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Research Article

Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome

  • Otto Erlwein,

    Affiliation: Jefferiss Research Trust Laboratories, Section of Infectious Diseases, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, United Kingdom

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  • Steve Kaye,

    Affiliation: Jefferiss Research Trust Laboratories, Section of Infectious Diseases, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, United Kingdom

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  • Myra O. McClure mail,

    m.mcclure@imperial.ac.uk

    Affiliation: Jefferiss Research Trust Laboratories, Section of Infectious Diseases, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, United Kingdom

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  • Jonathan Weber,

    Affiliation: Jefferiss Research Trust Laboratories, Section of Infectious Diseases, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, United Kingdom

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  • Gillian Wills,

    Affiliation: Jefferiss Research Trust Laboratories, Section of Infectious Diseases, Wright-Fleming Institute, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, United Kingdom

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  • David Collier,

    Affiliation: Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry (King's College London) De Crespigny Park, Denmark Hill, London, United Kingdom

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  • Simon Wessely,

    Affiliation: Department of Psychological Medicine, Institute of Psychiatry, King's College London, Camberwell, London, United Kingdom

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  • Anthony Cleare

    Affiliation: Department of Psychological Medicine, Institute of Psychiatry, King's College London, Camberwell, London, United Kingdom

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  • Published: January 06, 2010
  • DOI: 10.1371/journal.pone.0008519

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Authors Response

Posted by Anthony_Cleare on 12 Jan 2010 at 19:55 GMT

As the clinicians and scientists who provided the samples that were tested at Imperial, we wish to respond to some of the comments here and elsewhere regarding the patients who provided these samples.

In the paper we provided extensive details of the sample selection, criteria, assessments and investigations that are routine in our service, together with references/citations to all the material

To re iterate.

1. The criteria that we use are the Fukuda et al 1994 criteria that are far and away the most widely used across the world and in the research literature. We do not use the so-called “Canadian criteria”, which are designed for clinical use, not operationalised and do not translate easily for use in research. Even so, had we attempted to do so, a substantial proportion would have also met these clinical criteria.
2. The patients resembled those seen in secondary care and tertiary care services elsewhere – most particularly they are similar to those seen in clinics in Australia, USA, Scotland, England and Northern Ireland (Wilson et al, 2001; Hickie et al, 2009).
3. We follow the same psychiatric exclusion criteria as mandated by the Fukuda criteria. We do this on the basis of semi structured interviews and assessment that we have also published. In addition, we also exclude patients with chronic somatisation disorder as defined by DSM-IV, which is not required by the Fukuda criteria, but most experts and clinicians agree are a different population. This is only a small percentage of our referrals.
4. In answer to one question, yes, our patients all report both mental and physical fatigue, exacerbated by mental or physical effort. Nearly all also describe post exertional fatigue and malaise.
5. We have a standard laboratory protocol for investigations, which are performed on all those referred to the clinic, unless they have been done recently by the referring doctor. These are solely for the purpose of excluding other diseases that can sometimes mimic CFS, and are part of the differential diagnosis. This is standard practice in every CFS service of which we are aware and forms part of every definition of which we are aware, including the “Canadian criteria”. In addition to the standard work up, we also now routinely test for coeliac disease, because we found a 2% prevalence of undetected coeliac disease (Skowera et al, 2001). In answer to another question, we perform a 9.00 am cortisol as a screener for Addison’s disease.
6. In addition we also perform tests as part of research protocols. We always tell patients that these additional tests and investigations are not necessary clinically, and are performed with informed consent. Thus patients in our service have also co operated in studies of PET and fMRI neuroimaging, autonomic dysfunction, neurochemistry, respiratory function, vitamin status, anti nuclear antibodies, immune function, neuroendocrine function and genetics (see references). Hence it is untrue to state that patients at King’s for example do not show alterations in immune function – in fact they do - see Skowera et al, High levels of type 2 cytokine-producing cells in chronic fatigue syndrome." Clinical and Experimental Immunology 2004: 135: 294-302. Similarly, many of our patients also show altered neuroendocrine, neurochemical and other biological parameters, and we have published many examples of these (see references below). It is therefore simply untrue that we either seek to find no biological changes in CFS, or fail to report those that we do find.
7. On the other hand, it is true that those who receive a diagnosis of cancer would be and are excluded from a diagnosis of CFS and if this is detected they would be immediately referred to the relevant clinical services. It is possible that this may be a difference from the cohort originally reported in Science, if the Wall St Journal is correct (http://online.wsj.com/art...).
8. We do not perform these additional tests to confirm or refute a diagnosis of CFS, but to further understanding of the illness. If and when a properly validated diagnostic test is developed for use within the National Health Service, all our patients will be offered it free of charge, just as they are already offered diagnostic assessment, investigation and treatment free of charge.
9. We did not perform any selection in any shape or form of the samples that we hold to send to Imperial College, as again has been suggested.

Overall, we wish to emphasis, and to do so emphatically, that our patients are typical of CFS patients seen in specialist care elsewhere. We specifically refute the suggestion that our patients are in some way more “psychiatric”, whatever that means, than those with “real CFS”, an assertion that has been repeatedly made in other venues. The rates of co morbid psychiatric disorder, for which we routinely screen, are again similar to those seen elsewhere. We draw attention to another study that compared two services run in the same London teaching hospital, one by an immunologist, the other a psychiatrist, but showed no fundamental differences between the two (White et al, 2004). On behalf of the patients that attend our CFS clinic, we resent the implication that they are in some way different, less ill, less disabled, let alone less deserving, than CFS patients in any other service or setting. It is otherwise, and we have provided a wealth of published data to back this assertion.


Professor Simon Wessely, Professor of Psychological Medicine
Professor David Collier, Professor of Psychiatric Genetics
Dr Anthony Cleare, Reader in Neuroendocrinology



REFERENCES

Allain T, Bearn J, Coskeran P, Jones J, Checkley A, Butler J, McGregor A, Wessely S, Miell J. Changes in growth hormone, insulin, insulin-like growth factors (IGFs) and IGF-binding protein-1 in chronic fatigue syndrome. Biol Psychiatry 1997;41:567-573

Bearn J, Allain T, Coskaran P, Miell J, Butler J, McGregor A, Wessely S. Neuroendocrine responses to D-fenfluramine and insulin induced hypoglycaemia in chronic fatigue syndrome. Biological Psychiatry 1995;37:245-252.

Caseras, X., David Mataix-Cols, Vincent Giampietro, Katharine A Rimes, Michael Brammer, Fernando Zelaya, Trudie Chalder, Emma L Godfrey (2006). "Probing the working memory system in Chronic Fatigue Syndrome: An fMRI study using the n-back task." Psychosomatic Medicine 68: 947-955.

Caseras X, M.-C. D., Giampietro V, Rimes KA, Brammer M, Zelaya F, Chalder T, Godfrey EL (2008). "The neural correlates of fatigue: A fatigue provocation study in Chronic Fatigue Syndrome." Psychological Medicine 38: 1-11.

Cleare A, Bearn J, Allain T, Wessely S, McGregor A, O'Keane V. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. J Affective Disorder 1995;35:283-289.

Cleare AJ, Sookdeo S, Jones, J, O’Keane V, Miell J. Integrity of the GH/IGF axis is maintained in chronic fatigue syndrome. Journal of Clinical Endocrinology and Metabolism, 2000: 85: 1433-1439.

Cleare AJ, Miell J, Heap E, Sookdeo S, Young L, Malhi GS, O’Keane V. Hypothalamo-Pituitary-Adrenal axis function in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy. Journal of Clinical Endocrinology and Metabolism 2001: 86: 3545-3554.

Cleare AJ Keane, V, Miell JP et al. Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome. Psychoneuroendocrinology 2004;29:724-32.

Cleare AJ, Messa C, Rabiner E, Grasby P. Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635. Biological Psychiatry 2005: 57, 239-246.

Di Giorgio A Hudson, Jerjes W, Cleare AJ. 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychosomatic Medicine. 2005;67:433-40.

Heap, L., Peters T, Wessely S. Vitamin B status in patients with chronic fatigue syndrome Journal of the Royal Society of Medicine 1999: 92: 183-185.

Fritz E, Smith J, Kerr J, Cleare A, Wessely S, Mattey D. Association of chronic fatigue syndrome with human leucocyte antigen class II alleles. Journal of Clinical Pathology 2005;58:860-863.
Hickie I, Davenport T, Vernon S, Nisenbaum R, Reeves W, Hadzi Pavlovic D, Lloyd A, Are chronic fatigue and chronic fatigue syndrome valid clinical entities across countries and health care settings? Australian and NZ Journal of Psychiatry, 2009; 43:25-35.
Jerjes WK, Cleare AJ, Wessely S, Wood P, Taylor NF. Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome J Affective Disorder 2005: 87: 299-304.

Jerjes WT, NF; Wood, PJ; Cleare, AJ. Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome. Psychoneuroendcrinology. 2007;32:192-8.

Jerjes W, Peters T, Taylor N, Wessely S, Cleare A. Diurnal excretion of urinary cortisol, cortisone and cortisol metabolites in chronic fatigue syndrome. J Psychosom Res 2006: 60: 145-153

Peakman M, Deale A, Field R, Mahalingam M, Wessely S. Clinical improvement in chronic fatigue syndrome is not associated with lymphocyte subsets of function or activation. Clin Immun Immunopath 1997;82:83-91.

Saisch S, Deale A, Gardner W, Wessely S. Hyperventilation and chronic fatigue syndrome. Quarterly J Medicine 1994: 87:63-67.

Skowera, A., M. Peakman, et al. (2001). "High prevalence of serum markers of coeliac disease in patients with chronic fatigue syndrome." Journal of Clinical Pathology 54: 335-336.

Skowera A, Stewart E., Davis E, Cleare A, Hossain G, Unwin C, Hull L, Ismail K, Wessely S, Peakman M (2002). "Antinuclear antibodies (ANA) in gulf war related illness and chronic fatigue syndrome (CFS) patients." Clinical Experimental Immunology 129: 354-358.

Skowera, A., Cleare, A., Blair, D., Bevis, L., Wessely, S., Peakman, M (2004). "High levels of type 2 cytokine-producing cells in chronic fatigue syndrome." Clinical and Experimental Immunology 135: 294-302.

Underhill, J., Donaldson P, Mahalingam, M., Wessely A, Peakman M. (2001). "Lack of association between HLA and chronic fatigue syndrome." European Journal of Immunogenetics 28: 425-428.

Wilson A, Hickie I, Hadzi-Pavlovic D, Wakefield D. Straus S, Dale J, McCluskey D, Hinds, G, Brickman A, Goldenberg D, Demitrack M, Wessely S, Sharpe M, Lloyd A. What is chronic fatigue syndrome? Heterogeneity within an international, multicenter study. Australian & New Zealand J Psychiatry 2001: 35:520-527

White PD, Pinching AJ, Rakib A, Castle M, Hedge B, Priebe S. A comparison of patients with chronic fatigue syndrome attending separate fatigue clinics based in immunology and psychiatry. Journal of the Royal Society of Medicine 2002;95:440-4.

Winkler, A., Blair D, Marsden J, Peters T, Wessely S, Cleare A, (2004). Autonomic function and serum erythropoetin levels in chronic fatigue syndrome. Journal of Psychosomatic Research 56: 179-183.

Competing interests declared: Authors of the paper

RE: Authors Response

Herbiv4 replied to Anthony_Cleare on 12 Jan 2010 at 23:50 GMT

And to reiterate the criticisms that have been made in so many pleases already.... you did not provide patients suitable for a replication study.

If the Lombardi team manageds to use the Canadian criteria then what is hte big problem for anyone in hte UK to utilise the Canadian criteria?

What are you all frightened of.

And further more, your patients were all patietns who had attended your clinics and had probalby taken part in other studies.

Well how about choosing patients that have never participated in studies before.

How about chosing patients who are severaly affected and unabe to get to your clinics or to hospital appointments?

The 25% ME group has hundreds of members - severely affected patients with ICD-10 G93.3 Myalgic Encephalomyelitis - a condition that none of you actually recognise.

And just to close - you claim that as a group of psychiatrsits with no specialist interests in retro-virology that your patients who were seen in departments of psychiatry were not primarily patients who had mental health problems.

Yet your colleages are busily trying to have CFS reclasified to a somatoform category in ICD-11 and your colleagues in psychiatry interested in CFS are also trying to get CFS included in DSM-V.

And if you do not consider CFS to be a mental health issue then why was the NICE Guideline 53 discussed under the heading of mental health in a 2008 report the details of which are given below....

http://62.204.33.138/file...

South London and Maudsley NHS Foundation Trust

TRUST BOARD OF DIRECTORS – SUMMARY REPORT

Date of Board meeting: 25th November 2008

Name of Report: Implementation of NICE guidance (Annual Report 2008)

Authors: Rosie Peregrine Jones and Dr Rosalind Ramsay

Approved by: (name of Exec Member) Dr Martin Baggaley

Presented by: Dr Ros Ramsay

Purpose of the report:

To outline progress within the Trust against the guidance issued by NICE which is relevant to mental health services

[ ... ]

Mental health clinical guidelines

[ ... ]

53 Chronic fatigue syndrome April 2007 May 2007 CAEC November 2008 SNIG

Alastair Santhouse

Ian Brown

[ ... ]

AMH [adult mental health]

Chronic Fatigue syndrome Lead: Alastair Santhouse

[ ... ]

A true replication study will not be a valid study until it uses the precise patient selection criteria as used by the Lombardi team.

A true replication study will not be a valid replication study until it uses the precise testing and evaluation techniques as used by the Lombardi team.

Anything less is scientifically flawed and open to legitimate deconstrucrtion and dismissal.

Use the Canadain criteria and do your work properly.

Use patients you usually ignore - patients severely affected and not before "screened" by the profession of psychiatry just to avoid any conflicts of interest.

After all one more XMRV positive CFS patient is one less patient recrutied for CBT and Graded Exercise isn't it?

No competing interests declared.

RE: Authors Response

theath80 replied to Anthony_Cleare on 13 Jan 2010 at 13:15 GMT

I would like to state that, as a former patients at King's College Chronic Fatigue Clinic, I was offered none of the tests stated above. To quote:

'studies of PET and fMRI neuroimaging, autonomic dysfunction, neurochemistry, respiratory function, vitamin status, anti nuclear antibodies, immune function, neuroendocrine function and genetics (see references)'.

Nor was I offered a 9am cortisol test. I am in touch with many former patients of King's who similarly were never offered any bio-medical testing or bio-medical explanation of the disease. In contrast, we were given literature suggesting CFS was a result of bodily deconditioning occuring during an initial virus and later psycho-social maintaining factors.

I strongly dispute claims, as I know other patients will, that King's is committed to the type of bio-medical testing and research that this piece claims. It could be that the sample tested by the researchers had been subjected to such tests. However, neither myself nor anyone I am in contact with was offered anything in the way of testing, and had only had the most basic blood tests conducted by their GPs.

I believe the researchers at King's have a strong motive for wishing to contradict the findings of the WPI and judgement on these findings should be withheld until later, less biased tests are conducted.

No competing interests declared.

Different patients

EMGoudsmit replied to theath80 on 13 Jan 2010 at 16:44 GMT

Like a number of other senior mental health professionals, I have evidence frrom clinical practice and/or the literature that the patients being seen and described differ from those we would diagnose as having ME or post-viral chronic syndrome. Patients report back that others did not have what they did. Some describe prominent emotional issues such as anxiety. That other psychiatrists elsewhere tend to include as many patients with what we used to refer to as 'nervous breakdowns', where a cold may have been the straw that broke the camel's back, says little. A study amongst acute onset, previously healthy individuals who haven't had to deal with a messy divorce, an addict son or overwork, might be illuminating.

With about 96 symptoms, the Canadian criteria present a hge problem and patients need to recognise that. They may be helpful in the clinic, but they are too broad for research. The sole difference is perhaps that post-exertional fatigue has to be present. I doubt therefore, that the use of the latter would make a great difference. It's more important to exclude those with significant stress.

No competing interests declared.

RE: Different patients

tkindlon replied to EMGoudsmit on 14 Jan 2010 at 03:19 GMT

It is far from clear to me that the Canadian criteria are broader than the Fukuda criteria which only require 4 out of 8 specific symptoms.

Looking at the symptom lists, it would appear that most people who satisfy the Canadian criteria will satisfy the Fukuda criteria while many who satisfy the Fukuda criteria won't satisfy the Canadian criteria.

With regard to the number of symptoms, with a tickbox format, one does not need to read every part of each section of the Canadian criteria to find out if that criterion is satisfied.

The fact that the Canadian criteria might take a little more time than the Fukuda criteria needs to be weighed up against the importance of careful patient selection in research in particular.

No competing interests declared.

RE: RE: Different patients

EMGoudsmit replied to tkindlon on 17 Jan 2010 at 16:07 GMT

Please don't misunderstand me. I was considering an issue that might be addressed in future research. In the one study on the Canadian criteria I am aware of, the sample reported more symptomatology and in particular, more neurological symptoms than patients selected using the CDC criteria '94. We can interpret the findings in several ways. The discrepancy may reflect a true difference in sample characteristics, i.e. two different conditions or subsets. However, given the nature of the Canadian criteria, the results could also reflect the fact that the latter select people who have more symptoms, including neurological ones because there is more scope to do so. They are broader. One can continue to assume that the Canadian criteria select a different cohort but it might be timely to test the assumption, e.g. the next study could compare and contrast the results of those who meet the two sets of criteria, with those who meet only one.

Clinical criteria tend to be broader simply because there is no reason not to diagnose CFS in a patient who also has a comorbid disorder, e.g. arthritis. In research, those patients would be excluded as arthritis can add to pain and fatigue and therefore confound one's results. Pain is not a symptom of CFS which differentiates this illness from others. Sleep disturbances are also common and not unique to CFS. This is why some doctors are reluctant to use the Canadian criteria. Just as a physician would not diagnose appendicitis based on the symptom of pain in the right lower abdomen, so you need to identify a pattern or key symptoms to differentiate CFS from other disorders, notably chronic stress. Research has yet to show that the Canadian criteria are helpful in that respect. We know that the CDC criteria are not (Farmer et al). The above does not mean that a replication should not use the Canadian criteria. They must. I did not infer above that the Imperial paper is a replication. I merely hope that a replication also compares and contrasts, thus perhaps identifying why the results from the two studies are so different. What if the % infection turns out to be the same in the patients selected with the CDC criteria and the Canadian criteria? Given such a scenario, I would look at cortisol levels and history of stress. In my view, UK researchers tend to include more patients with chronic stress in their samples with 'CFS'. In that case, one would not expect to find evidence of ongoing infection in 60% plus.

Some doctors have issues with the number of symptoms in the Canadian criteria. Clearly. It seems constructive to address their concerns and do some additional statistics to help answer their questions. It's simple, using SPSS.

No competing interests declared.

One study found Fukuda cases were more prevalent than Canadian criteria cases

tkindlon replied to tkindlon on 20 Jan 2010 at 17:45 GMT

Just to add some figures to my last comment.

I have now looked up one population study which gives information on the relative prevalences of Fukuda and Canadian criteria patients[1].

It found 23 patients who satisfied the Carruthers/Canadian criteria for ME/CFS[2] and 32 who satisfied the Fukuda criteria for CFS[3]. 20 of the 23 who satisfied the Carruthers/Canadian criteria satisfied the Fukuda criteria, while the other 3 individuals had idiopathic chronic fatigue.


References:
[1] Jason LA, Torres-Harding SR, Jurgens A, Helgerson J.
Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome 2004; 12(1): 37-52.

[2] Carruthers BM, Jain AK, De Meirleir KL et al. Myalgic encephalomyelitis/ chronic fatigue syndrome: Clinical working case definition, diagnostic and treatment protocols. J Chron Fatigue Synd 2003; 11(1): 7-115.

[3] Fukuda K, Straus SE, Hickie I et al. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Int Med 1994; 121: 953-959.

No competing interests declared.

RE: Authors Response

stick replied to Anthony_Cleare on 13 Jan 2010 at 13:38 GMT

The authors are quite right to resist unfair characterisations of the patients involved in this study.

Nevertheless, Professor Wessely has in at least two publications specifically stated that: "No consistent pattern of immunological abnormalities is identified" in CFS patients (1) and (2) - an assertion that is at odds both with your statement in this response and with numerous other published studies that have demonstrated immune dysfunction in well-defined ME/CFS patients. So which is it to be? And, if you do indeed recognise immune dysfunction as being a factor in ME/CFS, would you please, for the sake of clarity, consider publishing retractions of previous, possibly misleading statements?

The same goes for Professor Wessely's support, again in (2), for Koch, et al.'s "VAMPIRE" study (3) which argued for only very limited blood testing of patients presenting with fatigue - a position that is bound to create confusion about whether or not patients with an ME/CFS diagnosis really have the disease or whether they have simply not been fully investigated for conditions that could be diagnosed from standard lab work.

The point is that it is not surprising, given Professor Wessely's previous published output, that questions about his understanding of ME/CFS have spilled over over into the issue of patient selection in your XMRV study.

Now that we know that at least one UK patient has tested positive for XMRV via the US test at VIPdx (4) would not the most sensible way of resolving this dispute be to submit samples from your cohort to WPI to determine whether your test is comparable to theirs?


1. Lyall M, Peakman M, Wessely S. "A systematic review and critical evaluation of the immunology of chronic fatigue syndrome" in J Psychosom Res. 2003 Aug;55(2):79-90. Abstract: http://www.ncbi.nlm.nih.g...

2. Harvey SB, Wessely S. "Tired all the time" in British Journal of General Practice, Volume 59, Number 561, April 2009 , pp. 237-239(3). DOI: 10.3399/bjgp09X420284, online at: http://rcgp.publisher.ing...

3. Koch, H, et al. "Ordering blood tests for patients with unexplained fatigue in general practice: what does it yield? Results of the VAMPIRE trial " in British Journal of General Practice, Volume 59, Number 561, April 2009 , pp. e93-e100(1). Online at: http://rcgp.publisher.ing...

4. Phoenix Rising, online at: http://forums.aboutmecfs....

No competing interests declared.

RE: RE: Authors Response

Kgeraghty replied to stick on 13 Jan 2010 at 18:54 GMT

Prof. Wessely et al.,

I believe you have added approximately 25 references in support of your original paper and your choice of selection criteria for patients used in the study. Of these 25 references, you are a co-author in about 14 of these references, and your colleagues at Kings and elsewhere are cited in many of the other references. It appears to me, as a humble researcher, that self-referencing does not do much to support ones thesis, to gain support for a view or methodology researchers seek the approval of a wider audience. Quoting oneself does not advance science. Prof. Wessely and his colleagues subscribe to a particular dogma concerning ME/CFS, therefore to use ones own work to support ones current work, only weakens the status of the current paper. Science is progressed when an individual or group achieves the support of the wider scientific community (T.Kuhn).

Lastly, science is in many ways, is a set of accepted methodology. Others have commented how the methodology followed at Imperial, differed greatly from that at the WPI. Science needs to remain a-political. Prof. Wessely's role in the insurance industry, as either paid or unpaid advisor, and his colleagues role in this area of the private sector, as well as his controversial stance on the aetiology and patho-physiology/ together with his views on treatment of ME/CFS, raises the issue of a conflict of interest in this paper, all of which creates doubt and the notion that this paper holds a political agenda. We can only move forward by having truly independent researchers replicate the WPI study, not deeply embedded political protagonists, such as Prof. Wessely et al..

This is my view as a humble observer and researcher in science!

No competing interests declared.

RE: Authors Response

AngelaKennedy replied to Anthony_Cleare on 13 Jan 2010 at 23:18 GMT

The authors’ reply to the concerns about patients selection for research for this paper raises more problems in addition to those of the original paper. My comments here should be read in addition to other problems raised by authors on this forum.

Firstly, the authors express some resentment towards those legitimately have questioned this research cohort and the criteria over the years, which is rather surprising. Contrary to the insinuation by the authors, no person on the Plosone responses forum has insinuated that the research cohort they use are somehow 'less deserving' than say, the WPI cohort, purely that they are a different type of patient, using different criteria that select a different population, and that this may cause problems with the findings, and claims made based on those findings, with regard to the British 'CFS' population. This is a reasonable concern to express, and such a deduction can be made based on the evidence the authors provide themselves in their paper, citations, and their response. For example, their paper states:

"Patients in our CFS cohort had undergone medical screening to exclude detectable organic illness".

In the authors’ response here, they also write:

"Thus patients in our service have also co operated in studies of PET and fMRI neuroimaging, autonomic dysfunction, neurochemistry, respiratory function,
vitamin status, anti nuclear antibodies, immune function, neuroendocrine function and genetics "

While patients being processed for a research cohort may well, indeed are likely, to have co-operated and had such tests done, this does not necessarily mean that patients with positive results are part of the research cohort. Indeed, positive results, which would indicate organic abnormality, would surely be likely to prevent a patient being selected for a cohort, by the very logic described in the author's paper here, by their own response (the additional tests are considered ‘not clinically necessary’?) and in at least one of their citations (Quarmby et al)? In the Quarmby et al paper, the cohort is described, in which the criteria used (in addition to 'Fukuda/CDC') is 'Oxford'. The Oxford criteria (Sharpe et al 1991) in particular actually do allow for patients who fulfil organic abnormality to be selected out of a research cohort. Indeed, Anthony David, referring to these, commented at the time:

"British Investigators have put forward an alternative, less strict, operational definition which is essentially chronic (6 months or more) severe disabling fatigue in the absence of neurological signs with myalgia, psychiatric symptoms and previous viral infections as common associated features.”

Here special attention needs to be paid to the term ‘previous viral infections’ and ‘absence of neurological signs’, in order to contextualise the cohort selection process applied using the Oxford Criteria.

It is therefore quite reasonable to presume that patients in the cohort described in the Erlwein et al paper are less likely to be suffering from organic abnormalities associated with 'CFS' populations than in other research cohorts. It is also rational to be concerned that the cohort described here may not be representative of many people diagnosed with 'CFS' in Britain. NICE guidelines for example, acknowledge that very little research has been done on ‘severely affected’ patients, who comprise, possibly at least 25% of the population of people given a ‘CFS’ diagnosis (though so little research has been done on ‘severely affected‘ in Britain, the true number is not yet clear). While patients potentially destined for a research cohort which weeds out ‘detectable organic abnormality’ may be subjected to a rigorous amount of investigations, those not undergoing this process do not undergo such testing, at least not in the NHS. Indeed, such investigations of clinical patients are severely proscribed in the majority of ‘guidelines’: NICE, and the RCPCH guidelines as just two examples. Ironically, Fukuda guidelines also make the following comment:

"The use of tests to diagnose the chronic fatigue syndrome should be done only
in the setting of protocol-based research.

In clinical practice, no additional tests, including laboratory tests and
neuro-imaging studies, can be recommended. Examples of specific tests (which
should not be done) include serologic tests for enteroviruses; tests of
immunologic function, and imaging studies, including magnetic resonance imaging
scans and radionuclide scans (such as single photon emission computed tomography
(SPECT) and positron emission tomography (PET) of the head.

We consider a mental status examination to be the minimal acceptable level of
assessment." (1994:)

That clinical populations are not to be afforded the types of investigations given to research populations makes the whole idea of ‘medically unexplained’ or ‘unexplained by disease’, or ’functional’ (as synonymous with ’non-organic’ or not discernibly organic‘) as common characterisations of CFS (including by at least one of the authors themselves in previous publications, for just one example, Page et al, 2003) highly problematic at best.

It is also significant that ‘CFS’ is so often described as a ‘diagnosis of exclusion’ (see, for example, the Centre for Disease Control CFS information website (Footnote: http://www.cdc.gov/cfs/cf...) . Certain research case definitions comply with this assumption, such as the Oxford Criteria (Sharpe et al, 1991) and CDC Criteria (Fukuda et al, 1994) Here, ‘diagnosis of exclusion’ also functions as a euphemism of ‘medically unexplained’. The key problem within this recurring theme in the literature, which most frequently remains un-addressed, is how a clinical patient’s condition can all too easily become ‘medically unexplained’ because of the practice of encouraging doctors to severely limit investigations in the first place: except, it would appear, ironically, in research populations in which ‘organic’ illness is being weeded out to provide the type of cohort that might fulfil ‘not organically ill’ definitions.

The issue of ‘disability’ also needs to be clarified. The references cited in the Erlwein paper to support the statement that the patient cohort was of ’high levels of disability’ refer only to ’disability’ in psycho-social terms or feelings of ‘fatigue‘, and not in terms of physical impairment, a key omission. Mundt et al’s paper in particular focuses on specific mental health problems and the social exclusionary effects of living with these. While in no way invalidating or trivialising the disability caused by mental health problems, it must be pointed out that both Mundt et al and Chalder Scales nevertheless fail to elucidate a high level of physical or physiological (say, for example, neurological, mitochondrial and/or cardiovascular) impairment, key problems present in people given a clinical diagnosis of ‘CFS’, usually related to specific organic abnormalities that can be found, if they are tested for in the first place.

With regard to the Canadian criteria (Carruthers et al), in fact they have undergone some ‘validation’. Jason et al found:

“…Canadian criteria selecting cases with less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurologic symptoms. The overall findings suggest that the Canadian clinical criteria appear to select a more symptomatic group of individuals than the CFS criteria, and these individuals do demonstrate less current and lifetime psychiatric impairment than those selected according to the CFS criteria. In contrast, the CFS group was not significantly different from the Chronic fatigue-psychiatric group in psychiatric impairment. Predictably, the Chronic fatigue-psychiatric group evidenced the highest frequency of current and lifetime psychiatric disorders… Overall, there were 17 significant symptom differences between the Canadian and Chronic fatigue-psychiatric group, but only 7 significant symptom differences between the CFS and Chronic fatigue-psychiatric group. Findings suggest that the Canadian criteria select a group of patients with more symptoms, and the Canadian criteria identify a group with higher levels of physical functional impairment and less psychiatric comorbidity. Findings from the present study indicate that the Canadian criteria does capture many of these cardiopulmonary and neurological abnormalities, which are not currently assessed by the current CFS case definition (Fukuda et al., 1994). However, it is worth noting that when the Fukuda et al. (1994) CFS case definition was conceived, the research had not yet been done investigating these abnormalities. In combination with symptom patterns, it is possible to conclude that the Canadian group does select individuals with greater impairment, particularly given the physical composite score, fatigue/weakness, neurologic and neuropsychiatric symptoms, as these symptoms can interfere with daily living and occupational performance. Results from this present investigation highlight the importance of contrasting different diagnostic criteria in order to gain a greater understanding of the syndrome now known as CFS. The findings do suggest that the Canadian criteria point to the potential utility in designating post-exertional malaise and fatigue, sleep dysfunction, pain, clinical neurocognitive, and clinical autonomic/ neuroimmunoendocrine symptoms as major criteria for future attempts to define this syndrome...” (http://www.mefmaction.net...)

In addition to using the Carruthers et al criteria (or ‘Canadian Criteria‘), the WPI give this information about their patient cohort in their supporting online material:

"Their diagnosis of CFS is based upon prolonged disabling fatigue and the presence of cognitive deficits and reproducible immunological abnormalities. These included but were not limited to peturbations of the 2-5A synthetase/RNase L antiviral pathway, low natural killer cell cytotoxicity (as measured by standard diagnostic assyas) and elevated cytokines particularly interleukin-6 and interleukin-8. In addition to these immunological abnormalities, the patients characteristically demonstrated impaired exercise performance with extremely low VO2 max measured on stress testing..." (www.sciencemag.org/cgi/co...)

It is therefore highly unlikely, as the authors indeed acknowledge in their reply here, that Erlwein et al were testing the same type of patient as those tested by the WPI, which inevitably makes the Erlwein et al findings- and perhaps some of the wilder claims that they have ‘cast serious doubt’ on the WPI‘s findings, unfortunately made in some of the lay media- not scientifically tenable. The failure of Erlwein et al to include such type of patient in their cohort, however. does not mean that such patients do not exist in Britain. Copious patient anecdotal experience, research reports, and charity surveys indicate that they do exist. Whether XMRV is present or not is another matter, but there are enough identifiable problems around patient selection alone with the Erlwein et al paper to indicate this is not a definitive disproving of the existence of the virus in Britain.

Ongoing neglect of the importance of establishing a possible ‘CFS’ patient population in Britain, clinically and in research settings, using the Canadian Guidelines, is preventing the development of knowledge that might help extremely ill and disabled people here in Britain.

The problems I have briefly outlined here do not fully express the range and depths of problems with regard to: the identity of an accurate ‘CFS’ population; the instabilities of ‘CFS’ criteria per se; the faulty concepts of ‘medically unexplained’ or ‘functional‘ and relation to ‘psychogenic‘ explanations for somatic illness; the vagaries of criteria that claim to facilitate a ‘diagnosis of exclusion’; and the psychogenic dismissal of serious organic dysfunction of patients given a ’CFS’ diagnosis, problems that have happened for many years. These problems are relevant to the Erlwein et al paper. Furthermore, they are highly relevant to all research that claim a psychological and/or behavioural aetiology to the condition or conditions that get deemed as ‘CFS’.

REFERENCES

Carruthers, B. et al (2003) “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols” Journal of Chronic Fatigue Syndrome, Vol. 11(1), pp 7 - 115.

Chalder, T. Berelowitz, G. Pawlikowska, T. Watts, L. Wessely, S. Wright, D. Wallace, E. P. 'Development of a fatigue scale' Journal of Psychosomatic Research Vol 37: Issue 2: Feb 1993: 147-153.

David, A.S. ‘Postviral syndrome and psychiatry‘ British Medical Bulletin: 1991: 47: 4: 966-988

Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. 'The chronic fatigue syndrome: a comprehensive approach to its definition and study' Ann Intern Med. 1994 Dec 15;121(12):953-9.

Jason LA, Torres-Harding SR, Jurgens A, Helgerson J. “Comparing the Fukuda et al. Criteria and the Canadian Case Definition for chronic Fatigue Syndrome”. Journal of Chronic Fatigue Syndrome 12(1):37-52, 2004

Mundt, J.C. Marks, I.MShear, K. Griest, J.H. 'The work and social adjustment scale: a simple measurement of impairment in functioning' British Journal of Psychiatry (2002) 180: 461-443

Page, L.A. Wessely, S. 'Medically unexplained symptoms: exacerbating factors in the doctor–patient encounter' J R Soc Med 2003;96:223-227

Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al ' Chronic fatigue syndrome: guidelines for research' J R Soc Med. 1991 Feb;84(2):118-21.

Competing interests declared: Social scientist critically evaluating 'psychogenic' explanations for somatic illnesses. Parent of adult who given a 'CFS' diagnosis as a child.

Comment of AngelaKennedy

justinreilly replied to AngelaKennedy on 21 Jan 2010 at 02:08 GMT


Exactly!!

I would like to add that the UK psychiatrist viewpoint suffers from a myopia, seeing only some leaves of some trees without a viable conception of the forest. They are met with tired people presenting at their clinics, have heard from other doctors that these people are somatisizers and this is the lens through which all future understanding flows.
Contrast this with the approach of the wisened clinicians at the start of the outbreak of a novel, discreet, unique, suddenly prevalent and extremely disabling infectious disease in 1983 and 1984. The clinicians' approach (including the Canadian Definition) was and is an attempt to answer the question: what is this unique, suddenly pandemic infectious disease? This is why the Canadian Definition is valid and the psychiatrists' conception of 'CFS' is not.
That is, to produce meaningful knowledge (i.e. science) one MUST study what ME/CFIDS IS (i.e. the disease described by the Canadian Definition), not an abstract inaccurate definition (i.e. Fukuda, Oxford and all others) no matter how much easier it makes the research.

No competing interests declared.

RE: Authors Response

Balbuie replied to Anthony_Cleare on 15 Jan 2010 at 17:51 GMT

I found the following statement in point 3 of Dr Cleare's response (below) to be quite extraordinary:

"We follow the same psychiatric exclusion criteria as mandated by the Fukuda criteria......In addition, we also exclude patients with chronic somatisation disorder as defined by DSM-IV, which is not required by the Fukuda criteria, but most experts and clinicians agree are a different population."

Why extraordinary?

Because of Professor Wessely and colleagues' long held and widely publicised view that CFS is a somatisation disorder (or medically unexplained syndrome, MUS)(1)(2)(3)(4)(5)

This theory is in complete defiance of the scientific evidence which clearly shows CFS to be an organic disease. As such, by definition, CFS cannot be a somatisation disorder.(8)(9) The same holds true for other terms like MUS and psychosomatic (1) (2) (3)

Somatoform disorder is defined in DSM-IV as follows:
"The most common characteristic of the somatoform disorder is the appearance of physical symptoms or complaints for which they have no organic basis."(6)

With such a profound turn around in thinking (if this really is the case) it would be helpful to all concerned if the authors could please clarify the following points:

1. Could you please state how all the authors defined CFS at the time of carrying out this research and do you still hold that perspective?

Lombardi et al unequivocally, on the basis of the scientific evidence, view CFS as an organic disease.

2. Could you please explain why you did not state in the paper that you had excluded patients with somatoform disorders.

3. If, as you say, you excluded patients in this research who had somatisation disorders, can you please explain why you cited papers in your reference list (for example, reference 9 by Wessely et al, "Chronic fatigue syndrome. A Practical Guide to Assessment and Management", 1997) which clearly classes CFS as a somatisation disorder.

3. And could you please explain why you did not cite papers, such as in Ref 8 & 9 below, which clearly show the organic basis of this disease?

4. Could you please inform readers when the 186 blood samples were taken, since, at least up until March 2009, Professor Wessely viewed CFS as a somatisation disorder(2).

Was the blood drawn after you had changed your minds about CFS being a somatoform disorder or before you changed your mind?

5.Could you please explain what has led to such a change of mind, no longer viewing CFS as a somatisation disorder?

Thank you for your time.

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REFERENCES
1. http://www.scielo.br/scie...
Chronic fatigue syndrome: an overview.
Cho HJ, Wessely S.
Rev. Bras. Psiquiatr. vol.27 no.3 São Paulo Sept. 2005
"Chronic fatigue syndrome is an exemplar of a medically unexplained syndrome."
"Similarly,functional somatic syndromes refer to groups of symptoms lacking disease-specific, demonstrable abnormalities of structure, and are usually defined by specialty or organ system. They include irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, multiple chemical sensitivity, chronic pelvic pain, temporomandibular joint dysfunction and more recently Gulf War syndrome."

This paper is titled "CFS: An Overview" yet please note that the references,(consisting of 6 papers) do not include any papers on biomedical research.

2. http://www.newscientist.c...
New Scientist, Opinion, "Mind over body?", Professor Simon Wessely, 13 March 2009. Please note that there is no mention of all the biomedical research showing CFS to be an organic disease.

3. http://www.iop.kcl.ac.uk/...
Research carried out at the Institute of Psychiatry, Kings College London, where three of the authors of this paper are based.
Part 4- The Project and the Post
"Background: Anorexia Nervosa (AN) and Chronic Fatigue Syndrome (CFS)are classical psychosomatic disorders......Aberrant emotional processing is a strong candidate as a maintaining factor for these disorders."

4. http://www.meactionuk.org...
From "Corporate Collusion?" by Professor Malcolm Hooper, Eileen Marshall and Margaret Williams, comments made by Professor Wessely over the years about CFS and CFS patients clearly showing how he views these patients and the disease:

"Wessely is on record as asserting that ME is merely a “belief” held by those who think they suffer from it; that ME patients’ muscle weakness is “simulated”; that efforts are made to over-interpret laboratory findings; that the average doctor will see ME patients are neurotic and will often be disgusted with them; that blaming a virus for the illness conveys advantages by protecting the victim from personal blame; that symptoms are simply normal sensations and are the result of “body-watching”; that ME is a “myth”; that ME is “learned helplessness”; that once validation is granted by a doctor, the ME patient may assume the “advantages of the sick role -- sympathy, time off work, benefits etc”; that ME symptoms have no anatomical or physiological basis; that patients’ aberrant beliefs are maintaining factors and that patients with ME exert a large and avoidable financial burden on health and social services.
(For individual references, see the December 2003 Briefing Paper for the House of Commons Health Select Committee: The Mental Health Movement: Persecution of Patients? which is available online at
http://www.meactionuk.org... )."

5. http://www.ncbi.nlm.nih.g...
Medically Unexplained Symptoms:Exacerbating Factors in the Doctor-patients Encounter, L A PAge, S Wessely, Journal of thew Royal Society of Medicine 2003:96:223-227
"This term (MUS) is now used in preference to "somatisation"

However I cannot find MUS in the DSM-IV

6. http://www.psychnet-uk.co...
Definition of somatisation disorder

7. http://www.meactionuk.org...
"Wessely’s Way: Rhetoric or Reason?"
Professor Malcolm Hooper and Margaret Williams
22nd March 2008

8. http://www.meactionuk.org...
List of reference and abstracts for some of the many biomedical research papers on CFS, plus inquest and autopsy information, see item 47 and 48.

9. Two further important references, 2009.
http://www.ncbi.nlm.nih.g...
J Clin Pathol. 2009 Dec 2.
Microbial infections in eight genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME).
Zhang L, Goudh J, Christmas D, Mattey D, Richards S, Main J, Enlander D, Honeybourne D, Ayres J, Nutt DJ, Kerr J.
St George's University of London, United Kingdom;

http://www.ncbi.nlm.nih.g...
J Transl Med. 2009 Nov 12;7:96.
Plasma cytokines in women with chronic fatigue syndrome.
Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG.


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No competing interests declared.