Systemic exertion intolerance disease diagnostic criteria applied on an adolescent chronic fatigue syndrome cohort - Wyller et al (2018)

Kalliope

Senior Member (Voting Rights)
BMJ Paediatrics open: Systemic exertion intolerance disease diagnostic criteria applied on an adolescent chronic fatigue syndrome cohort: evaluation of subgroup differences and prognostic utility

Objective Existing case definitions for chronic fatigue syndrome (CFS) all have disputed validity. The present study investigates differences between adolescent patients with CFS who satisfy the systemic exertion intolerance disease (SEID) diagnostic criteria (SEID-positive) and those who do not satisfy the criteria (SEID-negative).

Conclusion The findings question the discriminant and prognostic validity of the SEID diagnostic criteria in adolescent CFS, and suggest that the criteria tend to select patients with depressive symptoms.
 
Methods: 120 adolescent patients with CFS with a mean age of 15.4 years (range 12–18 years) included in the NorCAPITAL project (ClinicalTrials ID: NCT01040429) were post-hoc subgrouped according to the SEID criteria based on a comprehensive questionnaire.

There is a link to the NorCAPITAL study here.

https://clinicaltrials.gov/ct2/show/NCT01040429

I do not see any attempt to detect PEM. If they did not assess for PEM, they cannot possibly apply the SEID criteria since they require PEM to be present for a diagnosis.
 
There is a link to the NorCAPITAL study here.

https://clinicaltrials.gov/ct2/show/NCT01040429

I do not see any attempt to detect PEM. If they did not assess for PEM, they cannot possibly apply the SEID criteria since they require PEM to be present for a diagnosis.
I wonder how much money has been spent in total on the NorCapital study and these publications and what really has come out of it..

Now Wyller is doing a trial on music therapy as treatment for ME.
He wants to do an LP-study as well, but it hasn't been funded yet.
 
Now Wyller is doing a trial on music therapy as treatment for ME.
He wants to do an LP-study as well, but it hasn't been funded yet.

One can make the guess that SEID is being attacked because it's attached to the IOM report which states that the illness is not psychological in origin. If that paradigm were fully accepted, Wyller would find it harder to do the studies he has planned.
 
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The IOM report Clinician's Guide says (bolding mine):
  • Physicians should diagnose ME/CFS (SEID) if diagnostic criteria are met following an appropriate history, physical examination, and medical workup, including appropriate specialty referrals.
  • It is essential that clinicians assess the severity and duration of symptoms over the past month or more. Chronic, frequent, and moderate or severe symptoms are required to distinguish ME/CFS (SEID) from other illnesses.
Physicians diagnose SEID. Diagnosis is not done "post-hoc subgrouped according to the SEID criteria based on a comprehensive questionnaire."
 
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Regarding their detection of PEM, the paper says

A CFS symptom inventory for adults[20] has previously been used to develop an analogous inventory for adolescents.[8] A total of 24 common symptoms are evaluated in terms of frequency during the last month (5-point Likert scale ranging from never/rarer than once a month to present every day/almost every day, scored from 1 to 5).
This CFS symptom inventory seems to be the only place PEM could have been measured. Reference [20] is titled Psychometric properties of the CDC Symptom Inventory for assessment of Chronic Fatigue Syndrome and is about validating a questionnaire that includes "Unusual fatigue after exertion". The appendix to Reference [8] says
In accordance with a CFS symptom inventory for adults (52), we have previously developed a CFS symptom inventory for adolescents, assessing the frequency of 24 common symptoms during the preceding month. Each symptom is rated on a 5-point Likert scale, ranging from ‘never/rarely present’ to ‘present all of the time’. The inventory includes the eight accompanying symptom of the Fukuda-definition. ... The CFS symptom inventory for adolescents has been applied in routine clinical practice and in previous studies (8,31,53,54), and slightly modified according to experience.
So, without chasing down the references (8,31,53,54) found in the appendix to reference [8] of the original paper, it looks like SEID caseness must rest on how a participant answers a question about "Unusual fatigue after exertion" or similar. But it is certainly the case that they have not been clear and up-front about PEM which is surely central to their claimed conclusion.
 
The authors themselves say that

A strength of this study is the low rate of missing data. A limitation might be that data acquisition in the NorCAPITAL project was carried out before the SEID criteria were published. In particular, the phenomenon of PEM, which was highlighted in the IOM report, was not specifically attended to in the NorCAPITAL project. However, we find it justified from the SEID criteria to regard ‘increased fatigue after activity’ as a proxy for other PEM symptoms, in line with a previous study.
 
A similar study using NorCAPITAL data was carried out for the Canadian criteria and also concluded that the diagnostic criteria make almost no difference:

A total of 46 patients were classified as Criteria positive, 69 were classified as Criteria negative, and five could not be classified. All disease markers were equal across the two groups, except the digit span backward test of cognitive function, which showed poorer performance in the Criteria‐positive group. Also, the prognosis over a 30‐week period was equal between the groups.

https://onlinelibrary.wiley.com/doi/abs/10.1111/apa.12950

The diagnostic criteria for NorCAPITAL

To be eligible for the NorCAPITAL project, we required 3 months of unexplained chronic/relapsing fatigue of new onset, and in line with clinical guidelines the patients were not required to meet any additional symptom criteria. A standard form required the referral unit to confirm the result of clinical investigations considered compulsory to diagnose paediatric CFS according to national Norwegian recommendations (evaluation by paediatric specialist, extensive haematology and biochemistry analyses, chest X-ray, abdominal ultrasound, and MRI of the brain).

I'm not sure I'm ready to accept these conclusions because they seem rather unintuitive and not in line with other studies finding differences in illness severity when stricter criteria are used.
 
I think it’s important to see how the IOM criteria work in clinical populations. I would prefer to see studies done by actually applying the criteria when diagnosing patients, and comparing to other criteria, rather than this post-hoc retrofitting via other questionnaires. And I’d like much larger samples.

Asprusten et al explain:

“We used variables from the above-mentioned set of questionnaires to operationalise the criteria, and then used baseline data to decide whether a patient fulfilled the SEID criteria or not”

I think questionnaires are being over-valued in the field. But there is some potentially valuable data in the study that I’d like to have the energy to pore over.

It’s worth noting that the SEID-positive adolescents did not reach the cut-off for depression on the Mood and Feelings Questionnaire. They had higher scores on the scale, but as a group, were not depressed. I would have liked this to be clarified by the authors. I find it quite odd that it is not.

Asprusten et al report:

“The SEID-positive group had statistically significantly higher score on symptoms suggesting a mood disorder from the MFQ inventory (total score 23.2 vs 13.4, P≤0.001). We performed a sensitivity analysis by removing seven items from the MFQ likely to be positively answered by any fatigued person, but the difference remained statistically significant (total score 14.8 vs 8.46, P≤0.001).”

But scoring instructions for the MFQ clarify the possible cut-off for depression https://www.corc.uk.net/outcome-experience-measures/mood-and-feelings-questionnaire/:
“Scoring … a 27 or higher on the long version may indicate the presence of depression in the respondent.”

There’s more detail here about cut-off points: http://devepi.duhs.duke.edu/.\instruments\MFQ user.pdf

The Mood & Feelings Questionnaire is here: http://devepi.duhs.duke.edu/instruments/MFQ Child Self-Report - Long.pdf

There is both a short version and long version; given that Asprusten et al refer to a maximum score of 68, they must be using the long version. The link below refers to a maximum score of 66. There’s probably an explanation for this, maybe a slightly different version. I can’t access their reference 26 to check.

If the finding that adolescents meeting SEID criteria have higher depressive symptom scores than those who are simply chronically fatigued is reliable (and I’d want to see it replicated in a non-retrofitting study), well, that wouldn’t be surprising to me. Wouldn’t we expect patients who are more symptomatic to potentially have a greater emotional impact?

And so what if patients fulfilling SEID criteria have more subclinical depressive symptoms? If they do, and they need or want help with that, give it to them. Why would this invalidate the SEID criteria?

From Asprusten et al’s discussion:

“The SEID-positive group had significantly more depressive symptoms. Taken together, the findings question the validity of the SEID diagnostic criteria in adolescent CFS, and suggest that the criteria tend to select patients with depressive symptoms.

The SEID criteria have been criticised for not having predefined exclusion criteria, enabling patients with major depressive disorders to be diagnosed with CFS.37 The present sample should not contain patients with clinical depression disorder, given the predefined exclusion criteria of NorCAPITAL; however, patients with varying degrees of depressive symptoms were eligible. Our finding of higher depressive symptom scores among SEID-positive patients might theoretically be explained from overlapping symptoms in depression and chronic fatigue states. However, in a sensitivity analysis removing possibly overlapping items, the differences between the groups remained, strengthening the finding that the SEID-positive group has a greater depressive symptom burden.

And from their conclusion (also in abstract):

This study questions the discriminant and prognostic validity of the SEID diagnostic criteria in adolescent CFS, and suggests that the criteria tend to select patients with depressive symptoms.

Crucially, they didn’t find that SEID criteria are selecting patients with depression, just that in this fairly small retrofitting study, they’re selecting patients who have higher, but still subclinical, scores on a Mood and Feelings questionnaire.

I find it odd that they don’t even attempt to explain why those who fulfil SEID criteria might have higher scores on the MFQ. As clinicians, wouldn’t this be what you want to understand? I can't find any mention of the impact of illness on a person.

It reads more like an anti-SEID/IOM study rather than a trying-to-understand-so-we-can-help-make-patients-better piece.

If I were a paediatrician, this study wouldn’t change my views on the usefulness of the SEID criteria. I’d just want to see more studies with different methodologies. And I’d see how useful they were to me and to my patients in clinical practice.
 
I think it’s important to see how the IOM criteria work in clinical populations.

We haven't yet had a study that has examined this with good methodology and we need one. It is possible that the IOM criteria are worse than existing criteria (I'm assuming that all are flawed in one way or another and will be until more about the underlying biology is known).
 
I do not see any attempt to detect PEM. If they did not assess for PEM, they cannot possibly apply the SEID criteria since they require PEM to be present for a diagnosis.

it looks like SEID caseness must rest on how a participant answers a question about "Unusual fatigue after exertion" or similar.

My understanding is that supplementary file 1 bmjpo-2017-000233-SP1.pdf tells us how they used answers to items in other questionnaires to see whether patients fulfilled SEID PEM criteria (and all the others):

2. Post-exertional malaise (PEM)
Patient must fulfill all the specification pertaining to points 2.A, B and E, and one of 2.C/D.
2.A) Item from FSS: “I am easily fatigued”.
Score ≥ 5
2.B) Item from FSS: “Exercise brings on my fatigue”.
Score ≥ 5
2.C) Item from CFS symptom inventory:: “Does the fatigue get better or worse after walking slowly”?
Score ≥ 4
2.D) Item from CFS symptom inventory:: “Does the fatigue gets better or worse after doing hard school work”?
Score ≥ 4
2.E) Item from CFS symptom inventory: “If you think about the last month, how often have you been more fatigued the day after an exertion?”
Score ≥ 4

I'm not sure what we learn by taking individual items from six questionnaires and mapping them onto a diagnostic criteria set using what seem to be rules devised by the authors of this study (see supplementary file 1 bmjpo-2017-000233-SP1.pdf), then looking for correlations with other questionnaire scores and measures.

Edited to add final sentence.
 
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It reads more like an anti-SEID/IOM study rather than a trying-to-understand-so-we-can-help-make-patients-better piece.

This. In Norway he is critized for using too lax inclusion criteria in his studies, as he is not using any established criteria, and therfore not really studying ME/CFS. I'm reading this as another paper from him trying to argue that his approach is the correct one:

"A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary."

Edited to add - and for this reason, his studies wasn't included in the IOM-paper either, that led to the SEID-criteria. So this comes off as an attemped to argue against that decision as well.
 
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This. In Norway he is critized for using too lax inclusion criteria in his studies, as he is not using any established criteria, and therfore not really studying ME/CFS. I'm reading this as another paper from him trying to argue that his approach is the correct one:

"A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary."
Yes. Wyller is known for promoting the view that is doesn't really matter whether you use strict criteria or not. And now he has done a couple of studies he can quote himself from in order to prove it.
 
We haven't yet had a study that has examined this with good methodology and we need one. It is possible that the IOM criteria are worse than existing criteria (I'm assuming that all are flawed in one way or another and will be until more about the underlying biology is known).
The IOM report came with 4 recommendations. Among them (emphasis mine):
IOM Report said:
Recommendation 2:

The Department of Health and Human Services should develop a toolkit appropriate for screening and diagnosing patients with ME/CFS in a wide array of clinical settings in which these patients are encountered, including primary care practices, emergency departments, mental/behavioral health clinics, physical/occupational therapy units, and medical subspecialty services (e.g., rheumatology, infectious diseases, neurology, cardiology).

IOM Report said:
Recommendation 3:

A multidisciplinary group should reexamine the diagnostic criteria set forth in this report when firm evidence supports modification to improve the identification or care of affected individuals. Such a group should consider, in no more than 5 years, whether modification of the criteria is necessary. Funding for this update effort should be provided by nonconflicted sources, such as the Agency for Healthcare Research and Quality, through its Evidence-based Practice Centers process, and foundations.

I haven't seen any indication of either of these happening.
 
Just posting this for my own notes: The first thing that jumped out at me was this: METHODS DESIGN - "Data were collected between March 2010 and October 2012." Then I read this: STRENGTHS and LIMITATIONS: "...data acquisition in the NorCAPITAL project was carried out before the SEID criteria were published."

Then they state this: 'phenomenon of PEM, which was highlighted in the IOM report, was not specifically attended to in the NorCAPITAL project. However, we find it justified from the SEID criteria to regard "increased fatigue after activity" as a proxy for other PEM symptoms, in line with a previous study.'

The IOM does not state just fatigue as part of PEM AND they used the fatigue QUESTIONNAIRE from Trudie Chalder, of all people. You will find that under QUESTIONNAIRES. http://bmjpaedsopen.bmj.com/content/2/1/e000233

I cannot remember if you have written about this before @dave30th, but this is an FYI in case you ever want to in the future. I am sure this whole thread has interesting information.
 
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