Introducing #MEAction’s 2019 ME Research Summary

[ahimsa]

We are thrilled to announce the release of our 2019 research summary reviewing the most current and important research into myalgic encephalomyelitis (ME) and ME/CFS of the past 10 years.

Our research summary provides essential stakeholders with access to a compiled, digestible resource that can help them excel in their respective areas of expertise, including clinicians, health officials, government leaders, journalists, the next generation of researchers and, of course, the ME community.

People with ME have been dismissed and derided for their symptoms for decades making it imperative that we can point to a comprehensive summary of the scientific findings showing the physiological abnormalities found in our patient population. This is a powerful tool to share with your medical provider, and family and friends to educate them about the current research.

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!

 

[ahimsa]

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

If you find work like this valuable, we hope you’ll consider making a donation to support #MEAction. We are now 35% of the way to our US$100,000 goal and 87% of the way to our £10,000 target! It’s very important that we meet our June crowdfunding goal. Thank you for your support!

 

[ME/CFS Skeptic]

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.

 

[ME/CFS Skeptic]

This post and others from this thread have been copied or moved to a new thread here

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:

"Only a limited number of studies on blood volume have been performed in those with ME/CFS. Streeten and colleagues found in 12 female CFS patients that the RBC volumes were lower than that of female control subjects, but found in contrast that plasma and whole blood volumes were not significantly different from control subjects (6). Farquhar identified no significant difference in blood volume between ME/CFS patients and simultaneously studied age-matched controls (4), although there was a non-significant trend toward lower blood volume in those with ME/CFS. Hurwitz and colleagues examined 56 with ME/CFS (30 more severely affected and 26 non-severely affected). Total blood volume, erythrocyte volume, and plasma volume were not significantly different from 21 sedentary controls (5). However, when recalculating the reduction from ideal volumes, the percent total blood, plasma, and RBC volumes were all significantly lower in those with ME/CFS than in sedentary controls and also lower in those with severe ME/CFS compared to less severely affected individuals. Of interest, the mean absolute blood volume in our patient population (59 ml/kg) was mid-way between the values for those with severe ME/CFS (57 ml/kg) and non-severe ME/CFS (61 ml/kg) reported by Hurwitz et al. Newton et al. (16) found no significant difference for whole blood volumes between 41 with CFS and 10 healthy controls, but 68% of those with ME/CFS had a RBC volume below 95% of the expected mean volume for healthy individuals."

 

[ME/CFS Skeptic]

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.

 

[ME/CFS Skeptic]

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

"A two-day cardiopulmonary exercise test can be used to objectively identify post-exertional malaise, the cardinal symptom of ME."

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.

There were notable differences in VO2 on two-day CPET between people with multiple sclerosis, people with ME, and healthy controls. (Hodges, Nielsen & Baken, 2017).

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).

 

[Jonathan Edwards]

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.

 

[Jonathan Edwards]

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.

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

 

[ME/CFS Skeptic]

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:

Low NK cytotoxicity is not specific to ME/CFS. It is also reported to be present in patients with rheumatoid arthritis, cancer, and endometriosis (Meeus et al., 2009; Oosterlynck et al., 1991; Richter et al., 2010). It is present as well in healthy individuals who are older, smokers, psychologically stressed, depressed, physically deconditioned, or sleep deprived (Fondell et al., 2011; Whiteside and Friberg, 1998; Zeidel et al., 2002).

 

[ME/CFS Skeptic]

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

 

[Andy]

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:

A recent CureME paper reports this about NK-cells.

Of note, we did not find any differences in the proportions of NK cells in PWME, or in their differentiation status, their expression of KIR receptors or of activation markers ex vivo or following in vitrostimulation. Based on previous reports of abnormal NK cell function in ME/CFS (17–19, 24, 25, 27, 40) this was an unexpected finding, although is consistent with a small number of previous reports of normal NK cell proportion and function (21–23). In our system, we cultured PBMC for 18 h to allow time for direct and indirect cell activation: it is possible that differences in degranulation or cytokine production may have been observed with a shorter stimulation period. However, we did find significant differences in NK cell differentiation status and cytokine production in study participants across all clinical groups who were CMV-positive, detectable after the 18 h culture period. CMV has a dramatic effect on NK cells (28) and it is possible that undetermined CMV status was a confounding factor underlying previous reports of NK cell dysfunction in ME/CFS.

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

 

[TrixieStix]

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:

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).

 

[arewenearlythereyet]

Changed gut flora in ME/CFS patients compared to healthy controls

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.

 

[ME/CFS Skeptic]

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

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.

 

[Trish]

From what I have read the gut microbiome changes a lot with changes in diet, and presumably with some medications, not just antibiotics, and probably with supplements and probiotics etc. so it must be very difficult to filter out from all that variation anything that can be linked with disease, either as a causative or a downstream effect of the disease - apart from obvious gut infections. I don't think we can conclude anything useful on it in relation to ME yet.

 

[arewenearlythereyet]

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.

 

[Amw66]

Thanks to @Michiel Tack, I now have a PDF of the Streeten (Bell) (2000) paper on erythrocyte volume in ME/CFS. Table 4 of that paper shows that neither plasma volume nor total blood volume is altered significantly in the 12 women with CFS studied. This goes some way toward answering the gender question posed by @Amw66.

In view of the Fu (2010) study on POTS and the van Campen (2018/19) study on ME/CFS patients with orthostatic intolerance, perhaps we can draw the tentative conclusion that reduced plasma volume and reduced total blood volume are features of POTS, but not of ME/CFS in general. Results of blood volume and plasma volume tests would then depend on how many ME/CFS patients in the cohort also have POTS.

References:

Fu, Qi, Tiffany B. VanGundy, M. Melyn Galbreath, Shigeki Shibata, Manish Jain, Jeffrey L. Hastings, Paul S. Bhella, and Benjamin D. Levine. “Cardiac Origins of the Postural Orthostatic Tachycardia Syndrome.” Journal of the American College of Cardiology 55, no. 25 (June 22, 2010): 2858–68.

Campen, C. (Linda) M. C. van, Peter C. Rowe, and Frans C. Visser. “Blood Volume Status in ME/CFS Correlates With the Presence or Absence of Orthostatic Symptoms: Preliminary Results.” Frontiers in Pediatrics 6 (2018)

I think my point is more re research in general.

Chris Ponting only got a hit on a specific non hereditary gene as he looked at females only - within a mixed cohort it would perhaps never have been identified.

I think there is the potential for more differences. Given differences in immune and metabolic systems it would seem a not far flung idea.

When " new" to this illness, I could not believe there had been so little research on noted aspects for example _ the double spike in incidence relative to female age - an obvious one for hormonal/ endocrine systems. ( and I had zilch scientific knowledge at time) .
There is some now.

Science is waking up to the fact that gender matters eg recent differences in heart attack manifestations. We miss a trick if we don't t similarly differentiate.