What do we have if we do not have CFS?

I have always despised the concept and name “chronic fatigue syndrome,” created in 1988 to describe a group of patients who had previously been thought to have “Chronic Epstein-Barr Virus.” “CFS” is not scientific. It is a social construct, a shape-shifter, something that gets redefined as those in a position of power, or society at large, wish to redefine it. But it had one advantage. It helped researchers study a group of patients who have been sick for decades with a mysterious, apparently contagious, disease. It helped researchers define subgroups of patients who exhibited similar patterns of biomarkers and pathogens. If CDC defines CFS so that those patients are no longer considered to have the disease, then what can we say they have? And what is left that can be called “CFS”? Why would we study CFS at all?

Defining CFS so that it no longer fits “CFS” patients

In the late 1990s, it had become clear that “chronic fatigue syndrome” had been polluted as a research term because there were so many different – often conflicting – definitions in use. How could you compare a study conducted using patients from Simon Wessely’s psychiatric practice at King’s College, London – where patients with confirmable physical ailments were turned away – with a study conducted using patients from Dr. Dan Peterson’s practice at Incline Village, NV, one of the most-studied sites of a cluster outbreak in the 1980s? Over time Dr. Peterson and others had found tests that distinguished the cluster-outbreak patients from those with simple “chronic fatigue” – low natural killer cell function; the 37kDa Rnase-L defect; SPECT scan abnormalities; extremely low VO2 Max stress test scores; viruses such as EBV, HHV-6, and cytomegalovirus. Other researchers have found mycoplasma infections, mitochondrial dysfunction, abnormal immune cell ratios, NMH/POTS; myocarditis. The list goes on. Formally, they were all using the CDC’s 1994 Fukuda definition in their research, but practically speaking, the patients came from practices where clinicians had seen chronic fatigue syndrome in cluster outbreaks.

The result is research that defines subgroups of patients with patterns of biomarkers and pathogens. In fact, this was how Dr. Fukuda had imagined research would proceed with CFS. In the 1994 article that introduced what is called the “Fukuda definition” to the world, he wrote that “additional subgrouping or stratification of study cases into more homogeneous groups is necessary for comparative studies.” An entire section of the short (6-page) article was devoted to “Subgrouping and Stratification of Major Classification Categories”:

"In formal studies, cases of the chronic fatigue syndrome and unexplained chronic fatigue should be subgrouped before analysis or stratified during analysis by the presence or absence of essential variables, which should be routinely established in all studies. Further subgrouping by optional parameters can be performed according to specific research interests."

But CDC has steadfastly ignored that mandate. Instead of studying evidence of subgroups, CDC would take each new biomarker or virus, run a small study that sometimes even didn’t even test for the right laboratory finding, and then announce to the public that X or Y or Z was not “the cause” of “Chronic Fatigue Syndrome.” The Fukuda article is referenced only for the research definition – not for the imperative to subgroup into homogeneous classes. Most patients, clinicians, and researchers are probably unaware that the article even mentioned – let alone emphasized – the need to define homogeneous subgroups.

Twenty-five years after CDC was first asked to examine cluster outbreaks of the disease they would later name “chronic fatigue syndrome,” the website states as the first obstacle to diagnosis:

“There's no diagnostic laboratory test or biomarker for CFS.”

That simple statement shows the extent to which CDC missed the point of the Fukuda article. Fukuda assumed there would be no such tests that would hold for everyone. The tests would define subgroups.

Today on CDC’s website you will find an entire paragraph devoted to the testing that has identified the subgroups Fukuda envisioned – but CDC’s approach could not be further from what he had described. Some are listed as exclusions; others as experimental. In the latter case, one wonders how long after peer-reviewed publication does information continue to be viewed as “experimental.” Much of this information was first published 15 years ago. Perhaps more to the point, denying patients access to this testing also results in denying them access to treatment that has been found successful for patients who have such biomarkers or pathogens.

CDC’s emphasis on one test-one result also denies the reality that most patients with “CFS” (according to the original definitions) have more than one thing wrong with them. But there is no way to tell that from the CDC website (See

http://www.cdc.gov/cfs/general/diagnosis/testing.html)

"A number of tests, some of which are offered commercially, have no demonstrated value for the diagnosis of CFS. These tests should not be performed unless required for diagnosis of a suspected exclusionary condition (e.g., MRI to rule out suspected multiple sclerosis) or unless they are part of a scientific study. In the latter case, written informed consent of the patient is required. No diagnostic tests for infectious agents, such as Epstein-Barr virus, enteroviruses, retroviruses, human herpesvirus 6, Candida albicans, and Mycoplasma incognita, are diagnostic for CFS and as such should not be used (except to identify an illness that would exclude a CFS diagnosis, such as mononucleosis). In addition, no immunologic tests, including cell profiling tests such as measurements of natural killer cell (NK) number or function, cytokine tests (e.g., interleukin-1, interleukin-6, or interferon), or cell marker tests (e.g., CD25 or CD16), have ever been shown to have value for diagnosing CFS. Other tests that must be regarded as experimental for making the diagnosis of CFS include the tilt table test for NMH, and imaging techniques such as MRI, PET-scan, or SPECT-scan. Reports of a pathway marker for CFS as well as a urine marker for CFS are undergoing further study; however, neither is considered useful for diagnosis at this time."

While these tests might not be useful in “diagnosing” a single entity called "CFS", they are very useful in understanding and treating CFS. I have three of the four pathogens mentioned. I also have cytomegalovirus (CMV), which I imagine CDC considers exclusionary for CFS. I am abnormal in testing for three of the four immune markers mentioned plus the 37kDa Rnase-L which is listed there as a “pathway marker for CFS,” I have NMH; and I have abnormal SPECT scans.

More to the point, there is a subgroup of patients within the larger CFS-diagnosed community whose testing turns out almost identical to mine. So researchers identify a subgroup, but instead of using that to benefit patients, CDC insists it is either unrelated to CFS, or exclusionary for CFS.

Furthermore, the pattern of biomarkers and viruses - not a single test – is critical for understanding various subgroups that could now be defined empirically, if CDC permitted it. And by listing everything as if each was a single test, and each test represented a different disease, CDC effectively misleads anyone who comes to their website seeking an understanding of “CFS.”

I fit quite neatly into a subgroup of CFS patients who were caught up in a cluster outbreak in the north Tahoe area of Nevada in the winter of 1984-85. The Holmes definition of 1988 and the Fukuda definition of 1994 were both explicitly intended to describe those patients. When Congress voted for research funding and an advisory committee (today's CFSAC) for “CFS” in the Department of Health and Human Services, they did not mean for these resources to go to just any old thing CDC wanted to call “CFS” – they wanted to find answers for the people who got sick in the 1980s, and later, with a disease that appeared similar among oubreaks.

We have reached a point where CDC explicitly defines CFS to exclude the very patients they were charged with helping.

If the patient representatives on the CFSAC do not have “CFS” according to CDC’s restrictive parameters; if the researchers on CFSAC do not study “CFS” according to CDC’s website; if clinicians on CFSAC do not treat “CFS” as defined by CDC – precisely what is CFSAC supposed to do?

The issue is about to come to a head.

CDC insists that XMRV is not “the cause” of CFS. According to a reporter from the New York Times a month after the Science study had revealed the discovery that 2/3 of a sample of CFS patients had tested positive for the new retrovirus:

"Among those expected to try to replicate the XMRV findings is the Centers for Disease Control and Prevention. But 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."

True to his prediction, when Reeves did publish a study on XMRV, he did not find any of the virus at all (despite consistent findings in earlier prostate cancer studies that 2-4% of controls had the retrovirus).

It now appears clear that if the scientific community accepts XMRV as the third known human retrovirus, CDC will simply define CFS so that it is not related to XMRV – they will simply add XMRV to that paragraph that lists all of the testing that is “inappropriate” for CFS. Thus Reeves will always be right when he declares XMRV to be unrelated to CFS - because CDC will redefine CFS such that XMRV by definition will be unrelated to it.

I was in the Science study and I was positive for XMRV. So I’m out of the CFS club, it appears. But I was already kicked out by virtue of testing positive for so many viruses and biomarkers. More to the point – if CDC defines CFS in such a way that the very patients it was created to describe no longer fit the description, what is the point of having a disease category called CFS in the first place? What is the point of a division of CDC devoted to CFS studies? What is the point of an advisory committee at DHHS to coordinate agency activities regarding CFS?

From the beginning, “chronic fatigue syndrome” was a disastrous name chosen to replace “Chronic Epstein-Barr Virus” back in 1988. It could not have been more dismissive if it had been chosen by a focus group. “Chronic” as in “chronic complainer” and “chronic whiner;” “fatigue” as in “yeah, I’ve been tired lately myself;” and “syndrome” as in “syndrome of the month.” In the first decade of the name, comedians had a field day with it. As recently as this year, a popular comedy show in England mocked the name and the disease.

Researchers familiar with the disease known as Myalgic Encephalomyelitis (M.E.) in England and old Commonwealth nations, and Epidemic Neuromyesthenia in the U.S., expressed the opinion at the Holmes meeting in 1988 that the disease was most likely M.E. (Epidemic Neuromyesthenia was no longer being diagnosed). But that information was not even included in a footnote.

M.E. would not be linked to the mysterious illness of the late 1980s as a possible biomedical explanation except in reverse. British psychiatrists eagerly grabbed the name “chronic fatigue syndrome” to portray M.E. as a psychogenic illness, “neurasthenia” (formerly known as “the vapors”). According to the British psychiatrists (Simon Wessely, Peter White, Michael Sharpe, Trudy Chalder, among others), patients with CFS had allowed themselves to become deconditioned because of “inappropriate illness beliefs.” A course of “cognitive behaviour therapy” (CBT), to teach the patient she wasn’t really sick at all, followed by “graded exercise therapy” (GET), to get her back into shape and on the job, was all that was needed.

British psychiatrists used a definition that omitted the sickest patients, excluded anyone with a physically diagnosable condition, and included patients with depression and anxiety disorders. Nothing could be further from the Fukuda definition – yet even today, because they say it is “CFS,” the media and many medical experts assume it is the same thing.

For years CDC used the Fukuda definition. Today, however, they use what can only be called the “Reeves” definition, after William Reeves at CDC, who created a set of questionnaires that he claimed “operationalize” Fukuda, but do nothing of the sort. The questionnaires – explicitly modeled after those used by British psychiatrists – define a population that is not severely ill, and contains patients who suffer mainly from depression or anxiety disorders. In short, CDC has moved to join the British psychiatrists in portraying the disease as psychogenic in origin – CDC uses the term “stress” instead of “neurasthenia” (because neurasthenia is not an accepted diagnosis by U.S. psychiatrists – it was omitted from DSM-IV, along with “hysteria,” because of the strong gender bias associated with the diagnosis). As Reeves told the reporter, CDC expresses the view that “a history of sexual and emotional abuse were more likely to play a role [than viruses or biomarkers] in many cases.”

Cognitive Behavior Therapy and Graded Exercise Therapy (CBT/GET) are now prominently displayed on CDC’s website as treatment for the disease. For a patient such as myself, who had viruses and immune defects, CBT is not going to bring about a cure. And for those of us who score abysmally low on the VO2 MAX stress test, GET is downright dangerous. But we are supposed to have been weeded out. Who is left?

How convenient to have a moving target, the social construct “chronic fatigue syndrome,” so that as research reveals the biomedical roots of the disease, CDC can maintain that it’s really caused by stress – having portrayed all the results of biomedical research as either inappropriate or useless. What good are thousands of refereed journal articles into biomedical causation (according to Harvard professor Anthony Komaroff) if CDC redefines the disease each time to exclude the new discoveries?

What the future will bring

As CDC’s pattern (and Reeves’ confession) make clear, patients with XMRV are going to be defined out of the CFS population. Will they have their own division at CDC? Will they have their own advisory committee at DHHS?

As researchers begin to study patients with XMRV formerly diagnosed with CFS, they will discover the patterns that CDC has heretofore hidden from public view – patients such as myself, with multiple immune defects, opportunistic viruses, and the resulting damage to the central nervous system, the brain, and multiple systems of the body.

What about those who do not test positive for XMRV? Will they be left behind, defined as having psychogenic CFS?

Or will the medical community come to its senses and realize that the real disease is in the patterns? Will they finally understand that the subsets of this disease were diagnosable with biomedical markers a long time ago?

If we do not have chronic fatigue syndrome, what do we have?