Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of CFS

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Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of Chronic Fatigue Syndrome
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Russell, Alice, Hepgul, Nilay, Nikkheslat, Naghmeh, Borsini, Alessandra, Zajkowska, Zuzanna, Moll, Natalie, Forton, Daniel, Agarwal, Kosh, Chalder, Trudie, Mondelli, Valeria, Hotopf, Matthew, Cleare, Anthony, Murphy, Gabrielle, Foster, Graham, Wong, Terry, Schütze, Gregor A, Schwartz, Markus J, Harrison, Neil, Zunszain, Patricia A and Pariate, Carmine M (2018) Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of Chronic Fatigue Syndrome. Psychoneuroendocrinology. ISSN 0306-4530 (Accepted)

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Abstract
The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger.

This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present.

Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients.

Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1±1.5 vs. RF: 4.0±0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p = 0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls.

Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.

From: http://sro.sussex.ac.uk/80506/
 
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(Prof Carmine Pariante, Kings College London)


This is the youtube presentation of this study. Unfortunately he doesn't mention his kynurenine or tryptophan findings in this presentation...

If anyone has the article, I'd like to know the details of kynurenine / tryptophan findings.
 

Research 1st

Severe ME, POTS & MCAS.
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Sadly this is a hopeless paper by the Wessely School (Organic ME CFS deniers) on Chronic Fatigue.

KCL PACE trial cohorts are F48.0 psych patients for heaven's sake. Even if it was CDC criteria, that is still useless.

Their focus is fatigue in functional somatizers who respond to CBT/GET so irrelevant to us, but who they refer to as CFS/ME sufferers.

This means they can attribute ANY CAUSE to fatigue. It could be psych, it could be a virus, it could be a flying unicorn.

We all knew about interferon and cytokines decades ago in CFS research and psychiatric patients are well known to have the immunological findings they're discussing- so this paper is well avoided.

We also knew ages ago that MS patients given interferon have some CFS flu like reactions. Nothing is new and fatigue has nothing to do with living with ME especially when your research cohorts are the pathetic Oxford CFS criteria, designed by ME denislists which means the patients can have active depression and other history of past psychiatric disorders - ME and even CDC criterias don't allow for this or you end up researching depression associated fatigue- woops - accidentally on purpose and then link back to psychoimmunogenic stress states and a non specific infection thus veryfying everything the Wessely School have been saying since the 1990's, again by total fluke at the same university medical school. By chance....and Wessely is your colleague.....by chance too.

So this paper is the usual. Not researching ME patients with organic illnesses that occur in ME such as: heart arrhythmias, seizures, allergies, arthritis, osteoporosis, organ disease (gall bladder, liver, kidney), hypovolemia in subsets, adrenal failure in subsets, gastroparesis, PCOS, inflammatory disorders like Lupus or PMR etc, cystitis chronic infections, multiple autoimmune diseases, cancer and on and on. Note in ME patients, the word fatigue hasn't come up once. Strange that.....
 
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bertiedog

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This study felt to me several years behind the current research that is taking place with Ron and his group, plus Nancy Klimas' group, Jarred Younger etc.

I don't have any qualification in science which is quite unhelpful at this time but when I heard about this study that has been widely promoted on the BBC (I heard it first at 3 am when I should have been asleep) I had to pinch myself that I wasn't in fact dreaming because I think we knew about ME being involved in an overactive immune system such a long time ago so it was certainly no big deal. On the other hand I suppose its typical of the way our illness is addressed (or not) in the UK.

Pam
 

Richie

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Hello Research1st


KCL PACE trial cohorts are F48.0 psych patients for heaven's sake. Even if it was CDC criteria, that is still useless.

Their focus is fatigue in functional somatizers who respond to CBT/GET so irrelevant to us, but who they refer to as CFS/ME sufferers.
Given results of CBT/GET are so poor, even without changing the goalposts, who are these patients? I imagine KCL cohorts are a mixed bag. I ended up in CBT/GET years ago elsewhere and never had a trace of "fear of exercise" etc.

I'd like to know about ongoing IFN gamma, TNF alpha, eotaxin - provoked if appropriate (I'm not a biologist) and whole blood.
How does this fit in with TH1/TH2 dominant subgroups, how would these patients perform on VoMax 2 day test, and of course they are hep c so application to us is speculative.

Let's hope some good use is made of this, and that it does not end up down the "it was an immune hit" but now it's "functional" and btw, "functional = psychological".

Good thing about Pariante is that he is interested in immunological issues in depression and treats them, so in the case of mental illness he does not reason that the organic is irrelevant down the line from some original life event/organic insult, quite the opposite. But for depression he has ongoing markers, which is why the other cytokines might be interesting esp as IFN g, TNF alpha and eotaxin are implicated in some FM cases. Maybe his kynenurine/tryptopham ratios suggest to him that they are not relevant in post hep, but then they might not be relevant in TH2 activated ME?

More research and cooperation across groups is urgently required.
 

Richie

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Sorry some of the cytokine data is there in the sciencedirect paper.

TNF alpha is close to control levels in their CFS but considerably higher in post IFN alpha resolved fatigue and even more in persisting fatigue. Does pose the question as to what CFS constitutes here incl stage of illness.

Has there ever been a clear answer as to relationship between raised whole blood TH1 cytokines , raised provoked Th1 cytokines, length of illness, symptoms, VOx max performance, dorsal root ganglionitis contrast with TH2 elevated patients etc etc?

We'll never get anywhere fast without proper definitions, sub groups, correlations across biomarkers and between biomarkers and symptoms.
 

andyguitar

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There are some positive things about the way this research has been reported in the UK media. The general public who have a quick read of what is being said in most UK newspapers, will be a bit more likely to see ME/CFS as a physical illness AND one that they can relate to.
 

nandixon

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I like this study quite a lot, which is ironic given who the authors are. It's actually a potentially very important study because of the insight it may give into the underlying mechanism(s) that may lead to the development of ME/CFS. And that's regardless of whether the individuals who developed “persistent fatigue” (PF) after treatment with interferon-alpha really had ME/CFS or not - because there's a good chance that the mechanisms may overlap.

I believe that the single most important finding in this study is that, 4 weeks into treatment, the level of the cytokine interleukin-6 (IL-6) in the PF patients was more than double that of the individuals who didn't go on to develop PF (p = 0.011).

This finding appears very consistent with Dr Nancy Klimas's model for how the onset of ME/CFS may occur. Her ME/CFS model proposes that an immune activation event occurs on a concurrent background of an overactivated hypothalamic pituitary adrenal (HPA) axis. (Her Gulf War Illness model similarly proposes that an organophosphate exposure occurs on a background of an overactivated HPA axis. Both models were developed using US Department of Defense supercomputers, and in the case of GWI has already been validated in a GWI animal model.)

There are several cytokines that are known to increase the activity of the HPA axis, including IL-1 beta, TNF-alpha and, perhaps most importantly, IL-6. In fact there are apparently IL-6 receptors at multiple levels of the HPA axis, including the hypothalamus and adrenal glands.

It's been found that incremental increases in IL-6 result in corresponding increases in cortisol. It's also been found that IL-6 is capable of activating the HPA axis (increasing adrenocorticotropic hormone, ACTH) even in the absence of corticotropin-releasing hormone (CRH).

So it seems very likely that at at least week number 4 that the PF patients experienced an overactive HPA axis, at least relative to the patients who didn't go on to develop PF.

Why the levels of IL-6 increased so much in the PF patients is another matter and may be related to differences in underlying genetic propensities.

Just to briefly mention also that the (transient) elevation in IL-6 may also provide a possible mechanism for the development of over-activated CD8+ T cells, per Mark Davis's work, as this appears to be a known effect.

So I think this was actually quite a valuable study and we were lucky it was able to be done just before the use of IFN-a for the treatment of hep C was phased out. When I first saw the abstract a couple of weeks ago I immediately recognized the significance with respect to Dr Klimas's work because I'd been researching alternative ways to implement a treatment based on her model and this study gave me additional confidence in that model.

(Klimas has clinical trials in both GWI and in postmenopausal ME/CFS women currently underway using a two step sequential treatment of etanercept followed by mifepristone to first dampen the inflammatory process and then reset the HPA axis.)

@Janet Dafoe (Rose49) (Not sure if Ron Davis might be interested in this.)
 

Wayne

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I haven't read the whole study yet, but I have a hope it might become a catalyst for changing some of the dynamics regarding the whole vaccination mania our present culture is confronted with.

If it were to become commonly accepted that an "exaggerated immune response" is responsible for ME/CFS, then why wouldn't the whole concept of vaccinations--which are designed to created "exaggerated immune responses"--be called into question, in a major way? Especially since there's so much evidence that ME/CFS often starts after various vaccinations, particularly (as I understand) Hep. C and HPV (Gardasil).
 
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andyguitar

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Yes @Wayne the relationship between vaccination and ME/CFS has been around for a long time and it's odd that it is often overlooked. Particularly as the adverse effects are well documented in the 'Healthy' population.
 

pattismith

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Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of Chronic Fatigue Syndrome

" CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls."
low Kynurenine/trypto means low IDO activity. This very interesting because in Sickness Behaviour, the ratio is more often high (associated with IDO activation)

https://forums.phoenixrising.me/ind...arthritis-ido-gtp-ch1-bh4.63072/#post-1029438

;;;