CFI Spinal Fluid study from Lipkin and Hornig is out.

[Jonathan Edwards]

Perhaps. But that was offered only as an example.

My point stands: The greater history of testing ME/CFSers has been challenging because of lack of adequate control over who is included in the samples. That includes inadvertent sampling issues due simply to poor definitions and selection criteria.

So, it is very difficult to state concretely whether or not there are already tests out there that can discriminate between us and healthy controls.

I think that argument wears a bit thin if we are talking about diagnostic labs used by people like Dr De Meirleir. If Dr De Meirleir cannot recognise real ME then we don't know if the lab test distinguishes PWME. If he can then where is the paper from the lab that shows the distinction?

The dilution argument is very convenient but if there was a test that could reliably pick out PWME then even a fourfold dilution would not be a major problem - you just have 25% of 'ME' samples more than two standard deviations above the normal mean. I have seen results on PR for cytokines apparently 100 times the upper limit of normal. In the Hornig blood study the mean difference was more like 1.2 times. We do not have scatter plots but I rather doubt she had any values 100x normal. There is a rabbit loose here, or maybe more of a mammoth loose. Research labs need to sit down and sort out between themselves why the results are so inconsistent.

 

[duncan]

Convenience? I'm not sure I follow your logic.

I'm speaking to historical reality. It is no more convenient to me than a chronology.

 

[Jonathan Edwards]

Convenience? I'm not sure I follow your logic.

I'm speaking to historical reality. It is no more convenient to me than a chronology.

I think most scientists would understand what I mean by convenient. Something is convenient if it allows one to discard a piece of data that threatens one's point of view!!

I think at least we are agreed that nobody knows whether cytokine assays in clinical practice are any use to anyone - because the necessary validation has not been done.

 

[duncan]

Ah. Yes, I understood what the word "convenient" signified. But thank you for your explanation.

Unfortunately, what I was questioning was your train of thought that actually led you to feel it had any relevance to our little aside.

As for validation of tests, yes, we are in agreement.

 

[cigana]

FYI, I don't think RED Labs think of the IL-8 test as a marker for CFS, rather it distinguishes between healthy and unhealthy people.
Without wanting to speak for KDM, it's my impression he uses the full range of cytokine tests as some measure of inflammation and state of the immune system (i.e. in order to gauge if the patient will tolerate a particular treatment and/or how they respond to it). He's well aware IL-8 is non-specific, and doesn't seem to pay any particular attention to the very high values often found.

Speaking for myself, it's interesting how the RED cytokine tests matched my treatment. When I was on treatment, they were normal, when I was off treatment, they went back up again (this happened a few times, so it seemed consistent).

 

[leokitten]

I tried to upload the full PDF article for everyone here but the file is too large (2412 KB) for phoenixrising and it rejects it.

 

[Jonathan Edwards]

FYI, I don't think RED Labs think of the IL-8 test as a marker for CFS, rather it distinguishes between healthy and unhealthy people.
Without wanting to speak for KDM, it's my impression he uses the full range of cytokine tests as some measure of inflammation and state of the immune system (i.e. in order to gauge if the patient will tolerate a particular treatment and/or how they respond to it). He's well aware IL-8 is non-specific, and doesn't seem to pay any particular attention to the very high values often found.

Speaking for myself, it's interesting how the RED cytokine tests matched my treatment. When I was on treatment, they were normal, when I was off treatment, they went back up again (this happened a few times, so it seemed consistent).

No, I was not suggesting that anybody used IL-8 as a marker for CFS. It is just that the hugely high values people post on here do not seem to fit with what Dr Hornig found. The question then is whether high IL-8 is a reliable marker even of 'unhealthiness'.

I do not really buy the idea of using cytokine levels as a measure of inflammation, since the body has its own assay system for cytokine mediated inflammation, which is C-reactive protein. Rheumatologists never measure cytokines, they measure CRP. If PWME have a normal CRP then I am not sure raised cytokine levels say very much. They might indicate that there are cytokines doing some other sort of job, but probably not inflammation. There are lots of different aspects to inflammation, and parallel pathways, but most of the cytokine pathways seem to converge on an IL-6/CRP response. I am also not sure how IL-8 would tell us about the state of the immune system.

The basic issue for me is that if these labs can measure something that reliably correlates with clinical problems in PWME then it ought to be easy for them to document this in a paper in Nature that would have huge impact on ME research - especially if their figures are 100 times higher than Dr Hornig! And they could get a $5M research programme grant to solve the pathogenesis of ME. Yet they are not, and nor is Dr De Meirleir. There is a rabbit loose here.

 

[halcyon]

I do not really buy the idea of using cytokine levels as a measure of inflammation, since the body has its own assay system for cytokine mediated inflammation, which is C-reactive protein.

Does this system work across the blood brain barrier? Would inflammation localized mostly in the brain drive up CRP in the periphery?

 

[Jonathan Edwards]

Does this system work across the blood brain barrier? Would inflammation localized mostly in the brain drive up CRP in the periphery?

CRP is made in the liver in response to IL-6 made either locally or coming from the circulation. Inflammation localised mostly in the brain would probably not raise either IL-6 or IL-8 in the circulation. If enough cytokine was being made in the brain to show up in the circulation I think you would very likely either be unconscious or lying in bed with some nasty neurological signs.

I am happy to admit that biology often raises surprises but having spent thirty years studying inflammation, including doing cytokine assays, I am afraid to say that the results I see posted on PR do not make much sense to me. There is no doubt that some pretty bogus assays are out there being sold to PWME - the question is whether this includes the cytokine assays offered by commercial labs.

 

[Seven7]

@Jonathan Edwards I sent you a Message on this topic (had to much personal info to put here).

 

[leokitten]

I tried to upload the full PDF article for everyone here but the file is too large (2412 KB) for phoenixrising and it rejects it.

If anyone wants the full article send me a private message and I can email it to you.

 

[adreno]

I tried to upload the full PDF article for everyone here but the file is too large (2412 KB) for phoenixrising and it rejects it.

@wdb can you help?

 

[leokitten]

I tried to upload the full PDF article for everyone here but the file is too large (2412 KB) for phoenixrising and it rejects it.

Hi everyone I've compressed the PDF to be within PR size limits, attached is the full article

 

[Eeyore]

@Jonathan Edwards -

I agree with you that the values coming out of these laboratories than sell direct to patients are very suspect and likely of little clinical value. It is one of the reasons I have avoided them myself. I think the recent publication by Lipkin and Hornig is a lot more convincing.

I wouldn't assume that CRP is an all-encompassing marker of inflammation. It mostly reflects IL-6 - which does play a role in Th17 and TFH polarization - and CRP obviously is upregulated in many inflammatory processes. However, there are plenty of cases where there is extensive inflammation and normal CRP (commonly found in seronegative spodyloarthritides - many cases have elevated acute phase proteins, but a substantial minority do not, despite showing clinically obvious inflammation).

That said, I'm not at all convinced there is much inflammation in ME. I'm actually inclined to think the opposite. ESR is notoriously low in ME. It may be more likely that the immune system is polarized in an anti-inflammatory direction.

Furthermore, the BBB makes any study of cytokines in central neuroinflammation more questionable, which is presumably why Hornig and Lipkin are looking at CSF as well. The brain has its own immune system - microglial cells - that replicate when stimulated, and are not reconstituted from hematopoetic progenitors in the bone marrow as macrophages are. Microglia behave quite differently from other macrophages. For example, expression of IDO - the first enzyme in the kynurenine pathway - is negatively regulated by NO in macrophages, but not in microglial cells.

 

[Marco]

@Jonathan Edwards -

That said, I'm not at all convinced there is much inflammation in ME. I'm actually inclined to think the opposite. ESR is notoriously low in ME. It may be more likely that the immune system is polarized in an anti-inflammatory direction.

Not to make too much of it but the very low sed rates have always puzzled me. Mine has been 3 or less every time I've been tested.

 

[Eeyore]

Mine has almost always been 0, but it can be as high as 1 or 2. Even Medscape's description of Chronic Fatigue Syndrome mentions low ESR as the most replicable lab result in ME, going so far as to suggest that a high sed rate should make one seriously consider a missed diagnosis.

Unfortunately doctors are trained to look for a high ESR, even though there are a number of well described diseases with low ESR. Still, almost all docs will assume a low ESR is normal. Granted, that is much more often than not correct, but one should look at the whole picture, clinical/lab/history. It all goes to the root of the problem - doctors are not educated about ME at all anymore. If it is even mentioned in med school, antidepressants are suggested. Peers of mine who recently completed medical school have told me it was never mentioned - and these include some of the top medical schools in the US.

 

[Sushi]

Even Medscape's description of Chronic Fatigue Syndrome mentions low ESR as the most replicable lab result in ME, going so far as to suggest that a high sed rate should make one seriously consider a missed diagnosis.

I believe a low SED rate is associated with hypercoagulation--something that seems to be often found in ME/CFS. Many of us have taken the ISAC panel and found coag abnormalities.

Sushi

 

[Eeyore]

Hypercoagulation as measured by d-dimer or increased fibrinogen is strongly correlated with elevated ESR, not reduced.

There may (probably are) coagulation abnormalities. A number of patients seem to have some form of antiphospholipid syndrome (I have tested negative for this). My INR suggests my blood is a bit on the thin side - i.e. hypocoagulable. I also tend to bruise easily (and often have no idea where bruises came from).

Hypocoagulation or low levels of fibrinogen would be more likely to cause a low ESR.

 

[Mij]

My ESR and fibrinogen (ISAC) are both low.

 

[Valentijn]

My ESR has always or nearly always been high since I got sick. CRP was high too once when it was tested. And my inflammation can get bad enough to be visible, especially in reaction eating foods I'm technically not allergic to.

But I've only had ME for 4 years, so maybe I'm in an early inflammatory stage, prior to my immune system throwing in the towel.