IACFSME 2022 Virtual Medical Conference: Day 3 Presentations: 29 July (9 am to 4.40 pm EDT)

Dr Daiki Takewaki presented; he's part of the Yamamura group. [A lot of ground was covered, but very quickly.]

The microbiome affects all of the systems in the body implicated in ME/CFS. [Interesting to see it suggested that allergies are part of the ME/CFS picture.]

30-90% of people with ME/CFS report abdominal discomfort. Probiotics improves symptoms. [?] Faecal Matter Transplants have helped. [?]

Components of the healthy and ME/CFS microbiome
30 ME/CFS; 30 HC
Presented the findings on diversity differences and genera and species found. Later in the talk a useful chart of the findings of similar research was presented - 4 studies by different labs. For some things, like alpha diversity, which is variability of species in individuals; and beta diversity which is variability of species between two groups (ME/CFS vs HC), findings were all over the place. Some found more diversity in ME/CFS guts, and others found less.

It was interesting though to see some consistency with particular species/genera. For example:
Eggerthella - increased in ME/CFS in three studies
Faecalbacterium - decreased in three studies
Blautia - increased in two studies

Conclusion: gut dysbiosis was observed in this Japanese ME/CFS population.
[The rapidly increasing technology and knowledge of the human gut makes this a topic where we might see some good progress.]

Association of gut flora with symptoms and metabolomics
Mention was made of the Anti b adrenergic receptor antibody (ADRB) - there was a finding of it being positive in 30% of ME/CFS. Loebel et al? There was an association with ADRB and an increase in specific bacteria.

Yamamura's group has done work correlating ME/CFS PSQI answers (questions relating to sleep) and HADS answers (questions relating to depression and anxiety) with the prevalence of specific gut microbiome species. e.g. Use of sleeping pills, interrupted sleep, difficulty falling asleep, high anxiety, low anxiety - each were found to have associations with low or high levels of particular bacteria. e.g. Eggerthella was associated with high anxiety. [Obviously there are going to be lots of spurious associations, especially when dealing with multi-causal phenomenon such as interrupted sleep. Still, it's interesting work provided it is acknowledged as being preliminary and there isn't an immediate jump to treatments.]

Eggerthella lenta is a gram positive anaerobic bacillus that has been found to be associated with autoimmune diseases - Bennett 2020


Functional genes
Rather than trying to identify species, which is a rather fraught concept in the bacterial world with genetic swapping, the bacterial soup of the gut can be analysed to find functional genes. The group has found 229 genes increased and 442 genes depleted in ME/CFS guts. They found that the genes indicative of the capacity of the gut to make some amino acids is reduced in ME/CFS. For example, they found that genes for tryptophan biosynthesis were depleted in ME/CFS, and so they would predict that tryptophan production (and production of downstream molecules 5HT, serotonin, melatonin) is lower in ME/CFS.

One finding which they found puzzling was the marked enrichment of genes for vancomycin resistance on ME/CFS guts. Vancomycin is not a commonly used antibiotic, so there's no obvious reason why ME/CFS gut bacteria should have this genetic capacity.

Conclusion: some microbial components of the gut are associated with chemical and symptom characteristics of ME/CFS.

Question about treatment: in a mouse model, administration of arginine reduced the abundance of Eggerthella.

 

Bacteria are hosts to viral parasites, phages. Where bacteria are scarce and difficult to find, the presence of phages can provide a way to determine whether the host bacteria are present.

Chronic borreliosis can have an onset and ongoing symptoms that overlap clinically with ME/CFS.

Dr De Meirler's team has been looking at the presence of Borrelia species phages in ME/CFS using the qPCR technique. There are 20 different species of Borrelia, grouped into 3 types:
Lyme
Miyamotoi (a group with just the one species in it)
Relapsing fever

Recently a test has been developed that is provided by RED labs working with a Belgian university. The approach is to do one pass to see if any of the phages associated with borrelia types are present, then if they are, to do another test to identify the species of the Borrelia.

A study began in July 2019 with 130 ME/CFS patients (meeting Fukuda and ICC criteria); 90 healthy controls. Dutch and Belgian people
8 ml of venous blood is analysed with the Phelix Page Borrelia qPCR
Sensitivity is 100%; specificity is greater than 90%

106/130 people with ME/CFS were found to be positive for phage borrelia
93 for miyamotoi
13 for relapsing fever species
2 for miyamotoi + relapsing fever
1 - I didn't get that - Lyme?

18/90 controls were positive
10 for miyamotoi
3 for relapsing fever
2 for miyamotoi +relapsing fever
...

Presence of lyme was 0.8% in ME/CFS versus none in controls
Presence of miyamotoi was 72% in ME/CFS versus 11% in controls

Miyamotoi is a Borrelia species first isolated in Japan but found all over the world. It is still poorly understood. It was first found in humans in Russia in 2011. It can be transmitted direct from human to human, no need for the tick vector. There is a lot of intra-species variation, creating the possibility of some varieties being more pathogenic to humans than some others.

Dr Meirleir believes that it is a prime candidate to be a major one of the chronic infections that underlie ME/CFS. He thinks it needs further study.

Questions: why are the phages found in healthy people? Miyamotoi doesn't need ticks for transmission, so a history of tick bite isn't necessary. There is variation in miyamotoi, with some subspecies perhaps less pathogenic, and host-species interactions.

Can this finding be extrapolated beyond the sample population? Yes, people from all over the world have been tested and miyamotoi has been found.

 

(Note: technical difficulties resulted in the order of these talks being changed from that shown in the programme)

The conference had the capacity to poll the audience. Dr Bateman asked
"Can early intervention change the course of post-viral syndrome?"
52% of the audience agreed that it could, with a further 21%? thinking that it could somewhat. Dr Bateman, unsurprisingly for a doctor that treats post-viral syndromes, agreed.

"How likely is it that anxiety and stress affect the prognosis of post-viral stress syndromes?" Responses were much more varied, with roughly 10% for each of 1 to 10, with no support for 0 (not at all likely).

Dr Bateman gave the case study of identical twins, one of whom developed ME/CFS as a teenage, while her twin sister had not until recently catching Covid 19 in her forties.

The ME/CFS twin had a very bad patch in her early twenties when she became very sick and sleep deprived, with severe insomnia and was given numerous medications. She was diagnosed at that time with a mental illness which Dr Bateman thinks was incorrect. Dysautonomia has been a major component of her illness. The best intervention for her dysautonomia symptoms has been pyridostigmine. She is, even now, on a lot of medicines including LDN which Dr Bateman seems to support.

The non-ME/CFS twin is hypermoblle and has been on an SSRI since adolescence for OCD and "being a perfectionist". Both she and her sister have had thyroid issues. It was noted later - here is a woman who has had anxiety all of her life, with an identical twin with ME/CFS without anxiety, but still, she didn't have a post-viral condition until recently.

In 2021 the non-MECFS twin got Covid-19. She reportedly was terrified that she would get ME/CFS. She developed POTS and the anxiety and panic attacks escalated. She is on a lot of medication.

Dr Bateman believes that she was able to head off the development of ME/CFS by treating this woman's anxiety and fear, with early intervention to treat sleep problems and dysautonomia. She does have pain, sleep dysregulation and POTS, Dr Bateman is not sure if she has PEM.

The mother of the twins has had breast cancer but is fine.

Dr Bateman is working on a study looking at familial associations.

[I'm not sure what to make of this presentation. I felt a bit uncomfortable that these two women's situations were discussed publicly in such detail, as they are surely identifiable. My over-riding takeaway was that the medical profession have probably caused harm in both cases at least at some points, prescribing medicines that almost certainly have done more harm than good. I think it must be very easy for ME/CFS doctors to attribute improvements to the treatments they prescribe, and I'm not sure how valid such ideas of being able to "pull her out of it" are. I was left feeling a bit uncomfortable about the relationship of dependency on Dr Bateman that seems to have evolved. But, who knows?]

 

There were technological difficulties that delayed this presentation and were present throughout which created confusion. I found the format of the slides with large white letters on a black background, with red headings, difficult to look at , and I don't usually have visual sensitivity. Dr Siller talked about one patient in great detail, recounting symptoms and, again, a large number of medications including LDN and vitamins. Although the patient had only developed Long Covid in March 2020, she has been through a lot, and continues to be very unwell and she has my sympathy.

Dr Siller agreed with the audience that the woman has Long Covid, she said "mimicking the symptoms of ME/CFS" - we did not find out what she actually meant by that.

There wasn't much to take away from this presentation, not helped probably by the need to stop the presentation before it was finished due to running over time.

 

Leigh Jerome is a clinical psychologist. She talked a lot of good sense, nothing regular members of this forum don't know, but still good to hear them being said by a clinical psychologist who seems to make the effort to educate her fellow medical professionals.

She said things that most of us would support such as:
Remember that these people are going through a hard time; sadness and anxiety are normal and should not be pathologised
Not everyone with Long Covid will need to be referred for psychological therapy
Affective episodes might be dysautonomia
Don't ask have you been anxious? Have you been depressed? as the answers probably won't be helpful.
Don't offer anti-depressants to fix LC
Be aware that medications can have psychological effects
Telemedicine for non-ambulatory patients
Be aware of sensory sensitivities
Acknowledge the person's prior identity
Usefulness of peer-support
Document symptoms accurately
Talk with a calm demeanour

She suggested a BATHE approach:
Background - what is going on in your life?
Affect - How is it affecting you?
Trouble - What troubles you most about this?
Handling - How have you been handling this?
Empathy - that sounds very scary/frustrating

There was an audience survey and the correct answer to the question about what a doctor should do when faced with an LC patient was "Explain what LC is, its idiosyncratic nature and your intention to work collaboratively to develop an individual treatment plan". [Personally I have reservations about 'individual treatment plans' with well-intentioned medical professionals just trying stuff with no evidence to support what they do. But, that's me, and clearly most of the audience (and NICE too) think a treatment plan is the way to go.]

[She mentioned 'the NICE Guideline' in approving tones several times - I think she needs to be aware that NICE have a number of guidelines, some of which are ok (ME/CFS), some of which are terrible (chronic pain) and some don't say much but are rapid reviews that could change (Long Covid). So, she needs to specifically say the NICE ME/CFS Guideline if that is what she means.]

She suggested that the optimal treatment model for working with patients with LC is an integrated care model, with wrap around services, continuity of care, holistic, with a multidisciplinary treatment plan.

[I think psychologists whose natural inclination is to leap into providing curative CBT and doctors who think LC is just anxiety could learn a lot from listening to Leigh Jerome. I think she speaks their language and the things she is saying can limit the harm. That said, by the end of the talk I was wanting to throw relaxing scented candles at any nice wrap-around-service delivered calmly in subdued lighting. I think it is safe to say that I am not her target audience. ]

 

Here are my notes on this session. There were 3 short talks. Although grouped under the heading public health, they addressed very different issues, all important for ME/CFS.

3.00 pm - 4.00 pm
PUBLIC HEALTH 1

How to ensure the voice of the severely affected ME/CFS patient is heard in research
Helen Baxter, 25% ME Group, United Kingdom

Note: We have S4ME threads on 2 published papers by Helen Baxter and others on this topic.

Ensuring the Voice of the Very Severely Affected Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patient Is Heard in Research—A Model, 2022,Baxter

Life-Threatening Malnutrition in Very Severe ME/CFS, 2021, Baxter, Speight, Weir

Helen Baxter led research on people with very severe ME/CFS who are being tube fed. She described the awful situation they find themselves in in the UK, often not believed by doctors, severely malnourished, misdiagnosed with anorexia nervosa.

The 5 patients studied all improved once they were assessed and helped by a home enteral nutrition dietician. Some had difficulty swallowing, most didn't have the energy to eat.

The aim of this study was to learn about how such very severely affected people with ME/CFS could be included in research with appropriate adjustments and support. All 5 were very keen to be involved and to contribute to research. Most needed help from carers or researchers with providing information, needed to be able to cancel appointments at short notice, not be given any deadlines, and found phone better than home visits. Some need paper questionnaires, others manage better with brief phone calls or or texting.

All options need to be provided. Questionnaires need to be simple to manage. All 5 completed the study, one needing a year to complete it.
The conclusion was that people with very severe ME/CFS can, and want to, participate in research provided suitable provision is made, including providing support, and there are no time constraints.

i found this a really moving and valuable piece of work, and hope researchers on ME/CFS studies will explore the possiblity of including very severe patients in their research, and make suitable provision for them to do so where possible.
___________________

Identifying healthcare system barriers impacting the care of Canadians with myalgic encephalomyelitis
Rosie Twomey, University of Calgary, Canada

Working with the ICanCME Research Network, Dr Twomey is currently researching the difficult situation patients are faced with in Canada.
The study is in two parts, the first of which is undeway and consists of interviewing health care professionals with either experience treating ME/CFS or lived experience of ME/CFS with semi structured interviews on the topic of healthcare system barriers.
Preliminary results suggest areas of concern include lack of data, lack of clinical education, poor remuneration of clinicians specialising in ME/CFS so they leave the field, only 3 specialist centers in the whole of Canada, stigma, gender and ethnic bias, local variations in provision, and no clear structures and care pathways.
The second phase will be patient focus groups led by patients to discuss the issues raised by the clinicians.
They hope this research will catalyse more research funding and progress towards better care.

My comment is that although I don't know the health system in Canada, a lot of the issues sound very much like those experienced in many other countries too.


________________________


ME/CFS: limitations of vocabulary and language
Geoffrey Hallman, Southern Cross University, Australia

Hallman is studying the effect of cognitive dysfunction on people with ME/CFS communication with social institutions, including clinicians and others we have to deal with. His focus was particularly on words - both word finding problems and not having appropriate words understood by others to describe our symptoms, and the miscommunication and misunderstanding this creates. For example, we use the word 'fatigue' as an umbrella term to describe feeling very ill, whereas the hearer thinks 'tired' and dismisses it as a minor symptom everyone experiences.

Hallman conducted his study with interviews in patients' homes. He used 'grounded theory' and 'thematic analysis' to analyse the results.

Themes he found included the mix of difficulty word finding and different understanding of terms between the patient and clinician leading to misunderstandings and breakdown in communication. Patients have difficulty describing their symptoms and correcting false assumptions made by others.

He concludes that people in social institutions dealing with people with ME/CFS need to understand ME/CFS, to avoid jargon, to really listen and give iterative feedback to check they have understood, and suspend prejudice and assumptions.
_________________________

My overall takeaway from the 3 talks in this session is that if we had a really good medical care and research systems and equitable funding and recognition for ME/CFS, none of this research would be necessary. We on this forum are aware of all these issues raised in these 3 presentations, and how they could be overcome, but as it is, we need researchers like these to try to get the message across to the wider health care world just how badly served ME/CFS is at present.

 

Provocation studies

The sessions I watched yesterday that really gave me hope that real progress is being made were the 4 talks under the heading 'Provocation studies'. All were based on data from different aspects of a large 2day CPET study over 3 centers coordinated by the team led by Maureen Hanson at Cornell University.

The first 2 studies used questionnaires or activity tracking for 7 to 10 days before and after the 2 day CPET. The second 2 analysed blood samples from before and after the 2 CPET's.

11 am - 11.40
Provocation Studies 1

Recovery from 2-day cardiopulmonary exercise testing in persons with ME/CFS
Geoffrey E. Moore, Ithaca College/ Cornell University, USA

People with ME/CFS (N = 85) and sedentary controls (N = 75) did the 2 day CPET.

Recovery time was measured as the time taken to return to their pre CPET score on the Specific Symptom Severity (SSS) scale which uses a Likert scale for 9 domains including fatigue, impaired cognition, recurrent sore throat, tender lymph nodes, muscle pain, joint pain, headache, sleep disturbance, and PEM.

Symptom scores were recorded before and every 2 days after the CPET's for at least 10 days until the scores receded to the pre-CPET levels.

The results showed a huge difference.
The mean recovery time for the healthy controls was 2 days, with median 1 day and one outlier who took 10 days.
The mean recovery time for the people with ME/CFS was 12 days with one outlier who still hadn't recovered back to pre CPET level after a year.
There was no difference in recovery time by age, gender, or severity level.
Graphs of the average likert scores for each symptom over the recovery period showed an approximately linear decline back their 'normal'.
There was some between site difference with one site having slower recovery. They think that was probably because that site was harder to get to so the patients were more exhausted by the process.

The researcher commented that as a sports physiologist the slow recovery of pwME reminded him of sports people with overtraining syndrome.

The researcher commended the bravery of the patients being willing to participate knowing it would trigger PEM, and that there was a small risk of non recovery.
________________________


Physical activity levels in ME/CFS before and after a 2-Day Cardiopulmonary Exercise Test Protocol
Candace N. Receno, Ithaca College, USA

The planned presenter had Covid, so the presentation was done by her colleague Betsy Keller.

This reported on preliminary analysis of a small subset of patients from 2 of the sites.
People with ME/CFS (N = 27) and age matched sedentary controls with matched fitness level (N=7) wore an activity monitor on their dominant wrist for 7 to 10 days before and after the 2 day CPET.

Data was recorded as time spent each day at 3 activity levels - sedentary, light to moderate, and moderate to vigorous.

The pwME spent more time sedentary and less time moderate/vigorous activity than the controls. There was not a statistically significant overall change for each group before and after the CPETS, but there were some possible interesting patterns in the data that may become clearer once they analyse the data for all the patients.

From the Q&A
Dr Keller suggested that in future studies it would be better to use more sophisticated activity monitors on the thigh that can also record time spent upright.
Dr Keller and Dr Moore agreed that it would be useful to put the data together from their 2 studies to see whether activity level changes correlated with symptom changes.
They were each surprised to hear from each other that they had both observed parallels with overtraining syndrome.
___________________

See next post for the next 2 studies based on this research.

 

4.00 - 4.40 pm

PROVOCATION STUDIES

Plasma proteomics reveals a distinct response to maximal exercise and recovery pattern between females and males ME/CFS subjects
Arnaud Germain, Cornell University, USA

Blood samples were taken before and after each of the 2 CPET's, giving 4 samples for each patient.
ME/CFS N = 78 pwME (59 females and 19 males)
Sedentary controls N = 52 (35 females and 17 males)
Plasma proteomics tested for over 6000 proteins.

Significant differences were found between patients and controls, and between males and females and from before to after exercise.

With masses of data to analyse by all sorts of sophisticated methods, he just highlighted a few key differences found so far:
In females he highlighted differences between patients and controls in myoglobin.
In males he highlighted differences between patients and controls in
CD8A t cell surface glycoprotein.

There was also a big difference between males and females in the numbers of proteins (???), or maybe numbers of changes in proteins ? before and after exercise.
In the males the patients had a big change from before to after, whereas the controls it was much the same.
In the females it was the controls who had some change while the patients were the same.

Edit:
The proteomic response to exercise is different:
Between controls and ME/CFS patients
and
Between males and females.
Looking at the number of proteins that are different between patients and controls at each time point and for each gender:
In the females the number of proteins different between patients and controls increased significantly immediately after the first CPET, and was back down again by the next day.
In the males, the big increase didn't show until day 2.

I confess I didn't really understand the stuff about numbers of proteins - but the graphs were clearly showing some differences in something, especially in the male patients!

The main conclusions from this study, I think, are that sex differences in proteomics for pwME mean future studies should analyse them separately.

And that there are definite things happening differently in patients plasma proteins at all time points before and after exercise challenge compared to controls.


See next post for the next study.

 

Comprehensive gene expression profiling of the immune system in ME/CFS
Andrew Grimson, Cornell University, USA

30 patients and 30 matched controls. Blood samples take before the first CPET and 24 hours after. They collected data from lots of different immune cell types - PBMC's (peripheral blood mononuclear cells). They were looking for dysregulation in RNA transcription. This gave masses of data, each piece of data tracking back to a single cell. The test is called Single cell RNA sequencing, shortened to scRNA-seq.

There was little overall dysregulation between patients and controls, but there was dysregulation in specific cell types - some specific types of NK cells and some T cells.
Most of the dysregulation was in classical monocytes and platelets.

I got a bit lost with the next bit, but it seemed that there was a second test done on these cells to find out exactly which genes were dysregulated.

Here are my jottings about the monocytes and platelets, but I'll need to check the details when we get the videos to watch again, so don't take as gospel. If Dr Grimson wants to come on the forum and give us a clearer picture that would be great.

Jottings (edits added from second viewing):

Monocytes - Suppressed immune response, elevated gene activation primed to migrate into tissue to become macrophages. Could be a pro inflammatory effect.

Edit: 'Hypothesis: ME/CFS involves increased monocyte migration to tissue, resulting in elevated macrophage activity in tissue'.

Next purify some monocytes, validated, patients had a mix of normal and diseased monocytes. Correlated dysregulation with clinical and other ?
Edit: they are doing follow up experiment to validate their hypothesis so far with 4 patients and 4 controls by purifying and RNA sequencing, which showed clear between group separation, validating classical monocyte dysregulation in ME/CFS.
And another in follow up they found a significant high correlation between the proportion of monocytes that are dysregulated in a patient and their scores on a fatigue scale. They are excited by this as it may lead to further relationships being found between immune cells and symptoms.

Platelets - Major factor ... suppression post transcript... Elevation of genes that encode for platelet activation.
Platelets have functions in clotting and cell to cell communication ... network of interacting pathways through toll receptors.

Edit: This section was looking at which transcriptome functions are activated or suppressed after CPET, ie looking at what happens in PEM. They found that the major aspects of function activated after CPET were related to platelets, which are involved in coagulation, clotting and wound healing. Platelets are also very involved in communication between immune cells. And something about TLR's (toll like receptors?)

Hypothesis - PEM could be caused by platelet activation after CPET.

Edit:
'Hypothesis: ME/CFS involves abberant platelet activation, exacerbated during PEM'.

Now they are looking at t cells.

Edit: Final slide:
Summary and Future Directions
Gene expression atlas across the ME/CFS immune system
- ME/CFS research resource
- Comparison data set with Long Covid
- Current focus - T cell dysregulation


Q&A someone asked if this platelet finding could be an explanation for microclots being found by some researchers in LC and ME/CFS. And, tantalisingly, I've forgotten the answer.
Edit: The question referred to Resia Pretorius's work on blood clots in ME/CFS.
Dr Grimson says he has seen her preprint showing microclots in ME/CFS. He says he likes her work and they may be pointing to the same thing, but his work shows the main elevation of platelet activation is in PEM, not all the time. He suggested, I think, that there may be microclotting all the time, but that from their immune cell work, the major thing they found was the platelet activation at 24 hours after the CPET. And he agrees that they need to look coagulation changes after CPET.
______________________

I will rewrite this post when I've had a chance to watch the video again in a few weeks. I didn't want to leave it as found these sessions about the preliminary results from 4 different parts of the big 2day CPET study quite exciting and wanted to share the news that there are some really promising sounding findings and directions for future research.

Apologies for the scrappy nature of my notes. I was exhausted and trying to write notes with one finger on my phone while lying down (I can't physically hand write more than a few words) while listening and reading the screen. Too much for my poor little ME brain.

Edit: I have now watched again, limited this time by my sketchy understanding of the science. Edits added above.


Edit 26/10/22:
Now published as a preprint, see this thread:
https://www.s4me.info/threads/singl...om-provocation-2022-ahmed-hanson-et-al.30170/