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CDC Multi-site Study - An interview with Beth Unger

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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

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

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: (Click here to watch video on YouTube)

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I just listened to the CDC's 25th Feb telephone conference call.

Beth Unger said that the exercise study will begin soon.

They are awaiting approval from a research ethics committee, and expect to get approval soon.


On a separate note, stage 3 of the CDC's project will include both homebound and newly diagnosed patients.
 
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Beth Unger has said that the cognitive tests for the CDC multi-site study have been planned in consultation with Dr Gudrun Lange*.

Dr Gudrun Lange gave a talk on the CDC's 25th Feb telephone conference call.

I was very impressed by her talk, and so I hope her knowledge is reflected in the cognitive tests that the CDC use.

Lange mentioned that, in cognitive tests, ME/CFS patients are accurate but slower.
And she said that complex tasks show most difference from controls:
ME/CFS patients have difficulty with complex information processing and multi-tasking.

In a swipe at those who dismiss ME/CFS patients' cognitive problems, Lange said that ME/CFS patients do not amplify their cognitive problems (i.e. they do not invent them), but they have cognitive problems that may not be picked up by simple tests that do not test complex cognitive functioning.


This is exactly how I understand the nature of ME patients' cognitive function, from research studies that I've read.
i.e. for simple tasks our tests results can be normal, but differences show up on complex processing tasks, specifically processing speed during complex tasks.


* Gudrun Lange, Ph.D.
- Consultant Clinical Neuropsychologist, Pain and Fatigue Study Center, Beth Israel Medical Center, NY, NY.
- Professor, Department of Physical Medicine and Rehabilitation Rutgers University.
 
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Beth Unger has said that the cognitive tests for the CDC multi-site study have been planned in consultation with Dr Gudrun Lange*.

Gudrun Lange gave a talk on the CDC's 25th Feb telephone conference call.

I was very impressed by her talk, and so I hope her knowledge is reflected in the cognitive tests that the CDC use.

Lange mentioned that, in cognitive tests, ME/CFS patients are accurate but slower.
And she said that complex tasks show most difference from controls:
ME/CFS patients have difficulty with complex information processing and multi-tasking.
In an attack on those who dismiss ME/CFS patients' cognitive problems, Lange said that ME/CFS patients do not amplify their cognitive problems (i.e. they do not invent them), but they have cognitive problems that may not be picked up by simple tests that do not test complex cognitive functioning.


This is exactly how I understand the nature of ME patients' cognitive function, from research studies that I've read.
i.e. for simple tasks our tests results can be normal, but differences show up on complex processing tasks, specifically processing speed during complex tasks.


* Gudrun Lange, Ph.D.
Consultant Clinical Neuropsychologist, Pain and Fatigue Study Center, Beth Israel Medical Center, NY, NY.
Professor, Department of Physical Medicine and Rehabilitation Rutgers University.

Simon wrote a great article about the evidence on cognitive function in ME/CFS last year:
http://phoenixrising.me/archives/16688
 
Beth Unger has said that the cognitive tests for the CDC multi-site study have been planned in consultation with Dr Gudrun Lange*.

Dr Gudrun Lange gave a talk on the CDC's 25th Feb telephone conference call.

I was very impressed by her talk, and so I hope her knowledge is reflected in the cognitive tests that the CDC use.

Lange mentioned that, in cognitive tests, ME/CFS patients are accurate but slower.
And she said that complex tasks show most difference from controls:
ME/CFS patients have difficulty with complex information processing and multi-tasking.

In a swipe at those who dismiss ME/CFS patients' cognitive problems, Lange said that ME/CFS patients do not amplify their cognitive problems (i.e. they do not invent them), but they have cognitive problems that may not be picked up by simple tests that do not test complex cognitive functioning.


This is exactly how I understand the nature of ME patients' cognitive function, from research studies that I've read.
i.e. for simple tasks our tests results can be normal, but differences show up on complex processing tasks, specifically processing speed during complex tasks.


* Gudrun Lange, Ph.D.
Consultant Clinical Neuropsychologist, Pain and Fatigue Study Center, Beth Israel Medical Center, NY, NY.
Professor, Department of Physical Medicine and Rehabilitation Rutgers University.
Dont suppose anyone has a recording of this call? I was late, and it wouldn't let me in!
 
hi I've some questions:
*will Dr Lipkin do actual stomach muscle biopsies for this study?
*which criteria does it use to determine 'me/cfs' patients?
*it looks increasingly like the me community will have to self fund such studies but is there a more effective way of finding out about them as opposed to ill people having to go onto this site? There's nothing wrong with that in principle but many people just can't and no one I know with ME knows about this as they're too ill too actually expend scant energy as look stuff up. eg. is there a emailing system where the latest research appeals come to you? Maybe emails to all the a few people in the local support groups across the world who may be able to tell others in the group eg. via newsletters and email. It could be given a name like 'local support group information (or something better what with brain fog) . I've only found out about this by looking this up and I can't (or shouldn't) do that so often .. This way we'd maximise the money raised.
thanks for any info' out there
 
hi I've some questions:
*will Dr Lipkin do actual stomach muscle biopsies for this study?
*which criteria does it use to determine 'me/cfs' patients?
*it looks increasingly like the me community will have to self fund such studies but is there a more effective way of finding out about them as opposed to ill people having to go onto this site? There's nothing wrong with that in principle but many people just can't and no one I know with ME knows about this as they're too ill too actually expend scant energy as look stuff up. eg. is there a emailing system where the latest research appeals come to you? Maybe emails to all the a few people in the local support groups across the world who may be able to tell others in the group eg. via newsletters and email. It could be given a name like 'local support group information (or something better what with brain fog) . I've only found out about this by looking this up and I can't (or shouldn't) do that so often .. This way we'd maximise the money raised.
thanks for any info' out there
Hi shahida, and a very big welcome to the forum. :)

You've posted your message on a thread about the CDC's program, but you seem to be asking about Dr Lipkin's research.

If you're responding to a recent article about Dr Lipkin's proposed microbiome study, it would be best to post a comment on that thread.

If you'd like me to copy your questions over to the appropriate thread, then please let me know.

This is the recent article about Dr Ian Lipkin and the fundraising project:
http://forums.phoenixrising.me/inde...robiome-crowdfunding-campaign-launches.29252/
 
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Hi shahida, and a very big welcome to the forum. :)

You've posted your message on a thread about the CDC's program, but you seem to be asking about Dr Lipkin's research.

If you're responding to a recent article about Dr Lipkin's proposed microbiome study, it would be best to post a comment on that thread.

If you'd like me to copy your questions over to the appropriate thread, then please let me know.

This is the recent article about Dr Ian Lipkin and the fundraising project:
http://forums.phoenixrising.me/inde...robiome-crowdfunding-campaign-launches.29252/
yes thanks Bob it would be great if you could do that. My brain really can't handle computers well-sites are so 'busy'. my apologies but I'm sure you understand....
 
Simmaron Research has published a new blog on its website by Cort Johnson about the CDC's multi-site study. I don't think there's any new information in it.

Going Grassroots: Dr. Unger on the CDC’s Chronic Fatigue Syndrome Multisite Studies
Cort Johnson
November 8, 2014

http://simmaronresearch.com/2014/11...s-chronic-fatigue-syndrome-multisite-studies/

(If anyone wants to start a new thread about it then please do.)
 
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Dr Beth Unger refuses to remove the CDC's outdated "toolkit", and she has refused to recognize the CCC definition of CFIDS. Maybe if they did one of these two things, the CDC could be taken seriously.