The big XMRV news last week was that the NIH had confirmed the original WPI paper regarding XMRV and CFS. Or, as sue so eloquently put it:

http://www.mmdnewswire.com/xmrv-9040.html

HA read it and weep you stupid cunt

Unfortunately for the oh-so-civil sue, I wasnt entirely surprised at someone else in the US finding the XMRV-CFS connection (see my October 23, 2009 post on the topic). I am completely open to the idea that XMRV is endemic in the US, and is better able to infect certain immunocompromised citizens, which may or may not cause or perpetuate diseases of some kind. However, replicating the WPIs results in no way justifies the reasons I have written negatively about WPI in the past– Judy accusing other researchers of fraud/collaborating with snake-oil salesmen/supporting anti-vaxers, Annettes shockingly inappropriate behavior, or people randomly experimenting on themselves with antiretrovirals.

So, okay, I was patiently waiting for this paper to come out… when Grant Jacobs, a blagger in New Zealand alerted me to some ‘controversy’. Really? Controversy and stupid drama in XMRV research? Oh I just dont believe it!!!

But the story wasn’t as simple as that. Science has learned that a paper describing the new findings, already accepted by the Proceedings of the National Academy of Sciences (PNAS), has been put on hold because it directly contradicts another as-yet-unpublished study by a third government agency, the U.S. Centers for Disease Control and Prevention (CDC). That paper, a retrovirus scientist says, has been submitted to Retrovirology and is also on hold; it fails to find a link between the xenotropic murine leukemia virus-related virus (XMRV) and CFS. The contradiction has caused “nervousness” both at PNAS and among senior officials within the Department of Health and Human Services, of which all three agencies are part, says one scientist with inside knowledge.

*rubstemples*

*rubstemples*

*headdesk*

Sooooo… the ‘positive’ paper was submitted by Harvey Alter to PNAS. Harvey Alter is a NAS member, so this paper had, um, ‘a different peer review history’ than you all are accustomed to. Normally, you send a paper to a journal, and they send the paper out to three reviewers, and they give the journal editor a thumbs-up or thumbs-down. When you are a NAS member submitting to PNAS, you pick your own reviewers and send in your own reviews. So, you could, like Lynn Margulis, send a controversial paper out to seven people to get two ‘good enough’ reviews, and be accepted for publication.

Just to be 100% clear, Alter isnt doing anything ‘wrong’, even if he sent it out to 50 people to get two good reviews. He wouldnt be doing anything ‘sneaky’ and its not ‘cheating’, thats just the way things work at PNAS. Which he must understand is a valid concern for Average Joe/Jane scientists who also know how PNAS works. And considering the crap PNAS got for publishing that insane ‘caterpillars and butterflies are two different species!’ weird ass paper for Margulis, I dont blame them at all for being ‘nervous’ about not looking-before-they-leap into this controversy.

But I do think this is funny considering the holy hell that was raised over the first negative study at PLOS: “WARBLEGARBLE IZ NUT REVIEWEDED! PLOS SUX!”

EDIT 07-02-10– Yup.

… the journal’s editor-in-chief, cell biologist Randy Schekman of the University of California, Berkeley, sent the paper out for further review after government agencies requested the publication delay. That review came back with requests for additional studies, the scientist says.

Again, this does not mean Alter did something sleezy or wrong. It also doesnt mean that Alters reviewers are idiots or gave him softball reviews. But people are more critical with anon reviews than in non-anon reviews for colleagues. The PNAS editor didnt want to jump into anything before they sent it out to a few reviewers of their own, and the reviewers wanted a few more experiments. No big whoop, no massive government conspiracy, just exactly what would have happened if Alter sent the paper to a non-PNAS journal.

Anyway, now the ‘held up’ paper in Retrovirology from the CDC, was actually published this morning.

And its fine.

Western Blot– They looked for antibodies to XMRV in 51 CFS patients and 53 matched controls, 121 random blood donors, and sera from 26 people infected with a retrovirus (HTLV, HIV-1, and/or HIV-2). Their positive control sera lit up the appropriate bands for Gag and Env. None of the other samples had any antibodies to XMRV.

ELISA– They also sent the CFS + matched samples off to another lab for blinded testing– this other lab had no idea which samples were from CFS patients, and which were from the matched controls. With ELISAs, you put a LOT of the protein of interest (Gag, Env) into a well, instead of just a band in a gel in a Western, and look for reactivity. They found a couple weakly positive samples for Gag (not Env), one CFS, one control– but those couldnt be confirmed with a different test. They were also sent positive and negative controls, which they were also blinded to, and they properly identified them.

PCR– They used the same damn PCR as WPI, and then a separate primer set they designed. They could see 10 copies of XMRV diluted in human genomic DNA for their controls. They couldnt find it in whole blood or PBMC from the CFS+matched set, or 41 totally different (not the ones used in the Western test) blood donors.

They also sent their stuff to another lab for blinded testing, with blinded positive and negative controls. Positive were positive, negative were negative, and none of the experimental samples had any XMRV.

They used the same definition of CFS (1994 CDC Fukuda Criteria) as the Science paper. They used the same PCR conditions. They had two different labs blindly double check their findings two different ways. They couldnt find XMRV in healthy blood donors to an appreciable degree, much like BigPharma (WPI also did not find antibodies to XMRV in healthy donors, but for some reason is sticking with their 3.7% PCR number).

So what did this paper do ‘wrong’?

Whats the excuse now?

And what did Alter do that was so magically different that his lab could replicate the Science paper?

Comments

  1. #1 Charl
    July 1, 2010

    Apologies, just asked for your comment on this, but I ee you are way ahead of me :)

  2. #2 Kemanorel
    July 1, 2010

    And what did Alter do that was so magically different that his lab could replicate the Science paper?

    I’d check his bank statements…

  3. #3 Cain
    July 1, 2010

    OT but why no zombie shenanigans from erv? Sciblings with a tenth of the humor and wit of Abbie are getting involved and an Arnie zombie profile pic wold have been friggen sweet.

  4. #4 John
    July 1, 2010

    “They used the same definition of CFS (1994 CDC Fukuda Criteria) as the Science paper.”

    No they did not. They used the ‘revised’ 1994 criteria, also known as the 2005 ‘Empirical’ definition, which in 2007 found a prevalence between 6-10x of earlier prevalence rates, and which also has been criticized for using the ‘Role Emotional(RE)’ subscale of the SF-36 as an inclusion factor, among other things, with the RE subscale explicitly stating that ‘reduction in activity as a result of emotional disturbances’ must be present. Previous studies have shown that the RE subscale had the least correlation with CFS out of all SF-36 subscales.

    Meanwhile, despite the Empirical definition being published 5 years ago, no other research group in the entire world other than the CDC has used it even once, as well as the nation’s largest patient charity, the CFIDS Association, the DHHS Chronic Fatigue Syndrome Advisory Committee and the IACFS/ME all having recommended the CDC cease using the Empirical definition.

    The Empirical definition also picked out more men than women in the GCRC sample set used by CDC for this study, which in itself is unheard of(I honestly don’t know if that has ever happened before), with basically every single study done for the past several decades showing that the female to male ratio in CFS averages around 3:1, similar to ratios found in multiple sclerosis, lupus and other autoimmune disorders. How the female to male ratio works out when referring to retroviral infection is a whole another matter, but for now the facts is the facts.

    http://www.pophealthmetrics.com/content/5/1/5/prepub

    http://www.iacfsme.org/IssueswithCDCEmpiricalCaseDefinitionandPrev/tabid/105/Default.aspx

  5. #5 gf1
    July 1, 2010

    Ignoring the CFS stuff for the moment – there seems to be a real difference between two groups of XMRV studies. One linking it to prostate cancer and CFS and finding it in a relatively high number number of healthy controls, and another group finding no link with these illnesses and no XMRV in healthy controls.

    Even if we assume the CDC’s CFS included no WPI CFS patients, they still tested 225 individuals and found no XMRV. WPI was finding it in 4% of healthy controls.

    If these are blinded studies, could contamination explain this? Could XMRV contaminant show up in the blood samples of immuno-compromised patients, but be controlled in healthy controls? (Sounds unlikely to me, but I don’t really know).

    The stuff around Alter’s paper being held back seems barmy too.

  6. #6 Impish
    July 1, 2010

    This paper again highlights the problem with CFS research. There is no agreed upon marker for CFS. The group the CDC looked in for XMRV is flawed and doesn’t follow the commonly accepted criteria. It is generally called the “Reeves” criteria as it was developed by him. In effect they are looking for XMRV in tired people not those with CFS.

    ERV, did you actually read the whole study? The paper itself actually calls out the fact that they are using different criteria and suggests that this may be the cause of the differenct results yet your blog says it is the same…

    I really really wish the researchers would get their collective shit together and come up with some sort of commonly agreed upon criteria based upon measurable physical characteristics and stick to it. If one group is looking at frogs and another at lizards you are going to get different results.

    Again, there is a bunch of truly sick people who are not being helped by any of this scientific stupidity on either “side”.

    Basically this boils down to a paper examining the amount of XMRV in fatigued people which is still interesting.

    It again makes me wonder why people are looking for XMRV in blood when it was shown in the animal models as being hard to find. Why not look where the animal models shows it was hanging out. I realize the first paper said they found it there but if more information comes out showing that it is hard to find there why keep looking in the most difficult place to find the virus. It seems insane.

    If I was managing this I would:

    1) Establish a common criteria based on something that is measureable and can be agreed upon. There are several recent papers that suggest various bio markers.

    2) Standardize the test. As pointed out by this paper, this is difficult since at the moment there is an “absence of bona fide positive and negative control specimens
    from infected and uninfected humans to determine the analytical sensitivity and specificity of the detection assays”. Couldn’t they have used blood from prostate cancer patients or those found from throat swabs to see if they could find it there? Also couldn’t they have at least used samples from the animal controls from the CROI study? If you don’t know if your test can actually find XRMV is people who has it isn’t your test kind of a waste of time?

    3) Conduct real research

  7. #7 ERV
    July 1, 2010

    Kemanorel– Thats not fair. Hes got no incentive to do anything improper. But I also dont blame PNAS for giving it a closer look before they actually publish it.

    John– Is that the official answer, then? The 51 people in this study who have had CFS for an average of 13.9 years, dont have Real CFS? Because they used the revised 1994 CDC Fukuda Criteria instead of the 1994 CDC Fukuda Criteria, those poor saps were ‘just tired’?

    Okay.

    *blink*

    gf1– Thats a very good point. CFS people are thinking this is all a conspiracy against them, but this has been going on for years. “We can find XMRV in prostate cancer!” “We cant!” “We find an association between XMRV and an RNase L mutation!” “We cant!” “We find XMRV in CFS patients!” “We cant!”

    And we have no reason to believe any samples were blinded in the Science study. That word is never used in the paper, as far as I know. When you are doing subjective assays like looking for a band in an agarose gel (where WPI got their 3.7%) things get fuzzy. Remember how I was bitching about them not doing Real-Time PCR? This is why: quantitative Real-Time PCR is not ‘subjective’. It passes the threshold or it doesnt. They didnt find XMRV in healthy controls with any other test in that paper.

    impish– Did you actually read the whole study? Because this paper mentioned that the WPI paper used two criteria, which are totally different, and dont mention how both were used: the 1994 CDC and the 2003 Canadian Consensus Criteria for CFS/ME. So do do this ‘right’ these folks had to get people from two groups and not tell anyone why/how they chose those two definitions and which patients were what, instead of just the one?

    Once again, I point out the original papers shit description of their methods.

    And once again, CFS patients eating their own by saying these other people werent really sick, they are just ‘tired’. The exact same bullshit ‘Real CFSers’ send me hysterical, shrill emails about.

    The more I write about this, the more some of you totally gross me out.

  8. #8 daedalus2u
    July 1, 2010

    Finding random bacteria and viruses in the blood of people with CFS is not something new.

    http://www.ncbi.nlm.nih.gov/pubmed/12887507

    That does not mean that the random bacteria and viruses associated with CFS are causing it.

    It could be (my hypothesis) that what ever is causing CFS is also causing the random bacteria and viruses in the blood to not be cleared as rapidly.

    This is exactly consistent with my low NO hypothesis. NO regulates the ATP level. Under conditions of sepsis, NO levels are made very high via iNOS (expression of which is regulated by NFkB). This high NO level causes bacteria to not attach and form biofilms; the last thing you want bacteria to do inside your blood stream. If high NO is a sign of bacterial infection in sepis (which it is), maybe physiology uses the NO level as a signal to regulate autophagy inside those cells that have random bacteria and viruses in them? If your body doesn’t need to turn over the contents of immune cells via autophagy to get rid of phagocytosed random bacteria and viruses, it would be better not to.

    If your body doesn’t have enough ATP, maybe it is saving ATP and not turning over the contents of immune cells as rapidly via autophpagy? When immune cells containing internal bacteria have their ATP levels increased, they kill the bacteria inside. I suspect that this regulation of the immune system is a “feature”.

  9. #9 ERV
    July 1, 2010

    Attention freaks from the Phoenix forum, whom I recognize do not represent the CFS community as a whole. The full article of the blip I quoted just became live on Science. This is what your oh-so-civil emails are doing. Quote Dr. McClure:

    “Nothing on God’s Earth could persuade me to do more research on CFS.”

    God I pity the sane people with CFS.

  10. #10 Kemanorel
    July 1, 2010

    Kemanorel– Thats not fair. Hes got no incentive to do anything improper. But I also dont blame PNAS for giving it a closer look before they actually publish it.

    Sorry, it wasn’t fair of me. I also Poe’ed myself a bit. It was meant to be mostly snarky (though I’m a firm believer that every man has his price, and there’s always someone with motivation).

    I wasn’t seriously suggesting we go look at his bank records though.

  11. #11 Prometheus
    July 1, 2010

    Harvey Alter is pretty impressive.

    If he had an ulterior motive it would be the furtherance of his mandate to guarantee a disease free blood supply.

    He wants screening to include viruses that aren’t proven to be, but present a possibility of being, blood borne.

    That being said I don’t think he would ever put his thumb on the scale. He has too much to lose.

    It creeps me out a little in the context of WPI having just recently crawled into bed with Cerus/Intercept and their Blood System to “inactivate” XMRV.

  12. #12 Anonymous
    July 1, 2010

    Vernon has made the following comment on the CDC study. I am not a virologist so I would like to know your ideas on this……

    http://www.cfids.org/xmrv/070110study.asp

    “Further, the samples from these three study cohorts were collected using different types of tubes, each of which has a distinct way of being processed. As if this weren’t bad enough, none of the blood tubes used were of the same type used in the Lombardi study. (They used tubes containing sodium heparin that are intended for use with virus isolation). The blood tubes from the 18 Georgia registry patients are designed to collect whole blood and preserve nucleic acid; it is not clear where the plasma came from for these subjects since plasma cannot be obtained using these blood tube types.”

  13. #13 Jason
    July 1, 2010

    You might say that Alter did nothing wrong (I agree, fwiw), but, I feel like this is further evidence that track 1 submissions are just done.

    It’s a huge honor, already, to become a member of the NAS, but I think it’s time to dispel with track 1s. This is a problem, now.

  14. #14 Grant
    July 1, 2010

    Regards the McClure quote, ouch. It seem nuts to me. By being so busy snapping at the hand that feeds them, they’re alienating people from wanting to help them.

    ** Rushes off to download Science commentary **

  15. #15 daedalus2u
    July 1, 2010

    They are doing to CFS research what was done to autism. The anti-vax, anti-mercury zealots have poisoned the autism field with their crappy studies, distorted and cherry picked idea papers, and their latching on to fads by quacks that have killed children. They are trying to destroy the careers of good researchers they disagree with. Researchers have received and still receive death threats because of vaccines.

    http://www.sciencebasedmedicine.org/?p=5827

    The focus on vaccines and mercury has set back autism research by years. The pseudoscience of the anti-vaccine quacks has poisoned the field so that solid ideas that are “out there” (like my low NO hypothesis of autism) won’t even be looked at because the quacks have used up everyone’s patience.

    The same is happening with the disorder some call Morgellons, fibromyalgia and now CFS.

    I understand the desperation that people suffering from these disorders feel. Desperate people do desperate things. Doing desperate things does not increase scientific understanding. Allowing yourself to be exploited by quacks willing to exploit your desperation isn’t helping either.

  16. #16 Impish
    July 1, 2010

    ERV… You said “They used the same definition of CFS (1994 CDC Fukuda Criteria) as the Science paper.”

    This is WRONG!

    You then responded that the WPI also did a poor job in their paper with documenting who the patients were, which is fair enough. That just makes your original assertion that the patient groups in the two studies were the same even more wrong. How can you say that they are the same when a couple of hours later you are pointing out that the original study didn’t say exactly what patients they used?

    Some CFS patients are going off the deep end and opening themselves up to pseudo science which is screwed up. As is hassling the researchers (if they are honestly trying to do a good job).

    Vocal “scientists” like yourself making loud untrue statements doesn’t help. It makes them feel like they can’t trust scientists. If you are going to loudly publically make comments make sure you have your shit together or you are just making everything worse.

    Again, I really think it has to do with a lack of agreement as to what the illness actually is (which is mentioned in the CDC paper). The issue isn’t really the fatigue (although that is bad) but rather all of the other physical symptoms and the messed up immune system.

  17. #17 ERV
    July 1, 2010

    They both used the 1994 Fukuda.

    The Science paper also used the 2003 Canadian Consensus Criteria.

    So only the people that have CFS under the 2003 Canadian Consensus Criteria have Real CFS, and everyone else is faking?

    Thats why no one else can find XMRV in CFS patients?

  18. #18 Greg
    July 1, 2010

    “And what did Alter do that was so magically different that his lab could replicate the Science paper?
    I’d check his bank statements…”te

    Hang on a minute isn’t this accusing a scientist if fraud.

    Erv should you allow comments that accuse scientists of fraud. I mean you don’t allow Judy Mikovitz to make accusations like that do you. But the sort of accusations you and your blog make against her are even worse.
    Sorry young miss but you set yourself up as some sort of authority and how old are you. Harvey Alter played a major part in the discovery of Hep C. He as a lot of credibility. You are a nobody ERV.

  19. #19 Juicyheart
    July 2, 2010

    Past…. Cain shes blogging about zombie lit.

  20. #20 W. Kevin Vicklund
    July 2, 2010

    “They used the same definition of CFS (1994 CDC Fukuda Criteria) as the Science paper.”

    No they did not. They used the ‘revised’ 1994 criteria, also known as the 2005 ‘Empirical’ definition

    Sorry impish, but you’re wrong.

    From the abstract-

    Archived blood specimens were tested from persons with CFS defined by the revised 1994 CDC case definition

    This is the 1994 Fukuda definition. Here’s an excerpt from a site explaining the Holmes (1988 definition) and Fukuda (revised 1994 definition) criteria [bolding mine]:

    The Centers for Disease Control revised the 1988 CFS definition in 1994 (Fukuda, 1994). It is currently in use for research and clinical diagnosis in the US and most countries abroad. That these definitions were prepared by government bureaucrats, rather than by physicians who had collectively seen, studied and treated thousands of patients with the illness, is testimony to their validity (or lack thereof). Dr. Nancy Klimas from the University of Miami School of Medicine and long-time researcher into immune abnormalities in ME and CFS, commented on the revised 1994 definition: “…the resulting guidelines are rife with ambiguity. Symptoms are counted either as present or absent, without regard to severity or frequency.”

    Here, “revised 1994 definition” means that the definition was revised in 1994, not that it is a revision of the 1994 definition.

  21. #21 Impish
    July 2, 2010

    Is there another disease in which people constantly have the discussion about who has it? Seriously? Even the people who have it end up arguing about who have it among themselves.

    How can you study something when no one can agree what it is that you are studying? The CDC paper talks about how you should be excluding people who have some of the diagnositic markers used by other criteria.

    Until everyone decides whether they are studying fatigued people or people with a series of physical problems (like immune system imbalance, etc.). They should all quit publishing because it is simply so much noise and a waste of time, money and brain power.

    Seriously I have this picture in my mind of 2 scientists each holding a different animal which they both have called the exact same name and then each frantically typing out papers… Plinko’s have 4 ears says Bob… No they have 2 ears says george, etc. etc. etc….

  22. #22 daedalus2u
    July 2, 2010

    Impish, no. The only way disagreements in science get hashed out is by people publishing their differences and disagreements, doing more experiments and publishing those until they do get hashed out.

    Yes, there are disagreements about diseases all the time. The DSM is being re-written for exactly that reason, definitions of diseases change over time as more becomes known about them. This hasn’t happened much with CFS because enough basic research hasn’t been done to understand what it is, let alone how to treat it. Differential diagnosis is only useful for differential treatment. If there is no differential treatment, a differential diagnosis has no clinical utility.

    Articles in the scientific literature are communications from one scientist to another scientist. From one expert to another expert. They are not intended for lay readers. They are written by and intended for experts in the field. If experts in the field disagree, what role do non-experts have to step in and adjudicate that disagreement? Not much. Maybe a non-expert can pick up obvious errors. But subtle things? No, a non-expert doesn’t have the expertise to do that, no matter how much feeling and personal experience they bring to the issue.

    Consensus agreement in science only comes from the bottom up. If it comes from the top-down it is very likely wrong. Without knowing the physiology of CFS, it is impossible to know which symptoms are important. Without knowing which symptoms are important it is impossible to know what the physiology of CFS is caused by.

    The hype over this virus and CFS is not being produced by scientists (mostly), it is being produced by non-scientists with vested interests in the outcome; the WPI PR department, commercial interests, CFS patients who want “validation”. None of these have any effect on the reality of the results or whether or not all CFS is caused by this particular virus, or if any CFS is caused by this virus. No amount of lobbying is going to change reality.

  23. #23 ERV
    July 2, 2010

    See edit above– The PNAS thing was what I suspected. They sent it out for their own reviews, who in turn asked for more experiments. Exactly what would have happened to Alter with a non-PNAS journal.

  24. #24 Richard Jefferys
    July 2, 2010

    Has anyone looked for XMRV-specific CD4 and CD8 T cell responses? It seems like an obvious thing to do, and it would quickly raise a red flag if the results were not concordant with the virology.

  25. #25 gf1
    July 2, 2010

    That Nature article said that only three of the CDC CFS patients had acute onset. That is crazy low. It’s more normally around 50%.

    I really don’t see how these cohort issues can be the explanation for the differing results, but it has all been an eye opener for the way different groups are studying such different patients with CFS.

    It’s slightly amusing that for decades CFS patients have been complaining that psychological researchers are using ever looser definitions for what was originally seen as a serious neurological disorder. Now the CDC paper complains that the WPI may have skewed their results by looking at patients with signs of a serious neurological disorder, which should be exclusionary for CFS. It’s gone 180.

    I’m focusing on their results for healthy controls for now. When that settles down, and we get more confident the the testing is accurate, then we’ll have to sort out the CFS mess.

  26. #26 Impish
    July 2, 2010

    Thanks for the great responses. If I think of the papers as a conversation between a group of people the whole thing makes more sense to me.

    I do stand corrected about the criteria. I was busy and didn’t sit down with a printed copy. The devil is in the details. The “Georgia” patients were collected through a dodgy telephone methodology in which 50% of them hadn’t ever seen a doctor about their symptoms prior to be included in as part of the patient group. (http://www.cdc.gov/cfs/cfsgastudy.htm)

    I apologize for CFS patients. Seriously. This comment really explains why they are so upset, worried and willing to emotionally latch on to XMRV.

    “This hasn’t happened much with CFS because enough basic research hasn’t been done to understand what it is, let alone how to treat it.”

    This is a disease that has been around now for 30 years and so little research has been done into it that the scientists involved still can’t agree as to what it is. The criteria used by the CDC is so broad that the worry is on the part of people who are really really ill is that people who are not sick are getting into the studies and messing up the science. Here are the CDC criteria (http://www.fatigueregistry.org/Sites/fatigueregistry/Default.aspx?pid=678) :

    • Current severe fatigue persisiting for one month or longer
    • One of the following for at least one month:
    – Unrefreshing sleep,
    – Problems with memory or concentration, or
    – Unexplained joint or muscle pain in the lower extremities
    • Age: 12 to 59, inclusive
    • Body mass index (BMI) les than 40.0

    Frankly, if I was a researcher studying people who match the above criteria would seem on the boring side. They don’t sound particularly sick. On the other hand compare that to this group of patients (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876037/) whose immune systems are seriously messed up.

    “By ROC analysis, NKCC and dipeptidyl peptidase/CD26 were identified as potential biomarkers for CFS through their demonstrated accuracy in discriminating CFS patients from healthy controls.” The science of this is beyond me but from the little I can follow with my undergrad and wikipedia it way more accurately describes the immune system problems I can observe in my n=1 sample than the vague criteria.

    Here is a statement on the impact of CFS from the CDC ironically enough “CFS is a public health priority as less than 20% of patients have received a diagnosis and the average family of a CFS patient foregoes $20,000 in annual earnings, resulting in an annual loss of 9.1 billion in productivity for the United States.”

    I realize this is a bit off topic but given the negative impression I feel that researchers are getting of CFS I wanted to say something in a public forum.

    I (and most people who know a truly ill CFS patient) don’t care if it is XMRV or something else. We just want someone to figure it out. The person I know immune system is so messed up that she gets each and every virus that comes by. It has been like this for 30 years. Please help… that I hope is a fair bit more interesting than someone who has felt a bit tired for a few months and suffered from some leg aches.

  27. #27 ERV
    July 2, 2010

    Richard– Neat idea! But no :)

    Anon– Re: Vernons statements. I honestly dont ‘get’ Vernon. She was obsessed with the ‘tubes’ in her reply to the first negative paper. I think its weird. But let me break it down into a few chunks:

    1– This paper did not look for XMRV in 41 people. They looked for XMRV in 292 people. If all of the healthy people were healthy, and all the CFS patients were fakers, and all the HTLV/HIV patients werent immunocompromised, they ‘should’ have found evidence of XMRV in 10-11 people if WPIs 3.7% number is accurate.

    They found zero. Even in the HIV-1 patients.

    2– I had no trouble following where they got patients. Some were from GA. Some were from KS. All were age/gender/race/location matched with a healthy control. All were evaluated by physicians. You can read all about the KS cohort here (you can tell by the abstract this group doesnt believe in CFS by the way they said “CONCLUSIONS: Chronic fatigue syndrome constitutes a major public health problem.”) and you can read all about the patients and how they were evaluated under the heading “Clinical assessment”. I genuinely dont understand why Vernon was confused, here.

    3– I dont get the tube thing, at all. This isnt exactly an art. I use the same tubes for isolating plasma, any kind of white blood cell, viruses– Corning polypropylene tubes. The blood comes to us in a bag (youve seen them– just the collection bag every blood bank on the planet uses). *blink* And why do special tubes for ‘isolating virus’ matter, when no one has isolated virus directly from ‘positive’ individuals? The tube thing weirds me out.

    4– Once again, we have a Pro-XMRV–>CFS ‘scientist’ accusing other scientists of outright fraud. Vernon: “this was a study designed to not detect XMRV”. THIS IS NOT NORMAL OR ACCEPTABLE SCIENTIFIC BEHAVIOR. EVER.

    gf1– I am just completely grossed out. “CFS IS SO AWFUL! ITS WORSE THAN AIDS! POOR ME! POOR PITIFUL ME!! THE ESTABLISHMENT THINKS IM FAKING!” out one side of their mouth, and “NO ONE HAS CFS BUT ME! EVERYONE ELSE IS FAKING! EVERYONE ELSE IS JUST TIRED! FAKERS!” out the other side.

    impish– There is nothing ‘dodgy’ about it. CFS is underdiagnosed. They did phone surveys. If you said certain answers, you came in to see a physician, and were properly diagnosed with CFS. Turns out these people were sick, on average, of 13.9 years, and werent properly diagnosed over that period of time. You dont feel sorry for them for that, but instead call them fakers, the exact same thing you castigate non-CFS people for saying??

    WTF!

  28. #28 Impish
    July 2, 2010

    Hard to say if CFS is underdiagnosed or not since the diagnostic criteria are disagreed upon. I shouldn’t have called their methodology “dodgy”. That was unfair. It accurately found a group of patients that they are interested in and consider to have CFS according to their standards. This again highlights the root cause of the issue behind all of this research. No ageed upon completely objective marker that everyone agrees that:

    X indicator = CFS.

    No agreed upon indicator also means that saying you had something for a certain length of time is difficult as well.

    The study in Wichita suggests that using their methodology and criteria about 2.35% of all people have CFS which is a lot of people. I am not convinced what I think of as CFS (which I am sure you are going to jump on me for) is in 2.35% of the population. It would be a heck of alot more visable.

    I don’t remember calling them fakers? All I said is that under the criteria used by the CDC (which I listed) you are likely to get patients who don’t have the immune system dysfunction which seems to be one of the most visable and worst part of what is wrong with the person I care about.

    What I was saying is that the group that I am interested in is described thusly : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876037

    This describes what is happening to the person that I know using objective criteria which then can be used as a first step to hopefully to figure out what is wrong. I don’t care if you call it CFS or Oggly Boogly disease.

    I worry that as long as the researchers disagree about what CFS is there is going to be crap science all around. If the CDC papers recommendation is followed regarding changing the criteria to exclude people with certain physical illnesses it would exclude who I know with the disease. Again I am ok with it as long as they come up with a criteria for that group (as above) and someone is conducting research into what is going one with those people.

    I am hoping that people with disfunction as laid out in the above paper are interesting enough to researchers like yourself that it will catch your attention and you will look into it.

  29. #29 Prometheus
    July 2, 2010

    I can’t help myself. I love their forum.

    If Schadenfreude tastes like candy, Phoenix forums was built by Willie Wonka…..

    “We have far bigger enemies now than her.”

    “connected to Wessley, McClure”

    “doesn’t publish our comments”

    “paid to write for Science Blogs”

    “a factual dossier about her as a forum topic”

    Hey Abbie they say you are poo. ERV equals poo.

    I am giggling my head off. Yay poo.

  30. #30 Impish
    July 2, 2010

    Yes, Prometheus. A bunch of sick, desperate and scared people are upset and doing and saying stupid things out of panic.

    Certainly something to feel secretly good about. Good on you.

  31. #31 ERV
    July 2, 2010

    I think it goes without saying that a group of people stalking someone are, collectively, ‘sick’.

  32. #32 harold
    July 2, 2010

    I think the problem in this line of research is overwhelmingly related to the difficulty of making a correct diagnosis of CSF. I am rapidly coming to the conclusion that “unexplained chronic fatigue” would be a better terminology.

    I am NOT saying that to disparage in any way the suffering of the people who have this set of symptoms or who have been diagnosed with this disorder.

    Is there another disease in which people constantly have the discussion about who has it? Seriously?

    Yes, there are many disorders that can only be defined as a constellation of individually non-specific symptoms and/or laboratory tests, and this is NOT a “wrong” way to practice medicine. Many if not most valid diseases were recognized in this way; in many cases, development of definitive, specific testing follows recognition of a disease or syndrome. There is a feedback loop, as better testing may then lead to better elimination of false positives and a more refined definition of the disorder. The relationship between AIDS and HIV is a very clear example of this sort of development.

    Unfortunately, fatigue is a particularly non-specific finding.

    “• Current severe fatigue persisiting for one month or longer
    • One of the following for at least one month:
    – Unrefreshing sleep,
    – Problems with memory or concentration, or
    – Unexplained joint or muscle pain in the lower extremities
    • Age: 12 to 59, inclusive
    • Body mass index (BMI) les than 40.0″

    This list of symptoms could be found in anything from clinical depression to numerous modest chronic nutritional deficiencies to non-specific viral infections cause by well known modestly pathogenic viruses. Obviously, a competent clinician has ruled out all of the more obvious potential causes before someone is given the diagnosis of CSF.

    Nevertheless, I think unexplained chronic fatigue is the better terminology. We certainly can’t be sure that this group of patients are homogenous with respect to etiology.

    The definitive finding of a specific viral infection in a group of patients is ALWAYS at least of great interest (I am not saying that this finding alone would prove viral etiology).

    A problem here is that, given the hypersensitivity of modern PCR technology, we have to be sure that the apparent finding of viral infection is valid. Other valuable information would be quantified detection of virus over time and its relation to symptomology, and, as someone said, immune response, or its lack, in patients and controls.

    Clinical laboratory tests are standardized, but these claims are being made at the research level. Having said that, there does not seem to be an issue of positive tests in the normal controls, so false positives, while still a concern, are not overwhelmingly so.

    In short, although the patients are suffering, we can’t be sure that all the groups of patients studied have the same disorder – and that’s even true if the same current criteria were rigorously adhered to, and indeed, in this case, even if they actually have essentially the same symptoms, since these symptoms are so non-specific. Furthermore, we need to be sure that at least some of the patients actually do have the virus, and that the same finding is not common in asymptomatic controls. Then we can begin to think about the relationship of the virus to the symptoms.

  33. #33 Impish
    July 2, 2010

    “I think it goes without saying that a group of people stalking someone are, collectively, ‘sick’.”

    I agree. Stalking someone is messed up as is any other form of anti-social behaviour due to someone else not agreeing with you.

  34. #34 Impish
    July 2, 2010

    Thanks harold. Thanks for the information and comments. That is a much better written description of what I am trying to get at so I can be quiet now. I really hope the science follows along the path you laid out instead of what seems to be going on right now.

  35. #35 harold
    July 2, 2010

    Impish –

    Thank you.

    (I will note that prostate cancer is not the most straightforward and uncontroversial entity in the world either, but I won’t open that can of worms right now.)

  36. #36 Levi
    July 2, 2010

    Hmmm.

    Discrepant findings in different studies. Would it make any difference if the original patient cohort in the Science Paper were cherry picked by a selection process using software employing 27 different biomarkers together with Random Forest Algorithms designed in conjuction with experienced CFS clinicians to predict which people have the illness?

    Or that the new CDC research patient cohort was selected in good measure by a psychiathrist using a psychological questionaire designed to select for emotional disturbances and childhood sexual abuse? Just a hypothetical question.

  37. #37 ERV
    July 2, 2010

    Levi– As gf1 (and I) have tried to point out, it doesnt matter where they got any of the patients or how.

    Even if 100% of the people they used were 100% healthy, they still should have found ~10 people who were positive, according to the WPIs oft repeated 3.7% number.

    If 3.7% of the population is infected but healthy, there is no physical way the CDC could have ‘cheated’ or ‘gamed the system’, because they couldnt tell who would be positive before they tested, even if they picked 292 perfectly healthy people.

    In reality, the CDC did not pick 292 perfectly healthy people.

    So as Ive been saying for, what, 9 months now? The WPIs 3.7% number is indicative of a high false positive rate in their PCR. Its not real, even according to their own experiments, because they couldnt find XMRV antibodies in any of their healthy controls!

    But keep saying that all those people with CFS are fakers, really, Im loving this, asshole. “IM NOT FAKING… THEYRE FAKING! THEYRE JUST TIRED! THEY WERE SEXUALLY ABUSED!… IM REALLY SICK, THOUGH! DONT YOU DARE CALL ME A FAKER!” Asshole.

  38. #38 Levi
    July 2, 2010

    Right,

    All of the Zero+subject/Zero+control research so far would indicate that the 3.7% incidence in the general population is wrong and way high. The new CDC paper is throwing out a +-.1% number for the general population. How does that sound to you? This retrovirus has been out at least since 2006, we should at least have a handle on that number by now. Right?

    Assuming the CDC is correct with the .1% number, how would my hypothetical play out since you did not really address the question? The Science cohorts had all been tested into oblivion to establish biomarkers. Mikovits added the Random Forrest algorithms. Many of the CDC patients had never even seen a doctor until they became part of the study. Certainly the CDC paid little attention to biomarkers, let alone predictive methodology. And personally, I do not have a dog in this particular hunt, but I sorta like the ad-hominem stuff. Your thoughts are appreciated regardless.

  39. #39 qetzal
    July 2, 2010

    Levi,

    Two possibilities:

    1) Mikovits et al. somehow managed to come up with some near-perfect combination of markers and/or other selection criteria that enabled them to pull out a group of patients that are 66% XMRV positive. (Or 90+%, if you believe some of the their later anecdotal claims.) In that case, the vast majority of other patients who think they also have CFS (i.e. all the people tested in the various XMRV negative studies) actually have something unrelated to the WPI group.

    2) The Mikovits et al. data is somehow wrong.

    (1) is certainly possible, but I’ll admit my inclination is towards (2).

  40. #40 John
    July 3, 2010

    ERV, how is it you understand everything there is to understand about CFS when you know absolutely nothing about CFS? Is it some zen thing, a la “She who knows nothing knows everything”?

    No one is saying that the patients in the psychological and CDC studies are fakers. What people are saying, and have said many times before, is that fatigue is a common component of many ailments, including anxiety disorders, depression, PTSD, etc. Furthermore, there are two distinct groups of researchers involved in the field of ‘CFS’ research- one group who believes CFS is a primary behavorial disorder which is characterized by ‘abnormal illness beliefs’, ie a person believing themselves to be suffering from an actual disease instead of the supposed behavorial disorder the behavorialist believes them to be, combined with a phobic avoidance of exercise, and another group of researchers who recognise CFS to be an organic disease process which is completely distinct from any sort of behavorial ailment.

    Given the two different ‘models’ for the illness and the fact that ‘fatigue’ is a component of the aforementioned psychiatric disorders, wouldn’t it be reasonable to expect two completely different patient groups in the respective researchers studies? I wonder if the problem isn’t whether you understand this simple concept, but rather that you simply won’t allow yourself to believe that something so monumentally, totally, completely comprehensively and abysmally fucked up could be going on in the scientific field in 2010 with no one knowing about it. Except that lots of people know about it and have known about it for the past several decades, it’s just that no one will listen. ‘Kafka-esqe’ is the best descriptor I’ve heard applied to the situation CFS patients find themselves in.

    The thing is, none of the above psychiatric and/or behavorial ailments are characterized by the hallmark symptom of CFS, which is post-exertional malaise, ie the significant worsening of symptoms following even trivial amounts of exertion. Combine PEM with neurocognitive disturbances and unrefreshing sleep and you have the makings of a syndrome, or a collection of symptoms which characterizes a disorder. Chronic fatigue syndrome, in fact.

    In the 1994 CDC criteria, PEM, unrefreshing sleep and memory/concentration problems are optional. The Canadian Criteria, which was used in the Science study, makes them mandatory. It basically rests on the whims of the researcher. Psychiatric researchers can finagle people with anxiety disorders, depression, etc. into the 1994 Fukuda criteria, while the Canadian Criteria was created in an attempt to weed these patients out of CFS research. No one is saying these individuals are ‘fakers’, merely misdiagnosed.

    However this study did not even use the full Fukuda criteria, as explained above, it used the 2005 ‘Empirical’ definition which allows reduced activity as a result of emotional disturbance to qualify for the ‘fatigue’ symptom, with ‘reduced activity’ being a hallmark of depression, anxiety disorders, etc.

    From the Materials and Methods section of the study-

    “Illness classification
    Following clinical evaluation, participants who had no exclusionary medical or psychiatric conditions were diagnosed with CFS if they met criteria of the 1994 international case definition [23] as quantified by the CDC Symptom Inventory and ancillary criteria of the MFI and SF-36 [26, 31]. We used the MFI to assess fatigue status [28]. For classification as CFS, those with a score ≥ well- population medians on the general fatigue or reduced activity scales of the MFI were considered to meet fatigue criteria of the 1994 international case definition. Functional impairment was assessed by the medical outcomes survey short form-36 (SF-36) [29]. For classification as CFS, those with a score ≤ 25th percentile of population norms in the physical function or role physical, or social function, or role emotional subscales of the SF-36 were considered to have substantial reduction in activities as specified in the 1994 definition. Those who met at least one but not all 1994 criteria were considered unwell not CFS. Those who met none of the criteria were considered well.”

    The CDC basically pulled the various percentages and subscales of the SF-36 used to classify patients out of their asses based on a total of something like 10 patients in the Wichita study, with some suggesting the reason CDC did this was because they had lost so many patients to follow up from their initial telephone surveillance that they had to expand the criteria or they would have basically wasted the $2 million they had already spent in the previous years. It’s a whole another subject which you know absolutely nothing about yet are probably the world’s authority on at the same time just like everything else to do with CFS.

  41. #41 Smurfette
    July 3, 2010

    Once again, we have a Pro-XMRV–>CFS ‘scientist’ accusing other scientists of outright fraud. Vernon: “this was a study designed to not detect XMRV”. THIS IS NOT NORMAL OR ACCEPTABLE SCIENTIFIC BEHAVIOR. EVER.

    The weird thing is she’s not exactly pro-XMRV either. The WPI seems to hate her. She and the CFIDS Association were tarred and feathered and terrorized even before the first negative study came out for not being pro-XMRV enough. A vocal constituency demanded that she write these sorts of responses to each negative study. After she started writing these sorts of reviews, the terrorizing stopped. I think she is pandering to this vocal constituency. Which is wrong on many levels, but doesn’t even make sense on a wrong level since I doubt the people she’s pandering to are donors or even potential donors.

    The Georgia study showed that the application of the same 1994 CFS definition can produce prevalence estimates that vary up to 10-fold from other studies. So it’s possible that even using the same definition doesn’t mean a whole lot. However, even taking the worst-case scenario, let’s say only 10% of their CFS patients have actual CFS, you’d still expect them to find about 3 out of 51 CFS patients with XMRV if it were to match the WPI’s finding of 67% of CFS patients positive for XMRV. (Unless the application of the 1994 CFS definition in the Georgia and Wichita studies somehow totally excluded the WPI type of CFS patients.)

    http://www.pophealthmetrics.com/content/5/1/5

    We estimated that 2.54% of the Georgia population suffers from CFS, which is 6- to 10-fold higher than previous population-based estimates in other geographic areas. These differences may reflect broader screening criteria and differences in the application of the case definition.

  42. #42 Smurfette
    July 3, 2010

    The following articles make it sound like it was the authors’ own decision (via the Department of Health and Human Services) to put the paper on hold and conduct more experiments.

    http://news.sciencemag.org/scienceinsider/2010/07/journal-publishes-cdc-paper.html

    “UPDATE 2 July: The authors of the PNAS paper have decided it needs more work. Corresponding author Harvey Alter of the NIH Clinical Center, who is in Berlin this week, issued this statement on 30 June: ‘Our paper has not yet been accepted for publication. My colleagues and I are conducting additional experiments to ensure that the data are accurate and complete. Our goal is not speed, but scientific accuracy.’ NIH spokesperson John Burklow explained to Insider that the paper had been accepted, but Alter and his co-authors decided to ‘pull it back’ and revise it in response to questions raised by reviewers.”

    http://blogs.wsj.com/health/2010/07/01/cdc-teams-xmrv-chronic-fatigue-syndrome-paper-is-out/

    “John T. Burklow, a spokesman for NIH, says the FDA-NIH paper has been accepted for publication but that the authors decided to pull it back to conduct additional experiments.”

    Similarly for the other paper.

    http://online.wsj.com/article/SB10001424052748703374104575337160225739290.html

    “Kuan-Teh Jeang, editor-in-chief of Retrovirology, said the Switzer paper went through peer review and was accepted for publication when he got a call from the authors earlier this month. They asked that the Retrovirology paper be held.

    ‘My understanding was HHS [Department of Health and Human Services] wanted to get it straightened out. Both reports are from different branches of the government,’ Dr. Jeang said.

    In an email between scientists familiar with the situation, viewed by the Wall Street Journal, a researcher said the two teams were asked to put their papers on hold because senior public-health officials wanted to see consensus—or at least an explanation of how and why the papers reached different conclusions, said the people familiar with the situation.”

    http://blogs.wsj.com/health/2010/07/01/cdc-teams-xmrv-chronic-fatigue-syndrome-paper-is-out/

    “Switzer says that after the FDA-NIH team submitted a paper with results different from their own, the CDC group decided to take a ‘scientific pause’ to look at both papers, compare study methods and do additional experiments. After this review, they decided to proceed with publication—and he says no changes were made to their original manuscript.”

  43. #43 Andrew
    July 3, 2010

    Daedalus2u said:

    “They are trying to destroy the careers of good researchers they disagree with”.

    With respect, this is mostly BS. These angry crackpots are a very small minority. But the point is that if there was quality research conducted at a rate proportional to the economic costs of such diseases, then the effect of those voices would be much smaller. Right now, sufferers and advocates are fighting over scraps.

    By the way, some of us have actually had what has appeared to be a severe reaction to an immunisation. My “CFS” case was rapid onset, with symptoms starting about a week or so, perhaps slightly less (hard to remember exactly, I’d have to check medical records to confirm) after an oral polio immunisation. My symptoms have always been taken seriously by all medical practitioners involved, however most of the testing was to exclude known reaction mechanisms – eg Guillain Barre and the like.
    I’m not saying I know precisely what the cause was, it could have been a coincidence. Yet, until we have a reasonable explanation, the possibility itself cannot be ruled out.

    My symptoms now are not as severe, but it is still a real struggle to continue my BSc. It’s been over 10 years and I’m getting rather disappointed about the continued lack of quality research for CFS in general.

    ERV said:
    “You dont feel sorry for them for that, but instead call them fakers, the exact same thing you castigate non-CFS people for saying??”

    Actually, you are one of the primary people who is saying this. It is not helpful for you to lower yourself to such levels by engaging in such inflammatory sarcasm.
    Many others have suggested that while there may be shared aspects, CFS might not be a homogeneous condition in terms of etiology.
    It is perfectly reasonable to ask that specific subsets be tested – based on activity, particular biological markers and so forth.

    It is true that certain individuals involved have been very unprofessional (such as certain people from the WPI), but that doesn’t mean you should accuse Alter (a guy who has something to lose reputation wise) of anything much until his paper is actually released.

    I’m personally a bit pissed off about both the supposed (albeit temporary) censorship and these leaks/rumours – we shouldn’t be discussing “conformation” findings until after such research is actually published. But whatever, it’s done now…

  44. #44 gf1
    July 3, 2010

    This Science reply mentions the initial study being blinded: http://www.sciencemag.org/cgi/content/full/328/5980/825-d

    I can’t remember where I read this, and it sounds a bit crazy, but I thought I’d mention it as could be unsurprising for those who know about how Science mag works: Apparently Science mag weren’t that interested in the more ‘medical’ side of the WPI’s work. They were focused on the fact that they’d isolated XMRV from patient’s blood, etc. They weren’t so interested in the CFS stuff, and thought that the blinded testing was more appropriate for a medical paper than a Science one.

    If Science wanted the paper to focus on one set of things, and the WPI were committed to focusing on CFS, could that help explain why the paper seems to be rather cursory with some information?

    re The CFS patient selection stuff: It seems like the way CFS has been researched generally is even more screwey than I’d realised. I had been assuming that the different criteria were just broader or tighter (still potentially a problem). When you look at the reported characteristics though it really sounds like quite different groups of patients – with the new CDC paper talking about some of the signs the WPI used to diagnose as being potentially exclusionary under the CDC definition.

    Whatever happens with XMRV, I hope this encourages some higher up bods to come in a sort this out. It seems a crazy way to treat people. Currently CFS patients are not being tested for the kinds of things the CDC are saying could be exclusionary – and if they’re excluded from a diagnosis of ‘real CFS’ work should be put into finding out what is wrong with them.

  45. #45 ironlad
    July 3, 2010

    Why not a simple blind exchange study of WPI’s specimens at CDC and vice versa…. at least for starters.

  46. #46 SAWells
    July 3, 2010

    To John @39: you seem to have missed the bit where ERV is interested in virology, not CFS, and has been commenting on the highly dubious virology behind the supposed CFS/XMRV link- and of course the associated bad-science weirdness now surrounding Mikovits.

  47. #47 Levi
    July 3, 2010

    You guys should make allowances for bartenders that publish virology studies in scientific publications; they approach things a bit differently than the “ivory tower” crowd to be sure. I have no problem with smack-talking researchers (or grad students) on either side of this issue; blast away, but please get back to some science from time to time.

    Can anyone here tell me what is up with the goats in the new CDC study? Four years on from the initial Silverman publication in 2006, and we still have no bonafide XMRV positive humans to use for confirmation? What am I missing here? Or does it just not matter since as long as you are dealing with the correct gene sequences, you can put together a conclusion?

  48. #48 theshortearedowl
    July 3, 2010

    I have been following this serial drama for sometime now (thanks for sticking with it ERV, you rock), and there’s one thing that always bothers me. CFS is a condition with somewhat nebulous symptoms – please note that I am not even implying that it’s not serious – just that it’s hard to define clinically, and almost impossible to quantify. As Impish says, there is no test that says “X+ve you have CFS; X-ve, you don’t.” Furthermore, the symptoms are common to many different diseases.

    Subsequently, it is almost certain that patients diagnosed with “CFS” have a range of different “diseases”. That much I think people recognise. However, and this is the catch, there may not be any one “real CFS”. There may be a range of causes – diminished immune response, nutritional deficiencies, metabolic abnormalities, genetics, psychosomatic illness, chronic viral infection. These may *all* be real and valid causes of what is known as CFS. That’s even before the large numbers of patients who are just a bit tired and would rather whine to their doctor than deal with their problems or get some exercise (again, please note I am saying that these are not “real CFS” sufferers; but I know from numerous sources in the medical profession that these patients also exist).

    As with anything in medicine, anyone trying to sell you the “one true cause” can be considered full of it until proven otherwise (karma to Orac).

  49. #49 ERV
    July 3, 2010

    Levi– I dont believe that ‘you dont have a dog in this fight’, mainly, because Im not stupid. Also, its unwise to use that analogy on a blog that has a picture of a pit bull as the author image, but whatevs.

    Regarding the 0.1% figure, I referenced a post in the past I wrote on that topic in the OP.

    Smurfette– Glad youre still here. And this does sound like something scientists would do of their own volition. Its one thing to delay a paper a bit to do more experiments. Like I said, I dont think this is any different than what would have happened if Alter sent his stuff to, say, Journal of Virology). But its embarrassing as hell to have to retract a paper (people do sometimes just make mistakes, but retraction is the infamous result of fraud, see Andrew Wakefield). Id rather run through OKC naked than retract a paper (and OKC is a very large city, square mileage wise…) Its not a hard decision between the two options.

    Andrew– This time last year, I didnt know/care anything about CFS. But after interacting with CFS patients, I realize there are a few things YOU DO NOT DO, like, suggest they are faking, or that they are just tired, or that they are depressed, etc. If one makes such a suggestion to a CFS patient, they flip the fuck out. Thats fine, whatever. But the second these negative papers came out, the first fucking thing out of these same peoples mouths is, “THOSE PEOPLE DONT HAVE REAL CFS!!!”

    I ask very little from anyone. I do expect intellectual consistency. The people in all of these studies have been evaluated by physicians and diagnosed with CFS. I dont particularly care if every damn person diagnosed with CFS ‘just tired’, the hypocrisy of these people telling someone else, whom they have never met or evaluated medically, that they ‘dont have real CFS like I do’ is shocking.

    Throwing all of those people with the same syndrome as they have under the bus to protect their savior, the XMRV hypothesis and The Bartender. And then expect me to believe that they are ‘just interested in good science’ and will ‘follow science where it leads’.

    Bull. Shit.

    Also, I thought I made it very clear in my post and my comments in this post, I dont accuse Alter of anything, and actually go out of my way to point out he didnt do anything wrong… I swear I write in Greek or something…

    gf1– Oh! Youd think that is an important fact they would have put in the original paper… LOL! God that paper was crappy! I didnt read it critically at all last fall!

    ironlad– The Dutch group sent some of their samples to the WPI. The WPI ‘found XMRV’, but was unable to distinguish between the CFS and the healthy samples. Technically, they ‘found’ more ‘XMRV’ in the healthy controls. For some reason, WPI isnt publicizing this fact. They put all of their hateful letters online, and all of the responses… except the ones from the Dutch group. Hmmm…

    theshortearedowl– Very good point. But what gf1 and I have tried to point out, is that even completely ignoring the CFS diagnosis of these people and treating them all as normal healthy individuals (even the ones with HTLV or HIV-1/2), people cant find XMRV. It doesnt add up with the number the WPI keeps screaming, 3.7%, even if you take CFS out of the equation completely.

  50. #50 levi
    July 4, 2010

    ERV,

    You are probably not stupid. Respectfully, you might drop the quotes when you paraphrase someone rather than directly mis-quote them; its better form. Precisely what I meant by my statement of “personally, I do not have a dog in this particular hunt” is that I do not want or need a CFS diagnosis. So I am not throwing anyone with unexplained illness under the bus. I just am not lumping them all together under one umbrella diagnosis. I care about all of them. Really.

    To paraphase Dr. McClure from your quote above; Nothing on God’s Earth could persuade me to invite or accept a diagnosis of CFS from an M.D. It is the penultimate “wastebasket” diagnosis. Also, as far as I know, I am not XMRV positive, nor would I ever want to have an infection with a retrovirus that is likely mutagenic in humans, although that is not yet proven. You can have it, I don’t want it.

    You may have seen me post to Phoenix Rising and designated me to immediate villian status. Its ironic that I have been moderated with wrist slaps and had my posts deleted there for challenging them to think critically about CFS. Thats all I am asking here. Use your experience and knowledge and think critically. Qetzal did a fine job of that with my question, I know you can too if you choose to.

  51. #51 thomas_bernhard
    July 4, 2010

    Prometheus, either you completely misunderstand the concept of Schadenfreude (which I doubt), or you’re in complete denial about the degree to which you yourself epitomize it.

  52. #52 daedalus2u
    July 4, 2010

    Andrew #42, with all due respect, that insufficient resources are being focused on CFS is not the fault of people not working on CFS research. ERV has no role in determining levels of CFS research funding, why bitch at her because CFS researchers are doing sloppy and incomplete work and are not making any progress? A small minority of vocal crackpots has had a very large effect on autism research. This could easily happen in CFS research too. If it does, it will set back CFS research too.

    I have read a great deal on CFS, and I think this XMRV approach is a complete dead end and will produce zero benefits to CFS patients and no successful CFS treatments. I think that any benefits patients have perceived from antiretroviral treatments are due to placebo effects. In my opinion CFS research money spent on XMRV is CFS research money that is wasted. I think the approach that CFS research has been taking is misguided in general.

    The common symptom of CFS is fatigue. Many disorders have the symptom of fatigue. Is there any evidence that fatigue from CFS is fundamentally different than fatigue from any other source? No there isn’t. A state of fatigue is a common physiological state. There must be physiology that produces the state of fatigue, there must be physiology that resolves the state of fatigue. Very little is known about the physiology of fatigue because there has been little research on it because fatigue is such a common symptom, and there is the perception that “fatigue” can always be resolved with stimulants or via rest. These don’t work with CFS. Stimulants actually don’t resolve fatigue either, all they do is mask the feelings of fatigue, the physiology that results in the symptoms of fatigue is still there (and is made worse by stimulants). Because there has been little work done on fatigue, and then with crappy protocols, the fact that stimulants don’t really resolve fatigue is not appreciated. Stimulants resolve some symptoms, they do not resolve all symptoms, they do not resolve the underlying physiology that physiology invokes fatigue to protect itself from.

    I see the problem of fatigue in CFS as a problem in the control system that physiology uses to resolve a state of fatigue. Organisms exhibit fatigue for a reason, so that organisms don’t try to consume ATP that they don’t have the metabolic capacity to make. Voluntary muscle can be worked until it exhausts its ATP supply and dies. You can work your muscles to death, but it hurts like hell to do so. That is a “feature”, so you can run yourself to death while running from a bear. Fatigue keeps you from running yourself to death when a bear is not chasing you. This is why exercising when one has taken stimulants or pain killers is so dangerous, you mask the control signals of fatigue and pain and you can do serious damage to yourself.

    What causes fatigue is not enough ATP generation capacity in muscle. That ATP generation capacity in muscle is due to mitochondria. Mitochondria biognesis is triggered by NO. Not enough NO results in not enough mitochondria and eventually results in CFS (my hypothesis). I discuss how acute mitochondrial failure during immune system activation happens.

    http://daedalus2u.blogspot.com/2008/06/mechanism-for-mitochondria-failure.html

    What CFS research needs is more attention to the final common pathway(s) of fatigue. Many of those pathways involve nitric oxide physiology which is extremely difficult to study because there are so many degrees of freedom and they are all coupled.

    Because fatigue is such a common symptom of so many different diseases and disorders, no one wants to spend their research money on someone else’s problems. Fatigue research is “high risk” because you can’t just take a DNA sequence and get an answer the way you can looking for XMRV. The answer with XMRV may not mean anything in terms of CFS, but the research program will still have an “answer”, even if that “answer” gets us no closer to effective treatments for CFS. XMRV research for CFS is “low risk” because it is a problem that is easily stated and with enough money can be answered definitively. That the answer might not mean anything doesn’t enter into the “risk” calculation.

  53. #53 Impish
    July 4, 2010

    I think ERV paraphrases and ignores parts of comments to pick a fight which drives traffic I assume?

    Anyhoo… The changing numbers of how many people have XMRV is interesting.

    WPI says 3.7% The german study found 3.2% and the microarray found .1%.

    I would be interested in someone else looking for it in throat swabs.

  54. #54 Stephen Wells
    July 4, 2010

    Impish, do you seriously think ERV wants MORE CFS traffic?

  55. #55 harold
    July 4, 2010

    To document a significant relationship (that’s “relationship”) between CFS and XMRV the following would be required –

    1) CFS diagnosed in a reliable manner.

    2) Unequivocal detection of a viral load in some patients; unequivocal statistically significant difference between patients and controls. The current standard seems to be a binary approach – virus is sought with very sensitive PCR techniques and then designated as being “present” or “not present”. If this is the standard it should unequivocally be “present” more often in patients than controls to even consider a relationship.

    3) As I mentioned above, more detailed anaylsis of the relationship between detection and level of virus, and immune response to virus, with symptomology, would be of great interest.

    I ask very little from anyone. I do expect intellectual consistency. The people in all of these studies have been evaluated by physicians and diagnosed with CFS. I dont particularly care if every damn person diagnosed with CFS ‘just tired’, the hypocrisy of these people telling someone else, whom they have never met or evaluated medically, that they ‘dont have real CFS like I do’ is shocking.

    Lest there be any confusion, I strongly agree with this. Dismissing failure of another group to replicate original results with a cavalier assertion that they “studied people who ‘don’t really’ have CFS” is ridiculous.

    It is also true that the symptoms which undeniably cause suffering in this group of patients, which amount to unexplained chronic fatigue, are very non-specific. At this point in time, even people who were unequivocally correctly diagnosed, both meeting the criteria and having been throroughly studied to rigorously rule out other causes, could conceivably be a heterogenous group. That is just reality. This statement is most certainly not disrespectful to the patients who suffer from this issue.

    Issue “1)” above can be addressed by using concensus criteria, including ruling out of other obvious possible explanations of the symptoms. But until the disorder is better understood, heterogeneity of etiology remains possible.

    ironlad– The Dutch group sent some of their samples to the WPI. The WPI ‘found XMRV’, but was unable to distinguish between the CFS and the healthy samples. Technically, they ‘found’ more ‘XMRV’ in the healthy controls. For some reason, WPI isnt publicizing this fact. They put all of their hateful letters online, and all of the responses… except the ones from the Dutch group. Hmmm…

    If true, exceedingly strong evidence that critical issue “2)” above has not been adequately addressed, that they may be either generating false positives or detecting an incidental finding which is not related to CFS status, and that, by extension, their results are not meaningful. Critical. A particularly valuable (but costly) next step would be for an independent lab to attempt to replicate WPI’s original results, on WPI’s original samples, or at least samples from the original patients and controls. If even that fails to replicate the results, game over. If WPI’s results can at least be independently coroborated on their own samples, inappropriate methodology is still highly possible, but a higher level explanation for what is going on would need to be sought.

    But what gf1 and I have tried to point out, is that even completely ignoring the CFS diagnosis of these people and treating them all as normal healthy individuals (even the ones with HTLV or HIV-1/2), people cant find XMRV. It doesnt add up with the number the WPI keeps screaming, 3.7%, even if you take CFS out of the equation completely.

    Again, if true, a major concern. This suggests that there are serious differences in sensitivity between the groups. In an imaginary worst case scenario, and I exaggerate here for effect and don’t mean to refer to any real people, we might have a group who detects XMRV non-specifically in everyone, arguing against an oppositely incompetent group who can’t detect it in anyone. Less extreme variations are also a major problem if each group is trying to replicate the others results, while using non-comparable methodology.

    The whole thing is a confusing mess at present.

  56. #56 Prometheus
    July 4, 2010

    thomas_bernhard@#50

    “Prometheus, either you completely misunderstand the concept of Schadenfreude (which I doubt), or you’re in complete denial about the degree to which you yourself epitomize it.”

    Perhaps.

    It is probably better described as an infantile predilection for absurdity.

    Since I can’t stop people from turning a medical condition into a political religion I can only laugh at them or cry for them.

    I choose the former because abuse, unlike pity, preserves the self respect of people who have any quality of character to begin with.

  57. #57 ironlad
    July 4, 2010

    Thanks for the reply….

    The Dutch group sent some of their samples to the WPI. The WPI ‘found XMRV’, but was unable to distinguish between the CFS and the healthy samples.”

    can you give me the source for this info please…..

    also…in this regard….I have just seen that WPI in their press release the other day said they “sent 20 confirmed positive samples” along with their “methodology” to CDC in Sept 2009. I have not anything about this before. Do you know what happened.

  58. #58 qetzal
    July 4, 2010

    ironlad,

    See here.

  59. #59 goldfinch
    July 6, 2010

    Thanks, ERV, for the methods critique. I can criticize the inclusion criteria and such myself but I’m not fully qualified to examine the methods. I really want to understand this both because I’m a biologist (undergrad degree only) and because I’m a person with ME/CFS (which is why, so far, no further education but I sure hope that one day we figure out an effective treatment and I can pursue advanced degrees and, like, work a substantial amount).

    I prefer to call it ME/CFS because the name Chronic Fatigue Syndrome tends to cause confusion between the disease and the symptom of (persistent) fatigue, and tends to make the illness seem trivial (seriously, surveys show that medical students shown the exact same charts will attribute more seriousness to the patient’s condition if it’s called “Florence Nightingale Disease” or “Myalgic Encephalomyelitis” than they do when it’s called “Chronic Fatigue Syndrome”). If I had five dollars for every time I’ve complained to a doctor that my fatigue was preventing me from doing basic ADL’s and the doctor replied, “many Americans are fatigued”, I could have bought a whole semester’s worth of textbooks.

    The problem of inclusion criteria was brought up but I don’t think it was fully discussed. As was mentioned, there are several different definitions. Most of them can be found here. The 1994 “International” CDC case definition, or Fudka definition, is a follows:
    ” 1. Clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset (i.e., not lifelong), is not the result of ongoing exertion, is not substantially alleviated by rest, and results in substantial reduction in previous levels of occupational, educational, social, or personal activities.
    2. The concurrent occurrence of four or more of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours. These symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue.” The definition goes on to list a number of other common symptoms which may be present but “do not contribute to diagnosis.”

    The Switzer paper, however, described the condition thusly:
    “CFS is characterized by a severe debilitating fatigue lasting at least six consecutive months that is not alleviated with rest. Individuals with CFS also report various cognitive, sleep and musculoskeletal pain disturbances, and symptoms similar to those of infections diseases.”

    The Switzer paper gives no diagnostic weight to the additional diagnostic criteria of the Fudka definition (and they leave out the more specific ones entirely). Despite what they may say, they are not using the Fudka (1994 CDC “International”) definition. Their use most closely matches the Oxford definition, which requires only fatigue and allows a few additional very general symptoms. Although Oxford, by definition, rules out other medical conditions which would produce similar fatigue, it doesn’t rule out most other psychiatric conditions. It lacks specificity so, in practice, it includes many patients with other identifiable disorders which would explain the fatigue, as well as patients who are fatigued but do not fit into any of the other, more specific, definitions (including Fudka) of ME/CFS. The very general approach of the Oxford criteria makes about as much sense as if one were to study “febrile illness” and try to find common mechanisms and treatments among all such patients, describing their specific disease (not how the body produces fever). Less sense, really, since fewer diseases produce fever than produce fatigue.

    The Fudka definition and the Canadian definition are somewhat different, but the two definitions definitely have overlap. An advocacy organization estimates that 80% of persons with CFS (Fudka) have cerebrospinal inflammation (Myalgic Encephalomyelitis, the name used by the Canadian definition) and 20% do not, suggesting an extensive overlap. How that was determined is unclear. An examination of both definitions, however, should convince most people they have at least a fair degree of similarity.

    Switzer et al., however, argue that it’s appropriate that the XMRV-negative studies used 1994 CDC [sic] and Oxford (well, this does makes sense only when you redefine Fudka to match Oxford), but it’s not appropriate that Lombardi et al. used Fudka and Canadian.

    Probably the reason Lombardi added the Canadian to the US’s CDC definition was the known tendency for the CDC definition to be slippery in some researchers’ hands. (If post-exertional malaise was made a mandatory symptom, this would likely clear up a lot of the difficulty associated with use of Fudka. And yes, this type of fatigue characteristic of ME/CFS is different from ordinary fatigue one experiences from going to bed too late or from vigorous exercise… it’s more like how you feel when have a bad case of the flu, or how you would expect to feel if you were on an interminable forced march which exceeded all rational limits in general and your ability in particular, and you hadn’t quite enough rations, so that your body was always exhausted, never able to increase in fitness.)

    Switzer &co go on to complain that: “Most notably, the Canadian Criteria include multiple abnormal physical findings such as spatial [sic] instability, ataxia, muscle weakness and fasciculation, restless leg syndrome, and tender lymphadenopathy.”

    An odd gripe from a group purporting to use Fudka criteria, which specifically includes tender lymphadenopathy on the list of diagnostic symptoms (as well as difficulty concentrating or with memory, which is not out of line with, say, ataxia). And Fudka specifically includes balance problems on the common symptoms list.

    It’s also difficult to conceive how fatigue at such a severe level (“a dramatic decline in both activity level and stamina,” as the CDC reports, reducing at least by half one’s ability to carry out work or play) without admitting an alternate description of “muscle weakness,” especially when another criteria from the diagnostic-supporting set is post-exertional malaise (sickness reaction and pathologic length of recovery time after exertion–even relatively mild exertion; CFS does, after all, limit daily activities, not merely prevent one from training for a triathalon). Not to mention it’s difficult to imagine that half the Georgia patients with supposedly this level of fatigue for more than 6 months, never consulted a physician about it. Maybe some few who couldn’t afford a single office call or, conversely, maybe a few who could afford to drop their work hours down to part-time and didn’t mind not having a social life anymore, but, half?

    Switzer &co go on, “The physical findings in persons meeting the Canadian definition may signal the presence of a neurologic condition considered exclusionary for CFS and thus the XMRV positive persons in the Lombard study may represent a clinical subest of patients…”

    This is would be an extraordinarily peculiar contention if it weren’t so common among the Oxford/psychosocial crowds. In fact, the World Heath Organization classifies Chronic Fatigue Syndrome under classification ICD 10 G93.3 as a neurological disease. Japan classifies it directly between Lupus and MS. As noted, CDC’s own definition includes some neurological signs and symptoms. The Fudka and Canadian definitions exclude definite diagnosable conditions, such as Multiple Sclerosis and Myasthenia Gravis (which are supposed to have been ruled out by the physician prior to considering a diagnosis of CFS), but do not in any way exclude abnormal clinical findings or neurological signs and symptoms, provided these fall short of some definite alternate diagnosis.

    Those using Oxford, unfortunately, tend to encourage the primary care clinician (or GP, as they say over the pond) to not run very many tests on a suspected CFS patient (explaining that it’s not unusual to find some clinical abnormalities which, they insist, would not contribute to differential treatment) but to refer to patient to a psychiatric clinic. The psychiatric clinics then assert that the patients would never have been referred to such clinics if there were any biological abnormality present at all. It’s quite terrible.

    As to the Switzer remark about a clinical subset, kind of…. but definitely not. Patients with ME/CFS represent a subset [using mathematical language, not clinical] of patients with persistent fatigue (the Oxford definition). This makes about as much clinical sense as saying Pneumonia may represent a clinical subset of patients with febrile ailments. Or that the common cold may represent a subset of patients with headache. No serious researcher would investigate febrile illness or headache-producing ailments in order to understand or describe the entirety of such a “disease” or set of ailments, and it is difficult to understand why investigation of fatiguing illness is countenanced (are there many diseases which do not produce fatigue?).

    Okay, so much for inclusion.

    Switzer &co conclude: “These data do not support an association of XMRV with CFS.”

    The only conclusion which can be drawn from these data (absent consideration of any procedural or analysis problems) is a suggestion that XMRV is not endemic in the populations studied, something ERV mentioned.

    Or the Switzer study could help researchers decide which of the various procedures (Switzer, Lombardi, and of the three European groups) are best used to detect XMRV in a clinical setting, but this could happen only when the various studies and their respective procedures are replicated several times.

    The Switzer study cannot make any claims regarding CFS as a clinical entity because the study failed to define any particular clinical disease (although the study could support a non-association between XMRV and unexplained or uninvestigated fatigue generally).

  60. #60 ironlad
    July 6, 2010

    “I have just seen that WPI in their press release the other day said they “sent 20 confirmed positive samples” along with their “methodology” to CDC in Sept 2009. I have not anything about this before. Do you know what happened.”

    Seems like this started a buzz…… any more info on this. I have not seen anything else….

  61. #61 qetzal
    July 6, 2010

    goldfinch writes:

    The Switzer paper, however, described the condition thusly:
    “CFS is characterized by a severe debilitating fatigue lasting at least six consecutive months that is not alleviated with rest. Individuals with CFS also report various cognitive, sleep and musculoskeletal pain disturbances, and symptoms similar to those of infections diseases.”

    The Switzer paper gives no diagnostic weight to the additional diagnostic criteria of the Fudka definition (and they leave out the more specific ones entirely). Despite what they may say, they are not using the Fudka (1994 CDC “International”) definition.

    With all due respect, you seem to be overinterpreting a summary statement from the introductory part of the paper, and ignoring the much more detailed information from the methods section. The statement you quote isn’t meant to describe the authors’ formal definition of ME/CFS. It’s just a general description for the introduction.

    If you want to dispute the authors’ criteria for diagnosing ME/CFS, you need to address the detailed information under “Illness classification” in their manuscript (see page 17 at this link).

    Note: I’m not arguing that their actual criteria were fine, or that they were equivalent to WPI’s or anyone else’s. I don’t know enough about the different criteria to do that, and my interest is too peripheral to dig that far into it on my own.

  62. #62 gf1
    July 6, 2010

    This part from the paper makes it all reasonably clear (although as with qetzal, I feel a little out of my depth):

    “The 1994 International CFS case definition and the Canadian Consensus Criteria are different and do not necessarily identify similar groups of ill persons. Most notably, the Canadian Criteria include multiple abnormal
    physical findings such as spatial instability, ataxia, muscle weakness and fasciculation, restless leg syndrome, and tender lymphadenopathy. The physical findings in persons
    meeting the Canadian definition may signal the presence of a neurologic condition considered exclusionary for CFS and thus the XMRV positive persons in the Lombardi et al. study may represent a clinical subset of patients [11].”

    This just seems odd to me in a number of ways, but the clearest example is with tender lymphadenopathy. I’ve often seen tender lymph nodes being mentioned as a common feature of CFS. Medline Plus (apparently connected to the NIH) says:

    http://www.nlm.nih.gov/medlineplus/ency/article/001244.htm

    “Other symptoms:
    * Lymph node tenderness in the neck or armpit

    Physical examination may show:
    * Lymph node swelling
    * Lymph node tenderness”

    Now the CDC think this could instead indicate an exclusionary diagnosis instead?

    I’m a bit worried I’ve misunderstood something, as I’ve not seen anyone else complaining about this, but it all seems rather odd to me. I thought the above paragraph was rather creepy within the context of the prolonged debate that have been going on with regards to CFS diagnosis, and the role that the CDC and Reeves seem to have played within it.

  63. #63 hemiphage
    July 6, 2010

    “They used the same definition of CFS (1994 CDC Fukuda Criteria) as the Science paper.”

    No they didn’t, they used Reeves’ “Empirical definition” that bears hardly any resemblence to Fukuda. That still can’t explain zero findings though, but there are a number of other possible methodological flaws.

  64. #64 goldfinch
    July 6, 2010

    qetzal, my prior post was overly long and you must have missed my examples because of that. I’m not overgeneralizing their summary statment because the Switzer group specifically complained that the Canadian definition was diagnosed using certain symptoms which do appear in Fudka (and because they listed fatigue as the only diagnostic criteria–“patients may report x” is not diagnostic; it’s an extra symptom).

    Tender lymphs is one of the diagnostic characteristics of Fudka. Spacial instability, or loss of balance, is one of the other observed (extra) symptoms in Fudka. You cannot correctly state you’re using Fudka and then say diagnostic and other noted syptoms of Fudka are exclusionary. Fudka from the CDC I noticed that they don’t, there, identify it as Fudka but merely say they redefined Holmes because it wasn’t specific enough (Lord grant a similar desire for specificity today). The Trans-NIH Working Group for research on CFS inentifies Fudka as this revision. Holmes, Canadian, and Oxford are on that page, too (except they forgot the sore throat of Fudka). Extra symptoms from CDC. Notice Fudka: “sore throat; tender lymph nodes” and arthralgia are diagnostic-contributory. “Difficulty maintaining upright position, dizziness, balance problems or fainting” and “visual disturbances (blurring, sensitivity to light, eye pain)” are extra, and fall into possibly-neurological category, and correlate to loss of spacial orientation, a symptom Switzer complained about.

    The largest ME/CFS association in the US has an even longer list of other noted symptoms and includes muscle twitching (fasciculation).

    So the Switzer group says they’re using Fudka, but they’re not. They’re using Oxford, which fails to define any particular disease.

  65. #65 goldfinch
    July 6, 2010

    gf1, you should feel creeped out. :) You didn’t misunderstand; Switzer group use actual symptoms, at least one of which is diagnostic, of CFS as exclusionary criteria. Yes, Reeves (and he’s an author of the Switzer paper) and others at the CDC and a many European researchers want to study fatiguing illness as a whole instead of studying any particular disease. Argh.

    New topic: I found an article which said XMRV is found more endemic in the US than in England when looked at in connection to prostate cancer also.

  66. #66 goldfinch
    July 6, 2010

    sorry, wrong link in my #63, which should be: The Trans-NIH Working Group for research on CFS identifies Fudka as the mid 90’s revision to Holmes that the CDC is supposed to be using and that the NIH says is “the currently the accepted research definition.” (Trans-NIH page, no date, accessed today.) The actual Fudka with lymph tenderness and slight swelling.

  67. #68 hemiphage
    July 7, 2010

    Sorry, the link to the Kitei’s blog got mangled, this should work:

    http://www.cfscentral.com/2010/07/fdanih-paper-in-limbo-patients-unite.html

  68. #69 qetzal
    July 7, 2010

    goldfinch & hemiphage,

    The Switzer manuscript states:

    Following clinical evaluation, participants who had no exclusionary medical or psychiatric conditions were diagnosed with CFS if they met criteria of the 1994 international case definition [23]….

    Reference [23] is Fukuda et al. (1994) The chronic fatigue syndrome – a comprehensive approach to its definition and study. Annals Internal Med 121:953-959. That’s the Fukuda definition, right?

    A full-text link to Fukuda et al. is available on the CDC website here. It states:

    A case of the chronic fatigue syndrome is defined by the presence of the following: 1) clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset (has not been lifelong); is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial rEducation [sic] in previous levels of occupational, educational, social, or personal activities; and 2) the concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred during six or more consecutive months of illness and must not have predated the fatigue: self-reported impairment in short-term memory or concentration severe enough to cause substantial rEducation [sic] in previous levels of occupational, educational, social, or personal activities; sore throat; tender cervical or axillary lymph nodes; muscle pain; multijoint pain without joint swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and postexertional malaise lasting more than 24 hours.

    There’s no mention of spatial instability or loss of balance. Tender lymph nodes is a criterion, but that’s not necessarily the same as the “tender lymphadenopathy” of the Canadian criteria. As I understand it, the latter means the nodes are tender and swollen. I’m not an MD, so I can’t vouch for the significance of that difference, but perhaps Switzer et al. are objecting that swollen tender lymph nodes could indicate an ongoing infection, where tender but non-swollen nodes would not.

    Regarding exclusionary conditions, Switzer et al. state:

    The physician’s evaluation and routine clinical laboratory tests served to identify medical conditions considered exclusionary for CFS, specified in the 1994 case definition [23] as further clarified by the International CFS Study Group in 2003 [31].

    And indeed, Fukuda et al. have a section on conditions that exclude a diagnosis of CFS. Reference [31] (full text link) just clarifies those exclusionary conditions. It doesn’t seem to change them or add new exclusions. Interestingly, [31] contains the following statement:

    Designated accompanying symptoms include the following: [...]; and tender cervical/axillary lymph nodes. It is important to stress that these are symptoms not signs. Signs such as inflamed tonsils or swollen lymph nodes should prompt the search for alternative diagnoses.

    Again, this suggests that tender lymph nodes are viewed differently than swollen lymph nodes.

    In summary, your claim that Switzer et al. don’t really use the Fukuda criteria doesn’t seem to be supported by the published information.

  69. #70 Andrew
    July 7, 2010

    daedalus2u – given the funding available, CFS researchers are producing excellent results – the problem is very little money is spent in general due to CFS being placed in the ‘too hard’ basket.

    I always mention the pitiful amount of money spent on CFS research compared to the economic costs because it is so important. It really is a naked emperor and it needs to be repeated whenever CFS research is discussed.

    Published Estimates of economic costs to the USA (slightly dated) have ranged between $9 billion (2004 CDC estimate), to a more recent estimate of up to $24 billion, published in Dynamic Medicine (this info is from my notes..).

    How much is spent on research? Peanuts.

    I agree that viral testing is one of the few methods that still remain in the ‘not so hard’.
    Though I wonder why certain studies haven’t used proper live human controls. If you draw the blood fresh from both controls and patients, then it removes most of the uncertainty and potentially unecessary debate about the storage (seriously, some doctors are complaining about the types of tubes used!) and these cohorts of questionable/variable diagnosis that every XMRV study so far has used.

    As in a previous comment on ERV’s blog, I have also stated that I don’t believe that XMRV ’causes’ CFS, at least in a majority of cases. It is however interesting how viruses such as XMRV, various Herpes viruses, non-polio Enterovirus etc, have chronic reactivation in specific subsets. It is pretty clear there is an immune system component to this disease, but this may be a symptom rather than a causative factor.

    Anyway, good luck with your research.

  70. #71 gf1
    July 7, 2010

    Thanks for the qetzal. Funny that elsewhere swollen lymph nodes are mentioned as something to expect turning up upon a physical examination of CFS patients, but here it says that should lead you to a different diagnosis.

    The testing suggested in the paper you linked to is also far more extensive than most current CFS patients seem to have received. Maybe loads of CFS patients should be classed as having exclusionary conditions, but because of the way CFS is seen they’re unlikely to be identified?

    It all seems a shocking mess to me. We need an army of Dr Houses to go around examining all these patients individually and coming up with astounding medical revelations.

  71. #72 qetzal
    July 7, 2010

    OK, now I may have to eat my words, to some undetermined degree. I now see that the disagreement goes beyond what symptoms are used (i.e. those listed in Fukuda et al.). It also encompassed the specific way that they’re measured.

    Switzer et al. note that they used the Multidimensional Fatigue Inventory (MFI) and the Medical Outcomes Survey Short Form-36 (SF-36) to assess fatigue status and functional impairment. Apparently, some believe these methods give substantially different results from the “original” Fukuda. Some apparently call this the 2005 CDC Empirical Criteria (or similar).

    Here is one site I found that talks about this.

    So perhaps I’m wrong to argue that Switzer et al. used the “same” Fukuda criteria. Perhaps among CFS researchers, it’s agreed that the “Fukuda criteria” doesn’t include the use of MFI, SF-36, etc. I don’t know. All this does for me is further underscore the mess that’s been made of CFS diagnosis.

  72. #73 goldfinch
    July 8, 2010

    Qetzal, you’re correct that how symptoms are assessed are different.

    However, the list of criteria is still different. The difference between Fudka strictly applied and Switzer is a minimum of 5/9 versus 2/5 symptoms. Also Switzer mentions as exclusionary 1 diagnositc and 1 non-diagnostic symptom of Fudka….

    Fudka 1994 requires profound debilitating fatigue producing an at least 50% (they revised that to “significant”?) reduction in ordinary “occupational, educational, social, or personal activities”, plus at least 4 from a list of 8 additional diagnostic-supporting symptoms: http://www.cdc.gov/cfs/cfsdefinitionHCP.htm
    Some other symptoms are mentioned which are found in CFS but do not contribute to diagnosis under Fudka:
    http://www.cdc.gov/cfs/cfssymptoms.htm
    This is where you find “difficulty maintaining upright position, dizziness, balance problems or fainting”. Not diagnostic but observed (therefore allowed and not in any way exclusionary). So a minimum of 5 out of 9 diagnostic.

    Switzer requires severe (but does not seem to enforce that) persistent (it’s unclear that they enforce that, either) fatigue plus 1 symptom out of a list of 4. So a minimum of 2 out of 5 diagnostic.

    More links on the loosened definitions producing non-CFS in CFS category here:
    http://dps.sagepub.com/content/20/4/251.abstract
    http://www.biomedcentral.com/1741-7015/3/19/comments#337629
    Reeves is one of the authors of the Switzer paper.

    The lymph condition for CFS is tender (and possibly slightly swollen, but not swollen enough to produce an alternate diagnosis). Fudka and Canadian both exclude alternate diagnosis such as that produced by fully swollen lymphs. Canadian definition specifies “Tender lymph nodes”.
    http://orwh.od.nih.gov/cfs/aboutDiagnosis.html

    According to NIH, the one accepted research definition in the U.S. is 1994 strict Fukda. This is also the definition CDC uses under their CFS page. Both of these links are above.

    I hope that helps.

    I also think it’s very unlikely that XMRV causes CFS. I appreciate the media attention, I think, but it always seems to leave out the established physical findings. With or without XMRV, CFS is making progress in learning about the biology of CFS and even advancing possible laboratory tests to support diagnosis.

  73. #74 qetzal
    July 8, 2010

    goldfinch, you wrote:

    Switzer requires severe (but does not seem to enforce that) persistent (it’s unclear that they enforce that, either) fatigue plus 1 symptom out of a list of 4. So a minimum of 2 out of 5 diagnostic.

    Can you please point me to proof of this?

    The full text link to Switzer et al. is here. As I noted in comment #67, they clearly claim to have used Fukuda et al. (ref [23] in the manuscript) for diagnosing CFS. See the first sentence under “Illness Classification” on page 17. Fukuda et al. clearly require the debilitating fatigue plus 4 of the additional 8. I don’t see how Switzer et al. could claim they followed Fukuda while only requiring 1 out of a list of 4. And I don’t see anything anywhere else in the manuscript that’s consistent with what you’re claiming.

    So again, can you please point me to evidence to support what you’re saying? (Apologies if you already linked to it in a prevous comment, but if so, I missed it.)

    Regarding the spatial instability, your own link notes that such symptoms

    may be related to CFS, or they may indicate that you have another treatable disorder.

    That’s entirely consistent with what Switzer et al. said (page 14; emphasis added):

    The physical findings in persons meeting the Canadian definition may signal the presence of a neurologic condition considered exclusionary for CFS….

    They don’t say that spatial instability automatically excludes a diagnosis of CFS. Just that it *may* signal an unrelated condition, which (arguably) *could* be misdiagnosed as CFS.

    Regarding lymph nodes, I did see that the Canadian criteria seem to refer only to tender nodes, just like Fukuda. I’m not sure why Switzer et al said they include lymphadenopathy. That may well be a mistake on their part.

  74. #75 goldfinch
    July 9, 2010

    I may need to partially revise my statement as well… this is more complicated every time I look at it, and I made an error in not reading all of the study earlier… Switzer mentions patients assessed for 8 Fukuda criteria (without specifying what those 8 are) but says they were assessed using a symptom scorer with a Reeves citation. Complaints about the Reeves symptom scorer include criticism that one doesn’t necessarily need to have vary many of the symptoms to reach a positive score (it seems any one symptom can produce a score of up to 16 while only 24 points are needed to be positive) and fails to differentiate between CFS and major depressive disorders.
    http://www.biomedcentral.com/1741-7015/3/19/comments#337629
    read the study referred to here:
    http://www.co-cure.org/Jason-7.pdf
    and the study being dicussed here:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1183246/

    There were problems assessing fatigue and activities as well. Switzer states that fatigue was assessed through surveys as either due to fatigue or reduced activity without claiming fatigue (which would seem to include sedentary lifestyle choices).

    Similarly, reduction in activity was included when due to emotional causes or no specified causes were even if there was no reduction due to physical causes. CFS is not depression, as the CDC correctly explains. (Although depression may be comorbid as it is in other chronic disease, depression is not a feature of CFS itself and certainly not diagnostic-contributory. Many patients with CFS have no depression or any psychiatric condition).

    It remains unclear why Switzer says a diagnostic criteria of Fudka (sore lymphs) is exclusionary and a noted symptom (spatial instability or balance issues) is exclusionary.

    So I guess we could revise Switzer to 3/9-1, technically, but practically can be 0/8.

  75. #76 goldfinch
    July 9, 2010

    The reasons they don’t seem to enforce the criteria is because, for length, “There was poor correlation between illness classification during surveillance (recruitment classification) and classification by the same criteria during the clinical study.” Wichita cohort.
    And from your link (which was good; thanks for sharing)
    “Even with summed scores for the empirical case definition needing to be greater or equal to 25 (Reeves et al., 2005), the overall level of symptoms seems relatively low for patients with classic CFS symptoms (the criterion would be met if an individual rated only 2 symptoms as occurring all the time, and one was of moderate and the other of severe severity).
    “In addition, the 8 case definition symptoms were based on a time period comprising the last month compared to what is specified in the Fukuda et al. (1994) criteria, which states that: ‘There needs to be the concurrent occurrence of 4 or more of the following symptoms, and all must be persistent or recurrent during 6 or more months of the illness and not predate the fatigue.’”

    Severity:
    See previous post. Plus, half of the Georgia group had not ever consulted a physician for their “debilitating” fatigue. Ever. While there may be a few who couldn’t afford even a single office call, or a few who could drop work down to part-time and skip having a social life and be okay with all that and think they could tough or wait it out… but, half? Debilitated and not seeking help?

    balance issues:
    Switzer said they “may signal” a nuerological condition, but if they meant “may”, there should be no issue with this as a difference between Fukuda and Canadian, because the only difference is whether it’s required for diagnosis or optional–but both Fukuda and Canadian require investigation of other diagnosable conditions, so this symptom wouldn’t be needed when there were sufficient conditions to form an alternate diagnosis. This should be mostly a non-issue. Every patient diagnosed with Canadian meets Fukuda (although not every Fukuda meets Canadian, but still the use of Canadian can’t invaliadate Fukuda). Yet Switzer brought it up for some reason. It sure doesn’t seem to have been to point out that this symptom might *or might not* be exclusionary. It sounded to me (color me cynical because of the ongoing row over whether CFS is primarily physiological or psychological–when there’s abundant evidence it’s physiological, and the psychological crowd always wants to use less restrictive criteria such as Oxford or the “empirical” Reeves questionnaire revision) that they were saying CFS has no business having symptoms indicating possible neurological involvement.

    WHO classifies ME/CFS as a neurological disease.

  76. #77 gf1
    July 9, 2010

    I guess that all of the symptoms of CFS ‘may’ indicate another disorder.

  77. #78 qetzal
    July 9, 2010

    goldfinch,

    I think we’re mostly in agreement now. Switzer did use the Fukuda criteria, but used the Reeves 2005 approach as their method to decide whether the diagnostic CFS symptoms were present. The concern raised by critics is that the using the Reeves approach gives a substantially different set of patients than using the ‘original’ Fukuda (sans Reeves).

    It’s easy for me to believe that could be the case. I don’t have the medical training to really judge in this case, but there’s no question that how you score a clinical symptom can make a huge difference.

    The biggest thing that’s still unclear to me in that regard is how the symptoms are scored in the ‘original’ Fukuda approach. The reason clinical researchers develop things like the Reeves approach is to try to increase standardization across physicians, to ensure that everyone really is talking about the same group of patients. As best I can tell, before Reeves 2005, there wasn’t any standard method for scoring if a patient did or didn’t have any of the 8 Fukuda symptoms. If so, that raises the concern that different docs would be more likely to reach different conclusions on whether a given patient met the criteria.

    I assume Reeves 2005 is intended to fix that, but if it simultaneously gives a substantially different patient group than before, that’s obviously a big problem.

    I interpret the balance issue a bit differently than you. I agree that all the criteria (Fukuda, Canadian, Fukuda+Reeves/Empirical) require checking for other conditions. I think what Switzer was implying, with their comments on instability and “tender lymphadenopathy,” is that the Canadian criteria are biased towards misdiagnosis of other neurological or infectious/inflammatory conditions as CFS. It’s really no different than the others who argue that Switzer et al. are biased towards misdiagnosis in other ways. Each “side” is claiming that the other side is wrong because they’re not studying “real” CFS patients.

  78. #79 goldfinch
    July 9, 2010

    To answer previouis question, my fewer symptoms from Switzer came from the statement about the referral to Registry of Unexplained Fatiguing Illness and CFS: such referred patients “met criteria for unexplained fatiguing illness (fatigue for > 1 month) and having at least one other core CFS symptom during that period (unrefreshing sleep, problems with cognition or memory, joint or muscle pain in extremities) and did not have an exclusionary medical or psychiatric condition.” Evidently there is some feeling, whether from the Registry or from Switzer (or both), that these few are the “core” symptoms of CFS. This would approximate the Oxford criteria.

    Ok, about the scoring:

    Fatigue:
    Fukuda–severe fatigue that patient reports is substantially reducing activities (pt quantifies symptoms), is not resolved by rest, and is not from ongoing exertion. Must have lasted at least 6 months.
    Reeves–above criteria is considered to be satisfied if two items from the standard MFI survey reveals relatively increased rate of either general fatigue or reduced activity not necessarily connected to fatigue. (pt quantifies symptoms)
    Fatigue is not necessarily required under Reeves. Debilitation is not required under Reeves (any distinguishable reduction seems to qualify).

    Reduction of activity:
    Fukuda: decrease in activities (pt. quantifies as substantial), secondary to specific CFS symptoms such as fatigue and cognition difficulties.
    Reeves: decrease in activities (pt. quantifies) relative to population, for any reason (including secondary to personal/emotional problems)
    CFS symptoms causing the reduction in activity is not necessarily required under Reeves. Debilitation is not required (considers a full 25% of the population to have a pathological reduction of activities)

    Fukuda CFS-diagnostic symptoms:
    Fukuda: At least 4 of the symptoms must be concurrently present, not pre-dating fatigue. All 4 must be continuous or recurring.
    Reeves: At least 4 of the symptoms must be present, and the score of severityxfrequency of combined symptoms must be at least 25 (they don’t all need to be significant; two at 3×4, and two at 1×1 fulfills totally).
    It’s unclear whether Reeves assesses the comparative onset of these symptoms with “fatigue” (as they consider it above), but it doesn’t seem to do this. The symptoms don’t necessarily all need to be continuous or recurring, or otherwise significant.

    The difference in the “scoring” is that Reeves assigns numbers (which could aid in tracking a patient’s condition over time, in a way which can be quickly located in the records). The actual Fukuda criteria, however, are degraded with the Reeves surveys when used as a diagnostic tool: Reeves includes substantially less adverse effect, and Reeves allows Fukuda criteria to be considered as satisfied when they are not.

    Example: Myra has muscle aches and unrefreshing sleep. She reports a reduced activity as compared to her friends. She reports occasional slight difficulty concentrating and rare moderate headaches.
    No obvious sleep or other disorder is present and she doesn’t have bipolar disease or anything huge like that.
    Fukuda: she does not have CFS
    Reeves: she has CFS

    Either way, she may benefit from medical intervention. Sudying her case will not, however, aid in the understanding of CFS.

    Example: Lisa gets worn out from attempting ordinary housechores. If she tries to work longer or do the heavier chores, she’ll be wiped out for days. She has difficulty standing up for very long; she gets dizzy and feels sick and weak. She sometimes looses her balance for no apparent reason. She says all her cells feel nauseated. Her throat is often sore, especially on her bad days. She gets more migraines from more kinds of triggers than ever before. Although she always used to be very active, she can no longer do even moderate exercise for more than about 5 minutes, even though she may continue to try. She can’t work many hours and she can rarely manage social excursions, both due her CFS symptoms. She often has word-finding difficulties, and she can’t remember something she was just told 3 times in a row. She has joint pain, but no swelling or redness. She has an elevated ANA (or C-reactive protein), but no change in SED rate and no Lupus rash. Her other labs are fine. MRI is negative for MS or tumor. Physical neurological exam (walk on heels, grip this, close eyes while standing, etc.) detects no abnormalities. No CD or NK studies are performed. She keeps a generally positive outlook, although, being rational, she gets discouraged sometimes–this all has been going on a long time. (Or she may experience depression either as a result of her condition or as a comorbid condition.) She tries to strike a balance between maximum productivity and minimum symptoms, even though how much she can do without triggering a flare-up changes all the time.
    Fukuda: she has CFS
    Reeves: she has CFS

    Example: Sarah feels tired all the time. She isn’t very active, and she seldom goes out because it doesn’t sound fun. She tells her sister she’s an emotional mess. She takes sick days or leaves work early. She marks the survey indicating this is from emotional causes. Her muscles hurt, and she can’t seem to pay attention to anything. She gets occasional headaches (who doesn’t?). She also marks the survey for having occasional sore throat (that nasty smog). For whatever reason, doctors fail to diagnose her with any alternate ailment (or, they diagnose her with depression but not any of the major depressive disorders).
    Fukuda: She doesn’t have CFS
    Reeves: She has CFS

    Again, she’s definitely unwell and would benefit from intervention. Studying her case, however, will not contribute to knowledge about CFS.

    This is why I disagree that both could be useful criteria. Reeves/Switzer/Oxford group patients together who are not similar. While the surveys could be useful in identifying patients who need some kind of medical intervention, they cannot be used to identify or study any particular condition–the range of patient types included is too diverse. Reeves’ attempt to quantify symptoms numerically does not resolve any limitations of Fukuda.

    Example: Rita has an undiscovered exclusionary condition, but fits all the criteria of Fukuda.
    Fukuda: she has CFS (inappropriate use of definition)
    Reeves: she has CFS (inappropriate use of definition)

    No improvement from Reeves. Undiscovered condition is undiscovered condition, whichever criteria is used.

    An alternate criticism of Fukuda is that it includes people with only nonspecific symptoms (would qualify on: fatigue, aches, headache, difficulty concentrating, poor sleep, patholigic reduction in activity due to fatigue). Reeves, however, would include the same patient. In fact, Reeves would include a patient with most of these symptoms even if no fatigue was present and the reduction in activity was not pathologic. This is worse, not better.

    Since Reeves includes as diagnosic some symptoms which have no diagnostic relevance under Fukuda criteria and does not necessarily require all of the diagnostic symptoms of Fukuda, Reeves surveys and therefore Switzer cannot rightly be said to be using Fukuda.

    Fukuda is the official U.S. study inclusion criteria for CFS. It should be clear that Reeves is an inappropriate alternative which doesn’t necessarily describe CFS.

  79. #80 goldfinch
    July 9, 2010

    I forgot to discuss Canadian.

    It’s possible to simultaneiously meet both Fukuda and Canadian. Fukuda meets Canadian criteria 1 and 7 automatically. I don’t see how it could fail to meet 2 (loss of physical and mental stamina compared to substantially reduced activity due to fatigue and maybe cognition difficulties).
    Other Fukuda-diagnostic symptoms will fullfil any of these Canadian criteria: 2, 3, 4, 6a, 6c. Two of the three #6 items must be met. #6b contains no Fukuda-diagnostic signs or symptoms. #5 must have two items, 1-2 of which can be met using Fukuda diagnostic criteria.

    If you have Fukuda, you have a good start on the Canadian requirements, and not a huge percentage of Fukuda-diagnosed patients are going to have only 4 of the 4/8 Fukuda list and none of the extra Fukuda symptoms (some of which are Canadian-diagnostic), so there’s a good chance of many Fukuda patients meeting Canadian criteria. However, a large percentage of Reeves-diagnosed or Oxford-diagnosed could be expected to not meet Canadian.

    But you have, say, substantial new-onset fatigue substantially reducing activity level (C-1) with sub-diagnostic sleep problems (c-3), new headaches (C-4), muscle pain (C-4), and difficulty concentrating (C-5 1/2), and not much more than that, you would meet Fukuda but not Canadian criteria.

    Ok, examples:

    Myra
    Canadian: she does not have CFS
    (same as Fukuda/opposite of Reeves)

    Sarah:
    Canadian: she does not have CFS
    (same as Fukuda/opposite of Reeves)

    Lisa:
    meets criteria 1, 2, 4, 5, 6, and 7 from symptoms described in previous post.
    She also has unrefreshing sleep, poor sleep quality, and/or a sub-diagnositc sleep disturbance, meeting criteria 3. Canadian: she has CFS
    (same as Fukuda/same as Reeves)
    Or, she doesn’t have any of these (unlikely), falling shy of Canadian.
    Canadian: She doesn’t have CFS
    (opposite of Fukuda/opposite of Reeves)

    Rita:
    we’ll assume her undiscovered exclusionary condition meets all the criteria of Canadian as well (since we’re discussing a possible Canadian bias towards including undiscovered exclusionary conditions).
    She’s considered to have CFS.
    Since the exclusionary condition is undiscovered, she meets Fukuda and Reeves.

    While some would like to think diagnosis under Reeves would suggest “that symptom doesn’t belong” (for some of the Canadian symptoms, and evidently some Fukuda as well) and look harder for another disease, the fact is that any diagnosis is only as good as the diagnosing physician and if he thinks something is enough/ not enough to warrant, say, an MRI, it should get the same treatment under any of the diagnostic criteria.

    In practice, Oxford criteria (similar to practical effect of Reeves, especially since some appear to consider the Oxford symptoms as “the core symptoms of CFS”) includes patients meeting Canadian definition (like the girl locked in psychiatric clinic who died from dehydration because of her CFS and the fact that it wasn’t understood to be a physiological condition). Clinicians tend to explain the symptoms as stress, exaggeration, or somatization, as most of these are sub-clinical, can only be investigated with experimental tests (NK function, for example), or have little to no diagnostic value for other diseases unless enough other signs and symptoms of said other conditions are also present.

    So in the end, you have Reeves and Oxford including a larger number of patients from one side of the spectrum, but no significant change in patients meeting Fukuda or Canadian diagnosis. You’ve broadened the set on one end without making any effective difference on the other end.

    Fukuda, on the other hand, narrows the definition on the one end. Canadian narrows it a bit more.

  80. #81 goldfinch
    July 9, 2010

    Back to Rita, it’s actually highly unlikely she actually meets Canadian criteria unless she has both CFS and something else, because post-exertional malaise isn’t a feature of any other disease, except maybe fibromyalgia which isn’t CFS-exclusionary.

    It’s also highly unlikely because few other conditions have this breadth of symptoms.

    Possibly Lupus, but she would have other signs exclusive to Lupus, like the distinctive rash, and a characteristic set of multiple laboratory findings; to miss Lupus one would have to not be trying to diagnose her at all.

    Or she could have MS, but she would have characteristic symptoms such as marked weakness on one side or in one quadrant of the body. This would be easier than Lupus to miss if the diagnoser expected some neurological involvement (since MS diagnosis is mainly exclusionary), but with these symptoms (especially one-sided muscle weakness) an MRI is always indicated and this should help decide on the MS diagnosis. I’m pretty sure a physical neurological exam would turn up some clues, too, for MS.

    Most other conditions would have a much smaller set of symptoms and couldn’t explain the Canadian-diagnosed patient (I can’t actually think of any diseases I haven’t mentioned, which could produce this breadth of symptoms).

    So Canadian is generally superior in excluding alternate diagnosis, because Canadian requires at least one symptom (post-exertional malaise) which is not a feature of any exclusionary condition, including MS, and requires so many varied symptoms as to exclude most less complicated conditions.

  81. #82 goldfinch
    July 12, 2010

    I see I bored everyone with my soapbox… that’s ok; it was good for me to go through this to get everything sorted out in my head. Now I need to figure out how to make the point concisely to better use it elsewhere. :)

    Thanks, ERV, for posting my comments.

    Thanks, quetzal, gf1, and hemiphage, for the questions that made me look into what exactly Switzer et al. meant by Fukuda as quantified by Reeves. (I’d known something was fishy with the Georgia and Wichita cohorts, but I didn’t understand how they were getting the results they were when they were claiming to use Fukuda.) It took a bit more doing to find the Reeves surveys than it takes to find most studies when I know an author and even the title, but it was out there.

    ERV, could you do me a favor? for science? and for us PWC’s? Look at the Fukuda criteria here (CDC), here (NIH), or here (full publication), and compare it to the Reeves quantification study or if you’d rather, read my post #78 (the scoring section should be sufficient) or to the Jason study critique. You might find a need to edit your original post regarding same/different criteria between Lombardi and Reeves. :) I won’t ask you to change anything if you don’t agree, of course. I’m just asking you to check again using more details, when you have time.

    A great week to you all.

  82. #83 ERV
    July 12, 2010

    goldfinch– I just dont care about the criteria, honestly. Even if everyone in this (and all the negative studies) were 100% healthy (even ‘faking’ HIV and HTLV), they should have found XMRV if the WPIs numbers are right. And there should have been a slight bias (though maybe not as strong as WPI) if there was an association between XMRV and some kinds of chronic fatigue.

    But its just not there.

    Also, thanks for being patient with the moderation. I had to make ‘XMRV’ a keyword after a threat, so you all having a nice conversation get to reap the annoyance of that :(

  83. #84 qetzal
    July 13, 2010

    I agree with ERV above. For XMRV to really be associated with CFS, you have to argue that only WPI (so far) looked at the right patients, AND only WPI (so far) has been able to design and run a reliable PCR for XMRV in patient blood.

    Either of those is at least somewhat possible, but both at once is pretty dubious, IMO.

    For the moment, my bet is still on some kind of contamination in the WPI study. I hope the Alter study gets published soon though. That could change things considerably, if the supposedly positive findings hold up.

  84. #85 Peter W
    July 13, 2010

    Disclaimer: I herein risk stating the bleedingly obvious. Pardon requested if it is deemed such.

    The people I know with specialist diagnosed ME/CFS would not be found in a phone survey. They are bedbound or housebound and are not in a position to answer the phone – leaving that to their carers. Of course this applies to about 25-50% of the patient population. The rest can get around a bit. But it does mean that the non-clinically referred cohorts are inherently skewed away from real life clinical reality.

  85. #86 Levi
    July 14, 2010

    qetzal,

    Not true that only WPI (so far) has been able to run a reliable PCR for XMRV in patient blood:
    http://www.cdc.gov/eid/content/16/6/1000.htm

    Any science types care to make a comparison of the PCR methods used between this study and the the CDC study? Just leave CFS out of it and address the testing for XMRV please. Is testing for RT a good idea? Thanks

  86. #87 RRM
    July 14, 2010

    Peter W — Contrary to what you say, phone surveys are more likely to select real CFS patients. People that are ‘not sick but just depressed’, seem more likely to NOT pick up the phone when they hear that awful sound of the evil outside world….

  87. #88 qetzal
    July 14, 2010

    Levi,

    That particular study never looked in blood. They were looking for XMRV associated with respiratory tract infections, and all their samples were from that compartment (sputum, nasal swabs, bronchoalveolar lavage, and tracheal secretions).

    However, they cite two previous pubs as references for the PCR method. I don’t know if either of those tested any blood samples.

  88. #89 goldfinch
    July 14, 2010

    ERV, I didn’t mean to complain about moderation. Quite the reverse… I was babbling on and I really did mean to thank you for beginning this discussion with your entry and for posting all my long comments. I assumed any delay would be from not blogging 24/7. :) Threat, wow; it’s horrid that someone would do that.

    About the criteria, though… you did say it was the same, and, totally aside from XMRV discussion, it’s not. There’s tons of information “about CFS” which isn’t about CFS at all and this is harmful to people who actually have CFS, because doctors and neighbors and co-workers and family members are confused about what it is. PWC’s (people with ME/CFS) get a lot of flak (a lot! this is probably why we often come across as grumpy!) and seldom get much medical intervention–even for signs and symptoms which can be somewhat relieved by treating symptoms. We’re tired of being marginalized and part of the way marginalization is done (I’m not implying intention here, just effect) is by stacking the studies with major depressive disorder and other non-CFS patients. XMRV or no XMRV, it’s important to note inclusion differences. Besides, it’s bad science to make your inclusion criteria so broad that you don’t define something.

    About the XMRV, the Switzer study is potentially valuable in helping determine the distribution of the virus and/or determining how we can find it under in vivo conditions. Switzer makes an important improvement over the European studies by showing they could detect XMRV at least under in vitro conditions.

    But Switzer can’t tell us anything about ME/CFS because it uses a faulty rubric (Reeves symptom ‘quantification’/redefinition survey grading rules) which includes at least 36% major depressive disorders (a condition which excludes a diagnosis of CFS).

    About the distribution, Lombardi’s rate of distribution in the general population is not inconsistent with the Schlaberg study proposing a correlation of XMRV to prostate cancer, which as Denner mentioned (with a typo, though), found low levels (2%) of the virus in healthy controls.

    Of course, variable results are found in study of possible correlation between XMRV and prostate cancer, as well. This indicates either faulty techniques resulting in false positives, inherent difficulty of detection or faulty techniques resulting in false negatives, or uneven distribution. In any case, it will of course take more work before we can know whether XMRV is correlated to any disease and, if it turns out to be correlated, even more work before we can know whether it’s causative.

    qetzal, that answers your concern, too. It’s not only WPI finding XMRV. Also, I believe Lombardi looked in blood for XMRV and for bloodborne evidence of XMRV being in non-blood tissue (circulating antibodies).

    Regarding which are the “right” patients, I refer you to an earlier study dating to the period when a new interest in a condition would lead to the name “Chronic Fatigue Syndrome,” A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Herpesvirus has since been shown to be not correlated to CFS as a whole (to a subgroup, though; and this study didn’t claim HHV6 in the entire patient population, either), but they were finding CD4/CD8 T-cell ratio abnormalities and MRI findings (showing “edema or lesions”) back then, too, and, as you can see from the title, neurologic symptoms. WHO classifies CFS as a neurologic illness. It should be clear which ideology of CFS is divergant.

  89. #90 goldfinch
    July 14, 2010

    Also note that the German study also found XMRV in 2-3% of the general population, and in 10% of immunocompromised samples.

  90. #91 Levi
    July 14, 2010

    qetzal,

    Right you are, they did not look in blood. So there actually IS XMRV in +- .1 to 3.2 percent of the healthy population, but these folks can only be found by looking for the retrovirus in respiratory tract secretions, not blood. WPI excluded, if you do a PCR on the blood, then you will not find anything, as has been the case in all the repeated zero/zero negative studies so far.

    Why would you find XMRV in respiratory secretions like this study, but not in blood? Is this a testing problem? Any thoughts on this?

  91. #92 Peter W
    July 14, 2010

    RRM. not disagreeing with you. The point is not one of intent but ability. Patients I know need help with general daily tasks like eating and caring for themselves. Answering a phone is just not on their radar at all.

  92. #93 qetzal
    July 15, 2010

    @goldfinch

    qetzal, that answers your concern, too. It’s not only WPI finding XMRV. Also, I believe Lombardi looked in blood for XMRV and for bloodborne evidence of XMRV being in non-blood tissue (circulating antibodies).

    No it doesn’t. I was talking about detecting XMRV in blood. Lombardi et al. claimed they could do that in CFS pts. and in a few healthy controls. IIRC, none of the other published studies (pending Alter et al.) found XMRV in blood. That’s true for Schlaberg et al. as well – they looked in prostate tissue.

    Again, the point is that certain WPI supporters argue that all the failures to find XMRV in blood were due to faulty methods.

    @Levi

    Why would you find XMRV in respiratory secretions like this study, but not in blood? Is this a testing problem? Any thoughts on this?

    I don’t know for XMRV specifically, but I wouldn’t bat an eye at similar results for, say, influenza. If the virus proliferates in the respiratory tract, but not (usually) systemically, you’d expect to see it in sputum but not blood.

  93. #94 goldfinch
    July 15, 2010

    quetzal… so ppl can look in tissues and find 2-3% general prevalence, but if some happen to find a similar prevalence by testing blood, it’s wrong because no one else found it in blood? Even though the general prevalence is similar to others of the studies that found XMRV? There were also tissue studies that didn’t find XMRV. Those that don’t find it, don’t find it in tissues or blood, and those that do find it, find a low general prevalence. Yeah?

    You said, “For XMRV to really be associated with CFS, you have to argue that only WPI (so far) looked at the right patients, AND only WPI (so far) has been able to design and run a reliable PCR for XMRV in patient blood.
    “Either of those is at least somewhat possible, but both at once is pretty dubious, IMO.”

    The thing is, CFS “right” patients is really messy. It’s a huge issue and it’s really common for studies to be done on not-CFS patients. If you weren’t interested in CFS prior to the XMRV hype, you wouldn’t know this, but it’s quite the problem. There’s a veritable row in the literature.

    On the one hand you have the Royal College, Wessely, Reeves, and those guys who think CFS has a hugely significant “psychosocial” component and should be treated with cognitive behavioral therapy (CBT – eliminating supposed causative or perpetuating destructive thinking patterns and often attempting to convince the patient he’s not physiologically sick) and graded exercise therapy (GET – to treat supposed perpetuating factor of deconditioning). See articles like Moss-Morris, Rona (2005) which claim that CFS is a result of bad coping skills, unreasonable attention to symptoms, and expecting activity to produce adverse results [in any other context, we would call this behavior "learning" and deem it positive, but here it's seen as pathological ~goldfinch]. These folks use Oxford and Reeves and similar, producing a patient population representing varied conditions (including depression) and keep saying there’s no particular physiological pathology.

    On the other hand you have researchers finding abnormal cytokine expression, oxidative stress upon exertion, no psychosis unusual in diseased patients (similar to narcolepsy pts), no deconditioning role, oxidative DNA damage, HSP involvement, orthostatic issues, CD69 differences, suggestion of cardiovascular risk, low cardiac output, reduced muscle excitability, and suggest CBT isn’t very helpful and GET may be harmful because of the underlying physiological pathology, and that loose definitions aren’t specific and shouldn’t be used: note “Much of our ‘understanding’ of CFS does not apply to the small group of patients who fulfill the current (1994) CDC definition”.

    Note the Royal Colleges report which claimed CFS has a psychological component, is not related to a virus, should not be called ME (prior convention in Britain), and should be diagnosed with a “minimum number of investigations” and treated with CBT/GET (cognitive behavioral therapy and graded exercise therapy). The USA NIH’s Dr. Stephen Straus called this report “the finest contemporary position statement in the field” and remarked that “physicians and patients are well advised to read it” although it was likely to be controversial on both sides of the Atlantic. Yet the Lancet notes that the report finds too-high prevalence figures reflecting an overly-broad inclusion (sound familiar?) and points out that the report ignored available physiological evidence; the Lancet decided the Royal colleges report was “haphazardly set-up, biased and inconclusive, and is of little help to patients or their physicians.”

    So as you can see, it isn’t at all unlikely that Switzer tested a patient population not representative of CFS/ME; they certianly aren’t the first to do so.

  94. #95 goldfinch
    July 15, 2010

    A prostate study detecting the virus in serum.

    Again, I’m not suggesting we know anything of certainty about the virus’s distribution or being correlated to any disease. I’m saying it’s too soon to dismiss the possibilities.

  95. #96 qetzal
    July 15, 2010

    Re #94:

    No. That’s a prostate study detecting antibodies to XMRV in the serum. That’s completely different from using PCR to detect viral nucleic acids in the serum.

    Re #93:

    Finding XMRV in sputum or prostate tissue doesn’t really address the discrepancies regarding XMRV in blood. WPI says they find XMRV in blood in most of their CFS pts, and a few of their controls. Multiple other groups say they don’t find XMRV in blood from anyone.

    Does it make sense that other groups can design successful PCR assays to find XMRV in prostate tissue or sputum, but only WPI can (so far) design one that can detect it in blood?

    It’s possible, but strikes me as unlikely. If Alter’s data gets published and credibly supports WPI’s claims, I’ll feel differently.

  96. #97 RedDirtDevil
    July 16, 2010

    In my experience there is a strong relationship between reactivated (non-titer) EBV and HHV6 and chronic fatigue symptoms. I have several tests to prove it. From well-established mainstream labs. The two herpes viruses were “normal” (post-mono) until I unwisely underwent a lengthy course of antibiotics suggested by a well-meaning physician. The ensuing bout of gut issues left my chronic fatigue symptoms worse than ever. I would suggest to any researchers: collect a batch of CFS patients with provable (abovementioned) irregularities, then look for XMRV. My takeway from this experience is most of the other PWCs out there could be pushed into traceable reactivated herpes infections, provided their bodies were stressed enough. Having that on paper will get you doctors’ sympathy like nothing else; but I wouldn’t recommend it as a strategy.

  97. #98 daedalus2u
    July 17, 2010

    RDD, what you describe sounds like another example of the multiple observations of an association of random viruses and bacteria found in the blood of CFS patients. XMRV is likely just another example in addition to EBV and HHV6. Bacteria are found too, a variety of mycoplasms and others.

    It isn’t that these viruses and bacteria are the “cause” of CFS, even though they are associated with CFS. It is the CFS that modulates the immune system so that viruses and bacteria are not cleared from the blood as rapidly or as completely.

    If CFS was viral, and was transmissible by blood, there should be evidence of it in blood transfusion experience. If the prevalence of XMRV in healthy people is a few percent, and if XMRV causes CFS, then getting a blood transfusion should be a risk factor for CFS. It doesn’t appear to be.

  98. #99 gf1
    July 19, 2010

    @ daedalus2u:

    Do you have a link for any evidence on blood transfusions not been a risk factor for CFS? Or do you just mean that it’s not a known risk factor?

    One of the things that’s had me sceptical about XMRV/CFS from the start is that you’d have through a retroviral cause would have to predictable and identifiable risk factors for CFS, and this does not seem to be the case. But I’m not sure how much effort has been put in to looking (especially as the matter could be confused by differing diagnostic criteria).

    Even if it was just an opportunistic infection, it could still be a significant perpetuating factor for CFS (assuming there’s any connection what-so-ever). I guess it’s also possible than XMRV transmission is weird and wonderful in some unknown way.

    It will be interesting to see this NIH paper.

  99. #100 daedalus2u
    July 19, 2010

    gf1, I don’t have a link, but as far as I can tell (and I did look), receiving a blood transfusion is not a risk factor for developing CFS. That is I was unable to find a paper stating there was a risk.

    Canada has recently told people with CFS to not donate, but that is in response to the XMRV reports and an abundance of caution, not any data saying their is a risk.

    Things like trauma and infections do trigger CFS. I don’t see that there is any need for there to be aother virus that can trigger it too.

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