Hornig/Lipkin cytokine study out now - press release

[alex3619]

Sorry @alex3619 Thank you for pointing that out.

No need to be sorry, but I thought people might like to know. I hope more doctors start to actually look at the research rather than act like it does not exist.

 

[aimossy]

It was an ME moment... they would like to know I agree about the acting like it doesn't exist. There has been a phenomenal amount of press. It is good seeing it hit TV news.

 

[Sidereal]

they presumably must be referring to long-term effects of high IFNγ in the short-duration patients. (Otherwise, they seemingly have forgotten their own findings of lower IFNγ in long-duration patients, or are giving no significance to it relative to the controls.)

I'm confused by that section of the discussion. While their comments would certainly apply to short duration patients, it would have been useful to highlight the significantly lower IFNγ in long-duration patients. These findings have important clinical implications. They would go some way toward explaining why neurologists and psychiatrists when faced with a patient who has been "somatising" for years/decades get angry when the patient won't "admit" to being depressed and won't take SSRIs. Just a crazy thought but that could be because the patient is not actually depressed. Of course in those cases psychobabblers fall back on "masked depression" explanations etc.

SSRIs are not better than placebo for CFS in general, even in patients with comorbid depression.

Vercoulen et al 1996 Lancet. Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome

Methods In this randomised, double-blind study, we recruited 44 patients to the depressed CFS group, and 52 to the non-depressed CFS group. In each group participants were randomly assigned to receive either fluoxetine (20 mg once daily) or placebo for 8 weeks. The effect of fluoxetine was assessed by questionnaires, selfobservation lists, standard neuropsychological tests, and a motion-sensing device (Actometer), which were applied on the day treatment started and on the last day.

Findings The two groups were well matched in terms of age, sex distribution, employment and marital status, and duration of CFS. There were no significant differences between the placebo and fluoxetine-treated groups in the change during the 8-week treatment period for any dimension of CFS. There was no change in subjective assessments of fatigue, severity of depression, functional impairment, sleep disturbances, neuropsychological function, cognitions, or physical activity in the depressed or the non-depressed subgroup.

Judging by what people write here, SSRIs do seem useful for some symptoms for some patients. Subgroups, subgroups.

With regard to IFNγ/tryptophan/kynurenine/serotonin stuff, I hope researchers read the existing literature before re-visiting the same ground.

Sharpe et al 1997 BMJ. Increased brain serotonin function in men with chronic fatigue syndrome

Though depressive symptoms are common in chronic fatigue syndrome, patients with major depression have unchanged or lowered prolactin responses to D-fenfluramine,2 making it unlikely that chronic fatigue syndrome and depression share a common pathophysiology. [...] Raised brain serotonin activity might explain the excessive fatigue experienced by patients with the chronic fatigue syndrome.3 Increased prolactin release mediated by serotonin in the chronic fatigue syndrome might, however, be a secondary consequence of behavioural changes such as prolonged inactivity or disturbance of the sleep-wake cycle.

Bakheit et al 1992 BMJ Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome

There was no significant difference in baseline prolactin concentrations between patients with postviral fatigue syndrome and healthy subjects or those with primary depression. However, the percentage difference between peak and baseline values was significantly higher in patients with postviral fatigue syndrome than the control groups (one way analysis of variance: women, p = 0.003; men, p = 0.004). CONCLUSIONS--The results suggest upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome but not in those with primary depression. The buspirone challenge test may therefore be useful in distinguishing these two conditions. Larger studies are required to explore the potential value of drugs acting on central 5-hydroxytryptamine receptors in the treatment of patients with the postviral fatigue syndrome.

Buspirone challenge as a diagnostic probe? I wonder if this has been followed up on. @Countrygirl, am I misremembering this or did you mention there was a hospital administering buspirone to ME patients to see if they react badly?

Cleare et al 1995 J Affect Disord Contrasting neuroendocrine responses in depression and chronic fatigue syndrome

Baseline-circulating cortisol levels were highest in the depressed, lowest in the CFS and intermediate between the two in the control group (P = 0.01). Prolactin responses to the selective 5-HT-releasing agent d-fenfluramine were lowest in the depressed, highest in the CFS and intermediate between both in the healthy group (P = 0.01). Matched pair analysis confirmed higher prolactin responses in CFS patients than controls (P = 0.05) and lower responses in depressed patients than controls (P = 0.003). There were strong inverse correlations between prolactin and cortisol responses and baseline cortisol values. These data confirm that depression is associated with hypercotisolaemia and reduced central 5-HT neurotransmission and suggest that CFS may be associated with hypocortisolaemia and increased 5-HT function. The opposing responses in CFS and depression may be related to reversed patterns of behavioural dysfunction seen in these conditions. These findings attest to biological distinctions between these disorders.

 

[A.B.]

The opposing responses in CFS and depression may be related to reversed patterns of behavioural dysfunction seen in these conditions.

Yes, the CFS patients do so much, the depressed patients do so little.

The serotonin hypothesis of depression is probably nonsense anyway. I suspect 5-htp helps me because it raises cortisol (cortisone acetate also improves mood for me).

PS: for a criticism of the serotonin hypothesis:
Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature

 

[Jonathan Edwards]

I am very hapy with this news. I don’t wanne be negative but i don’t think there will be a significant change in the medical community at this point. Also i don’t expect more budget for research. So what did we ‘win’ with this medical campagne? Nothing yet. Paradigma change will only occure with substantial evidence and repliction. This is not the case yet. Cytokines will not lead to objective test because they are not consistent.

For example: il17a is not consistent [1] and Lipkin et al., think it is a very important finding. So his ‘house’ is not build on solid ground.
1. Journal of Translational Medicine 2009, 7:96 Plasma cytokines in women with Chronic Fatigue Syndrome Mary Ann Fletcher* 1,2, Xiao Rong Zeng1,2, Zachary Barnes1, Silvina Levis1,2 and Nancy G Klimas* 1,2 1Department of Medicine, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL USA 2Miami Veterans Health Care Centre, 1201 NW 16th St, Miami, FL USA

Maybe professor Edwards can explain these fluctuations of cytokine?

I have a question for professor Edward: can cytokines flair up or go down by both mental- or physical stress (running)?
Reply

My reading is that the new study is consistent with the Fletcher study in that IL-17 in ME/CFS as a whole is no different from controls. The raised levels are only apparent if the length of disease is considered.

I am beginning to think, looking at all the data plots, that maybe people are reading too much into the likely role of individual cytokines in symptomatology. As someone has pointed out the Hornig study pretty conclusively indicates that plasma cytokines do not cause symptoms directly in ME/CFS - since the symptoms are still there after 3 years.

So one might say that all this stuff is a barrel of red herrings. But I do not read it like that. All that I think we can expect to glean from studies like this is that 'something is moving around out there in the dark'. What the present study adds for me is that testing lots of cytokines you still seem to see something moving out there in the same way. Testing ME/CFS just against controls does not allow one to 'see moving in the same way' because it does not look at dynamic differences within the disease (different durations). I think there may be a really important lesson here. It is reminiscent of the way pharmacologists work. They do not take much notice of an effect until they can see a dose response curve or a kinetic profile over time - which way the thing is moving, so to speak.

I just had an idea that maybe these results could be telling us the opposite of what they first look like. What if in early disease there is a block to some generic mechanism that inhibits cytokine production or even clears cytokines by receptor uptake. Maybe in early ME/CFS cytokine receptor expression is downregulated so the cytokines float about for longer and do not do much. The levels look higher but nothing is happening. We have to think that is just as likely as the opposite. The consistent modest shift in levels between populations looks to me much more like some general shift in regulation of metabolism rather than specific signalling. This could all be wrong but the point is that all we are seeing is 'something moving out there in the dark'. We cannot be quite sure if it is moving left or right but it seems to keep doing the same sort of thing when we look several times. For me this is an essential step in tracking down something hard to detect. Making sense of it comes later, but to begin with all we need is a consistent marker of some pattern of change - you can even use that in treatment studies as a marker. It is no use for explaining why an individual has a particular symptom but it can allow us to track some consistent process in a population.

 

[MeSci]

This article seems to me to be all about trying to downplay the results, and suggest issues with the design of the study.... I gave it an 'unhelpful' rating on the website.

It also describes ME as 'debilitating exhaustion affecting their everyday life that does not go away with sleep or rest.'

 

[A.B.]

The consistent modest shift in levels between populations looks to me much more like some general shift in regulation of metabolism rather than specific signalling.

If this is merely some sort of energy conservation strategy, shouldn't all cytokines be lower and not just the ones that previously were high? Or can the body enact energy conservation strategies on an individual cytokine basis?

 

[cigana]

That Schutzer study used the infamous Fukuda criteria for diagnosing "CFS," meaning that PEM was not a strict requirement, but rather an optional requirement. So it may be hard to say how useful the specific results from it are.

The methodology might otherwise be good though when PEM is required.

It doesn't matter that they used Fukuda if they found unique problems. I would much rather be recognised and treated for a unique problem, than wait for the proof that you can line up a particular biomarker with a particular symptom (PEM). That proof may never come, so why wait for it when we already have unique proof of illness?

 

[Jonathan Edwards]

If this is merely some sort of energy conservation strategy, shouldn't all cytokines be lower and not just the ones that previously were high? Or can the body enact energy conservation strategies on an individual cytokine basis?

When I say 'metabolism' I am referring to cytokine metabolism specifically - sorry. So different cytokines may be affected differently if receptor expression is shifted differently for different groups. Quite a lot of cytokines share receptors in groups, with others sharing other receptors or receptor subunits so 15 cytokines going up-down versus middle and 5 going down-up versus middle would not be surprising.

 

[alex3619]

There could easily be shifts in cytokine receptor expression. This is not tested for. I do know some of us show very high sIL2r, and I am one of them. Issues occur with insulin and cortisol when receptor function or numbers are blocked. These are two I am familiar with, but I would suggest the same holds with all such receptors. There may also be common signaling pathways between them that can be overwhelmed.

One theory I find intriguing, and am awaiting publication, is that beta cortisol receptor expression is increased, which suppresses cortisol function regardless of actual cortisol levels. I am also aware that some with folate or B12 excess might not be utilizing these vitamins. More of something does not always mean an excess in functional terms.

Looking at insulin, for example, problems in insulin receptor functioning or subsequent signalling probably give rise to insulin resistance, and feedback loops of various kinds lead to even more insulin being released. More insulin matches more resistance.

A cytokine function suppression is therefore one possibility. One, one, out of many, unfortunately.

Research, research, research. We have to start somewhere though.

 

[Jonathan Edwards]

Yes, Alex, I was also wondering if there might be some relation to corticosteroid receptor dysregulation or blockade. The cytokine results might be a knock on effect from an HPA axis log jam. As you say, there are so many possibilities but this may be a start.

 

[lansbergen]

Yes, Alex, I was also wondering if there might be some relation to corticosteroid receptor dysregulation or blockade. The cytokine results might be a knock on effect from an HPA axis log jam. As you say, there are so many possibilities but this may be a start.

I tried cortico on two animals and the reaction scared me. Luckely levamisole saved their live. .

After the first one I said never again but the pressure to do it was so big I did another one.

Both were longtime sufferers.

 

[Gijs]

Thank you for you reply professor Edwards.

Alex do you refer to this article?
Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression.
Fatigue: Biomedicine, Health & Behavior. 2013 Oct 2. doi: 10.1080/21641846.2013.838444.
Meyer JD, Light AR, Shukla SK, Clevidence D, Yaled S, Stegner AJ, Cook DB

 

[Countrygirl]

Buspirone challenge as a diagnostic probe? I wonder if this has been followed up on. @Countrygirl, am I misremembering this or did you mention there was a hospital administering buspirone to ME patients to see if they react badly?

Yes, you remembered accurately. The Wonford Hospital in Exeter UK used to administer buspirone to determine, in their view, whether a patient had ME. If the patient keeled over in 20 minutes that was considered to confirm the diagnosis. Eventually, however, it came to be regarded as unethical to deliberately exacerbate a patient's condition in this way and it is no longer used. I am informed (and from my own experience) that ME is not generally accepted at the hospital as anything other than a mental heath condition.

 

[MeSci]

I tried cortico on two animals and the reaction scared me. Luckely levamisole saved their live. .

After the first one I said never again but the pressure to do it was so big I did another one.

Both were longtime sufferers.

Sufferers from what?

 

[MeSci]

Thank you for you reply professor Edwards.

Alex do you refer to this article?
Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression.
Fatigue: Biomedicine, Health & Behavior. 2013 Oct 2. doi: 10.1080/21641846.2013.838444.
Meyer JD, Light AR, Shukla SK, Clevidence D, Yaled S, Stegner AJ, Cook DB

There is a thread on that study here.

 

[Bob]

I just had an idea that maybe these results could be telling us the opposite of what they first look like. What if in early disease there is a block to some generic mechanism that inhibits cytokine production or even clears cytokines by receptor uptake. Maybe in early ME/CFS cytokine receptor expression is downregulated so the cytokines float about for longer and do not do much. The levels look higher but nothing is happening.

The latter scenario could potentially explain why there is no significant change in symptoms at 3 years despite a change in cytokine levels: if cytokine receptors are blocked/inhibited then the specific level of circulating cytokines may make little difference in terms of their effect.

It's rather a complex scenario to get one's head around though, and it raises many questions e.g: which receptors are blocked? (i.e. are all of them blocked or just selected receptors?); why are they blocked?; what is blocking them?; why do they remain persistently blocked?; what is the effect of the blockage? (i.e. does the blockage stimulate or inhibit the receptor expression?); why are so many cytokine receptors apparently blocked simultaneously? (i.e. do the various cytokine receptors have adequate similarities or shared features such that they could be inhibited by a single protein, pathogen or other single item?)

Cytokine research may help lead us in the right direction but I can't help feeling that abnormal cytokine levels, in themselves, are simply a downstream indicator of a fault in some other part of the immune system. It's such a complex system that a change in levels of various signalling pathways doesn't necessarily tell us much in itself. It gives us clues to follow.

 

[lansbergen]

Sufferers from what?

The infection I suspect

 

[MeSci]

The infection I suspect

But what infection? Your message is very puzzling, talking about giving something to animals which have suffered from something, and I can't understand what it means for people with ME.

 

[aimossy]

I love the paper - I think it's full of puzzle clues and new avenues of thinking around the problem, as many are highlighting. What about CD40 as a possible lead to something criminal elsewhere, wasn't it low in first 3yrs and uncoupled in long duration?