Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis

Abstract

Background: The authors have previously reported genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) based on expression of 88 human genes.

Aim: To attempt to reproduce these findings, determine the specificity of this signature to CFS/ME, and test for associations between CFS/ME subtype and infection.

Methods: Expression levels of 88 human genes were determined in blood of 62 new patients with idiopathic CFS/ME (according to Fukuda criteria), six patients with Q-fever-associated CFS/ME from the Birmingham Q-fever outbreak (according to Fukuda criteria), 14 patients with endogenous depression (according to DSM-IV criteria) and 29 normal blood donors.

Results: In patients with CFS/ME, differential expression was confirmed for all 88 genes. Q-CFS/ME had similar patterns of gene expression to idiopathic CFS/ME. Gene expression in patients with endogenous depression was similar to that in the normal controls, except for upregulation of five genes (APP, CREBBP, GNAS, PDCD2 and PDCD6). Clustering of combined gene data in CFS/ME patients for this and the authors' previous study (117 CFS/ME patients) revealed genomic subtypes with distinct differences in SF36 scores, clinical phenotypes, severity and geographical distribution. Antibody testing for Epstein-Barr virus, enterovirus, Coxiella burnetii and parvovirus B19 revealed evidence of subtype-specific relationships for Epstein-Barr virus and enterovirus, the two most common infectious triggers of CFS/ME.

Conclusions: This study confirms the involvement of these genes in CFS/ME.

Figure 1

Absolute fold-difference values (mean relative quantity (RQ) in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)/mean RQ in normal controls) for each of 88 CFS/ME-associated genes in eight CFS/ME subtypes (A–H).

Figure 2

(a) Medical Outcomes Survey Short Form-36 (SF36) domain and total scores for each chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) subtype: physical function, physical role (RP), bodily pain (BP), general health (GH), vitality (VIT), social functioning (SF), emotional role (RE), mental health (MH) and total score (Total). (b) Scores indicating occurrence and severity of 11 clinical symptoms for each CFS/ME subtype: headache (HA), sore throat (ST), swollen glands (GLA), cognitive defect (COG), muscle pain (MP), joint pain (JP), muscle weakness (MW), post-exertional malaise (PEM), sleep problems (SLE), fainting/dizziness (F/D), gastrointestinal complaints (GI), numbness/tingling (N/T), spatial span (SSP), verbal recognition memory (VRM). (c) Histogram showing the numbers of CFS/ME patients of each subtype occurring in each of the six geographical locations. (d) Epstein–Barr virus (EBV) antibody titres (viral capsid antigen (VCA) IgM, VCA IgG, early antigen (EA) IgG, Epstein–Barr nuclear antigen (EBNA) IgG) in each CFS/ME subtype and the normal comparison group. (e) Distribution of categories of EBV serostatus (seronegative, primary/re-activation, late phase of infection) in the CFS/ME subtypes, A–H, in CFS/ME (all subtypes combined) and in normal controls. (f) Log (base 2) of fold-difference values of 10 human genes known to be important in EBV infection, in eight CFS subtypes (A–H).