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 


  1. Thank you Mary for such a wonderful concise letter that sums up the concerns of our community. Well written and easy to understand. And has just the right balance in terms of tone.

  2. Actually the blog was not by Sanjay Gupta. I hope patients are more involved.

    I would like to point out though, that this study is looking more deeply in the immune systems of ME/CFS patients than any to date, and that it is being lead by the NIH's expert on the effects of infection on the nervous system and the subject of most of this blog, Brian Walitt, is mostly a coordinator and is not doing any of the research.

    To even suggest that this study - which is not investigating somatoform illness IN ANY MANNER - and which is devoted to investigating the effects of infection on the immune system, brain, metabolic systems and autonomic nervous system - is going to drag patients back to "square one" is ludicrous.

    I'm sorry to use such an inflammatory term but the idea that it could do that is unfair, inaccurate and not at all helpful...

    Mary knows that the NIH has stated that the CCC criteria is going to be used. She knows that the NIH stated that the Reeves criteria are going to be used for their questionnaires only. She knows that most of the patients are going to come from ME/CFS experts in the multisite study. She knows the patients are going to have to have infectious onset....

    It doesn't seem to make any difference.

    I don't get it..

    1. This comment has been removed by the author.

    2. Sorry you don't get it, Cort.

      Please understand how frustrating I find this. I believe Dr. Collins when he says he wants to do a good in-house study on ME/CFS. We are lucky to have someone of the caliber of Dr. Nath involved in the project. However, any research program is only as good as each component - and the data set is a very important component.

      The issue here is that there will only be 40 patients, and according to NIH, the Lead Associate Investigator will have a say in who those patients are. "The Lead Associate Investigator (LAI) will ... work with the CDC and the NIH ME/CFS executive committee to coordinate screening of potential participants for the study."

      Dr. Unger has said that they will include the Georgia study patients (diagnosed using Reeves) in the multisite study, which already concerned me. I am now further concerned that the cited article discussed the Reeves Definition without calling it the Reeves Definition. That unfortunately leaves us in the position of needing them to say specifically that THE QUESTIONNAIRES FORMERLY CALLED THE REEVES DEFINITION will not be used in the NIH study - which is indeed ridiculous, but there it is. Unger is another who will have final say in which patients are accepted for the study.

      I have taught statistics on the graduate level. I am deeply concerned that there will only be 40 patients. If any of those 40 patients do not actually have ME/CFS, it will only make matters worse.

      We have previously been in a situation where the people in charge of our disease at NIAID - including Dr. Fauci, head of NIAID since 1983 - were convinced it was psychosomatic (despite none of them having any training in psychiatry). My mother (then about 75), took me in my wheelchair took me to the first CFSCC meeting. Reeves started his presentation with a joke - he said "I'm going to make Tom Hennessy really happy - I'm going to say CFS is caused by a virus. [pause for effect] No I'm not. It's not caused by a virus." My mother whispered to me, "Did he just make a joke at the expense of a patient?" Yes, Mom, shh. Then she looked at the program. "Who's speaking," she asked. Dr. Reeves from CDC. "But it says here that he is in the Division of Viruses and Exanthums." Yep. "If he doesn't think it's caused by a virus, why is he still in charge of it?" BINGO! My 75-year-old Mom figured out in about 30 seconds what was wrong with that picture.

      Mom's 94 now - but I bet she'd figure out in 30 seconds what's wrong with this one, too.

    3. What a great and clear explanation about what is happening here, Mary. I have CFS, Sjögren and Endometriosis and of course there are biological causes. I feel insulted by these doctors that probably are more interested in their prestigious career than helping the patients.

  3. Mary, please do you have more info about this -

    "Dr. Unger has said that they will include the Georgia study patients (diagnosed using Reeves) in the multisite study"

  4. This was at (I think) the first - or only - public IOM meeting. She described the multisite study, and said that they are having trouble getting enough patients, but that's okay because they'll just fill in with Georgia patients. That's paraphrased, but I know she said it because I did a double-take.

  5. Thanks, Mary - this is a brilliant letter.

  6. This comment has been removed by a blog administrator.

    1. I'm sorry - advertisements are not permitted on this website. I had to delete your post.

  7. Hello Mary, I will be sad if you back out of you know where. I will email you directly. Barbara

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