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

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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.

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

With 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.

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.

A man who likes a challenge​

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Not 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.​

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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.​

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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.​

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

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"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.​

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

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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There are many ways you can help Phoenix Rising to continue its work. If you feel able to offer your time and talent, we could really use some more authors, proof-readers, fundraisers, technicians etc. and we'd love to expand our Board of Directors. So, if you think you can help then please contact Mark through the Forum.

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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.

 

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.

 

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

 

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

 

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

 

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.

 

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.

 

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?

 

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.

 

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.

 

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!!

 

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.

 

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

 

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.

 

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

 

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

 

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

 

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?

 

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.

 

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.