Cytokine signature associated with disease severity in chronic fatigue syndrome patients

[Snow Leopard]

From ScienceAlert: We've found even more proof that chronic fatigue syndrome is a real disease

Why do they choose these ridiculous headlines? Almost all of them do it. Why!?! Do they lack social awareness?

 

[Snow Leopard]

The results of Lipkin et al. did find mean TGF-beta elevated in short-term patients, but with only with a p-value 0.0666.

I don't much care about the arbitrary "short term patients" subgroup, but the overall p-value was 0.0694 (One-way ANOVA/GLM with independent variable of diagnosis (ME/CFS vs. controls))

So certainly a trend, when looked at with a meta-perspective along with the other 10 studies.

 

[Forbin]

My error - Lipkin et al. found mean TGF-beta elevated in short-term patients vs. controls, but the p-value was 0.5251, not 0.0666, as I said. I deleted my erroneous post.

0.0666 was the p-value of mean short vs. long-term TGF-beta (which was also elevated).

My apologies.

 

[Valentijn]

Why do they choose these ridiculous headlines? Almost all of them do it. Why!?! Do they lack social awareness?

At least they've stopped claiming it's the first time That did get a bit old after about the 50th time.

 

[Murph]

I'd be interested to know if the average values for all combined ME patients (regardless of severity) were similar to the control values for the mild-medium-severe distinguishing cytokines, and if the controls had a similar low-to-high range and distribution as the ME patients. If so, it would suggest that those cytokines weren't relevant to developing the disease, but only to severity.

Tables 2 gives a sense of whether the cytokines were different between the groups on average (they weren't except for those two) but doesn't indicate the standard errors.

 

[Daisymay]

"Declared interests

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


Well I've searched through the list of Cleare's publications on his page on the KLC website where he is based ( https://kclpure.kcl.ac.uk/portal/anthony.cleare.html ) and out of 256 papers there is the only one that I can find on inflammation in CFS and it's merely a systematic review so hardly an expert.....plus looking at his papers on other diseases (he's the group leader of the affective disorders group at KCL ie mood disorders) inflammation is not his line of work so not a convincing choice of expert for the SMC to come up with.

Here's the one paper on inflammation and CFS:

https://kclpure.kcl.ac.uk/portal/files/52995555/EAPM16_abstract_Strawbridge_et_al.pdf

Is chronic fatigue syndrome an inflammatory disorder?


Abstract - Aims Chronically elevated inflammation provides a putative target in the search of a meaningful biomarker for chronic fatigue syndrome (CFS). While research has investigated levels of inflammatory biomarkers in people with CFS compared with healthy controls, these groups have not yet been examined at a meta-analytic level. To evaluate the degree and direction of these associations, we identified the existing evidence and combined these.

Methods - A systematic review sought studies that compared levels of inflammatory proteins in people with a diagnosis of CFS. Using data from the included studies, meta-analyses compared levels of biomarkers measured in at least four studies. Results 48 studies were included following the systematic search, and thirteen biomarkers were examined in analyses. Tumor necrosis factor-alpha (TNFa), transforming growth factor-beta (TGFb), c-reactive protein (CRP), interleukins 2 (IL-2), 4 (IL-4), 1-beta (IL-1b) and 12 (IL-12) were elevated in people with CFS compared to controls; the remaining biomarkers (IFNy, IL-1a, IFNa, IL-8, IL-10 and IL-6) were not different between the two populations.

Conclusions - It is not possible at this stage to elucidate whether high inflammation in CFS is of primary pathophysiological importance or secondary to other factors (e.g. stressful experiences, sleep disturbances, physical deconditioning, endocrinological changes), and the role of inflammatory alterations in treatment is not addressed by these analyses. However, these results have potentially important implications for the understanding, classification and treatment for CFS, pending further investigations of inflammatory mechanisms.

 

[Cheshire]

New "expert" reaction from the SMC. Alan Carson (well known for his work on "functional neurological disorders"):

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.”

http://www.sciencemediacentre.org/expert-reaction-to-cytokines-for-chronic-fatigue-syndrome/

 

[Londinium]

New "expert" reaction from the SMC. Alan Carson (well known for his work on "functional neurological disorders"):

“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

Generally I would have some sympathy with this view and that a dualistic view of medicine is unhelpful except that the fear avoidance model explicitly views symptoms as imagined. Montoya is not claiming that psychological conditions are a figment of the imagination; he is criticising the view that ME/CFS is due to false beliefs on the part of the patient. It's the equivalent of treating clinically depressed patients solely with a leaflet that says 'you're not depressed; you just think you are'.

 

[TiredSam]

New "expert" reaction from the SMC. Alan Carson (well known for his work on "functional neurological disorders"):

This "expert" reaction caused an almost imperceptible raise of my weary eyebrow. Is any of this guff getting into the press any more? Prof. Macleod's statement got one sentence at the end of the Times article, almost an afterthought. Prof Cleare was ignored by the Telegraph. Any other newspapers even bothering with what the SMC has to say today?

 

[MeSci]

If you can run without crashing the next day, you don't have CFS/ME.

Or possibly on a subsequent day, if you carry on the activity? I think I used to be able to do this.

 

[Mrs Sowester]

It's made Hacker News!
https://news.ycombinator.com/item?id=14896255
And NPR
http://www.npr.org/sections/health-...elusive-lab-test-for-chronic-fatigue-syndrome

 

[alex3619]

Science Media Centre disagrees. No surprise here.

the study provides no evidence that inflammation actually causes CFS/ME.

This is a/ mostly correct and b/ mostly irrelevant. The researchers do not claim to have proven a cause. They ask the question as to whether symptoms (in this case severity) correlate with cytokines. That is different. Similar issues occur with the rest of the SMC article I have seen so far, and I am about to read the full thing to check for more issues, as well as any good points.

The comments are not as bad as I expected from the SMC given their track record. The biggest issue is the SMC responders do not actually address the paper, but a simplified version of the paper that they construct. Its opinion rather than scientific criticism. In other words, verging on politics not science.

 

[Murph]

It's made Hacker News!
https://news.ycombinator.com/item?id=14896255

There's a good comment on the Hacker News thread that introduced me to a new and relevant concept: the Simpsons Paradox.


>The thing that currently spazs me out is the Simpson Paradox (Yule–Simpson effect)
https://en.wikipedia.org/wiki/Simpson's_paradox

>In short, if your population has two (or more) diseases with similar enough symptoms that they are grouped together, statistical analysis can and does totally fail. And your experiment will produce garbage.

>So what if Chronic Fatigue Syndrome is really caused by a couple of different things, but with converging symptomology. You have a real catch 22 situation. Can't identify the cause of the disease without a consistent experimental group. Can't select a consistent experimental group without a functional test.

If the mild moderate and severe groups truly are distinctly different in cytokine levels it could easily explain the shortage of results we've seen.

Overall there's some smart people in that hacker News thread and some good comments.

 

[Snow Leopard]

The SMC comment has a point, namely these endless cytokine studies which don't attempt to find out why they are raised, don't move the field forward very much.

These are generic studies conducted by people who lack imagination. Doing the easy study, rather than choosing the tricky path - testing highly specific hypotheses.

 

[Mrs Sowester]

I will thank the clever person that sent me the link @Murph
Re. the Simpson Paradox, ME seems (in my opinion) to fall roughly into 3 subgroups (or 2 with the final 3rd made up of misdiagnosed people). That's going to cause more noise.

 

[Murph]

The SMC comment has a point, namely these endless cytokine studies which don't attempt to find out why they are raised, don't move the field forward very much.

These are generic studies conducted by people who lack imagination. Doing the easy study, rather than choosing the tricky path - testing highly specific hypotheses.

I also feel a touch glum about this study. One wonders if in advance they'd be able to say where the research would lead if certain cytokines were high and certain ones were low. With the results we got we don't seem to be able to get anywhere much. It's not clear to me if that's because of the results we got or if that'd be the case no matter what results we got. It's hard to be sure. Maybe the Leptin result is the sleeper one. It certainly ties in with Jared Younger's results.

On the other hand I generally find I understand the relevance of a study only once @Cort writes it up! So there's that to look forward to.

 

[RogerBlack]

Generally I would have some sympathy with this view and that a dualistic view of medicine is unhelpful except that the fear avoidance model explicitly views symptoms as imagined.

I don't believe that is officially the case.
They never come out and say that.
If you dig all the way down the rabbit-hole, you get to something like 'misinterpreting normal symptoms of exercise, anxiety and sleeplessness as being due to a disease state'.

They aren't saying that the symptoms are imaginary, but that the disease is.

 

[Sidereal]

This is a/ mostly correct and b/ mostly irrelevant. They do not claim to have proven a cause.

Sorry to have to be a naysayer but I do think biological studies should be subjected to the same careful scrutiny we subject psychosocial research to. Sadly, I have to agree with the SMC stooges in this instance (although their gleeful negativity is to be condemned).

The authors put out a press release full of rather puzzling, one could say hyperbolic, claims. I guess I'm just not smart enough to interpret their results because I can't fathom why they're saying the things they're saying to the media.

The news articles have quotes claiming that this study shows that ME/CFS is an inflammatory disease, that the symptoms are driven by cytokines and that this could become a diagnostic test. Montoya is also quoted as implying that psychological illnesses are made up which is incorrect (and very unhelpful from a public relations perspective). Ironically, inflammatory findings are much stronger in major depression and schizophrenia than they are in ME/CFS currently, and the reason for that is that those diseases have much more funding and many more researchers working on them.

If you look at the cytokine figure posted by @Simon on page 1, it provides very strong evidence that cytokine levels have nothing to do with symptoms given the strange cytokine-severity relationship where mild patients have lower cytokines than healthy controls, moderate patients have about the same levels as controls and severe patients have higher levels than controls but not really significantly so.

Not only that, but they also failed to replicate the previous massively hyped cytokine study by Hornig et al. so not only does this study add nothing new to our understanding of aetiology of ME/CFS (let alone a diagnostic test), it also refutes previous claims of short vs long-term ME/CFS cytokine 'subsets'.

The only thing of interest here, to my mind, is the TGF-beta finding which confirms what many other studies have previously shown.

 

[notmyself]

This doesn't sound like ME/CFS, btw. You might be barking up the wrong tree. In any case, I think it is best to keep individual cases out of this thread and just focus on the research. If not, the research threads are quickly drowned in test results, regimens and speculation.

If you can run without crashing the next day, you don't have CFS/ME.

Sorry to have to be a naysayer but I do think biological studies should be subjected to the same careful scrutiny we subject psychosocial research to. Sadly, I have to agree with the SMC stooges in this instance (although their gleeful negativity is to be condemned).

The authors put out a press release full of rather puzzling, one could say hyperbolic, claims. I guess I'm just not smart enough to interpret their results because I can't fathom why they're saying the things they're saying to the media.

The news articles have quotes claiming that this study shows that ME/CFS is an inflammatory disease, that the symptoms are driven by cytokines and that this could become a diagnostic test. Montoya is also quoted as implying that psychological illnesses are made up which is incorrect (and very unhelpful from a public relations perspective). Ironically, inflammatory findings are much stronger in major depression and schizophrenia than they are in ME/CFS currently, and the reason for that is that those diseases have much more funding and many more researchers working on them.

If you look at the cytokine figure posted by @Simon on page 1, it provides very strong evidence that cytokine levels have nothing to do with symptoms given the strange cytokine-severity relationship where mild patients have lower cytokines than healthy controls, moderate patients have about the same levels as controls and severe patients have higher levels than controls but not really significantly so.

Not only that, but they also failed to replicate the previous massively hyped cytokine study by Hornig et al. so not only does this study add nothing new to our understanding of aetiology of ME/CFS (let alone a diagnostic test), it also refutes previous claims of short vs long-term ME/CFS cytokine 'subsets'.

The only thing of interest here, to my mind, is the TGF-beta finding which confirms what many other studies have previously shown.

Sorry for my ignorance,are these pro inflamatory cytokines elevated in depression aswell?..i tought depression doesn't involve immune system that much.

 

[Sidereal]

Sorry for my ignorance,are these pro inflamatory cytokines elevated in depression aswell?..i tought depression doesn't involve immune system that much.

Yes.

A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression