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

Primary Epstein-Barr virus (EBV) infection in childhood is typically asymptomatic,but infection later in life results in a mononucleosis with the illness severityranging from asymptomatic to requiring hospitalisation. The illness is generallyshort-lived (four to six weeks following onset of symptoms), but persistentdisabling symptoms (lasting up to 6 months or longer) are well described inaround ten percent of individuals. The aim of this work was to characteriseimmunological and virological parameters in the peripheral blood, which correlatewith persistence of symptoms following EBV-induced mononucleosis. Subjectswere recruited prospectively following confirmed primary EBV infection, to allowblood samples and clinical data to be collected at multiple timepoints (baseline, 2weeks, 4 weeks, 3 months and at least 12 months later). Subjects with 6 monthsor more of disabling symptoms were defined as cases with control subjectsbeing those whose illness resolved within 6 weeks of enrolment. Cases werecompared with control subjects in terms of: cellular EBV viral load in theperipheral blood by PCR; development of antibodies against EBV VCA (IgG andIgM) and EBNA-1 (IgG) by ELISA; proportions of peripheral blood leucocytesubsets and their activation status by flow cytometry; the magnitude, kinetics ofdevelopment, and breadth of the CD8+ cytotoxic cell response by interferon-γ Elispot; cytokine levels in serum, and production by peripheral bloodmononuclear cells ex vivo; and gene expression patterns in peripheral bloodmononuclear cells by microarray. With the exception of gene expression, none ofthese parameters correlated with early resolution of symptoms or predictedclinical outcome following primary EBV infection. Antibody patterns suggest atendency to Th2 type immune response may be associated with persistentillness. Preliminary analysis of the gene expression studies indicates that thereare many genes involved in this complex disease requiring further investigation.Persistent illness following EBV infection is not associated with uncontrolled viralreplication, or chronic immune activation due to an aberrant primary immuneresponse