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Patients diagnosed with ME/CFS also fit systemic exertion intolerance disease criteria

Dolphin

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17,567
Patients diagnosed with Myalgic encephalomyelitis/chronic fatigue syndrome also fit systemic exertion intolerance disease criteria

Lily Chua, Jane L. Norrisa, Ian J. Valenciab and Jose G. Montoyaa

aStanford ME/CFS Initiative, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA;
bFormerly of Stanford ME/CFS Initiative, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA

ABSTRACT

Background:

Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) remains undiagnosed in up to 91% of patients. Recently, the United States-based Institute of Medicine (IOM) developed new diagnostic criteria, naming it systemic exertion intolerance disease (SEID).

Purpose:

We examined how subjects fit SEID criteria and existing ME/CFS case definitions early in their illness.

Methods:

A total of 131 subjects fitting 1994 Fukuda CFS criteria at the time of study recruitment completed a survey of symptoms they experienced during their first 6 months of illness.

Symptoms were drawn from SEID and existing criteria (1994 Fukuda, 2003 Canadian Consensus Criteria (CCC), and 2011 Myalgic Encephalomyelitis-International Consensus Criteria (ME-ICC)).

We calculated and compared the number/percentage of subjects fitting single or combinations of case definitions and the number/ percentage of subjects with SEID experiencing orthostatic intolerance (OI) and/or cognitive impairment.

Results:

At 6 months of illness, SEID criteria identified 72% of all subjects, similar to when Fukuda criteria (79%) or the CCC (71%) were used, whereas the ME-ICC selected for a significantly lower percentage (61%, p < .001).

When severity/frequency thresholds were added to the Fukuda criteria, CCC and ME-ICC, the percentage of these subjects also fitting SEID criteria increased to 93%, 97%, and 95%.

Eighty-seven percent of SEID subjects endorsed cognitive impairment and 92%, OI; 79% experienced both symptoms.

Conclusions:

SEID criteria categorize a similar percentage of subjects as Fukuda criteria early in the course of ME/CFS and contain the majority of subjects identified using other criteria while requiring fewer symptoms.

The advantage of SEID may be in its ease of use.

ARTICLE HISTORY
Received 24 May 2016
Accepted 21 February 2017

KEYWORDS Systemic exertion intolerance disease (SEID); Myalgic encephalomyelitis (ME); chronic fatigue syndrome (CFS); diagnosis; Canadian Consensus Criteria (CCC); Myalgic encephalomyelitis – international consensus criteria (ME-ICC)
 

Dolphin

Senior Member
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17,567
None of the four sets of criteria, operationalized in any way, initially identified more than 80% of all study subjects. This is not surprising as 30–80% of subjects from community- based studies report a gradual rather than acute onset of the illness [7,37]. Although most studies do not define the terms ‘acute’ or ‘gradual,’ in two different samples recruited with Fukuda criteria, 43% and 64% experienced illness onset occurring over a period of greater than 6 months, suggesting that some Fukuda-related symptoms may not develop until later [38]. Furthermore, we found that 14% and 21% of all subjects did not qualify for any of the four criteria during the first 6 months. Consequently, while current criteria are useful, there need to be further studies investigating which symptoms, features, and/or objective tests might allow for early, accurate diagnosis of more patients.
I didn't understand what they had done when I read the abstract initially. It is interesting that so many people can be missed.

I know myself that I only got some symptoms when I became more severely affected. And some of the ones that I did have initially were not that prominent (after I gave up sports).
 
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Dolphin

Senior Member
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17,567
Obtaining a diagnosis is reported as ‘the single most helpful event’ by 90% of patients affected by ME/CFS, allowing them to be less anxious or fearful, formulate ways to cope with their symptoms, and communicate with healthcare professionals and others [10].

[10] Woodward RV, Broom DH, Legge DG. Diagnosis in chronic illness: disabling or enabling--the case of chronic fatigue syndrome. J R Soc Med. 1995;88(6):325–329.
 

Dolphin

Senior Member
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17,567
For Fukuda criteria, where some published versions state ‘fatigue’ while others state ‘severe fatigue’, we have operationalized it in two ways: (1) requiring mere presence of fatigue, equivalent to at least a ‘1/ 1’ score (i.e. ‘mild/ a little of the time’) and (2) requiring a ‘2/2’ score to denote ‘severe fatigue’ (designated ‘Fukuda-severe fatigue’). For the CCC and ME-ICC, severity and frequency of symptoms are not specified in the original publications so we have evaluated symptoms using both the ‘1/1’ and ‘2/2’ scoring methods.
It is interesting that the criteria can be operationalised in different ways.

At 6 months of illness, SEID criteria identified 72% of all subjects, similar to when Fukuda criteria (79%) or the CCC (71%) were used, whereas the ME-ICC selected for a significantly lower percentage (61%, p < .001).
If use the 2/2 threshold, the figures drop to 56% for the Canadian clinical criteria and 45% for the international consensus criteria. They are 72% when Fukuda requires 2/2 for fatigue, the same percentage as SEID. (Table 2)
 
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Dolphin

Senior Member
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17,567
For SEID criteria, where ‘profound fatigue’ and unrefreshing sleep, PEM, and cognitive difficulties of moderate intensity must exist for 50% or more of the time to qualify, we counted these symptoms as significant only when they were rated by subjects as equal to two or more on both the DSQ intensity and frequency scales (‘2/2’ scoring), equivalent to at least ‘moderate intensity’ occurring ‘about half the time’.

Similarly, discrepancies in the prevalence of OI between our and Jason’s studies could be due to the less common symptoms (e.g. shortness of breath) they chose to represent OI and their institution of minimum severity/frequency thresholds for OI when the SEID criteria do not obligate such parameters[1]. OI affected 92% of our subjects, similar to the 80% prevalence recorded by Lapp et al. [28] through tilt table testing, and permitted an additional 13% our of subjects, who did not have cognitive impairment, to qualify for SEID. In contrast, 67% of Jason’s subjects [23] were afflicted by OI and OI symptoms only contributed an additional 2% of subjects being diagnosed with SEID. OI is important to recognize because it can be confirmed objectively and, in some cases, can be treated effectively, leading to higher function and quality of life [29,30].
I had missed that 2/2 not required for Orthostatic Intolerance in SEID as did Leonard Jason.
 

Dolphin

Senior Member
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17,567
Conclusions

Using existing data, SEID criteria appear to perform similarly to the most employed criteria, that is, Fukuda, and yet also cover a large percentage of those qualifying for other criteria. These results may help to allay concerns that application of the new criteria will exclude many patients diagnosed via any of the current criteria. Since some subjects did not fit SEID criteria, we recommend that other criteria be retained for the time being and not discarded yet. However, neither the CCC nor ME-ICC should be solely adopted for clinical diagnosis. Our data indicate that many subjects fitting Fukuda criteria would be missed, especially if symptom frequency/ severity thresholds are established as suggested by Jason et al. [39] Furthermore, the SEID criteria appear to be more user-friendly as a fewer number of symptoms are needed for diagnosis. The complexity of the CCC and ME-ICC are exemplified by the convoluted algorithms (Supplementary Materials, Table 1) that had to be constructed to classify subjects. These criteria would be even more difficult to apply in a busy clinical setting. Lastly, the number of categories and the diverse symptoms classified under each CCC or ME-ICC category do not solve the problem of heterogeneity introduced by the polythetic nature of Fukuda criteria. Instead, permitting even more categories and symptoms will lead to increased heterogeneity. Future studies should attempt to validate the SEID criteria and address further how SEID relates to the other definitions, for example, whether it is an entirely separate disease from, a subgroup of, or the severe end of subjects fitting Fukuda criteria.
 

joshualevy

Senior Member
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158
I think this is another in a long line of studies which show that all the commonly used case definitions of ME/CFS or whatever, are pretty much the same. My belief has always been that this CCC vs. ICC vs. Fukuda vs. Oxford vs. SEID vs. whatever was just an excuse to ignore studies that came to results that people didn't like. At a minimum, this study provides evidence that CCC, ICC, and Fukuda are pretty much the same, and (for example) research done with Fukuda is not any worse than research done with ICC or CCC. Another way to view it, is that to understand ME/CFS, we should look at all the studies done with all the case definitions,and not exclude those done with some of these definitions.
 

Sean

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7,378
CCC vs. ICC vs. Fukuda vs. Oxford vs. SEID vs. whatever...

At a minimum, this study provides evidence that CCC, ICC, and Fukuda are pretty much the same...


Drop Oxford from that list, because it almost certainly picks up too many false positives, and I agree with you. The diagnostic differences between the rest of them probably isn't enough to give one preference over the others. Mostly just comes down to which is the most practical to use in the clinic.
 

A.B.

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3,780
Agrees with my personal experience. My illness did start suddenly, but at first it was so mild that I didn't meet any case definitions. It was confusing. I could feel that something was wrong and that I was often exhausted from activity that had not been an issue before, and it had negative impact on my life but I couldn't put my finger on what the problem actually was. Only much later, when the illness had become more severe, I read about ME/CFS and realised that what I had been experiencing was PEM. And I may have made myself more ill by trying to push through the exhaustion and maintain normal activity levels.

It is much harder for patients with gradual onset to be correctly diagnosed because it may take years before they fully meet case definitions. In the meantime they're likely to be given some other diagnosis such as depression, and when more symptoms appear later, these are just seen as somatisation of depression, or comorbid IBS or whatever.

PS: an experienced doctor asking the right questions could have correctly recognised PEM even very early on because there clearly was a rest -> feel better -> increase activity -> crash cycle repeating over and over again.
 
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At a minimum, this study provides evidence that CCC, ICC, and Fukuda are pretty much the same...

Drop Oxford from that list, because it almost certainly picks up too many false positives, and I agree with you.
My problem with Fukuda is that it provides an opportunity for the unscrupulous researchers to select a cohort which primarily features some symptoms but not others. Eg, they could effectively exclude patients with PEM, and still call it Fukuda based on some of the less specific symptoms. It also makes it difficult to compare studies, even if they all use Fukuda, when Fukuda can mean so many different things.

A similar problem could occur in a clinical setting, though wouldn't have the same impact on how the disease is treated. But it would still result in the absurd marathon-running, pole-dancing, and world record paddle-boarding cure stories, and also doesn't help the people being mislabeled as having a disease where they lack the core symptoms. Hence I think the SEID criteria are far superior for clinical diagnosis.
 

joshualevy

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Drop Oxford from that list, because it almost certainly picks up too many false positives, and I agree with you.

Do you have any evidence that Oxford picks up too many false positives?

As a counter example, the PACE study got the same result for Fukuda and Oxford patients. Now even if you hate PACE, the fact that they got the same answers for Fududa and Oxford suggests that these two definitions are not that different.

Are you familiar with any study that got statistically significant different results from Oxford patients as compared to CCC or ICC or Fukuda or SEID patients? That's the data you need. I only know about the one study, and I agree that one study does not settle a question. But one study beats zero studies.
 

Sean

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Do you have any evidence that Oxford picks up too many false positives?

As a counter example, the PACE study got the same result for Fukuda and Oxford patients. Now even if you hate PACE, the fact that they got the same answers for Fududa and Oxford suggests that these two definitions are not that different.

Are you familiar with any study that got statistically significant different results from Oxford patients as compared to CCC or ICC or Fukuda or SEID patients? That's the data you need. I only know about the one study, and I agree that one study does not settle a question. But one study beats zero studies.
PACE modified their Fukuda criteria, in the direction of Oxford, which reduces the comparison value both within the study, and also to other studies that used a more standard version of Fukuda.

When the most recent AHRQ review removed Oxford based studies from their list, the treatment effect for CBT/GET disappeared, which implies that Oxford is selecting a significantly different patient group.

'False positives' may not be the best term. But there is clearly an issue with Oxford.
 

joshualevy

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PACE modified their Fukuda criteria, in the direction of Oxford, which reduces the comparison value both within the study, and also to other studies that used a more standard version of Fukuda.


I'm not sure where you are getting your information, but it's wrong. I just looked at the PACE trial's main paper, and also the Recovery publication. Both just say that the Oxford criteria was used. No mention of modifications. For the Fukuda definition, the modification was to tighten it (not loosen it, as you seem to think). In the real Fukuda definition, various symptoms must be seen in a six month period, but they required those symptoms to be seen in a one week period, so that significantly tightened the definition.


When the most recent AHRQ review removed Oxford based studies from their list, the treatment effect for CBT/GET disappeared, which implies that Oxford is selecting a significantly different patient group.

Wrong again. When the data based on Oxford is removed, in some cases the numbers remaining are too small to come to a conclusion (and the AHRQ reports that). However, in no cases did the Oxford based data come to a different conclusion than the non-Oxford based data. This is clearly shown on Table 7 of the Appendix (pages 12 and 13). Six different outcomes are compared (non-Oxford in column 5, Oxford in column 6). In each case, the results for non-Oxford match the results in Oxford. That's not likely to happen by accident, and is very strong evidence that non-Oxford and Oxford criteria are selecting a medically similar group of people.

The AHRQ team said as much in their conclusion: "Our sensitivity analysis would result in a downgrading of our strength of evidence on several outcomes which can be attributed to the decrease in power, dominance of one large trial, or lack of trials using criteria other than the Oxford (Sharpe, 1991) case definition for inclusion."

Note: "downgrading of our strength", but not change any of the results, and no differences between the results.

 
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Since PACE was a null trial for recovery, a slight effect on subjective measures only for 'improvement', and a null trial at long term follow up, the stuff about which Fukuda definition may have been used for subgrouping seems to me irrelevant.

For me, the important finding of both the PACE and FINE trials is that CBT and GET have no significant positive long term effect on anyone with any sort of chronic fatigue condition, whatever definition is used.

Thus by broadening the definition to six months fatigue, the researchers inadvertently disproved the psychosocial theory for all fatigue related conditions.

Ha ha ha!

Now all we need to do is find a way to get that message across to doctors and politicians etc. That's the hard part.
 
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In the real Fukuda definition, various symptoms must be seen in a six month period, but they required those symptoms to be seen in a one week period, so that significantly tightened the definition.
That's not tightening the criteria ... that's relaxing it. One week of symptoms is much more common and normal than 6 months of symptoms.

Wrong again. When the data based on Oxford is removed, in some cases the numbers remaining are too small to come to a conclusion (and the AHRQ reports that). However, in no cases did the Oxford based data come to a different conclusion than the non-Oxford based data.
When the Oxford data is removed, the effect of CBT and GET become insignificant. It doesn't matter if GET or CBT still look marginally better in Fukuda studies, if the math says it's not statistically significant.
 

Snow Leopard

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The AHRQ team said as much in their conclusion: "Our sensitivity analysis would result in a downgrading of our strength of evidence on several outcomes which can be attributed to the decrease in power, dominance of one large trial, or lack of trials using criteria other than the Oxford (Sharpe, 1991) case definition for inclusion."

If you need very large numbers to prove an effect is statistically significant, it is because the effect is inherently weak.

Efficacy should not require large sample sizes - even a 15/15 treatment/control trial is often sufficient to demonstrate efficacy. Larger trials are needed to demonstrate such treatments are safe because the incidence of side effects tends to be rarer (in drug trials for example), so the effect size is of course smaller and harder to measure without larger trials. The other use of larger trials (and replications) is to see if the treatment is generalisable over different diagnostic or entry criteria.

The overall conclusion is that the effect is weak, not generalisable to stricter diagnostic criteria, the effect is short term only (disappears at 2+ year followups) and the effect is only found on subjective, but not objective measures of functioning. The latter observation is explained by the fact that the treatment (both CBT and this type of GET) is mediated only through cognitive factors, by that I mean how we think about our symptoms and report them to our doctor (or other people) or on questionnaires is changed, but not much else.
 
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joshualevy

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joshualevy said:
In the real Fukuda definition, various symptoms must be seen in a six month period, but they required those symptoms to be seen in a one week period, so that significantly tightened the definition.

That's not tightening the criteria ... that's relaxing it. One week of symptoms is much more common and normal than 6 months of symptoms.

The one week vs. six months is not duration of symptoms! It is window during which symptoms were reported. So PACE's use of Fukuda required 4 symptoms during the same week, while normal Fukuda allowed 4 symptoms spread out over 6 months. Clearly the PACE definition is a much more serious disease. Here is the quote from the PACE Recover paper:
For the purposes of this study, the four or more symptoms needed to be present within the previous week of the assessment date, rather than the previous 6 months (Reeves et al. 2003).

Nothing was said about the duration of symptoms. I'm sorry you misunderstood the paper in this way, but it is clear that the PACE team used a tightened version of Fukuda, not a loosened version.