Illness progression in chronic fatigue syndrome: a shifting immune baseline

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Illness progression in chronic fatigue syndrome: a shifting immune baseline
  • Lindsey Russell†,
  • Gordon Broderick†Email authorView ORCID ID profile,
  • Renee Taylor,
  • Henrique Fernandes,
  • Jeanna Harvey,
  • Zachary Barnes,
  • AnneLiese Smylie,
  • Fanny Collado,
  • Elizabeth G. Balbin,
  • Ben Z. Katz,
  • Nancy G. Klimas and
  • Mary Ann Fletcher
†Contributed equally
BMC Immunology201617:3
DOI: 10.1186/s12865-016-0142-3
© Russell et al. 2016
Received: 7 August 2015
Accepted: 29 February 2016
Published: 10 March 2016


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.

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.

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.

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.


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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.


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Interesting, indeed. While this work is preliminary (as they pointed out) in terms of being diagnostic, it reinforces the Hornig finding that immune parameters change over the course of the illness.

Besides the valuable data about changing cytokine patterns and potential biomarkers, I appreciate the following:
1. They don't oversell their results, unlike the PACE trial. They recognize and publish the limitations of their work. That's good research reporting. The PACE trial authors could learn something from this, such as science is not advertising.
While the panel based on IL-1α, IL-6 and IL-8 levels in peripheral blood described here shows initial promise it remains paramount to further validate in a larger and even more varied cohort to ensure a robustness that would be compatible with clinical use.

2. Not only do we not have to engage in legal action to get the data for this research, we don't have to ask at all. It is provided along with the paper, as it should be.
Additional file 3: Table S6. Supplemental table containing the full data set used in this work including subject age, body mass index (BMI), diagnostic class (i.e. ME/CFS or control), cohort reference and illness duration as well as the normalized and coded values for each cytokine species measured in each subject.
Hello, PACE researchers! Why is providing the full data set no problem for this group of biomedical researchers, but is completely unacceptable to you psych researchers?

On a personally interesting note, my latest cytokine tests match the <18 yo short-term illness pattern much more than the >50 yo long duration illness pattern. My IL1a is extremely high at nearly 30 times the 90th %ile level and my IL8 is almost double the 90th %ile level. IL6 is one of the few normal cytokine levels in the 18 cytokine test panel. In other words, I am almost opposite to the pattern they found. I wonder what that suggests for me.

The potential biomarker set/pattern is 78-88% accurate, so I could be in the subset this doesn't match. Or something is going on with my immune system that is more akin to what happens in the young, short-term patients for some reason. Or maybe I don't have ME/CFS. :D

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