Findings from a clinical and laboratory database developed for discovery of pathogenic mechanisms in

[Bob]

Not open access, unfortunately.

A large multi-center study by Klimas, Bateman, Levine, Peterson, Hornig, Komaroff and colleagues.

"This paper introduces the Chronic Fatigue Initiative..."

Findings from a clinical and laboratory database developed for discovery of pathogenic mechanisms in myalgic encephalomyelitis/chronic fatigue syndrome
N.G. Klimas, G. Ironson, A. Carter, E. Balbin, L. Bateman, D. Felsenstein, S. Levine, D. Peterson, K. Chiu, A. Allen, K. Cunningham, C.G. Gottschalk, M. Fletcher, M. Hornig, C. Canning & A.L. Komaroff
Fatigue: Biomedicine, Health & Behavior 2015; 3:75-96
Published online: 24 Apr 2015
DOI:10.1080/21641846.2015.1023652
http://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1023652

Abstract

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic illness that is often disabling. This paper introduces the Chronic Fatigue Initiative, which conducted a large multi-center study to more fully characterize ME/CFS and ultimately to describe and understand the underlying mechanisms and pathogenesis of this illness.

Methods: A total of 203 patients with ME/CFS (cases) and 202 matched healthy controls (HCs) were enrolled from 5 geographically different expert clinical sites to create a well-characterized population linked to a national biorepository. ME/CFS subjects were compared to a one-to-one matched HC population for analyses of symptoms and illness severity. Cases were further evaluated for frequency and severity of symptoms and symptom clusters, and the effects of illness duration and acute vs. gradual onset.

Results: This study collected more than 4000 pieces of data from each subject in the study. Marked impairment was demonstrated for cases vs. controls. Symptoms of fatigue were identified, but also, nearly as frequent and severe, were symptoms of cognitive dysfunction, inflammation, pain and autonomic dysfunction. Potential subgrouping strategies were suggested by these identified symptom clusters: sleep, neurocognitive, autonomic, inflammatory, neuroinflammatory, gastrointestinal and endocrine symptoms.

Conclusions: Clearly, ME/CFS is not simply a state of chronic fatigue. These data indicate that fatigue severity is matched by cognitive, autonomic, pain, inflammatory and neuroinflammatory symptoms as the predominant clinical features. These findings may assist in the clarification and validation of case definitions. In addition, the data can aid clinicians in recognizing and understanding the overall illness presentation. Framing ME/CFS as a multisystem disorder may assist in developing therapies targeting the multifaceted domains of illness.

 

[Sasha]

Pity it's not open access - I'd like to know more about the subgrouping.

I like the conclusion!

 

[Bob]

Looks like it could be quite a significant paper. I'd like to read this one.

 

[aimossy]

It is probably the exact sort of paper Doctors need to be reading @Bob. I would like get/see this one too.

 

[jimells]

Conclusions: Clearly, ME/CFS is not simply a state of chronic fatigue.

Now tell me something we didn't already know 30 years ago...

 

[mango]

Construction of symptom cluster groupings

Symptom cluster groupings were derived from two methods: factor analysis of the DSQ and clinician-guided clustering.

The factor analysis of the DSQ performed previously by L. Jason’s group [20] yielded three factors: a large first factor which accounted for 31% of the variance included 31 items covering neuroendocrine, autonomic and immune symptoms. The second factor, composed of 8 items, explained an additional 5.8% of the variance and covered neurological and cognitive symptoms. The third factor, labeled PEM, explained 4.9% of variance and included a few extra items related to PEM but conceptually more distinct (fatigue/extreme tiredness, muscle weakness and feeling unrefreshed after waking). We used these established factors from Jason’s factor analysis to generate factor scores from our data. However, because the factor analysis was not specific enough (especially the first factor) to be clinically useful, we augmented this analysis with clinician-defined clusters. Our goal was to provide enough information to guide assessment and possible treatment targets.

Clinician-guided clustering involved grouping individual symptoms from the DSQ that were common to a particular cluster designation as assigned by a clinical expert (NK) consistent with the case definitions. The items from the CFI symptom checklist were subsequently categorized according to the labels from the clinician-defined clustering of the DSQ. The cluster labels were reviewed by clinical site experts and confirmed with reliability analysis. Clinician-based symptom clusters included fatigue/PEM, sleep, pain, gastrointestinal disorders, cognitive dysfunction, autonomic dysfunction, endocrine system dysfunction, inflammation, neuroinflammatory and neuromuscular dysfunction. The symptom clusters differed slightly between the CFI symptom checklist and the DSQ because the items on the two measures are somewhat different. [...]

Edited to add:
DSQ = DePaul Symptom Questionnaire

CFI = the Chronic Fatigue Initiative

The CFI symptom checklist = 'a general review of 50 symptoms for all potential cases and [Healthy Control]s to explore general health as well as potential clusters of symptoms relevant to ME/CFS. [...] For each symptom, the question asked of the prospective case or control was, “Over the past 6 months have you had [this symptom] frequently or constantly?” Each symptom was then noted by the interviewer as present or absent.'

(@Sasha)

 

[mango]

more about the subgrouping:

Acute vs. non-acute illness onset
ME/CFS participants with acute onset were significantly more likely to report a greater number of inflammatory symptoms (Table 4) than those subjects with gradual onset (F = 4.20, p = .042).For other symptom clusters, there were no significant differences between the acute as compared to non-acute onset groups. For individual symptoms (Table 5), participants with acute onset reported sore throats significantly more often than those with non-acute onset (t(199) = −2.90, p = .005). Participants with gradual onset evidenced significantly higher fatigue/extreme tiredness severity scores than those with acute onset (t(199) = 1.92, p = .05). Those with gradual onset also endorsed significantly higher severity scores than those with acute onset (x¯ = .72, SD = 1.06) for the symptom of “sleep all day/stay awake all night” (t(197) = 2.34, p = .02).

Illness duration <3 years vs. duration =>3 years
Although the severity of autonomic dysfunction symptoms was significantly greater in ME/CFS with illness duration of less than three years vs. equal to or more than three years (F = 3.93, p = 0.049), the overall presence or absence of the seven autonomic dysfunction symptoms did not differ between short and long duration subsets except for dizziness or fainting. Dizziness or fainting was present in 92% of ME/CFS patients with less than 3 years duration vs. 78% of those with duration ≥3 years (χ2(1) = 4.80, p = 0.03).

For individual symptoms (Table 5), participants with illness duration less than three years had higher average fatigue/extreme tiredness severity levels than those with duration equal to or greater than three years (t(199) = 2.26, p = .025). Those with duration less than three years also had higher severity levels for the following symptoms: difficulty paying attention (t(199) = 2.10, p = .037), feeling unsteady on your feet (t(200) = 2.67, p = .008), shortness of breath (t(200) = 2.25, p = .025) and fever (t(198) = 2.03, p = .044). In addition, participants with duration equal to or more than three years had higher average frequency scores than those with duration less than three years for the following variables: bloating (t(200) = −1.96, p = .051) and tender/sore lymph nodes(t(200) = 1.23; t(200) = −2.19, p = .03).

 

[mango]

(I'm not sure how much one is allowed to share wrt copyright etc... please let me know if I've exceeded the limit!)

 

[mango]

 

[aimossy]

 

[mango]

[…] cases must have had a previously confirmed diagnosis of ME/CFS, as established by an expert clinician, that met one or both of two internationally recognized case definitions: the “1994 Fukuda criteria” […] and/or the “Canadian criteria” Of note, cases were not excluded for depression unless it was melancholic depression or depression with psychotic features.

 

[mango]

Based on the premise that underlying pathology would be greater in those patients in early stages of the illness, we oversampled for cases whose illness had begun suddenly and within the previous three years. Thus the study required that no fewer than 50% of enrolled cases at each participating site have an acute onset of their illness. if the illness started in a week or less (determined to be acute) or a month or more (determined to be gradual). at least 25% of the sample was required to have had less than three years elapse since the original onset of ME/CFS.

I found this a bit "interesting":

[Healthy controls (HC)] could not have had sexual relations with any ME/CFS case or any other person who had ever been diagnosed with ME/CFS.

It is interesting to note that the gastrointestinal symptom cluster, which is not a part of the case definitions used for ME/CFS in this study, were also more frequent and more severe in cases as compared to HCs [...]. In addition, symptom clusters with at least one symptom endorsed by over 90% of the ME/CFS cases included not only fatigue/PEM/sleep, but also cognitive dysfunction, autonomic dysfunction, pain and inflammatory symptoms.

The fatigue cluster had the highest average severity rating. Several other prominent symptom clusters were sleep, cognitive dysfunction and neuroinflammatory (sensitivity to light and noise), followed by pain and neuromuscular symptoms.

It is important to note that PEM, which is a required symptom in the Canadian case definition, but not required in the 1994 Fukuda criteria was present in 97.5% of patients, and reflects the weight this symptom plays in the expert clinician’s classification of ME/CFS.

The ME/CFS cases were markedly different than the healthy control cases in the reported frequency of every symptom addressed across all of the domains of illness: fatigue, cognitive dysfunction, sleep, autonomic symptoms, inflammation, neuroinflammation, pain, neuromuscular and endocrine symptoms. Within cases, clinician defined symptom clusters from the DePaul Questionnaire were endorsed at a moderate or higher level by 64.9% or more of cases. These clusters included fatigue and sleep, cognitive dysfunction, pain and inflammatory symptoms. For individual symptoms, 49.9% of the cohort reported gastrointestinal (GI) symptoms, 55.5% had symptoms reflecting endocrine dysfunction and 54.5% reported symptoms consistent with a neuroinflammatory state.

 

[mango]

The data set is particularly useful for comparison and refinement of case definitions. Sufficient data are available to compare the 1994 Fukuda, the Canadian 2003 clinical criteria and the newer 2010 Jason research operationalization of the Canadian 2003 definition. Our findings showed that 100% of the cohort met Fukuda criteria, 90.4% met the Canadian 2003 (clinical) definition and 70.8% met the Canadian research definition (5). The Jason operationalization of Canadian criteria of 2003 has more stringent research criteria, which requires PEM, pain and higher frequency and severity scores.

Most importantly, the CFI has established a large clinical and laboratory assay database from subjects with clearly established ME/CFS and age- and gender-matched health control subjects, as well as a biorepository of samples processed and stored for optimal integrity. These resources can be utilized to facilitate research efforts in ME/CFS and may aid in addressing the most critical questions about this complex illness with respect to improved diagnosis and targeted treatments.

 

[alex3619]

(I'm not sure how much one is allowed to share wrt copyright etc... please let me know if I've exceeded the limit!)

For text its 10%. Not sure about tables. (Or it used to be, I haven't looked into this in many years.)

 

[jimells]

(I'm not sure how much one is allowed to share wrt copyright etc... please let me know if I've exceeded the limit!)

Keep digging! There's gotta be a pony under all that data!

 

[mango]

Keep digging! There's gotta be a pony under all that data!

unfortunately i don't have a trained eye for this sort of thing, i'm sure someone else could find and highlight other/better parts and details russell on twitter mentioned that he'll have a look at it, and perhaps @Bob has something to add?

 

[Dolphin]

(I'm not sure how much one is allowed to share wrt copyright etc... please let me know if I've exceeded the limit!)

The severity question was: “Over the past six months, how much has this symptom bothered you?” and was scored 0 = symptom not present, 1 = mild, 2 = moderate, 3 = severe and 4 = very severe. For any group of cases (e.g. for females), the average score (ranging from 0 to 4) and variance were calculated. The frequency question was: “Over the past six months, how often have you had this symptom?” and was scored 0 = none of the time, 1 = a little of the time, 2 = about half of the time, 3 = most of the time and 4 = all of the time.

 

[Dolphin]

 

[Dolphin]

 

[Seven7]

I just want to make a comment, in Klimas group even thought they use CCC, they run A LOT of tests and they use it to diagnose also, is not just you are CCC, they account for NK activity, T cells, B cells and the whole immune profile...... So I trust the patient pool.

We fill out the SF-36 every time you have a CFS consult (the in person one). So they track the progress over time. Is helpful for one self also.