What evidence is there that ME/CFS is more autoimmune than chronic infection?

[Mij]

@Hip my understanding is that exercise improves OI.

http://www.niams.nih.gov/health_info/bone/osteogenesis_imperfecta/exercise_activity.asp

"Children and adults with OI will benefit from a regular program of physical activity to promote optimal function through muscle strengthening, aerobic exercise, and recreational pursuits. Specifics of the exercise program vary depending on the person’s age, level of function, severity of OI, and needs and desires. A well-designed program can combine activities to prevent problems as well as to restore function."

 

[adreno]

Right, or it could be that the CSF sample contained too few short duration patients to influence results.

I think you are right about that. I remember reading somewhere that they were mostly long term patients.

 

[Jonathan Edwards]

VanElzakker's theory provides a model to understand the entire biochemical route, detailing how a viral infection can ultimately lead the end symptoms of ME/CFS. Whether this theory turns out to be right or wrong, in any case, it is quite astounding that it offers this explanatory scope. That just that scope in itself makes it very interesting as a theory.

Can you think of any other ME/CFS biomedical model with the same scope? Let me know if you find one.

I had a look at VanElzakker's 2013 Hypothesis paper. The thing is that his 'entire biochemical route' is what everybody else slots into their hypothesis too. I could slot the phagocytes and cytokines into whichever of my 6 theories I was thinking about. His article reads a bit like a PhD student who thinks he is a professor on a radio programme. I don't see the detail I would like to see to make this idea special. The vagus goes everywhere - so it can explain everything, more or less. And he gives the impression of not being too firm on his background microbiological knowledge. I cannot think of any bacteria that are likely to hide in parasympathetic ganglia. Also it does not seem to have a lot to do with Dr Chia's work as far as I can see. And I cannot quite see how it deals with the time scales of PEM.

Without any data to separate it from other ideas I am not overexcited to be honest.

 

[justy]

In the UK in 2011, there were 1.73 recorded cases per 100,000 population:

Im sorry but I cant read the whole thread right now and just want to mention this idea that Lyme is rare in the UK is a massive fallacy - just as the US govt has had to revise their Lyme figures from a mere 30,000 cases a year to 300,000 the UK govt and health depts. have their heads in the sand about Lyme. If you want to read all about the politics around Lyme, diagnosis etc and the disgraceful way Lyme patients have been treated by the NHS and Porton Down then you need to get over to some UK Lyme forums. There are scores and scores of people who remember a tick bite, had a bulls eye rash and still did not receive testing and treatment but later in life were told they had 'M.E'.

Many of these people, once they receive appropriate testing and treatment, which is usually self financed are recovering from their so called M.E/CFS.

This is a scandal on a huge scale and further muddies the waters for people who have M.E but don't have these chronic infections (and that doesn't include me because I have so far racked up 4 infections to date.

To say there is no risk from ticks and Lyme in the UK is not only wrong but endangers peoples lives and health. I live in West Wales and my dog came home one day with over 30 ticks attached to him and the vet gives him a course of antibiotics if that happens to be on the safe side. They are carried not just by deer and sheep but by birds and grey squirrels and foxes so are potentially in every area of Britain. There is also a very high incidence of tick exposure in Scotland and many people infected there.

The Lyme community in the UK is no better treated than the M.E one and we have very many similarities including a crossover patient group.

 

[Sidereal]

Can you explain, Sidereal, how you think listing and comparing ME/CFS symptoms and sickness behavior symptoms amounts to an opinion!?

This is a careful study of these symptoms, and a careful consideration of similarity as dissimilarities between them.

No, you cited the Maes narrative review as evidence that PEM is a symptom of sickness behaviour and that it occurs in cancer. That's his opinion. There is in actuality zero evidence that PEM occurs in any disease other than ME/CFS because it hasn't been studied in cancer or any other disease (referring to published evidence on 2-day CPET).

 

[Sidereal]

To say there is no risk from ticks and Lyme in the UK is not only wrong but endangers peoples lives and health.

I think you are misinterpreting what I said Justy. I wasn't endorsing the official Lyme numbers in the UK or making the claim that there is "no risk" of Lyme in the UK. I was making a relative risk comparison with endemic areas in Europe where risk is huge, even allowing for underreporting of cases in the UK.

 

[justy]

I think you are misinterpreting what I said Justy. I wasn't endorsing the official Lyme numbers in the UK or making the claim that there is "no risk" of Lyme in the UK. I was making a relative risk comparison with endemic areas in Europe where risk is huge, even allowing for underreporting of cases in the UK.

Im sorry Sidereal my comments were not specifically aimed at you - I used your figures that you quoted to talk bapout the general argument against the Lyme hypothesis and got carried away without realising it looked like I was talking to you directly. My apologies.

Just to add - I don't know if this is true but it occurs to me that if it is endemic in these areas then Drs are looking for it and treating it early (which is usually successful). If on the other hand you live in a country where it is not recognised by Gps due to training issues, and is under reported, undertested and undertreated then ypu have many people who become chorncially sick for many years who are then given the wastebasket dx of CFS by lazy GP's.

YES despite my history as a gardener and camping out a lot I have never been offered an NHS Lyme test.

 

[Sidereal]

Im sorry Sidereal my comments were not specifically aimed at you - I used your figures that you quoted to talk bapout the general argument against the Lyme hypothesis and got carried away without realising it looked like I was talking to you directly. My apologies.

No worries.

 

[Sidereal]

Just to add - I don't know if this is true but it occurs to me that if it is endemic in these areas then Drs are looking for it and treating it early (which is usually successful). If on the other hand you live in a country where it is not recognised by Gps due to training issues, and is under reported, undertested and undertreated then ypu have many people who become chorncially sick for many years who are then given the wastebasket dx of CFS by lazy GP's.

YES despite my history as a gardener and camping out a lot I have never been offered an NHS Lyme test.

No doubt there is a knowledge deficit among doctors in places like the UK. Having said that, the infection rates of ticks themselves vary from area to area in Europe so there is a genuine difference in the risk of getting bitten by an infected (rather than a harmless) tick.

 

[adreno]

Doctors seem pretty ignorant about tick borne diseases everywhere - even in high endemic areas.

 

[Hip]

The vagus goes everywhere - so it can explain everything, more or less.

I appreciate that the vagus innervates many organs in the torso, but where the vagus goes is not really that important as far as Michael VanElzakker's theory is concerned. It's whether the vagus is infected or not that is the only issue. It is the satellite glial cells surrounding the vagus that are assumed to contain the infection in his theory.

The beauty of his theory is that it offers an explanation why there are several pathogens associated with ME/CFS: the theory posits that the pathogen itself does not matter so much, all that matters is whether the pathogen can infect the vagus or not.

Enteroviruses are known to infect glial cells, so they certainly stand as candidates in this vagus nerve infection theory.

And he gives the impression of not being too firm on his background microbiological knowledge.

He is from a psychological background, but is making a laudable attempt to bridge psychological symptoms and microbiological phenomena. Something I wish more psychologists would do. He has created the scaffolding of a theory.

Also it does not seem to have a lot to do with Dr Chia's work as far as I can see.

Well, Dr Chia's work has shown an infection of the stomach in ME/CFS, and Chia has pointed out that enterovirus in the stomach can infect and travel along the entire vagus nerve, reaching the brain in about three days, by the mechanism called retrograde axonal transport (RAT).

So the stomach infection might have import for VanElzakker's theory.

Other ME/CFS studies have shown other organs to be infected with enterovirus. The early British studies often took muscle biopsies from ME/CFS patients, and found a very significantly increased prevalence of enterovirus in their muscles, compared to controls.

I think Chia focused on the stomach in his studies simply because the gut is one of the main reservoirs of enterovirus infections (hence the name enterovirus), so possibly he thought that was the best place to look for these viruses. But I don't really know why he chose the gut rather than the muscles as his focus.

There may be no special significance to the stomach infection — apart from a possible role as a route to infecting (or IL-1β-activating) the vagus nerve, which innervates the stomach. The stomach, like the muscles, may just be the place where you will most likely find the infection.

And I cannot quite see how it deals with the time scales of PEM.

This is something I have been thinking about for a while. As mentioned above, I was toying with my own theory of PEM being due to the large increase in IL-6 that occurs after exercise. IL-6 is one of the sickness behavior cytokines.

The interesting thing about IL-6 released by physical exercise is that this IL-6 can remain high in the blood for days, and so this conceivably might be driving PEM, because this is the right sort of timescale for PEM. One study found that "unaccustomed exercise can increase IL-6 by up to sixfold at 5 hours post-exercise and threefold 8 days after exercise". Reference: here.

Even if recombinant IL-6 is injected into healthy subjects, the "subjects reported fatigue and felt more inactive and less capable of concentrating". Ref: here.

IL-6 signaling is quite complex; as you know, IL-6 has both pro-inflammatory and anti-inflammatory pathways. I try to explore how these pathways might be linked to PEM in more detail in this post.


My IL-6 theory is not an original idea, though. This idea was considered by some researchers in the UK a few years back. See the short article on their research I pasted below. These researchers found that ME/CFS patients do not have higher post-exercise IL-6 levels, so concluded that IL-6 from exercise could not be the cause of PEM.

However, that conclusion might be wrong: these researchers were not viewing ME/CFS from the sickness behavior perspective, and many not have considered that ME/CFS patients, who may already be in a state of chronic sickness behavior, might be much more sensitive to the effects of IL-6 than healthy people.

I think that ME/CFS patients may well be much more sensitive to the effects of IL-6 from exercise, and it is this sensitivity which causes PEM.

Is my idea of ME/CFS patients' increased sensitivity to IL-6 feasible?

Well, this study appears to show that IL-6 can amplify the sickness behavior-inducing effects of IL-1β and TNF-α. So therefore, if IL-1β and TNF-α are already present in ME/CFS patents due to chronic infection induced-sickness behavior, the addition of a large release of IL-6 from the muscles during exercise may conceivably greatly increase sickness behavior.

This great increase sickness behavior would then explain PEM, as PEM tends to involve a significant increase of ME/CFS symptoms.


It would be easy enough to test this increased IL-6 sensitivity theory of PEM: all you'd have to do is inject some willing ME/CFS patients with recombinant IL-6 (a similar amount to that released during exercise), and if this then caused PEM to appear, you will have pretty much proven the IL-6 sensitivity theory of PEM.

I'd be happy to try this experiment on myself, but I am one of those rarer ME/CFS patients that does not suffer much PEM after physical exercise.

IL-6 As A Possible Cause of PEM Research Study

UK researchers funded by Meruk looked at the IL-6 cytokine levels during exercise. There are a number of really good reasons to think IL-6 might be involved in the post-exertional malaise experienced in ME/CFS. It’s actually produced from muscles and becomes elevated when muscles contract and, not surprisingly, IL-6 levels go up significantly during exercise. It is also produced by the smooth muscle cells that line the blood vessels – an interesting point given the possible vascular problems in CFS.

Since it has pro-inflammatory characteristics it could contribute to the pain and flu-like feelings experienced in ME/CFS and it actually upregulates IL-10, a cytokine that has been shown to be elevated in ME/CFS studies. Plus, Il-6 levels go up in response to muscle damage.

In short, IL-6 seems like the perfect cytokine for PER but, even though these researchers looked for both it and its receptors, they were unable to find any differences between controls and ME/CFS patients before or after a submaximal exercise test. Important oxidative stress products called F2 Isoprostanes were significantly increased in ME/CFS both before and after exercise – thus validating prior study results.

This investigation has demonstrated that patients with CFS do not have altered plasma levels of IL-6, sIL-6R or sgp130 either at rest or following exercise. F(2)-isoprostanes, however, were consistently higher in CFS patients.


Study: www.ncbi.nlm.nih.gov/pubmed/20230500

Article source: here.

Erratum: I believe the actual IL-6 paper the above article refers to is this one.

 

[Jonathan Edwards]

OK, Hip, so we have some suggested ways that the jigsaw pieces might fit together to be the lady's hat. Let me do a devil's advocate on them, like we used to in the lab on a Friday afternoon after Linda had got a couple of bottles of wine in - the way we got answers, even if dozens of theories lay dead on the floor by the end.

I appreciate that the vagus innervates many organs in the torso, but where the vagus goes is not really that important as far as Michael VanElzakker's theory is concerned. It's whether the vagus is infected or not that is the only issue. It is the satellite glial cells surrounding the vagus that are assumed to contain the infection in his theory.

If it does not matter where the vagus nerve goes then there is no specificity to predictions one might make that could be confirmed by experiment, so that is a pity. There are no data on infection in the nerve itself so I am feeling Michael has no traction yet. And I think we may need to be careful about his broad brush idea of glial cells all around. I may be wrong but I think microglia are found in the central nervous system. In peripheral nerve, like vagus, there will be macrophages around (I am not sure where satellite comes into this - various sorts of 'satellite cell' are something else) but are they microglia? And why should macrophages around a nerve contain organisms rather than macrophages everywhere else? It would not be infection of the nerve, as in Chia's transportation up the axon, because that is inside the nerve. I am finding it hard to get the bits to fit.

The beauty of his theory is that it offers an explanation why there are several pathogens that are associated with ME/CFS: the theory posits that the pathogen itself does not matter so much, all that matters is whether the pathogen can infect the vagus or not.

Yes, but that is a bit embarrassing because different pathogens tend to differ in where they like to hide. EBV hides in B cells. Brucella hides in sacroiliac joints. Syphilis hides in the aorta, TB in the top of the lung. Polio clobbers anterior horn cells. Absolutely nothing is known to hide in the vagus, despite a century and a half of hard work by pathologists. This is where I think Michael might benefit from reading a 1960s infectious disease textbook.

He is from a psychological background, but is making a laudable attempt to bridge psychological symptoms and microbiological phenomena. Something I wish more psychologists would do. He has created the scaffolding of a theory.

Yes but I was from a joint physiology background when I came to find that I might have to learn about B cells and I did a lot of homework before I put pen to paper. A scaffolding without any cross-clamps can be unstable.

Well, Dr Chia's work has shown an infection of the stomach in ME/CFS, and Chia has pointed out that enterovirus in the stomach can infect and travel along the entire vagus nerve, reaching the brain in about three days, by the mechanism called retrograde axonal transport (RAT).

So the stomach infection might have import for VanElzakker's theory.

But it doesn't because it is in a (subtly) different place. The nitty gritty doesn't get you the lady's hat.

Other ME/CFS studies have shown other organs to be infected with enterovirus. The early British studies often took muscle biopsies from ME/CFS patients, and found a very significantly increased prevalence of enterovirus in their muscles, compared to controls.

Again we are wandering into a different theory...

This is something I have been thinking about for a while. As mentioned above, I was toying with my own theory of PEM being due to the large increase in IL-6 that occurs after exercise. IL-6 is one of the sickness behavior cytokines.

Yes, but then you need to have something wrong in muscle, not vagus. If the vagus is mediating an excessive afferent response to exercise the muscle IL-6 will be acting on hypothalamus and any theory that tickles up that causal chain will predict the same thing. IL-6 can certainly remain high for several days after exercise but that does not produce sickness behaviour it produces 'Jesus I overdid it on Sunday, I can still hardly walk and its Wednesday, I must be unfit (not ill)'. The link up is too vague. There has to be a reason why there is PEM rather than coming back from a holiday in Nepal feeling great but shattered. Maybe that is vagus nerve sensitivity but my guess is that pretty much everyone else's theory can slip in a parallel sensitivity somewhere. So yes, sensitivity to IL-6 is fine, but maybe everybody else is using that card too. What I don't get in a vagus infection theory is the weird timing of PEM although I admit that that is hard to explain whatever theory one has.

I can see some useful bits of jigsaw here but I am still not sure that they are the lady's hat.

 

[barbc56]

That's not a study, it's a narrative review. An opinion piece essentially.

Yes, even the title says this.

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior.

The main author* is known for this especially when he writes in collaboration with the second author*. As far as the second author I'm sure he thinks what he writes is true, but IMHO we are seeing the Dunning-Kruger effect. In spades!

This vagus nerve infection / sickness behavior theory of ME/CFS is the only one so far that, theoretically at least, explains the entire disease process from initial infection, all the way up to the final end symptoms (or at least most of the symptoms.

This is a logical fallacy, as there are probably several conditions that fall under the umbrella diagnosis of me/cfs/seid.

The fallacy of the single cause, also known as complex cause, causal oversimplification, causal reductionism, and reduction fallacy,[1] is a fallacy of questionable cause that occurs when it is assumed that there is a single, simple cause of an outcome when in reality it may have been caused by a number of only jointly sufficient causes

http://en.m.wikipedia.org/wiki/Fallacy_of_the_single_cause

Whether this could be one of the causes, I don't know. But I'm wary of statments like this.
Barb

*Don't want to give these authors a google bump but it's probably too late for that.

ETA I can't seem to fix the different size text, even when I select all and change the font size.

Argg, after edit and clicking Save Changes, all the text is now the same size.

 

[barbc56]

fit together to be the lady's hat

This one belongs in the British/American ect. thread. I have never heard this phrase before. I do get the meaning from the context. Now, I just need to find the thread!

 

[MeSci]

So this is where the vagus nerve infection becomes very interesting: this infection may cause both sickness behavior, which explains the bulk of ME/CFS symptoms, and also OI, which covers the remaining ME/CFS symptoms.

I don't think these two can cover all my ME/PEM symptoms. I don't have OI for one, and for another, my PEM is like a cross between flu and a hangover, and I am pretty sure from the symptoms that they are due to liver overload, probably with exertion-induced lactate, and consequent loss of fluid and electrolytes, although I am not sure of the precise mechanism by which this occurs.

And it is an eminently testable theory: once post-mortem studies are performed, so that the vagus nerve in ME/CFS patients can be checked for infection, we will know whether VanElzakker's theory is right or wrong.

That will/would only prove an association, not causation.

 

[Sidereal]

The main author* is known for this especially when he writes in collaboration with the second author*. As far as the second author I'm sure he thinks what he writes is true, but IMHO we are seeing the Dunning-Kruger effect. In spades!

Ouch!!

 

[halcyon]

Absolutely nothing is known to hide in the vagus, despite a century and a half of hard work by pathologists.

Poliovirus, and I believe enterovirus 71, have been found in peripheral vagal neurons in animal models. I'm not aware of any work that has looked at the vagus nerve of ME patients postmortem.

 

[barbc56]

Ouch!!

I tried to be gentle.

 

[Sidereal]

I don't think this disease is a cytokine-driven show. Given the severity of the symptoms (i.e. total incapacitation and pain), if inflammation were the key factor, I'd imagine we'd see some damage on muscle and gut biopsies after months or years of accumulating PEM.

PEM is due to intracellular acidosis IMO. Ramsay and others knew ME wasn't myositis. The persistent non-cytolytic enterovirus in the muscle, if it is there, is not causing obvious inflammation. If I recall correctly, and that may not at all be so due to Swiss cheese memory, in his book he speculated in passing that the virus may be interfering with normal muscle metabolism / enzymatic function producing early and excessive fatiguability.

Goldstein, the epitome of a guy interested in brain loops, had some ideas about the postexertional exacerbation of symptoms involving central mechanisms, I can't remember the specifics but it involved defective IL-1 signalling (which the Hornig CSF study would seem to corroborate).

 

[Jonathan Edwards]

Poliovirus, and I believe enterovirus 71, have been found in peripheral vagal neurons in animal models. I'm not aware of any work that has looked at the vagus nerve of ME patients postmortem.

Yes, but you can find anything in an animal model designed to find it. A lot of these organisms have evolved to interact with tissue specific proteins that are also species specific.

And of course viruses in neurons goes with Chia and not VanElzakker.