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

[msf]

Oh, and in the absence of much for either model, I think the best patients can do is to try to work out which makes more sense in their own case. For me, the evidence that I have a chronic infection is far more substantial than the evidence that I have a purely autoimmune condition. Leokitten, how confident are you in the Lyme diagnosis?

 

[msf]

Sorry, bit of a tautology there: the evidence that I have a chronic infection is far more substantial than the evidence that the one auto-antibody I have tested positive for is causing all my problems.

 

[Hip]

I was simply referring to all the negative tests PWME have in clinical practice. We still have, as far as I know, no convincing study showing that PWME have more evidence of ongoing infection than normal people.

Have you glanced at all the British studies (a concise overview given here) on enterovirus in ME/CFS, which were conducted from the early 1980s onwards? This research culminated with the work of John Chia in the US in the mid-2000s, which replicated these British findings. These studies, and there are quite a few of them, found enterovirus RNA was as much as 20 times more prevalent in ME/CFS patients compared to healthy controls.

 

[Snow Leopard]

There is an underlying assumption in many of the presented viewpoints above, that all ME/CFS cases are the same.

As for me, I've never had any of the usual infectious suspects so none of those can explain my illness.

 

[Hip]

As for me, I've never had any of the usual infectious suspects so none of those can explain my illness.

Are you saying you were tested negative for enterovirus by either ARUP Lab, or by stomach tissue biopsy?

 

[Snow Leopard]

Are you saying you were tested negative for enterovirus by either ARUP Lab, or by stomach tissue biopsy?

Not by PCR, sadly as it is not available in my country.

But my illness was triggered directly after a vaccination, not a virus. Well actually, that's not true, but it would mean that I contracted Polio from the live attenuated vaccine and it was an ongoing infection...

 

[Jonathan Edwards]

Have you glanced at all the British studies (a concise overview given here) on enterovirus in ME/CFS, which were conducted from the early 1980s onwards? This research culminated with the work of John Chia in the US in the mid-2000s, which replicated these British findings. These studies, and there are quite a few of them, found enterovirus RNA was as much as 20 times more prevalent in ME/CFS patients compared to healthy controls.

I have not had a chance to look at all of these but a number of them do not really address the central question. Those that are controlled studies that I have seen have significant technical issues to query. It may be that there is something here that should not have been ignored but the resume I had from a colleague who used to work with several of the virologists involved was that in the end it tends to be hard to know what to make of finding enterovirus particularly in gut. I will keep an eye out but I am not persuaded so far.

 

[msf]

I value Prof. Edward's input on this forum, and I have learnt a lot from autoimmune disease from him, but if there is not sufficient evidence to say whether ME is autoimmune, infectious, or something else, perhaps PR should consider inviting a viral expert and an expert in chronic bacterial infections onto the board. Then we would really see some fireworks! I know medicine and science in general aren't democratic, but I think there is something to be said for having a mix of specialties, particularly when the exact nature of the disease is still to be determined.

 

[Hip]

in the end it tends to be hard to know what to make of finding enterovirus particularly in gut.

I think a gut enterovirus infection could easily explain ME/CFS symptoms, by the following mechanism:

As you undoubtedly know, the sickness behavior state, which is induced by the inflammatory cytokines IL-1β, TNF-α and IL-6, has symptoms very similar to those of ME/CFS, and it has been proposed that ME/CFS may simply be a chronically maintained state of sickness behavior (at least in part).

We know from Jonathan Kerr's work (see my post here) on parvovirus B19-triggered ME/CFS symptoms that parvovirus infection induces these exact three inflammatory cytokines in the body. So that's good indication that the IL-1β, TNF-α and IL-6 may play a causal role in precipitating ME/CFS symptoms.

So this is interesting, because we have both an explanatory theory (the sickness behavior mechanism) and empirical evidence (Kerr's studies on parvovirus) that IL-1β, TNF-α and IL-6 may be may causing ME/CFS.

And when I checked myself on PubMed, I found that one commonality of nearly all ME/CFS-associated pathogens was the fact they all induce these particular three cytokines. Not all pathogens do this. So that is further evidence of the involvement of these cytokines in ME/CFS.


So what is so special about an enterovirus infection in the stomach? Well, the vagus nerve, which is the nerve that triggers sickness behavior when it detects the cytokine IL-1β, innervates much of the stomach. Thus, if even this low-level "smoldering" enterovirus infection of the stomach is only chronically producing small amounts of IL-1β, the close proximity of this infection to the vagus nerve may cause a significant and chronic triggering of sickness behavior.

So here you have a nice theory of how an enterovirus infection of the stomach may cause ME/CFS.

The above theory is just a variation of Michael VanElzakker vagus nerve infection / sickness behavior theory of ME/CFS.

 

[snowathlete]

We don't know. (And more clinicians should admit that, even if they have ideas).

But, I am far less convinced by the idea of bacteria being causative, than I was a couple of years ago.

In my opinion it is probably an autoimmune/auto inflammatory illness perhaps triggered or maintained by virus.

I think it's best to be wary of any doctor who is attached to a pet theory, such as your LLMD particularly in the face of conflicting evidence (such as Rituximab so far looking very promising).

 

[halcyon]

I was simply referring to all the negative tests PWME have in clinical practice. We still have, as far as I know, no convincing study showing that PWME have more evidence of ongoing infection than normal people.

And what about all the people that haven't been tested? I've started a poll on enterovirus testing, and so far the majority of patients that have responded haven't even been tested for these viruses. We can't say something doesn't exist if we've only looked under the streetlight.

 

[msf]

Who is LLMF? I didn't notice this member in the thread. Without knowing what there theory is, I'm not sure if Rituximab would be conflicting evidence, since a lot of the advocates of chronic infection talk about an auto-immune element in the illness.

 

[Jonathan Edwards]

And what about all the people that haven't been tested? I've started a poll on enterovirus testing, and so far the majority of patients that have responded haven't even been tested for these viruses. We can't say something doesn't exist if we've only looked under the streetlight.

That is non-sequitur halcyon. The relevant numerator is the number of chronic infections indicated by test and the denominator is the number of times it has been tested for. Instances of not testing do not affect the mathematics. If we are to have a rigorous scientific argument I think we need to keep to basic logic!!

 

[msf]

I agree, but as someone pointed out in the recent Lyme thread, absence of evidence is not evidence of absence. Especially given the fact that ME is a diagnosis of exclusion, and that this will remove positive results (for Lyme, for example) from the sample.

 

[Jonathan Edwards]

I think a gut enterovirus infection could easily explain ME/CFS symptoms, by the following mechanism:

As you undoubtedly know, the sickness behavior state, which is induced by the inflammatory cytokines IL-1β, TNF-α and IL-6, has symptoms very similar to those of ME/CFS, and it has been proposed that ME/CFS may simply be a chronically maintained state of sickness behavior (at least in part).

Trouble is, TNFa, IL-1b and IL-6 are hugely non-sepcific. They figure strongly in rheumatoid arthritis and ankylosing spondylitis, to mention the first two inflammatory diseases to come to my mind. And their presence is normally flagged by a raised CRP which in ME there isn't. It's all much too vague for me, I am afraid. Moreover, there is no critical dynamic structure to the theory - why does it go on being chronic when cytokine production from initial infection would be expected to be brief. I realise that one option is cytokine production confined to brain, and that could be brain stem attached to vagus nerve, but in my experience something as local as that would show some other tell tale signs if there were ongoing infection. And if the problem was chronic cytokine production in the stomach I think there might be nausea but not a lot of the other features.

My first degree was in art history and one of the modules was the study of attribution - learning how to tell who painted a picture. The guy who made that a science was called Morelli. What he said was that if you want to be able to tell for sure if Botticelli painted a picture look at the way the fingernails are painted because painters always do that their particular way and forgers never bother to get it quite right. The general impression is unreliable. The pernickety details are what matter. I don;t see the pernickety details fitting for enteroviruses yet. Details of timing, of other predicted symptoms, etc etc. I only began to believe I understood RA when I found that dozens of pernickety details fell into place - like why there is inflammation of the ocular sclera, or why the subclass of autoantibody is different from Waldenström's purpura.

 

[adreno]

As you undoubtedly know, the sickness behavior state, which is induced by the inflammatory cytokines IL-1β, TNF-α and IL-6, has symptoms very similar to those of ME/CFS, and it has been proposed that ME/CFS may simply be a chronically maintained state of sickness behavior (at least in part).

It seems some people believe these systems are digital, when they are in fact analogue.

 

[msf]

Prof. Edwards, why would you expect the cytokine production to be brief? This is not what the studies of HIV and HCV showed, as Lipkin et al noted in their recent paper.

 

[Jonathan Edwards]

I agree, but as someone pointed out in the recent Lyme thread, absence of evidence is not evidence of absence. Especially given the fact that ME is a diagnosis of exclusion, and that this will remove positive results (for Lyme, for example) from the sample.

But what we have is evidence of absence - at least in comparison to normal people with available test - another non-sequitur I think! And Lyme is unlikely to skew the denominator much, since at least int he UK it is very rarely diagnosed. I suspect that 95% of people who look as if they have ME clinically have negative screening for infection in the sense of being no different from healthy people.

 

[leokitten]

Hopefully some time in the near future there will be an effective treatment for enterovirus infections, here's one example:

http://en.wikipedia.org/wiki/Favipiravir

One company, Chimerix, the developer of brincidofovir which will soon replace Valcyte for betaherpesvirus infections (CMV, HHV-6, HHV-7) has also shown that the drug has some activity against RNA viruses.

 

[Sidereal]

Studies that have looked for infections in ME have mostly looked where it is most convenient for the researchers to look (blood) rather than where an infection would be if in fact it is there: brain stem, the diencephalon, muscle (including heart), gut.