ME/CFS, case definition, and serological response to Epstein-Barr virus. A systematic literature review

Background: The levels of antibodies to Epstein-Barr virus (EBV) in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have been compared to healthy controls in many studies. However, the results are inconsistent. Purpose: The objective of this systematic literature review was to determine whether differences in EBV serology between ME/CFS patients and controls vary with the case definition that is used. Methods: MEDLINE, EMBASE, and earlier reviews were searched for studies in which the serum levels of antibodies to EBV-antigens in ME/CFS patients were compared with those in persons without ME/CFS. Results: 27 studies were identified. The levels of antibodies to EBV in ME/CFS patients differed from those in controls in 14 studies. The differences in EBV serology that were revealed, were almost exclusively signs that may indicate higher EBV activity in the patient group. The serological differences between patients and controls were seen in the 2 studies in which ME/CFS was defined using the Canadian criteria, in 5 of the 9 studies using the Holmes criteria, in 1 of the 2 studies using modified Holmes criteria, in 2 of the 6 studies using the Fukuda criteria, and in 4 of the 7 studies using less known criteria. The single study using the Oxford criteria, showed no difference between cases and controls. Conclusions: There seems to be increased EBV activity in subset(s) of ME/CFS patients. The data do not allow firm conclusions about EBV antibody levels varying with the illness case definition used.