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

Already the abstract is annoying me.

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...

 

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.

 

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

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.

 

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

 

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 authors suggest that these findings are in line with other 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.

 

(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.)

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.

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.