Dimensions of pure chronic fatigue: psychophysical, cognitive and biological correlates in the CFS

[Jonathan Edwards]

The use of "psychosomatique" in french is a bit ambiguous. For a few people, it effectively deals with the interaction between mind and body. My previous GP told me that to a certain extend, all diseases are psychosomatic. I don't know if he really meant it or if he wanted me to swallow the pill. But for most of the doctors, it clearly means "there's nothing wrong with you, you've got a psychiatric disorder".
French spoken in Belgium is not very different from that spoken in France, so I guess it means the same.

Thanks Cheshire,
That suggestion of mine was obviously wrong. But it looks from Valentijn's stuff that this was a case of 'let's not upset the journal reviewers, we will intone the mantra and get this published so that people can see the data'. The alternative is usually academic suicide and not much use to patients.

 

[Valentijn]

OK so maybe the first author is a guy called Dan and maybe he works in a psychiatry department. But if he is saying 'still often consider...' is this the right time to put a boot in?

The ridicule is still appropriate - if the journal or other parties required it to be inserted, then they earned in fair and square. And if it's what the authors actually believe despite their own evidence to the contrary, then it's what they deserve.

When an author is forced to add a statement they don't agree with, it would be nice if they offered an explicit explanation somewhere. Though admittedly that isn't always a practical option.

It's all so much easier when authors have written non-journal published solo opinion pieces, and/or made semi-private statements to government agencies that later get revealed, a la Simon Wessely Saves us the effort of trying to decode the various terminologies and contradictions they put out publicly!

 

[Cheshire]

Thanks Cheshire,
That suggestion of mine was obviously wrong. But it looks from Valentijn's stuff that this was a case of 'let's not upset the journal reviewers, we will intone the mantra and get this published so that people can see the data'. The alternative is usually academic suicide and not much use to patients.

I wouldn't say "obviously wrong", as I said, it can be used in the meaning you pointed to. I think the use of words and their deep meaning is a real issue in those diseases with unclear etiology and physiopathology, that's why we can sometimes get easily upset.

 

[Esther12]

It may not be surprising, Esther, but is it sensible? Let's imagine our Belgian scientist is a 32 year old post doc who only has half a salary because the boss cannot get a proper fellowship salary for her. She has tried to publish this in four journals, all of them rejecting it and now at last she gets it in a journal nobody knows much about but at least shows some interest. She works on ME because her sister's boyfriend has it and she thinks it's worth living in a tiny flat on half a salary to do something interesting. She would like to have kids but her boyfriend is out of work and she is desperate to get a permanent job. She follows PR because she is interested in what people think and what she gets is swear words just because she put in a word that she thinks is uncontroversial. And this is a paper that, forgetting that one word, is sufficiently eye catching scientifically for Bob to flag it up for me on another thread. If the data can be confirmed this is exactly the sort of work we are all desperately hoping to see in the journals. It might mean that we have a marker that will allow us to do some decent trials. Why don't we talk about that?

OK I made all that up. But nobody has a duty to do research on any disease in the 'free market' society we live in. People work in science because it interests them. They find themselves in a hire and fire situation where they have to do work on whatever they can get grants on - if they are lucky to get grants. I gave up at 60 because I could never get the grants to pay my staff properly, despite having published one of the most cited papers in the last decade. I am now sufficiently interested in ME (maybe partly because a friend's son has it) to go back to the lab, unpaid. I have spent the last week drawing up diagrams to try to get a better idea of what mediators might be involved, after meeting some really impressive ME researchers last month at IiME. I need to see this paper but can't so far.

Maybe I'm just saying that if somebody finally shows signs of opening the door best not keep kicking it with your left foot! They might shut it again.

I pretty much agree, and may entirely depending upon what is meant by 'sensible' - a word I've come to rather take against recently... It's often not 'sensible' for those in positions of weakness to react against those who have power over them, even if they have been poorly treated. Best to be concerned with what is honest and accurate than concerned about the consequences imo, or else much of the population could end up in grovelling passivity. I had said that that I thought it would be best to be cautious about interpreting their use of the word 'psychosomatic' here, and I've myself not read this paper myself, so can't really comment too much on this case though.

I think people should try to only make informed and reasonable criticisms of other people's work, but I also think that it's best to not be too concerned about hurting the feelings of more powerful sections of society just because that's more likely to cause one problems in the future. It seems that some researchers are willing to misrepresent the evidence in a way which harms patients without being too concerned about our feelings!

Even for just this abstract, we could easily imagine ways in which claiming CFS is psychosomatic could affect the judgements of those with authority over CFS patients in a way which makes their lives more difficult. Personally, I think we've got bigger things to worry about, but the real political power researchers have over patients (particularly for a condition like CFS), does mean that a few stray words from them can have much more impact than a load of patients being angry on an internet forum.

 

[A.B.]

If psychosomatic simply means "symptoms involving the brain and body", why are there no special words to indicate "symptoms involving the gut and the body" or the like?

I think psychosomatic is still code for "psychological problems converted into physical symptoms", it's just that Freud has been discredited so they can't openly say that.

Furthermore, why are treatments for psychosomatic illness mental treatments? CBT/GET is about challenging false illness beliefs, not treating both the body and the mind. CBT/GET proponents are generally against pharmacological treatment.

If it looks like a duck, swims like a duck, and quacks like a duck, then it probably is a duck (even if it has a label that says chicken).

 

[Marco]

Realpolitik aside, these IL8 findings do appear to be a bit of an outlier as I don't recall significantly elevated IL8 as being a consistent finding and 'spot' cytokine assays are notoriously unreliable.

But, these aren't the only Benelux researchers associating IL8 with 'fatigue'. This

http://www.jneuroinflammation.com/content/pdf/1742-2094-9-205.pdf (full text)

paper associates IL1-b stimulated IL8 production with severe fatigue in military personnel post-deployment with the longtitudinal design suggesting that it is reactivity to IL1-b (in vitro) rather than overall levels that determine fatigue levels and that this reactivity is 'acquired'.

'Fatigue' of course is not just a peripheral physiological problem but also a central/behavioural one so no surprise then that IL1-b also promotes IL8 production by CNS microglia :

http://www.jimmunol.org/content/160/4/1944.abstract

 

[Jonathan Edwards]

Don't get me wrong Esther, I have been hurting the feelings of powerful sections of society all my life, despite it costing me an arm and a leg in salary upgrade. Anything that calls itself cognitive behavioural therapy must be as phoney as King Charles 1sts hairdo. It is just that reading the abstract and snippets again and again I cannot find any good reason to think that Dan in the sleep lab is the bogeyman portrayed. What worries me is that if it looks like a duck to a PWME even if it has four legs and says bow-wow, a PWME will call it a duck. If something stinks by all means shout it from the rooftops, but make sure it stinks first. Has any of us except Bob actually managed to read this yet?

 

[Jonathan Edwards]

Realpolitik aside, these IL8 findings do appear to be a bit of an outlier as I don't recall significantly elevated IL8 as being a consistent finding and 'spot' cytokine assays are notoriously unreliable.

But, these aren't the only Benelux researchers associating IL8 with 'fatigue'. This

http://www.jneuroinflammation.com/content/pdf/1742-2094-9-205.pdf (full text)

paper associates IL1-b stimulated IL8 production with severe fatigue in military personnel post-deployment with the longtitudinal design suggesting that it is reactivity to IL1-b (in vitro) rather than overall levels that determine fatigue levels and that this reactivity is 'acquired'.

'Fatigue' of course is not just a peripheral physiological problem but also a central/behavioural one so no surprise then that IL1-b also promotes IL8 production by CNS microglia :

http://www.jimmunol.org/content/160/4/1944.abstract

That all figures Marco. If only one could get a handle on what is going to be consistent here... Maybe some acquired immune cofactor (??antibody) sensitises myeloid cells to IL-8 production. We were discussing last week that it would make sense for a circulating factor other than cytokine to promote local cytokine production to induce symptoms - explaining the paucity of changes in circulating cytokines. But then we seem to have some circulating IL-8 in this one? Wish I could find the paper. Bob?

 

[Esther12]

It is just that reading the abstract and snippets again and again I cannot find any good reason to think that Dan in the sleep lab is the bogeyman portrayed. What worries me is that if it looks like a duck to a PWME even if it has four legs and says bow-wow, a PWME will call it a duck. If something stinks by all means shout it from the rooftops, but make sure it stinks first. Has any of us except Bob actually managed to read this yet?

Yeah, it could well be people were too critical because of misinterpreting the abstract, and I was worried about that myself. Just because there have been problems in the past doesn't mean that we should jump to assuming the worst. I think that the history of unreasonable views and prejudices around CFS, and the often underhand way in which they are expressed, can lead to a degree of paranoia. Also though, I've had a few experiences in the past where I thought other patients were being paranoid and unreasonable, and later came to realise that it was actually that I was ill-informed and naive! There are problems with CFS research that I would not have believed possible a decade ago (perhaps indicating the lazy trust in the processes of science of an outsider).

 

[Valentijn]

Realpolitik aside, these IL8 findings do appear to be a bit of an outlier as I don't recall significantly elevated IL8 as being a consistent finding and 'spot' cytokine assays are notoriously unreliable.

http://cvi.asm.org/content/12/1/52.full (higher - sudden onset)
http://www.biomedcentral.com/content/pdf/1479-5876-7-96.pdf (lower)
http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8986.2010.00978.x/abstract (higher after exertion with more symptoms, normal prior to exertion)
http://cvi.asm.org/content/17/4/582.full (no significant difference during the night)
http://iv.iiarjournals.org/content/25/3/307.full (higher)

So it soundss like severity of symptoms, recent exertion, and/or sudden onset might be factors in ME/CFS patients having elevated IL-8 compared to controls.

 

[Valentijn]

Yeah, it could well be people were too critical because of misinterpreting the abstract, and I was worried about that myself. Just because there have been problems in the past doesn't mean that we should jump to assuming the worst. I think that the history of unreasonable views and prejudices around CFS, and the often underhand way in which they are expressed, can lead to a degree of paranoia.

I'd think it's safest to assume that "psychosomatic" means "psychosomatic" until shown otherwise

 

[A.B.]

Is there any connection between this finding of elevated IL-8, the German EBV findings, and recent research implicating B-cell?

 

[user9876]

That all figures Marco. If only one could get a handle on what is going to be consistent here... Maybe some acquired immune cofactor (??antibody) sensitises myeloid cells to IL-8 production. We were discussing last week that it would make sense for a circulating factor other than cytokine to promote local cytokine production to induce symptoms - explaining the paucity of changes in circulating cytokines. But then we seem to have some circulating IL-8 in this one? Wish I could find the paper. Bob?

I was wondering if there is a wide variety of measurement results because of the different ways they are taken. Light http://www.ncbi.nlm.nih.gov/pubmed/20230500 reported that cytokines change after activity (if I have understood the abstract correctly). So I was wondering if some results are taken after subjects have effectively done some exercise in getting to the hospital for testing and then a wait where as others are done in more accessible places. I know, for example, some hospitals in cities have little close parking so I was wondering if these types of factors could come into play. Thus would more regular testing over time (and home based) be useful?

 

[natasa778]

Wondering if these earlier findings could add anything to the discussion

Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue

As Chronic Fatigue Syndrome (CFS) has been known to follow Epstein-Bar virus (EBV) and other systemic infections; our objective was to describe differences in immune activation in post-infective CFS (PI-CFS) patients and recovered controls. We studied 301 adolescents prospectively over 24 months following the diagnosis of monospot-positive infectious mononucleosis (IM). We found an incidence of CFS at 6, 12 and 24 months of 13%, 7% and 4% respectively.

... Univariate analysis indicated that cytokines IL-2, IL-5, IL-8 and IL-23 were significantly different, in either mean or median expression, in PI-CFS patients compared to subjects that had recovered. To investigate these differences we estimated how individual cytokines might rank on the basis of their performance in assigning subjects to the correct diagnostic class, namely PI-CFS or recovered controls. As expected, the results presented in Table Table11 indicate that as individual biomarkers IL-5, IL-8 and IL-23 ranked consistently in the top 3 positions based on both the area under the receiver operating characteristic curve (AUC) and the Wilcoxon U statistic. In terms of AUC, IL-8 was the single best discriminator between groups (0.34 above 0.50).

 

[WillowJ]

As an aside, I think some people are being a bit hard. Some poor Belgian has spent a lot of time measuring cytokines in a disease and now she finds the patients hurling obscenities at her because her translation is not that good.

I think some of the comments in this thread related to the state of the literature in general (some of mine did, anyway), which is possibly unfair to the authors of this paper.

Still, it's difficult for us patients not to see every word in every paper as a battle in a propaganda war. Probably because we live the situation constantly. I had not previously considered that putting some of the "zombie science" wording in a paper might lead to better publication prospects, and I'm glad you explained this.

 

[Marco]

Wondering if these earlier findings could add anything to the discussion

Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue

Looks like there might be more consistency in these findings than I'd previously thought.

The Production of Interleukin-8 Is Increased in Plasma and Peripheral Blood Mononuclear Cells of Patients with Fatigue
Matthew Sorenson1*, Leonard Jason2, Athena Lerch2, Nicole Porter2, Jonna Peterson3, Herbert Mathews4

The findings demonstrate a clear association between fatigue and IL-8. The ability to identify an inflammatory marker in association with fatigue could provide a means of identifying those who may be at risk for the development of this disorder.

http://file.scirp.org/Html/7-2400110_17756.htm

 

[natasa778]

Wondering if these earlier findings could add anything to the discussion

Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue

This is also quite interesting:
Spinal Fluid Abnormalities in Patients with Chronic Fatigue Syndrome

of the 11 cytokines detectable in spinal fluid, (i) levels of granulocyte-macrophage colony-stimulating factor were lower in patients than controls, (ii) levels of interleukin-8 (IL-8) were higher in patients with sudden, influenza-like onset than in patients with gradual onset or in controls

Klimas et al. found LOWER IL-8 in spinal fluid in their study if I remember correctly? I also came across another study by Broderick using a wider cohort of idiopathic ME, where IL-8 in blood was found to be lower than controls. I cannot find those studies again now, but wondering if they accounted for types of onset in their cohorts. (btw IL-8 seems to be grossly elevated in patients with all types of acute and chronic viral infections, from hepatitis to HIV and HTLV, both in blood and spinal fluids).

Another thing worth investigating apart from type on onset might be the levels of il-8 relative to illness duration - not sure if IL-8 was part of the picture in Lipkin's recent findings, where levels of certain cytokines/immune pathways were shown to change in patients who have been ill for more than 3 years.

 

[alex3619]

As I said earlier, to really analyze a paper requires the paper and not the abstract. That doesn't mean we wont have grounds to criticize it, we might, but it means we will be doing so on accurate information ... and we might just be pleasantly surprised.

Having said that, the casual use of "psychosomatic" is always a red flag to me. Its a signal to watch something closely.

 

[user9876]

Having said that, the casual use of "psychosomatic" is always a red flag to me. Its a signal to watch something closely.

Academics have to publish and sometimes it is easier when using the language used by their peers particularly the language used by journal editors and reviewers. Some may use such language as its common place in the literature without thinking about the semantics. In a different field I've noticed that younger European researchers whose English is not great tend to fall back on stock phrases in an attempt to get the style right. Personally I couldn't even contemplate writing anything in a foreign language.

They seem to have set up an interesting experiment which would also suggest they don't agree with the psychosomatic label.

 

[Leopardtail]

That all figures Marco. If only one could get a handle on what is going to be consistent here... Maybe some acquired immune cofactor (??antibody) sensitises myeloid cells to IL-8 production. We were discussing last week that it would make sense for a circulating factor other than cytokine to promote local cytokine production to induce symptoms - explaining the paucity of changes in circulating cytokines. But then we seem to have some circulating IL-8 in this one? Wish I could find the paper. Bob?

I appreciate the point you are trying to make here Johnathon. There are I think two things in play here:

1. the psychiatric lobby has been less than honest in their research using a wide variety of methods that at best could be called 'bad science' at worst 'designing the research to prove them correct'.
2. there is a fundamental lack of democracy in that most of us cannot access the research without paying a substantial fee. When hundreds of very similar papers are involved that creates a fundamental "dark rooms" culture under which point 1 above is operating.

In short the level of scientific rigour is far too low. Improve that and people will trust the research as per diabetes.