Cytokine signature associated with disease severity in chronic fatigue syndrome patients

[M Paine]

On the surface reading this paper is encouraging, but the disparity between these findings and the Columbia findings is disparaging. Hard to know if the differences in findings are related to the cohorts used, the methods, or just that these Cytokine analysis are too volatile to be useful. I don't know. What does seem clear is that there's way more work to do before this is useful in a clinical setting.

 

[BruceInOz]

P values shown are for the significance of the linear trend. Only statistically significant linear trends adjusted for multiple comparisons (P < 0.05) are shown.

View attachment 22764
(from powerpoint slide provided by PNAS so presumably fine to show here).

Although this may provide an interesting piece of the puzzle, I can't see that it leads to a diagnostic test as claimed in some of the media reporting on the study.

The plots of the different cytokine levels for controls, mild, moderate and severe that Simon included in his post above are mostly below normal for mild, consistent with normal for moderate and above normal for severe. This correlation with severity is the interesting part but they cannot distinguish moderate from normal.

 

[Murph]

When I originally saw they found two of 52 cytokines were significantly different, I was worried. That is roughly what you'd expect to find at random.

However, they say they've controlled for false discovery rate. The maths of all that is beyond me but it is apparently an established approach.

https://en.wikipedia.org/wiki/False_discovery_rate

(I'd prefer a method where they test the finding on a validation sample rather than mathematical hijinks, but only because I can grasp the former approach.)

As you can see in this table, the p values are adjusted up by a lot. For examples p=.0365 becomes p=.4914. p=0.0002 becomes p=0.0052. (the adjustment factor varies with how small the unadjusted p value is but that's up to a 26 fold increase in p value). That provides some level of assurance of actual statistical significance.

Anyway, all this means the TGF beta finding seems real and encouraging.

 

[mfairma]

I didn't think that there was any problem with that brief intro on you. I can understand that it probably feels a bit odd for you though, and it does feel a bit like your story is just tacked on at the start.

I appreciate that. If I knew in advance, I might have been less taken back by it.

But, I was more irritated before that surprise when I read that awful Telegraph article.

 

[Murph]

The finding of higher cytokines in more severe patients raises more questions than it answers. Like, why the heck do mild patients have lower cytokine levels than controls. And why do moderate patients seem to be basically the same as the controls? Bad luck if you're a moderate patient wanting a diagnostic test. :\

Unless we want to discount the milds and moderates it is not so simple as cytokines causing the symptoms. I'm tempted to say cytokines could be a downstream issue but that would be speculation.

The linear association between severity and cytokine levels requires some seriously creative hypotheses to explain. It's possible it won't replicate, just like Hornig's duration/severity link.

But.

The 'ascending steps' just keep showing up in the graphic below. There's no equivalent descending steps in any of the 51 cytokines they studied. It's damn intriguing.

 

[AndyH]

Can someone please write a comment telling them that slurs/insults are NOT APPROPRIATE IN HEADLINES!!!!!!!
I mean you don't put slurs in articles about other minority groups, so why us?

https://www.cps.gov.uk/legal/d_to_g/disability_hate_crime/
"Chronic fatigue syndrome is also called chronic fatigue and immune dysfunction syndrome. It describes a serious chronic condition in which individuals experience long periods of fatigue accompanied by physical and cognitive symptoms. Never ever use terms such as: Yuppie Flu; malingering; or hypochondria; as they inappropriately imply personality disorders. Say: a person with chronic fatigue syndrome."

 

[Woolie]

Wow my irony meter just went into the red:

“Contrary to the authors’ assertions, the study provides no evidence that inflammation actually causes CFS/ME. Just two out of 51 measures of inflammation were increased in patients, but this could just as easily be a consequence of the illness and its effects on people’s lives.

I love how these guys have one rule for themselves and another rule for everyone else.

 

[Woolie]

https://en.wikipedia.org/wiki/False_discovery_rate

FDR correction is a way of reducing the chances of getting statistically significant findings by chance alone. If an analysis yields a p value below .05, this means that the chances are less than 1 in 20 that the two samples being compared were in fact drawn from identical populations. You're still not certain (because you can never be certain), but you figure 1 in 20 is a reasonably conservative assessment.

This is okay, but think about what happens when you do 20 comparisons? By the 1 in 20 reasoning, at least one of them will be false positive effect (due to chance).

So researchers consider that we need to be more stringent as we increase our numbers of comparisons.

The Bonferroni method is the traditional way of doing this. You simply divide the p value by the number of comparisons you plan to do. So if you do 1 comparison, you stick with the .05 value. But if you do 2 comparisons (double the chance of a false positive effect), you half that to .025. And if you do 20, your p value for assessing each of these comparisons is .0025.

But some researchers have argued, based on statistical reasoning and simulation studies, that the Bonferroni method may be way too stringent when you are dealing with massess of comparisons. This is because it assumes that all comparisons are independent, which is unlikely to be the case. The FDR method is a less conservative way of correcting. Its the one most commonly used in fMRI studies, were you have thousands of comparisons.

 

[GreyOwl]

Science Media Centre disagrees. No surprise here.

Why would SMC ask a psychiatrist to pass "expert" opinion on an immunology paper?

More on Cleare:

Minor thing. Anthony Cleare testifying on the role stress plays in causing CFS...
March 2012
http://forums.phoenixrising.me/inde...n-the-role-stress-plays-in-causing-cfs.15075/

CORPORATE COLLUSION?
Professor Malcolm, Hooper Eileen Marshall, Margaret Williams
SEPTEMBER 2007
http://www.meactionuk.org.uk/mw/2007/corporate-collusion.pdf

Dysfunctional beliefs in ME/CFS?
Margaret Williams
27th March 2004
http://www.margaretwilliams.me/2004/dysfunctional-beliefs-in-mecfs.pdf

A NICE DILEMMA?
Margaret Williams
15th December 2008
http://www.margaretwilliams.me/2008/a-nice-dilemma.pdf

An open letter to the "Wessely School" psychiatrists
Margaret Williams
14th October 2004
http://www.margaretwilliams.me/2004/an_open_letter_14oct04.pdf

Vilified but Vindicated?
Malcolm Hooper, Eileen Marshall, Margaret Williams
29th April 2005
http://www.margaretwilliams.me/2005/vilified-but-vindicated.pdf

SINISTER SCIENCE?
Margaret Williams
5th June 2004
http://www.margaretwilliams.me/2004/sinister-science.pdf

THE FAILURE OF NICE TO ADDRESS ITS REMIT re: “CFS/ME”
Professor Malcolm Hooper, Margaret Williams
8th December 2007
http://www.margaretwilliams.me/2007/failure-of-nice-to-address-its-remit.pdf

 

[Murph]

Wow my irony meter just went into the red:

I love how these guys have one rule for themselves and another rule for everyone else.

Also, the Science Media Centre quote from Cleare is wrong. He says two cytokines are high. That's not right. Two are different from controls. One high, one low. I've asked on Twitter for them to retract the statement.

 

[IreneF]

i ask in a post earlier about proinflamatory citokines..nobody answers,maybe here i have some more luck..is really no way to lower this pro inflamatory citokines?..literally all my symptoms that i have now are caused by inflamation..i don 't think i ahve any problems with oxygen use,mithocondria or aerobic,anaerobic systems ..i can run longer and faster than most people of my age..So i guess my fatigue and the other symptoms must be caused by chronic inflamation..Doctors in my country are unaware of me/cfs,,When i told him about chronic inflamation he told me that with my normal crp,esr ,fibronogen and complete blood count and immunoglobins all good i will just spend money for nothing doing the citokine panels...cause they will come back normal..

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

 

[A.B.]

Activin is part of the TGF-beta superfamily (what that means, I don't know) and another study this year reported increased activin B levels in patients.

 

[silky]

I have a question. Are increased cytokines associated with autoimmunity? Or is it the innate immune system?

 

[Jill]

Is TGF beta high in rheumatoid or other inflammatory illnesses?

 

[Murph]

Here's one for @Hip and anyone else following the mTor hypthesis. it's pretty interesting - links with nk cells and metabolism.

(nb. beware confirmation bias. The existence of this paper doesn't necessarily imply any special link between mTor and tgf beta. The more I search PubMed for mTor the more I find it is linked to just about everything.)

TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway.
Viel S1, Marçais A2, Guimaraes FS3, Loftus R4, Rabilloud J2, Grau M2, Degouve S2, Djebali S2, Sanlaville A5, Charrier E1, Bienvenu J1, Marie JC6, Caux C5, Marvel J2, Town L7, Huntington ND8, Bartholin L5, Finlay D4, Smyth MJ9, Walzer T10.
Author information
Abstract
Transforming growth factor-β (TGF-β) is a major immunosuppressive cytokine that maintains immune homeostasis and prevents autoimmunity through its antiproliferative and anti-inflammatory properties in various immune cell types. We provide genetic, pharmacologic, and biochemical evidence that a critical target of TGF-β signaling in mouse and human natural killer (NK) cells is the serine and threonine kinase mTOR (mammalian target of rapamycin). Treatment of mouse or human NK cells with TGF-β in vitro blocked interleukin-15 (IL-15)-induced activation of mTOR. TGF-β and the mTOR inhibitor rapamycin both reduced the metabolic activity and proliferation of NK cells and reduced the abundances of various NK cell receptors and the cytotoxic activity of NK cells. In vivo, constitutive TGF-β signaling or depletion of mTOR arrested NK cell development, whereas deletion of the TGF-β receptor subunit TGF-βRII enhanced mTOR activity and the cytotoxic activity of the NK cells in response to IL-15. Suppression of TGF-β signaling in NK cells did not affect either NK cell development or homeostasis; however, it enhanced the ability of NK cells to limit metastases in two different tumor models in mice. Together, these results suggest that the kinase mTOR is a crucial signaling integrator of pro- and anti-inflammatory cytokines in NK cells. Moreover, we propose that boosting the metabolic activity of antitumor lymphocytes could be an effective strategy to promote immune-mediated tumor suppression.

 

[Forbin]

FWIW, The Telegraph updated its article to say:

Leptin tells the brain when the stomach is full and is the reason that people lose their appetite when ill.
http://www.telegraph.co.uk/science/...ory-disease-blood-test-could-easily-diagnose/

 

[Valentijn]

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.

He was involved in research where patients did better on hydrocortisone, so he damned well knows better:

This study shows that low-dose hydrocortisone results in significant reductions in self-rated fatigue and disability in patients with chronic fatigue syndrome. Moreover, about a third of patients had a clinically significant reduction in fatigue, most to a level at or below that of the general population, with accompanying reductions in disability.
Cleare A, Heap E, Malhi G, Wessely S, O’Keane, V, Miell J. Low dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet 1999;353:455-458

 

[Kalliope]

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

 

[Valentijn]

The timing of this couldn't be worse for the BPS crew, who are probably planning a media onslaught for tomorrow, when suddenly a science article in the Telegraph overnight doesn't even give them a mention.

Their current set of quotes seem more blatantly spun and stupid than usual. Are any of the articles even using them?

This seems the most interesting finding. No idea what it means, but it is a distinct pattern.

It might indicate that disease onset and severity of disease are determined pretty independently of each other. Eg, maybe there's one or more triggers, then a genetic inflammatory reaction kicks in.

There's already a lot of mutations on various genes known to regulation immune reactions to specific infections. So these are somewhat common mutations which mean that someone reacts more strongly to an infection, and has a better chance of beating it - but also has a better chance of damage to the eyes and/or heart from the inflammatory reaction.

The mild patients may simply be the ME patients whose genetics or other factors cause their immune system to chill out, even when under attack, whereas severe patients might have immune systems which freak out more.

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.

 

[arewenearlythereyet]

Their current set of quotes seem more blatantly spun and stupid than usual. Are any of the articles even using them?


It might indicate that disease onset and severity of disease are determined pretty independently of each other. Eg, maybe there's one or more triggers, then a genetic inflammatory reaction kicks in.

There's already a lot of mutations on various genes known to regulation immune reactions to specific infections. So these are somewhat common mutations which mean that someone reacts more strongly to an infection, and has a better chance of beating it - but also has a better chance of damage to the eyes and/or heart from the inflammatory reaction.

The mild patients may simply be the ME patients whose genetics or other factors cause their immune system to chill out, even when under attack, whereas severe patients might have immune systems which freak out more.

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.

It would also be interesting to see what happens for patients in remission who have previously been more severe?