title: Illness progression in chronic fatigue syndrome: a shifting immune baseline.
abstract: BACKGROUND
  Validation of biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) across data sets has proven disappointing. As immune signature may be affected by many factors, our objective was to explore the shift in discriminatory cytokines across ME/CFS subjects separated by duration of illness.
  
  
  METHODS
  Cytokine expression collected at rest across multiple studies for female ME/CFS subjects (i) 18 years or younger, ill for 2 years or less (n = 18), (ii) 18-50 years of age, ill for 7 years (n = 22), and (iii) age 50 years or older (n = 28), ill for 11 years on average. Control subjects were matched for age and body mass index (BMI). Data describing the levels of 16 cytokines using a chemiluminescent assay was used to support the identification of separate linear classification models for each subgroup. In order to isolate the effects of duration of illness alone, cytokines that changed significantly with age in the healthy control subjects were excluded a priori.
  
  
  RESULTS
  Optimal selection of cytokines in each group resulted in subsets of IL-1α, 6, 8, 15 and TNFα. Common to any 2 of 3 groups were IL-1α, 6 and 8. Setting these 3 markers as a triple screen and adjusting their contribution according to illness duration sub-groups produced ME/CFS classification accuracies of 75-88 %. The contribution of IL-1α, higher in recently ill adolescent ME/CFS subjects was progressively less important with duration. While high levels of IL-8 screened positive for ME/CFS in the recently afflicted, the opposite was true for subjects ill for more than 2 years. Similarly, while low levels of IL-6 suggested early ME/CFS, the reverse was true in subjects over 18 years of age ill for more than 2 years.
  
  
  CONCLUSIONS
  These preliminary results suggest that IL-1α, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Russell
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada. gbroderick@nova.edu.|Miami Veterans Affairs Medical Center, Miami, FL, USA. gbroderick@nova.edu.|Institute for Neuro-immune Medicine, Nova Southeastern University, Suite 3440 University Park Plaza, 3424 South University Drive, Fort Lauderdale, FL, 33328, USA. gbroderick@nova.edu.
authors.forename: Gordon
authors.identifier: http://orcid.org/0000-0002-3588-8252
authors.initials: G
authors.lastname: Broderick
authors.affiliation: Department of Occupational Therapy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Taylor
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Henrique
authors.initials: H
authors.lastname: Fernandes
authors.affiliation: Department of Medicine, University of Miami, Miami, FL, USA.|Miami Veterans Affairs Medical Center, Miami, FL, USA.
authors.forename: Jeanna
authors.initials: J
authors.lastname: Harvey
authors.affiliation: Department of Medicine, University of Miami, Miami, FL, USA.|Miami Veterans Affairs Medical Center, Miami, FL, USA.|Institute for Neuro-immune Medicine, Nova Southeastern University, Suite 3440 University Park Plaza, 3424 South University Drive, Fort Lauderdale, FL, 33328, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Barnes
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: AnneLiese
authors.initials: A
authors.lastname: Smylie
authors.affiliation: Miami Veterans Affairs Medical Center, Miami, FL, USA.
authors.forename: Fanny
authors.initials: F
authors.lastname: Collado
authors.affiliation: Department of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Balbin
authors.affiliation: Division of Infectious Diseases, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Katz
authors.affiliation: Miami Veterans Affairs Medical Center, Miami, FL, USA.|Institute for Neuro-immune Medicine, Nova Southeastern University, Suite 3440 University Park Plaza, 3424 South University Drive, Fort Lauderdale, FL, 33328, USA.
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Klimas
authors.affiliation: Miami Veterans Affairs Medical Center, Miami, FL, USA.|Institute for Neuro-immune Medicine, Nova Southeastern University, Suite 3440 University Park Plaza, 3424 South University Drive, Fort Lauderdale, FL, 33328, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Fletcher
mesh_terms: D000293:Adolescent; D000704:Analysis of Variance; D015992:Body Mass Index; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D016002:Discriminant Analysis; D018450:Disease Progression; D015673:Fatigue Syndrome, Chronic / Q000145:classification / Q000276:immunology* / Q000473:pathology*; D005260:Female; D006801:Humans; D008875:Middle Aged; D017697:Premenopause; D012044:Regression Analysis; D015203:Reproducibility of Results
chemical_list: D016207:Cytokines
keywords: Chronic fatigue; Classification model; Cytokines; Immune signaling; Menopause and immunity