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Cytokine signature associated with disease severity in chronic fatigue syndrome patients

TreePerson

Senior Member
Messages
292
Location
U.K.
If we assume none of the participants of Dr Montoya's study was clinically depressed, wouldn't it still be interesting that CFS patients have some of the same distinctive metabolic test results you can find in depression?

I wouldn't say the fact that depressed people might have similar cytokine profiles makes Montoya's study less valuable.
Well I'd be disappointed because I am so sick of the idea that we must be depressed. I'm really hoping for studies that show a marked difference between the two illnesses.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Well I'd be disappointed because I am so sick of the idea that we must be depressed. I'm really hoping for studies that show a marked difference between the two illnesses.
Komaroff wrote one and it was highly cited. He used spectral coherence EEG I think. Its not exactly an easily available test though, at least I have not seen it commercially available yet.
 
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2,087
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.

I agree and would go so far as to say my level of interest in this paper is close to zero.

The thing is, most people on here know or probably think this study is at best a tiny step in the journey to a biomarker or diagnostic test.

Should we be negative towards the media coverage?

I am enjoying it, the BPS folks must be in shock that such a non study is stealing their thunder.

Media are reporting on it the same way they used to with PACE, dont ask any questions just accept what is given.

Kind of enjoyable, my double standards guilt is gone.

Time are getting in on the act too.

http://time.com/4883113/chronic-fatigue-syndrome-lab-test-cfs/
 

Wonkmonk

Senior Member
Messages
1,006
Location
Germany
Well I'd be disappointed because I am so sick of the idea that we must be depressed.

Oh, yes, sure, but I actually didn't mean to say CFS patients are just depressed. I'm certainly not, that I know for sure.

What I was pointing out was that there may be some similar processes going on with respect to cytokines in depression and CFS, and that by itself is - as I think - an interesting finding.

You get fever if you have a common cold or mononucleosis. That doesn't make it the same disease, but some reactions of the body are the same.

With respect to depression and CFS, some reactions of the body may also be the same. But that, of course, doesn't make it the same disease, too. But it's an interesting finding - if confirmed - that some metabolic reactions may be similar.
 

Murph

:)
Messages
1,799
The benefit of this study will be if the data lead to hypotheses.

For me the most intriguing finding is the way the 17 cytokines show a correlation with disease severity.
Screen Shot 2017-08-02 at 8.54.25 AM.png


1. The study presents one hypothesis. They suggest severe patients have a greater 'challenge' present, (a persistent infection maybe) and are experiencing higher symptoms as a result ,while mild patients have dialled down their immune systems to prevent symptoms.

A response with lower levels of cytokines may represent a down-regulatory effort by the immune system in an attempt to attenuate more severe immunopathology, resulting in milder or even no symptomatology. A response with higher levels may indicate that the immune system is dealing with a greater challenge that is more likely to result in immunopathology and symptoms. ME/CFS patients in the mild category (with cytokine levels in the lower range) would be protected from more severe disease through this mechanism, whereas those in the severe category would suffer on the opposite side of the spectrum. In addition to a response to an inflammatory trigger, these cytokine findings associated with severity also suggest a dose–response defect in the metabolism or excretion of cytokines.

2. Another hypothesis might be that they've not observed a persistent feature of the disease but differences in the way people of different severity react to mild activity. From what I gather, patients had to show up at Stanford for the blood draws. Could be the more severe people are seeing the early stages of their PEM response while for mild people this is inside their zone and so they are not exhibiting PEM. In this case the study results would be snapshots of different levels of PEM, rather than permanent features of mild vs severe. (This is something Jarred Younger's longitudinal work may be able to confirm, it's good he was involved in this study.)

3. umm. open to hearing other people's hypotheses...!
 
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alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
3. Another hypothesis is that whatever mechanism is behind the severity its disturbing some deep metabolism or genetics. The cytokine shifts are a result of that, not a cause of the increased severity. Cytokines do not explain ME, but once ME is understood it might explain the cytokine changes. Cytokines might explain some symptoms, but this has yet to be proven.

This hypothesis is not currently actionable because first we need a testable causal mechanism.

We probably need to look at things that change after activity, not independently.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
So how could a lab test tell you if you have CFS or not?
The short answer based on this research is they do not. I want to finish reading the paper before I say much more, it might take me a few days though.

This test might be useful once you have a disease diagnostic test, as it might measure severity. You still need to be sure of the basic diagnosis though.

One implication we might find though is that results we are finding in the more severe patients might not replicate well in the less severe patients.
 

cigana

Senior Member
Messages
1,095
Location
UK
I notice the ME patient subgroups have larger standard deviations for all 17 cytokines.
Does that mean we could identify patients based on how frequently they exceed the standard deviations of the control group?

For example: if a person has 3 cytokines in excess of 2 control standard deviations then they are 50 times more likely to be a patient than a control.
 

pattismith

Senior Member
Messages
3,931
Worms again?

I liked the CFS=Vampirism theory. :whistle:

I always figured I was a kind of zombie! :rofl:

Would we take advantage of drinking freash blood? :confused:

STAT: Blood markers of chronic fatigue syndrome could pave the way to a diagnostic test
Overall, people with CSF only had two cytokines that significantly differed in quantity compared to healthy controls. However, when researchers divided people with CSF into mild, moderate, and severe groups, they found that the levels of 17 cytokines increased with increasing severity of the disorder. Thirteen of these cytokines were proinflammatory, meaning they cause inflammation in the body. The results were published Monday in Proceedings of the National Academy of Sciences.

Do we know which two cytokines they are? Do we know if levels in CFS patients are beyond normal ranges or only slightly more elevated than for healthy controls?
 

user9876

Senior Member
Messages
4,556
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.

I agree the results look strange.

If they claim the results are severity based then I would like to have seen scatter charts of measure vs severity with some form of regression looking for trends. But really I would like to see an activity prior to measurement vs measure scatter chart for both controls and patients; I feel that would be a better proxy for severity at the time of measurement than a question. If we assume they are measuring a dynamic system then fluctuations need to be taken into account. What I would really like to see is multiple readings for the same patient/control over time that looks at severity/activity vs cytokines.

The advantage of a scatter graph/regression approach is it avoids hiding things in arbitrary class boundaries. When does mild become moderate? Does the body suddenly switch to allow a point to be pulled from a different distribution when crossing a threshold?

I worry that each test views each measure as independent (with multi-test correction) rather than doing a multivariate analysis. Which of the variables are correlated (or negatively correlated) and does this start to tell a story.

As a Biomarker there is overlap between the distributions rather than saying that their is a high chance that data is drawn from different distributions they should be giving ROC curves or a confusion matrix with chosen thresholds to show they can use the data to classify (not to mention proper cross validation!).
 

FMMM1

Senior Member
Messages
513
I have a question. Are increased cytokines associated with autoimmunity? Or is it the innate immune system?

Please excuse the rather garbled (rushed reply)

I was listening to a DVD of Ron Davis's talk at the ME Research International ME Conference 2017 last night and (from memory) he said that we don't know what driving the inflammation - it could be autoimmunity -- the thing in the blood turning off healthy cells could be an auto antibody.

If you look at this paper re an autoimmune disease model "Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy" you'll see that initially cells produced high levels of a pro-inflammatory cytokine then switched to producing anti inflammatory cytokines i.e. when the autoimmunity was switched off.

So the high levels of a pro-inflammatory cytokine simply indicate inflammation which could be due to auto immunity or some other cause.

The following study looked for possible targets for autoimmune antibodies in ME CFS but I'm not sure the technique is widely accepted at this time: "Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity".

Not sure how to summarise back to Ron Davis we don't know what driving the inflammation [indicated by high levels of pro inflammatory cytokines] - it could be autoimmunity

PS - I'm not a scientist so the above post has a low level of confidence
 

Londinium

Senior Member
Messages
178
Just a couple more thoughts from me. Running it through my normal mental checklist for such studies I'm reassured by:
  • It is published in a high quality, non-predatory journal;
  • The selection criteria seem ok (1994 CDC criteria and 96%-97% of patients have PEM and/or cognitive impairment);
  • Decent sample size;
  • Reasonable match (race aside) between patients and healthy controls;
  • They've corrected p values for multiple comparisons.
But some worries around:
  • Main finding is due to a subgroup analysis, which appears to be post-hoc;
  • No validation cohort / attempt at replication;
  • Press release doesn't quite match the study (often not the fault of a study's author, it should be noted)
Whilst I agree with some of the criticism above that this doesn't look like it'd provide a useful blood test, given that the patient group cannot be distinguished from healthy controls. That would be enough for me to normally write this off as a decent biomarker study...

...but there is an interesting parallel to be drawn between the results of this cross-sectional study and the (initial, unpublished) results coming from the longitudinal study currently underway at the Younger Lab. They too are finding a correlation between certain cytokines and severity of symptoms, and again finding that whilst this correlation exists the actual cytokine levels on average are within normal tolerances. This seems consistent to me and if the case would indicate that cytokines drive the disease but it would appear that there is some kind of abnormal response to these cytokines or that the cytokines are correlated with another disease process that is doing the actual damage.

So, overall, slightly over-optimistic press release aside, this is an interesting study and I'm interested as to whether this cross-sectional result will be replicated in a longitudinal study.

What I was pointing out was that there may be some similar processes going on with respect to cytokines in depression and CFS, and that by itself is - as I think - an interesting finding.

Which is entirely plausible given the increasing interest in using anti-inflammatory drugs to treat severe refactory depression. There was a BBC report recently on a new trial using auto-immune treatments (I don't think it was Rituximab, it was another monoclonal antibody, IIRC) - I'll see if I can find a link if I don't get beasted at work today.
 
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Messages
3,263
If we assume none of the participants of Dr Montoya's study was clinically depressed, wouldn't it still be interesting that CFS patients have some of the same distinctive metabolic test results you can find in depression?

I wouldn't say the fact that depressed people might have similar cytokine profiles makes Montoya's study less valuable.
Yea, but its probably more likely that depression, as a construct, is just a confused mix of all sorts of diverse problems. Just talking on another thread about intervention studies that use anti-inflammatories to treat certain kinds of depression. They don't really seem to treat the core features of the depression - the sadness and negative thoughts - they mainly reduce the somatic symptoms, fatigue, poor concentration sleep problems etc.
 

Sean

Senior Member
Messages
7,378
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 sure that it rules out cytokines being involved, just that the levels in a given patient are not diagnostic on their own, though they may possibly be of some value in determining the severity.

The consistent overall pattern of severity ranking across the different cytokines is the novel and interesting bit for me. That needs explaining, and could be a fruitful line of inquiry.