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Levin LI, Munger KL, Rubertone MV, et al. Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis. JAMA. 2005;293(20):2496–2500. doi:https://doi.org/10.1001/jama.293.20.2496
Author Affiliations: Division of Preventive
Medicine, Walter Reed Army Institute of Research, Silver Spring, Md (Dr Levin);
Departments of Nutrition (Ms Munger and Dr Ascherio) and Epidemiology (Drs
Spiegelman and Ascherio), Harvard School of Public Health, Boston, Mass; Channing
Laboratory, Department of Medicine, Brigham and Women’s Hospital and
Harvard Medical School, Boston, Mass (Dr Ascherio); Army Medical Surveillance
Activity, US Army Center for Health Promotion and Preventive Medicine, Washington,
DC (Dr Rubertone); US Army Physical Disability Agency, Washington, DC (Dr
Peck); and Virolab Inc, Berkeley, Calif (Dr Lennette).
Context Infection with Epstein-Barr virus (EBV) has been associated with an
increased risk of multiple sclerosis (MS), but the temporal relationship remains
Objective To determine whether antibodies to EBV are elevated before the onset
Design, Setting, and Participants Nested case-control study conducted among more than 3 million US military
personnel with blood samples collected between 1988 and 2000 and stored in
the Department of Defense Serum Repository. Cases were identified as individuals
granted temporary or permanent disability because of MS. For each case (n = 83),
2 controls matched by age, sex, race/ethnicity, and dates of blood sample
collection were selected. Serial samples collected before the onset of symptoms
were available for 69 matched case-control sets.
Main Outcome Measures Antibodies including IgA against EBV viral capsid antigen (VCA), and
IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse
and restricted early antigens, and cytomegalovirus.
Results The average time between blood collection and MS onset was 4 years (range,
<1-11 years). The strongest predictors of MS were serum levels of IgG antibodies
to EBNA complex or EBNA-1. Among individuals who developed MS, serum antibody
titers to EBNA complex were similar to those of controls before the age of
20 years (geometric mean titers: cases = 245, controls = 265),
but 2- to 3-fold higher at age 25 years and older (cases = 684,
controls = 282; P<.001). The risk of
MS increased with these antibody titers; the relative risk (RR) in persons
with EBNA complex titers of at least 1280 compared with those with titers
less than 80 was 9.4 (95% confidence interval [CI], 2.5-35.4; P for trend <.001). In longitudinal analyses, a 4-fold increase
in anti-EBNA complex or anti–EBNA-1 titers during the follow-up was
associated with a 3-fold increase in MS risk (EBNA complex: RR , 3.0;
95% CI, 1.3-6.5; EBNA-1: RR, 3.0; 95% CI, 1.2-7.3). No association was
found between cytomegalovirus antibodies and MS.
Conclusion These results suggest an age-dependent relationship between EBV infection
and development of MS.
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