Revisiting IgG Antibody Reactivity to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Its Potential Application to  Disease Diagnosis

Abstract

Infections by the Epstein-Barr virus (EBV) are often at the disease onset of patients suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome  (ME/CFS). However, serological analyses of these infections remain inconclusive  when comparing patients with healthy controls (HCs). In particular, it is unclear  if certain EBV-derived antigens eliciting antibody responses have a biomarker  potential for disease diagnosis. With this purpose, we re-analyzed a previously  published microarray data on the IgG antibody responses against 3,054 EBV-related  antigens in 92 patients with ME/CFS and 50 HCs. This re-analysis consisted of  constructing different regression models for binary outcomes with the ability to  classify patients and HCs. In these models, we tested for a possible interaction  of different antibodies with age and gender. When analyzing the whole data set,  there were no antibody responses that could distinguish patients from healthy  controls. A similar finding was obtained when comparing patients with  non-infectious or unknown disease trigger with healthy controls. However, when  data analysis was restricted to the comparison between HCs and patients with a  putative infection at their disease onset, we could identify stronger antibody  responses against two candidate antigens (EBNA4_0529 and EBNA6_0070). Using  antibody responses to these two antigens together with age and gender, the final  classification model had an estimated sensitivity and specificity of 0.833 and  0.720, respectively. This reliable case-control discrimination suggested the use  of the antibody levels related to these candidate viral epitopes as biomarkers  for disease diagnosis in this subgroup of patients. To confirm this finding, a  follow-up study will be conducted in a separate cohort of patients.