Immunological and virological correlates of persistent illness following primary Epstein-Barr virus infection

Abstract

Primary Epstein-Barr virus (EBV) infection in childhood is typically asymptomatic, but infection later in life results in a mononucleosis with the illness severity ranging from asymptomatic to requiring hospitalisation. The illness is generally short-lived (four to six weeks following onset of symptoms), but persistent disabling symptoms (lasting up to 6 months or longer) are well described in around ten percent of individuals. The aim of this work was to characterise immunological and virological parameters in the peripheral blood, which correlate with persistence of symptoms following EBV-induced mononucleosis. Subjects were recruited prospectively following confirmed primary EBV infection, to allow blood samples and clinical data to be collected at multiple timepoints (baseline, 2 weeks, 4 weeks, 3 months and at least 12 months later). Subjects with 6 months or more of disabling symptoms were defined as cases with control subjects being those whose illness resolved within 6 weeks of enrolment. Cases were compared with control subjects in terms of: cellular EBV viral load in the peripheral blood by PCR; development of antibodies against EBV VCA (IgG and IgM) and EBNA-1 (IgG) by ELISA; proportions of peripheral blood leucocyte subsets and their activation status by flow cytometry; the magnitude, kinetics of development, and breadth of the CD8+ cytotoxic cell response by interferon-γ Elispot; cytokine levels in serum, and production by peripheral blood mononuclear cells ex vivo; and gene expression patterns in peripheral blood mononuclear cells by microarray. With the exception of gene expression, none of these parameters correlated with early resolution of symptoms or predicted clinical outcome following primary EBV infection. Antibody patterns suggest a tendency to Th2 type immune response may be associated with persistent illness. Preliminary analysis of the gene expression studies indicates that there are many genes involved in this complex disease requiring further investigation. Persistent illness following EBV infection is not associated with uncontrolled viral

replication, or chronic immune activation due to an aberrant primary immune response.