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Ann Clin Transl Neurol. 2018 Sep 17;5(10):1222-1228. doi: 10.1002/acn3.636. eCollection 2018 Oct.

Heterogeneity in association of remote herpesvirus infections and pediatric MS.

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Department of Neurology Johns Hopkins University Baltimore Maryland.
Department of Neurology Stony Brook University Hospital Stony Brook New York.
Department of Pediatrics University of Utah Salt Lake City Utah.
Mellen Center for Multiple Sclerosis Cleveland Clinic Cleveland Ohio.
UCSF Regional Pediatric MS Center San Francisco California.
Children's Hospital of Philadelphia Philadelphia Pennsylvania.
Lourie Center for Pediatric MS at Stony Brook University Hospital Stony Brook New York.
University of Texas Southwestern Medical Center Dallas Texas.
Washington University Pediatric MS and other Demyelinating Disease Center Washington University in St. Louis St. Louis Missouri.
Center for Pediatric-Onset Demyelinating Disease at the Children's of Alabama University of Alabama Birmingham Alabama.
Children's National Medical Center Washington District of Columbia.
The Blue Bird Circle Clinic for Multiple Sclerosis Texas Children's Hospital Baylor College of Medicine Houston Texas.
Rocky Mountain MS Center Children's Hospital Colorado University of Colorado at Denver Aurora Colorado.
Pediatric Multiple Sclerosis Center at Loma Linda University Children's Hospital Loma Linda University Loma Linda California.
Lurie Children's Hospital of Chicago Chicago Illinois.
Mayo Clinic Pediatric MS Center Mayo Clinic Rochester Minnesota.
Pediatric MS Center New York University New York New York.
Pediatric Multiple Sclerosis and Related Disorders Program at Boston Children's Hospital Harvard Medical School Boston Massachusetts.
Partners Pediatric MS Center Massachusetts General Hospital Boston Massachusetts.
Department of Neurology University of Utah Salt Lake City Utah.
Primary Children's Hospital University of Utah Salt Lake City Utah.
The Pediatric MS Center at the Jacobs Neurological Institute State University of New York at Buffalo Buffalo New York.
School of Public Health University of California, Berkeley Berkeley California.
University of Oklahoma Health Sciences Center Oklahoma City Oklahoma.



While 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.


Cases 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.


A 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.


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.

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