Are there subgroups of chronic fatigue syndrome? An exploratory cluster analysis of biological markers, Asprusten et al, 2021

[Sly Saint]

Abstract
Background

Chronic fatigue syndrome (CFS) is defined according to subjective symptoms only, and several conflicting case definition exist. Previous research has discovered certain biological alterations. The aim of the present study was to explore possible subgroups based on biological markers within a widely defined cohort of adolescent CFS patients and investigate to what extent eventual subgroups are associated with other variables.

Methods
The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL) has previously performed detailed investigation of immunological, autonomic, neuroendocrine, cognitive and sensory processing functions in an adolescent group of CFS patients recruited according to wide diagnostic criteria. In the present study, hierarchical cluster analyses (Ward’s method) were performed using representative variables from all these domains. Associations between clusters and constitutional factors (including candidate genetic markers), diagnostic criteria, subjective symptoms and prognosis were explored by standard statistical methods.

Results
A total of 116 patients (26.7% males, mean age 15.4 years) were included. The final cluster analyses revealed six clusters labelled pain tolerant & good cognitions, restored HPA dynamics, orthostatic intolerance, low-grade inflammation, pain intolerant & poor cognitions, and high vagal (parasympathetic) activity, respectively. There was substantial overlap between clusters. The pain intolerant & poor cognitions-cluster was associated with low functional abilities and quality of life, and adherence to the Canada 2003 diagnostic criteria for CFS. No other statistically significant cluster associations were discovered.

Conclusion
Within a widely defined cohort of adolescent CFS patients, clusters could be delineated, but no distinct subgroups could be identified. Associations between clusters and constitutional factors, subjective symptoms and prognosis were scarce. These results question the clinical usefulness of searching for CFS subgroups, as well as the validity of the most “narrow” CFS diagnostic criteria.

Trial registration: Clinical Trials NCT01040429

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02713-9

 

[Andy]

such as reflected in the Canadian diagnostic criteria of CFS (sometimes referred to as the International Consensus Criteria of ME/CFS)

Hmmmm...

Accordingly, studies from our own institution question the validity of the Canadian-criteria [18] as well as the SEID-criteria [19] for diagnosing CFS in adolescents.

I'm starting to see the frame that the authors are working within.

To be eligible for the NorCAPITAL project, we required 3 months of unexplained chronic/relapsing fatigue of new onset. The patients were not required to meet any additional symptom criteria, in line with clinical Paediatric guidelines

So they are looking to see if there are identifiable sub-groups of chronic/relapsing fatigue.

This is how they assessed PEM

Finally, the symptom of post-exertional malaise (PEM) was charted by a single item: “How often do you experience more fatigue the day after an exertion?”, scored on a 5-point [1,2,3,4,5] Likert scale.

Study strengths and limitations

A strength of the present study is the detailed characterization of CFS pathophysiology within several domains. Limitations include the relatively low number of CFS patients, leaving some of the clusters with few participants, and the study should therefore be regarded exploratory. Also, the study included adolescent patients only, and it is unknown to what extent results can be generalized to adults. Further research should seek to validate the present findings in a larger cohort of adult CFS patients.

The question on how to measure fatigue is a controversy in the field of CFS. The present study assumed a priori that fatigue is best conceptualized as a subjective sensation [76]; accordingly, a validated instrument based on self report (the Chalder Fatigue Questionnaire) was selected to operationalize fatigue. We acknowledge, however, that other researchers maintain that fatigue should be measured by objective standards (e.g. activity recordings). Also, recent findings suggest that the symptom of post-exertional malaise (PEM) is even more central to the phenomenon of CFS than previously understood, and that it should be assessed with comprehensive, validated instruments [77]. Unfortunately, these instruments were not available when the present study was planned.

I could have saved myself the bother of reading what I did and just spotted that Wyller is one of the authors.

 

[Kalliope]

Wyller is co-author. Here's from my notes from attending a lecture by him in 2019:

He believes fatigue is fatigue. It makes no sense to try splitting the long lasting fatigues into a lot of sub groups based on diagnoses. He prefers simple diagnostic criteria and criticises the Canadian criteria.
He believes that if you have a long term fatigue consequential for daily activities which can't be explained by other current physiological or psychological illnesses, then you have an unexplained fatigue or what is called CFS/ME. A lot of British researchers agree with him.

It’s important to offer empathy, hope and explanations. It’s a serious condition and there’s no solutions as simply thinking oneself better. But one can recover.
Many children and adolescents, in fact most of them, recover. It's important to tell them that, considering the importance of expectations.

Full notes shared on the forum here.

 

[Midnattsol]

If I had the energy I'd compare this to their previous work on why the criteria doesn't matter, but I can't say I feel like it. Seems like many of the same arguments.

 

[Hutan]

Also, recent findings suggest that the symptom of post-exertional malaise (PEM) is even more central to the phenomenon of CFS than previously understood, and that it should be assessed with comprehensive, validated instruments [77]. Unfortunately, these instruments were not available when the present study was planned.

It's nice that the researchers seemed to end up understanding that PEM is a fundamental symptom of ME/CFS. It's a shame they didn't know that before choosing to spend their time on a study characterising CFS.

These results question the clinical usefulness of searching for CFS subgroups, as well as the validity of the most “narrow” CFS diagnostic criteria.

No, 'These results question the clinical usefulness of searching for CFS subgroups with the variables that we used.'

 

[rvallee]

Oh yeah really nice that this self-proclaimed expert is noticing *checks note* the hallmark symptom of the disease he claims expertise in. I guess they don't have a choice to talk about it now that the cat's out of the bag with LC. Funny that it says "than previously understood" when they are quite literally talking about themselves who simply refused to hear anything about it and laughed it off as somatization or whatever. "Nobody knew that", says person who genuinely did not know that despite pretending to be an expert on the topic.

I, an astrophysicist, noticed today for the first time that the Sun, get this, is the same thing as those other shiny things in the sky. Can you imagine that?! I certainly did not and it's my job!

Give a decade or two and he will even start to notice it may be related to infections somehow. I really am looking forward to the first occurrence of one of them seriously writing that fatigue is actually not the only symptom of ME and how nobody noticed that before. Real galactic brains we have here.

Around 2050 they may even start noticing this brain smoke, or something. Which of course nobody noticed before.

 

[Mithriel]

He believes that if you have a long term fatigue consequential for daily activities which can't be explained by other current physiological or psychological illnesses, then you have an unexplained fatigue or what is called CFS/ME.

You have captured the basic, dreadful, unscientific ghastliness of what we face. "Current physiological illnesses" indeed! They do not believe ME to be a physiological disease so there is nothing to explain the fatigue! I do not believe that arsenic is poisonous so the victim must have died because they stopped wanting to live. I do not believe that heavier than air objects can fly so magic must exist to get people from the US to the UK.

 

[ME/CFS Skeptic]

I think few respected ME/CFS experts would think it is a good idea to make subgroups based on the markers and measurements used in this study. As far as I'm aware nobody is doing so or proposing to make that subdivision.

Most ME/CFS experts, however, think it is a good idea to differentiate a group suffering from severe chronic disability, post-exertional malaise, cognitive dysfunction, etc. from other patients who suffer from unexplained chronic fatigue without these characteristics. That's probably the reason why some are using the Canadian Consensus Criteria.

So if the Canadian criteria don't correlate well with the subdivision that most would think is not advised, then this is what is to be expected and not really an argument against those criteria.

I think the authors of this paper do have a point in criticizing the authors of the Canadian and International Consensus Criteria for arguing in terms of pathological processes such as low-grade inflammation or metabolism impairments instead of simply focusing on clinical characterics.

 

[Hutan]

It's nice that the researchers seemed to end up understanding that PEM is a fundamental symptom of ME/CFS. It's a shame they didn't know that before choosing to spend their time on a study characterising CFS.

Notwithstanding this, (that PEM is fundamental to a definition of ME/CFS), I have been wondering if ME/CFS symptoms are a particular subset of possible symptoms arising from related processes during and after an infection.

One of the prompts for the wondering is the case of chikungunya on Reunion Island where large numbers of people have been reported with a spectrum of symptoms, including those grouped as 'fibromyalgia', 'chronic fatigue' and 'ME/CFS', as well as small numbers of cases of overt arthritis-type damage, after chikungunya infection. So, the idea is that there is some common mechanism accounting for quite a broad range of symptoms currently grouped into multiple named illnesses - perhaps even things like GBS - (along with different mechanisms that produce the variety of pathology phenotypes).

I'm not saying this is so, just musing aloud really.