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The GIST

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Bronc Brings a UK perspective to U.S. ME/CFS matters as he talks with Avindra Nath and Vickie Whittemore as he digs into the big intramural study and the road ahead for the National Institutes of Health (NIH)

The GIST

  • With the ME community in the UK struggling, nearly 3 years later, to get local and regional ICB’s (Integrative Care Boards, which commission health services) to implement the new guidelines from NICE issued in October 2021, Bronc turns his attention to the U.S. with an interview with two ME/CFS experts from the National Institutes of Health (NIH): Dr. Avindra Nath and Vickie Whittemore.
  • While the Nath intramural study has produced some controversy Bronc cites two UK ME/CFS researchers who called it “an important paper” and “a prime example of the research required to deepen our limited understanding of this complex disease and ultimately identify treatments.”
  • Nath said his long-standing interest in studying inflammatory and infectious diseases of the brain, particularly how viruses establish a chronic infection in the brain and/or cause a neuroinflammatory process led him to take on the intramural study.
  • He asserted that the study “convincingly demonstrated the biological basis of the disease that cannot be explained by deconditioning and psychological factors” and identified several novel targets for modifying the course of the disease.”
  • Nath proposed that the inability of naïve B-cells to mature and produce effective fighting (i.e. antibody-producing cells when presented with an infection) is driving ME/CFS. That idea fits past studies which found that problems producing energy have stopped the B-cells in ME/CFS patients from maturing. It also fits with the possibility that ME/CFS is an autoimmune disease, as problems with B-cell maturation have been associated with an increase in autoantibodies.
  • Interestingly, the main target of the virus most linked with ME/CFS – the Epstein-Barr Virus – is B-cells.
  • Other major findings include dramatic sex immune and metabolite differences between men and women, proteins in the cerebral spinal fluid that could serve as a biomarker, and downregulation of a part of the brain called the temporal-parietal junction, which is involved in initiating physical action.
  • The effort preference finding and the Effort-Expenditure for Rewards Task (EEfRT) have generated controversy. THE EEfRT task has been mostly used in psychological diseases but has been used in Parkinson’s Disease as well – a disease which, like ME/CFS, features basal ganglia dysfunction linked with reduced “reward”.
  • Nath noted that the study suggested immune modulatory therapies could be helpful and proposed that “platform” clinical trials be used to more cheaply assess possible treatments. (The NIH’s RECOVER Initiative recently embraced platform studies and Nath has begun an IVIG trial in long COVID.
  • The Roadmap Initiative was an in-house effort to spark NIH efforts on ME/CFS by highlighting research opportunities.  While some small initiatives came out of it (clinical trial working group, a genetics working group, and new NIH funding mechanisms to support exploratory research) no new funding designed specifically for ME/CFS has emerged.
  • Instead, the NIH dropped one ME/CFS research center – leaving its hallmark ME/CFS research centers program at 50% of its original funding (adjusted for inflation). A new ME/CFS funding opportunity is expected, however, sometime around the end of the year.
  • Maureen Hanson’s NIH-funded ME/CFS research center will do a deep dive into the muscles, the immune system, and platelets. Ian Lipkin’s center will focus on genetics, finding evidence of past infections, and assessing antibody levels. 
  • The NINDS Institute is also creating what appears to be the first NIH funding opportunities for post-infectious diseases (including ME/CFS, FM, POTS, Lyme, etc.). Funding levels, however, are unknown.

 

 

 

 

Here in the UK, the ME community is struggling, nearly 3 years later, to get local and regional ICB’s (Integrative Care Boards, which commission health services) to implement the new guidelines from NICE issued in October 2021. It is quite clear that the medical establishment in the UK still does not take the education of health professionals about ME seriously. I speak to medical students at my local university regularly and none have had any training about ME – never mind the fact that many have not even heard of our illness.

False promise

Bronc reports that the UK has not delivered on its promise to implement the NICE guidelines

The coroner’s inquest into the tragic death of Maeve Boothby O’Neill from ME, at the young age of 27, has further revealed the many failings of the NHS when it comes to the treatment and care of people with severe ME. Insufficiently educated health professionals regarding the understanding and treatment of ME stood out like a sore thumb.

To compound matters, here in the UK there is a derisory amount of money being invested into biomedical research into ME. Both the medical establishment and politicians from the Labour government display no sense of urgency about improving the lives of people with our illness.

While the study has sparked controversy Karl Morten said he was excited about the “next steps”.

As the U.S. NIH/NINDS ME research roadmap of May 2024 notes, “Time is life, especially where life-diminishing diseases are concerned.” This lack of urgency fits perfectly with the damning report issued by the UN Committee on Disabilities in April of this year. This UN report noted that disabled people in the UK face “systematic violations” of their human rights.

There is some comfort to be had from the research and plans for further research from NIH/NINDS in the United States. A new study from the NIH in the United States, which lasted eight years, and had more than 70 authors from 15 countries, was published in Nature Communications in February of this year. This study, “Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome”, clearly states that ME is a biological illness whose primary characteristics are immune dysfunction and brain abnormalities.

While the study has sparked some controversy, it has also been welcomed by several scientists in the field of ME research and beyond. Prof Karl Morten, Principle Investigator, Nuffield Department of Women’s & Reproductive Health (NDWRH), John Radcliffe Hospital, University of Oxford, said:

“This is such an important paper and one I am so pleased to see come out. With our meagre research budgets we can only dream of running a study like this.”

 

“The brain appears to be potentially driving the patient’s response. The big question is why? Is something still going on we are not yet aware of? The immune system is dysregulated and appears to still be showing an antigen response. Is this suggesting a foreign entity is still present or has the system gone rogue? The differences in many of the symptoms appear linked to male/female differences. This is important as we have perhaps got bogged down trying to understand the vast number of different and changing symptoms for too long.”

 

“Can we now start to hone in on what is really important? I am very excited about next steps and the major funders now need to step up and provide sustainable global funding for ME/CFS research.”

Dr Katharine Seton, Research Scientist, Quadram Institute Bioscience, said:

“This comprehensive study on a well-defined subgroup of ME/CFS patients serves as a prime example of the research required to deepen our limited understanding of this complex disease and ultimately identify treatments. Historically, studies investigating ME/CFS have often focussed on singular aspects of the disease, largely due to inadequate funding for this disease. These fragmented studies merely offer isolated pieces of a larger jigsaw puzzle. However, the current paper stands out with its extensive author list, featuring experts from diverse disciplines collaborating to assemble these pieces and reveal a more complete picture. This interdisciplinary approach is crucial for advancing our understanding of this disease.”

This study, as important as it is, was not perfect and had a number of important weaknesses. It did not include people with severe ME, it only had 17 participants, did not include people with ME without an infection prior to onset, and included a somewhat dubious term to explain why people with ME respond differently to healthy people in physical exercise challenges.

The Avindra Nath Interview

Avindra Nath

Avindra Nath, the leader of the study, believes the disease may begin in dysfunctional B-cells

Dr. Avindra Nath, Clinical Director and Senior Investigator at NINDS and one of the co-authors of the above study, took time out from his busy schedule to talk about the findings of this 8-year study. Meanwhile, his colleague Dr Vicky Whittmore, Programme Director at NINDS, also gave some input regarding the ME research roadmap agreed by NIH/NINDS in May of this year.

Responses to questions 1-4 by Avindra Nath, M.D, Clinical Director and Senior Investigator at NINDS. Responses to questions 5-6 by Dr. Vicky Whittemore, Programme Director at NINDS.

How did you get involved in the field of ME research?

Avindra NathI have had a long-standing interest in studying inflammatory and infectious diseases of the brain, particularly how viruses establish a chronic infection in the brain and/or cause a neuroinflammatory process.

In 2015, Dr. Francis Collins, the NIH Director at that time, approached me to see if I would be interested in taking a fresh look at ME/CFS and develop a clinical protocol to study it. With the help of Dr. Brian Walitt, a rheumatologist, we put together a team of 75 experts across NIH to take a deep dive into the clinical characteristics and pathophysiology of the illness.

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Due to my expertise in infections, we recruited a specific cohort of patients whose ME/CFS was clearly triggered by an infection and made sure that there was no other underlying illness that could explain their symptoms.

These patients were admitted to the NIH Clinical Center for a period of one to two weeks and underwent a very large battery of tests. This is the most extensive study done to date on ME/CFS and has transformed our understanding of the disease.

Sadly, here in the UK and in many other countries there are many doctors who still believe that ME/CFS is a somatic psychological illness. This has held back treatments for people with ME who have suffered decades of health inequalities. Yet earlier this year, you and a group of colleagues from NIH in the United States, published a new detailed study, Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, which looks inside the bodies of people with ME.

From looking at your findings, it appears that you clearly noted that ME is a physical disease whose key characteristics are immune dysfunction and brain abnormalities. Is that a fair assessment of your findings? If so, please can you briefly explain these findings for the layperson?

Avindra Nath: Yes, that is correct. We hope that one of the major takeaways from our study is that we have convincingly demonstrated the biological basis of the disease that cannot be explained by deconditioning and psychological factors.

We have further identified several novel targets for modifying the course of the disease. We hope these findings will change the minds of many. All the same, I am certain that once we have a biological therapy for ME/CFS, it will provide definitive evidence for the biological basis of the disease.

We found that post-infectious ME/CFS is a multisystemic disease, with involvement of the immune system, autonomic nervous system, the brain, and the gut. We believe that the primary defect is in the maturation of B cells which

B-cell Activation

Nath believes and other studies have found that B-cell activation process gets stuck early on…

leads to immune exhaustion and activation of innate immune responses.

NoteNath proposes that the inability of naïve B-cells to mature and produce effective fighting (i.e. antibody-producing cells when presented with an infection) is driving ME/CFS. 

This jives with several ME/CFS findings: first, that the illness is often triggered by an infection. Second, it fits with two UK studies by a B-cell specialist named Geraldine Cambridge which suggest that problems producing energy have stopped the B-cells in ME/CFS patients from maturing. Interestingly, similar energy production problems appear to be occurring in the T-cells as well. 

Nath’s idea also fits, oddly enough, with the possibility that ME/CFS is an autoimmune disease, as problems with B-cell maturation have been associated with an increase in autoantibodies. (B-cells are major drivers of many autoimmune diseases.)

Problems with B-cell maturation can also produce “inflammaging” where the immune system seems to be prematurely aging -something that may be happening in ME/CFS in T-cells as well. Note that the biggest agent of viral reactivation in ME/CFS – the Epstein-Barr virus – primarily infects B-cells.   

Nath’s idea appears to be the immune system attempting to compensate for the B-cell exhaustion by ramping up the activity of the innate immune system which is: a) designed to produce a kind of holding action to give the B and T-cells time to mature; but b) is not effective at ridding the body of pathogens; and c) produces a lot of inflammation to boot. 

The gist is that with the B-cells knocked down (and possibly the T-cells since they appear to be exhausted as well), the innate immune goes bonkers producing inflammation all the while inadequately controlling the pathogen. A 2021 study suggested the B-cells in ME/CFS are indeed reacting to a pathogen.

On the T-cell front, three studies this year have found T-cell exhaustion in ME/CFS and one hypothesis proposed T-cell exhaustion the main driving the disease. 

There were also distinct sex differences; women had markers of overactive B cells and men had greater T cell activation. This suggests that potential immune therapies would need to be tailored accordingly.

Innate vs adaptive immune response

Nath believes that wonky B-cells leave the innate immune system – which is not designed to destroy pathogens – to carry the load.

We found that several metabolites in the cerebrospinal fluid of individuals with PI-ME/CFS were dysregulated. Of all the tests that we performed, these had the best potential for serving as a biomarker of the disease.

Note – Interestingly, given Nath’s focus on B-cell exhaustion, one of the main findings in the cerebral spinal fluid part of the intramural study was exhausted killer T-cells. Exhausted T-cells are the subject of a major NIH grant to Liisa Selin in the U.S.

We also found differences in an area of the brain called the temporal-parietal junction, which plays a role in integrating information, evaluating, and initiating physical action. This area, which drives the motor cortex, showed decreased activation in the ME/CFS participants. Abnormalities in this brain network and imbalances in catecholamines, chemicals that help regulate the nervous system, might help explain some disease symptoms.

We did not find any structural abnormalities but multiple functional or network abnormalities, which gives hope that the disease is treatable and possibly reversible.

The study acknowledges that post-exertional malaise is central to the disease. However, some researchers and many people in the ME community felt unhappy with the term ‘altered effort preference’ as an explanation for the origin of fatigue.

Your study suggests that healthy people chose harder physical tasks than those with ME. For those of us with ME, it is not simply a matter of choice. I often don’t leave the house not because I don’t want to go outside but because I am physically unable to leave the house most of the time. Can you explain why you chose the term ‘altered effort preference’? Do you accept that people with ME are physically unable to do the same physical tasks as healthy people?

Avindra NathYes, we agree, that could very well be the case. Effort-Expenditure for Rewards Task (EEfRT) is a well-established neurophysiological test. As shown in our manuscript, effort preference is a neurobiological consequence of an immune response to the infection.

Changes in the basal ganglia have been associated with fatigue in ME/CFS, FM and other disorders

Note – the Effort-Expenditure for Rewards Task (EEfRT) has been most commonly used in research on major depressive disorder (MDD), particularly to study anhedonia (the inability to feel pleasure) – which ME/CFS patients do not have. The test has also been used to explore effort expenditure in a disease – Parkinson’s disease – which may have substantial connections to ME/CFS.

The basal ganglia are disrupted in both diseases and appear to be particularly vulnerable to inflammation. Basal ganglia damage is also associated with ‘psychomotor’ slowing and fatigue, both of which are found in ME/CFS.

Several studies have found problems with basal ganglia functioning in ME/CFS and fibromyalgia. Andrew Miller’s ability to link basal ganglia dysfunction in ME/CFS with the “unrewarding rewards” he found might fit with effort preference findings in Nath’s study.

Unrewarding Reward: The Basal Ganglia, Inflammation and Fatigue In Chronic Fatigue Syndrome

For many of us with ME, the pace of research into our illness appears agonizingly slow. There has been a dire lack of research into potential treatments which may mitigate some of the symptoms of ME. Does your research point to any potential treatments for ME?

Avindra Nath: Yes, our study suggests that immune modulatory therapies should be considered as disease-modifying treatments. These would need to the tailored to the patients to target the predominant immune abnormality in that individual. These medications can have serious side effects; hence they need to be studied in the context of a clinical trial.

It is necessary to conduct clinical trials and study pathophysiology in the context of these clinical trials. One such method might be to consider a platform trial where multiple agents can be studied and compared against one another with a single placebo arm.

Note – Nath has proposed that “checkpoint inhibitors”  be used to reset the immune system in ME/CFS. If something is holding B and T-cells back from performing correctly in ME/CFS, checkpoint inhibitors could take the brake off of them, allowing them to thrive and remove the pathogens or pieces of pathogens that Nath believes keep tweaking the immune system.

Nath is remaining engaged in the post-infectious disease space. He’s begun an IVIG long COVID trial and an intensive long-COVID study with a larger cohort. Nath said, “That’s how I can benefit the ME/CFS patients a lot faster than I could otherwise”. 

Nath’s idea of using platform trials has been embraced by the RECOVER Initiative in long COVID. 

Vicky Whittemore Interview

Vicky Whittemore

Vicky Whittemore leads the ME/CFS effort at NINDS.

Many scientists in the field of ME research welcome the intramural study as presenting a number of ‘compelling findings’ that will be of great benefit to future research into the illness. Having said this, the low number of study participants is one limiting factor of this study.

It is quite clear that further research is needed to find the causes of ME, to find biomarkers for the illness, and to discover potential treatments as well. Can you tell our readers about the NIH Initiative, the NIH ME/CFS Research Roadmap, for further research to improve our understanding of this debilitating neuro-immune disease? Does this roadmap include the involvement of the ME community?

Vicky WhittemoreThe ME/CFS Research Roadmap is an ambitious report developed by a Working Group of NINDS Council that included researchers, clinicians, leaders of advocacy organizations, as well as five people with lived experience. These individuals were absolutely essential to creating the Roadmap so that future research and clinical trials are not only scientifically valid and impactful but carried out with the needs of people with ME/CFS in mind.

The goal of the Roadmap was to assess current ME/CFS research activities and identify opportunities and gaps in ME/CFS research to identify targets for the development of treatments.

Twenty-one people with ME/CFS, caregivers, spouses, and others with lived experience planned and ran eight topic area webinars with open Q&A sessions. Speakers included people with lived experience and leading experts in ME/CFS from around the world. We focused on answering three key questions: what do we know, what don’t we know, and what do we need to do to accelerate research to move toward clinical trials?

The broader ME/CFS community played a major role in the Roadmap. We hosted public webinars and crowdsourcing campaigns, resulting in over 400 suggestions for research directions from the community.

The Roadmap report was presented to and accepted by the NINDS Council in May 2024.
Our next steps may include plans to form a clinical trial working group, a genetics working group, and new NIH funding mechanisms to support exploratory research.

The Roadmap webinars are part of the strategic plan effort for ME/CFS at the NIH.

The Roadmap was designed to spark interest and create more funding for ME/CFS. So far that hasn’t happened.

The full ME/CFS Research Roadmap report and topic area webinars (also called the ME/CFS Research Roadmap Webinar Series) are posted on the NINDS website. Note – the Roadmap was accepted in July and no new funding has been announced. Please sign MEAction’s petition to Director Bertagnolli to provide funding to support the Roadmap.

Sign the Petition Here 

The ME/CFS Roadmap Report of May 2024, noted the urgency of promoting research into ME and asserted that the number of ME/CFS trials needs to be ‘dramatically increased’.

I found no mention of the issue of suicidality, however, amongst people with ME. In 2018, the Lancet ran a piece that noted that people with ME had a six times higher suicide rate than the rest of the general population.

In an interview with Professor Leonard Jason in 2023 on this subject, he stated that the high rates of suicide amongst pwME is an ‘unacknowledged public health crisis’. Will the ME/CFS Roadmap Research Report incorporate the issue of suicide amongst people with ME?

Vicky Whittemore: The ME/CFS Research Roadmap report is finalized and has been accepted by the NINDS Advisory Council. The Trans-NIH ME/CFS Working Group is moving forward with follow-up from the initiative to address the research priorities identified in the report. We acknowledge that there are important areas, like suicidality, that were not addressed in the report and may be addressed through additional working groups going forward.

National Institutes of Health (NIH): If you or someone you know is struggling or having thoughts of suicide, call or text 988 or chat online to connect with the 988 Suicide & Crisis Lifeline. The Lifeline provides free and confidential support to people in suicidal crisis or emotional distress 24 hours a day, 7 days a week, across the United States. In life-threatening situations, call 911.

At the NANDSC Roadmap meeting, you said something about a new funding opportunity for ME/CFS. Can you explain what that is?

We are currently working on developing a new funding opportunity for ME/CFS.

Dollars

This appears to be the first grant package the NIH has specifically designed for post-infectious diseases. the amount of funding is unknown.

Note – this was explained by one person as a kind of make-up for not funding the third ME/CFS research center. Time will tell, but whatever it is, it’s apparently expected by the end of the year.

Two new funding opportunities for infection-associated chronic illnesses, including ME/CFS, are expected to be published in late October (see NOT-NS-24-105 and NOT-NS-24-1 08).

Note – This appears to be the first funding mechanism the NIH has produced for post-infectious diseases. Note that the RECOVER Initiative for long COVID was mandated by Congress. On its own, NIH has provided surprisingly few grant opportunities for long COVID or for post-infectious illnesses. 

One funding opportunity (NOT-NS-24-105 ) provides large (ROI) grants and the other (NOT-NS-24-1 08) smaller (R21) exploratory grants. The funding opportunities have not been published and we do not know how much funding they will provide or how many grant awards are expected.

Interestingly, the NIH’s immune institute (NIAID) is not partnering with NINDS on these awards. That’s a bit surprising given that the new NIAID director, Dr. Jeanne Marrazzo, has shown interest in post-infectious diseases and ME/CFS. We will see if NIAID supports the new ME/CFS funding opportunity. 

These appear to be excellent grant packages that will explore “ongoing exacerbated inflammatory response, microvascular and/or thromboembolic dysfunction, pathogen-induced autoimmunity, bioenergetic failure with metabolic and mitochondrial derangements, gut dysbiosis, and the reactivation of latent pathogens.” It was particularly good to see bioenergetic and metabolic derangements in there. The only question at this point is how much funding they will provide.

Is it true that the NIH is dropping one ME/CFS research center and only funding two now?

The initial RFA resulted in funding one Research Center at Cornell University (U54AI178855). The RFA was reissued and an additional Center at Columbia University (U54NS137199) was funded. Funding decisions are based on a rigorous peer review process that prioritizes support for grant applications most likely to make highly impactful contributions to ME/CFS research. We cannot share any details from the reviews because they are strictly confidential.

Note – It was disappointing that the NIH: a) failed to fund a third center; and b) did not increase funding for the two centers to account for inflation. The NIH’s failure to do that leaves its funding ME/CFS research centers funding program at about 50% of its original 2017 level. Nor has the NIH funded followup studies to the Nath study – which was putatively designed to provide clear avenues for ME/CFS research – or the Roadmap Initiative. 

Maureen Hanson’s Cornell Group will continue its exciting muscle, and immune studies

Maureen Hanson’s ME/CFS research center will continue to use the multi-omic single-cell profiling it used to produce such excellent results. (Instead of cells being assessed en masse, they are assessed one by one.) The lab will do a very fine-tuned assessment of the gene expression in ME/CFS muscles, identify which cells exercise is damaging, and expand its exciting work on monocytes and platelets, and the role they play in inflammation and coagulation.

Ian Lipkin's Columbia Group

Ian Lipkin’s Columbia group will dig deep into antibodies, search for past infections, and create a US based GWAS study (to complement DeCode ME)

Ian Lipkin’s ME/CFS research center – will create a smartphone app that will determine over the course of a year if antibodies can help explain ME/CFS patients’ symptoms. It will also work with Solve M.E. to identify 5,000 people with ME/CFS whom it will employ in Genome Wide Association Studies (GWAS) in the U.S. to determine if common gene mutations can help explain ME/CFS. It will compare its results with the DeCodeME results in the UK. Finally, it will use cutting-edge technology (peptide-based phage display) to uncover past infections in samples of chronic fatigue patients and healthy controls taken before the coronavirus epidemic.

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