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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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"

 

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.

 

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

 

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...]

 

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!

 

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.

 

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"?

 

Looking for evidence without preconceptions

This is in reply to a number of posts, particularly those by 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.

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.

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:

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.

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.

 

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]

 

That's right. "Thousands"

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

 

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."

 

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.

 

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.

 

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.

 

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); .

 

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 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

 

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

 

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.

 

[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.