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.

The relationship of XMRV to CFS and M.E.

I know that the “hot” topic of the moment is whether XMRV or the gamma retroviruses in general can be transmitted by way of blood donation, but I would like to back off for a minute and survey the problem.

I happened to be watching “And the Band Played On” last night, and I noticed that they were looking at material from lymph nodes, not from blood draws, when they discovered HIV. That’s very interesting for those of us who suffer from M.E. (given the hopelessly dismissive name “chronic fatigue syndrome” by the U.S. CDC in 1988), because, at least for those of us in the U.S., tender lymph nodes are a major characteristic of the disease. Dr. David Bell once pointed out that patients with this disease can point to lymph nodes other people don’t even know they have.

Why are we not looking at lymph nodes instead of just blood serum?

It seems to me that the primary issue is whether or not up to a million Americans, sick with a disease that has been given a stupid name and garbage diagnosis by the CDC, actually are carrying a retrovirus or family of retroviruses. CDC has been “studying” this disease for 25 years, yet freely admits that 85% of patients – at least 850,000 people – have the disease but no diagnosis.

Research in France suggested that the disease pools in the lungs of patients – boy would THAT be bad news! Why are we not looking for it in sputum, then?

Understand that a retrovirus – ANY retrovirus – is going to be transmissible through blood and body tissue because it becomes part of your DNA, and eventually finds its way all over your body. A better question, perhaps, is whether the mechanisms that have been used to keep from transmitting HIV and HTLV will work with a different family of viruses, the gamma retroviruses, where XMRV fits.

We do not know much about how gamma retroviruses in humans. XMRV was the first one found, almost five years ago, in patients with a particularly virulent form of prostate cancer). However, there is a lot of research into gamma retrovirus behavior in the animal world. So that part of it should not be that difficult.

In contrast, finding consistent and homogeneous data sets of patients with M.E. among those diagnosed with CFS the way recommended by CDC (by first starting with people who are fatigued, and then eliminating any possible physical cause), cannot be done without acknowledge the failure of the CDC approach.

Now I come to Exhibit A – me, moi-meme, I.

I was in the Lombardi et al study in “Science” (October 9, 2009), and I was positive for XMRV. Hmm, I thought, that’s interesting.

Interesting but not, for me, earth-shattering, because I already had plenty of abnormal test results and viruses! I have been the patient of two excellent specialists on this disease – Dr. Marsha Wallace of Washington, DC (who no longer practices), and Dr. Dan Peterson of Incline Village, NV, who has been treating patients with this disease and participating in research studies about it, since a major cluster outbreak occurred in the Tahoe-Truckee area, or North Lake Tahoe, where Incline Village is situated, in 1984-85. They knew I had what the cluster outbreak patients had, and every biomarker, every chronically activated virus, was another step in understanding what has caused these outbreaks.

I personally believe I was caught up in an outbreak centered on Cherry Hill, NJ, an area that contributed a large share of the students at Villanova University outside Philadelphia, where there was an outbreak of Epstein-Barr in 1990 that swept up not only students, but faculty as well, including two other members of my department besides me. My full collapse did not occur until later; I have often wondered if the information that was censored or dismissed in the late 1980s and early 1990s might have spared my transition into the hellish state of progressive M.E. on October 24, 1994.

More to the point, however, is that if anybody has what the CDC calls CFS, I do. (For the record, I do not have what the British psychiatrists call "CFS.") Let’s go back over some of what I test positive for besides CFS, shall we? (This is testing done most recently in 2008 and 2009, when I was in relapse off the experimental immune modulator Ampligen. I have been back on Ampligen for ten months, and many of these tests have better results now.)

1. Immune biomarkers: 37kDa Rnase-L, a natural killer cell function of 3%, and abnormal cytokine counts.

2. Active viruses (some even active in my spinal fluid): recurring EBV (comes and goes – the rest are active all the time off medication); HHV-6 Variant A; HHV-7; cytomegalovirus; and three strains of Coxsackie B.

3. Abnormal SPECT scan and very abnormal VO2 MAX scores.

4. Abnormal Holter Monitor test and abnormal 24-hour BP/pulse test; diagnosed NMH/POTS

5. Hashimoto’s thyroiditis; hypothyroidism apparently caused by an inability to convert T4 to T3 (I take supplemental thyroid medication to keep my T7 panel normal).

6. Major symptoms: Severe pain behind my eyes and in the back of my neck 24/7, plus frequently occurring severe headaches. Photophobia, sensitivity to loud noises, tinnitus, parathesias, severe muscle weakness (to the point of collapsing to the floor), ataxia, blackouts, expressive dysphasia, central auditory processing (CAP) difficulties, dyslexia, dysgraphia, loss of volition (what I would call "the pause," as if someone had punched the pause button on my control panel), and profound confusion.

7. Other diagnosed related symptoms: inexplicable difficulty falling and staying asleep, myofascial pain syndrome, dropped left foot (that clears up on medication – I have no idea why), inability to pass a Romberg test.

See? XMRV was, well, okay, something new. And I find the research on both XMRV and the gammaretroviruses convincing, but then, I am not a scientist (although I can read statistics – and know how to put together a data set and how to evaluate one put together by someone else).

It is extremely important that while the light is shining on retroviruses, we not forget these other problems represented in one case – me – and that I share these viruses and biomarkers with a large number of my fellow patients (those who have had the money to get the tests, because by and large you have to pay cash for them, as I also have to pay cash for the treatment – the CDC is doing a tremendous job for the insurance industry). I have friends with infections I don’t have as yet – parvovirus, Lyme, mycoplasma, clamydia pneumonae. That we know of. And I have some things my friends don’t have.

We also have lost people to myocarditis (infection of the heart muscle), rare cancers such as stem cell cancer, and sometimes, just too many things wrong at the same time.

By and large this is a disease of immune defects, multiple infectious assaults, and resulting damage to the neurological, endocrine, cardiac, and biomechanic mechanisms.

The disease bears a resemblance to MS not only in symptoms, but also in having different flavors. I know patients who were sick in late adolescence, recovered completely, then relapsed again in their late 30s or 40s. I know patients who thought they had recovered until they started training for a marathon (one was a navy SEAL), which then threw them into a total bedridden state. I know patients who got very sick, got a bit better, and plateaued – have remained at that level, not well but not as sick as they originally were.

And then there are the people that call themselves “25-percenters” in the UK, because the best guesstimate would be that 25% of patients with M.E. have this disease in a progressive form that just keeps getting worse, and worse, and worse, leading eventually to a premature death. I believe I was a 25-percenter myself, saved from a lifetime in a one-person horror show by access to Ampligen. (I do not mean this to be an advertisement for Ampligen; I happen to respond unusually well to the drug. However, that should say something about both the drug and the patient, should it not?)

I have gone off Ampligen twice – the first time, after being on it 20 months and paying roughly $40,000 for the privilege (my parents helped my husband out with other bills), I thought I was cured. I had a wonderful year, which some of us call the “Ampligen honeymoon.” And then, at Cal Ripken’s last baseball game, October 6, 2001, I blacked out. When I came to, I was back in M.E.-land again, full throttle. The next day I had forgotten, and when I sleepily tried to get out of bed, I crumpled to the ground. Oh. That again. I could not get tested for the Rnase-L defect, but HHV-6 was back in spades.

It took seven months to get back into an Ampligen program, this time at Hahnemann Hospital in Philadelphia, about an hour from my home and accessible by train if I did not feel like driving. Once back on it, I swore I would not go off. The costs (including co-pays and testing not covered by insurance) was now down to about $20,000 a year, precisely my after-tax disability income. Our children were grown. We lived on Bob’s income.

But in January 2008, the head of my practice in Philadelphia died. Though he was not my doctor, he was technically the principle investigator on my “study.” In February I was informed that I could no longer receive Ampligen at Hahnemann. To my knowledge, no other Phase III patients (most of whom were patients with severe cancers) were cut off. They reapplied twice, but were denied.

In September 2008, I relapsed. And in the ensuing months, we did the testing that I listed earlier in this (increasingly long!) missive.

So there you have it. I have been back on Ampligen now for ten months. I can read again, I can drive a car, I can walk along Lake Tahoe, and all the symptoms I associate with encephalitis and meningitis – that is, encephalomyelitis – are gone. But I still suffer from pain, and stamina is still a major problem. My VO2 MAX scores remain abysmal. Unfortunately, since this drug is delivered by twice-weekly infusions, I am forcibly separated from my husband of 35 years, which to me is a terrible hardship. But then I see so many others with my disease who have suffered more, and I think I should not say much about being so homesick, about missing my dearest husband so much. After all, Lake Tahoe is not such a bad place to be marooned.

I’m just one case. Okay. But I will close with something an economist once said:

Anecdote is the singular of data.

I’m just one case, among many. When will we study the other aspects of my disease, of our disease? What else do we already know about M.E. (or “CFS”)? How many desperately ill people are out there, undiagnosed, untreated and confused? When I walked to Hahnemann on cold days, I would pass homeless persons huddled over heating ducts, and I would wonder how many of them had my disease.

There are one million people with some aspect of my disease, and 850,000 have no diagnosis. Of those who are diagnosed, only a handful are getting treatment. Where are the rest?

Where are the rest?