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

I'm increasingly thinking that all forms of acute flaccid paralysis/myelitis (and respiratory failure), including Poliomyelitis are in fact all forms of Guillain-Barré syndrome. The symptoms and long term outcomes are identical, the only difference is the underlying infectious trigger.

 

This sounds a lot like herpesviruses in the US during that time! I haven't really dug into the 1980s outbreaks yet but did start reading about Tapanui Flu (NZ) and the methods and POV in that paper are all profoundly shaped by the concept of fatigue + herpesviruses. It's hard to know if we're looking at the different diseases or if it is the same disease but the way that it is described, defined, tests run, etc. shape the disease into the image of its time. One of the points (I think) I'm driving to is that 30s-50s were the age of polio, 80s, herpesvirus, and now it's all microbiome + metabolomics. People have found interesting things at every stage, but the lens also profoundly shaped the view. We need to be very, very careful of that.

I do think that this present-day category of ME comprises people living with a number of post-infectious states (and possibly other triggers). I don't really need a theory of everything, but for those of us whose ME was precipitated by an enterovirus, I want us to have access to an anti-enteroviral in our lifetimes, one that would work on the weird, latent form of the virus. We need one, anyway, to help people with acute myocarditis, for example.

I am not sure I entirely understand your question, so forgive me if this doesn't answer it. With the Royal Free outbreak, there were actually several other outbreaks happening around the country at roughly the same time, including one in Middlesex Hospital, one North Finchley and another in Dalston. Often the outbreaks were observed in hospitals because a) there were people there to observe them and b) hospital staff were getting repeatedly exposed. But in Punta Gorda, Florida, for example, where a proper and extensive house to house survey was confirmed, the outbreak happened throughout the community. Medical staff were just affected at a higher rate.

Even the 1934 Los Angeles outbreak, it wasn't restricted to the hospital. I just came across a report of the "polio" outbreak in San Francisco as well as a report of polio in 1934 in California at large, and it's clear to me that the entire state was hit with it, whatever "it" was. It was likely a mixed epidemic that included poliovirus + another enterovirus. The latter had the epidemiological features of every pre-1984 ME outbreak (higher attack rate, no mortality, higher morbidity, affecting adults more than children, women more than men). Note: some of these sources are obscure enough that I've never seen them referenced in any of the review articles of the 1950s, 70s or 90s. I think my survey will unearth tidbits no one has written about before.

I'm forgetting which paper it was (maybe on one of the outbreaks in New York) but the author noted that the idea that these are confined to institutions is likely false. They also thought this but when they did a survey of the surrounding area, they also found many cases in the community, and offered that in many case studies, no one looked, but if you did survey they community, you would likely find other clusters.

I mean the epidemiology, symptoms, and course, not findings. I also mean that it is much easier to see that people have been hit by the same thing when you are there within the first few days and weeks of the acute illness, a phase of the illness which today, no clinician or researcher has access to. I think there is a lot to learn there to generate hypotheses for future work.

Why do you think these outbreaks didn't have an illness classifiable as ME/CFS? The concept (well, of ME) was invented to define these outbreaks. If anything, it's the endemic cases that have muddied the waters. There's no doubt the chronic phase looks very similar across what are probably a lot of causes, but there is no reason to think that the acute phase did. Also, we are so different in our symptom presentations. My cognitive abilities have absolutely been affected but are mild in comparison to my muscle fatiguability. Put another way, I have massive muscle PEM but little cognitive PEM. I know people who are much the opposite, who could never do the work that I am able to do but can go for a mile-long walk every day. We look at each other with amazement as what abilities do remain seem completely out of reach. These differences in symptom presentation may have to do with individual factors, but they may also have to do with the differences in our precipitating triggers.

My onset looks exactly like the disease described in the epidemic literature. But if you looked at me one year later and asked me what my current symptoms were, you would never know that.

I'm not sure why that is the case. A lot of what we know re: persistence comes from autopsy studies or biopsies of sick people. It's very hard to get tissue from healthy controls. In the studies that we have been done, in controls you either find the virus at much lower rates or not at all. Again, I'm very early in my reading on this and think it's important to read much more widely than the ME literature.

I think if anything they tell us keep digging. Virus infected cells die when everything works well. There are numerous pathogens, though, that try to prevent apoptosis as a survival strategy (is my understanding). One way to do this is to alter mitochondrial function, since mitochondria play a key role in cell death. At any rate, when Coxsackie persists, it isn't killing cells. Same with herpesvirus. By definition, a persistent infection isn't inducing apoptosis because apoptosis *is* the host defense.

Enteroviruses have been found in two post-mortem brains. We need a large enough brain bank to a study. It's really, really a shame that after decades we don't have a proper repository of tissue. People often died without a plan in place besides a vague intention to donate their bodies, but there was nowhere to send them to. Now there is, at least in the US. I'd like for us to do a full court press and educate people re: the process, but I'm very wary of hastening anyone's suicide plans. So we need to think about what is the right way to do this.

I think just getting all of the references into one place would be a really good first step, which is why MEpedia is of value. Think of it as a precocious undergraduate or very good graduate student writing a literature review for you. A proper published review yes absolutely would require authors with expertise (in each virus). It's 1000% about the assays and methods used, which vary with every study, some of which are very good and some of which are total junk, and no one can know that outside of their field. That's true in the measurement of enteroviruses. It's true in brain imaging. It's true in metabolomics, which has huge issues of reproducibility across labs.

I do think knowing where we have been is absolutely useful, even if the answer is "nowhere." I guarantee you researchers aren't reading everything. They can't possibly. No one has read all the epidemic literature. The only person I guarantee has read all the Coxsackie/Enterovirus literature is John Chia, but I would be surprised if he has read everything on HHV-6. I doubt that infectious disease doctors focused on herpesviruses have read on enteroviruses. I see researchers making fundamental errors/assumptions about each other's sub-sub-sub fields all the time. The "we ran a high throughput analysis of blood and didn't find infection, therefore there is none" is just one example. We have almost no epidemiologists in this field. We have precious few neuroscientists. So if you were to ask people, "What do we know so far" about X, the answer you get will depend a lot on who is in the room. Unless there are people out there who are completist about reading the literature not only of ME but of whatever that specific element is (e.g., enteroviruses, microglial activation, exercise physiology, etc), but I don't know how that is humanly possible.

And anyway, what we know so far absolutely matters, but equally important is: what question do we ask next? There are so many hypotheses under or un-explored from the work that has already been done. I'm not going to do that research, but I hope at least to inspire new people who can.

 

Acute flaccid myelitis aka paresis was the reason I turned up at the A/E. Long term I didn't recover hence the CFS diagnosis later.

Long term outcomes of GBS (which certainly covers the symptoms in that list) suggest a substantial subset of patients suffer from long term fatigue.
"Fatigue, pain and muscle weakness are frequent after Guillain-Barré syndrome and poliomyelitis"
https://link.springer.com/article/10.1007/s00415-009-0018-z

I personally suffer from PEM with objective signs - specifically circulation/OH issues and unable to achieve the same performance at anaerobic threshold on the 2 day CPET, despite having above average VO2Max for my age on the first day.

I don't however believe that my condition is due to chronic enterovirus infection - the trigger was different. I definitely believe these "outbreaks" are of interest, but are they really outbreaks, or simply natural statistical clustering that we are calling outbreaks because we like to identify patterns in the noise?

 

They were outbreaks.

 

Thanks @JenB,

I don't think observations like that fifty odd years ago take us very far. As far as I can see they looked at polio serology and it was negative. That makes it quite difficult to see how the outbreak could be due to a a virus similar enough to polio to produce cross-immunity. It is conceivable but a hundred and one viruses might have some cross reactivity with polio virus and they might be different in each outbreak.

The problem for me is this looks all too much like scientists hoping they have found what they set out to find. At this point in history there was, judging by Acheson's review, an interest in 'polio-like' viruses, rather reminiscent perhaps of people looking for AIDS-like viruses ten years ago. As I mentioned before viruses like Coxsackie were popular topics of conversation for a decade or more (?1960-85!) just as streptococci and rheumatic fever (and the microbiome, although it wasn't called that then) were in rheumatology. Enthusiasts will have gathered every crust of evidence that might support their hypothesis, including whiffs of cross-immunity. On closer inspection though it does not seem to hang together. And we still have no idea whether it is relevant to people who are ill now, apart from the few still ill from these outbreaks.

Thinking back to the 1950s/ very early 1960s none of my schoolmates were diagnosed with ME but some were diagnosed with polio only to miraculously recover completely. And strange illnesses of acute onset attributed to infections were not uncommon. I suspect quite a lot of adolescents get post-viral syndromes with quite varied symptomatology. If such illnesses are assessed by orthopaedic surgeons (which seems have been the case in at least one 'ME' outbreak according to Acheson) the observations may not be terribly reliable.

By the 1970s and through the 80s virologists like my mother systematically went through viral serology on hundreds of thousands of kids with infections until it was decided that the really nasty viruses had gone and there was little point. Arguably this sort of situation was grossly overstudied for about twenty years. 'Royal Free Disease' was known of but nothing consistent was found to explain it. What was consistently found was evidence of late-onset EBV infection preceding ME.

 

What do you mean by showing some sign of being diseased?

Re: sensitivity to light, these kinds of sensitivities were observed very early on in many outbreaks, when patients were still in the acute phase and were in hospital (http://me-pedia.org/wiki/Epidemic_myalgic_encephalomyelitis#Symptoms). The virus/host reaction to the virus was causing these symptoms as soon as two weeks after infection.

I think as someone said earlier, the gut is accessible, but the latent virus is presumed to be in the gut, muscles, heart, brain (places where it has also been found).

As to whether these are just historic errata, I think one thing that has changed significantly at least in the US is the cost of healthcare. I can't imagine any of these patients who were observed for weeks in hospitals every staying in a hospital now for more than 24 hours. I've gone into ERs with stiff neck & back (but no or low grade temperature! which they view as a sign nothing is wrong but is classic for ME), stabbing pain in heart, ataxia, muscle weakness, numbness, light/sound sensitivity, dizziness, tachychardia, etc. and have been sent home every time. AND was told at Mass General by a neurologist who clearly thought I had a functional disorder "this is the most common thing we see in the ER," whatever that means. I'm sure this same pattern is happening, we've just trained doctors not to recognize it. If you send us away and don't examine us, how do sporadic acute onset cases or even clusters to make it into medical journals?

We need a case definition for acute/epidemic ME that is different from the chronic phase. I don't care if no one ever presents like that again. At least, then, we would whether people are presenting but just flying under the radar, and could study them.

 

They are not identical. Polio knocks off motor neurons patchily - it is asymmetrical. GB is symmetrical and diffuse and I am fairly sure the pathology is quite different. GB is sensorimotor. Polio is purely motor being specific for anterior horn cells. You may be too young to have had polio victims riding the same bus as you in the 1950s. Most of them had one flaccid leg.

 

Cross-immunity in the population is different from cross-reactivity with whatever assays they had at the time. I don't really understand the assays, but they generally involved egg yolks and monkey autopsies. Did they have the technology to have measured cross-reactivity? Regardless, yours was not the conclusion researchers contemporary to the epidemics came to. In nearly every case, the conclusion was "we couldn't isolate the virus, but we think it's an enterovirus." At least to them, absence of polio /= absence of enterovirus. I can only assume they understood the limits of their tests even though again, I don't really understand how they worked. Also, in later outbreaks, they did have the ability to measure some (not all) other enteroviruses, but running a test for polio couldn't tell you whether or not you had a Coxsackie A or a Coxsackie B virus or an echovirus, let alone an unidentified enterovirus. At least, that's my understanding.

Did you see the Finland/Estonia study? That seems to suggest Coxsackie B4 and poliovirus are similar enough to produce cross-immunity.

I think it's important to go beyond Acheson's review and look at the primary literature and to what people were observing in the moment, not what people like Acheson saw looking backwards. Whether it's the 1930s, 1940s, or 1950s, the majority of the authors conclude their specific outbreak was likely due to an enterovirus. And again, as others later noted, some of these authors were ignorant of each others' outbreaks.

It's not in the serum. And Coxsackie B is still a nasty virus! It is a common (I think the most common) cause of aseptic meningitis and a common cause of myocarditis.

I think it's really fucking cool that your mother was a virologist! I can't imagine what it must have been like to be a woman in science in her days.

 

Also re: your mates + polio. In 2012, I show up with my symptoms to an ER and am diagnosed with a functional disorder and sent home. If it was 1940, they would have admitted me under suspicion of polio. Neither reaction tells us anything about what was actually going on. I absolutely agree it's about the lens of the time. I don't think the disease people observed in the 30s/40s/50s went away. Rather, we changed.

To me this means, we need to learn how to observe and follow people in the acute phase. We could learn a lot if we did that, rather than defining the disease as what happens to the people who don't recover and are chronically ill X time later.

EDIT: Sorry, I misread your original post completely. You wrote some WERE diagnosed with polio and then recovered? (Don't a proportion of people w/ polio get temporary paralysis and then recover?)

 

Thanks @JenB, I will try to unpick some of that.

When I say [stomach mucosa] showing some signs of disease I mean some indication that the immunoperoxidase stain, claimed to tag a virus protein, is tagging something that shows some sign of altering the appearance of the cells. I spent about ten years using immunohistochemistry as my main research tool. I am very familiar with all the pitfalls. Most published pictures of immunoperoxidase staining like this are artefacts. And I am prepared to admit that I published some artefacts myself before I learnt to know all the false positives. What I remember seeing are gastric mucosal samples stained with immunoperoxidase with the cell structure looking entirely normal. Without that finding being confirmed by other labs the chances are it is an artefact.

Even if there were viral protein in otherwise healthy stomach I do not see how that would explain sensitivity to light. Sensitivity to light in acute infections, as in these outbreaks, is nearly always part of the cytokine response mounted by the immune system when virus gets into the bloodstream and lymphatic tissue. If the people having gastric biopsies were typical of ME patients they would not show signs of cytokine responses like fever or raised CRP. It does not fit. The light sensitivity of ME is not the light sensitivity of acute viral infection. Things have to fit properly to make sense in this story. I don't see that.

I am not aware of the immunostaining done on gut having also shown up on other tissues but I would be interested if it had. When Dr Chia presented his view on this to IiME the evidence for presence in brain seemed to relate to very few cases (maybe one) that did not seem to be typical ME. Again, things have to fit.

You mention 'stiff neck & back , stabbing pain in heart, ataxia, muscle weakness, numbness, light/sound sensitivity, dizziness, tachychardia, etc.'. But these are general features of acute viral infections of pretty much any sort. Maybe these days doctors do not do a neurological exam but for the ten years I was a resident and fellow I always did and it is not difficult to pick up neurological deficits that go beyond the non-specific features of viral reaction. I would say at least from 1970 to 1990 that was the norm and at that time we sent of viral serology and pretty much never got anything useful back.

So I am not sure what you mean by a case definition of acute/epidemic ME. If it is Acheson's paralytic disease with signs of brain or spinal cord damage that seems to me to be so different from ME as we generally understand it to be irrelevant to the interests of ME sufferers as a whole. If it is more an acute presentation of the symptoms most people with ME complain of I see that as impractical since 99% of people with symptoms like that in the acute situation just have a nasty viral infection and will be better in a week. The key thing about ME is that it never goes away.

And it is difficult to have a case definition for epidemic or outbreak cases until you know you have got an outbreak, by which time it would be too late.

The more I think the more it seems to me these outbreaks are red herrings. They distract from the illness itself - the long term disabling condition that affects about 0.2% at any one time.

 

Hmm. Some forms of GBS are motor only, especially in children, so the asymmetry seems to be most significant difference.

edit: there is discussion of asymmetrical GBS:
https://www.ncbi.nlm.nih.gov/pubmed/17122947

edit 2: Ventral Horn involvement in GBS
https://www.ncbi.nlm.nih.gov/pubmed/1395335
https://www.sciencedirect.com/science/article/pii/014067369190606P (AMAN)

 

I don't think they do. Polio produces paralysis by killing anterior horn cells. Once dead there is no recovery.

 

I haven't had to think about this for years but I am pretty sure that whereas polio kills cell bodies GB is a demyelinating axonal condition. Completely different pathology.

 

Sorry to pick points at random but I'm not sure where to start otherwise!

No, it's the antibodies that were looked for in the serum, not the virus. Sure, Coxsackie can be nasty and can cause meningitis and myocarditis but it turned out not to cause all the mysterious things virologists thought it might cause in the 1970s.

My mother went into medicine during the Second War. I suspect as in other walks of life being a woman suddenly didn't matter so much then. Her sister drove an armoured car. Pretty much as soon as she qualified she was asked to set up a pathology laboratory in Southampton and by the 1960s she worked at the Central Public health Laboratory where I think about 80% of staff were women. Before they abolished technical staff and replaced them with cheap PhD students a lot of labs ran mostly on female staff. The bosses tended to be men, for sure, but not all. But we digress.

 

But I think that is just thinking 'this is like polio, maybe the virus is like polio'. Medical science is often dominated by pretty simplistic arguments. The first hand accounts are a mess to be honest. Neurological diagnosis is done by fitting together a complex set of data including tone, power, co-ordination, reflexes and sensation. Without the full dataset it is very difficult to interpret. What I have seen is not enough to pin anything down.

 

Cross reactivity refers to serological testing for antibodies, not egg inoculation or animal inoculation with autopsy. Serology was certainly around then. I did cross reactivity practicals as a student in the 1960s. Cross immunity is expected to be partly based on antibody cross reactivity in vivo and partly T cell response cross reactivity. The process is complicated but what we have reported does not fit into an easy explanation in terms of immune response.

I think Acheson mentions that for the Iceland outbreak polio and Coxsackie serology were negative.

 

Were tissue reservoirs involved?

 

Has anyone looked at this in mucosa yet? I know that there have been alterations seen in muscle cells, but I haven't read anything re: mucosal cells. Are you saying that in the absence of clear signs of the disease, if we find positive tests for a virus, then we should be suspicious it is a false positive? Do you have some ideas in that case why ME patients would have a higher false positive rate than controls? Would the ELISA test in Chia's study have a similar issue to the immunoperoxidase stain?

Why would sensitivity to light not have the same cause in the case of an ongoing infection? I've never had serious light sensitivity, but after onset, my sound sensitivity in that first year would always co-occur with infection. I remember my first episode of sound sensitivity came on in a restaurant and I developed a fever and sore throat hours later. It would come back in w/ recurrent infection symptoms. Same with my autonomic symptoms. It was only when in chronic phase – when for some reason I became completely unable to have fevers or sore throats anymore – that it came with "crashes." Do we really know what causes these sensitivities? It just seems a stretch to me to say that my sound sensitivity then and my sound sensitivity now are independent/different symptoms.

I need to take a deep dive into the enteroviral studies. Will take careful note of methods as I do.

Maybe. I'd never had any of these symptoms in my life before, though. And yeah, I was rarely examined. I am still amazed how many times I've gone to a hospital, reported that I was unable to walk, and no one ever asked to observe me walking. Fine if it was ultimately non-specific, but no one connected my symptoms to an infection, even though I was having constant symptoms of infection. The infectious disease doctor didn't care about or understand the neurological symptoms. The neurologists didn't care about the infective onset. It was all more than a little ridiculous.

If you look at the symptoms gathered here: http://me-pedia.org/wiki/Epidemic_myalgic_encephalomyelitis#Symptoms this looks *a lot* like the ICC. So we've already collated these symptoms (and I have no idea how much the ICC authors' views were shaped by historic descriptions of ME v. contemporary research v. their own clinical experience) but they aren't really structured in a time order. I think an epidemic definition would make note of the length of the incubation period (4-7 days), the pattern of infectious spread within the community, the symptoms of the prodromal period, and the time from that until the onset of muscle fatiguability and CNS/ANS involvement. Surely that might help us recognize cases early and also distinguish them from onset via other types of infections. Don't focus solely on Acheson. What the individual outbreak studies describe is a symptom complex that looks very, very similar to the ICC. So yes, it is absolutely the same symptomatology (unless you think the ICC is an inaccurate description). I think the epidemic form of the disease should be of interest to ME sufferers who meet the ICC definition.

And re: 99% getting better, that wasn't true of the outbreaks. There was a very high rate of long-term disability that authors made frequent note of, far higher than in polio (and in the case of poliovirus, we know what the acute, intermediate, and long-term symptoms look like in every arm of outcome). Maybe there was a virus that caused long-term disability that existed in pre-1960 and is no longer with us. I just think if it was still with us, there is a good chance we wouldn't even notice because the public health/medical/surveillance infrastructure has changed so much.

Why couldn't we create one based on the 75 descriptions we already have? Maybe it's a historic curiosity. Maybe it enables someone to recognize the pattern if/when they see it.

 

No worries! I wasn't really sure what you were referring to in the OP. It is really interesting that people thought Coxsackie was the cause of everything in the 1970s because reading the 1980s, it definitely sounds like herpesviruses were the flavor of the decade. I do fear that now, it's the microbiome. Whenever a new frontier of measurement opens up, there's this initial optimism that everything that was once mysterious will be revealed by that new thing (the new virus, the new measurement technique). If I were to restart my Ph.D, maybe I would go into history of science!

Still badass, though. I don't think the war had as profound an effect in the US (for obvious reasons). Or maybe it did and I'm just young(ish) and still assume that progress is strictly increasing. I just know how hard it still is for female Ph.D students now in a variety of fields, especially mathematics and I imagine various sciences.

 

Agreed! But I don't think the standard should be "can be pinned down." Surely nothing has been pinned down, but I think we should look at what is interesting and unanswered. Far more fruitful than rejecting scant evidence or filling in the gaps with guesswork is to ask, if we want to test whether X is true, what evidence would we need? What experiments could we run? What observational data would be useful? With scant evidence, it's just as unwise to reject it as it is to try to fill in the gaps with conjecture. Better to just note "this evidence exists" without drawing conclusions one way or another. And may you think it's a red herring and that scant evidence should be left to history. I'd want to gather more data so we could either confirm or reject these implicit hypotheses: a) a subset of ME patients had as their trigger an enterovirus b) that enterovirus persists in muscle and brain tissue c) the persistence of the virus causes or contributes to symptoms d) the eradication of that virus improves outcomes.

We definitely don't know enough to reject these hypotheses, but I guess the answer to my initial question of why is no one looking into this further is probably that either a) no one finds this interesting or b) few people care about enteroviruses anymore (in general) and those that do aren't working in this field. Maybe when we have a brain bank or if methods change or improve or if new evidence becomes available, there will be reason + interest again.