Metagenomic search for infectious agents using monozygotic twins discordant for CF

[oceanblue]

A problem with the Dubbo cohort is that 98-99% were better or didn't have CFS at 2 years. If one wants to see what causes CFS to stay, patients who get stuck with it/don't get better could be said to be more interesting.

Prospective studies on post-infective cohorts, like Dubbo, are focused on the difference between those that recover normally from Glandular Fever etc, typically within a few months, and those that do not and go on to develop CFS. They're well set up to look at what goes on in the first 6 months or so of illness. As you say, most of these CFS patients then recover within 2 years.

I would be interested to know how CFS patients from such studies compare with other CFS patients at the same stage. In other words, if you took a group of patients who had just reached the 6-month CFS threshold and followed them for the next 2 years, what would their recovery rates be like, and would they be significantly different from Dubbo? All the prognosis studies I've seen start with patients who on avearge have been ill for quite a few years.

 

[Dolphin]

Prospective studies on post-infective cohorts, like Dubbo, are focused on the difference between those that recover normally from Glandular Fever etc, typically within a few months, and those that do not and go on to develop CFS. They're well set up to look at what goes on in the first 6 months or so of illness. As you say, most of these CFS patients then recover within 2 years.

I would be interested to know how CFS patients from such studies compare with other CFS patients at the same stage. In other words, if you took a group of patients who had just reached the 6-month CFS threshold and followed them for the next 2 years, what would their recovery rates be like, and would they be significantly different from Dubbo? All the prognosis studies I've seen start with patients who on avearge have been ill for quite a few years.

Yes, I agree. Have sufficient numbers in each group to compare the two groups.

 

[Dolphin]

Snow Leopard highlighted:

Two affected individuals (4.5%) reported sudden onset of fatigue.

(It's the same cohort as current study)

http://www.plosone.org/annotation/l...notation/71f37267-372a-4c29-be7f-ec35f74ad8a3

Unusually low rate of sudden onset of fatigue for a CFS cohort

This looks to be a very well-designed study.

One finding I noticed, which may have an effect on the generalisability of the findings, is the low rate of participants who reported "sudden onset of fatigue": 4.5% (2/44) (See Table 1).

Generally much much higher rates of sudden onset of the symptoms have been reported in the CFS literature.

[About the only exception that I can recall are the CDC studies in recent years. However, they use an unusual way of defining CFS[1] which covers 2.54% of the population[2], a prevalence rate much higher than previous estimates of the CFS calculated using similar methodologies to estimate prevalence [0.235% (95% confidence interval, 0.142%-0.327%) and 0.422% (95%
confidence interval, 0.29%-0.56%) respectively][3,4]. A study[5] was recently published which found that 38% of
those with Major Depressive Disorder who don't have CFS would incorrectly be classified as having CFS using the empirical/Reeves criteria[1]. A critique[6] of the
empirical/Reeves criteria[1] has been published and other comments have been published online alongside the initial paper[7] and on the website of the International Association for CFS/ME[8]].

This low rate of sudden onset cases suggests, at the very least, that the findings may not apply to post-infectious cohorts of CFS patients. This, of course, is not necessarily
a fault in the design of the study's design; the authors appear to have applied commonly used criteria for CFS diagnosis[9,10]. The problem (for want of a better word) would appear to lie with these criteria and generally
the heterogeneity that has been associated with the condition[11].

References:

[1] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome--a clinically empirical approach to its definition and study. BMC Med. 2005 Dec 15;3:19. http://www.biomedcentral....

[2] Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007 Jun 8;5:5.
http://www.pophealthmetri...

[3] Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536. http://dx.doi.org/10.1001...

[4] Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37. http://dx.doi.org/10.1001...

[5] Jason, LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2008, doi:10.1177/1044207308325995.

[6] Jason, LA, Richman JA. "How Science Can Stigmatize: The Case of Chronic Fatigue Syndrome". Journal of Chronic Fatigue Syndrome, Vol. 14(4), 2007 http://listserv.nodak.edu...

[7] Various. Comments on the empirical/Reeves definition/criteria for CFS. http://www.biomedcentral....

[8] Problems with the New CDC CFS Prevalence Estimates. Leonard Jason, Ph.D., DePaul University
http://www.iacfsme.org/Is...

[9] Fukuda K, Strauss SE, Hickie I, Sharpe MC, Dobbins JG, et al. (1994) The chronic fatigue syndrome: a comprehensive approach to its definition and study. Annals of Internal Medicine 121: 953-959.

[10] 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.

[11] Jason LA, Corradi K, Torres-Harding S, Taylor RR, King C. Chronic fatigue syndrome: the need for subtypes.
Neuropsychol Rev. 2005 Mar;15(1):29-58. Review.

 

[Dolphin]

Agreed.....I don't mind if they got better - I was better two years later - but I do recall most of them worked their way out of it....

I'm not sure if "worked their way out of it" is the exact wording I'd use as it suggests they conquered it through hard work. While they simply got better like with the adolescents with EBV where 13% satisfied the criteria at 6 months but only 4% at 2 years.

I wonder how many of these twins had been to see a doctor? This was a random sampling survey like the CDC.....

This is disappointing but you know what they are not doing? They are not stressing them...they are not requiring them to ride on a bicycle or doing jumping jacks -- and several studies have shown that things really start showing only after you do that... I would consider the study design to be obsolete, really. Remember the Light study - same receptor levels at baseline - big difference after exercise.

If they are going to measure anything -pathogens, cytokines, gene expression - I think they should knock them on their butt first.

Good points.

 

[Dolphin]

The major assumption of this study is the idea that the pathology and therefore mRNA expression is constant amongst the cohort. But if this assumption is not true, does this study have sufficient power to detect differences, considering the results are all pooled together?

Good point.

I know we constantly preach 'cohort, cohort, cohort'. But is anyone listening? I wonder how the results would change if indeed they did test a male only group with sufficient size?

Good point. The menstrual cycle for one is known to have a big influence on lots of functions.

 

[oceanblue]

Fatigue scores

Table 1 from this study shows a big difference in fatigue between patients and healthy twin on the Visual Analogue Scale (VAS):

Affected twin: Median=69 (IQR 49-77)
unaffected twin: Median=19 (IQR 10-51)

I don't know how the VAS scale compares with other fatigue scale used such as the Chlalder scale but no doubt the authors will point to these results as evidence that the CFS twins were seriously fatigued.

Of course, the SF36 measures activity levels rather than fatigue, but you would expect a strong correlation between the two. Something doesn't add up here.

 

[Dolphin]

Table 1 from this study shows a big difference in fatigue between patients and healthy twin on the Visual Analogue Scale (VAS):


I don't know how the VAS scale compares with other fatigue scale used such as the Chlalder scale but no doubt the authors will point to these results as evidence that the CFS twins were seriously fatigued.

Of course, the SF36 measures activity levels rather than fatigue, but you would expect a strong correlation between the two. Something doesn't add up here.

Yes, it is interesting and I think with a normal CFS cohort the two would correlate. But, these were chosen to have fatigue by definition so it's not surprising they don't have low fatigue scores. However, only 2 of them recall a sudden onset. So it would be interesting to know how many would be seen as depressed for example.