≡ Menu

CDC Multi-site Study – An interview with Beth Unger

The CDC multi-site clinical assessment of CFS/ME is now underway, and Bob took the opportunity to interview Dr Beth Unger, the lead scientist in charge. The outcomes of this significant study are likely to be widely influential and the means by which the CDC employ objective measures has become something of a hot potato, especially in relation to exercise testing…

Elizabeth, R. Unger, PhD, MD Chief, Chronic Viral Disease Branch

Elizabeth, R. Unger, PhD, MD
Chief, Chronic Viral Disease Branch

The CDC department that oversees chronic fatigue syndrome, under the leadership of Dr Beth Unger, has begun a large study using data from 450 ME/CFS patients, collected at seven well known clinical sites across America (see below).

The CDC website describes the study as a “multi-site clinical assessment of chronic fatigue syndrome (CFS) to characterize patients with CFS or myalgic encephalomyelitis (ME) in clinical practices of clinicians with expertise in CFS/ME.”

“The study started in 2012 and aims to enrol 450 patients. Any patient (aged 18 – 70 years) that is managed or diagnosed with CFS, post-infective fatigue (PIF) or myalgic encephalomyelitis (ME) at any of seven participating clinical sites is eligible for participating in the study.”

No specific official clinical criteria (such as the Fukuda CFS criteria or the Canadian Consensus Criteria for ME) are required for patient recruitment. Instead, the participating clinicians are asked to use their own clinical judgement to include CFS/ME/PIF patients in the study.

The CDC website says: “The study will examine the differences and similarities between CFS/ME patients in the clinical practices of experienced CFS clinicians.” “The data collected using a standardized approach from expert clinical practices will be used to address the CFS case definition. Ultimately, this study aims to improve how we measure illness domains of CFS. This may allow patients to be sub-grouped to improve therapy and allow the underlying biology to be discovered.”

On paper, the CDC seems fairly ambitious in its aims: 

“CDC is fully committed to working with the CFS Advisory Committee (CFSAC) and DHHS to develop consensus about the case definition and name of this devastating illness. The need is not only for a case definition but also for reproducible standardized approaches to applying it, as well as for biomarkers to refine subgroups within the overall CFS patient population.”

The first stage of the study collected subjective measures from the patients, including clinical assessments and medical histories.

Dr Unger has said that ‘biologic’ measures are crucial to further characterize and sub-group patients, and has indicated that the early stages needed to be self-report measures in order to test the logistics of such a large study. She has said that the logistics were found to be successful in the first stage, and that they are now moving on to the second stage.

The second stage will enroll paediatric/adolescent CFS patients, as well as recruiting the controls (healthy people and people ill with other fatiguing illnesses), as comparison groups.

The devil is in the detail…

Dr Unger seems to be taking a robust evidence-based approach to defining the illness, illnesses, or subsets. If the study is done well, it could turn out to be a ground-breaking project, but if done badly, it could be worse than meaningless. If objective biological tests are not included in the long-term, then this might turn out to be a large but very shallow study, costing a lot of money and not providing any ground-breaking answers.

Depending on its ultimate design, and its implementation, this large study could potentially be ground-breaking. Extensive objective and biological measures are not yet included in the study, but the study is evolving, and Dr Unger explains that the current study may pave the way to, and enable, future biological testing in better defined cohorts.

However, strong feelings of discontent have been expressed – by patients and advocates – over Dr Unger’s decision not to include extensive objective or biological testing from the start. One such objective test that has been called for, is a two-day cardio-pulmonary exercise test (CPET), which seeks to measure cardio-pulmonary efficiency (by measuring values such as: effort, energy expenditure, oxygen intake, and heart rate) when patients use an exercise bicycle in two separate tests on consecutive days.

Hooked up for a CPET

Hooked up for a CPET

In small studies by Dr Christopher Snell and colleagues, CFS/ME patients were seen to have fairly similar CPET results to sedentary healthy controls on the first day’s test. But, significantly, for one of the efficiency measures, the healthy controls improved in performance in the second day’s test, whereas the performance among the CFS/ME patients was substantially worse on the same test.

This has been seen as a means of objectively demonstrating the symptom of post-exertional malaise – considered a key symptom of CFS/ME – and Dr Snell has said that this abnormal response to exercise is something he has seen only in these patients (see: Repeat Test Reveals Dramatic Drop in Exercise Capacity).
 
Dr Snell’s latest research study was small, but these intriguing initial results, if replicated by larger studies, may well confirm that 2-day CPET testing is a useful biomarker for the disease.
 
Members of the Chronic Fatigue Sydrome Advisory Committee (CFSAC) have suggested that Dr Unger contact Dr Snell to discuss the merits of a two-day CPET, which she has now done. We do not know the extent to which they discussed his research, or what will occur as a result, but Dr Snell has hinted that Dr Unger appeared to be open minded to including such a test at some stage in the future – indeed she does not rule it out in the answers provided to my questions (below).
 
The plans for the CDC’s study currently include a one-day CPET test, along with 48-hour post-exertional cognitive tests and post-exertional self-reported illness and symptom scores. Dr Snell has indicated that he believes there may be  merit in using the proposed post-exercise cognitive tests and post-exercise symptom scores. It is possible that these measures may demonstrate post-exertional symptom exacerbation unique to CFS/ME patients, or a subgroup of CFS/ME patients.
 
But it seems clear that Dr Snell and many patients are of the opinion that a two-day CPET should be included. The CDC study is of such significance that it seems a wasted opportunity not to do so.

Interviewing Dr Unger

There is limited official information available about the study, so I recently put some questions to the CDC. In reply, Dr Unger explained that she considers it important to first of all collect a comprehensive range of subjective data that will enable, stimulate, and pave the way for further studies using biological testing.

The questions and answers are quoted below, exactly as they were asked and responded to. The answers were received on December 19th, 2013.

1. What are you ultimately hoping to achieve from your study e.g. to create a new clinical or research diagnostic criteria, to determine biomarkers, to define subsets, to discover any research leads?

We hope that this study will help determine the best measures of the major illness domains of CFS.  These include measures of function, pain, fatigue, sleep, and additional symptoms cited in various case definitions.  These measures are needed in order to determine if patient subsets can be identified that will correlate with biologic measures that could guide therapy. 

These measures are also important to assist researchers in selecting patients that are better defined, a feature of study design that will help the field achieve replication and validation of results.  In addition, we hope that our study will contribute to developing outcome measures needed for clinical trials. The data collected in this study will be useful in evaluating current and proposed diagnostic criteria, but creating new CFS case definition criteria is not a goal.

Our study will also provide descriptive analyses of the clinical management of CFS by the participating experts.  Information on medication and other therapeutic and management tools could begin the process of developing evidence-based guidance for best practices for CFS care.

2. What data are you collecting about the patients? What biological/objective testing are you carrying out, or are you likely to add to the study? Are you collecting any tissue samples, and if so, what tests will you perform on the samples? If you are collecting DNA, what are you looking for in the DNA e.g. genetic predisposition?

 In the first stage of the study we are collecting standardized self-reported measures of CFS illness domains.   These include measures of function, pain, fatigue, sleep, and additional symptoms cited in various CFS case definitions.  We are also using data abstraction forms to collect information from study participants on the history of the present illness, detailed medical history, medications, lab test results, family history, infection and immunization history, and physical examination. 

In this second stage of the study, which began November 2013, we are collecting saliva to measure the wakening cortisol response.  We are also collecting blood to create a small biorepository of DNA and RNA that could be used to replicate promising findings from other groups.

3. Is the methodology of the study evolving as you proceed i.e. are you adding more elements to the study as you feel you need to? Is the study open ended? How will you know when your study is complete i.e. what data will you have collected? what type of conclusions will you have made?

The study methodology is evolving. Follow-up of patients involved in the first stage of the study will be continued in the second stage using a smaller set of questionnaires that will give data on disease course and on how well the instruments measure changes in their health.

The second stage will enroll pediatric/adolescent CFS patients. In addition, we are enrolling healthy people and those ill with other illnesses that include fatigue as comparison groups. Other components that are being added in the second stage include measures of cognition and exercise capacity as well as response to exercise. 

The study is currently being conducted under a contract that allows one-year extensions for up to five years if funds are available. While data collection will end when the contracts are closed, analysis and publication of the findings will continue. The study is expected to provide data to support new initiatives throughout the CFS research community.

4. Are you seeking to have an over-arching definition of fatiguing illnesses or is your focus on well defined subsets? Are you seeking to attempt to define subsets of the current Fukuda CFS diagnosis? Do you consider that post-exertional malaise (aka post-exertional neuro-immune exhaustion) i.e. delayed and prolonged post exertional symptom exacerbation that is not relieved by rest, could potentially define a distinct subset of Fukuda CFS? Are you actively looking for such a subset?

A new definition of CFS is not the objective of this study. We do believe the study will help identify subsets of CFS patients, and equally important, will provide the tools for clinicians and researchers to use to identify similar subsets. An essential feature of this study is that we did not use a case definition to enroll patients. The study relies on the clinical expertise of those physicians who have extensive experience in caring for those with CFS. 

Post-exertional malaise or post-exertional neuroimmune exhaustion is an important characteristic of CFS with no currently validated measures. We believe that the data collected in our study will help identify the best options for either measuring post-exertional malaise, or for identifying measures that correlate with this characteristic.

5. I have heard patients and advocates expressing concern that it is very important that your exercise testing is carried out over two days, but you have highlighted the practical difficulties of such a study. Could a small exploratory two-day testing program be carried out, with patients who are safely able to participate, to see how useful the results are?

Our primary objective is to measure the exercise capacity in as many of the enrolled patients as possible using a standardized protocol, and to monitor the post-exertional response for 48 hours with online cognitive testing and visual analogue scales of fatigue, pain, and symptoms. 

Maximal cardio-pulmonary exercise testing (CPET) with one day of testing and 48-hour follow-up of cognition was developed in consultation with Dr. Gudrun Lang (cognition), and Drs. Dane Cook and Connie Sol (exercise). We chose the one-day test so that more patients could be tested at multiple sites with rigorous standardization. 

The two-day test would require an additional overnight stay for those patients who travel long distances to attend clinic, and excludes those who are most severely affected because of the heavy physical toll. In developing the protocol, we strived to find a balance between testing that would yield meaningful data in the broadest representation without placing an unnecessary burden on the patients.

Results of the study will guide the next steps.  It may be that a trial of a two-day protocol could be indicated for some patients or to explore other aspects of the illness.

6. Over the years, the CDC has not always been popular with the ME/CFS community. Is there anything you can say that will provide patients with confidence in the CDC’s current program and with your department’s general attitude towards the patient population and the illness? Is the CDC making a fresh start with regards to ME/CFS? 

CDC’s CFS Program is committed to reducing the clinical morbidity associated with CFS while at the same time improving the quality of life for CFS patients and their families. We are focusing on projects addressing the most pressing needs associated with CFS. During our meetings with  CFS advocacy groups, we heard repeatedly about the need for improved health care services for CFS patients.

We currently have two types of initiatives related to this identified need. First, our study to collect data on CFS patients in multiple clinical practices; and second, developing educational materials, particularly targeted to healthcare providers, to advance the recognition and treatment of CFS.

Additional Information:

The seven participating clinical sites:

  • Pain and Fatigue Study Center, NY ………….. (Lead clinician: Dr. Benjamin Natelson)
  • Center for Neuro-Immune Disorders, FL ….. (Lead clinician: Dr. Nancy Klimas)
  • Open Medicine Clinic, CA ……………………….. (Lead clinician: Dr Andreas Kogelnik)
  • Sierra Internal Medicine Associates, NV …. (Lead clinician: Dr Daniel Peterson )
  • Fatigue Consultation Clinic, UT ………………. (Lead clinician: Dr Lucinda Bateman)
  • Hunter-Hopkins Center, NC …………………….. (Lead clinician: Dr Charles Lapp)
  • Richard Podell Clinic, NJ …………………………. (Lead clinician: Dr Richard Podell)

Summary of Objective Tests:

Current or proposed objective testing and biological sample taking:

  • One-day maximal cardiopulmonary exercise testing (CPET); with 48 hour post-exercise online cognitive testing (and also pain and symptom questionnaires) to attempt to identify post-exertional changes.
  • Saliva to measure morning (wakening) cortisol response
  • Blood samples to create a small bio-repository of DNA and RNA that could be used to replicate promising findings from other groups. 
  • Natural Killer (NK) cell function and counts; sample for serum archive.
  • Blood sampling for gene expression changes.

Possible future tests (i.e. tests that have not been proposed but not ruled out):

  • Two-day CPET. 

Further Reading:

Multi-site Clinical Assessment of CFS
CDC website  (click here)

Redefining ME/CFS? CDC Chief Reveals First Fruits Of Multi-Center Doctor Study At FDA Stakeholder Meeting
Simon McGrath, 11 May 2013  (click here)

Opportunity Lost
Jennie Spotila, 10 September 2013  (click here)

Discussion of Dr Snell’s recent two day CPET study
Repeat Test Reveals Dramatic Drop in ME/CFS Exercise Capacity
Simon McGrath, 29 Jul 2013  (click here)

Advocates Rebuffed: CDC Whiffs On Opportunity to Prove Reduced Exercise Capacity Present in Major Chronic Fatigue Syndrome Study
Cort Johnson, 15 September 2013  (click here)

Phoenix Rising Forum Discussion – New Dr Snell paper on exercise and CFS  
(click here)

CFSAC committee meeting – Spring 2013
Beth Unger discusses the CDC’s multi-centre study – YouTube Video:
(Click here to view video on YouTube)

CFSAC  committee meeting – Spring 2013
Stage 2 of Multi-site CFS Study – YouTube Video:
 
 

Shop via one of these links and Phoenix Rising gets up to 8% of your spend at no cost to you!
Phoenix Rising’s US Amazon Store Phoenix Rising’s UK Amazon Store
Phoenix Rising's store with all our big-name affiliates

{ 91 comments… add one }

  • Roy S January 31, 2014, 4:04 am


    Dr. Unger, if you are reading this, why can't you do at least some 2 day CPET testing to compare it to the 1 day testing? Testing their validity ASAP could be extremely useful and might salvage a little trust from the patient community. It can't be fun to be continually criticized.

    Thanks for the article, Bob.

  • lnester7 January 31, 2014, 8:16 am

    To all,

    I have had the one day testing and I am extremely active patient. I work 40h and I was in one of my best days and even though I thought I would not see anything in the one day exercise, It was fast and obvious. My AT was 115 and took 5min to reach. So I could demonstrate without too much taxing to my system.

    I am getting the 2 day one next and I will compare the differences, I will post back here to see if it is too much difference, but you will prove the disability issue with a day one.

  • Simon January 31, 2014, 8:24 am

    Thanks for a fine article, Bob. I thought you asked the questions we wanted answers to. And thanks for mentioning my article too!

    I do think this study could provide a treasure trove of data and hope it will be accessible to any researchers that want it. Wish they had taken more biological samples eg blood that could be processed in many different ways, as opposed to being restricted to DNA/RNA and NK cell function.

    I applaud the attempt to find outcome measures (questionnaire) that meaningfully measure change – self-reports are used by researchers of all persuasions but almost none of them have been shown to be good measures of change – which is actually the key thing you need in a clinical trial. Don't suppose they are using actometers as an objective measure of activity? Would be one way to validate the questionnaires.

    I also think the 48-hour follow-up on symptoms and congnitive performance after a maximal test will be valuable. The Lights found differences in gene expression (and symptoms) after a single moderate exercise test. It would be interesting to run the Snell test on a random subgroup of patients to see how well the results from the single (CDC) and double (Snell) maximal exercise test compare.

  • Firestormm January 31, 2014, 9:37 am

    Interesting comment and experience from Els on our Facebook page: https://www.facebook.com/PhoenixRisingMECFS/posts/10152239014773384?stream_ref=10

    Especially in relation to observing PEM at 72 hours – which I think tends to apply to me in most cases – or at least between 48 and 72 hours.

    In order to take this into account, she exerted herself the day before she took the 48 hour test. However, I am not sure if this then makes a 'test' for PEM rather counter-productive or if it means we should be considering testing over a longer period to really establish the symptom.

    As a test of functionality at the time – I can see the test has merit – but as something that is diagnostic of the disease – 'a marker' – I really can't see it myself. Not until bigger and better studies are done.

    We did talk about this a lot when the Snell work was published. This need to ensure that patients doing the test were similarly exerting beforehand – maybe even having them on-site as it were the day before to all relax or at least measure and take into account what activity they had performed before testing took place e.g. distances traveled etc.

    And of course – as Unger herself says above – such a test is not suitable for all with ME. I sure as heck couldn't do the exercise bike at the moment and I consider myself more able in other respects…

    Be back later…

  • Christopher January 31, 2014, 12:15 pm

    Our government is content to just keep slowly doing fruitless studies until we all eventually die out. Why bother caring?

    The only time the feds gave us any attention is when researchers started getting too close to the truth. It was only THEN that they decided to spend money to shut us up and move the illness to that of "autoimmunity" and "inflammation of unknown etiology" – just enough research to placate patients but not enough to get anywhere with treatment. And what, we should be overjoyed that after decades of willfully neglecting physiological research into our disease that we're finally getting some crumbs?

    We're not going to get anywhere with this ass-covering bullcrap. Why we tolerate this abuse by our government I do not understand.

    (deep breaths, Chris, deep breaths)

  • AzizaJ January 31, 2014, 12:39 pm
    Firestormm

    Interesting comment and experience from Els on our Facebook page: https://www.facebook.com/PhoenixRisingMECFS/posts/10152239014773384?stream_ref=10

    Especially in relation to observing PEM at 72 hours – which I think tends to apply to me in most cases – or at least between 48 and 72 hours.

    In order to take this into account, she exerted herself the day before she took the 48 hour test. However, I am not sure if this then makes a 'test' for PEM rather counter-productive or if it means we should be considering testing over a longer period to really establish the symptom.

    As a test of functionality at the time – I can see the test has merit – but as something that is diagnostic of the disease – 'a marker' – I really can't see it myself. Not until bigger and better studies are done.

    We did talk about this a lot when the Snell work was published. This need to ensure that patients doing the test were similarly exerting beforehand – maybe even having them on-site as it were the day before to all relax or at least measure and take into account what activity they had performed before testing took place e.g. distances traveled etc.

    And of course – as Unger herself says above – such a test is not suitable for all with ME. I sure as heck couldn't do the exercise bike at the moment and I consider myself more able in other respects…

    Be back later…

    That is a very valid point. My own 2-day test was inconclusive. I even performed a little better the 2nd day. The first day I had not slept very well, and started with acidosis in my legs even before the test. The 2nd day I had had a good night's rest (at least relatively), and no acidosis when I started. I'm sure this affected the results.

    And like Els, my PEM usually hits the 2nd day after exertion (so after 48-72 hours).

    Also, I had my tests relatively close to home (only one hour of travelling). I was wondering how this is for most US patients, when they have their tests. Do they have to travel far (read exert themselves a great deal) before they are tested? How does that affect the test?

  • Kati January 31, 2014, 1:24 pm

    Once more the CDC will rely on self-report of pain and other symtoms post exercise test. The only objective value will be the cognitive test, which could in my opinion be skewed whether the patient is upright or reclinng.

    when I did my exercise test a couple of ear ago, I developped arrythmia during the test and it was still present the net day.

    I can't believe that in 2014 there is no money for patients with ME and for the CDC to perform a truly scientific study on patients who have this poorly researched disease which yanks highly functioning from payroll. This is in the light of President Obama who has announced an extra 100 millions for HIV AIDS only 2months after government shut down last fall.

    Basically what the 1day exercise will show is that we are deconditioned. dr Snell and Staci Stevens will confirm that too.

    As I am awaiting for being called into doing it, I will ask if I can 'purchase' a day 2 for myself. After a couple of medical reports saying I am refusing 'treatment' of meditation, group therapy and naturopath and yet another specialist who will say that I refuse CBT and GET, I will need to prove that indeed I am sick and doing the very best for myself.

  • SOC January 31, 2014, 1:47 pm
    Kati

    After a couple of medical reports saying I am refusing 'treatment' of meditation, group therapy and naturopath and yet another specialist who will say that I refuse CBT and GET, I will need to prove that indeed I am sick and doing the very best for myself.

    What (and where practicing) so-called ME/CFS specialist is using only meditation, group therapy, naturopathy, CBT and GET? Sheesh! :rolleyes: I can see ignorant GPs doing that, but "specialists"? Really? Come on folks, get into the 21st century.

    I'm sorry to hear that's the kind of "specialist" treatment you get, Kati. :hug:

  • heapsreal January 31, 2014, 7:46 pm

    I think it looks promising as they are testing known physiological problems with cfs/me such as the exercise tolerance/pem and the nk function stuff. I guess its not about finding anything new but replicating previous findings. If one day they could add the exercise tolerance test and nk function test to the CCC then i think this will definately be an improvement on diagnosing cfs/me. Im sure there are more tests they could add but this is a good start and its not just going off a list of random symptoms. Once they can narrow the group down to what truly is ME then better studies and treatments hopefully will come.

  • SOC January 31, 2014, 8:13 pm

    I'm still uncomfortable with the amount of questionnaires compared to objective measures. For a start, questionnaires are only as good as the questions asked. Bad questions give unclear or inaccurate responses. I'm not sure the CDC folks understand the illness well enough to ask appropriate questions. We don't need any more "Have you been overly fatigued in the last 6 months?" Let's hope the expert clinicians and researchers are giving the CDC lots of help with this.

    There's the possibility that something positive will come out of this study. The inclusion of our experts is highly encouraging. I won't be comfortable until I see the results, though. :p

  • Bob January 31, 2014, 9:09 pm

    Here is Dr Unger' s presentation to the IOM committee. It is quite a good over-view of the project but I don't think it includes any new information.

    Presentation – click here to view on YouTube.

    Q&A's – click here to view on YouTube.

  • ggingues January 31, 2014, 9:18 pm
    Christopher

    Our government is content to just keep slowly doing fruitless studies until we all eventually die out. Why bother caring?

    The only time the feds gave us any attention is when researchers started getting too close to the truth. It was only THEN that they decided to spend money to shut us up and move the illness to that of "autoimmunity" and "inflammation of unknown etiology" – just enough research to placate patients but not enough to get anywhere with treatment. And what, we should be overjoyed that after decades of willfully neglecting physiological research into our disease that we're finally getting some crumbs?

    We're not going to get anywhere with this ass-covering bullcrap. Why we tolerate this abuse by our government I do not understand.

    (deep breaths, Chris, deep breaths)

    @Christopher Couldn't agree with you more! Ready to burn this sucker down!!

    GG

  • Firestormm February 1, 2014, 4:48 am

    Well, it makes a marvelous difference to watch and listen to a presentation from IOM that is not subject to problems with internet signal, or sound, I must say! Struggling to watch the IOM meeting the other night (day 1), led I believe to my subsequent issues experienced (day 3). Talk about PEM :ill:.

    And that wasn't unusual physical exertion of course: which brings me to another point about the CPET – it is stimulated by physical and not mental exertion: so we also need some means of measuring objective mental exertion and any affect or influence it has on PEM as a symptom (if indeed following all of these attempts to determine what PEM might be, it continues to exist as a separate symptom).

    If I over-exert mentally, to a significant extent, on Day 1, and don't rest on Day 2 but try and continue my normal routines (which include mental 'work'), then on Day 3 I will feel bad effects. Is this any different to physical exertions, and physical PEM? It may well be but perhaps we need to learn more about it. And what about the combination of physical and mental over-exertion?

    We are also no closer to determining a cause. There have been hints, but if looking at physical exertion – over and above 'a norm' – then why should we feel 'worse' after a delay? And why should that delay be different (perhaps) for each of us – could it be based on the nature and/or duration of the exertion? The 'level' of our individual disability? What factors might contribute to delaying any negative effects? And do those effects occur all the time i.e. what is the actual trigger – is there a 'level' at which an 'event' is triggered?

    I took a long time – 1-2 years – to build up to the routine I have now and baring exceptions like the flu, I can manage to do what I need to do at the level of functioning I now experience generally. But any interuption to that routine – like viewing the IOM conference the other night (which ran from 6-10pm UK Time) and was well outside of my routine – tends to screw me over but to variable degrees.

    I find it easier to pace any over-exertion on the physical front and find it easier to manage than mental exertion, but whilst I do anticipate a 'crash', I don't avoid overdoing things but instead try and plan for them. It's the unexpected or unintended events now that catch me out – or the unavoidable. Also I experience terrible sleep, and an especially 'bad night' will f**** me up in similar fashion to a bout of PEM, but it occurs almost immediately.

    I think unraveling PEM has a way to go, but I am pleased that they seem to be trying to get to grips with it – at least in part. Always was too loose a symptom for me – and for my doctors – to really place much faith in. One of the hardest I found to make others believe is real: 'Well, we all feel bad the next day, after doing too much the day before." Etc. etc. So I do hope that this CPET when properly validated can help alleviate some of this concern: though quite how practical it will be as a test in a surgery – or when it might be used – I don't know.

    It bothers me that as a 'test' it implies that at some point a level of 'pass/fail' might be employed. And what if you 'fail' at the time of taking it? ME is a fluctuating condition. I also can't help but worry, that such a test could be used by some unscrupulous Benefit Agency as a determinant for work capability…

    OK that might be wholly unrealistic, but at some point when tests become the norm for our condition (whatever that proves to be), and the results feature in medical records, then it will filter into our assessed ability to work. Might be a good thing, might not. I can't help worrying though – especially if people are overly praising of such things before they have been properly validated.

  • daisybell February 1, 2014, 7:37 pm
    Firestormm

    Well, it makes a marvelous difference to watch and listen to a presentation from IOM that is not subject to problems with internet signal, or sound, I must say! Struggling to watch the IOM meeting the other night (day 1), led I believe to my subsequent issues experienced (day 3). Talk about PEM :ill:.

    And that wasn't unusual physical exertion of course: which brings me to another point about the CPET – it is stimulated by physical and not mental exertion: so we also need some means of measuring objective mental exertion and any affect or influence it has on PEM as a symptom (if indeed following all of these attempts to determine what PEM might be, it continues to exist as a separate symptom).

    If I over-exert mentally, to a significant extent, on Day 1, and don't rest on Day 2 but try and continue my normal routines (which include mental 'work'), then on Day 3 I will feel bad effects. Is this any different to physical exertions, and physical PEM? It may well be but perhaps we need to learn more about it. And what about the combination of physical and mental over-exertion?

    We are also no closer to determining a cause. There have been hints, but if looking at physical exertion – over and above 'a norm' – then why should we feel 'worse' after a delay? And why should that delay be different (perhaps) for each of us – could it be based on the nature and/or duration of the exertion? The 'level' of our individual disability? What factors might contribute to delaying any negative effects? And do those effects occur all the time i.e. what is the actual trigger – is there a 'level' at which an 'event' is triggered?

    I took a long time – 1-2 years – to build up to the routine I have now and baring exceptions like the flu, I can manage to do what I need to do at the level of functioning I now experience generally. But any interuption to that routine – like viewing the IOM conference the other night (which ran from 6-10pm UK Time) and was well outside of my routine – tends to screw me over but to variable degrees.

    I find it easier to pace any over-exertion on the physical front and find it easier to manage than mental exertion, but whilst I do anticipate a 'crash', I don't avoid overdoing things but instead try and plan for them. It's the unexpected or unintended events now that catch me out – or the unavoidable. Also I experience terrible sleep, and an especially 'bad night' will f**** me up in similar fashion to a bout of PEM, but it occurs almost immediately.

    I think unraveling PEM has a way to go, but I am pleased that they seem to be trying to get to grips with it – at least in part. Always was too loose a symptom for me – and for my doctors – to really place much faith in. One of the hardest I found to make others believe is real: 'Well, we all feel bad the next day, after doing too much the day before." Etc. etc. So I do hope that this CPET when properly validated can help alleviate some of this concern: though quite how practical it will be as a test in a surgery – or when it might be used – I don't know.

    It bothers me that as a 'test' it implies that at some point a level of 'pass/fail' might be employed. And what if you 'fail' at the time of taking it? ME is a fluctuating condition. I also can't help but worry, that such a test could be used by some unscrupulous Benefit Agency as a determinant for work capability…

    OK that might be wholly unrealistic, but at some point when tests become the norm for our condition (whatever that proves to be), and the results feature in medical records, then it will filter into our assessed ability to work. Might be a good thing, might not. I can't help worrying though – especially if people are overly praising of such things before they have been properly validated.

    I agree with you. I find that mental exertion is in some ways worse than physical for making me feel unwell. If I am having a good spell, I can walk for over an hour (slowly) with no apparent after-effects. I recently had two weeks off work and felt great! ( that is to say I actually didn't wake up every day feeling unwell) But as soon as I am back at work which I am still trying to do, I feel unwell again. The sustained cognitive load is what seems to bring on most of my symptoms.
    If I end up not working, I can't see any dr without significant experience of ME concluding that I am not fit for work. But as soon as I work, I feel ill.

  • 5150 February 1, 2014, 9:45 pm
    Christopher

    Our government is content to just keep slowly doing fruitless studies until we all eventually die out. Why bother caring?

    The only time the feds gave us any attention is when researchers started getting too close to the truth. It was only THEN that they decided to spend money to shut us up and move the illness to that of "autoimmunity" and "inflammation of unknown etiology" – just enough research to placate patients but not enough to get anywhere with treatment. And what, we should be overjoyed that after decades of willfully neglecting physiological research into our disease that we're finally getting some crumbs?

    We're not going to get anywhere with this ass-covering bullcrap. Why we tolerate this abuse by our government I do not understand.

    (deep breaths, Chris, deep breaths)

    We Need To Find The Root Cause(s). We Need Treatments. We Don't Need Leftover Crumbs Studies.
    Unger and Sebelius: what a pair to draw. More Stonewalling.

  • biophile February 1, 2014, 10:41 pm

    Thanks Bob. I have not combed over the article yet, but the lack of 2-day testing annoyed me more than I thought it would. I understand many patients cannot do this test, I would be very reluctant to do it because of my current state (I would have been glad to do it in the earlier less-severe years of the illness), but the option should be there for a subgroup. Researchers behind the CPET test for CFS are saying there needs to be a two day test for the best data.

    Subjective questionnaires are important, and we do need large studies employing them, but part of me cannot help but see the CDC multi-site study as the sort of preliminary fluffery that should have already been done 20 years ago. So some important data should be collected, but more of the same, and a great opportunity lost, sort of like the PACE Trial adding on a whole bunch of questionnaires but then omitting one of the most important measures i.e. actigraphy by actometers.

    I think don't think a single CPET test is going to be utterly useless though. Many patients are worried that a single test will just serve an agenda to show that patients are merely deconditioned. However, what a single day test does show is that CFS patients can have similar fitness levels as healthy sedentary controls who do not experience CFS symptoms or PEM. That in itself is a convincing argument against the primary deconditioning hypothesis.

    Simon mentioned that the Lights found (biological) abnormalities corresponding to PEM after a single test. Unfortunately, the CDC multi-site study is not taking any blood samples after the exercise test either? It appears however that the methodology can be added to if there is adequate funding. So it sounds like there is hope that the CDC may not (but probably will anyway) miss a great opportunity to validate some previous clues.

  • Bob February 1, 2014, 11:09 pm
    biophile

    …part of me cannot help but see the CDC multi-site study as the sort of preliminary fluffery that should have already been done 20 years ago.

    Yes, I agree. This study should have been carried out 20 or 30 years ago. The way I see it is that the CDC has done next to nothing in the past, in terms of useful research. So the CDC doesn't have any useful data on ME. I think Beth Unger is starting afresh. She has to start somewhere, and I think this is a good place to start. Unfortunately it's 20 or 30 years too late, but that's not her fault. She has emphasised, repeatedly, that this is only a starting point, and that the study will evolve. But no one trusts the CDC, so they need to demonstrate their intentions with actions. But even purely using self-reports, and clinical history (inc vaccination history, and past/current pharmaceutical prescriptions), I think a large study like this may potentially give some exceptional ground-breaking info.

    biophile

    I think don't think a single CPET test is going to be utterly useless though. Many patients are worried that a single test will just serve an agenda to show that patients are merely deconditioned. However, what a single day test does show is that CFS patients can have similar fitness levels as healthy sedentary controls who do not experience CFS symptoms or PEM. That in itself is a convincing argument against the primary deconditioning hypothesis.

    A single CPET study on it's own is going to be pretty useless, I imagine, although it may contribute to determining some subsets. But I think the 48 hour post-exertional cognitive tests and self-reports may well have some merit, and may well come up with some interesting results. The reason a two-day CPET test is informative is because the second test assesses and objectively measures the post-exertion reaction. But 48 hour post-exertional cognitive tests may also measure PEM (i.e. changes as a result of a post-exertional reaction.)

    biophile

    Unfortunately, the CDC multi-site study is not taking any blood samples after the exercise test either?

    I don't think they are taking post-exertional blood samples. I haven't seen that proposed.

    biophile

    It appears however that the methodology can be added to if there is adequate funding. So it sounds like there is hope that the CDC may not (but probably will anyway) miss a great opportunity to validate some previous clues.

    It all boils down to whether Unger is honest, open-minded and competent.
    I'm hopeful that she's doing her job with good faith, but the CDC has a lot to prove.
    I think that Unger may have reset the CDC's program for CFS, which is what she needed to do.
    And if starting from scratch, I can't fault her approach of collecting large amounts of data and 'following the evidence' (i.e. without bias or prejudice), which I think is exactly what we need.

    But, yes, if she adds objective biomedical tests, then the study could be transformed into something incredibly meaningful and ground-breaking, if carried out competently and honestly.

    I'm cautiously optimistic, but I'll be sceptical until we see some meaningful results, and a solid demonstration of good faith.

  • heapsreal February 2, 2014, 12:12 am

    i think the good research is going to come from the private type researchers like kdm, montoya, dr K, dr P, need the $$ to go to those guys to get the job done.

  • Firestormm February 2, 2014, 3:41 am

    I wonder if the following examination were to be repeated on patients with ME similar observations might be made (PEM in Gulf War Illness) June 2013:

    Exercise Challenge in Gulf War Illness Reveals Two Subgroups with Altered Brain Structure and Function

    Abstract

    A hallmark complaint of subjects with Gulf War Illness is post-exertional malaise; defined as an exacerbation of symptoms following physical and/or mental effort.

    To study the causal relationship between exercise, the brain, and changes in symptoms, 28 Gulf War veterans and 10 controls completed an fMRI scan before and after two exercise stress tests to investigate serial changes in pain, autonomic function, and working memory.

    Exercise induced two clinical Gulf War Illness subgroups. One subgroup presented with orthostatic tachycardia (n = 10). This phenotype correlated with brainstem atrophy, baseline working memory compensation in the cerebellar vermis, and subsequent loss of compensation after exercise.

    The other subgroup developed exercise induced hyperalgesia (n = 18) that was associated with cortical atrophy and baseline working memory compensation in the basal ganglia. Alterations in cognition, brain structure, and symptoms were absent in controls.

    Our novel findings may provide an understanding of the relationship between the brain and post-exertional malaise in Gulf War Illness.

    Introduction

    …The effects of 2 bicycle exercise stress tests performed on consecutive days on widespread pain (hyperalgesia), autonomic regulation, and working memory function were studied in 10 controls and 28 Gulf War veterans who met the 1998 CDC case definition criteria for GWI over a four day period [4]….

    Not that I am saying this research was good or bad, obviously is in need of replication; but apart from the observed sub-groupings, it is I think important to note that PEM is not exclusive to ME. Maybe they should also try Snell's testing methods on GWI and also use controls from other chronic conditions (I know Snell has said that his observation in ME was unique but a study using, say, MS patients as well as healthy people, as controls, might also better enable the point from his initial research to be better established as something definitive for ME).

  • Firestormm February 2, 2014, 3:59 am
    heapsreal

    i think the good research is going to come from the private type researchers like kdm, montoya, dr K, dr P, need the $$ to go to those guys to get the job done.

    I agree, in part, but would like to see more of them joining together, providing samples, as some of them did for the Lipkin study, for example. There seems little doubt now that those more familiar with our condition will be the ones to carry out the research – will less funding coming from Govt. sources: but they MUST by joining together do these studies on significant numbers of patients.

    I really can't put into words how much I loathe seeing small studies be produced that appear 'interesting' and then never get replicated. I think our condition has had more than enough of these 'pilots' and it's time to really begin replication and/or large powered studies that will negate spurious hypotheses from the past that have been borne on such pilots, or will move the science forward recognisably.

    There is also something to be said I think for being a little cautious in believing a study 'good' because a known 'expert' is behind it. I would like more openness with respect to protocols, and peer-review, as part of or prior to any public effort to raise funds. But when push comes to shove, I would rather see researchers doing it privately, than not doing it at all. And times have definitely changed – we can't rely (not that we could) on Govt. funding for science – and in that I don't think we are much different than in other illnesses – though the $ spent are of course proportionately less.

  • heapsreal February 2, 2014, 4:01 am

    @Firestormm i guess its bound to happen in other disorders, but its not something that has been tested in other conditions. It does show disability though.

  • heapsreal February 2, 2014, 4:05 am
    Firestormm

    I agree, in part, but would like to see more of them joining together, providing samples, as some of them did for the Lipkin study. There seems little doubt now that those more familiar with our condition will be the ones to carry out the research – will less funding coming from Govt. sources: but they MUST by joining together do these studies on significant numbers of patients. I really can't put into words how much I loathe seeing small studies be produced that appear 'interesting' and then never get replicated. I think our condition has had more than enough of these 'pilots' and it's time to really begin replication and/or large powered studies that will negate spurious hypotheses from the past that have been borne on such pilots, or will move the science forward recognisably.

    hopefully if these private guys come up with something then they might get more govt research dollars. The aussie researchers Peterson is working with at griffith uni are getting reasonable govt grants here, its not in the cancer range $$ but its more then they have done in the past. When issues start arising and being replicated then the govt are going to have to act.

  • Firestormm February 2, 2014, 4:07 am
    heapsreal

    hopefully if these private guys come up with something then they might get more govt research dollars. The aussie researchers Peterson is working with at griffith uni are getting reasonable govt grants here, its not in the cancer range $$ but its more then they have done in the past. When issues start arising and being replicated then the govt are going to have to act.

    That is reassuring news, Heaps :)

    I wonder what the breakdown of expenditure are for this CDC Multi-site, IOM (well we know is $1m), and NIH P2P? Combined they must amount to a fair whack I guess.

  • Christopher February 2, 2014, 6:45 am
    Bob

    She says she's 'following the evidence' (i.e. without bias or prejudice), which I think is exactly what we need.

    They already have all the evidence they need to push for fast tracking certain treatments. Ignoring decades worth of biomarkers related to inflammation and immune dysfunction as well as successful treatment trials (ampligen, rituximab) already shows bias and prejudice.

    We already have the data we need to start addressing treatment. They are content to poke and prod us as we keep suffering. We have to stop allowing the abuse and neglect to continue.

  • Christopher February 2, 2014, 6:46 am
    Firestormm

    That is reassuring news, Heaps :)

    I wonder what the breakdown of expenditure are for this CDC Multi-site, IOM (well we know is $1m), and NIH P2P? Combined they must amount to a fair whack I guess.

    Pennies when we need dollars, Firestorm. Pennies.

  • Valentijn February 2, 2014, 11:06 am
    Firestormm

    Not that I am saying this research was good or bad, obviously is in need of replication; but apart from the observed sub-groupings, it is I think important to note that PEM is not exclusive to ME. Maybe they should also try Snell's testing methods on GWI and also use controls from other chronic conditions (I know Snell has said that his observation in ME was unique but a study using, say, MS patients as well as healthy people, as controls, might also better enable the point from his initial research to be better established as something definitive for ME).

    GWI is a pretty bad example to use to show that PEM is not unique to ME/CFS … the symptoms of the two conditions overlap completely, to the extent that they might very well be the same disease, or subsets of the same disease. The only real difference is that GWI includes a group defined by their career, which isn't actually relevant to who a disease decides to pick on.

    Most likely, they have ME/CFS, but have a very specific pathway into getting it: military vaccinations, certain chemical exposures, etc. But that fits pretty well with the ME/CFS concept of the disease being triggered by different types of infections, vaccine reactions, and exposures to chemicals such as organophosphates.

  • roonie February 2, 2014, 11:12 am

    has anyone ever seen a government do any good for it people…..ever. One look at the lyme fiasco should tell us all to pick the fight up to a new level. We need protests so the rest of the world see us on the news..not hiding in a back corner watching the lives of ours and, in many cases , our families fall to pieces.

    Why did they want to keep changing the name of the illness every few years….its to keep us all confussed…..thats why. To keep the new patients devided from the old ones. Im with Christopher on this one! They have something to hide. Its quite possible they already know what this illness is. People …get ready. Did you see Nelson Mendella sit back on his Laurells

  • jimells February 2, 2014, 11:29 am

    This "study" is a cruel joke. I'm going to apply for a grant to study fevers. I'll ask a bunch of folks if they think they might have a fever. That will qualify them for the study. Then I'll ask them how hot and sweaty they feel.

    Thermometers will not be allowed – they are just too much trouble, what with the cost, and sterilizing, and having to read them.

    Unger and her ilk are guilty of criminal negligence, but we are the ones serving a life (or death) sentence.

  • Ember February 2, 2014, 6:04 pm

    Dr. Unger writes that “a new definition of CFS is not the objective of this study.” But in November 2011 she described this study as preparatory to a meeting of experts charged with revisiting Fukuda 1994:

    Going by what has happened at CDC in the past, we will next convene a meeting of experts. CDC does not decide any of this on its own. That is why I always say it is not CDC’s definition. For good, bad, or indifferent, just like in the ACIP [Advisory Committee on Immunization Practices], CDC implements what the committees and the recommendations are. That is how the 1994 case definition got established. 1994 is long enough ago that everyone agrees it definitely needs to be revisited.

    It will be most helpful when we actually have some data to guide that discussion. Given that we are at the beginning of the contract and we are just beginning to collect the data, if all goes well, we hope that we will have the data in a one‐year time frame. We can anticipate that it will be at least one year before we could start the dialog in the process.

    Learning from other consensus‐building organizations that I have been involved in, you have a meeting, but you need to have committees and upfront discussion and dialog before the meeting. You have things posted for comment, dialog, and discussion. Everybody needs to have a voice in what the final product is.

    What has become of Dr. Unger's plan to revisit Fukuda 1994?

  • Bob February 2, 2014, 8:54 pm
    Ember

    What has become of Dr. Unger's plan to revisit Fukuda 1994?

    I don't know, but perhaps she realised that the evidence base was woefully inadequate, and decided instead to embark on a large evidence collecting program? The proposed 'one year' study has turned into a large five year study. Although Unger says that the specific aim of the CDC study is not to create a new diagnostic criteria, I hope that is the direction where it is ultimately heading, in practice. (Assuming that Unger is working in good faith, and competently etc.) Unger is looking for evidence to distinguish patients from controls (i.e. healthy controls and patients with other fatiguing illnesses), and for evidence to create subgroups, and for evidence that can be used to diagnose patients.

    If Unger isn't sticking to her previous ideas (as quoted in Ember's post above), then I think it's probably a very good thing based on this extract from Ember's quote:

    Going by what has happened at CDC in the past, we will next convene a meeting of experts.

    Both halves of that sentence, coming from the CDC, is enough to send ice cold shivers up the spine of any ME patient!

  • Ember February 3, 2014, 7:24 am
    Bob

    (Assuming that Unger is working in good faith, and competently etc.) Unger is looking for evidence to distinguish patients from controls (i.e. healthy controls and patients with other fatiguing illnesses), and for evidence to create subgroups, and for evidence that can be used to diagnose patients.

    Those aren't assumptions that I can make given that Dr. Unger refuses to use the 2-day CPET or even to disclose whether or not her cohort meets Fukuda or the CCC. She admits that the data are there but contends, “It still, I think, requires some interpretation and discussion.” Those apparently aren't her strong suits.

    Dr. Unger's so-called study looks to me more like an extended fishing expedition. She concluded her comments to the IOM smiling coyly, “So we're just starting. Just a start.” After 20 years, the ICC and CCC languish, and no initiative has been undertaken to replace the CDC's 1994 research definition. Patients are left to suffer or die.

  • Christopher February 3, 2014, 7:32 am
    Ember

    Those aren't assumptions that I can make given that Dr. Unger refuses to use the 2-day CPET or even to disclose whether or not her cohort meets Fukuda or the CCC. She admits that the data are there but contends, “It still, I think, requires some interpretation and discussion.” Those apparently aren't her strong suits.

    Dr. Unger's so-called study looks to me more like an extended fishing expedition. She concluded her comments to the IOM smiling coyly, “So we're just starting. Just a start.” After 20 years, the ICC and CCC languish, and no initiative has been undertaken to replace the CDC's 1994 research definition. Patients are left to suffer or die.

    This is an alternate version of the AIDS crisis where no one demanded that the federal government help its citizens.

  • Marco February 3, 2014, 11:43 am
    Valentijn
    Firestormm

    Not that I am saying this research was good or bad, obviously is in need of replication; but apart from the observed sub-groupings, it is I think important to note that PEM is not exclusive to ME. Maybe they should also try Snell's testing methods on GWI and also use controls from other chronic conditions (I know Snell has said that his observation in ME was unique but a study using, say, MS patients as well as healthy people, as controls, might also better enable the point from his initial research to be better established as something definitive for ME).

    GWI is a pretty bad example to use to show that PEM is not unique to ME/CFS … the symptoms of the two conditions overlap completely, to the extent that they might very well be the same disease, or subsets of the same disease. The only real difference is that GWI includes a group defined by their career, which isn't actually relevant to who a disease decides to pick on.

    Most likely, they have ME/CFS, but have a very specific pathway into getting it: military vaccinations, certain chemical exposures, etc. But that fits pretty well with the ME/CFS concept of the disease being triggered by different types of infections, vaccine reactions, and exposures to chemicals such as organophosphates.

    PEM can also be found in post-concussion syndrome which makes it a bit of a stretch to blame infection, vaccinations or chemical exposure solely (looks to me like the problem is in the brain) :

    http://www.ncbi.nlm.nih.gov/pubmed/23252441

    Probably not a good idea to mention graded exercise :

    http://www.hindawi.com/journals/rerp/2012/705309/

  • Firestormm February 3, 2014, 11:45 am

    @Marco Ta matey. I shall have a butcher's later :)

  • Valentijn February 3, 2014, 12:22 pm
    Marco

    PEM can also be found in post-concussion syndrome which makes it a bit of a stretch to blame infection, vaccinations or chemical exposure solely (looks to me like the problem is in the brain) :

    http://www.ncbi.nlm.nih.gov/pubmed/23252441

    Probably not a good idea to mention graded exercise :

    http://www.hindawi.com/journals/rerp/2012/705309/

    That doesn't sound like PEM, as it's limited to cognitive abilities and seems to be immediately after activity, not a day or two later. Duration of cognitive impairment is also not specified – so it's quite a stretch to equate the results of that study with PEM.

    And the 2nd link is specifically referring to symptoms during an exercise test, not afterward. Hence it really sounds like exercise intolerance rather than PEM.

  • Bob February 3, 2014, 12:30 pm
    Valentijn

    That doesn't sound like PEM, as it's limited to cognitive abilities and seems to be immediately after activity, not a day or two later. Duration of cognitive impairment is also not specified – so it's quite a stretch to equate the results of that study with PEM.

    And the 2nd link is specifically referring to symptoms during an exercise test, not afterward. Hence it really sounds like exercise intolerance rather than PEM.

    Yes, it's important to always remember that PEM in ME has a distinct nature. It's not just post-exertional malaise, and it's not just post-exertional fatigue. It's a delayed post-exertional exacerbation of any/all ME symptoms, in response to even minimal exertion, that isn't resolved by ordinary rest, etc.

    We have to define PEM in ME before comparing it to other diseases which feature post-exertional symptoms.

  • Bob February 3, 2014, 12:49 pm
    Bob

    Assuming that Unger is working in good faith, and competently etc.

    Ember

    Those aren't assumptions that I can make…

    I agree that the CDC has to prove itself.
    I'm watching what they are doing with an open mind: sceptical but not judging Unger by the past failings of the CDC.

    If I was Beth Unger, I might be start exactly where she is starting.
    I'd be pressing a reset button, and re-starting the CDC's CFS program from scratch with a large study using patients from the clinics of widely acknowledged ME expert clinicians.
    And I'd want to follow the data.
    Yes, we desperately need objective biomedical investigations, but (in my opinion) she's got to start with basic data collection which should have been done 20 years ago.
    She's made it clear that her data is intended to be used for future biomedical investigations.

    Ember

    …given that Dr. Unger refuses to […] disclose whether or not her cohort meets Fukuda or the CCC. She admits that the data are there but contends, “It still, I think, requires some interpretation and discussion.” Those apparently aren't her strong suits.

    Yes, she doesn't seem to be good at discussion.

    The study did not recruit participants using either Fukuda or CCC, so perhaps they are a mixed cohort.
    I suspect that they will probably mostly meet Fukuda, and perhaps the majority will also meet the CCC, because they come from secondary care clinics (suggesting long-term and more severe symptoms).
    But I think that Unger is right not to focus on these criteria.
    She is investigating the data from all ME/CFS patients diagnosed by expert clinicians.
    Hopefully she will be using diagnostic criteria, at part of the study, but that shouldn't be the focus.

    The focus should be on finding subsets based on the data, and then seeing if these match the existing diagnostic criteria or not.
    It would be a shallow and ill-conceived project if Unger was purely attempting to match her data to existing diagnostic criteria.
    For it to be meaningful, and ground-breaking, she's got to assess the data with an open mind, looking for unexpected patterns in the data and attempting to define subgroups based on the data and not on pre-existing (consensus) diagnostic criteria.

    If the data matches the existing diagnostic criteria then that will be a very useful finding. But it might not.

    Ember

    Dr. Unger's so-called study looks to me more like an extended fishing expedition.

    I think I agree with that. That's what I want her to be doing. Fishing for all the data she can, and analysing it.
    Yes, she must move on to including comprehensive biomedical testing, and I hope she will, quickly.
    If she doesn't then the trust of the patient community will not be gained.
    At the moment there is zero trust.

    Anyway, these are just my own opinions. I know that many don't agree.

  • JKN February 3, 2014, 4:31 pm

    I feel like a stranger in a strange land with all of this talk about the CPET test. I took a cardiac stress test 9 years ago which cause very severe disease progression and heart damage. I am now in diastolic heart failure as a result of this stress test. I also lost my ability to talk.

    "Findings which suggest mitochondrial metabolic dysfunction similar to mitochondrial encephalomyopathy in CFS patients led CFS expert Professor Paul Cheney to comment. ‘The most important thing about exercise is not to have patients do aerobic exercise. I believe that even progressive aerobic exercise is counter-productive. If you have a defect in mitochondrial function and you push the mitochondria by exercise, you kill the DNA.’ Numerous heart, lung, brain and other abnormalities also show strong evidence that exercise can have extremely harmful effects on CFS patients in many different bodily systems, permanent damage may be caused, as well as disease progression." (Williams 2004, [online]).

    "Not only is it inappropriate for CFS patients to undergo a treadmill stress test or be pushed toward age-predicted target heart rates, but this is potentially dangerous." Philipa Corning, Ph D, Vice President Quest 61, 2003

    Dr. Paul Cheney wrote (www.cheneyresearch.com), "We have a rising case load of diastolic dysfunction seen in 97% of our CFS cases (avg. age 49) and some appear to have what I would call compensated diastolic heart failure. I would define compensated DHF in CFS as an extremely low cardiac output with a cardiac index (CI) below 2.0 and very poor functional capacity combined with the inability to stand which is the corollary in DHF to the inability to lay down flat in systolic heart failure (SHF). Heart failure patients are typically below 2.0 in CI. I have several CFS patients below that number and they cannot stand still for more than 15-30 seconds without having to sit down or fall down. Walking or moving helps which makes sense as that would increase filling pressures and equivalent to laying down. They might be diagnosed as having orthostatic intolerance by others."

    "Recently, Jason et al (2006) reported that the mean age of patients with myalgic encephalomyelitis/chronic fatigue syndrome dying from heart failure, i.e. 58.7 years, is significantly lower than the age of those dying from heart failure in the general US population, i.e. 83.1 years."

    So I am totally shocked by these exercise tests going on. Unless, I have a different disease, which I don't believe I do, or that there is a difference between ME and CFS, then I don't understand why PWCs taking this cardio test aren't having the same horrific results that I've had. If these tests expand in this study, and PWCs aren't warned of the possible results of severe permanent disease progression, then I fear what might happen to some patients.

    Furthermore, I don't understand why there are no research studies going on today reg. the effects that ME/CFS has on the heart, i.e. this is one of the main causes of death from ME/CFS.

    When I look at the current research most of it seem irrelevent to me. None of it is going to save my life.

    So I just wanted to put out this warning for PWCs taking these cardio stress tests, because there seems to be no serious warning out there. I don't think most ME/CFS doctors understand the possible consequences.

  • SOC February 3, 2014, 6:27 pm
    Bob

    I agree that the CDC has to prove itself.
    I'm watching what they are doing with an open mind: sceptical but not judging Unger by the past failings of the CDC.

    If I was Beth Unger, I might be start exactly where she is starting.
    I'd be pressing a reset button, and re-starting the CDC's CFS program from scratch with a large study using patients from the clinics of widely acknowledged ME expert clinicians.
    And I'd want to follow the data.

    I understand that point — that Dr Unger may understand that the CDC needs to start over with it's view of ME/CFS. What frustrates me is that she seems to think that only the CDC can do valid research on ME/CFS and therefore their research must start at absolute ground zero. No respect for the work already done by many talented researchers. It seems she feels the need to reinvent the wheel of ME/CFS knowledge.

    We don't have time for the CDC to mess around for 20 years getting up to speed doing their own research to find out what we already know.

    That said, the CDC is (technically) not a medical research organization, they're a public health organization. Original research should be coming out of other branches of HHS. So maybe the focus on operation… rationalizing… whatever that word is :confused:… diagnosis makes sense in terms of their particular responsibility. They're not focused on figuring out what's wrong with us, or how to treat it, just telling doctors how to know who has it. Kinda pointless given we don't have any established treatment even if we're diagnosed. :meh:

    It would (supposedly) allow them to study how big of a problem ME/CFS is, which is definitely part of their public health remit, so the current research may give them some future work. Which, of course, is a benefit to them even if it isn't much help to us. :rolleyes:

  • Ember February 3, 2014, 6:48 pm
    Bob

    For it to be meaningful, and ground-breaking, she's got to assess the data with an open mind, looking for unexpected patterns in the data and attempting to define subgroups based on the data and not on pre-existing (consensus) diagnostic criteria.

    Subgroups presuppose groups, and identifying them may not be ground-breaking:

    Optional Considerations

    Classifying patients by subgroups to enable the comparison of patients within the diagnosis of ME may be helpful in some studies.

    1 Onset: acute infectious or gradual.
    2 Onset severity may be a good predictor of severity in the chronic phase.
    3 Symptom severity: mild, moderate, severe, very severe.
    4 Criterial subgroups: neurological, immune, energy metabolism/transport or eclectic.

    By insisting that Dr. Unger "assess data with an open mind, looking for unexpected patterns," are you denigrating the time-honoured practice of hypothesis testing?

  • SOC February 3, 2014, 7:12 pm
    JKN

    I feel like a stranger in a strange land with all of this talk about the CPET test. I took a cardiac stress test 9 years ago which cause very severe disease progression and heart damage. I am now in diastolic heart failure as a result of this stress test. I also lost my ability to talk.

    "Findings which suggest mitochondrial metabolic dysfunction similar to mitochondrial encephalomyopathy in CFS patients led CFS expert Professor Paul Cheney to comment. ‘The most important thing about exercise is not to have patients do aerobic exercise. I believe that even progressive aerobic exercise is counter-productive. If you have a defect in mitochondrial function and you push the mitochondria by exercise, you kill the DNA.’ Numerous heart, lung, brain and other abnormalities also show strong evidence that exercise can have extremely harmful effects on CFS patients in many different bodily systems, permanent damage may be caused, as well as disease progression." (Williams 2004, [online]).

    "Not only is it inappropriate for CFS patients to undergo a treadmill stress test or be pushed toward age-predicted target heart rates, but this is potentially dangerous." Philipa Corning, Ph D, Vice President Quest 61, 2003

    Dr. Paul Cheney wrote (http://www.cheneyresearch.com), "We have a rising case load of diastolic dysfunction seen in 97% of our CFS cases (avg. age 49) and some appear to have what I would call compensated diastolic heart failure. I would define compensated DHF in CFS as an extremely low cardiac output with a cardiac index (CI) below 2.0 and very poor functional capacity combined with the inability to stand which is the corollary in DHF to the inability to lay down flat in systolic heart failure (SHF). Heart failure patients are typically below 2.0 in CI. I have several CFS patients below that number and they cannot stand still for more than 15-30 seconds without having to sit down or fall down. Walking or moving helps which makes sense as that would increase filling pressures and equivalent to laying down. They might be diagnosed as having orthostatic intolerance by others."

    "Recently, Jason et al (2006) reported that the mean age of patients with myalgic encephalomyelitis/chronic fatigue syndrome dying from heart failure, i.e. 58.7 years, is significantly lower than the age of those dying from heart failure in the general US population, i.e. 83.1 years."

    So I am totally shocked by these exercise tests going on. Unless, I have a different disease, which I don't believe I do, or that there is a difference between ME and CFS, then I don't understand why PWCs taking this cardio test aren't having the same horrific results that I've had. If these tests expand in this study, and PWCs aren't warned of the possible results of severe permanent disease progression, then I fear what might happen to some patients.

    Furthermore, I don't understand why there are no research studies going on today reg. the effects that ME/CFS has on the heart, i.e. this is one of the main causes of death from ME/CFS.

    When I look at the current research most of it seem irrelevent to me. None of it is going to save my life.

    So I just wanted to put out this warning for PWCs taking these cardio stress tests, because there seems to be no serious warning out there. I don't think most ME/CFS doctors understand the possible consequences.

    The CPET test is not the same test as the walking cardiac stress test.

    The CPET is done on a bicycle, not a treadmill. The bicycle does not force a particular speed on the patient the way a treadmill does. The cardiac stress test only records EKG and BP. The CPET also includes pulmonary gases, so the tester knows when the patient has reached his/her anaerobic threshold and can adjust the test accordingly so as not to severely overwork the patient. The cardiac stress test has all patients exercising at the same speed and incline, healthy or ill. That can be a serious problem with PWME. The CPET (properly performed for PWME) allows for adjustment of work depending on the capability of the patient.

    I suspect that the CPET test (properly done for PWME) is not as severe as many PWME fear. I've done it (the one day test) twice now and neither time was it as terrible as I expected. Both times it was done in the office of an ME/CFS specialist by people who understand the illness. The test ran about 8 minutes. The pedaling resistance was set so easy that it was like waving my legs around, not pushing with any power at all. I didn't feel great afterwards, but I didn't have a massive crash, either.

    I do not have mild ME/CFS. I'm about 5/10 on most scales. I couldn't walk more than 100 ft without PEM the last time I did the test, so it's not like I'm not susceptible to PEM or have a high threshold for PEM.

    I'm not saying the test is trivial for all PWME. I think many of us have some (relatively small) consequence such as several days to a week of moderate PEM, but not a long-term crash. It's important to note that it is NOT the same test as the cardiac stress test most people imagine, which would probably seriously crash most of us, especially when done by technicians unfamiliar with the limitations of PWME.

  • Bob February 3, 2014, 7:49 pm
    Ember

    Subgroups presuppose groups, and identifying them may not be ground-breaking:

    Optional Considerations

    Classifying patients by subgroups to enable the comparison of patients within the diagnosis of ME may be helpful in some studies.

    1 Onset: acute infectious or gradual.
    2 Onset severity may be a good predictor of severity in the chronic phase.
    3 Symptom severity: mild, moderate, severe, very severe.
    4 Criterial subgroups: neurological, immune, energy metabolism/transport or eclectic.

    I think there's a wide consensus that CFS and CFS/ME are heterogeneious, and that ME might be heterogenous.
    I personally think it's absolutley essential to use data to attempt to identify subgroups, in order for research to advance.

    Yes, there are various subgroups that are already defined, but Unger is carrying out a massive data analysis, and perhaps she may find unexpected groups, based on the data. I hope she is cross-referencing with already-defined subgroups, such as the ones you've identified here.

    Ember

    By insisting that Dr. Unger "assess data with an open mind, looking for unexpected patterns," are you denigrating the time-honoured practice of hypothesis testing?

    I think it would be narrow minded if the only hypothesis being tested was whether patients fit into currently defined diagnostic criteria. I hope that Unger is testing the collected data against Fukuda and the CCC/ICC. But I think many of us agree that CCC and ICC, although vastly preferable to Fukuda, are not set in stone.

  • Bob February 3, 2014, 7:59 pm
    SOC

    The CPET test is not the same test as the walking cardiac stress test.

    The CPET is done on a bicycle, not a treadmill. The bicycle does not force a particular speed on the patient the way a treadmill does. The cardiac stress test only records EKG and BP. The CPET also includes pulmonary gases, so the tester knows when the patient has reached his/her anaerobic threshold and can adjust the test accordingly so as not to severely overwork the patient. The cardiac stress test has all patients exercising at the same speed and incline, healthy or ill. That can be a serious problem with PWME. The CPET (properly performed for PWME) allows for adjustment of work depending on the capability of the patient.

    I suspect that the CPET test (properly done for PWME) is not as severe as many PWME fear. I've done it (the one day test) twice now and neither time was it as terrible as I expected. Both times it was done in the office of an ME/CFS specialist by people who understand the illness. The test ran about 8 minutes. The pedaling resistance was set so easy that it was like waving my legs around, not pushing with any power at all. I didn't feel great afterwards, but I didn't have a massive crash, either.

    I do not have mild ME/CFS. I'm about 5/10 on most scales. I couldn't walk more than 100 ft without PEM the last time I did the test, so it's not like I'm not susceptible to PEM or have a high threshold for PEM.

    I'm not saying the test is trivial for all PWME. I think many of us have some (relatively small) consequence such as several days to a week of moderate PEM, but not a long-term crash. It's important to note that it is NOT the same test as the cardiac stress test most people imagine, which would probably seriously crash most of us, especially when done by technicians unfamiliar with the limitations of PWME.

    There have been times during my illness when 8 minutes of the mildest exercise would have caused me a severe relapse, lasting for months. I was especially reactive during my first 3 years of illness. I'm more stable now, after discover pacing and implementing it strictly, but my last relapse was severe for about 6 months, and then continued moderately for months after that.
    I'm not sure how I'd currently react to an 8 minute maximal CPET test, but I'd be too cautious to attempt it, unless going through a prolonged stable spell.

    If anyone is brave enough to attempt such a test in the name of science, then I'd be very grateful to them, but I think we've all got to be honest with ourselves that such a test could potentially be damaging to patients. I know we are desperate for answers, but we've also got to protect each other.

    Patients have got to go into such a test with eyes-wide-open, and being fully informed and fully aware of the potential for adverse effects.
    Personally, I'd recommend that new patients are not put through such a test, as they wouldn't have a full insight into the nature of their post-exertional reactions, and so can't make an informed decision about it.

  • SOC February 3, 2014, 8:01 pm
    Ember

    By insisting that Dr. Unger "assess data with an open mind, looking for unexpected patterns," are you denigrating the time-honoured practice of hypothesis testing?

    Keeping an open mind while looking as what's going on and searching for patterns is the first step in science. It is called observation. It comes before the formation of a hypothesis. It's what hypotheses are based upon. First you have to develop the hypothesis, then you test it.

  • SOC February 3, 2014, 8:12 pm
    Bob

    There have been times during my illness when 8 minutes of the mildest exercise would have caused me a severe relapse, lasting for months. I was especially reactive during my first 3 years of illness. I'm more stable now, after discover pacing and implementing it strictly, but my last relapse was severe for about 6 months, and then continued moderately for months after that.
    I'm not sure how I'd currently react to an 8 minute maximal CPET test, but I'd be too cautious to attempt it, unless going through a prolonged stable spell.
    If anyone is brave enough to attempt such a test in the name of science, then I'd be very grateful to them, but I think we've all got to be honest with ourselves that such a test could potentially be damaging to patients. I know we are desperate for answers, but we've also got to protect each other.

    Patients have got to go into such a test with eyes-wide-open, and being fully informed and fully aware of the potential for adverse effects.
    Personally, I'd recommend that new patients are not put through such a test, as they wouldn't have a full insight into the nature of their post-exertional reactions, and so can't make an informed decision about it.

    I understand that many patients are afraid of the test. Exercise can be very risky for us. I'm simply suggesting that absolute rejection when you've never even seen the test done might be counterproductive.

    An 8 minute maximal CPET test is not 8 minutes of maximal exercise, btw. It's only maximal (your own maximum) at the end.

    I wonder if it might be informative to have a poll or some way of gathering info that would allow all members who have had the test to report the consequences they suffered. That might give us a better sense of whether it is truly dangerous for PWME and whether we should therefore discourage it's use… or conversely, whether patients are not reporting serious consequences and the test can safely be used a valuable objective measure for research studies.

  • Ember February 3, 2014, 8:22 pm
    SOC

    Keeping an open mind while looking as what's going on and searching for patterns is the first step in science. It is called observation. It comes before the formation of a hypothesis. It's what hypotheses are based upon. First you have to develop the hypothesis, then you test it.

    Can you articulate Dr. Unger's study design? Is she proceeding without research questions or hypotheses? Notice that she rejects Dr. Klimas' suggestion in the first 75 seconds here:

    This quotation from “Research questions, hypotheses and objectives” may provide a useful commentary on Dr. Unger's "data-driven" approach:

    The primary research question should be driven by the hypothesis rather than the data.1,2 That is, the research question and hypothesis should be developed before the start of the study. This sounds intuitive; however, if we take, for example, a database of information, it is potentially possible to perform multiple statistical comparisons of groups within the database to find a statistically significant association. This could then lead one to work backward from the data and develop the “question.” This is counterintuitive to the process because the question is asked specifically to then find the answer, thus collecting data along the way (i.e., in a prospective manner). Multiple statistical testing of associations from data previously collected could potentially lead to spuriously positive findings of association through chance alone.2 Therefore, a good hypothesis must be based on a good research question at the start of a trial and, indeed, drive data collection for the study.

    A good hypothesis should precede and drive a study's data collection.

  • Bob February 3, 2014, 8:25 pm
    SOC

    I wonder if it might be informative to have a poll or some way of gathering info that would allow all members who have had the test to report the consequences they suffered. That might give us a better sense of whether it is truly dangerous for PWME and whether we should therefore discourage it's use… or conversely, whether patients are not reporting serious consequences and the test can safely be used a valuable objective measure for research studies.

    I'm not sure that would be helpful. Just because either a minority or a majority of patients have found the consequences of a CPET test to be acceptable for themselves, does not mean that it would be safe for everyone.

    I'd rather have open honest discussions about it and allow individuals to decide for themselves whether or not it would be safe for them.

    Some of us will decide it would be relatively safe for us to participate while others will decide it would be dangerous or potentially dangerous for us.

  • roonie February 3, 2014, 10:40 pm

    i think we should all do what Jim Wilson did with lyme here in Canada……raise a few dollars …..open up our own labs….hire our own docs…..get er done! There is now a treatment center in his province of British Columbia to treat lyme and other associated illnesses……even cfs/fibro.

  • heapsreal February 3, 2014, 10:55 pm

    If they just tested dam people who fit the ccc for nk function, rnaseL, 2 day exercise test. Im sure klimas and co have some kind of research on cytokine patterns. Check for viral reactivations and common bacterial infections.

    Come on how dam hard is it? Theres 30yrs of research and we have biomarkers just have to use the dam things.

    It seems like they just want to invent the dam wheel. Aarrgghh! !!!

  • taniaaust1 February 3, 2014, 11:22 pm
    heapsreal

    If they just tested dam people who fit the ccc for nk function, rnaseL, 2 day exercise test. Im sure klimas and co have some kind of research on cytokine patterns. Check for viral reactivations and common bacterial infections.

    Come on how dam hard is it? Theres 30yrs of research and we have biomarkers just have to use the dam things.

    It seems like they just want to invent the dam wheel. Aarrgghh! !!!

    To me avoidance of doing 2 day exercise tests is to try to play the illness down as much as the CDC can do. It shows lack of change (I believe they are only doing what they currently are doing due to public pressure, they will keep doing as little as they can do)