A Primer for XMRV and XAND

On October 9, 2009, an article was published by Judy Mikovits et al in the highly prestigious research journal Science announcing the findings that a newly discovered retrovirus, called XMRV, had been found in 67 percent of a sample of patients diagnosed with CFS over a period of 25 years. There are only 3 known human retroviruses: HTLV, HIV (which leads to AIDS), and now XMRV. The importance of this finding cannot be overstated. The Cleveland Clinic had already found XMRV in roughly 10 percent of prostate cancer patients, but the more startling news had been that it was present in 3.4 percent of controls. That was too high. So they began to look for other possible roles this virus played.

The new Whittemore-Peterson Institute, or WPI, combined resources with the Cleveland Clinic and the National Cancer Institute (one of the National Institutes of Health, or NIH) to arrive at this startling conclusion. Mikovits is Research Director of the WPI, a private research institute created four years ago in association with the University of Nevada at Reno.

Here is a quick primer for those who have been diagnosed with CFS or M.E., and the many who have XMRV but have yet to be diagnosed. I am a social scientist, not a hard scientist, so keep in mind my viewpoint is that of the lay public. I will add more information and sources over time, but right now this basic primer should be of help.

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XMRV is not CFS

XMRV cannot be CFS because CFS means too many different things in the realms of medicine, research, and popular culture. Formally, CFS is what we call a "socially constructed concept."

For example:
According to British psychiatrist Peter White, CFS is a condition of unexplained symptoms that results from "inappropriate illness beliefs." It is best treated with Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET). And this is pretty much the version of CFS that has been adopted by Britain’s National Health Services and their "NICE" medical guidelines.

Patients diagnosed by White and other British psychiatrists as having CFS cannot have any physical explanations for their symptoms. Therefore they cannot have XMRV.

Another way of putting that is: the moment a patient diagnosed in the UK with “CFS” is diagnosed with XMRV, he or she is suddenly free of the interim diagnosis of CFS. By the British medical establishment’s own rules. That means that any statement by “CFS” experts in Britain such as Peter White, Trudy Chalder, Michael Sharpe, or Simon Wessely, with regard to XMRV, is out of their field of expertise – they are all psychiatrists.

The U.S. CDC has several definitions for CFS, but the one in current use in their current study of a group of patients in Georgia does not permit any significant physical symptoms. If those patients have XMRV, then it’s a pretty vapid retrovirus!

It is no wonder that the head of the CDC’s program on CFS for the past twenty years, Dr. William Reeves, immediately responded that none of the CFS patients in his big, new Atlanta-area study would have the virus. "Dr. William C. Reeves, who directs the agency’s research on the syndrome, has said that he does not expect to find the virus in blood samples from patients. He said that no other studies had ever proved a virus to be the cause, and that stress and a history of sexual and emotional abuse were more likely to play a role in many cases." (See ”A Big Splash from an Upstart Medical Center,” New York Times, 11 November 2009).

I agree. Few of Dr. Reeves' patients will turn out to have XMRV. That is because for twenty years he has been studying “fatiguing illnesses” – not anything to do with the immune defects and viruses that caused cluster outbreaks of disease all over the United States. The patients he studies are not the ones from the cluster outbreaks, and if he tripped over one, he wouldn’t know what diagnosis to give them.

When Dr. Mikovits found that 95% of CFS patients from a large selection of practices in the U.S. had XMRV, it was a result that will not be replicated by the U.S. CDC using its own data sets of “CFS” patients. Because all over the world, CFS has been redefined as a disease of “fatigue,” and patients so diagnosed have nothing to do with the original cluster outbreak patients for which the name was created. We patients and our doctors have known this for a long time.

At the first CDC-sponsored conference to come up with a name for the new disease, several experts present suggested that these were outbreaks of Myalgic Encephalomyelitis, a neurological disease that has been diagnosed for over half a century in the UK, and has been coded under neurology by the World Health Organization for forty years. The disease is characterized by significant central nervous system (CNS) dysfunction, brain dysfunction, and muscle pain (myalgia). But the CDC rejected that name, too, because there was no evidence of inflammation, they said. They did not include a reference – not even a footnote – to the possibility that “CFS” was actually “M.E.” in the 1988 Holmes article. The link was not made until British psychiatrists, acting in concert with Dr. Straus of NIH, used it backwards: M.E. was really CFS, and CFS was really neurasthenia – a neurosis.

For years the CDC and NIH have brushed off all evidence that subgroups of the total set of people with a “CFS” diagnosis have very specific immune defects and active viruses, because it wasn’t true for all of them. Well, now that doesn’t matter, does it?

Finally, XMRV cannot be the same thing as CFS because it was first discovered among victims of prostate cancer – apparently at least 10 percent have XMRV. Unless prostate cancer is considered a form of CFS (to my knowledge it is not), then XMRV cannot be CFS.

XMRV is not CFS.

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XMRV is a Retrovirus

Viruses fall into classifications. Polio is an enterovirus. Epstein-Barr is a herpes virus. XMRV is a retrovirus. And there are categories within categories. Human Herpesvirus 1 (HHV-1), or herpes simplex virus, causes cold sores. And that’s about it. But HHV-8 causes Karposi’s sarcoma in AIDS patients – and kills them. None of the viruses just mentioned have anything to do with what we know as “the cold.”

What makes this discovery so profound is there are only three retroviruses known to be active in humans: HTLV, HIV – and now XMRV.

Unlike other viruses, XMRV attaches itself to you DNA - becomes part of your DNA. It is with you forever, in a very different way than other viruses.

Retroviruses cause problems by creating an environment for other viruses to flourish and even transform themselves into something new. Above all, they cause immune dysfunction.

Let’s look at HIV, then.

HIV is important because it either causes, or is so close to the cause as to be indistinguishable for practical purposes, AIDS. In fact, the name was chosen to refer to AIDS – Human Immunodeficiency Virus – HIV.

AIDS itself means Acquired Immune Dysfunction Syndrome. Ironically, when the CFS outbreak first occurred – in the middle of the AIDS outbreak – many patients on both Coasts called the disease HIV-negative AIDS. Quite a comedown in how you perceive the disease from HIV-negative AIDS to “chronic fatigue syndrome,” isn’t it? Many patients still refer to the disease as CFIDS – Chronic Fatigue and Immune Dysfunction Syndrome. But from the first article and definition (Holmes, 1988) from CDC, the agency has insisted that they were studying Epstein-Barr negative mononucleosis – best described as being tired all the time for no good reason. Chronic Fatigue Syndrome. As they’ve branched out into the study of all Fatiguing Illnesses, it’s no wonder that Dr. Reeves does not think any of his patients will have XMRV. Many – perhaps most - won’t. But they were the wrong patients to be studying in the first place, weren’t they?

Patients diagnosed with HIV aren’t sick yet. They are quite normal (which has made it easier for them to advocate for action to be taken against the disease – we don’t’ know we’re sick until we’re really sick).

The CDC and WHO both consider a patient to have AIDS when he has both HIV and an enumerated AIDS illness such as Karposi’s sarcoma (a type of skin cancer that was relatively benign and limited to elderly Mediterannean men) or pneumocystic pnsumonia, once an extremely rare opportunistic disease.

HIV alone does not equal AIDS.
HIV + Karposi’s Sarcoma = AIDS
HIV + pneumocystic pneumonia = AIDS

Just as there are perfectly healthy people walking around with HIV, there are perfectly healthy people walking around with XMRV. My husband could be one of them. (Yet another set of people due for early testing - healthy family members of patients who are sick and have XMRV.) Bob has been perfectly healthy the entire time I have had the disease, and this is true of a lot of ME/CFS spouses. Perhaps he is a carrier.

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XAND is to XMRV as AIDS is to HIV

XAND means XMRV Associated Neuroimmune Disorder, and XAND is to XMRV as AIDS is to HIV. We may not end up with the name XAND. It could end up being called AIDS II (since it now appears AIDS, or Acquired Immune Dysfunction Syndrome, is a category, not a single disease). It could end up with a different name altogether. But for the same of this essay, we will go with XAND, which is to my knowledge the only name that has been formally used for the disease that XMRV causes.

As the many of the diseases and immune defects that caused the AIDS epidemic had already become known by the time HIV was discovered, so too many diseases and immune defects associated with XMRV are already being studied in the context of original CFS patients – or CFIDS patients – or M.E./CFS patients (a compromise name recognizing the placement of CFS in the M.E. code under neurological diseases in WHO’s ICD-10 – but the U.S. is still on ICD-9 and does not recognize the connection). ME/CFS has the best diagnostic guidelines, the Canadian Consensus Document - and already some patients so diagnosed have already tested positive for XMRV.

So that is our AIDS. The disease that popped out in the 1980s that the CDC did not deign to actually study, choosing instead to create a "new" disease entity that they described as the result of upper middle class women trying to have it all. It is not the disease that, today, they define mainly as an inability to handle stress because of childhood emotional injuries.

Our AIDS is the disease behind an outbreak of geographic clusters of serious diseases throughout the United States in the 1980s, often (but not always) tied to Epstein-Barr Virus; often described as a bout of the flu that refused to go away. Our AIDS is the disease that the CDC refused to study at all. And our AIDS has been permitted to spread as a result.

There is one intriguing difference between HIV and XMRV. HIV apparently causes AIDS by permitting the AIDS abnormalities and diseases to flourish in an infected body. Dr. Mikovits has commented that XMRV appears to have the potential to cause neurological symptoms by itself.

For now, we could easily - immediately - begin to turn to our "AIDS" - to the cluster of conditions we already know are associated with CFS. Over the past 25 years, using homogeneous population groups that fit either the Holmes or Fukuda definition, or both, clinicians and researchers have come up with a number of immune defects and viruses associated with their “CFS” samples. (Again, not the CDC’s CFS samples. The CDC would be the first to tell you that.)

It begins with M.E., which has been associated with coxsackie B for years.

Patients from the cluster outbreaks in the U.S. are prone to immune defects such as T-cell inversions, natural killer cell dysfunction, and a defective form of Rnase-L. They were far more likely than the normal population to have HHV-6 (particularly Variant A), Cytomegalovirus (CMV), mycoplasma, a particular enterovirus that caused severe IBS symptoms, and parvovirus B19. Conditions such as parathesias, photophobia, chronic hypothyroidism, chronically low adrenal levels (never formalized into a disease name), and the autonomic nervous system dysfunction known as NMH/POTS (neurally mediated hypotension/postural orthostatic tachycardia syndrome) were brusquely dismissed with a sample of, say, 35 patients. The press release would say, for example, “HHV-6 has no statistical relationship to CFS.” And that would be the end of that.

Each time researchers discovered a biomarker or virus connected to a cluster of patients who fit the Holmes or Fukuda research definitions of CFS, the CDC or NIH brushed it aside because the finding was never a “perfect marker for CFS.”

But it is an ill wind that blows nobody good.

Because of all that research, we are starting out with a list of possible cofactors with which to connect the retrovirus XMRV to the disease XAND.

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What is XAND?

Note:XAND is a proposed name already in use, but it will take years for it to become official. Since XMRV is a newly discovered disease, we believe that the use of the new name XAND from the beginning will avoid confusion resulting from existing definitions for associated diseases.

XAND (I've never heard it pronounced, so I pronounce it ZAND) stands for XMRV Associated Neuroimmune Disorder.

To understand it, let’s go back to the AIDS model again.

HIV by itself is not AIDS. You have to have one of many defining diseases to be diagnosed with AIDS.

HIV + Karposi's sarcoma = AIDS
HIV + pneumocystic pneumonia = AIDS

So what is XAND?

XMRV + natural killer cell dysfunction = XAND
XMRV + active HHV-6 = XAND
XMRV + active CMV = XAND
XMRV + T-cell abnormalies = XAND
XMRV + coxsackie B = XAND

The disease that XMRV has now made it possible to diagnose is XAND.

And, depending on funding, this can happen very quickly. As I mentioned, we already have a lot of candidates for co-factors in terms of patterns of immune markers and viruses. All we need is to put the two together.

It would be nice if the CDC and NIH took over at this point. But patients, advocates, clinicians and researchers who have danced the dance with both agencies for a quarter of a century - while this retrovirus was permitted to spread unabated [Dr. Peterson has a patient sample from 1984 that contained the retrovirus] - they did everything in their power to hide it.

While there are obviously new scientists and researchers at NCI and DHHS who want to do the right thing, we are understandably nervous about all the bureaucratic officials still there who were part of the quarter-century cover-up.

For years, NIAID refused to fund any research into “CFS” unless it included a study of major melancholic depression. Since 2000, NIH has funded less than 5 million dollars of research into CFS (and not some other project disguised as CFS) - $5 per adult known to have the condition.

For obvious reasons, none of us are particularly thrilled at the idea of CDC controlling the research, either. As Dr. Nancy Klimas pointed out during the October 29 CFSAC meeting, it was the CDC that slammed the door on retrovirus research on CFS patients in 1991. We’d be just as happy to let Dr. Reeves pursue his fatiguing illnesses off into the sunset.

One suggestion has been that, in the beginning, due to the urgency, perhaps research funding on XMRV and the public face of XMRV should be placed directly in the head office of the Department of Health and Human Services. With the United States in the middle of the greatest potential health care overhaul in United States history, that is not very likely.

That is why we must support outside institutions such as the Whittemore-Peterson Institute and the British group InvestinME, until the government accepts the responsibilities of this very serious, contagious illness.

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Myalgic Encephalomyelitis

Where does XMRV fit in with M.E., or Myalgic Encephalomyelitis?
Perhaps M.E. is a cofactor: XMRV + M.E. = XAND.

Margaret Williams has suggested a natural relationship because of decades of evidence that M.E. is related to coxackie B. (See The Role of Viruses in M.E., 2009.)

Perhaps we can divide M.E. into ME-XMRV and ME-Ramsay (just as there are cases of prostate cancer that have nothing to do with XMRV).

Unlike CFS, M.E. is a disease, a disease that has been diagnosed for half a century and coded under neurological diseases in ICD-10, the World Health Organization's current International Classification of Diseases (G93.3) - and it has been there for FORTY YEARS.

The whole “CFS problem” might not have gotten away from us had the authorities followed the advice of specialists who strongly suggested, in 1987, that the 1980s outbreaks were due to M.E.

And M.E. would be a well-known disease today, as M.S. is, had it not been for a cult of British psychiatrists who claimed to follow the theories of "biopsychosocial" medicine (and whose answers fit well the needs of insurance companies and national health agencies to save money after the unexpected jolt of AIDS).

How silly it will look to have attributed the results of a retrovirus to "inappropriate illness beliefs."

Pay me now or pay me later. Every year the authorities refused to face this disease head-on, they saved money in the short run by leaving patients out in the cold. But they also increased costs in the long run by ensuring the disease would spread from the tens of thousands to millions - and now, without an end in sight.

Had everyone involved dealt with the “CFS” outbreaks as outbreaks of M.E. at the time, we would not have anywhere near so many people sick today. Perhaps they did not have M.E., but we would have learned a lot about what they did have. And patients with M.E. would not have been sacrificed to the effort to bury CFS.

The CDC and other agencies have suggested that the 3.5% estimate for the normal population effectively makes the retrovirus endemic. Really? If it is indeed too late to stop the spread, precisely whose fault would that have been? I don't think I want to take their recommendation that there is no need to continue to study the disease. Just how long do we want to play chicken with it?

Mr. President: Please appoint a private commission of retroviral, XMRV, and originalCFS and M.E. experts to organize the funding, testing, and treatment of patients with XMRV and XAND. Please do so as soon as possible because we have already lost 25 years, and this is a contagious disease.

The good news is that the answers are only a blood test away. It is a matter of organization, care, and funding. This time, let's get it done right.

Let's insist that the correct terminology for diseases in the context of a retrovirus be used. The CDC always said that when there was a scientific reason to drop CFS, we would drop CFS. WE MUST INSIST UPON IT THIS TIME.

XMRV is not CFS.
XMRV is to XAND as HIV is to AIDS.
After 25 years, time to study the right disease. Let's conquer XAND.

Mary M. Schweitzer, Ph.D.

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Postscript

There are, as usual, those who have rushed to "disprove" this study - but none has run a replication study - that is, they have not used the same process nor the same criteria for the data base. A very good essay on this subject can be found here:

http://www.meactionuk.org.uk/exposing-more-anti-xmrv-spin.htm

Hundreds of thousands of patients diagnosed with "CFS" are going to want to take the test, which is currently being offered at VIP labs in Reno.

It is probably a bit premature to get tested now. This research is in very early stages, so don't pin your hopes on a single test. It would be better to work through a physician, particularly one familiar with the comorbidities that turn XMRV into XAND, or a physician who would change your treatment protocol if it turned out you had XMRV. However, most ME/CFS patients in the United States have no one to work with who comes close to being a specialist on the disease they have, and I can understand the desire to find out if what you believe in your heart is true: there is a retrovirus underlying the whole problem. I just want to warn patients not to be discouraged if these early tests don't turn out to be positive. There is a lot that will come from this research.

Currently the NIH and WPI are working together to create a test that is quicker and easier, and can be performed by commercial laboratories with a high degree of both accuracy and specificity. That test could be available within a year. The NIH's main interest is in finding a way to ensure that XMRV does not get into the blood supply (and that current supplies can be tested for it).

This is a new experience for CFS patients. Usually tests that have been found to explain symptoms in patients have been noticed by the federal government just long enough to do a quick test dismissing the marker or virus as "the cause of CFS." It's been an enormous source of frustration for me, because I have been in more than one of these studies, and I test positive for quite a few immune markers and viruses that CDC ignores. Indeed, there's a paragraph on CDC's website for CFS that actually says not to give patients suspected of having CFS the testing that has shown a lot of what is wrong with me, and led the way towards treatment.

I'm not used to having a disease connected to CFS being taken seriously. And we're already getting quickly done studies that do not use the same methods, or the same type of data set, as the Whittemore-Peterson Institute and the National Cancer Institute - and claim, as in the old days, that they have "disproved" that XMRV can be a "cause" of CFS.

For the past twenty-five years, biomedical research into CFS has met with this type of dismissive response, and I'm certain the researchers who "can't find" XMRV think they're going to kill it as well. But that's not going to happen this time. It is not going to happen, because XMRV is a retrovirus, because XMRV also causes a virulent form of prostate cancer, and because too many scientists are already working on sophisticated research trying to decipher what XMRV actually does in the body.

There are still very important questions to be answered.

Personally, I'd like to know how I got it! The cluster outbreaks of the 1980s did not spread in a way one would associate with a retrovirus - how did those patients end up with it?

How is the virus transmitted or activated? Is XMRV by itself a symptom-causing disease, in addition to the peculiar role a retrovirus plays in conjunction with other diseases? What diseases are activated by XMRV? What treatments are already available, and how long will it take to get new treatments to patients? What does it mean that roughly 3.5% of apparently healthy people are positive for XMRV?

For a good summary of the issues involved, by a clinician in the center of the battlefield for 25 years, read Dr. David Bell's description of XMRV and XAND in the Lyndonville News. Another good written summary of the research and its meaning for patients with M.E. and CFS diagnoses can be found at the website for the British organization MERGE.

The taped presentations of Dr. Daniel Peterson and Dr. Coffin at the CFSAC on October 29, 2009 also make excellent introductions. Go to the main CFSAC website at http://www.hhs.gov/advcomcfs/. Click on "Day 1 videotape" in the box to the right of the page. You need to have RealPlayer to view it (it can easily be downloaded for free at RealPlayer if you do not already have it.) Dr. Peterson's presentation begins at roughly one hour and 23 minutes into the video for Day 1, and Dr. Coffin's presentation follows.

I have had the disease derisively called "CFS" for two decades; I have been unable to work for 15 years. My natural killer cell function is 2%; I have the abnormal Rnase-L. I suffer from recurring bouts of Epstein-Barr, and I have chronically active cytomegalovirus (CMV), HHV-6 (Variant A), and HHV-7. I responded well to the immune modulator Ampligen but the FDA has so restricted it that it has been two years since I have been able to get it anywhere within driving distance of my home - which means anywhere from New York City to Washington, DC. Right now I am very ill, and getting worse.

And I have XMRV. Having XMRV makes sense - it makes sense in light of what is wrong with me, and it makes sense in that Ampligen, an experimental immune modulator, has worked well for me while I am on it - but several months after I have had to go off it (twice - one year the first time, seven months the second), I have relapsed badly. That would be in keeping with the behavior of a retrovirus.

The private Whittemore-Peterson Institute needs your help to continue this work. It is a nonprofit institution founded by the parents of a patient who has had the disease for over 20 years - since she was 12. A donation as low as $5 will help speed up the time it takes to get people tested, identify cofactors, start treatment with existing remedies, and continue research on the nature of the disease and new treatments to offer.

Other similar nonprofit patient-run institutions created to support research include Invest in ME in the UK, and the HHV-6 Foundation.

Our world is about to change.

Mary M. Schweitzser, Ph.D.