A prospective study of Epstein-Barr virus antibodies and risk of non-Hodgkin lymphoma

Severe immunosuppression is an established risk factor for non-Hodgkin lymphoma (NHL), but an association with subclinical immune dysfunction is unclear. We conducted a case-control study nested in the Physicians' Health Study and the Nurses' Health Study cohorts to determine whether patterns of antibody response to Epstein-Barr virus (EBV) were associated with NHL risk. We measured antibody titers against viral capsid antigen, early antigen, and Epstein-Barr nuclear antigen (EBNA-1 and EBNA-2) in blood samples collected before diagnosis from 340 cases and 662 matched controls. Using conditional logistic regression, we estimated rate ratios (RRs) and 95% confidence intervals (CIs) for elevated versus normal titers and the ratio of anti-EBNA-1 to anti-EBNA-2 titers (≤ 1.0 vs > 1.0). We found no association between EBV serostatus, elevated titers, or an EBNA-1/EBNA-2 ratio ≤ 1.0 and NHL risk overall. For chronic lymphocytic leukemia/small lymphocytic lymphoma, suggestive associations were noted for elevated anti-EBNA-2 (RR, 1.74; 95% CI, 0.99-3.05), anti-viral capsid antigen (RR, 1.58; 95% CI, 0.79-3.14), and EBNA-1/EBNA-2 ratio ≤ 1.0 (RR, 1.52; 95% CI, 0.91-2.55). There was no evidence of heterogeneity by subtype. Overall, we found no evidence that EBV antibody profile predicts NHL risk in immunocompetent persons, with the possible exception of chronic lymphocytic leukemia/small lymphocytic lymphoma.