Science asks authors to retract XMRV-chronic fatigue syndrome paper; when they refuse, issue Expression of Concern

It’s Expression of Concern Day here at Retraction Watch. Earlier, we reported on two such notices regarding the complicated case of Milena Penkowa. And now we learn that a 2009 Science paper linking XMRV, or xenotropic murine leukemia-related virus, to chronic fatigue syndrome  (CFS) that has been dogged by questions from the start, is the subject of another Expression of Concern. Such expressions, as we’ve noted, often, but do not always, precede retractions.

The Wall Street Journal reports that Science editor-in-chief Bruce Alberts and executive editor Monica Bradford asked the authors of the paper to retract it last week, after two studies scheduled to published in this week’s Science threw even more doubt onto the findings. But “study co-author Judy A. Mikovits of the Whittemore Peterson Institute for Neuro-Immune Disease said “it is premature to retract our paper,” leading Alberts to issue the Expression of Concern, which begins:

In the issue of 23 October 2009, Science published the Report “Detection of an infectious retrovirus, XMRV, in blood cell of patients with chronic fatigue syndrome,” a study by Lombardi et al. purporting to show that a retrovirus called XMRV (xenotropic murine leukemia virus-related virus) was present in the blood of 67% of patients with chronic fatigue syndrome (CFS) compared with 3.7% of healthy controls (1). Since then, at least 10 studies conducted by other investigators and published elsewhere have reported a failure to detect XMRV in independent populations of CFS patients.

In this week’s edition of Science Express, we are publishing two Reports that strongly support the growing view that the association between XMRV and CFS described by Lombardi et al. likely reflects contamination of laboratories and research reagents with the virus.

Any study suggesting a cause for CFS — especially a potentially treatable one — is likely to generate a tremendous amount of buzz, and this study was no exception, Alberts notes. The 2009 paper has been cited 137 times, according to Thomson Scientific’s Web of Knowledge, although of course many of those citations cast the findings in a negative light.

The Expression of Concern was initially scheduled to be published in the June 2 issue of Science, but editors there released it early, according to a note from the journal’s press office:

Information pertaining to these articles has entered the public domain due to circumstances beyond our control, and the articles are being made available now, for immediate release, to avoid confusion or speculation about the research.

We’ve asked for specifics on those circumstances, and will update with anything we hear back.

Update, 10:55 a.m. Eastern, 5/31/11: Science tells us it was the WSJ story that made them release the material early.

Once that news story was published we felt it would be most useful to journalists, scientists  and the public, including doctors and patients whose lives have been affected by chronic fatigue syndrome, to make the information being published in the journal available right away.

So was this an embargo break, and would the WSJ face sanctions?

No, we had not yet even routed the Science Press Package notice on this story, and further we have no evidence that the Wall Street Journal reporter obtained any information from us whatsoever. They seem to have acted upon an independent tip.

Update, 6:10 p.m Eastern, 6/7/11: Added “syndrome” to headline to use the proper name of the condition, and “to chronic fatigue syndrome  (CFS)” to third sentence, as it had been mistakenly omitted.

26 thoughts on “Science asks authors to retract XMRV-chronic fatigue syndrome paper; when they refuse, issue Expression of Concern”

  1. “They seem to have acted upon an independent tip.”

    Since the WSJ article says they have copies of the correspondence between the Science editors and Judy Mikovitz et al, I would suggest that the source of the tip is rather obvious.

  2. Whoa, this is big.

    My prediction of what’s going to happen is that some of the original authors decide to sign a retraction and move on to other science, while others maintain that there’s something in XMRV and continue to study it. I’ve no idea who’ll fall into each camp, but I’d be very surprised if they all agree to retract it.

  3. It’s a fascinating case study, isn’t it? And I assume a lesson to other authors who may someday be asked to retract a paper. From the science journalist point of view, these authors would have been better off with a neat little retraction than such a public slap in the face.

  4. Mikovitz’s letter points the fingers at others:

    “This is especially so in light of the gross disregard for the integrity of the scientific process by the apparent willful breach of your embargo by one of the authors or their collaborators.”

    But weird to conjoin “apparent” and “willful.” Hard to figure out the sequence of events, but it looks like the WSJ article was first, and that was written by a journalist who has been distinctly sympathetic to Mikovitz et al.

  5. There is no evidence of contamination, only conjecture. The Mikovits 2009 samples were blinded and processed the same way, how would only very few controls get contaminated but the majority of CFS patients get contaminated? The CDC tested the Mikovits 2009 samples for contamination and did not find any. The CDC also tested 20 positive samples and could not find positive, which is another strike against contamination and suggesting their methods cannot detect the virus in a clinical sample. There is the Lo/Alter 2010 study which found 7% and 85% of controls and patients, respectively, positive for MLV-related viruses. It would be an unlikely coincidence if the Lo/Alter samples were also contaminated at similar rates for both patients and controls as the Mikovits 2009 samples. The Whittemore-Peterson Institute has never worked with a cell line positive for XMRV such as 22Rv1 and has never detected contamination. The contaminationists have never explained the detection of antibodies, the electronic micrograph of XMRV, the transmission of infections virus to uninfected samples. Mikovits has recently published a distinct cytokine signature in XMRV-positive CFS patients which is consistent with other retroviruses such as HTLV-1. Harvey Alter has, as recently as one month ago, called the contamination conjecture “illogical”.

  6. The thing is, its not just the Lombardi paper that should be retracted, but all the positive results for XMRV in humans from Urisman onwards. It seems a lot of virologists have made the same mistake…

  7. Would any really smart person out there like to find out where the money for the negative studies came from?

    Follow the money….

  8. XMRV – Contamination and Loss of Prestige.

    To whom it may concern,

    Post Viral Fatigue Syndrome (PVFS) is categorised by the World Health Organisation (WHO) in the 10th edition of the International Classification of Diseases (ICD-10) as a physical/neurological illness in section G93.3 (ICD-10-G93.3) where it is also listed as Benign Myalgic Encephalomyelitis or ME. The WHO acknowledge that the term Chronic Fatigue Syndrome is used as a ‘colloquial reference’ to PVFS/ME[1]. There are many thousands of peer-reviewed scientific papers underpinning the biomedical nature of PVFS/ME(CFS). Unfortunately however, there is a long, dirty and well-documented history of political vested interests skewing the scientific process as far as PVFS/ME(CFS) is concerned[2]. The experience of the ME community in this respect is far from unique[3] but few other patient groups and associated medical/research professionals have had to put up with quite the degree of sustained adverse political lobbying and assault that afflicts the field of PVFS/ME(CFS).

    In May 2011, Editors of the prestigious journal ‘Science’ asked the co-authors of the 2009 paper that linked Chronic Fatigue Syndrome to infection with a gamma retrovirus, known as XMRV[4], to voluntarily retract the paper[5] following other studies that have failed to detect the retrovirus. Dr Judy Mikovits, one of the ‘Science’ XMRV paper’s key authors has robustly refused to retract: citing the fact that other studies have indeed found evidence of human gamma retrovirus infection, that no study to date has replicated or disproved her original research, that other major scientific investigation into gamma retrovirus infection is ongoing and that the science on the matter is very far from settled[6]. Following the extraordinary request of the ‘Science’ journal editors, the scientific literature, established media and the internet have, not surprisingly, been awash with heated and detailed comment, claim and counter-claim. However, two key points that seem to be understated or lost altogether in coverage by much of the established media are:

    1. If human gamma retrovirus infection was not really present in in subjects studied and findings were simply an erroneous laboratory contamination issue then how on earth have more than one group of researchers found significantly more such alleged ‘contamination’ in patient subjects than control subjects? This simply defies logic.

    2. Until the research techniques and patient selection criteria used in the original Lombardi and Mikovits et al study have been properly and independently replicated and shown to be both seriously flawed and indicative of malpractice there should be absolutely no question of their paper being withdrawn from the journal ‘Science’. Premature and unwarranted calls for such retraction defies professionalism.

    In taking the precipitous and extraordinary action that they have regarding said Lombardi and Mikovits study, the editors of ‘Science’ have opened themselves up to the accusation that they are caught up in a very different ‘contamination’ issue to the one they write about. Namely the contamination of what should be independent scientific editorial with undue political considerations.

    The editors now stand accused of having caved-in to behind-the-scenes pressure. Pressure that has absolutely nothing to do with genuine science but everything to do with political lobbying by vested interests. The ‘Science’ journal is often described as being one of the most “prestigious” in its field. It is now viewed by many to have sunk to the level of the gutter press. In my opinion it is the editors of ‘Science’ that need to retract, not Lombardi and Mikovits et al.

    Anglia ME Action
    June 2011


    For accuracy, full reference needs to be made to the three-volume published/book version of ICD 10 (especially the alphabetical index/volume 3 as well as the tabular list/volume 1) and additional WHO comment as comprehensive coverage of the ICD is not given on the WHO website. The bibliographic details of all three ICD-10 volumes are:

    – International Statistical Classification of Diseases and Related Health Problems – Tenth Revision – Second Edition: Volume 1 – Tabular List – ISBN: 92 4 154649 2.

    – International Statistical Classification of Diseases and Related Health Problems – Tenth Revision – Second Edition: Volume 2 – Instruction Manual – ISBN: 92 4 154653 0.

    – International Statistical Classification of Diseases and Related Health Problems – Tenth Revision – Second Edition: Volume 3 – Alphabetical Index – ISBN: 92 4 154654 9.

    [2] See, for example, documents at the following URLs:

    [3] See for example: Professor Bruce Charlton – Zombie Science – a sinister consequence of evaluating scientific theories purely on the basis of enlightened self-interest, Medical Hypotheses (2008) 71 327-329, DOI: 10.1016/j.mehy.2008.05.018:

    [4] Lombardi VC, Ruscetti FW, Das Gupta J, et al. (October 2009). “Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome”. Science 326 (5952): 585–9. doi:10.1126/science.1179052. PMID 19815723.

    [5] Editorial Expression of Concern, Science Express, Published Online 31 May 2011. Science DOI: 10.1126/science.1208542
    Also see Wall Street Journal comment at:



  9. I have just read the post from Anglia ME Action and started to follow the citations that appear at the end of the post…
    The “Zombie Science” editorial is entertaining.
    It is linked at its end to three other items, the first being an article about the “vested interests” who are against Myalgic Encephalitis being accepted as a physical (as opposed to mental) disease. Unfortunately the other two items are rants against the acceptance of Anthropogenic Climate Change(APC), the first being a long piece that seems to state there is a conspiracy to ram APC down our throats. (I had some trouble reading that one because of its rampant run-on sentences.)

    My question is this: what are these “vested interests” that are against ME as a physical disease? Are they really a group of psychiatrists who want to prevent medical physicians from taking over their ME patients? And/or a group of British civil servants who are trying to prevent ME from being a “covered illness”? And/or a group of private insurance companies doing the same?

    This strains my credulity, to say the least.

    In the face of ten studies which failed to find the virus in question, are we to believe that only the one lab actually knows how to detect it? Surely it can’t be that hard to detect?

    What is going on here? My interest is piqued, and I long for an authoritative review article which dissects the issues and studies in question and reveals the consensus (not the “truth”) on this issue.

    1. The WPI lab is not the only lab that can find it. FDA found MLV-like retroviruses in ME/CFS patients also. And, actually, some viruses are hard to detect. Just as the early days of HIV, it was not easy. Ian Lipkin, who is heading up the large NIH study into XMRV, spoke about the many viruses that have not been discovered yet. Why? It’s not that easy to detect them. Think of this… the easy ones have already been found.

      Emory University is reporting that XMRV disappears from the blood within three weeks. But, it is in multiple organs after that.

      Also, we should note, WPI also reports an immune system response to XMRV. So there is something there. I appreciate that Levy and Coffin give alternative theories for ME/CFS. Levy saying autoimmune and Coffin saying possibly another virus. Hopefully they have now become interested and will look for answers to this illness that afflicts 1 million Americans.

      The point is that it is too early for consensus. And I too long for an authoritative review article looking at the issues. At a conference this past week, many meeting abstracts showed positive for MLV-like retroviruses in ME/CFS patients with special care to not have contamination.

      Francis Ruscetti, respected retrovirologist at NCI, says XMRV found in all CFS patients who have non-Hodgkins lymphoma:

      Blinded study of ME/CFS patients from a location of a cluster (outbreak) of the disease in the 1980s provides evidence of human infection: (This is an NIH study.)

      Tina Tidmore

  10. I know what vested interests are. For example, there are the vested interests that would prefer the public know nothing and do nothing about Anthropogenic Climate Change: the companies that dig and burn coal for electricity, for example.
    But what about those other vested intereests? The ones that don’t want us to know that Myalgic Encephalitis is caused by a virus? Who could they be? Please enlighten me.

    1. I’d think those looking for a virus have a stronger reason to find it, considering they are professionally looking for viruses. Not so interesting to say “can’t find anything there”.

      Of course, when a virus is found and the pharmaceutical industry develops (expensive) drugs against said virus, we can find people who either proclaim the virus innocent or non-existent, or better yet, blame the drugs for the disease (HIV comes to mind). Which does not mean there is a/no virus responsible for ME, that’s well beyond my knowledge to comment on.

  11. I can’t help but carry on, because I just spent hours looking at the references from ME Anglia Action, actually just those under [2] which all seem to emanate from an Emeritus Professor Malcom Hooper, who has a serious bone to pick with the Medical Research Council. Specifically, the PACE trial on CFS/ME treatment, which Dr Hooper has indicted at great length for horrific violations of research propriety. I necessarily characterize his complaints with some condensation, possibly even flippancy, because he seems to go on forever with his indictment, using terminology which is frighteningly damning in each detail.

    If even a small portion of his indictment is accurate, I would think that Dr Wessely and members of the Medical Research Council would be hung from a yardarm by now. From the tenor of his statements, it would appear that he is being ignored by the powers that be.

    In any case, the “vested interests” are insurance companies that don’t want to pay for disability for people suffering from ME/CFS because it’s “Not a Medical Illness” but “all in your head.”

    Forgive me for naivete, but I thought that one is just as disabled if it’s all in one’s head as if it’s a systemic illness caused by a virus.

    At any rate, the complaints look like a bad case of consparacy-itis and irrelevant to the issue of whether the paper should be retracted for failure to show a viral etiology for ME– or not. That’s just my personal opinion, of course, and I could easily be mistaken.

    The other paper, that is the PACE trial, sounds like it should be retracted too, but that’s entirely separate from this paper, that is the one purporting to show the viral etiology.

    More enlightenment please–specifically about the other research that failed to detect this virus–was their methodology good enough to detect it if it were there?

  12. To those who have spent hours following up on this:

    Thank you. Keep being skeptical of everything you can be. Further reading will be rewarded.

    The line of thinking, “if those things are true, then something would have been done about it by now” can lead you to dismiss a claim (because of modus tollens, which is valid but not sound because the premises might or might not obtain) or to discover something big (by impelling you to look for unsoundness).

    It reminds me of the joke about the efficient market theorist who saw a $100 bill on the sidewalk but didn’t pick it up because if it were genuine, somebody would have picked it up.

  13. First, insurance companies do not pay out disability for “mental illnesses” as they do to biomedical ones – most contracts allow a maximum of 3 or 5 years – some none at all – and this can be lifelong. Second, health insurance companies limit the number of doctor visits they will cover for a “mental illness.”. All of this is a deep injustice to people with serious diseases such as bipolar disorder or schizophrenia, but the point here is that insurance companies have a perverse economic incentive to incorrectly label a physical disease “mental.”

    Second, if M.E. (Myalgic Enceohalomyelitis, the name the disease had been known by in the British Commonwealth since th 1950s) were the type of mental illness diagnosed by British psychiatrists – neurasthenia (the vapors) or somaticizing (feeling physical symptoms because of emotional problems), then the treatment they espouse – Cognitive Behavior Therapy to teach the patients they aren’t sick at all, followed by Graded Exercise Therapy to get them back jn shape – would, as they claim, reverse the illness and return them to health. But even in their own recent (very expensive) “PACE” study in the UK, most patients stayed the same or got worse. So it is a harmful misdiagnosis.

    One million Americans suffer from this illness, and NIH spends almost nothing on research. When a number of cluster outbreaks occurred in the 1980s, CDC finally had to go look at one, but concluded it wasn’t really an outbreak, just a lot of similar diagnoses, rather insulting to all concerned. Since many cases begin with Epstein-Barr virus (mono, glandular fever), at first it was labelled Chronic EBV, but in 1988 the US CDC adopted the stunningly dismissive name “Chronic Fatigue Syndrome.” In keeping with their views, they have kept no record of reported outbreaks.

    I have suffered from this disease for almost two decades, and have been fortunate to have a husband and family who can take care of me. I have also been fortunate in that I have been in a number of cutting edge studies. I do well on a Phase III immune modulator/antiviral, but because it is Phase III, it is hard to get and expensive. I have been on it 9 of the past 12 years – off it, my immune markers show up, along with active viruses, and I return to an invalid state. It is not a fate I would wish on anyone. I have lost the drug again and am hoping to get it back before relapsing again.

    My immune markers include the 37kDa Rnase-L defect and a natural killer cell function that is nearly zero. The active viruses include HHV-6 Variant A, HHV-7, and cytomegalovirus. I suffer ataxia, photophobia, short-term memory loss and difficulty forming memories at all, expressive dysphasia, sensitivity to bright lights and loud noises, blackouts, and massive confusion. There is terrible pain behind my eyes and in the back of my neck 24/7, migraine-level (but symmetrical) headaches, and muscle pain. When the disease is at its worst, I have to spend most of my time curled up in bed in a dark room listening to movies (can’t look at the screen – too painful). I can only leave the house in a wheelchair and do not always have the strength even for that.

    Fortunately, the immune/antiviral treatment enables me to walk, read, write, drive a car – simply wonderful things other people take for granted.

    Teenagers get this disease, and because of misconceptions, they and their families can be tormented by disbelieving school or protective services authorities. I have friends who were teenagers when they got sick and are now in their 40s. At least I had a chance to marry, have children, and have a successful career – also to ski and travel. They have not been able to experience a normal life.

    I tested positive for antibodies to XMRV in the Lombardi et al study, but I am no invested in a retrovirus as the cause of the disease. What does concern me is the absence of funding for anything else.

    And as a scholar, I am appalled that qualified scientists would be asked to retract their findings on the basis of a new discovery (that a retrovirus could be created by the practice of reusing the same cell lines over and over in research) that they could not possibly have known about. Retraction should be reserved for serious violations of scholarly ethics. A research program should not be required to be shut down so quickly.

    My own instinct is that we are an innovation or two away from being able to conduct research or diagnose patients as easily as it is with, say, strep. As far as viruses go (all types), they remain somewhat elusive, and we stand where they did with microbes in general in the late 1800s, when epilepsy, third-stage syphillis, tuberculosis, polio, and other diseases were thought to be hysterical or caused by dissolute living. Remember, as late as the 1960s, MS was called “hysterical paralysis,” and autism “cold mother syndrome.”. Anyone who thinks we have nothing new to learn about disease is mistaken.

  14. In 2003 I was severely criticized for doing experiments in NCI aimed to prove that the ovine lung cancer virus (JSRV) may enter human lungs and cause the same form of cancer in humans, namely bronchioloalveolar adenocarcinoma (BAC). The human and ovine receptors for the viral entry are almost identical by sequencing. At the time the prevailing dogma among epidemiologists was that animal viruses do not enter human bodies and do not cause human diseases. Well, times have changed and nobody disputes that animal viruses may enter and replicate in human tissues. I think it’s a trivial task to prove that XMRV can enter and replicate in human tissues, however the real problem will arise how to apply the Koch postulate and prove the causal relationship between XMRV and CFS. On the other hand, it seems to me that there exists some kind of mental block to accept causality in biology

    1. Mmmm. Koch’s Postulates placed the germ theory model on a solid scientific footing, but scientific progress always goes forward.

      Dr. Racaniello wrote on his blog, “The limitations of Koch’s criteria are even more obvious when we consider viral diseases, which were not yet discovered when the postulates were formulated. Thomas Rivers, who has been called the ‘father of modern virology’, wrote:

      ‘‘It is unfortunate that so many workers blindly followed the rules, because Koch himself quickly realized that in certain instances all the conditions could not be met. . . . Thus, in regard to certain diseases, particularly those caused by viruses, the blind adherence to Koch’s postulates may act as a hindrance instead of an aid.’’

      Another method of proving causation is Bradford Hills Criteria of Causation.

  15. 1, It is certainly true that private insurance companies discriminate against “mental” illness, as opposed to “physical” illness, along a number of lines, including not paying for psychiatric care, limiting psychiatric hospitalization, etc.
    It appears to me that this is a side effect of a societal bias that is of extremely long standing.
    2. The research on XMRV has not reached a consensus, as seen in this “requested retraction” and “expression of concern.”
    3. There are known instances of institutional discrimination against unpopular lines of research.
    4. It is difficult to determine in many individual cases, on a clinical basis, what is the etiology of illness and/or disability (there being a limited range of symptoms and a vast range of causes)
    Therefore, we should lobby for an equal treatment of medical and psychiatric illness by insurance companies and institutions, and an open-minded approach to research and medical/psychiatric care. Personally, I believe that the ultimate solution to this problem will involve single-payer medical “insurance”, something like Medicare for everyone. Private medical insurance and fee for service payments introduce systemic biases into the medical care industry that inflate prices and discriminate against some types of patients and illnesses.

  16. Thanks to Tina for the inside information.
    It stands to reason that viruses able to integrate themselves into host DNA would be difficult to detect.
    Why, in the presence of significant corroborating studies, would they ask the original paper to be retracted? They use terms such as “purporting” (that has a negative connotation to me, as in “alleged”) and “strongly support the growing view” and “likely represents”–as if there is a strong case for contamination. Yet others say contamination is highly unlikely on the face of it.
    Why, I ask you, would “political” forces be so bold as to “allege” nearly incompetent work in the original paper? Are they so sure or are they pulling out all the propaganda stops?
    What is going on here? Does the insurance industry think that they can dictate the diagnostic process? Probably. After all, they have enormous lobbying power, enough to prevent a single payer system from being instituted in the United States, enough to persuade Republican congressmen to propose dismantling Medicare in favor of a system that would reinstate their control of the payment system for everyone over 65 (I’m talking about vouchers, an absurd and obscene scheme that could only represent the wet dreams of the CEO’s of private insurance companies.)

    My contribution: “Chronic fatigue” is really a symptom, not a disease. It only rises to the level of “syndrome” when it can be seen as completely agnogenic. For example, one would not say that a person with active rheumatoid arthritis (RA) has chronic fatigue syndrome, when persistent fatigue is a classic symptomic of RA.
    For example, again, if I were presented with a patient who has lymphadenopathy and fatigue, “chronic fatigue syndrome” (CFS)would be pretty low on my list of possible diagnoses. Particularly if that patient had pharyngitis, or even just complained of a sore throat. That is what is see being wrong with the diagnosis of CFS.
    The same applies to “Benign Myalgic Encephalitis”(BME)–a patient with fever, headache, and cerebral dysfunction (say, paralysis of an upper limb) doesn’t strike me as a candidate for BME.
    Therefore, when I hear “one million sufferers of CFS” I think “a half million misdiagnoses.” This has been my clinical experience: clinicians have difficulty making complex diagnoses accurately. This has been a pattern recently: Attention Deficit Disorder was first underdiagnosed, then overdiagnosed. Bipolar disorder was first underdiagnosed, then grossly overdiagnosed.
    It seems to me likely that, when the dust finally settles, we will have a large number of cases of chronic XMS infection plus a large residuum of sufferers from chronic fatigue who are still not being taken seriously (nor thoroughly evaluated) by their harried primary providers.

    Take all the above with a large grain of salt. It represents the personal opinion of a thoroughly burned out general practicioner.

    1. I appreciate the opportunity to discuss such matters with you. Just for your info, I am a patient and have no training or experience in medical care. I am a former newspaper editor and publisher. From my home, I now work toward ME/CFS awareness. Full disclosure.

      Not only are viruses that go into DNA likely hard to find, but also those with low replication. A study just came out that showed the Lyme bacteria goes into lymph nodes and continues there with immune system making attack, but not strong enough to do away with it. Is this true of viruses? Look at chicken pox, which can lay dormant, then be reactivated in the form of shingles. EBV manifests differently. It can cause mono, or later, Burkitt’s lymphoma. In both shingles and Burkitt’s lymphoma, an immune system weakness is associated with it. H. pylori is another example. It is in 80% of population. Most are asymptomatic. When does the level of infection come up to the point of disease? Clearly, when there are symptoms. There are other factors that may determine whether this person with H. pylori is experiencing symptoms while someone with the same level of infection does not. But as you know, for years, the paradigm was that ulcers are caused by stress and acid, and the presence of H. pylori had nothing to do with symptoms, because that bacteria was ubiquitous. We now know that although it is common, in some people, it causes disease.

      HTLV is in 30-50% of Japanese population. Causes disease in 5-7% of those positive. Is it immune system, genetics, other infections, organ of infection that makes the difference in those 5-7% who get disease? It’s not just virus activity. For example, in HIV, a person is considered to have AIDS when the virus is present and replicating AND the T-cell is below a certain amount. It isn’t just virus activity alone that leads to symptoms. But of course, virus activity does contribute to the disease. And if T-cells are 205, which is 5 above what is considered to be “AIDS”, does that man any symptoms you have are not related to the HIV virus infection?

      At what level of infection activity will symptoms be seen may be different in different people, and may be one part of many factors in a patient that causes the symptoms in that person. Maybe if you have low EBV activity, no symptoms. But could it be low level EBV activity, low level Coxsackie activity, low level Lyme activity, all of which taken individually would be considered asymptomatic, put together cause symptoms? Tests of these individually would be in asymptomatic range, according to the arbitrary threshold. But put together, what is all that infection doing to body?

      Additionally, even if not replicating, could these have influence on gene activity?

      Medicine is now relying on objective tests to tell them what is causing symptoms. However, the tests or interpretation of tests is still not objective or accurate and solely arbitrary based on the majority of people not having symptoms at that level. In the 19th century, physicians listened to the patients and diagnosed based on what patients say. When objective tests came on the scene, doctors thought diagnosing on that would be more accurate. Ironically, if the tests aren’t perfect, dismissing a diagnosis based on a “normal” test may lead to just as much inaccuracy. (hypothetically) At the same time, psychology / psychiatry stepped in to offer their services for doctors who have patients whose tests fall in the “normal” range and still have symptoms. They created and named many new psychiatric conditions that relieve the physician of dealing with the ambiguity of a sick patient who doesn’t get better, has no known drug for treatment and has no objective abnormal biological test result (according to the standards set of what is normal). The two forces collided to cause a disservice to those who have illnesses, and physicians, where scientific technology can not “see” the abnormality. We are still learning much about immune system, the many parts and what is considered normal and abnormal. We know even less about how these may contribute to disease / symptoms. Just because you can’t find it in a blood test or microscope doesn’t mean it isn’t there. It may mean the knowledge of science is not enough to know what to look for or is not able to detect or to determine the “normal range”. And could this be true of viruses that have not been discovered yet?

      You don’t seem to be from US. (Correct me if I am wrong.) I will tell you the opposite of your theory is true in US. The figure of 1 million Americans is a conservative figure. CDC says 1-4 million. Patient organizations use the lesser figure. Why would patients use the lesser figure, seems counter productive to awareness and advocacy? Because we want government agencies and researchers to study the true disease (ME/CFS) of the outbreaks in US and UK and around the world. By government agencies broadening the definition which would include some who do not have ME/CFS, corrupts the effort to find biomarkers and understanding of the pathogenesis. We want answers and good science, not high numbers.

      By blurring the lines between the outbreak disease reported to CDC and the symptoms that are also associated with psychological conditions, doctors will misdiagnose ME/CFS patients as having depression. Why? There is a quick drug treatment for depression. There isn’t for ME/CFS. Drug development makes it easy and puts responsibility back on the patient. And, doctors feel pressure to have an answer, have a treatment, and most of all, they want to make people well. If you move the person to another diagnosis that has treatment, has answers, might make person well, then physician will want to put them in that diagnosis. Better than physician having to say, “You have ME/CFS, but there is no treatment. You have lost your career and will likely spend rest of your life in a constant flu-like state with many more hours in the bed. We’ll try to lessen your symptoms, but that’s all we can do. Have a nice day.” Physicians want to heal.

      Also, the symptoms from the outside look and sound similar to depression (although very different experience for the patient). This may explain why CDC says 80% of people with ME/CFS have not been diagnosed. (So what were they diagnosed with?) If you did not use the CDC community sampling number, but you went by those with the diagnosis, the count would be far, far less. The problem here is there is much more under-diagnosis, not over-diagnosis. (not to say some individual cases go the way you say) ME/CFS is not a reportable disease, so we don’t know how many actually have the diagnosis. But we have that one study that showed 80% who have it have not been diagnosed.

      All this reminds me of early days of AIDS.

      Patients want clear diagnostic criteria for better research. Best and most narrow that is used today is the Canadian Consensus Criteria. The hallmark symptom of ME/CFS, which can now be objectively measured with gene activity, is post exertional malaise. (FYI there is an effort now, even with government agencies, to subgroup based on biological findings.)

      Here is a theoretical question… If people have XMRV and have symptoms, they may ultimately be given a new diagnosis, possibly XMRV Neuroimmune disease (just making something up here). And then, possibly those who have low level, but active EBV infection, chronic, are given a new diagnosis as scientists learn the same lesson as H. pylori. Then same happens for other infections. Could it be that people with these infections were misdiagnosed as having ME/CFS? Or could it be ME/CFS is really chronic infection disease, just different infections for different people? And after we get all those with XMRV with a different diagnosis, will we have to go through this all over again after another retrovirus is discovered in those left over?

      The problem is that someone, somewhere, arbitrarily decided CFS is defined as symptoms with no biological explanation. So when something biologically abnormal is found in a patient, they no longer have CFS. So how in the world will we find the biological abnormalities in this disease if by definition, there is none and you do not include any in your study who have it. Arbitrary. For example, many who specialize in ME/CFS treatment and some researchers know that heart disease often develops in people with ME/CFS. When such develops, does that mean they no longer have ME/CFS and likely always had undiagnosed heart disease (cardiomyopathy)? Or could it be that cardiomyopathy is a complication caused by ME/CFS?

      1. Yes. Thank you for your thoughts. I am in fact a US resident; ironically, during much of my time in active medical practice, I had no medical insurance and couldn’t afford much medical care. It’s only with Medicare that I recently have been able to pay for needed treatments.
        Enough about me. The simple answer to your speculations is that all infectious diseases present on a continuum of severity. A new infectious agent is usually highly virulent; as it learns to coexist with its host, it will produce milder illness. In milder cases, the host’s ability to resist affects the severity of illness greatly.
        With medicine, the situation is also evolving. Shortly after bacteria were discovered to cause disease, virtually all diseases were blamed on bacteria (by some practicioners.) The development of antibiotic treatments began to demonstrate more clearly that not all illnesses are etiologically related to bacteria. Similarly, the development of antidepressant drugs began to show more clearly that not all chronic agnogenic fatigue is caused by depression.
        The problem is that, after a twenty minute visit (if you’re lucky, you’ll get that long) the doctor has to put down some sort of diagnosis. It is very tempting to put down a diagnosis which is not supported by the evidence, ie jump to conclusions. Depending on one’s biases, one could say “depression” or “H. pylori infection” when confronted by a chronic stomach-ache that comes and goes, worsened by stress and bad food, relieved by rest and a bland diet.
        The fact is that even diseases with a clear organic etiology will usually respond, at least partially, to nonspecific measures that also help depression and post-traumatic stress disorder. Response to treatment, unless extremely dramatic, is not a good indicator of etiology, despite popular and medical prejudice.
        Unfortunately, being retired, I’m not familiar with new developments in the diagnosis of CFS; for example, you mention the objective measurement of post exertional malaise (PEM) by gene activity. If there is some way to objectively correlate PEM with infection, regardless of agent (not necessarily XMRV) then making an organic diagnosis would be much easier.
        As things stood when I was working, one could not quantify such things and therefore was forced to say “you have chronic fatigue syndrome, for which there is no known etiology. Go and sin no more.” (Just kidding.)
        Actually, the situation in the past with overdiagnosis of psychiatric disorder was no better than it is today. In the early nineteenth century, hysteria was an extremely popular diagnosis in women who didn’t feel well but didn’t have obvious physical signs of disease. Now we are much more aware that serious organic illness can be present in people who have nothing wrong by physical examination. Not that most doctors can make the distinction; it all depends on whether the doctor trusts the patient to know that “it’s not all in my head” and then pursues the issue with laboratory tests.
        Anyway, it is difficult with common conditions like cardiomyopathy to establish an etiologic relationship to other common conditions like CFS. Not that it can’t be done–obviously, some viruses cause profound cardiomyopathy at once–but it would require, first, establishing a correlation independent of other known etiologies, then establishing an etiologic mechanism, such as preferential destruction of cardiac myocytes or even dysfunction of their mitochondria.
        Proper practice would be to only make a diagnosis of CFS when no etiology is apparent. Once an etiology for the symptom of fatigue and/or PEM is established, the diagnosis of CFS should be dropped and a diagnosis of, say for example, chronic active Epstein-Barr infection (with immune dysfunction or cardiomyopathy or even generalized myopathy) could be made.

        The first requirement is a perception that research on the etiology and treatment of CFS would be rewarding. Awareness of the societal cost of this syndrome is important; with other diseases, such as AIDS, public awareness has driven intense research efforts.

  17. The easiest way to demonstrate “post-exertional fatigue” or “post-exertional malaise” is with a two-day VO2 MAX stress test, a test that is considered the gold standard by the American Heart Association for showing how the body uses oxygen and releases carbon dioxide during exertion.

    In a recent study by Christiopher Snell et al, it was shown that even high-functioning patients with CFS (Fukuda 1994 definition) could not sustain normal aerobic exercise function two days in a row. A control group of deconditioned patients performed identically with the CFS group on the first day. On the second day, the controls did as well as they had on the first – but scores of the CFS group dropped in half. That means that on the second day they could not get oxygen to their cells in what should be simple aerobic exercise.

    My own specialist, Dr. Dan Peterson, has been using this test as a diagnostic tool for over a decade. Those of us who are very sick cannot do the test at all – I used to ski, so I really pushed myself to walk that treadmill for less than 0 minutes (at which point I achieved maximum heart rate, which is where you take the measure). My scores were below 15, consistent with a patient who has congestive heart failure – except I do not have congestive heart failure. As mentioned above, I do have a boatload of viral infections. HHV-6A and cytomegalovirus are even active in my spinal fluid when I cannot get the experimental immune modulator that, in my case, gets the viruses to go dormant.

    The consistent evidence from biomechanics experts as to the body’s inappropriate response to what should be aerobic exercise was so strong that at a workshop at NIH in April, observers agreed that an exercise challenge test should be a requirement in identifying patients to participate in studies on correlation or causation in ME/CFS.

    Finally, Dr. Seitz, I would like to sincerely thank you for your contributions to this discussion. I am not sure you are as burned out as you think.

    Mary M. Schweitzer, Ph.D.

  18. That should be in less than 10 minutes of walking briskly on a treadmill – sorry for the mistake.

    I’d also like to add that research by DePaul psychologist Leonard Jason has found that, in general, despite the degree to which this disease interferes with normal life, less than half of CFS (Fukuda 1994 definition) meet the criteria for a depressive disorder. Other research has suggested that ME/CFS patients’ scores on the MMPI closely resemble the scores of patients with MS, which would make sense because there are a lot of crossover symptoms.

    Dr. David Bell, who wrote about the Lyndonville, NY, cluster outbreak of the mid-1980s in both a book and follow-up articles, suggested that the easiest way to distinguish between a patient with primary depression and one with primary ME/CFS is to ask the patient to come for a short walk while the doctor ran an errand. A depressed patient will say, “no, I’ll wait until you get back. I don’t feel like it” – but if you can persuade the depressed patient to do a little exercise, they often feel better. In contrast, the patient with CFS (Fukuda 1994) will say “Oh, I wish I could! I miss walks so much!” or something to that effect, and as the VO2 MAX tests showed, will be made worse by the exercise.

    In other words, depressed patients express anhodenia, while ME/CFS patients express sadness and frustration. The question “Do you enjoy the tints you used to?” (answer yes or no) always stumps me. No, I don’t go skiing every winter like I used to. I wish I could. I know I would enjoy it!

    The other symptom besides post-exertional malaise (or relapse) that is unique to ME/CFS (this time I am using the Canadian definition, though it should be true of Fukuda as well) is significant cognitive and CNS dysfunction. Patients experience a range of symptoms from problems with word-finding and short-term memory loss to ataxia, expressive dysphasia, pain behind the eyes, a stiff neck, headaches, and massive confusion. Some experience seizures, blackouts, parathesias, and vertigo (which author Laura Hillenbrand listsbas her worst symptom). All have muscle pain to some degree.

    Patients can function well enough during the day to hold down a full or part-time job (collapsing when off work), or they can be wholly bedridden. M.E. Patient groups estimate roughly one-fourth are bedridden or housebound.

    And patients do die of complications of the disease, though we can’t get statistics on it because at that point CDC always reclassified them out of CFS. We tend to know about the children of activists – Sophia Mirza, who died in the UK of dehydration after being sent to a mental hospital against her will because her doctors refused to believe she could not swallow (the autopsy showed damage to the basal root ganglia consistent with esophageal incompetence); Casey Fero died in his sleep at the age of 23 (the autopsy found he died of a heart attack; he had myocarditis, with both old and new scarring showing he had been suffering from it for years – while doctors had been telling him to buck up and shake it off), and the luminescent young writer Alison Hunter, who died of complications at the age of 19.

    In short, this is such a serious disease, and it impacts so many people, that we have trouble getting people to believe it simply because they cannot believe so many severely ill people could have been abandoned for so long.

    But if you replace the word “patient” with “entitlement,” it becomes easier to understand.

    1. Agree with all Mary’s comments. And really appreciate insight of Conrad’s comments. Here is the study of PEM in genes:

      Agree with Mary that VO2Max is also objective marker for PEM in ME/CFS patients, and likely more accessible.

      These findings are fairly recent, within last 3 years. As is often the case, the studies have small number of cohort because ME/CFS is near the bottom in government research funding. (Extreme disparity when compared to other similar disease, such as MS, which has half as many patients.)

      Here is the gene study: By the way, they also found they could distinguish between ME/CFs patients and MS patients using this test. The differences, even from MS patients were considerable, off the chart, so to speak. (sidenote- this is breakthrough research as it means that pain and fatigue may now be objectively measures. This would have big impact on other illnesses as well.)

      So we are seeing distinguishable biomarkers (there are many others) for this disease, yet that knowledge has not gotten from researchers to physicians. So it is a separate entity, although there may be subgrouping. Just as in cancer, there are many different forms.

      Further evidence that it is a separate entity is the outbreaks of this disease. In fact, in US, the CDC came up with the name “chronic fatigue syndrome” after they went to Incline Village, Nevada to study the outbreak (or cluster) in that city. In the same year, Lyndonville, NY had outbreak. In a town of 900 residents, the sole physician in the town ultimately had over 200 ME/CFS patients, many of whom are still sick. Outbreaks of this disease under other names have often been seen in hospitals including two prominent ones: Royal Free Hospital in 1950s and Los Angelas Hospital in 1930s.

      These are clearly not cases of mono, ubiquitos nature of EBV. And the evidence indicates it is viral. So, call it CFS, call it ME, call it chronic infection disease, call is lesser AIDS or whatever, but that is the disease that we need to find the etiology for. And no answers have come. A highly transmissible retrovirus, which makes 25% or fewer sick, with some recovering and some not, and crippling the immune system so that other infections flourish makes sense. Interestingly, XMRV is type of gamma retrovirus. Another gamma retrovirus is Feline Leukemia Virus. FeLV is transmissible, with some getting sick and recovering, others having chronic illness from immune system dysfunction (with extreme fatigue) and ultimately dying. (By the way, as Mary said, people do die from ME/CFS. And average lifespan is about 20 years younger than healthy.)

      If medical community continues to say CFS is not a real illness, just a name for symptoms of other illnesses not yet diagnosed, then we will not get research funding and we will never know what caused those outbreaks.

      I wish you were still practicing.

  19. It’s a basic rule, but it bears repeating: depression is not a wastebasket diagnosis; it has specific symptoms that can be elicited by careful history taking. Anhedonia is one. The symptom in which you feel better after someone takes you for a walk is another, not mentioned in the texts. Depression is improved by light exercise, usually in a social context(possibly this has to do with the release of endorphins.).
    Clearly this is the opposite of “post-exertional malaise.”
    Careful history taking followed by physicial examination followed by specific investigation (more than just a CBC, U/A, and CXR) will always yield a better (more specific) diagnosis. Specific investigation has been lacking for “CFS” but with the general availability of the tests mentioned by Tina (such as V02max) this will change.
    XMRS is a good candidate for an etiologic virus. Time and research will tell if it or some other is causative.
    This comment thread is probably long enough now. I’ll just add that I too wish I were still practicing.

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