A Dozen Different Diseases? Stephen Holgate Calls for Radical Change in ME/CFS Research

August 15, 2013

Professor Stephen Holgate says ME/CFS is a spectrum of disorders that need to be understood through new approaches, and patients must be partners in research. Simon McGrath reports.

Image from Wikimedia

Houses of Parliament, site of Prof Holgate’s talk

ME/CFS probably isn’t one disease, or even a few different ones – but could be as many as fifteen. So said Professor Stephen Holgate, Chair of the UK Research Collaborative (CMRC), when he addressed the Forward ME Group in the House of Lords on 2nd July. He also argued that a radical New Science was needed to tackle ME/CFS and said patients must be partners in research. Not bad going for one talk.

More than a dozen different diseases?

Most researchers believe ME/CFS is more than one disease, and quite a few believe even ME is more than one, but I was surprised when Stephen Holgate said that ME/CFS could have twelve to fifteen different ‘causal pathways’. That’s an awful lot of different illnesses mistakenly lumped together in one pot. I asked Stephen about the number and he said that at this stage nobody knows for sure, but it’s highly likely to be fifteen or even more disease process, given it’s such a heterogeneous condition. There are, he mentioned, fourteen different causal pathways in Breast Cancer, seemingly a far more uniform illness. However, he added that some of the ME/CFS causal pathways will probably be interlinked, so it could come down to five or six underlying disease mechanisms. That would still be half-a-dozen different diseases – and it could yet be more. Stephen refers to ME/CFS as ‘a spectrum of disorders’ and has said that looking for the cause is a lost cause (Nature Reviews: Neuroscience 2011).

New Science needed

Microscope, funkyWith such complexity, it’s perhaps not surprising that little progress has been made to date. Professor Holgate said some researchers new to the field had been shocked by the poor quality of much ME/CFS research, and even commented that some had ‘made a career’ out of ME/CFS theories that could be shaky.

Also, while medicine has made great progress in many areas, it has been struggling to tackle the remaining problems, particularly chronic illnesses. A fundamental issue, he said, is “the breakdown of the linear relationship between cause and effect”. That was a bit over my head, so I asked him to elaborate: he’s always been amazed by the ability of our bodies to restore themselves in response to adversity, such as an infection – either compensating in part or restoring normal function. He believes that the complex networks responsible for this ability of the body to restore itself have gone awry in ME/CFS, and perhaps other chronic illnesses too.

He says the only way to tackle such a complex problem is, ultimately, to track down and understand the individual causal molecular pathways: if you know the pathway you know the way to deal with the disease, and that was the way to get the drugs industry involved. Identifying the pathways is a big challenge, but Stephen Holgate believes that now is a fantastic time to study ME/CFS as new techniques emerge that are up to the job.

Mega-study planned: 5,000 patients

To have any hope of identifying many different diseases (or causative pathways) within the umbrella definition, a lot of patients are needed; and there are early plans for a study involving a 5,000-strong cohort of patients. The idea is to explore everything: phenotypes, genotypes, gene expression, cells, cytokines, metabolites and more. Some of these individual features have been researched before, but not all together: and never on such a scale. High quality scientists would then have to be involved to look at applying the new technologies to the data generated from patients. But there has to be a multi-disciplinary approach, and nurses, for example, would be just as important as mathematicians in this operation.

A man who likes a challenge

Stephen HolgateNot many scientists choose to work with ME/CFS. Even fewer when, like Stephen Holgate, they already have impressive careers (he’s made several key discoveries about asthma for example). But Holgate positively sought out ME/CFS research and its politics.

He told the former Chief Executive of the Medical Research Council (MRC) that ME/CFS was a problem that needed sorting out – and was promptly asked to attempt just that. He began in late 2009 with a workshop and the MRC Expert group on ME/CFS, which ultimately led to MRC grants of £1.6 million ($2.3 million) for biomedical research in 2012. It was followed by the launch of the UK CFS/ME Research Collaborative (CMRC) earlier this year, endorsed by the MRC and two other major research institutions.

So Stephen Holgate gets things done, but why did he choose to get involved? In an interview he revealed that what he most loved about being a scientist was new challenges, particularly helping others who deal with “complex issues around complicated diseases” – a nice summary of ME/CFS, which he gave as an example.

Asked what he would like to be remembered for as a scientist he replied:

“That I was prepared to listen and take on difficult challenges and continue even if prevailing opinion was against me!”

This could be just what the field needs.

Stephen Holgate is the MRC Clinical Professor of Immunopharmacology and has been a visiting professor at both Harvard and Yale universities in the US.

New computer technology would be used to probe the mass of data, with the aim of finding distinct groups of patients who ‘cluster’ together with similar features, which should make it easier to home in on different causal molecular pathways in different types of patients. It is identifiying causal pathways that will lead to a much deeper understanding of ME/CFS and, hopefully, provide targets for drug therapy too.

Stephen Holgate’s vision for ME/CFS research requires a radical change. The majority of research funded in the UK to date assumes that whatever triggers ME/CFS, it is perpetuated by patients’ flawed beliefs and behaviours. The new approach focuses instead on differences between patients, to see what this might reveal about different underlying causal mechanisms. Though of course, as yet, nothing is proven. Also, if he is right, and there are up to fifteen different causal processes involved, it might explain why biological findings have been inconsistent across the small-scale studies we have seen to date.

Patients as Partners in Research

• breakdown in trust  patients to help shape research agenda

Stephen Holgate acknowledged that over the years there had been a breakdown of trust between patients, healthcare providers and researchers. He wants to change that, pointing out that in most areas of medicine the patient voice was now valued and recognised. (Read about the growing Patient Revolution here.) The ME Association’s Dr Charles Shepherd said the new CMRC Executive wants patients to attend meetings so that they could meet researchers. Holgate added it was also so patients can help set the research agenda – wow!

Patients, charities and the public must come to the CMRC’s Annual CFS/ME Scientific Conference, which starts next year (details yet to be announced). He would like to set a half-day aside for patient involvement, but is discussing with charities how best to do this.

With plans to engage with patients in setting the research agenda, and a new approach to research, we could well be at the start of a new era in the UK for the understanding of ME/CFS.

Note: unfortunately I wasn’t at Forward ME Group meeting, and wrote this from the extensive meeting minutes, with some additional information from Stephen Holgate himself. Any errors are my own.

Simon McGrath tweets on ME/CFS research:

  

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82 comments

{ 82 comments… read them below or add one }

Sasha August 15, 2013 at 1:30 pm

Great article, Simon. This is a very positive development. I bet we'd all like to be one of the 5,000 volunteers!

Has there not recently been a CAA-funded study that attempted to define groups of patients by clusters of symptoms? I can't remember the data source or the number of patients involved.

I like Prof. Holgate's strong push towards biomedical research and his wish (and the CMRC Executive's) to involve patients in setting the research agenda. These are all very positive signals.

If anyone is reading the article on the home page, you may overlook (as I did) the sidebar giving an interesting bio of Prof. Holgate – if you missed it, have a look. It makes it very clear we're extremely lucky to have him.

Thanks again, Simon.

Nielk August 15, 2013 at 1:31 pm

Thank you Simon for the hard work writing this article. I am impressed with Dr. Holgate's willingness to tackle this complex disease. I like the large scope and scale of the suggested study. It seems true that the latest findings and thoughts about ME/CFS point to the fact that it might not all be one disease. I am just a bit confused. You mention the example that he mentioned about breast cancer showing many causative agents, yet breast cancer is just one disease. Could it be that ME/CFS likewise is just one disease state resulting for different causes and/or pathogens?

Kina August 15, 2013 at 1:48 pm

Excellent article Simon. :)

Sushi August 15, 2013 at 1:58 pm

Simon

To have any hope of identifying many different diseases (or causative pathways) within the umbrella definition, a lot of patients are needed; and there are early plans for a study involving a 5,000-strong cohort of patients. The idea is to explore everything: phenotypes, genotypes, gene expression, cells, cytokines, metabolites and more.

Very interesting! I guess at this point how those 5000 would be chosen and participate would be just speculation. Though it would seem that they would have to be located in the UK, for logistical reasons.

Thanks so much for writing this up.

Sushi

Simon August 15, 2013 at 2:09 pm


Sasha

Great article, Simon. This is a very positive development. I bet we'd all like to be one of the 5,000 volunteers!

If anyone is reading the article on the home page, you may overlook (as I did) the sidebar giving an interesting bio of Prof. Holgate – if you missed it, have a look. It makes it very clear we're extremely lucky to have him.

Has there not recently been a CAA-funded study that attempted to define groups of patients by clusters of symptoms? I can't remember the data source or the number of patients involved.

Thanks, Sasha!

And yes, I agree that we are very lucky to have Stephen Holgate. Like Ian Lipkin, he has an abundance of other good opportunities and to have such able people taken a leading role in ME/CFS bodes very well for the future.

And there is a CDC study underway that has a similar aim, the multi-clinic study with around 500 patients. To date, this has a greater emphasis on clinical data but is a similar idea (also, it is already funded, unlike the current plan which is at an earlier stage – though I would never bet against Stephen Holgate getting what he wants).

Nielk

Thank you Simon for the hard work writing this article. I am impressed with Dr. Holgate's willingness to tackle this complex disease. I like the large scope and scale of the suggested study. It seems true that the latest findings and thoughts about ME/CFS point to the fact that it might not all be one disease. I am just a bit confused. You mention the example that he mentioned about breast cancer showing many causative agents, yet breast cancer is just one disease. Could it be that ME/CFS likewise is just one disease state resulting for different causes and/or pathogens?

This is where it gets complicated! Breast cancer refers to tumours in the breast, and what Stephen was saying is that there are 14 known, separate causal pathways that lead to breast cancer. So whether it would be breast cancer or breast cancers, I'm not quite sure. I think the choice of treatment depends on the precise type of breast cancer (eg particular mutations/causal pathways) so this is more than splitting hairs. The more we know, the more complicated things get.

With ME/CFS, what Stephen is saying is that there are probably many different causal molecular pathways, but some of these will be related. He said several of the molecular pathways could be part of the same disease mechanism, or 'causal network'. You could see each of these causal networks, or disease mechanisms, as one Disease, with ME/CFS then being made up of multiple diseases.

You might picture it like this:
View attachment 5484

But he is saying ME/CFS is more than one disease.

Another way to look at it is to roll back a couple of decades to when thyroid and adrenal problems leading to fatigue were often misdiagnosed as ME/CFS (still are, occasionally). These problems were not the same disease as ME/CFS, even though they can 'look' very similar. There could be several other such diseases that lurk under the current ME/CFS banner, completely unrelated to one another in causal or mechanistic terms, but appearing to be similar on the surface.

Hope I haven't gone on too much there.

And glad you liked the article.

Sasha August 15, 2013 at 2:16 pm


Simon

And there is a CDC study underway that has a similar aim, the multi-clinic study with around 500 patients. To date, this has a greater emphasis on clinical data but is a similar idea (also, it is already funded, unlike the current plan which is at an earlier stage – though I would never bet against Stephen Holgate getting what he wants).

The results of the study I'm thinking of were presented at the FDA workshop earlier this year, I think – just can't remember much more about it. o_O

Nielk August 15, 2013 at 2:21 pm


Sasha

The results of the study I'm thinking of were presented at the FDA workshop earlier this year, I think – just can't remember much more about it. o_O

Sasha – are you thinking of Susan Vernon's presentation at the FDA regarding the study being conducted with Biovista?

Simon August 15, 2013 at 2:26 pm


Sasha

The results of the study I'm thinking of were presented at the FDA workshop earlier this year, I think – just can't remember much more about it. o_O

That's the same one – I wrote that blog from the FDA video of Elizabeth Unger's presentation.

Sasha August 15, 2013 at 2:28 pm


Nielk

Sasha – are you thinking of Susan Vernon's presentation at the FDA regarding the study being conducted with Biovista?

I think that was about treatments but the study I vaguely remember was about clustering patients according to symptoms (which I suppose could have been a prelude analysis to identifying treatments)… :confused:

alex3619 August 15, 2013 at 4:48 pm

I have been saying for years that ME may be two or more different diseases, and CFS may be many different diseases. That is the way the evidence stacks up. It still requires more evidence to be sure though. Holgate is right about a lot of it in my opinion, including the need to focus on molecular mechanisms, but that could just be my bias as a biochemist coming out. There is a problem with that assumption though. Even with, for example, fifteen mechanisms identified, we still have to interpret those within the complex seething molecular cauldron that is the human body. A molecular mechanisms reductionist claim, and its not wrong, may be useful but to really interpret it you have to look at the big picture too. Fortunately for us the rise of systems biology may give us the tools to do that.

I also think that if there are fifteen underlying causal mechanisms, again to use that example, there will be common pathophysiological consequences. Indeed one big issue in our research that I have written about before is much of what we know may be pathophysiology and not tell us much about causation. It does tell us a lot about symptoms however.

Treatment for symptoms only requires an understanding of pathophysiology. A cure is best developed by understanding ultimate causation. Advances in both directions are beneficial, but to have a good cure (as opposed to a very problematic one) requires that we understand a broad diversity of molecular interaction in ME. However even a bad cure is better than no cure. I suspect Rituximab will turn out to be a bad cure, and an OK treatment. If we understood the mechanisms better then we could optimize such treatments better.

xchocoholic August 15, 2013 at 5:30 pm

Hopefully they will eliminate all the "pwcs" with known causes first. I'm just talking
about the ones who completely heal via treating their known cause.

So far we know
about celiacs, lymies, moldies, potsies, and those with thyroid and adrenal
problems. I feel like I've forgotten a known misdiagnosis.

Of course they'll be some pwcs with all the above who still qualify as pwcs.

Great news ! I hope this entices others who like a challenge.

tc … x

Erik Johnson August 15, 2013 at 5:51 pm

Can't eliminate the Moldies.

Biotoxin exposure is part of what started the CFS syndrome.

Doctors just didn't know it.. because they never acted in accordance with the basic purpose of creating a syndrome:

To look for the unknown factors.

taniaaust1 August 15, 2013 at 6:05 pm

In response to Erik Johnsons post.. I dont see how it could take anything away from ME clusters outbreak group as it would help to define that group as being its own depending on what they find separates all the groups.

Maybe some of the ME outbreaks too have been different things and not even exactly the same? Who knows (some of the outbreaks have been described quite differently but of cause that may also be due to the speciality fields or interests of whoever was studying it and reported at the time, different things will stand out to different people).

Nielk.. There are different kinds of breast cancer. My grandma was very unfortunate she got breast cancer which they thought was successfully treated but then developed a completely different kind of breast cancer (an extremely aggressive rapid growing kind) which killed her

……………………….

Thanks for this article, it helps give me hope that this illness may be figured out my lifetime. We so need good scientists like this one in the field, helping move things forward for us.

This scientists thoughts are on par to what Ive always believed, that there are many different illnesses involved (the ME outbreak group being one or maybe even that group may be two or three different things). I believe quite a few new illnesses will be found.

I think within our group, they are quite likely to discover also new atypical presentations of well known illnesses too, which will form new views around those illnesses as well. Maybe some of the diagnostic criteria for some other illnesses are needing some tweeking as may be missing some with those illnesses due to how illnesses are defined, not always being great. I believe new subgroups of other well known things will be found.

Erik Johnson August 15, 2013 at 6:07 pm

That would be redefining ME as whatever five thousand putative ME diagnoses have, instead of what the Royal Free survivors had.
And taking CFS away from the evidence and illness that started it. Substituting a new dataset.

Then combining two mistakes in one, calling it ME/CFS and compounding the error.

Whatever you came up with, you'd have to inform Dr Peterson's original CFS cohort that they don't have their own syndrome, but are some kind of peripheral subset, and probably not even CFS at all.

Oh, we've seen that trick before, haven't we?
But it was the CDC that pulled it last time.

taniaaust1 August 15, 2013 at 6:25 pm


Erik Johnson

That would be redefining ME as whatever five thousand putative ME diagnoses have, instead of what the Royal Free survivors had.
And taking CFS away from the evidence and illness that started it. Substituting a new dataset.

Then combining two mistakes in one, calling it ME/CFS and compounding the error.

Whatever you came up with, you'd have to inform Dr Peterson's original CFS cohort that they don't have their own syndrome, but are some kind of peripheral subset, and probably not even CFS at all.

Oh, we've seen that trick before, haven't we?
But it was the CDC that pulled it last time.

How would you explain myself fitting the ME international consensus criteria (my illness started out as a virus just like ME does, my illness is just like what Cheney and David Bell talks about with their patients) and my sister who developed what fits as CFS from accidently drinking from my glass? She hasnt got none of the ME abnormalities I do showing on her her test results and she doesnt met the ME international criteria (she's now been sick for 2 years, she does get post exertional symptoms). How can I not think she hasnt got what I do esp seeing she seems to have caught her illness from me. (I have 2 others in my family sick too, one of the others does meet the ME criteria while the other also doesnt)

No matter what we do, due to not enough being know about ME, the whole thing is ONE HUGE MESS with us trying to draw a line between the illness but no one really knowing where the lines lay so it all comes down to some chance what defination you are going to fit under. Maybe there are others like my sis who may have ME but dont currently fit the current definition (note I do like the ME definition so my post isnt certainly one against it..but it is probably missing some with ME.. either that or I wrongly fit it myself).

I think anyway no matter which views we have, we all agree its a huge mess. Till they find the ME virus? or whatever, it will continue being a huge mess.

Erik Johnson August 15, 2013 at 6:49 pm

Only an academic mind would see fit to make a puzzle easier to solve by shaking fifteen of them together and trying to solve them all simultaneously.

ME is first and foremost, everything that was known about the Royal Free cohort.

CFS is the term for the illness and evidence under scrutiny by the Holmes committee, when they felt compelled by the weight of that evidence to contrive a syndrome in order to study it.
(Yes, even the stuff in Osler's Web that they… strangely saw fit to leave out of the definition.)

Deviation from those parameters must be carefully considered for inclusion.
Not because they might be less severe, but to avoid complicating the problem.

I'd stick with the basics. But that's just simple-minded me.

Bob August 15, 2013 at 6:57 pm

I see Erik's point…
It would be silly to ignore geographical outbreaks when investigating ME/CFS.
But Peterson has provided his samples to Lipkin (and to Beth Unger, and I assume his own Simmaron research projects), so his patient cohort is being investigated.
I don't know how many outbreaks we've had in the UK (memory fails me) but I think they are very unlikely to get investigated, because I don't think the patients have been closely followed by any current doctors or scientists. I might be wrong.
In any case, most people with CFS/ME are not from outbreak areas, so they also need to be investigated, and subgrouped.
I think the proposals are a promising and necessary step forwards for CFS/ME research.
Like Tania, it gives me reason to be optimistic.
Especially because I think Stephen Holgate is very capable, with the best motivations.

Erik Johnson August 15, 2013 at 7:05 pm

The point of creating a new paradigm called "Benign Myalgic Encephalomyelitis" in response to the Royal Free outbreak was that the authors felt they were on strong enough ground to delineate a discrete illness entity.

This was a step up from "Iceland Disease" and "Epidemic Neuromyasthenia"
But ONLY if you consider to ME to be the evidence that constituted the REASONS the authors were on strong ground.
To set these aside and think of ME as "everything in general", is moving ME below the standards which gave the entity a strong enough footing to qualify as a discrete entity.
—————————————–

http://findacureclub.weebly.com/uploads/5/2/5/1/5251327/acheson_amjmed.pdf

The Clinical Syndrome Variously Called Benign Myalgic Encephalomyelitis,
Iceland Disease and Epidemic Neuromyasthenia
E.D. Acheson, D.M., M.R.C.P.

The Case for a Clinical Entity
It is significant that the first review of the
syndrome under discussion was entitled, “Not
poliomyelitis”45; the second, “A new clinical
entity?”22. In later articles entitled, “Epidemic
myalgic encephalomyelitis”46, “Benign
myalgic encephalomyelitis”46a and “Epidemic
neuromyasthenia”15,16, the authors considered
themselves on sufficiently strong ground to
describe and name the syndrome. This
sequence indicates that the first and minimum
requirement in the definition of an entity is the
essentially negative one of showing that the
syndrome is not an unusual manifestation of a
disease already recognized. Later, as evidence
accumulates, it may be possible to define the
disorder in positive terms.

Erik Johnson August 15, 2013 at 7:08 pm

This is exactly what happened with "CFS"

By finding new evidence, Cheney and Peterson moved the "CEBV Syndrome" entity up to a level that the CDC couldn't ignore. (The CDC just didn't TELL you about all that evidence. Nice trick, eh?)

It is easy to bypass the CDC contrived confusion by conceiving of CFS as.. "The illness AND EVIDENCE under scrutiny by the Holmes committee"

In this way, we have two discrete databases, for easy analysis.

One called ME, and one called CFS.

So we can see where they overlap.

Erik Johnson August 15, 2013 at 7:35 pm

I can assure you that Dr Peterson's cohort is NOT receiving a proper epidemiological assessment.

To do that, one would have to consider the environmental milieu and the particulars of their geographic circumstances,
in addition to what may be found in the blood.

Esther12 August 15, 2013 at 7:46 pm

Thanks Simon. While I'm still deeply sceptical about the research collaborative, Holgate does seem keen to move things in more sensible direction. Lets hope he manages it.

xchocoholic August 15, 2013 at 8:24 pm


Erik Johnson

Can't eliminate the Moldies.

Biotoxin exposure is part of what started the CFS syndrome.

Doctors just didn't know it.. because they never acted in accordance with the basic purpose of creating a syndrome:

To look for the unknown factors.

Hi erik,

Hope you're doing well. Always good to hear a success story.

I have to disagree with what you wrote here. If you believe what others are saying about
healing from CFS, CFS isn't just from biotoxin exposure. I listed the causes that I've been reading about
for the last 8 years but I'm sure I forgot something.

Even the NIH identified celiac disease as a common
misdiagnosis as far back as 2006. That's when I found the info on their celiac website.

I just remembered that I left out heavy metal poisoning.
Dr mark hyman was dx with cfs but later said his was from heavy metals.

Fwiw, my cfs started with a bug of some sort that infected my lungs. I was given multiple rounds of an antibiotic that I now suspect was a flouroquinolone. I'm still trying to recover from an exposure to this med
back in Jan 2013. My shoulders and knees went into spasm. My whole body went into spasm in 1990 after
I took antibiotics. I "think" my body was too weak from 1990 – 2005 from my lousy diet to repair itself.

Sure there could've been a biotoxin involved
but identifying that in 1990 would've been impossible based on the level of medical care I received.

Fwiw, I wonder how often medical communities make the effort to report an outbreak of
any kind. tc … X

Erik Johnson August 15, 2013 at 8:38 pm

I know for a fact that this new "CFS" syndrome was created due to mold-evidence because the only reason I agreed to help start it was to obtain research into this overlooked clue.

It is impossible for mold to "not" be a part of what the syndrome was coined to solve.
But as I say, no doctors believed us, and so it remained ignored for many years.
It wasn't until Dr Ritchie Shoemaker recognized the phenomenon that I finally got PART of the research that I started the syndrome for.

There is more, that still remains to be investigated.

http://www.cfsuntied.com/toxicmold.html

xchocoholic August 15, 2013 at 9:35 pm

Hi erik,

I'm trying to relate to what you're saying about being in on the new cfs syndrome trend but
all I see is how horribly mishandled all these patients were. Our cfs doctors collected info
on patients mostly based on symptoms not test results. Several of the tests I had were to verify
that I was telling the truth about my symptoms and confirm my cfs dx.

For ex, imho, your doctor should've looked into mold exposure with you. Mine should've
tested my genes for celiac and asked about flouroquinolone exposure. And if they'd looked
at all their patients for clues on what was causing their cfs and treated it, we'd have a lot less pwcs.

The reason I want those pwcs who've healed from known misdiagnosises out of the picture is to
see what we have left. Only then will the data be manageable so hopefully can we find what's stopping the
rest from healing.

Sorry if I hijacked this thread. I'm excited about this project. Tc .. X

Erik Johnson August 15, 2013 at 9:47 pm

My doctors were Peterson and Cheney. I did ask, and both of them refused.
No such testing existed back then, as toxic mold had not yet been discovered.

This is why mold was not connected to the new syndrome, and remains unconnnected because to revisit the evidence would be to admit that some was overlooked.

Which is why I am not about to agree that someone else like Prof. Holgate can define CFS based on other people.
To do so means they have no intention of ever revisiting the original CFS outbreak.
And should they find "CFS is something else" our phenomenon will stay officially unexplained forever, no matter how many people know the real story.

rosie26 August 15, 2013 at 9:59 pm

With all the different illnesses that are thrown in to the mix of the ME/CFS umbrella, no big surprise that researches believe there are multiple causes for ME/CFS. Well hopefully, they can sort the ME ones out of it. ? Then we can work out from there "if" there are multiple causes or one cause for ME.

Erik Johnson August 15, 2013 at 10:04 pm

What right does anyone have to consider ME – CFS or "ME/CFS" an umbrella?

There was Epidemic Neuromyasthenia and Iceland Disease up until Siguurdsons, Ramsay and Richardsons evidence refined it up to a new level with viral evidence, thermograms and electromyograms. It was called ME.

There was "CEBV Syndrome" up until Cheney and Peterson stumbled over a discrete set of abnormalities outlined in Osler's Web. This entity matched nothing in the CDC's literature, and this was called CFS.

Why would I agree that ME and CFS are "anything and everything"… when I know they are not?

heapsreal August 15, 2013 at 10:20 pm

Neuro immune illness has been mentioned before to cover the wide variety of possible conditions but still narrows things down to the physiological issues of neurological symptoms and abnormalities with immunological symptoms and abnormalities. From there it can be broken down into sub sets for better treatments etc.

Example of myself i would say i have a neuro-immune illness (NII) with low nk function, lymphocytosis and viral reactivations. So its describing the abnormalities found in testing. Others could maybe say they have NII with orthostatic intolerance, seizures and immunoglobulin defiencies. I dont know if we need to be in specific groups but maybe outlining the major dysfunctions found. I dont think its neccessary to list every symptoms though. Also gets us away from the whole fatigue tired thing, sure its a symptom but as we know everyone is fatigued and tired and every illness has this to some degree.

Firestormm August 15, 2013 at 11:18 pm


Erik Johnson

What right does anyone have to consider ME – CFS or "ME/CFS" an umbrella?

There was Epidemic Neuromyasthenia and Iceland Disease up until Siguurdsons, Ramsay and Richardsons evidence refined it up to a new level with viral evidence, thermograms and electromyograms. It was called ME.

There was "CEBV Syndrome" up until Cheney and Peterson stumbled over a discrete set of abnormalities outlined in Osler's Web. This entity matched nothing in the CDC's literature, and this was called CFS.

Why would I agree that ME and CFS are "anything and everything"… when I know they are not?

Erik – without wanting to take this off-topic – out of interest where would 'toxic mold' (and I never have understood what this is meant to really mean), fit then? And when Holgate embarks on this research (if he embarks on this research), will he not determine mechanisms that might constitute 'toxic mold' if indeed there are any? I mean how else do you reasonably hope things will move forward in the direction you think they must? I know you are angry about the way things have turned out – as am I in some similar respects I suspect – but we are where we are now: we can't go back in time and smack some heads together.

n.b. I am not familiar with Ramsay, for example, ever referring to 'toxic mold' in any of his writing – are you able to cite a reference? Thanks.

Firestormm August 15, 2013 at 11:40 pm


rosie26

With all the different illnesses that are thrown in to the mix of the ME/CFS umbrella, no big surprise that researches believe there are multiple causes for ME/CFS. Well hopefully, they can sort the ME ones out of it. ? Then we can work out from there "if" there are multiple causes or one cause for ME.

Simon maybe you can help my own understanding out in this regard :)

I can see how taking blood (and other things?) from patients with a diagnosis of our condition; and analysing at the molecular level will result hopefully in an ability to 'cluster' patients together according to the results (and based on what is looked for – something we do not know about at this point).

What I can't see is how these results might always relate to symptoms and/or even alternate diagnoses. I would also like to talk a little about how, as a result of this work (and other work like it), we could see a different definition/determination of what constitutes ME.

What I mean to say is, that at present we have theory after theory, based on various attempts to interpret presented symptoms and patient history; based sometimes on actual analysis of tissue or mechanisms; based on whoever is being studied and then applied in part or whole to the population i.e. generalised – and this generalisation is often unsubstantiated (something I hope Holgate's work and others like it will also eventually help overcome).

So we have a picture of what ME is and isn't – although even generally agreed consensus seem to get fuzzy round the edges each time a new study comes out (or criteria) and is absorbed into the mix. Even if it only takes root with some members of our community and/or some medical and practising experts: it can raise issues of course perhaps especially when it challenges 'ancient' ideas or when it leads to recommendations for a specific treatment (drug or otherwise).

So if Holgate's work is to be meaningful (i.e. accepted as significant), we could arrive at a different way of viewing ME. We could in fact end up with something not being called ME or CFS.

This might depend on where each of us – individually – subsequently fits as a result of any new recommended testing of course; but it might also mean that those who can't be categorised (for want of a better word); are effectively left in a much-diminished 'pot' with a different label or with the label of ME or CFS.

Now that 'pot' could encounter the kind of management interventions that we see now being applied to CFS/ME in the UK. Indeed these techniques could also be still applied in other respects i.e. they may not disappear. Which is fine, if you are not in it of course, or if they help you as an individual. So you may face these current recommendations if your molecular findings are unable to be treated by a drug.

You can only receive an alternate diagnosis and treatment by drug, if an alternate diagnosis exists that fits with your molecular abnormality; and if that can be attached to your presented symptoms and is deemed to account for your poor state of health. Can molecular findings account for 'pain' or even 'muscular aches and pain'? See what I am getting at. Not saying they can't, not saying they can either.

All the various testing that some patients have, pay for, and report on (here on PR for example), might be said to – in part – have been determined at the molecular level. If a 5,000 strong study does lead to grouping of similarities then great: I would be most pleased with the recognition that might come from that.

However, not all the resulting interpretations or treatments will be considered by the community as favourable – and we should be prepared for that also I think. Look at the chemical (molecular) abnormalities that can be revealed and then applied to psychiatric conditions and treated with psychiatric drugs or therapies for example.

But whatever the outcome I will be welcoming of it I think as I am of this idea. It's the interpretations that will ever be most talked about and about which we should be prepared.

How am I doing? :)

Edited for comprehension – mine and yours!!

Erik Johnson August 15, 2013 at 11:43 pm

Ramsay didn't know about toxic mold. It means exactly what it sounds like.
Mold that has surprisingly profound neurotoxic effects.

Toxic-Mold did not enter the US literature until after researchers already decided that the mystery illness must be a virus.
Having made that decision, the new syndrome of CFS was coined to look for a "possibly unique medical entity".
But researchers had already made up their minds.

The head banging has never stopped, but it's mostly researchers banging their heads against the walls, because for some strange reason, they forgot how science is supposed to be done.

They said they wanted to know about "CFS"… so I told them.
The ball is in their court.

Firestormm August 15, 2013 at 11:50 pm


Erik Johnson

Ramsay didn't know about toxic mold. It means exactly what it sounds like.
Mold that has surprisingly profound neurotoxic effects.

Toxic-Mold did not enter the US literature until after researchers already decided that the mystery illness must be a virus.
Having made that decision, the new syndrome of CFS was coined to look for a "possibly unique medical entity".
But researchers had already made up their minds.

The head banging has never stopped, but it's mostly researchers banging their heads against the walls, because for some strange reason, they forgot how science is supposed to be done.

They said they wanted to know about "CFS"… so I told them.
The ball is in their court.

OK. Thanks for that :)

Erik Johnson August 15, 2013 at 11:55 pm

I know how crazy it sounds, but I can't do anything about it. Yes, I had the full "viral onset", but chronic mycotoxin exposure is what set the stage.

This is what hit us at "Ground Zero for CFS".

http://www.moldreporter.org/blog/ch…otoxicosis-may-be-indistinguishable-from-cfs/

Chronic Trichothecene Mycotoxicosis May Be Indistinguishable From CFS

Objective: Chronic exposure to trichothecene mycotoxins (mold-produced toxins) is known to be both immunotoxic and neurotoxic in animal studies. Accidental exposure to these toxins can occur when toxigenic molds grow in buildings and release spores into the air. The objective of this research was to review the available evidence which suggests that chronic inhalation of certain mycotoxins produces a constellation of symptoms and laboratory abnormalities consistent with the Chronic Fatigue Syndrome (CFS).
Method: Both a hand-search and a MedLine-based search of the literature were conducted. Personal communications with key researchers in the field and presumed victims of chronic mycotoxicosis were included.
Results: In 1982, concerned that trichothecene mycotoxins might be used as a chemical warfare agent, the Department of the Army commissioned the National Research Council to review the available literature on the potential health effects of exposure to trichothecene mycotoxins. They concluded that there was no well-defined cohort of people that had been exposed via inhalation, the presumed route of interest on the battlefield. Thus the potential health effects of inhalation exposure were not known.
In 1986 Croft et al., with funding from the Army, reported chronic inhalation mycotoxicosis in a household in Chicago. (See “Airborne Outbreak of Trichothecene Toxicosis” in Atmospheric Environment 20: 549-552.) Subsequently, reports or presentations of chronic mycotoxicosis in several homes, office buildings and a hospital have been published. For every published report, experts in the field relate several unpublished cases.
In California, two episodes involving groups of residences have been reported in the lay press since 1994. Most, but not all cases have involved molds which produce trichothecene-class mycotoxins. Sev-eral of the published reports explicitly state that the symptom constellation experienced by mycotoxin vic-tims is similar or identical to CFS. Almost all of the published reports are consistent with a diagnosis of CFS.
At a 1994 conference dedicated primarily to mycotoxigenic fungi, Pierre L. Auger reported that most of his patients met the 1988 CDC criteria for CFS. Cognitive impairment was significant. He referred several of these victims to an occupational neurologist, who diagnosed them with “toxic encephalopathy.” Auger reported evidence of immune system impairment in many of his patients. Eckardt Johanning reported evidence for immune dysfunction in a cohort from an office building in New York. In addition to laboratory findings such as reduced natural killer cell number, clinical findings included recurrent vaginal candidiasis and bacterial infections. Several of his cases were severely disabled.
Although longitudinal data on patients is very limited, at least one cohort has been followed for ten years. Fewer than 20% of the victims reported complete recovery. Most reported some recovery. About 10% either did not recover or became worse.
Most aspects of chronic trichothecene mycotoxicosis are consistent with CFS, including the symptoms, laboratory findings and recovery profile. It is suggested that further research is warranted to determine if a subgroup of patients diagnosed with CFS are actually suffering from mycotoxicosis.
References
Johanning E, Morey PR, Jarvis B (1993): Clinical-Epidemiological Investigation of Health Effects Caused by Stachybotrys atra Contamination. In Seppanen O, Steri J, Kainlauri E (eds): “Indoor Air 93″ Helsinki: FiSIAQ, 1:225.
Printed with permission from RJ Kelly, Lawrence Livermore National Laboratory, University of California at Livermore.

Erik Johnson August 16, 2013 at 12:17 am

Ironically, the guy who wrote this article was a colleague of Rich Vankonynenberg, and was giving us both an education in trichothecene toxicosis at the very same time in 1997.

————————————————————————-

Sat Oct 16, 2004 6:04 pm
Message #17887

> Hi, Erik.
>
> One thing you might be interested in:
> I attended the conference, and I spoke with Dr. Kenny de Meirleir.
Among other things, he said that he believes that the Truckee
> outbreak of CFS was caused by mold.
>
> Rich Vankonynenberg

Hi Rich, I had heard this through my mold contacts.
And also that Robert Suhadolnik had come around to considering this
as well.
FINALLY!
It only took twenty years of screaming this for someone to finally
listen.
What can I say?, except,
NEENER NEENER NEENER!

-Erik

Guido den Broeder August 16, 2013 at 4:11 am

Drop the CFS and it's just the one disease, ME.

Even 5000 patients won't be enough to study the myriad of pathways that are hiding under the CFS umbrella

Firestormm August 16, 2013 at 4:36 am


Guido den Broeder

Drop the CFS and it's just the one disease, ME.

Even 5000 patients won't be enough to study the myriad of pathways that are hiding under the CFS umbrella

Indeed.

Myalgic Encephalopathy :)

Stands aside for flood of protest :ninja: :D

Heart Face August 16, 2013 at 4:44 am

Great article Simon thank you. I have to wonder though, as SH has finally said what we've all been thinking for the past forty years, why has he agreed to a collaboration with Simon Wessely and Esther Crawley who should be as far away from the illness as possible?

Firestormm August 16, 2013 at 4:54 am


Heart Face

Great article Simon thank you. I have to wonder though, as SH has finally said what we've all been thinking for the past forty years, why has he agreed to a collaboration with Simon Wessely and Esther Crawley who should be as far away from the illness as possible?

Just remind me where Wessely fits with this? He is not a part of the CMRC initiative. I think you will find that White was appointed, and Crawley; and others of course – see link.

biophile August 16, 2013 at 6:19 am

Research consistently shows that roughly half of people who meet symptom criteria for CDC defined CFS have a wide range of exclusionary medical and psychiatric conditions which disqualify them from a CFS diagnosis. It might be much worse for the Oxford criteria; the PACE Trial excluded 80% of candidates who were provisionally thought to have CFS.

This suggests that the presence of broadly-defined "CFS-like" symptoms has very poor specificity. CFS became one of the greatest wastebasket diagnoses of all time for so-called medically unexplained physical symptoms. It is ridiculous to believe that medical science has reached a point of discovering and appropriately classifying all significant diseases.

So it should surprise no one at all that it may not just involve heterogeneous pathways to a similar outcome or singular end-state, but probably includes a wide range of undetected but disparate disease processes. Stricter definitions of ME, such as the ICC, should help to reduce heterogeneity, but I think there needs to be both broad and narrow approaches.

And dare I say, perhaps those that respond positively to CBT/GET (presuming there is more to it than response biases in non-blinded trials), have different clinical characteristics and disease processes going on than those who do not.

Erik Johnson August 16, 2013 at 6:55 am

It looks like people have never read Osler's Web by Hillary Johnson and they don't understand what happened with CFS.

The CDC and Stephen Straus of the NIH were embarrassed and humiliated by what they thought to be a couple of hick doctors at a ski resort who overturned their "CEBV Syndrome" hypothesis. The CDC was forced to grudgingly concede to the new evidence-base and make a gesture of "scientific response".
But to cover up their incompetence and malfeasance, the new syndrome was deliberately made to be vague (not totally wrong, but hopelessly ambiguous) and throw in one line about "To maximize chances of identifying persons with a possibly unique medical entity" JUST IN CASE there was one. The frosting on the cake was the deliberately trivializing name.

The CFS definition itself tells you not to think of the description as being the disease.

So… if you read the fine print and follow the instructions, there is really nothing all that wrong with the definition.
It never said the illness was fatigue, nor did it claim that the "unique medical entity" was NOT "ME".

The CDC just stood back and let the confusion roll, acting like "Who, us? WE never said it wasn't serious or real"

wdb August 16, 2013 at 6:56 am


Guido den Broeder

Drop the CFS and it's just the one disease, ME.

ME is largely defined by a set of symptoms e.g. International Consensus Criteria so I don't see any reason to exclude the possibility it may be more than one disease (probably a significantly smaller number though than CFS or CF).

Even if you want to take ME literally as inflammation of the brain and spinal cord then a) that would only account for a sub-set of those diagnosed with ME and b) would still not exclude the possibility of more than one underlying cause.

Erik Johnson August 16, 2013 at 7:06 am

People can run around in circles all they want, claiming that nothing is known about CFS and that it is all very confusing.
Which is apparently the primary means of keeping CFS "confusing".

But that only works up to the point of being confronted by the facts.

The entire procession of events and the evidence that led to the creation of the syndrome are fully documented.

We know, and always did, everything that was reported in Osler's Web.
——————————————————————————————-
http://www.imet.ie/imet_documents/BYRON_HYDE_little_red_book.pdf
A Brief History of Myalgic Encephalomyelitis and an Irreverent
History of Chronic Fatigue Syndrome
-Byron Hyde M.D.
The 1988 CDC definition did several things, all of which caused
immeasurable confusion.
Why did the 1988 CDC definition damage our knowledge and
understanding of the epidemic and endemic disease? Remember that in
describing the Lake Tahoe epidemic this committee were describing a
typical Myalgic Encephalomyelitis Epidemic

MEsupport8 August 16, 2013 at 7:09 am

THANK YOU! This is so obvious, it has been a source of great frustration that so many years have been wasted lumping millions of people together based on one symptom – fatigue. There are adrenal people, GI/yeast people, immune/NK function people, HHV6 and other Herpes people, thyroid people, etc. etc. etc. I (and I'm sure many other patients) am more than happy to continue to pool our resources and maintain a united front until they can definitively identify and solve separate illnesses and tease them out of the large group of uncared for patients, and certainly to house all under an umbrella of related pathways where they exist thereafter, but no research can ever produce any useful results if we continue to vaguely define the patients in each study and then wonder why their symptoms, and the treatments they respond to, are so inconsistent with each other.

I have severe genetic immune-pathway ME, which bears little resemblance to the many patients I encounter who have adrenal or thyroid issues, aside from the fact that many of us struggle to work and are on disability. We are all sick, but no wonder my doctors fail to treat me, when I am bedridden with a completely failed immune system and failed body and they are using people who have a completely different illness for their research! "CFS" is the name for "multiple different diseases lumped together because we don't care enough about any of these patients to learn what they actually have or how they are different – they are all tired, let's just throw them away" – can somebody PLEASE get that stupid name out of our "medical" institution in the US, so patients can finally be treated like people with doctors who actually care what has gone wrong in their individual bodies!! I am sick of being a throwaway person in my own society, and in my medical community, when I have so much evidence to give if only somebody wanted to study me as part of a subset, not constantly throw all my test results into a pool of hundreds of unrelated results for yet another study that wastes research dollars and precious time. Have a brain, we are not all the same, we are not just to be thrown away on the pile of the "fatigued" for us all to rot together in meaninglessness. Ask the patients for once, we could tell you in moments what it seems to be taking doctors decades to think of on their own!

[Argh! - rant... Just have to get it out sometimes...]

Legendrew August 16, 2013 at 7:44 am

Good article – interesting content and nice to see someone putting a lot of hard work into ME research. Hopefully in 5 years time we could have an answer as to what causes all the suffering and might even have a treatment to stop it!

Erik Johnson August 16, 2013 at 8:28 am

My confidence that this is "good research" is seriously tempered by my wonderment that they simply won't just come and ASK.

They might be surprised at what we have always known.

Nielk August 16, 2013 at 8:42 am


Erik Johnson

My confidence that this is "good research" is seriously tempered by my wonderment that they simply won't just come and ASK.

They might be surprised at what we have always known.

What do you mean by "us"?

Simon August 16, 2013 at 8:45 am

Looking for evidence without preconceptions

This is in reply to a number of posts, particularly those by Erik Johnson:

Erik Johnson

That would be redefining ME as whatever five thousand putative ME diagnoses have, instead of what the Royal Free survivors had.

And taking CFS away from the evidence and illness that started it. Substituting a new dataset.Then combining two mistakes in one, calling it ME/CFS and compounding the error. Whatever you came up with, you'd have to inform Dr Peterson's original CFS cohort that they don't have their own syndrome, but are some kind of peripheral subset, and probably not even CFS at all.

Erik Johnson

Only an academic mind would see fit to make a puzzle easier to solve by shaking fifteen of them together and trying to solve them all simultaneously.

ME is first and foremost, everything that was known about the Royal Free cohort.

Erik Johnson

What right does anyone have to consider ME – CFS or "ME/CFS" an umbrella?

I don't think it's about rights – a broad range of illness is already being categorised as ME/CFS. The real question is how to get clarity, and understand what's really going on. And I believe what's being proposed with the 5,000 cohort study will do that.

Let's say there is a true ME, as defined by Ramsey: that should still show up as a unique cluster with a distinct biological/clincial signature. Unless of course it was a unique illness that only applied to those in the original outbreak, or also including those since who were part of a later infectious outbreak with identical symptoms. If that's the case, it might not show up in this study, but if it only covers a tiny number of people, we still need to work out what's wrong with everyone else.

So here is how the clustering is supposed to work: Take 5,000 patients and profile them every way you can: clinical data, symptoms, onset type, comorbidities, biological data eg gene expression, proteomics, NK types, genotypes and so on. The idea is that real, distinct diseases will form clusters, or rather patients with the same disease will cluster together, and away from patients with different underlying disorders:

View attachment 5487
For this approach to work, you need to include the right factors eg NK status or genotype. Since we don't know what the right factors are, the approach is to throw the net wide and get data on everything conceivable: computing technology and fancy statistical approaches will still find the clusters even if there is a huge amount of noise (non-relevant factors) in the data. [edit: assuming that the data does include they key factors].

One possible outcome is that there will be a single cluster that exactly matches ME as defined by Ramsey. Or as defined by ICC. This would be validation of those criteria. And the rest could be an indistinct mess. More likely, there will be several clusters that don't exactly match existing case definitions, and some indistinct mess too. As Stephen Holgate said during the Forward ME meeting, current definitions are arrived at by groups sitting around tables: the best we have right now, but need validation with biological data.

geeky backround to clustering
There's a really interesting paper by a guy called Kendell about how clustering works (more on it here), but the idea is that similar patients – or rather patients with similar proflies cluster together. Kendell was a pyshcologist (arguing that most psychological case definitions had no validity), but he based his work on that of microbiologists trying to identify different bacterial species before DNA sequencing came along.

xchocoholic

Hopefully they will eliminate all the "pwcs" with known causes first. I'm just talking about the ones who completely heal via treating their known cause.

So far we know about celiacs, lymies, moldies, potsies, and those with thyroid and adrenal problems. I feel like I've forgotten a known misdiagnosis.

Yes. And hopefully they will divide what's left into other causes that, with further study, will become known. And treatable.

Erik Johnson August 16, 2013 at 9:09 am

I'm sure all these "alternate CFS's" are very interesting, but I wasn't present for them.
I speak for the original CFS.

—————————————————–

http://www.talkhealthpartnership.com/forum/viewtopic.php?f=493&t=4566&p=13661#p13661

Re: Is ME infectious?
Postby Erik Johnson on Fri Aug 16, 2013 3:14 pm

I'm a survivor of the 1985 Lake Tahoe epidemic, a graduate of Truckee High School, and a Holmes et al "CFS definition patient-study group" participant as a prototype for the new syndrome of "CFS"

We have had a few more minor outbreaks since then, but nothing like the huge "Mystery Illness" incident that sickened thousands of people.

This strange illness is full of bizarre contradictions.
At times spreading like wildfire through groups of closely associated people, yet with people from these very groups seemingly unable to transmit it to anyone else.

I saw a pattern immediately. A strange "exception to the rules" in which the flu-like illness turned from noninfectious to wildly contagious.

The contagion occurred when people in the early "shedding phase" of viral illness were all in the presence of moldy buildings, particularly ones with Stachybotrys Chartarum.
Only then, was the disease easily passed from one to another.

The Truckee "teachers lounge" incident that caused Dr Peterson to call the CDC, starting the path to the new syndrome, is a very well described example of this process.

I contacted the teachers at Elk Grove, and they found the very same "toxic mold" that we in Truckee did.

The clues are right there. Simply ask yourself, "If this were a purely viral illness, then why did the one teacher who made the effort to get out of that lounge manage to avoid becoming ill?"

-Erik Johnson

http://www.ncbi.nlm.nih.gov/pubmed/8148452
Clin Infect Dis. 1994 Jan;18 Suppl 1:S43-8.
Concurrent sick building syndrome and chronic fatigue syndrome: epidemic neuromyasthenia revisited.
Chester AC, Levine PH.
Georgetown University Medical Center, Washington, D.C.
Sick building syndrome (SBS) is usually characterized by upper respiratory complaints, headache, and mild fatigue. Chronic fatigue syndrome (CFS) is an illness with defined criteria including extreme fatigue, sore throat, headache, and neurological symptoms. We investigated three apparent outbreaks of SBS and observed another more serious illness (or illnesses), characterized predominantly by severe fatigue, that was noted by 9 (90%) of the 10 teachers who frequently used a single conference room at a high school in Truckee, California; 5 (23%) of the 22 responding teachers in the J wing of a high school in Elk Grove, California; and 9 (10%) of the 93 responding workers from an office building in Washington, D.C. In those individuals with severe fatigue, symptoms of mucous membrane irritation that are characteristic of SBS were noted but also noted were neurological complaints not typical of SBS but quite characteristic of CFS. We conclude that CFS is often associated with SBS.
PMID: 8148452 [PubMed - indexed for MEDLINE]

Erik Johnson August 16, 2013 at 9:12 am

That's right. "Thousands"

The few hundreds that made it to Cheney and Peterson's office were only the tip of the iceberg.

Waverunner August 16, 2013 at 9:41 am

Great news. This could be a major move into the right direction!

Here's what I said on August 7th.

"There are a few reasons why things are so messed up with CFS but the biggest problem in my eyes is the lack of diagnostics. There are thousands of possibilities where things can go wrong in the human body. From infections, to autoimmune disease, to genetic defects, to toxins, to the microbiome etc.. Now the medical problem is, that we are not willing and/or not able to test for these things.

So if we look at a patient population of CFS it likely is highly heterogeneous. And even if we look at two patients who suffer from the same infection, they both have a different genetic makeup which can influence the outcome or the treatment success tremendously. In conclusion we can say, that we don't know the reason for CFS in each patient. In the worst case, 10 PWCs suffer from 10 different diseases but all are labeled CFS. This is a gigantic problem because as long as you are not able to differentiate between these patients, you won't be able to conduct reliable studies. What would be the results if you study a patient group that consists of one person with diabetes, one with cancer, one with HIV and one with IBD and try to find a common cause or a working treatment? The study would be a complete mess because the cancer patient doesn't need insulin and the IBD patient doesn't need chemotherapy.

A better way would be to take 1,000 CFS patients and run all kinds of tests of them. After you did this, you cluster the patients into groups, according to similar diagnostic markers (e.g. one group that seems to have an active herpes virus infection). Then you start specific treatments for each cluster and see if it works.

What we do at the moment is, we conduct research studies on 10 to 30 patients with CFS. We find all kinds of abnormalities but we have no cause. We then conclude that more research is needed and that's it. This explains why we still have not one single treatment and not one single reliable test for CFS, although this illness exists for countless decades now. As long as this doesn't change, it will be the same for the next decades as well."

Erik Johnson August 16, 2013 at 11:14 am

Very strange to see all these calls for research, when they won't even research the evidence that started the syndrome.

Not even ask a few questions.

And it would be so easy, too.
I used to think it was because it didn't occur to them, but after offering to talk and being turned down, it looks pretty clear that resolving the original CFS incident is not exactly what they have in mind.

Bob August 16, 2013 at 12:10 pm


Erik Johnson

Very strange to see all these calls for research, when they won't even research the evidence that started the syndrome.

Erik, I don't know if you are aware, but the proposed research, discussed in the article, would be UK-based, and Stephen Holgate is a UK scientist. And UK patients want investigations into the illness/es that UK patients have. The proposed research doesn't stop anyone from investigating Dan Peterson's patients.

Erik Johnson August 16, 2013 at 12:12 pm

Any researcher, anywhere in the world that uses the term "Chronic Fatigue Syndrome" is making a reference to something very specific, about which I have the authority to speak.

Science doesn't have territorial boundaries.

Erik Johnson August 16, 2013 at 12:18 pm

Prof. Holgate does not have computer access that crosses the water?
He has no means to make contact with the original source of CFS?

Professor Wessely was in contact with Stephen Straus, and congratulated him on his handling of the situation.
Clearly, the British psychs had no problem knowing about our phenomenon, and omitting the exclusion for psychiatric disease.
——————————————————————–
The 1988 Holmes Definition for CFS
Chronic Fatigue Syndrome: A Working Case Definition
Ann Intern Med. 1988; 108:387-389

Other clinical conditions that may produce similar symptoms must be excluded by thorough evaluation, based on history, physical examination, and appropriate laboratory findings. These conditions include

chronic psychiatric disease, either newly diagnosed or by history (such as endogenous depression; hysterical personality disorder; anxiety neurosis; schizophrenia; or chronic use of major tranquilizers, lithium, or antidepressive medications); .

Erik Johnson August 16, 2013 at 12:50 pm

I see the message was amended to include that nothing is stopping anyone from investigating Dr Peterson's patients.

So true, and they must! If their intent is to resolve the outbreak which caused Dr Peterson to call the CDC for help.
Which was the point and purpose of creating the new syndrome.

Ecoclimber August 16, 2013 at 12:58 pm


Erik Johnson

I see the message was amended to include that nothing is stopping anyone from investigating Dr Peterson's patients.
So true, and they must! If their intent is to resolve the outbreak which caused Dr Peterson to call the CDC for help.
Which was the point and purpose of creating the new syndrome.

I woud be interested on your take, Eric, of people who become ill from "Valley Fever" Coccidioidomycosis, is caused when people inhale the spores of the Coccidioides fungi.

Do you believe that Valley Fever has relationship to your illness?

http://news.yahoo.com/flu-valley-fever-increases-arizona-california-160350415.html

Erik Johnson August 16, 2013 at 1:21 pm

Nope. This stuff was amazing. You had to see it!

Guido den Broeder August 16, 2013 at 3:16 pm


Erik Johnson

My confidence that this is "good research" is seriously tempered by my wonderment that they simply won't just come and ASK.

They might be surprised at what we have always known.

This.

Simon August 17, 2013 at 8:28 am


Firestormm
rosie26

[RE Finding multiple causes]

Simon maybe you can help my own understanding out in this regard :)

Not sure if I have understood right, but i think you are asking:

  1. Are any clusters actually likely to relate to underlying Diseases?
  2. What does it mean for patients if new diseases are found within ME/CFS?

If not what you want, please shout.

1. Clusters vs Diseases/Symptoms

What I can't see is how these results might always relate to symptoms and/or even alternate diagnoses.
… Can molecular findings account for 'pain' or even 'muscular aches and pain'?

Fair questions. Check out my earlier attempt to explain clustering, where the key point is finding the critical factors that do relate to underlying disease status. Most factors, including aches and pains, will be secondary to the disease and so much 'noise' when it comes to finding causal pathways. Of course, we don't know which those distintive factors are (which individually or collectively would be biomarkers for the specifc disease), hence the plan to capture as many different factors as possible: genes, gene expression, proteins, clinical symptoms etc. IF the 'real' factors are within the mass, plenty of computing power and robust statistical techniques (there are a lot developed and developing for just this kind of big data problem) should find meaningful clusters relating to underlying disease.That is the theory of the approach anyway.
- edit: and having found clusters, the key step is then replication on a fresh sample…

And while it may be difficult to nail exactly how a disease causes a symptom, if you can find a disease, there's a good chance most of the symptoms are down to it: aches and pains are common to many types of infection – probably down to cytokines or other immune responses. If you can fix the disease and the symptoms vanish, that's what really matters.

2.What does it mean for patients if new diseases are found within ME/CFS?

I would also like to talk a little about how we could see a different definition/determination of what constitutes ME… If [the study works] we could in fact end up with something not being called ME or CFS.

.. it might also mean that those who can't be categorised (for want of a better word); are effectively left in a much-diminished 'pot' with a different label or with the label of ME or CFS.

Now that 'pot' could encounter the kind of management interventions that we see now being applied to CFS/ME in the UK. I..So you may face these current recommendations if your molecular findings are unable to be treated by a drug.

However, not all the resulting interpretations or treatments will be considered by the community as favourable – and we should be prepared for that also I think. Look at the chemical (molecular) abnormalities that can be revealed and then applied to psychiatric conditions and treated with psychiatric drugs or therapies for example.

...It's the interpretations that will ever be most talked about and about which we should be prepared

It's good to consider the implications.

For me, though, the overriding concern is to understand the true nature of the illness(es) as the best way to find really effective treatments. Follow the science, really, but in terms of any fall-out, I think it will be very slow so we will have time to adapt:

Plenty of time to get used to any findings
Putting together the cohort of 5,000 will probably take a few years, (assuming it does secure funding); then probably at least another 2 years before the results of any research on the cohort is available. That will hopefully reveal clusters and give clues at to molecular pathways.

Then at least another few years to nail down the first pathways (assuming they exist). And at least 5 years to find a drug and get it to market. So well over a decade in total, and that's just to tackle some of the disease clusters. We won't be waking up any day soon to discover that we all have one of several new, previously undisovered diseases within ME/CFS – or are orphaned in an undiagnosed mishmash of leftovers.:)

Firestormm August 17, 2013 at 8:46 am

:thumbsup:

Sasha August 17, 2013 at 8:49 am


Simon

Putting together the cohort of 5,000 will probably take a few years, (assuming it does secure funding); then probably at least another 2 years before the results of any research on the cohort is available. That will hopefully reveal cohorts and give clues at to molecular pathways.

It would be nice to do some joiny-uppy stuff and have any patients entering clinical trials (such as the Rituximab trial) also get included in this database.

Firestormm August 17, 2013 at 10:55 am


Sasha

It would be nice to do some joiny-uppy stuff and have any patients entering clinical trials (such as the Rituximab trial) also get included in this database.

I agree. And like the phrase 'joiny-uppy' too :) Am wondering if there has been anything with which we might compare. Some other disease that was looked at in this way, in the recent past on such a large scale? What say you Simon my man? :)

Erik Johnson August 17, 2013 at 4:28 pm

As I examined the history of antecedent epidemics, an interesting thing stood out.
Aside from the doctor or doctors who identified their own outbreak, the incident is never followed up.
Even if others use the name, researchers want to study "In their own backyard"

The name, the entity, the outbreak, and all the evidence gets lost as it shifts from one to the next.
Over and over. It's like throwing all the game pieces off the board, starting back at square one.

Oblivious to what they threw away, when they "moved on".

Some of what they threw away was worth knowing, but since they didn't know how much they had lost,
they called it "progress" anyway.

———————————————————————————-

"I'll tell you what I was most angry at. A group of scientists that came in this community. Did a study, and did not come back and tell us what had happened"
-Gussie Baker 1955 Punta Gorda Outbreak

Simon August 18, 2013 at 3:06 am


Sasha

It would be nice to do some joiny-uppy stuff and have any patients entering clinical trials (such as the Rituximab trial) also get included in this database.

It's an important point about how information gleaned from clinical trials integrate into big research cohorts like this. I don't know how practical it is to combine them directly: over on the Rituximab thread, Jonathan Edwards commented on the possibility of combining the proposed UCL study with the Norwegian one and said that while it makes good theoretical sense, the more complicated any study becomes, the harder it is to get high quality data. He said in practice it works better to do such things separately.

However, if the UCL study finishes before the cohort recruitment is complete, maybe there is a chance to enroll then UCL patients into the cohort. Could be worth suggesting to UCL, once the study is settled?

Alternatively, the 5k cohort study could be used to explore and build on any UCL findings. Let's say they discover that certain patients respond well to rituximab, and others don't, and they have identified the key factor, eg NK cytotoxicity levels. They could then test for that in the Cohort, to see what proportion of patients generally are likely to respond well to ritux.

Firestormm

I agree. And like the phrase 'joiny-uppy' too :) Am wondering if there has been anything with which we might compare. Some other disease that was looked at in this way, in the recent past on such a large scale? What say you Simon my man? :)

Er, good question. Though in his talk, Stephen Holgate, emphasised how now was the time to study ME/CFS because of the emergence of new techniques, so I don't know if such an in-depth study has been done before, since this is the cutting edge. Maybe that's part of the appeal. Will try to find out if the approach has been used before.

Sasha August 18, 2013 at 3:21 am


Simon

It's an important point about how information gleaned from clinical trials integrate into big research cohorts like this. I don't know how practical it is to combine them directly: over on the Rituximab thread, Jonathan Edwards commented on the possibility of combining the proposed UCL study with the Norwegian one and said that while it makes good theoretical sense, the more complicated any study becomes, the harder it is to get high quality data. He said in practice it works better to do such things separately.

I agree that trying to add on to a pre-existing trial would have the downside of complicating matters but enrolling patients in what are essentially two separate studies (the trial and this cohort) wouldn't add complexity to either, just more scope for additional analysis. I think it would make sense to include the trial participants in the cohort before they get treated, as a further opportunity to distinguish responders from non-responders, and to have them in a study where they'll be getting longitudinal follow-up (I think) at no extra cost to the Rituximab trial.

Simon August 18, 2013 at 5:07 am


Sasha

I agree that trying to add on to a pre-existing trial would have the downside of complicating matters but enrolling patients in what are essentially two separate studies (the trial and this cohort) wouldn't add complexity to either, just more scope for additional analysis. I think it would make sense to include the trial participants in the cohort before they get treated, as a further opportunity to distinguish responders from non-responders, and to have them in a study where they'll be getting longitudinal follow-up (I think) at no extra cost to the Rituximab trial.

It's hard to know how feasible this is, not least because right now, neither study is funded (or even applied for in the case or Rtx) so we don't yet know the mechanics. My guess is that, because the 5k cohort is so big, it's tapping into clinics in a big way – which presumably means the BACME clinic network. If so, they will be gathering data from their own regular patients, probably new patients so the time spent on diagnosis etc is time already budgeted for. That means they wouldn't automaticlly welcome having to add a separate group to their study, esp if it meant taking clinician time away from regular clinic work.

Thinking aloud here, one possibility is, if UCL contacts whoever plans the cohort (it's not Stephen Holgate's study AFAIK), they could arrange to recruit for that study via clinics particpating in the cohort (they have to find the patients somewhere, and there are BACME clinics in London). That would minimise any duplication of effort in having patients in both studies. There may be many practical reasons why this wouldn't work, but might be worth discussing the possibility with JE on the Rituximab thread.

I agree that it would be good if the same patients figured in both studies. And potentially, if a mechanism to cooperate easily can be found, it could apply to other UK studies too, eg Julia Newton's work – which is what you were originally suggesting, I think. So that would be another reason to explore this now.

Erik Johnson August 18, 2013 at 7:45 am

No interest in this unusual incident = No interest in the incident that started CFS.

"This seemed to be evolving, before our eyes, from a flu-like illness into something else"
-Dr Paul Cheney

"… and it seemed to be spreading. Through the local hotel and casino, two area high schools, members of a girls basketball team."
-Dr Nancy Snyderman

"That's when we wondered, Hey, maybe we better call somebody. This is really unusual."
-Dr Paul Cheney

Nielk August 18, 2013 at 8:27 am

Hi Rick,

Thank you for this. It is Important to inform people of what really happened. I just finished reading "Osler's Web" for the second time and I'm very interested to hear more a out it.
I feel though that this is important enough to have its own separate thread.

Erik Johnson August 18, 2013 at 3:05 pm

If Professor Holgate were serious, reading Osler's Web would be a good start.
Then he would know that CFS was not begun as an umbrella term for "anything and everything"

August59 August 18, 2013 at 7:12 pm

I believe that by the conclusion of the CFI:Lipkin study there will be a significantly new set of players in the field of diagnostic criteria due to the strong advancement in technology and testing medium (serum, urine, saliva, tissue and spinal fluid). Diagnostic testing has ran out of room by trying to find everything in serum for sure. There is probably room in urine and saliva, but spinal fluid and tissue samples will have to be a part of a definitive analysis at some point. Unless some new types of analysis are developed which is very possible. Ultrasound, forms of MRI's and very small tissue samples of tissue and spinal fluid.

Allyson August 18, 2013 at 10:40 pm

Thanks Simon – great article – 15 sounds about right !
Not read all posts but here in Australia lots are now being re- diagnosed with LYME, POTS/OI and EDS -
Ehlers-Danlos Syndrome so these are likely among the 15 along with other CTDs it seems

Lyme had been dismissed here for years

cheers

Ally

Allyson August 21, 2013 at 11:15 pm

And I should add that as EDS makes y ou more prone to other illnesses it may be likely that some have EDS AND Lyme disease – the overlap in symptoms will make it hard to differentiate but may explain why some seem to respond well to Lyme treatment while others do not – they may have underlying POTs or EDS so the symptoms never disappear even if the Lyme is treated

ALly.

Erik Johnson August 22, 2013 at 9:08 am

It had been my impression that researchers wanted to know what happened in the local area high schools, a casino, and a girls basketball team, because it was really unusual.

25 years of utter unresponsiveness and lack of any questions or investigation indicates otherwise.

Simon August 22, 2013 at 12:30 pm


Firestormm

Am wondering if there has been anything with which we might compare. Some other disease that was looked at in this way, in the recent past on such a large scale? What say you Simon my man? :)

I asked Stephen Holgate who replied:

Cancer is leading the way here. Other complex diseases are following especially Rheumatoid Arthritis, Inflammatory Bowel Disease, Psoriasis, Type 2 Diabetes, Multiple Sclerosis and Alzheimer's Dementia. All very exciting!

So it is being done, though I'm afraid I don't have any more specifics from the Professor. However, a recent Nature paper on Cancer gives an idea of the approach:

Like the proposed ME/CFS study, it was on a huge scale – looking at 7,000 indiviudal cancer genomes for 30 different types of cancers (ie looking at the specific mutations in each of 7,000 individual's cancer). From this they identified 21 common 'mutational signatures' – a common pattern of DNA mutations eg there is one mutational signature caused by damage from UV radiation. Which is pretty cool.

But it wasn't a case of one mutational signature being linked to one type of cancer. Each person's cancer carried at least two different mutational signatures (and not every individual with the same type of cancer would have exactly the same mutations).

What they found was that some mutational signatures cropped up in many different types of cancer. For instance, one mutational signature common in breast cancer was also found in 16 of the 30 types of cancer studied. Wheras some of the mutational signatures were only ever found in one type of cancer.

So they started off with 30 different types of cancer. But when they looked at the molecular level – specifically at the types of DNA mutations underlying the cancers, they found a very different pattern, with some DNA mutational signatures cropping up in lots of different cancers.

The scientists think that by better understanding the precise mutations involved they will learn a lot about the causal mechanisms of cancer.

This cancer study used some pretty-intensive mathematical computational approaches, which is just the sort of approach that Stephen Holgate has advocated to make sense of a lot of data from 5,000 ME/CFS patients.

Look like ME/CFS is moving to the forefront of science – which is probably where it needs to be if such a complex illness is ever going to be cracked.

Short video about the Nature Cancer study:

Firestormm August 22, 2013 at 12:35 pm

Simon appreciate it. And do pass my (our) thanks to Prof. Holgate as well :)

Erik Johnson August 22, 2013 at 12:39 pm

And suppose I were to refuse to agree that whatever Professor Holgate is calling CFS is exactly the same as the illness that started CFS?

Which I see no reason to do, until researchers agree to incorporate all of the actual evidence which led to Dr Peterson and Dr Cheney calling the CDC for help with our little problem.

MeSci August 27, 2013 at 10:33 am


Simon

Plenty of time to get used to any findings
Putting together the cohort of 5,000 will probably take a few years, (assuming it does secure funding); then probably at least another 2 years before the results of any research on the cohort is available. That will hopefully reveal clusters and give clues at to molecular pathways.

Then at least another few years to nail down the first pathways (assuming they exist). And at least 5 years to find a drug and get it to market. So well over a decade in total, and that's just to tackle some of the disease clusters. We won't be waking up any day soon to discover that we all have one of several new, previously undisovered diseases within ME/CFS – or are orphaned in an undiagnosed mishmash of leftovers.:)

Hopefully not only drug treatments will be considered. I would expect that some of the clusters would be amenable to other treatments which do not have such long lead times as drugs, and better safety profiles. Also, some existing drugs with known safety profiles may be useful ('repurposing'), which again can be brought into use relatively quickly.

Simon August 28, 2013 at 2:10 pm


MeSci

Hopefully not only drug treatments will be considered. I would expect that some of the clusters would be amenable to other treatments which do not have such long lead times as drugs, and better safety profiles. Also, some existing drugs with known safety profiles may be useful ('repurposing'), which again can be brought into use relatively quickly.

Yes, drug repurposing could be a shortcut eg rituxmab, if there are any suitable available. What other treatents did you have in mind?

MeSci August 29, 2013 at 3:34 am


Simon

Yes, drug repurposing could be a shortcut eg rituxmab, if there are any suitable available. What other treatents did you have in mind?

I was thinking of things that some of us already find helpful such as dietary changes and supplements. It's a difficult process working out which foods and supplements help which people, and we may never quite find the optimal mix. Subgrouping patients might help us to do this, so that the interventions are more effective, and maybe even bring about remission or that four-letter c-word…(says to self – go on – say it – OK – cure!) :)

MeSci September 14, 2013 at 11:18 am


Waverunner

Today, it costs 100,000 times less than it once did to create a three-dimensional map of a disease-causing protein
There are about 300 times more of these disease proteins in databases now than in times past
The number of drug-like chemicals per researcher has increased 800 times
The cost to test a drug versus a protein has decreased ten-fold
The technology to conduct these tests has gotten much quicker

"Given all these advances, why haven’t we cured cancer yet? Why haven’t we cured Alzheimer’s? Why haven’t we cured Parkinson’s?"
The answer likely lies in the bloated process and downright hostile-to-innovation climate for FDA drug approvals in this day and age.

What reason(s) would you postulate for the fact that non-US researchers have also failed to cure cancer, Alzheimer's and Parkinson's in non-US jurisdictions under different regulatory systems?

Waverunner September 14, 2013 at 12:41 pm


MeSci

What reason(s) would you postulate for the fact that non-US researchers have also failed to cure cancer, Alzheimer's and Parkinson's in non-US jurisdictions under different regulatory systems?

That's an excellent question. I can't give you the perfect answer but in my eyes the main reason is the observation, that most healthcare systems all over the world reflect more or less what the FDA does. In Europe you have nearly the same regulatory hurdles as in the US. In fact, you seem to have these hurdles in all developed countries.

Simon December 7, 2013 at 10:24 am

At the Action for ME 2013 AGM Stephen Holgate gave a talk that covered much of the same ground as his talk to the Forward ME Group featured in this blog (plus some more material, I think). The video of that AfME talk is now available here:

It is quite long, but it's a cracker starting off with Florence Nightingale (who very probably had ME) and sweeping through medicine to the present day and the development of new technologies that could be just what's needed to solve ME/CFS.

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