Current Research Provides Insight into the Biological Basis and Diagnostic Potential for ME/CFS. Sweetman et al. (2019)

[John Mac]

Commentary piece.

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person.

ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians.

There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness.

Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2–3 years that promise new leads towards an effective clinical diagnostic test that may have a general application.

Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness.

These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing.

https://www.mdpi.com/2075-4418/9/3/73

 

[Trish]

Already the abstract is annoying me.

ME/CFS is a severe fatigue illness...

...the ongoing remitting/relapsing etiology of the illness

No mention of PEM, still that bothersome 'fatigue illness' description. And as far as I know, many if not most pwME don't have any remissions.

Anyone just reading the abstract will come away with the impression that ME consists of remitting and relapsing fatigue. If only...

 

[InitialConditions]

We are being bombarded with low-quality commentary pieces that get us no closer to our goals. I believe this is in part driven by the huge interest in journal papers on this subject. They often become the most highly downloaded and shared papers in the respective journals.

 

[Trish]

It's part of a special issue of Diagnostics on ME/CFS. I think, correct me if I'm wrong, it is tied to the recent Australian ME conference.

 

[DokaGirl]

Even some of those onside still use fuzzy terms like "fatigue illness", and "cfs". It would be more helpful if they improved descriptions and terminology.

No remission here - ever. Do they perhaps mean waxing and waning, but still ill? Or, do they mean sick, then recovered, then
sick again, and so on?

The "recent" IOM report is not so recent now (February 2015). In terms of medical progress, maybe it is seen as recent, but I don't think many pwME waiting for better treatments including respect, as well as effective medications see this report as just having happened.

 

[dave30th]

The journal publisher has previously been accused of publishing so-called "predatory" journals.

https://en.wikipedia.org/wiki/MDPI#Controversial_articles

 

[Londinium]

Abstract aside, it's not a particularly bad paper. Doesn't add anything new but does provide a reasonable commentary on some recent results.

 

[Ravn]

Anyone just reading the abstract will come away with the impression that ME consists of remitting and relapsing fatigue. If only...

Yes. Especially since the article is better than that. As it should be, given some of the authors' personal experience of ME. Authors are:
Eiren Sweetman 1, Alex Noble 1, Christina Edgar 1, Angus Mackay 1, Amber Helliwell 1, Rosamund Vallings 2, Margaret Ryan 3 and Warren Tate 1,*

It's part of a special issue of Diagnostics on ME/CFS. I think, correct me if I'm wrong, it is tied to the recent Australian ME conference.

Correct.

A positive note: looks like there'll be another paper from this group, based on Sweetman's PhD work if I've interpreted things correctly (bolding mine)

We have collected cytokine (Bio-Plex Human Cytokine 27-plex Assay) [37] and microRNA [38] expression data from patient and control plasma (TaqMan miRNA array), and also genes (RNAseq transcriptome [~13,000 gene transcripts] [38], and SWATHMSprotein expression data [~1800 proteins], publication in preparation) from peripheral blood mononuclear cells (PBMCs) [38]. Statistically significant changes were identified, despite the small size of the study group with age/gender matched controls. Despite patient heterogeneity in age, gender, and stage of illness, similar patterns of changes in specific processes and pathways were observed. We identified significant dysregulation of immune/inflammatory pathways and oxidative stress linked to metabolic and mitochondrial dysfunction. Immune, inflammatory, cytokine and
apoptosis pathways were enhanced, while mitochondrial function, general cellular metabolic and lipid metabolic pathways were suppressed [38].

 

[Mithriel]

Ramsay spoke about the variability of ME as one of its defining signs. Relapsing/ remitting could simply mean that symptoms are not the same all the time. I can see fine this morning, maybe not tomorrow. This evening I could have a bad headache, yesterday I had to spend the afternoon in bed instead of my recliner and so on.

In other diseases things stay much the same. Untreated thyroid levels don't go back to normal but my heart rate goings down.

I do wish they would take more care about what they write though. It should be explicit and match our experience.

My pet hate is not emphasising that PEM is often DELAYED. It is very different from other illnesses where they feel they get worse after exertion but they are not fine for 2 or 3 days then collapse so it is an important point that it happens at all.

 

[MEMarge]

Here is the link to the whole special edition.

https://www.mdpi.com/journal/diagnostics/special_issues/ME_CFS

Includes a paper by McGregor et al, the CureME team, Lenny Jason et al and Frank Twisk re ICC.

 

[Hutan]

Most recently, a phase II trial of a mixture of the Central Nervous System (CNS) stimulant Ritalin (methylphenidate hydrochloride) and mitochondrial support nutrients (KPAX002) [31] suggested that there was a trend towards improvement in fatigue.

It's odd to highlight this treatment combo - there was no significant result. thread on KPAX in CFS here

Two behavioural interventions, graded exercise therapy (GET) and cognitive behavioural therapy (CBT), have been controversial treatments for ME/CFS [11]. ...
CBT by contrast is a psychotherapy approach that encourages patients to analyse their symptoms and develop strategies to function around them. Undoubtedly this approach has benefitted some patients in managing and living with their disease.

I'm a bit surprised that this group doesn't seem to understand that the type of CBT promoted by the BPS supporters is aimed at correcting false illness beliefs rather than helping people cope with the changes the illness brings. One of the authors is New Zealand's only specialist ME/CFS doctor; if she's letting that statement through then it seems that she's missed a large part of the debate about ME/CFS treatments.

 

[Hutan]

As there is no single molecular biomarker test for ME/CFS, there are long delays and high costs involved in the diagnostic process, with increased potential for misdiagnosis, all of which fundamentally impedes patient care.

Many potential diagnostic biomarkers have been identified by researchers—almost all of which indicate the involvement of improper immune function, inflammation, and signs of autoimmunity, e.g., differences in cytokine profiles, natural killer (NK) cell function, or responsiveness of T-cells, in ME/CFS.

To date, research into clinically useful diagnostic biomarker identification for ME/CFS has been limited generally to small cohorts (with study sizes frequently
<10, and rarely with validation in larger cohorts above n = 40).

A further limitation to biomarker discovery is the lack of any comprehensive follow-up studies of potential biomarkers with different ME/CFS patient groups, or comparing ME/CFS with other similarly presenting illnesses.

Another important factor obstructing biomarker discovery is the use of different diagnostic criteria from the many available to define the ME/CFS patient group, preventing meaningful comparisons between studies. While the majority of research groups do use the 1994 Fukuda criteria, as discussed earlier, the Fukuda criteria may confound clinical or diagnostic biomarker studies as it imprecisely defines ME/CFS symptomology and fails to exclude patients with a psychiatric disorder.

The lack of follow-up studies, or failure to validate the results of an original study, has meant that potential biomarkers have rarely progressed to clinical trials.

This is a nice discussion of the need for a biomarker, and of problems which have prevented potential biomarkers getting to clinical trials.

Paraphrasing a bit:

Need for biomarker - diagnosis process currently involves long delays and high costs and frequent misdiagnosis
Problems:

• small cohorts
• infrequent validation, especially against different ME/CFS cohorts (e.g. diagnosed by a different clinician) and against cohorts with illnesses with similar symptoms (and, I'd add, sedentary healthy controls)
• different diagnostic criteria - makes comparisons difficult

 

[Hutan]

There's some discussion around the group's transcriptome study, highlighting three upregulated genes:asIL8; NFKBIA and TNFAIP3. The paper says all of these are early responders to Tumour Necrosis Factor-induced Nuclear Factor kappa-lightchain-enhancer of activated B cells. My understanding of this is that the upregulation of these genes is a response to the inflammation, an attempt to reduce it.

The differences between ME/CFS and Control cohorts look pretty modest on a graph, but are statistically significant for IL8 and NFKBIA in a study with a small number of participants. There's a lot of overlap between the results for people with ME and healthy controls though. (edited to add the graph)





The conclusion about this study is that:

The increase in expression of these three gene transcripts in the ME/CFS group implies that there is an unwanted excess activity of NF-κB and inflammation in ME/CFS, driven by TNFα.

The authors suggest that these findings are in line with other studies:

Indeed, increases in IL-8 and TNFα have been identified in several ME/CFS cytokine and immune studies.

The upregulation of these genes is downstream of inflammation and of course these genes might only be upregulated in pwME following exertion. So perhaps the overlap in results between pwME and controls isn't such a big problem. Perhaps not all of the pwME had PEM when they were tested. Perhaps some of the pwME have an inadequate response to inflammation, but do have inflammation.

It certainly would be interesting to see this study done on a bigger sample of patients.

 

[Hutan]

(with apologies to those who already know all this; I assume all of these molecules have been discussed in depth many times before. If I did know it at one point, I've forgotten it.)

There's a discussion of the study the group did on protein kinase RNA-activated (PKR) as a potential biomarker for ME/CFS.

They note that PKR is phosphorylated when activated, so that's how it can be identified. And that they made (?) antibodies to identify the active and inactive forms, which sounds impressive to me.

They say that PKR has been called the 'universal immunological abnormality' in ME/CFS in this referenced paper (from 2008 - shouldn't something so universally abnormal have been shouted about more? Interesting mix of authors.)

Meeus, M.; Nijs, J.; McGregor, N.; Meeusen, R.; De Schutter, G.; Truijen, S.; Fremont, M.; Van Hoof, E.; De Meirler, K. Unravelling intracellular immune dysfunctions in chronic fatigue syndrome: Interactions between protein kinase R activity, RNase L cleavage and elastase activity, and their clinical relevance. In Vivo 2008, 22, 115–122. [PubMed]

Anyway. The text says that healthy controls had undetectable phosphorylated PKR in protein extract of PBMC cells, unlike pwME. They calculated the ratio of phosphorylated PKR (pPKR) to inactive, unphosphorylated PKR (PKR) and made this graph:



which does suggest a pretty good differentiation in the PBMCs (peripheral blood mononuclear cells - includes T cells, B cells and NK cells). The difference between the two cohorts' PBMCs was significant, and that was with just 9 pwME and 9 controls.

(But I'm not sure how they were able to say that the healthy controls had undetectable levels of pPKR. Because the controls must have had levels more than zero to make the ratio positive? )

They also said that not all of the patients scored positive for pPKR either; they suggested that maybe this was because their illness had been going on a long time.

There wasn't much about what PKR actually does in the paper, just a bit saying it has a key role in the innate immune system. Wikipedia tells me it is activated in response to double-stranded RNA introduced into a cell by a virus. It's quite an interesting read, that Wikipedia entry.

Binding to dsRNA is believed to activate PKR by inducing dimerization and subsequent auto-phosphorylation reactions.

That makes it sound as though there needs to be a viral infection to activate the PKR.

So I assume an activated PKR (ie pPKR) means an activated innate immune system, and the authors are thinking something along the lines of what Hornig suggested, that the immune system gives up being activated after some years of making an extra effort.

But, is there a viral infection causing ME/CFS and activating the PKR, or is something going wrong to activate the PKR some other way? Or is this whole finding just the result of the fact that people with ME/CFS often have infections, that are a downstream effect of having ME/CFS?

So, I think, PKR is another one to watch out for in larger repeat studies.