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An unbiased metagenomic search for infectious agents using monozygotic twins discordant for chronic fatigue

Patrick F Sullivan*, Tobias Allander, Fredrik Lysholm, Shan Goh, Bengt Persson, Andreas Jacks, Birgitta Evengård, Nancy L Pedersen and Björn Andersson*

BMC Microbiology 2011, 11:2  doi:10.1186/1471-2180-11-2

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Atypical cohort characteristics, means the findings are not generalisable to all subjects

Andrew Kewley   (2011-07-21 12:02)  Flinders University email

The methods of this study are certainly interesting, however one must question the value of doing such a study when the cohort is atypical of the disease in general.

Rapid onset after viral infection is widely reported among cases of Chronic Fatigue Syndrome and those are the cases which are most likely to involve infectious agents.

However in the previous study by this group, which utilised basically the same twin cohort, it was stated that only two subjects reported sudden onset of fatigue [1].

Secondly, the median SF-36 physical functioning composite score of 41 is atypically high for a CFS cohort.

In a recently published study measuring the functional status of CFS subjects and their carers, the mean physical functioning composite score of CFS subjects (n=170) was found to be 26.8 [2]. The severity in the twin cohort looks very mild in comparison.

Twin cohorts certainly reduce bias with regards to selection of matched controls. But given the heterogeneity of CFS, these particular findings can only be generalised to a subset of subjects who have mild fatigue and had gradual, rather than rapid onset.

Future twin studies should make sure the mean physical functioning of the cohort is more typical of Chronic Fatigue Syndrome in general.

[1]
Byrnes A, Jacks A, Dahlman-Wright K, Evengard B, Wright FA, et al. (2009) Gene Expression in Peripheral Blood Leukocytes in Monozygotic Twins Discordant for Chronic Fatigue: No Evidence of a Biomarker. PLoS ONE 4(6): e5805. doi:10.1371/journal.pone.0005805
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0005805

[2]
Nacul, LC et al. (2011) The functional status and well being of people with myalgic encephalomyelitis/chronic fatigue syndrome and their carers. BMC Public Health 2011, 11:402doi:10.1186/1471-2458-11-402
http://www.biomedcentral.com/1471-2458/11/402

Competing interests

None declared

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"SF-36 physical function" should read "SF-36 PCS" I believe

Tom Kindlon   (2011-02-09 11:12)  Irish ME/CFS Association - for Information, Support & Research email

There are 8 SF-36 subscales: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social functioning, Role-Emotional and Mental Health. There are also two composite scores: Physical Composite Score (PCS) and Mental Composite Score (MCS).

Following the link used in the text http://www.sf-36.org/nbscalc/index.shtml , one can see the population norms for Sweden: (Mean, SD) Physical Function(ing) (87.9, 19.6), Role-Physical (83.2, 31.8), Bodily Pain (74.8, 26.1), General Health (75.8, 22.2) Vitality (68.8, 22.8), Social functioning (88.6, 20.3), Role-Emotional (85.7, 29.2), Mental Health (80.9, 18.9), Physical Composite Score (PCS) (50.0, 10) and Mental Composite Score (MCS) (50.0, 10).

We are told that the Physical Function score (Median, IQR) for the unaffected twins is (48, 39-52). These are not SF-36 physical functioning scores of healthy individuals e.g. one would expect a higher median (remember that the population mean is 87.9) and one would expect a score higher than 52 as part of the IQR.

Given we are given only two values, I presume what the authors mean when they say "SF-36 physical function" and "SF-36 mental function" is SF-36 Physical Composite Score (PCS) and SF-36 Mental Composite Score (MCS).

This is important as it tells one both the health of the unaffected twins but also the health of those with Chronic Fatigue Syndrome and idiopathic chronic fatigue: a group with a physical function score (median, IQR) (41, 27-48) is quite severely affected. However, if those are Physical Composite Scores they are a relatively mildly affected cohort for CFS cases.

Competing interests

No competing interests

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Questions about 'CFS' and 'ICF' selection criteria of cohort

Angela Kennedy   (2011-01-13 11:25)  Comment made in independent capacity email

With regard to the cohort under study, I note that the authors write that their analysis sample consisted of "45 pairs of monozygotic twins discordant for clinically evaluated chronic fatiguing illness" and that "32 met criteria for CFS and 13 for ICF with a median duration of chronic fatigue of 8 years with no significant difference between
affected twins with CFS and ICF" (1). They then reference both the Fukuda et al criteria (2), and Reeves et al criteria (3), though I believe the latter in error, as the actual Reeves et al criteria were apprently produced in 2005 (4). Perhaps the authors could clarify whether this is the case.

Both criteria have been critiqued for their inclusion of non-neurological and psychological symptoms and exclusion of neurological symptoms (5), in opposition to the 'Canadian' clinical criteria (6) for ME/CFS, which has recently been
produced as research criteria (7) . The Reeves et al criteria have come under particular criticism for their methodology in defining 'CFS' patients as suffering fatigue and psychological symptoms only, and excluding patients with neurological symptoms (5). The Canadian Criteria have also been demonstrated in a further study to identify ME/CFS patients with significant differences from Fukuda defined 'CFS' patients (8) . That idiopathic chronic fatigue is a different illness entity to chronic fatigue syndrome (which is used as a synonym for the WHO ICD-10 stated neurological condition Myalgic Encephalomyelitis (at G93.3) has been acknowledged, by the WHO themselves (9), and by the American Medical Association (10).

With this in mind, I ask these questions of the authors:

1. Of the patients defined as 'idiopathic chronic fatigue' sufferers, how many were defined as such by Fukuda criteria, and how many by Reeves criteria, as such?

2. Of the patients defined as 'chronic fatigue syndrome' sufferers, how many were defined as such by Fukuda criteria, and how many by Reeves criteria, as such?

3. Why did the authors not acknowledge, as part of their discussion, the problem of the differences in criteria identification of chronic fatigue syndrome patients, including the issue of neurological symptoms identified by the

'Canadian' criteria, and how these may differ to patients identified as 'CFS' under other criteria? Since the Canadian criteria have been available since 2003, and further validation work has been produced, it is problematic that these
criteria, and the methodological problems thrown up by the discordancy of the different criteria, were not even mentioned. At the very least this should have been discussed in a 'limitations' of study' section, for example, to acknowledge that 'Canadian' defined patients were not part of this cohort.

REFERENCES

(1) Sullivan, P. F. et al 'An unbiased metagenomic search for infectious agents using monozygotic twins discordant for chronic fatigue' BMC Microbiology 2011, 11:2 doi:10.1186/1471-2180-11-2.

(2) 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.

(3) Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, et al. (2003) Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res 3: 25.

(4) Reeves, W. C. Wagner, D. Nisenbaum, R. Jones, J. F. Gurbaxani, B. Solomon, L. Papanicolaou, D. A. Unger, E. R. Vernon, S. D. Heim, C. 'Chronic Fatigue Syndrome - a clinically empirical approach to its definition and study' BMC medicine 2005 3: 19. Also available via open access: http://www.biomedcentral.com/1741-7015/3/19

(5)Jason, L. A. Najar, N. Porter, N. Reh, C. 'Evaluating the Centers for Disease Control's Empirical Chronic Fatigue Syndrome Case Definition' Journal of Disability Policy Studies (2009) 20: 93.

(6) 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.

(7) Jason, L. A. Evans, M. Porter, N. Brown, M. Brown, A. Hunnell, J. Anderson, V. Lerch, A. de Meirleir, K. Friedberg, F. (2010) 'The Development of a Revised Canadian Myalgic Encephalomyelitis-Chronic Fatigue Syndrome
Case Definition' American Journal of Biochemistry and Biotechnology 6 (2): 120-135.

(8) 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

(9) WHO classification details cited in CFIDS Chronicle: Summer 1990:144

(10) JAMA issues correction. Journal of the American Medical Association 1990 (referring to the issue dated 4th July 1990 and article entitled Chronic fatigue: A prospective clinical and virologic study by Deborah Gold et al:264:1:48-53).

Competing interests

Social Sciences lecturer and researcher with specific interest in critical analysis of psychogenic explanations for somatic illness. Family member was given 'CFS' diagnosis.

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