Thursday, March 17, 2016

Open Letter to Dr. Sanjay Gupta on In-House NIH Study of ME/CFS

The following is a response to Dr. Sanjay Gupta's blog on the upcoming in-house NIH study on ME/CFS, which can be found at this site:  Medpage Today

Thank you for highlighting the first in-house study on patients with ME/CFS in two decades.

Over one million American adults suffer from ME/CFS.  A quarter of a century (28 years) after CDC adopted the dismissive name "chronic fatigue syndrome," 85% of these - that's 850,000 people - have no diagnosis.  CDC has long advocated treatments recommended by British psychiatrists of the so-called "biopsychosocial school."  The British psychiatrists argue that the patients perhaps once had a disease, but they became afraid of acting normal.  They are left with deconditioned bodies, which makes them look sick and contributes to what are called "false illness beliefs."  Thus they recommend Cognitive Behavior Therapy (CBT) not as it would normally be used - to help the patient adjust to having a chronic illness - but instead to address "false illness beliefs" and teach the patient she does not need to stay inactive; that goes hand-in-hand with a reconditioning program called Graded Exercise Therapy to return the patient to normal.  The combination is generally called CBT/GET.

It is important to note that these psychiatrists are quick to say that just because they call the disease "neurasthenia," they do not mean to say it is wholly psychiatric.  They say our criticism of their insistence that ME/CFS is a somatoform disease is due to prejudice against psychiatry, and a false adherence to "Cartesian mind-body dualism."  That is actually not true.  The criticism of their theory rests on their assumption that the patient suffers from MUS's (Medically Unexplained Symptoms); the criticism of CBT/GET is even simpler - it is due to evidence that neither helps patients, and graded exercise actually makes them worse.

For years, however, these psychiatrists have successfully deflected criticism of their work by instead criticizing their doubters.  In 2007 they were awarded a £6 million ($8 million) grant to prove, once and for all, whether the diagnosis and treatment they and NHS has been using for 2 decades is the best available.  The study was published in Lancet in 2011.  There were numerous problems with the study (for example, objective markers were dropped halfway through the study, and the goals for patients were actually changed mid-study).  Advocates have asked to see the anonymized raw data, but the principle investigators have refused, labeling these requests "vexatious." 

Recently Berkeley journalism and public health professor David Tuller published a series of articles on the problems in the PACE trials, on the highly-regarded blog site of Columbia University virologist Vince Racaniello.  Tuller and a group of scientists have asked to see the anonymized data.  This time they weren't told their request was vexatious (Dr. James Coyne, an open-data advocate from outside the ME/CFS community, was).  Instead, they were told they could not access the data because it would not be fair to the patients.  That's an odd response - they've already shared the data with the Cochrane Review (although the Cochrane Review study authors included one of the PACE study PI's), so one would think it has already been anonymized.  At any rate, one would think they know how to anonymize data sets - or no study involving clinical trials could ever be published!  Requests are making their way through the appeals process.  The Coyne request is more complicated - it is not a FOIA request; rather, Dr. Coyne is on the editorial board of PLOSOne, a series of e-journals that require authors to share data.  It is in that context that Dr. Coyne has asked for anonymized data from the study - and in that context he was told his request was vexatious.  Stay tuned - the PACE controversy is far from over.

The Tuller articles can be accessed online beginning here:  PACE: Trial by Error - Coyne's blog critiquing the PACE study can be found here: Uninterpretable: Fatal flaws in PACE .

It is odd that NIH would not be aware of the controversies surrounding the PACE study, particularly given that both CDC and NIH have frequently taken the advice of psychiatrists involved in the study, such as Peter White, Michael Sharpe, and Simon Wessely (the latter is not an author but was a participant).    for example, psychiatrist Peter White, who has been Chief Medical Officer of Scottish Provident Insurance Company and continues to advise Swiss RE, a multinational re-insurance company, led the 2009 evaluation of CDC's program on CFS. 

This position - that the disease is really a form of somatoform disorder - has haunted patients with our disease for 3 decades.  The authors do not recognize the large body of literature on physical abnormalities in patients.  Many of the studies on biomedical markers and evidence are small sample because it is next to impossible to get funding from NIH for this disease - at most, NIH has allocated $6 million/year for one million patients, roughly one percent of what they give to Multiple Sclerosis, itself hardly an overfunded disease.  So it becomes a tautology - no funding because there is no large-sample evidence of biomedical abnormalities; no large samples because there is no funding.

The choice of name - "chronic fatigue syndrome" - coupled with publicity about the disease being cured by "cognitive behavior therapy" and "graded exercise" and statements to the press that it is actually a somatoform disorder (what the public calls psychosomatic) - has led to mistreatment and  lack of any treatment at all even for the minority of patients who have a diagnosis.  Patients have also found themselves the butt of jokes because of the name - recently the cartoon strip Blondie took a pot-shot at patients for the latest name for the disease, SEID (Systemic Exertion Intolerance Disease)

I have gone through this rather lengthy detour because I wanted to be sure that you understood the patients' concerns about Dr. Walitt, who has been designated Lead Associate Investigator on this study.  This is the quote from the article cited on your blog that concerns us:  

"The discordance between the severity of subjective experience and that of objective impairment is the hallmark of somatoform illnesses, such as fibromyalgia and chronic fatigue syndrome."  

That article was published last year.

We know that the British psychiatrists who promote "CFS/ME" as a somatoform disorder will say exactly what Dr. Walitt said - that the only reason we are disturbed by the diagnosis is that we believe in the false Cartesian dichotomy of mind and body.  Walitt's defense for having so casually labelled CFS a "somatoform" illness was an oblique remark about the head being connected to the body.  Please forgive us if that sets off alarm bells.  And no, claiming to have found a biological cause for somatoform disorders does not alleviate our concerns. 

For three decades patients with this disease have endured the stigma of the name - chronic fatigue syndrome (chronic as in chronic complainer, fatigue as in "Yeah, I feel tired lately myself," and syndrome as in syndrome of the month), and the presumption of the disease being  - in the vernacular - psychosomatic.  We are not prejudiced against psychiatry.  But we are no happier being told our disease is psychiatric in nature than you would be if told your hot appendix was due to faulty thinking.  The entire thesis of these psychiatrists rest on the belief that patients' symptoms fall in the category of MUS's (Medically Unexplained Symptoms), and therefore when patients insist their disease is biomedical in nature, they are exhibiting false illness beliefs.  These psychiatrists have published articles claiming the disease is somatoform in nature without bothering to respond to the actual biomedical literature on this disease - indeed, if all you read was the psychiatric literature on this disease, you would not know that there is peer-reviewed published research on biomedical factors behind the symptoms.  Let me suggest this recent article from DePaul psychologist Leonard Jason summing up the current state of the literature on various symptoms of the disease:

Indeed, the Institute of Medicine of the National Academy of the Sciences stated firmly that the evidence on biomedical abnormalities in this disease is so strong that no one should look at it as psychiatric any more.  You can find their report (and less lengthy material) here:

We are encouraged by Dr. Collins' interest in the disease, and the plans Dr. Nath has for the study are exciting.  However, given they are only going to look at 40 patients, we are very concerned about the possibility of bias in patient selection.  Early on we were told (apparently by accident) that the Reeves definition (2003) was going to be used.  This definition - actually a set of questionnaires - is wholly unacceptable.  It is modeled on the questionnaires used by the British psychiatrists, and a study has already shown that a cohort chosen using these questionnaires brings in patients with anxiety and depression instead of ME or CFS at the same time it fails to identify the most severely afflicted ME/CFS patients.  It is very telling that independent researchers have ignored the Reeves definition completely.  In that context, we find it concerning that CDC has just published an article on the Georgia cohort (diagnosed using the Reeves criteria) where they discuss the questionnaires without once mentioning Reeves' name - that is, without informing the reader that these questionnaires are precisely the ones created by the late Bill Reeves at CDC that have been called the "Reeves definition."  The unexpected sleight of hand has us concerned that the Reeves definition will be used by simply not calling it the Reeves definition.  It will help for them to then diagnose the patients using the Canadian Consensus Criteria, but having used the old Reeves definition as a filter risks deeply biasing the selection process.  With only 40 patients in the study, we are baffled that they would even take a chance on inserting these biases (Reeves questionnaires and Walitt's belief that the disease is somatoform in nature) into the project.

Over the past 30 years there have been numerous breaches of faith with patients.  CDC was even chastised by Congress in 1999 for diverting the paltry funds allocated to study CFS to a different disease entirely.  In the meantime, more patients come down with the disease every year, and very few fully recover. 

Despite the name, CFS is not characterized by "fatigue."  (You might want to fix the headline to your article, which referred only to "chronic fatigue.")  The identifying features of ME/CFS are post-exertional worsening of symptoms (as measured in two consecutive days of CPET studies), and significant cognitive dysfunction.

Many patients have already been shown to have significant immune defects - abnormally low natural killer cell function, abnormal cytokine patterns, and the abnormal 37kDa Rnase-L defect.  Many patients have been shown to be battling chronic viral infections, particularly the beta herpesviruses (CMV, HHV-6A, and HHV-7) and EBV (mono).  Others have Coxsackie B (an enterovirus) and/or adenoviruses.  To drag the medical community back to square one, when the disease was labeled a somatoform disorder, is extremely distressing.  Dr. Walitt may believe that somatoform diseases have a physical explanation (abnormal cytokines in the brain) - but he is still saying they are somatoform diseases.  

This is the first NIH study in 20 years on a disease that impacts one million adult Americans.  The first study on a disease that leaves 500,000 Americans completely unable to earn a living.  The first study on a disease that can attack teenagers and leave them disabled in their 40s.  There are patients who were never able to go to college, never able to date or marry, never able to have children, never able to have a career, and they live in fear of losing their parents as they age because they need a caregiver.  The first study on a disease that has killed patients from specific causes such as myocarditis (when the viruses get into the heart muscle), cancer, and general system failure.  The first study of a disease that has led to far too many suicides, because no one in the medical profession has been there for the patient, and the government has offered no hope of a better future.

Given that NIH is only using 40 patients because, they say, that is all they have the funds for, given the severity and prevalence of the disease, and given everything patients have been put through, I do not think it is too much to ask to dispense with the services of Dr. Walitt - someone who only last year breezily declared CFS a somatoform illness.  I do not think it is too much to ask of CDC that they not rebrand the Reeves questionnaires to sneak the Reeves definition back into the study. 

I do not think it is asking too much to have just one community-recognized ME/CFS specialist (perhaps Dr. Jason) on the ME/CFS expert committee. 

And I do not think patients are asking too much to be involved in the decision-making process. 

Thank you for your time and interest, Dr. Gupta.  I hope that you take our concerns seriously.  See also my open letter to Drs. Collins and Nath:  An Open Letter to Dr. Collins and Dr. Nath 

Friday, March 4, 2016

An Open Letter to Dr. Collins and Dr. Nath on the NIH internal ME/CFS study

Note: As of Sunday, March 6, NIH has dropped the somatoform comparison group.  Thank heavens!  But they are still looking for "the underlying physiology of fatigue."  So I still wish they would spend as much time learning about M.E. as they have spent deciding on the [admittedly admirable] lineup of tests.

Dear Dr. Collins and Dr. Nath:
I echo the sentiments of many ME/CFS patients in expressing concerns about the way the in-house NIH study on ME/CFS is proceeding.
The stated hypothesis of this new study is that: post-infectious ME/CFS is triggered by a viral illness that results in immune-mediated brain dysfunction."  Is that really all there is to the hypothesis?  Dr. Wallit's participation raises troubling questions as to whether that is so.  The comparison groups chosen for this study also suggest there is more to the hypothesis than we have been told.  
I beg you, Drs. Collins and Nath, please rethink the hypothesis - and Dr. Walitt's role in this study. I also ask you to rethink the comparison groups. This disease has been a serious problem in the US for 30 years, and for 30 years both NIH and CDC have obstructed the creation of a strong biomedical research community – nevertheless, it has existed. 
What has happened here?  A hypothesis created by people who know next to nothing about this disease is being plonked on top of us. If I may say so, yet again.  Why?
Make no mistake about it, fellow patients: Dr. Walitt is playing with somatoform diseases here – he just thinks there’s a biological cause for them. 
He seems insulted that we might be unhappy about his inclusion.  All I can say is that anybody who uses the words "chronic fatigue syndrome," "fibromyalgia," and "somatoform illnesses" in the same sentence is unacceptable in a preliminary study of my disease sponsored by NIH.  
Last March Dr. Walitt published an article containing the following sentence:  "The discordance between the severity of subjective experience and that of objective impairment is the hallmark of somatoform illnesses, such as fibromyalgia and chronic fatigue syndrome. " (Chemobrain: a critical review and causal hypothesis )
I really do not care if Dr. Wallit is looking for a physiological cause for what are called "somatoform" illnesses.  The problem is that he thinks ME/CFS is a somatoform illness.
Then there are the comparison groups.  Where did these come from?  Two comparison groups:  post-symptomatic Lyme Disease patients, and patients with physical somatic disorders.  The choices of comparison groups themselves suggest that the research hypothesis for this project has not been fully revealed to patients.
With only enough money to put 40 ME/CFS patients in the study, may I ask why we are bothering with comparison groups at all?  Does it not make more sense to do this first study with ME/CFS patients v. controls - and then use more ME/CFS patients?  
Since 1998 I have known that i had the defective 37kDa Rnase-L and a severe case of HHV-6A. Later testing showed natural killer cell dysfunction (in my case, a natural killer cell function of 2-3%) and abnormal cytokine patterns. In 2009, Dr. Dan Peterson found active HHV-6A and CMV in my spinal fluid. Do you think that my serious encephalitic and neurological symptoms could have had something to do with that evidence? The immune defects and viruses go away on Ampligen and come back 7-12 months off it. I am a sample of 1, but there are more like me. Many more. We have patients improving on the antiviral Vistide at Dr. Peterson's (I cannot take Vistide; my liver markers shoot up).  The late Martin Lerner had patients on both Vistide and another antiviral, Valcyte;  Dr. Jose Montoya at Stanford has had success with Valcyte as well.  
Please pay attention to this evidence.  Talk to clinician/researchers.  
If not – then please run that hypothesis past some non-psychiatric specialists in our field before running with it in the first NIH internal study on our disease since Straus discovered (to his dismay) that we have abnormally LOW levels of adrenaline (patients with major mood disorders tend to have abnormally HIGH levels of adrenaline) 20 years ago.  Dr. Straus had planned to be able to say we really had depression; hence his disappointment. (Psychiatists in the UK - and CDC's CFS group - finally found a use for Straus's adrenaline study in the unsupported hypothesis that patients had too many stressors earlier in life and had, in effect, run out of mechanisms to cope with them.  If that were true, wouldn't one expect to find this disease much more common in Kosovo, parts of Africa, and in the embattled mid-east?  Why hasn't it popped up in refugee communities internationally?)
Perhaps you could put this off until you can hold a workshop with recognized ME/CFS experts. I am confident we could pull one together quickly.
The well-respected British organization, Invest in ME , is holding a research conference May 3 in London.  I am certain they would include you if asked.  Another international research organization for this disease, IACFS/ME (International Association for CFS/ME) is meeting in Miami in October. Put this on a workshop there, or let them help you set up an earlier one. Or ask the public members of CFSAC to help you create a workshop. Ask any of us to help you create a workshop. You need to discuss the hypothesis and comparison groups with the longstanding biomedical ME/CFS community before committing to them. 
In the beginning of 2000, ignoring the existence of CFSCC, the late Stephen Straus of NIAID and CAM at NIH ran a "state of the science" meeting about "CFS" with the usual suspects (if you forgive my saying so) – the psychiatrists from the UK who have had an inordinate amount of influence on perceptions of this disease both abroad and within HHS. After pressure from Congress he relented to having ONE public member from CFSCC attend (Nancy Klimas). But Congress continued to ask for a more objective  conference. Donna Dean had just been placed as head of CFSCC, and she ran a conference the next fall that was fantastic – full of science and discussions with researchers who had previously known nothing about the disease. Unfortunately, there was a presidential shift in 2001 and CFSCC was shut down (to emerge, weakened, as CFSAC almost three years later). Dr. Dean left, and nothing happened again until 2011, when Dennis Mangan ran another excellent State of the Knowledge conference at NIH, which then came to naught. 
When researchers do not know the very long history of this disease (technically going back to atypical polio in 1934, but practically speaking, back 60 years to the Royal College outbreak and creation of the terms myalgic encephalomyelitis in the UK and epidemic neuromyesthenia in the US), they make blunders. They can be perfectly well-meaning, but this topic is a mine field and requires someone who knows the history to navigate it. I am discouraged that once again NIH is going off on its own, as if we were never here at all.
One last way to salvage this study.  Simply ditch the hypothesis and comparison groups and run it as a study of potential biomarkers in ME/CFS, without prejudging their meaning.
This is a very raw hypothesis. I love the scientific evidence you want to bring to bear, but I wish you were working on biomarkers for ME/CFS – not the physiological basis for "somatoform" illnesses.

Mary M. Schweitzer, Ph.D.