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expert reaction to cytokines for Chronic Fatigue Syndrome

Researchers publishing in Proceedings of the National Academy of Sciences (PNAS) report a link between chronic fatigue syndrome and cytokine concentrations that correlate with the disease’s severity.


Dr Alan Carson, Reader in Neuropsychiatry, University of Edinburgh, said:

“Researchers from Stanford University have reported a link between CFS and a number of immune-system cytokines, whose concentrations in the blood correlated with the disease’s severity. The laboratory aspects of the study are well conducted and emerging laboratory techniques have allowed this study to be conducted with greater precision than previous reports.

“What is less clear is who the patients were and the description of how they came to be recruited, their diagnostic work up and concomitant medication use is much less persuasive. That said it I wouldn’t doubt the main findings that there are alterations in cytokine response in the condition and that elevated TGF-β in particular is elevated. There have been reports on this for the previous 2 decades and a meta analysis of 38 papers in 2015 demonstrated it as a consistent finding (Blundell et al 2015).

“As that 2015 paper commented, what is less clear is what that means – one of the signature features of ME/CFS is post exertional malaise; patients feel awful after activity. The previous studies of TGF-β showed its levels did not correlate with this core phenomenon, which begs the question of what the inflammatory role actually is.

“This study therefore confirms what was already known but doesn’t take the field forward. In particular as it was cross sectional in nature we don’t know whether the findings were the cause or the effect of living with ME/CFS or indeed the result of a confounding factor – e.g. antidepressant medication may cause increases in TGF-β and sleep disturbance has an effect on cytokines.

“It is highly unlikely, contrary to the researchers claim, that this will lead to a blood test any time soon – not least on the grounds it has been well known for some time but the elusive test is no closer.

“One area that does deserve some criticism is in the associated press release rather than the paper itself. It quotes Montoya, who oversees the Stanford ME/CFS Initiative, as saying:

I have seen the horrors of this disease, multiplied by hundreds of patients,” he said. “It’s been observed and talked about for 35 years now, sometimes with the onus of being described as a psychological condition. But chronic fatigue syndrome is by no means a figment of the imagination. This is real.

“Although perhaps not his purpose the comments suggest that patients with psychiatric or psychological conditions have imaginary conditions and patients with inflammatory disease are somehow more worthy and have ‘real’ illness. In fact the understanding and acknowledgement of altered immune system cytokine response in depression is far more elucidated; and known to be associated with disease development rather than a response to the condition. This perhaps reflects a general problem within ME/CFS research and its associated politics that too often it is played out against a 19th century view of the brain and its function rather than a modern integrative neuroscience perspective.”


Prof. Anthony Cleare, Professor of Psychopharmacology & Affective Disorders, King’s College London’s Institute of Psychiatry, Psychology & Neuroscience, said:

“Contrary to the assertions in the press release, the study provides no evidence that inflammation actually causes CFS/ME. Raised levels of inflammatory markers have often been found in studies of CFS/ME, and this study does find one out of 51 of the measured cytokines raised and another one lowered in CFS/ME patients overall compared to control subjects. A larger number of cytokines were found to be lower in mild cases but higher in severe cases of the illness. However, Increased inflammation could just as easily be a consequence of the illness and its effects on people’s lives. For example, CFS/ME sufferers may have sleep problems or depression, both of which can cause elevated inflammation, and neither of which were measured in this study. They may also take medication that can alter the cytokines measured in the study, and the authors do not fully state what medication patients were taking.

“Thus, it is premature to assert that CFS is an inflammatory disease. There remains no basis to use cytokines as a diagnostic test.

“Importantly, there is no indication that the course of illness is linked to any measures of inflammation, or that treating inflammation benefits patients, which would be needed to suggest this is an important step in helping patients with this serious and disabling illness.

“What we need are longer term studies that examine the course of CFS/ME over time, to see whether raised inflammation is linked to the course or progression of illness, and studies on whether giving medicines to reduce inflammation improves the illness.  Neither this study nor the previous body of research in the field suggest this is the case.”

  *Prof. Cleare’s comment was amended at his own request to correct comment about the ‘authors’ assertions’ to ‘assertions in the press release’, statement about ‘two out of 51’ to ‘one out of 51 measures of inflammation’ and to highlight that the ‘authors do not fully state what medication patients were taking’ (14:57 01/08/2017)


* ‘Cytokine signature associated with disease severity in chronic fatigue syndrome patients by Montoya et al. published in Proceedings of the National Academy of Sciences on Monday 31st July.


Declared interests

Dr Carson: “I chaired the writing group for Scottish Good Practice Statement on ME/CFS. I have given independent testimony in Court on a range of neuropsychiatric topics including various fatigue states (50% pursuer 50% defender).”

Prof. Cleare: “Professor Cleare has published papers and hold grants investigating links between inflammation and CFS.”

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