The reason why people thought ME/CFS was due to enterovirus in the 1980s is that in the 1980s everyone thought everything was due to coxsackie B. Jo Cambridge did her PhD on coxsackie B in childhood myositis and we talked of nothing else for about five years. Coxsackie seemed to cause every weird and wonderful symptom you could think of and it had the attraction of being elusive and mysterious. By 1990 we had concluded that it had nothing to do with anything much except rather rare post-infective reactions affecting cardiac and skeletal muscle. And as far as I am aware the study of Incline Village did not confirm specific enterovirus involvement. Enterovirus was the fashionable speculation, not the data.
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.
There is also a problem with drawing conclusions from the 'outbreaks of ME', which I think you appreciate. If we model causation mathematically in terms of genetic, environmental and internal stochastic factors there is a paradox for these outbreaks. If they are due to common viruses that continue to be important in the causation of ME/CFS then why is there such a high local concentration of people affected at these times? With a common virus you may get an outbreak at the Royal Free this week and next week it will be Leeds Royal Infirmary and the week after Bart's Hospital and then Aldershot Barracks and so on. Isolated outbreaks are either due to rather restricted microbes where there are local propagation conditions (like hepatitis A in children's homes or Legionella in the Royal Free air conditioning some years later) or, presumably, they are due to microbes that have some unusual mutation and then die out. Otherwise, these outbreaks should occur repeatedly whenever a new group of people without immunity come together.
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.
It was clearly quite wrong to conclude that the Royal Free outbreak was mass hysteria and therefore ME/CFS is mass hysteria. On the other hand post viral fatigue with odd neurological symptoms is commonplace and I strongly suspect that a lot of the cases in these outbreaks never actually have an illness usefully classifiable as ME/CFS. And my understanding is that we do not really have much useful information about these outbreaks. (I am not sure what yo mean by well-defined.) Did we learn anything helpful from Royal Free or Incline Village? We probably learned something useful from Dubbo, where there are well recorded data but my impression is that the classic outbreaks may if anything muddy the waters for understanding ME/CFS today.
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.
If it is uncontroversial that enterovirus persists in tissue presumably it is uncontroversial that this is consistent with being healthy. We only have reason to blame a microbe for an illness if it is found more often in the illness than in healthy people and in most cases the distinction is pretty stark. I don't think we have any reliable evidence for enterovirus being present in ME/CFS more than normal. Subsets are of no interest until you have the basic observation on prevalence.
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 don't think there is any real analogy with polio. As you say polio causes a trivial acute infection in many. It also kills motor neurons in some and the pathology and clinical signs are barn door obvious. ME/CFS does not remotely resemble either of these situations. I don't think changes in respiration in cells in culture tells us anything either. Virus infected cells are very sick - they often die. I don't think that tells us anything likely to be relevant to a metabolic shift in muscle in PWME following exertion.
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.
I think there may well be value in examining brains from PWME post mortem, although there are significant practical problems with that. If narcolepsy is due to subtle cellular loss in a specific part of the brain then maybe something similar occurs in ME. I think it extremely unlikely that any virus would be found, however. I agree that current medical research has moved away from viruses but that is not so much because we have forgotten. At least those nearing 70 remember virus research only too well.
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 agree that it would be good to have a comprehensive review of what we do know about viruses and ME, but I think it needs to be done by people who know all the pitfalls of virus research. Sadly, as of now I tend to go with the answer that the assembled scientists gave me at the 2014 IiME colloquium when I asked 'how much do we know so far'. The answer was an immediate chorus of 'nothing'. It is hard to motivate people to write a review that will end up saying that we have no information that really takes us anywhere. But maybe that is what we do need. The alternative is enthusiasts producing things like the Cochrane review of exercise therapy and most reviews these days - which are just ways of trying to persuade others to believe what the authors believe because it helps their CV.
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.
