Why has 'persistent enteroviral infection' been dropped as a research strand in ME/CFS? (Jen Brea asking)

[duncan]

From Mikovits to Lipkin to Montoya, and I think a couple in between, there have been studies noting some abnormalities in cytokine production, if memory serves me. Wasn't it Lipkin who opined something about overactive cytokine production pre-three years, underactive post?

More recently, doesn't Mark Davis suggest some cytokine irregularities?

I can talk chemokines, but then I'd have to veer into Borrelia, and I suspect no one wants that.

 

[arewenearlythereyet]

Oh, I don't know. Today autoantibodies are in favor in some camps, or some kind of immune dysfunction. Three to five years down the line, who knows? Something is causing all that cytokine/chemokine activity.

I don’t think anyone is arguing that the immune system isn’t dysfunctional, perhaps it is? But if it is, it certainly doesn’t follow that this is due to a virus? It also seems increasingly unlikely it’s down to autoimmunity. I think studies on immunology are important but not focusing on finding evidence of viruses.

The problem really is that we have inadequate epidemiology, predisposition, no biomarker etc .....if you have some of these things you can start to make some educated guesses with a level of confidence. Otherwise you are just throwing stuff at the wall and hoping something sticks.

I’m in favour of doing the basics first to at least generate the clues (and possibly help quality of life) before we start doing all the unknown theoretical science stuff (microbiome etc). I think as patients we do clutch at straws and the unknown has some kind of appeal ...but we have to remember that research on ME is yet to really start since funding has been so low for so long.

Having said that, allocating small funds for prioneering ‘out there’ theories is ok ..as long as expectations are managed and you don’t compromise the other less risky stuff.

I would like the basics done with the big government funded money and the charities to fund more out there studies via phd’s Etc

Of course we need a lot more government money to do that. Until then our focus should be for a biomarker etc not high risk projects.

 

[JenB]

@JenB
I am open to being proved wrong.

@JenB
If there are specific neurological symptoms then they should be assessed by formal neurological examination. As I mentioned before, neurological exam is remarkably precise at pinning down any specific nerve lesion. It takes about a year of specific neurology training to get to that level of precision so a lot of physicians are not able to deal with subtle problems but a neurologist should be. Specific neurological problems due to local virus infection are in general pretty easy to identify by a neurologist. It is pretty much the same as an electrician doing a circuit check on a house wiring. The recurrent neurological symptoms described by people with ME in general do not show up on exam and nobody knows why that is, but it makes local viral infection pretty unlikely.

I think we're on the same page but it sounds like you're both recommending that I consult with a neurologist but also saying that the recurrent symptoms ME patients have won't show up on an exam. This is what happened in my case and unless I was seeing a neurologist for a specific sub-specialty, I would be loathe to try to see one again. It's unlikely they could help and reasonably likely I'd just get diagnosed with conversion disorder again. Even if I were to schedule an appointment with a neurologist now, it's doubtful I would be symptomatic by the time I saw one. I were, there is a good chance my presentation would not (as the neurologist who diagnosed me wrote in my chart in 2012) comport with any known pattern of lesion. These symptoms are not a case of permanent nerve lesion but rather is transitory, e.g., due to inflammation or a microcirculatory issue.

My neurological symptoms are well-described in the ICC and here: http://me-pedia.org/wiki/Epidemic_myalgic_encephalomyelitis and none of them are new. I just haven't had them since 2012. If I had new symptoms, then I would definitely go.

Yes but you can’t clutch at every straw. At some point you need to prioritise...especially when there are limited funds.

You also need to consider risk as well...so tackling the low hanging fruit first makes more sense than chasing all the dreams and ideas.

In my world, innovation is curtailed to around 20% of your budget and the 80% goes to what is the most likely to succeed.

We seem to have very little to go on from the reactivated/smouldering virus theory. Just saying “then we should investigate it” when all the available evidence suggests it’s a non starter seems strange to me, especially while the basics haven’t been done yet.

Again, funds are not limited. The NIH has complained over and over again that there are not enough applications. What is limited are the number of researchers in this field. It would absolutely do us good to bring in new people who are already working in areas not currently being researched within our field.

I really can't see how this is clutching at straws: http://me-pedia.org/wiki/Coxsackie_B_virus#Myalgic_Encephalomyelitis http://me-pedia.org/wiki/Epidemic_myalgic_encephalomyelitis That to me registers as a lot of suggestive evidence worthy of deeper inquiry.

In the case of herpesviruses, there are already well-established, highly effective treatments, so that is among the low-hanging fruit of all. These drugs do help some people, sometimes to the point of full resolution of symptoms. I don't know what work is required to understand what that subset is, but we should do it so that people can have access to them through the NHS, if the evidence is there. I agree that the research hasn't been done yet for that to become a part of the standard of care, but that's a far cry from saying there's no there there. I don't know what level of evidence would be required for people with ME in the UK to be able to trial antivirals.

In these studies at least, the subset is often defined as people presenting with high titers

http://dominatufatigacronica.com/bl...ment-of-142-herpesvirus-patients-with-CFS.pdf
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.23411
https://www.sciencedirect.com/science/article/pii/S1386653206700099

This is a highly unusual case because the HHV-6 was chromosomally integrated but a specific (and therefore measurable via PCR) example of the general form: https://www.sciencedirect.com/science/article/pii/S1386653212002119

It breaks my heart a little that these studies aren't on MEpedia. So my totally annoying, broken record plea: please contribute whatever you learn from these conversations there. Yes, the forum can be searched but without consolidating information into a digestible form w/ footnotes, so much that gets shared is ephemeral and hard to find again.

 

[arewenearlythereyet]

Again, funds are not limited. The NIH has complained over and over again that there are not enough applications

I beg to differ ...if we are advocating for certain avenues of research, I would prefer that this energy is directed to more plausible avenues like adequate epidemiology rather than “I think I have a mystery virus that is acting in a way that no one yet has discovered and so far is unknown to science” or ‘me is about microbiome’ but let’s not worry about the fact that we don’t understand healthy biome yet and it will take years to get a healthy reference.

we will get so much more for all PWME by focusing on a hunt for a biomarker and many replicated studies on epidemiology and identifying the presence of subsets or not. All this bonkers out there stuff is putting the cart before the horse. Perhaps spend the next 10 years working on things that will improve the lot of the many rather than gambling the money away on a high stakes game?

 

[JenB]

I beg to differ ...if we are advocating for certain avenues of research, I would prefer that this energy is directed to more plausible avenues like adequate epidemiology rather than “I think I have a mystery virus that is acting in a way that no one yet has discovered and so far is unknown to science” or ‘me is about microbiome’ but let’s not worry about the fact that we don’t understand healthy biome yet and it will take years to get a healthy reference.

we will get so much more for all PWME by focusing on a hunt for a biomarker and many replicated studies on epidemiology and identifying the presence of subsets or not. All thins bonkers out there stuff is putting the cart before the horse. Perhaps spend the next 10nyears working on things that will improve the lot of the many rather than gambling the money away on a high stakes game?

These are not mystery viruses...

Agree re: investing in epidemiology. That is another area of this field totally lacking.

We can advocate all we want but it's the panel who decides how to allocate funding based on the merits of each individual application. In the case of directed funding, if there were a specific RFA for a specific area of study, it would be put out by the relevant institute. I doubt they are interested at this point, but if the National Institute of Allergy and Infectious Disease put out an RFA for the study of any aspect specifically re: the role of infection, I really doubt it would "take away" from any other area of study currently underway. Regardless, no patient/advocacy groups are advocating to the NIH "study this specific hypothesis." I would never do that. The NIH would never assent to that. We're trying to grow the pie. One way to do that is to get new researchers (and a much larger number of researchers) to submit applications.

For those patients for whom the issue is chronic infection, we aren't going to a find single, novel biomarker. In those cases, the marker is specific to the infection. In the case of Kristin Loomis's kids (whose kids had a dx of CFS, ultimately found to be caused by CIHHV-6), the pursuit of a biomarker would have been meaningless. What they did ultimately have were the means to find the specific cause of their symptoms, in part because CIHHV-6 is unique in that you can actually measure the virus directly.

 

[Guest 102]

The problem is that it is now clear that the reason why these physicians thought it was enterovirus was spurious. They appear to have thought it was enterovirus because they thought that there were signs of neurological involvement that mimicked polio. However, in retrospect it is clear that none of these patients had anything like polio.

I suspect that the physicians involved were infectious disease experts rather than neurologists. In one outbreak apparently they were orthopaedic surgeons. The reports we are left with do not suggest that anyone actually identified substantive nerve or muscle pathology.

.

Ramsay was certainly an infectious diseases consultant, though Behan is a consultant neurologist and identified mitochondrial abnormalities, but that was from patients with a whole bunch of viruses, not just enterovirus.

This may be off topic, and not at all asking for medical advice, but have been meaning for a while to ask you Jonathan if you see any significance in my developing idiopathic bilateral (anterior) uveitis around nine years ago. I feel sure ME must have been implicated since uveitis is so uncommon in healthy population. Thank god, all has been quiet for a number of years now and I see consultant opthalmologist 6 monthly for review. He always tells me to avoid stress, which of course is more easily said than done (the initial uveitis followed a v stressful period while novel was being published).

I think uveitis occurs in RA patients too?

My experience made me v interested in the Rituximab ME trials - this was before they were proven negative.

 

[JenB]

@arewenearlythereyet Can I ask you to at least acknowledge that this is not "bonkers out there stuff." This is the research of serious people trying to figure out what is happening to us, some of whom are faculty at Stanford and Harvard. And there are concrete findings. Many. Enough to keep looking.

 

[duncan]

we will get so much more for all PWME by focusing on a hunt for a biomarker and many replicated studies on epidemiology and identifying the presence of subsets or not. A

It is hard to argue this. I am not smart enough to prioritize. I would suggest, though, that one avenue of exploration does not necessarily have to exclude another.

 

[arewenearlythereyet]

@arewenearlythereyet Can I ask you to at least acknowledge that this is not "bonkers out there stuff." This is the research of serious people trying to figure out what is happening to us, some of whom are faculty at Stanford and Harvard. And there are concrete findings. Many. Enough to keep looking.

When I say ‘bonkers/out there” I mean high risk of failure/chancy. I am not averse to risk but this needs to be a measured risk and balanced against other things.

I think each research study should be assessed on its own merits not where it’s come from. Personally I don’t care where they are from and from experience I dont think university status is necessarily a measure of quality of research ...or well known journals for that matter.

I disagree that research funding is unlimited ...so I will carry on calling for a more objective based focus from funders rather than scattergun which I think will spread things too thin and take a lot longer (20-30 years) ...but I guess that’s probably not going to happen since we are at the whim of few researchers who are prone to only doing the interesting “out there stuff”.

 

[JenB]

When I say ‘bonkers/out there” I mean high risk of failure/chancy. I am not averse to risk but this needs to be a measured risk and balanced against other things.

I think each research study should be assessed on its own merits not where it’s come from. Personally I don’t care where they are from and from experience I dont think university status is necessarily a measure of quality of research ...or well known journals for that matter.

I disagree that research funding is unlimited ...so I will carry on calling for a more objective based focus from funders rather than scattergun which I think will spread things too thin and take a lot longer (20-30 years) ...but I guess that’s probably not going to happen since we are at the whim of few researchers who are prone to only doing the interesting “out there stuff”.

When you say “out there” I hear “woo” or questionable training/methods, which is not what I associate with top institutions (which is not to say the work can’t be poorly executed or just plain wrong).

I hear now that you really mean is high risk of failure or low chance of yield. That’s a different thing entirely. But surely building on the evidence that exists is not high risk? Re: studying infection, it strikes me as low risk because you are not starting from zero (you can see the work of people who have gone before you, both pos and some neg results and design even better experiments). There is also the possibility of high yield, because you may not have to begin a long development of a novel drug from scratch, but can use treatments that are already on the market.

I see doing huge scans that are hypothesis-free for biomarkers as very high risk (high variance) but it’s work that must be done since we don’t really know where to look, or rather, have too many possibilities to narrow on a single one.

I am sorry but I don’t understand the disconnect. Are you saying that the published work on persistent infection and antiviral treatment of those infections is BS or that it’s not interesting enough to warrant further research?

Surely a really low-risk study would be to replicate those findings (from the enteroviral research or herpesvirus research) in a large cohort and using improved/more up to date methods. And surely getting patients standard access to drugs that improve and in some cases resolve symptoms is worthwhile?

Regardless, this is not a top down thing where you or I get to decide the work of others, nor will this conversation have any bearing on any concrete outcome. I think this is veering a bit off topic from discussing the research itself, which is what I would like to get back to.

 

[Forbin]

I have it. I have been diagnosed with ME/CFS by no less the three worlclass ME/CFS experts. My vestibular damage was confirmed at the NIH in a six-hour test.

Balance problems have long been recognized in ME. It's certainly not universal, but nor does it seem to be all that uncommon. Connecting the problem to orthostatic intolerance seems to have been a more recent development, and it clearly contributes to many cases. On the other hand, there also seems to be vertigo that is more specifically related to a vestibular disorder and is independent of standing.

Back in the early 80's, I had a battery of tests at the highly-regarded House Ear Clinic in Los Angeles. It was ultimately suggested that my balance problem was due to an impairment of the blood flow to the smallest blood vessels of the vestibular system. This seems like it might be consistent with other work suggesting that blood flow is restricted in the small blood vessels in ME/CFS.

Here is an excerpt from a 1987 ABC Nightline program on the then "new" phenomenon of "the chronic fatigue syndrome." Guest Gidget Faubion-Jones then headed the "Chronic Fatigue Syndrome Society" (née "Chronic Epstein-Barr Virus Society") out of Portland, Oregon. The group had some 12,000 members at one point. Dr. Komaroff was also a guest on this program.

Dr. Timothy Johnson: Gidget, in your hearing from these patients, what is their primary problem or complaint? What is their frustration? How do they talk to you about it?

Gidget Faubion-Jones: The biggest frustration is getting a proper diagnosis and getting treatment. Part of our biggest problem is that 80% of our people suffer from vestibular disorders. There are only 14 vestibular clinics right now in the world, and that makes it very difficult for these patients to get diagnosed. I should mention that there was a recent study done on cerebral impairment on a lot of our patients, that was a recent study done out of Berkeley by the way, and it basically points out the fact that it is a very devastating disease particularly with brain stem damage and other neuro-psychology type aspects.

Dr. Johnson: All right. I'm going to jump in on that point because your language may have lost a few of our viewers. You are in fact describing some balance problems, some inner ear problems, as you suggest, even some problems with the brain stem. Uh, back to Dr. Komaroff. Is that in fact a common feature of this disease?

Dr. Anthony Komaroff: Balance problems, dizziness, is a very common feature, and in some of the patients who are tested with formal tests of dizziness, there does seem to be a disorder of the balance center.

Dr. Johnson: OK.

In 1986, Dr. Melvin Ramsay described the onset of the disease this way:

"Although the onset of the disease may be sudden and without apparent cause, as in those whose first intimation of illness is an alarming attack of acute vertigo, there is practically always a history of recent virus infection associated with upper respiratory tract symptoms though occasionally there is gastro-intestinal upset with nausea and vomiting."
http://www.name-us.org/defintionspa...:_A_Baffling_Syndrome_With_a_Tragic_Aftermath

I'm not suggesting that vertigo / dizziness is universal in ME, but nor do I think it is all that uncommon. Orthostatic intolerance no doubt accounts for many cases, but something else - perhaps also related to blood flow - may be going on.

 

[Alvin]

Again, funds are not limited. The NIH has complained over and over again that there are not enough applications. What is limited are the number of researchers in this field. It would absolutely do us good to bring in new people who are already working in areas not currently being researched within our field.

I really wonder why they don't fund research recently even though they keep saying this.

Is it because they are lying and this is meant to BS us into thinking they are willing but "can't"?

Is it because they fund a specific percentage of applications only so we need 50 applications per 1 funded and they only got 49 good ones (I'm making up numbers)?

Is it because they don't like who is applying, they did call Dr Davis and Stanford a whole bunch of names on the second application.

Is it because the reviewers are terrible or biased against ME/CFS?

Is it because of something else?

Their rep was questioned repeatedly at the Montreal conference about this and just kept repeating the same phrase that the money is there ask for it and would not explain why they keep refusing applications just that the money is there and ask for it (and they have a affinity for grad students (iirc))

 

[Milo]

Some of the best researchers in the world, notably Dr Lipkin (the virus hunter) and dr Davis looked for signs of infection and did not find it. It is truly painful to return over and over to past theories which haven’t gained much momentum except for 2 physicians, one of whom sells his own compound to treat it (and it’s not cheap) and the other one who collects a lot of money from patients in the context of a socialized health care system.

Coxackie B virus is not even tested here in Canada, or you need to send the blood to the federal lab. Viral titers are only available to the HIV and transplant patient population. You’d think that after all these years, over 25 years since the Incline Village and Lydonville outbreaks, they would it figured out and it would have been mainstreamed? Moreover, the IgG titers represent a past infection. The clinical gold standard to proving an infection would be a PCR to confirm the presence of virus in the blood.

Dr Davis said many times that while tissue could be tested for infection, it is an invasive procedure that involves risk and it would be tough to justify such study if current methods can detect metabolites and DNA particles in the blood, which circulates everywhere in the body, including through the tissues. He didn’t find it. He is still looking.

Maybe the ‘hit and run’, then wreak havoc theory, at this point makes a lot of sense.

Maybe what we are facing is the consequence of that initial infection, just like often time MS is triggered by EBV. An autoimmune process. The jury is still out in our case, and the clock is ticking. I am willing to be wrong.

 

[Jonathan Edwards]

any significance in my developing idiopathic bilateral (anterior) uveitis around nine years ago

It may well be relevant to whatever your disease process is. Uveitis does not occur in RA, or in any B cell drive diseases I can think of off hand. It is a characteristic feature of the MHC Class I (HLA B) associated T cell disorder ankylosing spondylitis. You are pretty likely to carry HLA-B27.

 

[Jonathan Edwards]

@arewenearlythereyet Can I ask you to at least acknowledge that this is not "bonkers out there stuff." This is the research of serious people trying to figure out what is happening to us, some of whom are faculty at Stanford and Harvard.

I have to be honest that I agree with @arewenearlythereyet. People at Stanford or Harvard or Cambridge or UCL or anywhere else with a top name do bonkers out there stuff all the time these days. Science is a travesty of what it was in the 1980s. Everyone is following a fashion and most of them do not seem to understand basic underlying principles. The problem has always been there but it has completely swamped productive science. People in my old department are studying completely meaningless things.

Like a jigsaw there are always bits in biomedical science that look as if they might fit somewhere. The real work is in showing that they do not actually fit there so must fit somewhere else.

 

[chrisb]

What @JenB has described seems to me a very good statement of the sudden, spontaneous, and, unfortunately, frequent relapse for which the term Post Exertional Malaise does not begin to do justice, and is in fact wholly inadequate and misleading.

The question which I would put to those who do not accept the persistent virus hypothesis is, what other model of illness could account for the variety and severity of the symptoms which so closely imitate those of viral infection? Are there any other conditions which present with symptoms of similar variety and severity in the absence of some pathogen?

@Hip I came across the paper Viral persistence and disease: Cytopathology in the absence of cytolysis.
JC de la Torre P Borrow MBA Goldstone
British Medical Bulletin(1991) Vol 47 no 4 pp 838-851.
I don't understand the detail but there seems to have been a substantial body of work at that time trying to understand how virus might evade discovery. Oldstone is quoted by Archard and by Behan at the time. Do you know what became of this?

 

[Sasha]

I'm just watching Ron Davis's talk at the IiMER conference (just got the DVD). In it, he says that the blood circulatory system is the sewer of the body and no matter where an infection is in the body, cell-free fragments of that infection's DNA will end up in the blood to be got rid of.

Wouldn't that mean that stomach biopsies aren't necessary to detect virus in stomach tissue?

In his talk, he's also talking about his attempts to detect viruses, including HHVs (and is so far coming up null in comparing cases vs controls, though I haven't finished watching the talk).

 

[adambeyoncelowe]

I'm just watching Ron Davis's talk at the IiMER conference (just got the DVD). In it, he says that the blood circulatory system is the sewer of the body and no matter where an infection is in the body, cell-free fragments of that infection's DNA will end up in the blood to be got rid of.

Wouldn't that mean that stomach biopsies aren't necessary to detect virus in stomach tissue?

In his talk, he's also talking about his attempts to detect viruses, including HHVs (and is so far coming up null in comparing cases vs controls, though I haven't finished watching the talk).

Some infections don't have DNA though, right? Is the same true of RNA, in that case?

 

[Jonathan Edwards]

what other model of illness could account for the variety and severity of the symptoms which so closely imitate those of viral infection? Are there any other conditions which present with symptoms of similar variety and severity in the absence of some pathogen?

It is worth remembering that most symptoms of viral infection are due to immunological and neural responses, with a major hypothalamic component. Feeling terrible after typhoid vaccination is almost entirely due to triggering of a hypothalamic response by endotoxin or lipopolysaccharide. Similar symptoms will occur with all sorts of other insults like poisons or in illnesses where toxic products are generated internally like porphyria, sickle cell disease or familial Mediterranean fever. So mimicking viral illness is easy - just tickle the hypothalamus. What I think may be of more interest are the neurological or muscular symptoms that fooled Acheson and maybe Ramsay into thinking about polio but which turned out not to be based on anything similar and I suspect on careful clinical assessment would have been seen not to be similar. People with ME have sensory symptoms and problems using muscles, and even sometimes involuntary movements, that do not resemble what you get in viral illness much at all. That suggests that ME is not just ticking the hypothalamus. It is something we do not yet have a grip of - because it is different - there is no close analogy with other illnesses. But that should not worry us. There is no close analogy for lots of illnesses. Rheumatoid nodules are totally unique in presentation and have a unique causation. Psoriasis is unique and has a unique causation.

 

[Sasha]

Some infections don't have DNA though, right? Is the same true of RNA, in that case?

I don't know. But Ron is saying that he's trying to develop a probe for RNA in the blood now (but expects it to be difficult because RNA is unstable).