Inflammatory proteins are altered in chronic fatigue syndrome-A systematic review and meta-analysis

Neurosci Biobehav Rev. 2019 Dec;107:69-83. doi: 10.1016/j.neubiorev.2019.08.011. Epub 2019 Aug 26.


Immune dysfunction has been posited as a key element in the aetiology of chronic fatigue syndrome (CFS) since the illness was first conceived. However, systematic reviews have yet to quantitatively synthesise inflammatory biomarkers across the literature. We undertook a systematic review and meta-analysis to quantify available data on circulating inflammatory proteins, examining studies recruiting patients with a CFS diagnosis and a non-affected control group. Results were meta-analysed from 42 studies. Patients with CFS had significantly elevated tumour necrosis factor (ES = 0.274, p < 0.001), interleukin-2 (ES = 0.203, p = 0.006), interleukin-4 (ES = 0.373, p = 0.004), transforming growth factor-β (ES = 0.967, p < 0.001) and c-reactive protein (ES = 0.622, p = 0.019). 12 proteins did not differ between groups. These data provide some support for an inflammatory component in CFS, although inconsistency of results indicates that inflammation is unlikely to be a primary feature in all those suffering from this disorder. It is hoped that further work will elucidate whether there are subgroups of patients with clinically-relevant inflammatory dysfunction, and whether inflammatory cytokines may provide a prognostic biomarker or moderate treatment effects.

Keywords: CFS; Chronic fatigue syndrome; Inflammation; ME/CFS; Meta-Analysis; Systematic review.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Biomarkers / blood
  • C-Reactive Protein / metabolism*
  • Fatigue Syndrome, Chronic / blood*
  • Humans
  • Inflammation / blood*
  • Interleukin-2 / blood*
  • Interleukin-4 / blood*
  • Transforming Growth Factor beta / blood*
  • Tumor Necrosis Factor-alpha / blood*


  • Biomarkers
  • Interleukin-2
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • C-Reactive Protein