The P2P Draft report is out

[Nielk]

I think many of us would be happy if the CCC (or at least patients with PEM) were to be routinely used at least as a subset in research. Admittedly, clear-cut PEM would be extremely difficult to precisely determine for individual researchers, without a biomarker, but we'd like to see some effort to define and investigate a cohort of patients with PEM, at least as a subset. That doesn't mean excluding any other patients from research.

It's interesting that the measure for fatigue for example or depression, is taken at value. A form is filled out by the patient and it is accepted that the patient is "fatigued" or "depressed. Why is it that when it come to PEM/PENE, all of a sudden there is a need for tools of measurements? Why not accept the word of the patient?

In other words, as a patient, if the researcher accepts my word that I am fatigued, I have pain and/or I am depressed, why stop particularly at PEM? How do you measure for example a sore throat, feeling fluish, feeling of heaviness, feeling like not being able to move, feeling weak, feeling paralyzed?

It seems to me like this is all about politics. HHS has clearly demonstrated in the past 20 years that they do not want to accept that we suffer from unique symptom of PEM. Why else are they stubbornly holding on to their Fukuda Criteria? Why not listen to the stakeholders and the community?

They claim that there are no acceptable studies proving PEM. (regardless of the Snell and Lights studies) Even if that is true, why not believe the patients? If they believe the patients' subjective symptoms of the Fukuda, why not believe the subjective symptoms of the CCC and ICC?

 

[Nielk]

I would like to remind members that if they choose to protest the P2P, they can send in their letter of protest to:

Sylvia.Burwell@hhs.gov (Secretary of HHS)

Francis.Collins@nih.hhs.gov (Director of NIH)

Tomfrieden@cdc.gov (Director of CDC)

Please see sample letters of protests HERE from advocates Eileen Holderman and Jeannette Burmeister.

Edit - corrected link.

 

[SOC]

As Prof Edwards points out above, even in more established diseases like RA there are some with the disease who's symptoms do not conform to the usual norm. So is it right to exclude people at this stage, who actually might genuinely have the same disease, perhaps even caused by the same thing, but presenting differently for who knows what reason?

And there you have the difference between a clinical definition and a research definition. A research definition needs to identify the clear, unquestionable patient population so that the research is as clean as possible. Not all genuine patients are included in the research definition of any illness. The research definition is the strictest definition of the illness, not the complete definition.

A clinical definition is broader and includes less clear cases. It allows for the treatment of patients with less obvious presentations.

We need a clear research definition, which IMO has to include PEM. Our research will continue to be a mess without one. We also need a clinical definition which would include a larger population for treatment purposes.

Writing a tight research definition does not exclude people from treatment. Excluding questionable cases from research, but not treatment is common across medical research. It should be no different for ME.

 

[Jonathan Edwards]

Concerning the ICC, you assume that “the expert ME/CFS doctors writing the ICC want to define some sort of causal process, probably 'neuroimmune.'” You object, “And there is/are no such thing/s as 'neuroimmune systems.'” You do concede, “I can see that exhaustion might be of neuro-, rather than say muscular or metabolic origin....” But then you argue, “Yes but it goes on to say that the idea is that the underlying pathophysiology is neuroimmune and the simple association of symptoms does not make sense of the term. Inability to produce energy is not neural or immune in itself so they must mean it has a neuroimmune cause.”

Where does the ICC use the term “neuroimmine” to describe the underlying pathophysiology of PENE?

'The underlying pathophysiology of PENE involves a profound dysfunction of the regulatory control network
within and between the nervous systems (36, 37) This interacts with the immune and endocrine systems
affecting virtually all body systems, cellular metabolism and ion transport.(38 )The dysfunctional activity/rest
control system and loss of homeostasis result in impaired aerobic energy production and an inability to
produce sufficient energy on demand. A test-retest cardiopulmonary exercise study revealed a drop of 22%
in peak VO2 and 27% in VO2 at AT on the second day evaluation.(39) Both submaximal and self-paced exercise
resulted in PENE.(40) These impairments and the loss of invigorating effects distinguish ME from depression.'


Quoted by Nielk from the ICC Primer as I said in the first place.


I also remember somewhere in the Primer it saying that the ICC criteria were deliberately chosen to emphasise the underlying neuroimmune pathology, but I cannot find the link just at the moment.

Edit: Here it si:

The rationale for the development of the ICC was to utilize current research knowledge to identify objective, measurable and reproducible abnormalities that directly reflect the interactive, regulatory components of the underlying pathophysiology of ME.

 

[Jonathan Edwards]

@Jonathan Edwards, did we ever draw your attention to the study by the Lights on PEM that was published a few years ago? There's a spectacular chart showing what happens at various intervals after you exercise PWME compared to sedentary healthy controls (and I had thought PWMS but maybe that was another paper). The chart was so spectacular they were on the journal's front cover when it was published but I'm having a job finding it.

Yes, I looked at that study in detail. I found it hard to interpret. It looked like an initial trawl of lots of genes that would need replicating on a few targets genes to get statistical meaning. I have not seen anything subsequently. I was also a bit flummoxed when I asked Julia Newton what she thought of the Lights' work and she said she had never heard of anyone called Light.

 

[Jonathan Edwards]

Is the fatique you are thinking of the kind that makes your arms so heavy you can not lift them enough to comb your hair or get dressed? You can not make it to the toilet?

Yes, indeed. Someone with end stage heart failure cannot even lift their head and shoulders off the bed. Someone with severe hypothyroidism may be completely immobile.

 

[Tuha]

@Jonathan Edwards what do you think - how much money would we need to really boot ME research and to start to understand it significantly?

 

[Jonathan Edwards]

@Jonathan Edwards what do you think - how much money would we need to really boot ME research and to start to understand it significantly?

That's an unanswerable question but I can think of several sort of answers.

1. We do not need any more money, we need clear thinking. The work we did developing rituximab for RA was never given official funding. We just scraped money together from other things to do some quite simple experiments.

2. To be realistic we probably need at least five groups working on ME with a budget of $750,000 per annum - which is about $4M per annum. More would increase the chance of success so maybe $40M is more sensible but most of it would probably be wasted.

3. If all the money spent on supplements went to research we would probably have about $400M p.a. and that would do it!

 

[Marco]

I was also a bit flummoxed when I asked Julia Newton what she thought of the Lights' work and she said she had never heard of anyone called Light.

That's a little surprising and disappointing as it seems to me there's potentiallly quite an overlap between Newton's work showing ANS dysfunction and the Lights' metabolites/sensory pathways.

This is a useful paper predating the gene expression paper which sets out in more detail why they went poking around after particular genes :

Myalgia and Fatigue: Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes.
Authors
Light AR, Vierck CJ, Light KC.

http://www.ncbi.nlm.nih.gov/pubmed/21882454

 

[Ember]

'The underlying pathophysiology of PENE involves a profound dysfunction of the regulatory control network

within and between the nervous systems (36, 37) This interacts with the immune and endocrine systems

affecting virtually all body systems, cellular metabolism and ion transport.(38 )The dysfunctional activity/rest

control system and loss of homeostasis result in impaired aerobic energy production and an inability to

produce sufficient energy on demand. A test-retest cardiopulmonary exercise study revealed a drop of 22%

in peak VO2 and 27% in VO2 at AT on the second day evaluation.(39) Both submaximal and self-paced exercise

resulted in PENE.(40) These impairments and the loss of invigorating effects distinguish ME from depression.'



Quoted by Nielk from the ICC Primer as I said in the first place.



I also remember somewhere in the Primer it saying that the ICC criteria were deliberately chosen to emphasise the underlying neuroimmune pathology, but I cannot find the link just at the moment.


Edit: Here it si:

The rationale for the development of the ICC was to utilize current research knowledge to identify objective, measurable and reproducible abnormalities that directly reflect the interactive, regulatory components of the underlying pathophysiology of ME.

You've objected repeatedly to the use of the term “neuroimmune” to describe a causal process or the underlying pathophysiology of PENE. However, I can't find that the ICC uses the term “neuroimmine” in that way, and it certainly isn't found in anything that you've quoted here.

 

[WillowJ]

Having read and thought I find it hard to formulate a response, but here goes. It seems that this was a committee that brought together some experts in ME research and some people with broader healthcare agendas, the latter presumably intended to provide balance and overview. In the event the output reflects the interests of the people involved - rather transparently.

The good news is that the experts include some people who are pushing for exactly the right things. The bad news is that the 'overviewers' seem to have muddied this with politically correct padding and off-target proposals of their own. Goodness knows what the political impact will be but my impression is that we should be pleased that a few very good minds got together to think about strategy and whatever they produced in terms of a report they probably benefited both themselves and the ME community by comparing ideas.

The specific research issues highlighted look sensible to me. Neuroimaging. Immunological assessment. Replication and consensus formation on findings like NK cell function. Population based cohort studies with systematic data and sample collection to assist the above. Continued screening for pathogens. Maybe none of that is so new but it seems a good set of choices.

They also say some sensible things about the difference between statistical significance and clinical significance and significant to the patient. I would like to have seen something a bit sharper edged on that though.

I am sceptical about a stakeholder group producing 'ideal' criteria. As Heapsreal says, money would be better spent on other things.

This group seem to have made a decision to declare their belief that ME 'is not a disease of psychological etiology'. That sounds good but is this actually thought through or is it just a convenient response to 'listening to patients'? That may sound cynical but it would cost them nothing to say this because they know it will go down well. On balance I think they can be taken as meaning what they say. Dr Hornig is a psychiatrist but one definitely interested in the immunological side of brain disease. I would have liked to see more scepticism about CBT and GET but what they do say is actually pretty non-commital (they said people improved rather than 'it works') and they do say that these are not primary treatments.

The fly in the ointment is that the alternative scenario that seems to be offered is in some ways even more worse than the PACE based option. CBT and GET are seen as part of a wider multimodal treatment, including 'self-management' provided by a 'multidisciplinary team'. Where is the trial that even hinted at this approach? What are the unproven modalities recommended. They admit there is no evidence to support 'self-management' strategies but the assumption seems to be that this needs rectifying because these strategies are obviously a good idea.

In my experience 'self-management' and 'multidisciplinary team' are code words for 'pass the buck'. Doctors like them because they can pass the buck. Nurses and physios like them because they feel important if they are allowed to carry the buck they have been passed. Health systems like self management because it sounds cheap, although it is in fact expensive so never works. And as far as I can see what we already have is the real self management - PWME trying to get on with their lives because the multidisciplinarians don't have any skills to offer. Or if they do it is because certain dedicated people have just listened to patients and offered to share the experience with other patients. So this all sounds to me the sort of guff that medical education departments get into rather than just taking time to look after people as best you can.

There is, unfortunately, a definite sense that the people in charge of this group are using it as a piece of mumbo jumbo propaganda of the sort you get in health sciences departments. But maybe that does not matter.

And I cannot quite make out why homeopathy is in their either - other people have had thoughts on that. What I think they should say is that trials should be done on alternative therapies by the people making money out of those therapies- and that they should be obliged to do so just as the conventional people are.

The important thing for me is that underneath all this I see that certain key individuals have met and will have taken a little further forward the collaborative and consensus based spirit that I perceive emerging from ME research in maybe the last two or three years. And they have not been locked out of the public relations process even if they are getting on with things without creating as much hot air as some others.

That's a very good analysis. I really like your point that self-management and multimodal therapies are a very, very dangerous strategy. We are already doing this, and it's not NIH's job to tell us to carry on curing ourselves. Or to say we should get nicely marketed self-help courses. I hope everyone writes to tell them how much this is dodging responsibility.

Lines 362-264 "The modest benefit from CBT should be studied as adjunct to other modalities of treatment such as self-management. Future treatment studies should evaluate multimodal therapies."

Here are the lines to reference for noting what kinds of specialists there should be:

Lines 311-315 "Although many health care providers do not fully understand ME/CFS, primary care clinicians will be instrumental in ensuring that patients are treated or referred to appropriate specialists. We believe ME/CFS is a distinct disease that requires a multidisciplinary care team (e.g., physicians, nurses, case managers, social workers, psychologists) to optimize care"

Regarding "not psychological", I think this is really meant to mean "not psychosomatic". Certainly psychological diseases in general are physiological, and it's not like we need to argue there is nothing similar at all between ME and psychological diseases, many of which cause cognitive difficulties (for example). However most psychological diseases cause much less physical debility, and somewhat more depression and other "affective" issues (on average, comparing pooled patients). So this categorization could set up expectations which might cause problems in research design or in clinical practice.

 

[Scarecrow]

You've objected repeatedly to the use of the term “neuroimmune” to describe a causal process or the underlying pathophysiology of PENE. However, I can't find that the ICC uses the term “neuroimmine” in that way, and it certainly isn't found in anything that you've quoted here.

Neuroimmune would be shorthand for this bit of the extract quoted. I don't think that Jonathan Edwards is alone in using the word in this way:

'The underlying pathophysiology of PENE involves a profound dysfunction of the regulatory control network
within and between the nervous systems (36, 37) This interacts with the immune and endocrine systems

 

[WillowJ]

2. Since they mentioned demographic bias concerns, move research out of the office of research on womens health ORWH since 25-30% who have ME/CFS are men and lack of ethnic consideration. As it stand now, there is a discriminatory component to the research

Yes, we don't seem to have a permanent funding structure trhough ORWH. They should move us to a proper Institute, whether NIAMS, NIAID, NINDS, or maybe NIGMS. This by itself, I think would give us access to funding.

 

[Ember]

I don't think that Jonathan Edwards is alone in using the word in this way...

The objection was over the usage of the term by the ICC:

The idea was that the neuroimmune bit is the cause. And there is/are no such thing/s as 'neuroimmune systems'. It isn't even good English. There is a nervous system and there is an immune system. Sorry but this is not a serious scientific analysis.

 

[user9876]

It's interesting that the measure for fatigue for example or depression, is taken at value. A form is filled out by the patient and it is accepted that the patient is "fatigued" or "depressed. Why is it that when it come to PEM/PENE, all of a sudden there is a need for tools of measurements? Why not accept the word of the patient?

I think there are huge problems in taking a value from a form as a quantity for fatigue or depressed. I don't see how it can be justified mathematically and certainly not in terms of quoting the mean and SD from these forms. We should be pointing out the problems in the measures already used not saying can't we measure PEM in the same way.

Having said that I think it would be useful to characterize PEM but then to do something like the Lights are doing and look for changes in the body. But how could PEM be characterized? Is it the time delay, the severity of the symptom increase vs the activity, is there a activity threshold below which it isn't noticed or is it a more gradual (non-linear) function.

 

[Aurator]

How do you measure for example a sore throat

The answer to that one is, in some cases, relatively easily. I have had observable laryngitis and pharyngitis (confirmed by an ENT consultant) since the onset of my illness two years ago. Is this observable inflammation a symptom that can be attributed merely to the patient's illness perceptions? No, so what happened was that the ENT consultant understandably sought an explanation that fell within the range of his own knowledge and experience, and suggested that I had airway reflux and needed to amend my diet.
I amended my diet (there was actually very little wrong with it to begin with) and six months later it had made no difference. I still have the laryngitis and pharyngitis that started with the viral infection that precipitated or at least accompanied the start of this illness two years ago. No further explanation has been offered to me for the continued pharyngitis and laryngitis.

 

[Anne]

The fly in the ointment is that the alternative scenario that seems to be offered is in some ways even worse than the PACE based option. CBT and GET are seen as part of a wider multimodal treatment, including 'self-management' provided by a 'multidisciplinary team'. Where is the trial that even hinted at this approach? What are the unproven modalities recommended. They admit there is no evidence to support 'self-management' strategies but the assumption seems to be that this needs rectifying because these strategies are obviously a good idea.

In my experience 'self-management' and 'multidisciplinary team' are code words for 'pass the buck'. Doctors like them because they can pass the buck. Nurses and physios like them because they feel important if they are allowed to carry the buck they have been passed. Health systems like self management because it sounds cheap, although it is in fact expensive so never works. And as far as I can see what we already have is the real self management - PWME trying to get on with their lives because the multidisciplinarians don't have any skills to offer. Or if they do it is because certain dedicated people have just listened to patients and offered to share the experience with other patients. So this all sounds to me the sort of guff that medical education departments get into rather than just taking time to look after people as best you can.

Exactly!

I see a huge red flag with "multimodal" therapy being highlighted in the report (mentioned several times) and a multidisciplinary care team (e.g., physicians, nurses, case managers, social workers, psychologists) being recommended.

This is very much in line with the general current thinking on syndromes with "diffuse symptoms" and the recommendations given by the psychiatrists wishing to label many conditions as Bodily Distress Syndrome. It is not a viable way forward for ME/CFS research or care.

I think this is one thing we really should try to change (if possible): to get 'multimodal therapy' out of the report, as well as the current version of multidisciplinary team. What should be recommended, instead, is biomedical research and biomedical specialist care for ME/CFS patients. There should be multidisciplinary teams, but they should consist of immunologists, rheumatologists, neurologists, experts on ortostatic issues, etc. Centres of Excellence where patients could be referred and biomedical research organized are crucial.

 

[Anne]

Multimodal treatment is being promoted as a therapy for chronic pain:
https://clinicaltrials.gov/ct2/show/NCT02248363
"Multimodal rehabilitation (MMR) distinguishes itself as an interdisciplinary-coordinated (e.g., physician, occupational therapist, physiotherapist, and psychologist) intervention using a bio-psycho-social view of chronic pain."

 

[Bob]

I see a huge red flag with "multimodal" therapy being highlighted in the report (mentioned several times) and a multidisciplinary care team (e.g., physicians, nurses, case managers, social workers, psychologists) being recommended.

This is very much in line with the general current thinking on syndromes with "diffuse symptoms" and the recommendations given by the psychiatrists wishing to label many conditions as Bodily Distress Syndrome. It is not a viable way forward for ME/CFS research or care.

I think this is one thing we really should try to change (if possible): to get 'multimodal therapy' out of the report, as well as the current version of multidisciplinary team. What should be recommended, instead, is biomedical research and biomedical specialist care for ME/CFS patients. There should be multidisciplinary teams, but they should consist of immunologists, rheumatologists, neurologists, experts on ortostatic issues, etc. Centres of Excellence where patients could be referred and biomedical research organized are crucial.

Great points Anne. (These issues have been mentioned before, but it's good to revisit them.) If anyone could make a submission along these lines, that would be great. (It's a really important issue, but i think I won't be able to stretch to covering these points.)

 

[Anne]

The multimodal model mentioned in the draft report has been applied to ME in a few places in Scandinavia, among others Stockholm, Sweden. In Stockholm the Health Board decided to see if the health care needs of ME patients could be met by a multimodal therapy model. They initiated a project with a multi-team, involving nurses, physiotherapists, psychologists, social workers. Now, around 5 years later, the project has been evaluated and it has been concluded that this model did not at all meet the needs of the ME patients. The treatment model was very similar to the CBT-exercise model. Many patients actually experienced deteriorated health.

In Stockholm, there is now agreement between the multi-team project management and other caregivers, patients and politicians that the multimodal model did not serve the ME patients well. Instead, what is needed is biomedical specialist care. While psychologists, social workers, physiotherapists can be useful for ME patients (if they are knowledgeable about the biomedical disease mechanisms in ME, PEM, etc), the money is much better spent on a multi-disciplinary team of physicians, including a neurologist, an immunologist/infectious disease specialist, a rheumatologist, etc. The politicians in Stockholm have announced that a new ME centre will be established, focusing on biomedical specialist care with only one nurse/administrator and all the other resources spent on ME knowledgeable physicians.