Introducing #MEAction’s 2019 ME Research Summary

Full article = https://www.meaction.net/2019/06/12/meaction-releases-an-updated-me-research-summary/

Direction link to PDF file = http://www.meaction.net/wp-content/uploads/2019/06/19_MEA_Revised_2019_Research_Summary_190610.pdf

Many thanks to @JaimeS and the whole ME Action team!

 

PS - I thought I'd add this note about fundraising for ME Action

 

I think it's great to have such an overview so patients can inform others about current ME/CFS research. Because of the direct links to pubmed it's also really easy to check out the studies.

Just one remark: the overview only lists 'positive' studies that claim to have found something. I think there are studies on some of the same subjects that couldn't confirm the results. So I'm a bit concerned that the document gives a too optimistic overview of what is currently known about ME/CFS. Patients might get the impression that scientists have confirmed all sorts of pathological abnormalities in ME/CFS and that this is somehow being denied, for example by government agencies or insurance companies. In the past patient organizations in Belgium have asked for the government to pay for blood tests for cytokines, NK-cells or RNASE-L etc. because it was thought that these were established findings in ME/CFS. In retrospect, I don't think this was very helpful. So perhaps a little more skepticism towards biomedical ME/CFS research would do some good.

 

One example: The ME Action research summary suggests that a reduced blood volume has repeatedly been found. That seems to contrast with how the latest study on this topic summarized the findings thus far (I should say that I haven't read all of these studies myself, though). The study by Van Campen et al. (2018) is open access so I can quote it at length:

 

Another example is the reference to the studies by the Lights on gene expression after exercise. As I understand it, attempts to replicate these results by Cook or Lloyd didn't work out.

 

Regarding the 2day CPET procedure: I don't know if this is true:

I don't think we know yet if the abnormalities on the 2day CPET (mostly reduced workload at VT, not VO2) can be seen as a measurement of PEM.

Don't think this is correct. In the Hodges et al. study there was no significant difference in VO2 between ME/CFS patients and MS controls on day 1 (ME/CFS patients actually had a higher VO2 max and they did a little better on the second exercise test, while the MS-group's VO2 measurements declined).

 

I think your caveat is right @Michiel Tack. Overegging information when relating to medical providers is not necessarily helpful.

I was reasonably convinced that the low blood volume phenomenon was real so I am interested in your analysis.

 

I agree. For several reasons this statement is not valid.

 

Something similar can be said of the cytokine and NK-cell studies. Cytokine studies usually contradict each other and there isn't really a pattern that stands out yet except perhaps for TGF-β, as Peter White's review suggested. Several studies have tested cytokines post-exercise but most have found little abnormal. And regarding NK-cells I think there are some more recent studies yet to be published that didn't find any differences. I think that at the NIH conference both Lipkin and Wallitt said they found no abnormalities. It is also good to keep in mind what the IOM-report said about NK-function:

 

I don't really have an analysis. From reading the overview of Van Campen, I got the impression that most studies have found negative results (I haven't read all of those studies though). I think David Bell has stressed reduced blood volume in ME/CFS patients in lectures, but I don't know if this is supported by research data (perhaps I should have a look at the studies - EDIT hope I haven't spoken before my turn).

 

Ok, an exposition!

 

It would be interesting if we could work out which findings seem most robust or promising in ME/CFS research.

I was thinking of:

• Increased risk of ME/CFS after EBV-infection,
• Reduced workload at the ventilatory threshold during the repeated CPET procedure
• Elevated ventricular lactate
• Abnormal metabolomics
• Changed gut flora in ME/CFS patients compared to healthy controls

 

A recent CureME paper reports this about NK-cells.

Open access at https://www.frontiersin.org/articles/10.3389/fimmu.2019.00796/full#h5

 

Did a quick scan of the papers and I don't think there is a study that reported reduced blood volume in ME/CFS patients compared to controls.

Newton et al. (2016) reported an association between reduced cardiac volumes and blood volume in CFS but the blood volume in patients was not significantly different than in controls.

Hurwitz et al. (2010) could not find significant differences in blood volume ME/CFS patients compared to controls, so they focused on differences from the ideal blood volume which did provide statistically significant results compared to controls.

Van Campen et al. (2018) reported lower blood volume in ME/CFS patients compared to normal reference values, but their study didn't use controls.

Street et al. (2000) found no difference in blood volume in ME/CFS patients compared to controls as did Farquhar et al. (2002).

And Miwa & Fujita (2011) wasn't about blood volume but about cardiac stroke volume if I understand correctly.

 

Open Medicine Clinic tested my NK Cell Function and it came back as very low. It was used as evidence that I had ME/CFS. Turns out I did not have ME/CFS and actually have autoimmune disease (without any positive AI blood markers).

 

I doubt there is much to say on this until they establish what healthy actually looks like which is miles off.

I would suggest that using clearly recognised and proven tests should carry more weight than the breakthrough science that uses unproven techniques and methods with yet to be established reference ranges.

Gut biome anyway is clearly way downstream imo and whether it’s a product of metabolite disruption/ high histamine, hormone disregulation or even peripheral neuropathy is yet to be proven. The lack of proof in gut biome stems from us not knowing enough about it in general to make any really sound hypotheses at this stage.

 

Good point.

But if ME/CFS patients would repeatedly show a different gut microbiome composition compared to healthy controls, and if other illnesses also show a different gut flora compared to healthy controls as seems to be the case, then perhaps this could be seen as a biological abnormality that can be replicated? And perhaps in the future, we'll be able to tell what a particular gut flora tells us about what's happening in the rest of the body. Hmm.. I seem to speculate a lot, so perhaps you're right.

 

I think as @Trish says it’s very difficult to tell because of how many things in normal life affect the microbiome (fibre in the diet, bacterial loading of certain foods, stomach acid secretion, balance of carbs vs other food groups, vitamins and minerals, having a GI infection, inflammation etc etc etc.).

Added to this that we don’t yet know enough detail at a species/strain level and this makes it pretty difficult to draw any firm conclusions. At the moment we don’t even know what variation within flora is important , how species interacts with each other or with the human metabolism or what variation between test subjects is normal for healthy (there could literally be 100’s of ways of skinning the cat depending upon diet and the fact that we are exposed to a wide variation of foodstuffs being an omnivore).

Most of the studies to date are very general and use experimental test methods. Discussion normally says...’more work needed’ since there are no conclusions, just very generic correlations that may turn out to be nothing at all. So in short we don’t have an idea as to what a healthy control looks like that is meaningful...yet.

From reading a lot of nutritional science articles and papers there is a level of frustration from the probiotic companies that they can’t make claims yet or extol the virtues of probiotics. The EU is sticking to its guns though and insisting that health benefits need to be explained and that loose correlations are insufficient. I personally agree with this stance, having seen so many poor studies that drive misconceptions and false leads.

I personally think we are 10-20 years off having anything useful to say for the healthy let alone anything relevant to PWME, but I may be being pessimistic. I suspect the current ‘cause of obesity” fad will blow itself out due to the timescale and then funding will diminish significantly, unless it can be linked back to cancer or some other money spinning outcome.

I think it’s interesting and merits further study though but it is challenging due to the enormous amount of variables at play.

 

This topic has interested me so, like Michiel, I've tracked down some of the published work. I think Michiel is correct that David Bell often spoke of CFS patients with dramatically decreased blood volume. I believe I saw this in a YouTube video of a talk he gave in Australia years ago. If this is a common finding, decreased blood volume could account for the 30% decrease in cardiac end-diastolic volume and the 25% decrease in cardiac output reported by Hollingsworth (2012).

In contrast, Vermeulen (2014) reports no significant difference in cardiac index, and Farquhar (2002) found no difference in cardiac output (4.1 vs. 4.2 L/min), no significant difference in blood volume, and no significant difference in plasma volume (58.3 vs. 64.2 mL/kg) in 17 (Fukuda) CFS patients compared to 17 age- and gender-matched controls. Moreover, when Bell and colleagues (Streeten, 2000) revisited this subject, they did not find decreased plasma volume in 12 women with ME/CFS. Streeten et al. do report subnormal erythrocyte volume in CFS but I've not been able to find more than the abstract of this paper online. Seeing the data would help us interpret the conclusion of "subnormal erythrocyte volume" and its relationship to blood volume.

Some of these papers are among those cited by Michiel in another post. The Farquhar study is worth reading.

Hollingsworth, K G, T Hodgson, G A MacGowan, A M Blamire, and J L Newton. “Impaired Cardiac Function in Chronic Fatigue Syndrome Measured Using Magnetic Resonance Cardiac Tagging.” Journal of Internal Medicine 271, no. 3 (March 2012): 264–70.

Vermeulen, R. C., and I. W. Vermeulen van Eck. “Decreased Oxygen Extraction during Cardiopulmonary Exercise Test in Patients with Chronic Fatigue Syndrome.” J Transl Med 12 (2014): 20

Farquhar, William B., Brian E. Hunt, J. Andrew Taylor, Stephen E. Darling, and Roy Freeman. “Blood Volume and Its Relation to Peak O2consumption and Physical Activity in Patients with Chronic Fatigue.” American Journal of Physiology-Heart and Circulatory Physiology 282, no. 1 (January 1, 2002): H66–71.

Streeten, David H. P., Delsa Thomas, and David S. H. Bell. “The Roles of Orthostatic Hypotension, Orthostatic Tachycardia, and Subnormal Erythrocyte Volume in the Pathogenesis of the Chronic Fatigue Syndrome.” The American Journal of the Medical Sciences 320, no. 1 (2000): 1–8

@Jonathan Edwards Is there other evidence for decreased blood volume as a common feature of ME/CFS that we should consider?