Sweden planned study: Cell biological/Immunometabolic changes in myalgic encephalomyelitis, ME, Rosén et al (MECELL)

Anna H

Anna H

Senior Member (Voting Rights)
Professor Anders Rosén and Eirini Apostolou, PhD, at Linköping University are planning a study consisting of 3 subprojects, looking at cytokines, EBV enzyme, antibodies and reactivated retro virus etc in blood and saliva samples from 200 mild, moderate and severe ME patients and 200 controls.
They will be working with the ME clinic Stora Sköndal and Per Julin, Bragée ME Center and Björn Bragée and Bo C Bertilson, as well as Jonas Bergquist at the Uppsala ME Research center.

Due to the pandemic they submitted a change application to additionally test subjects for covid-19, to follow people who get infected, before, during and after the infection, to find clues to what causes the infection to turn into post viral syndrome etc in some patients. For this purpose they added 200 controls (so 400 controls total) and changed the project title to "A study of the immune system's response to SARS-CoV-2 coronavirus to better understand and treat possible fatigue after Covid-19 infection", but the research purpose and everything else in the research protocol is the same.

Both applications have been approved.

Polished Google translation of the Research plan:
Research plan for Anders Rosén, Professor, and Eirini Apostolou, Postdoctoral researcher, at Linköping University, Department of Clinical and Experimental Medicine; Department of Cell Biology.

Title of the research project:
Cell biological/Immunometabolic changes in myalgic encephalomyelitis, ME, also called chronic fatigue syndrome

Background and purpose of the study:
New research shows complex interactions between infections, the immune system and energy metabolism in ME (Blomberg / Rosén Front Immunol 2018). This new field of research is called immunometabolism and involves the interaction of the immune system with the energy power plants of the cell, the mitochondria. A physical trauma such as a back injury or a severe infection,
for example glandular fever caused by Epstein-Barr virus (EBV) are usually 'trigger' events, accompanied by inflammation, upon the onset of ME (Blomberg et al Front Immunol 2019). It has recently been reported that the mitochondria in ME patients are dysfunctional (Naviaux et al. PNAS 2016; Fluge et al. JCI Insight 2016), but the exact cause of this is not known.

That is why we intend to identify
this in 3 subprojects, in order to understand the severe exertional fatigue that afflicts ME patients. In the long term, the findings may enable curative therapy, which is lacking today:

Project 1. Saliva and plasma samples and white blood cells in blood from ME patients (200) and healthy matched individuals (200) will be analyzed over a 3‐month period to see whether the herpes virus EBV is reactivated more frequently in ME patients compared to blood donors.
Analysis of cytokines/cell signals, EBV enzyme/dUTPas (Williams et al Clin Ther 2019), antibodies, especially IgA class, as well as reactivated endogenous retroviruses, that are normally found latent in 8% of our DNA, and secreted with certain infections, autoimmune conditions and cancer (Chen et al. Oncogenesis 2019).

Saliva samples are collected in special tubes once per week at the patient's home and frozen at -20 degrees.

Project 2. Mitochondria are similar to bacteria, with their own circular DNA. They live symbiotically inside our cells and produce chemical energy: ATP. They also participate very actively in regulating cell death and the immune system (Weinberg et al. Immunity 2015). We will analyze the blood levels (plasma and white blood cells) of the mitochondrial peptide humanin and its analogs (which have protective properties), in ME/CFS patients (200) and in controls (200), among other things.
Autoantibodies to mitochondria and viruses will also be analyzed.

Project 3. When a cell danger response occurs, the mitochondria secretes their unique mitochondrial DNA (mtDNA)
(Ingelsson/Rosén et al. PNAS 2018). With sensitive digital PCR technology, we will analyze mtDNA longitudinally for 3 months in mild (70 patients), moderate (70 patients) and severe ME (70 patients), and 200 healthy controls.

Participants in the study:
We will be working closely with two ME clinics - Bragéekliniken (Björn Bragée, MD and Bo Christer Bertilson, MD) and Stora Sköndal (Per Julin, MD), and also with Professor Jonas Bergquist at the ME‐research center in Uppsala.
The clinics are already diagnosing and treating ME patients, which facilities sampling and recruitment.
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Polished Google translation of the change application :

A change application was submitted on 17 April:


Because of the Covid-19 pandemic, all research subjects (patients and healthy controls) are potential disease carriers. Therefore, we must make an addition to the study and test all participants for SARS-CoV-2 virus andantibodies to the virus, as well as expand the control group to the double size.
The core scientific purpose remains the same: What immunological mechanisms are involved in ME/chronic fatigue syndrome? We know from previous studies that the disease in a notable 70% of the cases is triggered by a severe viral infection, such asEpstein-Barr virus (EBV)-caused glandular fever, Coxiella burnetti (Q fever), Ebola virus (Ebola bleeding fever), or SARS-CoV-1 virus in 2003 (post-SARS syndrome, where 6% of those infected had extreme chronic fatigue more than 12 months after infection). The Covid-19 pandemic, strangely enough, therefore provides a unique opportunity to analyze 'Healthy' individuals before, during and after a SARS-CoV-2 infection in order to identify which immunological parameters can produce a persistent fatigue syndrome.

A new scientific report (https://www.researchsquare.com/article/rs-21580/v1) from Wuhan, China (April 7, 2020) presents strong evidence that the SARS-CoV-2 virus infection triggers re-activation of the latent EBV virus , causing symptoms similar to glandular fever (fever, inflammation) in about 50% of the Covid-19-positive individuals.
This interaction between SARS-CoV-2 and EBV is very important for us to investigate (EBV is already included in the original study), to better understand why some people suffer from chronic fatigue syndrome and thus being able to treat the condition.

[...]
The benefit of this addition to the study is the unique opportunity to monitor the same research person over time - before, during and after the virus infection, which facilitates a better understanding of anti-SARS-CoV-2 immunity, but also why some suffer from extreme fatigue.
[...]
The title of the project is changed due to Covid-19 (A study of the immune system's response to SARS-CoV-2 coronavirus to
better understand and treat possible fatigue after Covid-19 infection), but the scientific purpose is exactly the same as described above.
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Applications to the Swedish Ethical Review Agency (both in Swedish) :

https://www.dropbox.com/s/ejenjpt1pu0361a/Rosén Grundansökan m signatur o bilagor 1 2 3 4 5 12 dec 12 2019.pdf?dl=0

Change application:
https://www.dropbox.com/s/6bnycdlxc6g320w/Rosén Ändringsansökan Dnr 2019-06218 insänt 17 april 2020.pdf?dl=0
 
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Grigor said:
I think they're referring to this study? Small though.

https://www.researchsquare.com/article/rs-21580/v1
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I am not sure it means anything. Antibody levels do not prove reactivation. The other variables tested look irrelevant.

The Swedish study looks to me like re-inventing the wheel. The sad fact may be that if a fashion for biological research in ME starts up it may largely be wasted on repeating searches for things that are not likely to be there and that have shown it isn't there several times before.
 
Thanks for posting this @Anna H !

When you say the application has been approved, does that mean it has received funding and is it ready to start?

If it has received funding, who paid for it? The universities or is there some kind of Swedish research institute where researchers have to apply?

Many thanks in advance!
 
Michiel Tack said:
Thanks for posting this @Anna H !

When you say the application has been approved, does that mean it has received funding and is it ready to start?

If it has received funding, who paid for it? The universities or is there some kind of Swedish research institute where researchers have to apply?

Many thanks in advance!
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Thank you! :)

Yes, it's ready to start. The preliminary start date was set to Jan 1st, 2020, but they had to make changes to the original application and then came in with their own change application. I've tried to find out if they have started recruiting but haven't found anything.

In the application it's stated that no financial agreements have been made with any outside parties and that there are no financial interests for anyone involved, I can only assume that means the University of Linköping is financing the study. It's the only information I can find about funding I'm afraid.

Edit: I have sent an email to Anders Rosén, asking if it's correct that the University is funding the studie.
 
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@Michiel Tack

I received the following answer from professor Anders Rosén:

"Hi Anna!

Thank you for your email and your encouragement and interest in our research project.

We began the study this spring and have conducted sampling of 103 healthy controls and will begin to include ME patients now in August, as the study aims to monitor immunity once every quarter, including viruses: corona, EBV, HERV.

If you want to join or know of any ME patient who wants to join the study, feel free to contact me or Eirini.

I'm happy to hear that you saw our ethics application and have read up on it.

Regarding the financing - at the moment we don't have any funding from OMF, or RME, but we will apply for grants. Linköping University provides us with premises and instruments, but not with salaries, which are the largest expenses. We have gotten grants from the Cancer Foundation for the overall theme: The connection between Infection-Autoimmunity-Leukemia / Lymphoma, . I have 2 employees and would like to hire another one for the extensive immunological studies we do, but for that we need to apply for additional grants. I myself (as a senior professor) work non-profit with 5% salary. If you know of any more sources of funding, feel free to let me know about these.

Kind regards from the summer cottage in Småland's countryside,

Anders"

I haven't responded yet, thought I would ask if anyone knows of any other potential funding sources before I do?
 
I sent the following letter to Anders Rosén :

[...] Great that you have received a grant from the Cancer Foundation.

Since you are also look at COVID-19 and the development of PVF, the study should be even more interesting to finance, I think, so I really hope that RME and / or OMF can help with funding.

I asked around in the ME community about alternative funding and got the following tips:

https://www.meresearch.org.uk/

Hjärnfonden

Neuroförbundet

The EU perhaps?

(Recently, several parliamentary questions were put to the European Commission regarding the ME / CFS resolution, if it will be followed up on, and whether additional funds will be allocated to investigate the long-term effects of Covid-19 and the link between the virus and ME / CFS, links below.)

https://www.europarl.europa.eu/doceo/document/E-9-2020-003764_EN.html
https://www.europarl.europa.eu/doceo/document/E-9-2020-003909_EN.html
https://www.europarl.europa.eu/doceo/document/E-9-2020-003779_EN.html

I would like to participate but I have hypothyroidism, which was an exclusion criteria, so unfortunately I can't. I also receive home visits from my health care providers at Stora Sköndal because I have severe ME, therefore I wouldn't be able to travel to the clinic once a month for 3 months without getting PEM and risk a deterioration of my condition. Still I'm only at the milder end of severe ME.

This makes me wonder when it says in the study protocol that the research persons will be divided into a mild, medium and severe group, while at the same time it says that blood samples will be collected in conjuction with visits to the ME clinic.

Does this mean that only those who can manage to travel there will be included, or will the patients who already receive home visits from Sköndal and Bragée have blood samples collected during home visits, but it's not made explicit in the protocol?

If this means that all research persons will only have blood samples collected when visiting their ME clinic, I can imagine two scenarios:

Either those with severe ME (which by definition means you're too ill to travel to a health care providera without suffering PEM afterwards and risk a deterioration that can be long-lasting or permanent) will not be included in the study and those who are classified as severe ME actually have moderate ME. This would lead to misleading results that can't be generalized to people with severe ME.

Or, severe ME patients will travel to their clinic 3 times in 3 months and suffer PEM, a worsening of symptoms, which include the risk of permanent deterioration. The tricky thing is that you never know if a deterioration will become permanent or not, so that would pose a great risk to those people, who may not even be aware of it themselves. For me, it took many years to realize this. It is difficult even for many specialists to understand the extent of the risks associated with overexertion.

These are some of my thoughts, I hope it's ok that I share them.

I have talked to several people who are interested in participating and I have conveyed information about the study, etc. to them. Not everyone lives near any of the ME Clinics and they wondered if they could participate from 'a distance'. One person who lives in Gothenburg, for example. I guess it does not work, but wanted to convey that anyway, just so you know there is a lot of interest in your study. [...]


Here is his answer :)

Thanks Anna!

Your letter was well worth reading, with many good and important advice and thoughts, especially about severe ME-patients.

We will soon begin to coordinate the inclusion of ME patients countrywide in the study and I will make sure to address the issue of home visits then.

Have a great summer!

Warmly,

Anders
 
Things that will be tested (from the first post)

Saliva and Plasma and White Blood cells (saliva collected weekly over 3 month period)
  • Cytokines/cell signals
  • EBV enzyme/dUTPas
  • antibodies especially IgA class
  • reactivated endogenous retroviruses
Plasma and White blood cells
  • humanin (a mitochondrial peptide)
  • autoantibodies to mitochondria and viruses
  • 'other things'
Mitochondrial DNA outside the mitochondria
measured longitudinally for 3 months​


Some of these have been tested before. Cytokines certainly have, and we have nothing much to show for all that testing. But are all the things in that list really a waste of time to look at? What would be worth looking at from the planned samples?



 
Humanin:
Identification of a prosurvival neuroprotective mitochondrial peptide in a mammalian hibernator, 2019, Storey et al
A ground squirrel had tissue-specific levels of a humanin analogue when hibernating - more in the brain. (so will levels in blood tell us anything anyway?)

A possible role for mitochondrial-derived peptides humanin and MOTS-c in patients with Q fever fatigue syndrome and CFS, 2019, Raijmakers et al
In monocytes (type of white blood cell)
Hutan said:
So, actually the data can be lined up with increasing humanin levels:
asymptomatic Q fever seropositive controls = 354 (292-393)
CFS patients = 364 (316-387)
QFS patients = 371 (325-384)
healthy controls = 395 (372-409)

Hmm. Here's the chart.

screen-shot-2019-05-16-at-11-30-42-pm-png.7262

With only 10 people in each cohort, that's not a convincing result. And, for the other peptide MOTS-c, there was no difference between the 4 cohorts.
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Fair enough for criticism of humanin then, it's not looking like a great prospect, in blood samples at least.
 
Measuring things always raises a chance of finding something but this does not look like efficient use of resources.
I think the project is left over from the work done by Jonas Blomberg, who died a couple of years back I think. Jonas was intelligent and creative but his idea of an autoimmune attack on mitochondrial components was a long shot. Rosén is about my age (70) and formally retired. The two of them published a hypothesis paper a while back.

The other point is that to pick up anything reliably you really need to take the approach the UK ME Biobank have used - getting something close to a population-representative cohort and doing careful control/disease matching. The Biobank team looked at a lot of similar things to those on the Swedish shopping list. They had the advantage of having a world class NK cell group. Whether they found any real immunological signal or not is unclear although the MAIT cell study is interesting.
 
I dont know, I still feel that our best chance of finding something will be when someone has strong PEM. Obviously it would be a challenge ethically and practically, but when it gets so bad i struggle to read, write and exist, there must be something measurable going on, although critically; it might not be traceable in the blood.

Ps: Just to elaborate on why I think it might be easier during PEM, is that I can imagine that years of physiological adaptation to the the disease mechanism, might,make it harder to discover when not in PEM.

Sorry if I went off track a little bit here mods
 
Björn Bragée writes about the study on his Facebook page (5 September):


Google Translate said:
Research study on ME, the immune system and Covid-19 (Corona)

Today, when autumn begins little by little, I devote myself a bit to starting several research projects and invite the thousands of patients who have ME diagnosis with us to participate, so sharing a little info here and on the clinic's FB page to appease your curiosity.

NOTE! We can at this stage only offer our own diagnosed patients with ME to participate, and they will receive more detailed information.

PS Most of the upper floor you see here now belongs to the ME center.

Study of the immune system against SARS-CoV-2 coronavirus to better understand and treat any fatigue that may occur after Covilad-19 [sic] infection:

The purpose of the study is to investigate the underlying mechanisms of post-viral fatigue syndrome, which can occur after virus infection, such as SARS, EBV, Ebola virus. The vast majority of people infected with the virus recover after the infection, but a small proportion (prevalence in the population is about 0.4%) suffer from persistent severe fatigue, which largely overlaps with the condition myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Myalgic means muscle aches; encephalomyelitis means inflammation of the spinal cord/brain; CFS is an abbreviation for chronic fatigue syndrome. 70% of ME/CFS patients report viral infection as the trigger.

This study focuses on how the cell's energy production in the mitochondria interacts with immune monitoring of viruses in our body and control of inflammation. Findings from these studies may enable new concepts for the treatment of post-viral fatigue syndrome and ME/CFS. Today there is no cure, only symptom relief is available.

New research shows a complex interplay between infections, the immune system and energy metabolism. In 2003, the coronavirus SARS-CoV caused extreme fatigue, so-called post-SARS syndrome in 6% of patients. It has recently been reported (April 7, 2020) that current SARS-CoV-2 virus can activate Epstein-Barr virus (which is dormant / latent in 95% of adults) and cause glandular fever-like symptoms: fever, swollen lymph nodes, muscle aches, loss of appetite, inflammation / cytokine storm. These data suggest an interaction between these two viruses: SARS-CoV-2 and EBV.

Therefore, we intend to clarify this relationship in healthy adults over 18 years without viral symptoms to monitor their immune system over time 6 months (+ a final test at 12 months) and in patients who have already been diagnosed with ME / CFS according to the Canadian criteria.

The research leader is prof. em. Anders Rosén at Linköping University.

Patients with the diagnosis at the Bragée ME center receive information through 1177.se
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The study is called MECELL for short. @Anna H, maybe you could add "MECELL" to the thread title and/or as a thread tag, for searchability purposes?
 
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