting the complex nature of viral exposure and genetic factors.…”

Environmental and genetic risk factors for MS: an integrated review

“…Herpes simplex virus (HSV ): Children with prior exposure to HSV‐1 have a modestly increased risk of having pediatric MS. This is mostly seen in Whites and DRB1 ‐negative individuals …”

“…Cytomegalovirus (CMV) : A few studies have suggested a protective association of prior CMV infection with adult and pediatric MS while several have reported no association …”

Multiple Sclerosis in Children: Current and Emerging Concepts

“…Finally, two U.S. studies reported that seropositivity for herpes simplex virus 1 increased the risk for MS in children who were white and did not have the HLA-DRB1 Ã 15:01 risk allele. 18,19 Smoking, Air Quality, and Household Chemicals Second-hand smoke exposure is a risk factor for MS in children. In one population-based case-control study in France, children who had at least one parent who smoked at home had double the adjusted risk for a diagnosis of MS. Risk was higher for older children (adjusted risk ratio: 2.49), suggesting that a longer duration of exposure increases risk.…”