A summary of the Massachusetts ME/CFS conference

On 23 October 2021, the Massachusetts ME/CFS & FM Association organized an online conference titled “Advances in our understanding of ME/CFS and the effects of Long COVID”. It had an impressive lineup with ME/CFS researchers from three ME/CFS Collaborative Research Centers funded by the National Institutes of Health (NIH). Speakers included Dr. Avindra Nath, Clinical Director of the National Institute of Neurological Disorders and Stroke, and Dr. Ian Lipkin, a distinguished epidemiologist from Columbia University. This blog post provides a brief summary of the conference.

Caveat: the information provided in this blog post was based on quick note-taking during live presentations. It is, therefore, possible that it contains some inaccuracies. Before making strong conclusions, we recommend waiting until the videos of the conference (or even better: the publications of the presenters) become available online.

Boston, Massachusetts by night

Vicky Whittemore

Vicky Whittemore, Program Director at the NIH, started the conference by describing three research and communication tools:

  • ME/CFSnet provides an overview of resources and news about the ME/CFS research centers.
  • SearchME/CFS is an interactive search tool where researchers can look for biospecimens that are available for ME/CFS research.
  • MapME/CFS offers a database with results from ME/CFS research.

Whittemore clarified that the NIH plans to fund ME/CFS research centers for another 5-year period. The Funding Opportunity Announcements (FOA) are currently being reviewed at the NIH and she expected that they will come out soon. If we understood correctly, the current centers will have to submit applications and compete with others in order to get the grants and continue their work.

Avindra Nath

Dr. Avindra Nath mostly talked about the intramural NIH study on ME/CFS. Unfortunately, this extensive research project was suddenly interrupted by the coronavirus pandemic. From Dr. Nath’s presentation slides, it looked like only 17 ME/CFS patients and 21 healthy volunteers were successfully recruited into the study. This was largely due to stringent selection criteria. Patients were required to have a documented infectious onset and be ill for less than 5 years. Dr. Nath clarified that many patients said their illness started after infection but did not have clear documentation of this. This was the most selective requirement.

But even after extensive screening, there were still quite a few patients who turned out to have another illness than ME/CFS. One slide shown during the talk indicated that 27 patients consented to “Visit 1” but only 17 were labeled as “adjudicated PI-ME/CFS”. At the end of the webinar, Nath clarified that there were multiple exclusionary illnesses including cancer, Parkinson’s disease, myositis, and multiple sclerosis. Interestingly, of the 25 healthy controls, 4 were also rejected because of an exclusionary illness (these persons were not as healthy as they thought they were).

Dr. Nath also shared some of the early results of the intramural NIH study. One image showed that ME/CFS patients had a maximum force during a handgrip strength test similar to the healthy controls but that their “time to fatigue” was much shorter. Patients also reported increased pain sensation, cognitive symptoms, and mild anxiety and depression, although for all of these measurements there was substantial overlap with the healthy control group. During question time somebody asked why depression was not more common in ME/CFS patients given the debility and severity of their illness. Dr. Nath responded that those with more severe depression were excluded from the study to avoid confounding results.

The NIH researchers also looked at Natural Killer (NK) cell function and took skin biopsies to test nerve fiber density. Both looked normal but because the sample size was small, the comparisons might have lacked statistical power to find subtle differences.

Clearer differences were found during a cardiopulmonary exercise test. At the anaerobic threshold, ME/CFS patients had decreased work rate and rate of oxygen consumption. There were also differences in mitochondrial function after exercise. ME/CFS patients showed lowered maximal respiration and decreased spare respiratory capacity compared to healthy controls.

Nath also said that their investigation of the gut microbiome validated some of the findings of Dr. Ian Lipkin at Columbia University. One of the moderators of the conference asked him what results of the intramural study he found most striking and Dr. Nath’s answer was: the big differences between men and women in the immunology data (which weren’t shown on the slides). 

Ian Lipkin

Dr. Ian Lipkin, the next speaker, agreed and said that he also saw sex-specific and age-specific differences in his results. Throughout the talk, he emphasized that ME/CFS is likely a very heterogeneous condition. Much of Dr. Lipkin’s research focuses on the microbiology of ME/CFS. He has found, for example, that ME/CFS patients have more bacteria in their feces than healthy controls and that there are differences in the types of bacteria in the gut. Butyrate-producing bacteria, for example, were decreased which, according to Dr. Lipkin, might provide a rationale for clinical trials of prebiotics or probiotics.

He also explained how his research team uses stressors in ME/CFS research because these might amplify abnormalities which makes them easier to detect. One slide reported that ME/CFS patients displayed a heightened inflammatory response after exposure to extracts of Candida or bacteria. This response was higher in women and particularly in those older than 45.

Dr. Lipkin also reported that mitochondria of ME/CFS patients are slow to recover. One of his slides showed that citric acid decreased in controls after the exercise test, while it accumulated in ME/CFS patients. According to Lipkin, this might point to a block or impairment of the Krebs cycle (the main source of energy for our cells). There was, however, a large overlap between the results of patients and controls.

Dr. Lipkin then went on to talk about his paper on antigen-driven clonal B cell expansion, the same type of expansion of B-cells, he said, that one would see during infection. He stressed that these findings were independently confirmed by a Japanese group earlier this year.

In the last year of their current grant award, his team at Columbia is searching for evidence of a past infection using antibody tests. In addition, they are searching for genetic markers of susceptibility to ME/CFS, planning animal models, and extending their studies to Long Covid and Gulf War Illness to look for similarities and differences with ME/CFS.

Derya Unutmaz

The next speaker was Dr. Derya Unutmaz from The Jackson Laboratory (JAX). His research focuses on immune profiling, the gut, metabolomics, and how these three interplay. He gave the example of Th17 cells which are shaped by the microbiome and involved in a variety of immune diseases. Dr. Unutmaz’s previous findings indicated that Th17 cells are also disrupted in ME/CFS, something that he hopes to replicate in a new cohort.

He also talked about a study with 150 patients and controls that are followed up over time. His team aims to identify frequencies and functional subsets of immune cells with the plan to generate more than 300 data points per patient. This would be the largest prospective immune profiling data available on ME/CFS patients. They have now also included 40 patients with Long Covid to compare their data with that of ME/CFS patients.

Dr. Unutmaz continued that his team’s first microbiome findings are going to be submitted for publication. He said the results are similar to what Dr. Lipkin described and that ME/CFS is likely a very heterogeneous disease. Surprisingly, patients who have been ill for a relatively short period of time (less than 4 years) showed the most significant microbial dysbiosis. Long-term patients looked like healthy controls but had more metabolic disturbances.

Dr. Unutmaz’s team is working further on metabolomics. Again, the idea is to collect lots (about 500.000 one slide said) of data points, including from metabolites that have not been identified yet. To goal is to link these findings to data on immune cells and the gut to form a multi-system analysis.

Finally, Dr. Unutmaz talked about Long Covid. He doesn’t think it’s all the same as ME/CFS but there are many similarities. He suggested that research into Long Covid might provide useful insights into the early stages of ME/CFS. His microbiome study and an intruiging 2015 immunology study by Dr. Mady Hornig and colleagues from Columbia University suggest that the early stage of ME/CFS might look different than later presentations. 

Maureen Hanson

Dr. Maureen Hanson from Cornell University picked up on the microbiome research Dr. Nath, Dr. Lipkin, and Dr. Unutmaz talked about. She said that her team investigated this back in 2016 and indeed found lower bacterial diversity and butyrate-producing bacteria in ME/CFS patients. But Dr. Hanson stressed that these abnormalities were not specific to ME/CFS and have also been reported in other illnesses such as Parkinson’s disease, ulcerative colitis, Crohn’s disease, alcoholic fatty liver disease, etc. This made her pessimistic that they would be able to find the reason for these changes in the gut. In Dr. Hanson’s view, this is not what’s driving the disease. She wants to find the underlying cause, the final common pathway and she had the impression this lead wasn’t taking her there.

For the rest of her presentation, Dr. Hanson talked about other routes that might bring better clues. She explained that Dr. Dikoma Shungu was doing interesting PET and MRI scans but that this work was disrupted by the coronavirus pandemic. Dr. Hanson said it would be interesting to know if the Japanese report of neuroinflammation can be confirmed.

Another study of her team looked at plasma metabolites of 60 ME/CFS patients and 45 controls. Arnaud Germain presented these findings at the 2021 IACFS/ME meeting. When there were significant differences in metabolites, they tended to be lower in ME/CFS patients. This was consistent with hypometabolism but Dr. Hanson stressed that there was considerable overlap between the results of patients and controls. Additional samples are being collected of 90 ME/CFS patients and 90 controls for additional analysis.

Dr. Hanson’s team is also looking at metabolites before, after, and between exercise tests. She notes that metabolites of the citric acid cycle are affected by exercise but that they recover in the 24 hours afterward. In her view, this suggests that they are probably not the cause of the post-exertional malaise patients report. Other pathways, however, were disturbed after exercise and did not restore during the recovery period (her slides mentioned: metabolism of cysteine and methionine, glycerol lipid, and primary bile acid biosynthesis).

Dr. Hanson went on to discuss her paper (Madranano et al. 2020) showing dysfunctions in CD4+ T cells and CD8+ cells in ME/CFS patients in ways known to occur during chronic immune activation. A current study led by Jessica Maya is finding abnormalities in fatty acid oxidation in T- and NK Cells.

Then Dr. Hanson talked about a gene expression study led by Dr. Andrew Grimson. She explained that many findings on gene expression in total blood or total lymphocytes of ME/CFS patients are not reproducible. She thinks this might be because such analyses mix many different cells, making it hard to tell if some are abnormal or not. Therefore the study by Dr. Grimson’s lab is looking at different types of blood cells separately. This will provide greater resolution to identify differences between ME/CFS and control subjects. The data is still under analysis but Hanson thinks it’s going to be extremely important.

Finally, Dr. Hanson said that her group is also interested in studying similarities and differences between Long Covid, Gulf War Illness, and ME/CFS. She explained that Long Covid is interesting because it shows that people can develop debilitating and long-term symptoms after an asymptomatic infection. She speculated that this might also have happened in ME/CFS patients who do not recall an infection as the trigger of their illness.

Lucinda Bateman

The last speaker was Dr. Lucinda Bateman. She is Clinical Director of the Bateman-Horne Center, collaborator on two NIH ME/CFS Collaborative Research Centers, and a prominent member of the US ME/CFS Clinician’s Coalition. She mostly talked about her preliminary research on Long Covid. Her view is that current ME/CFS research is largely based on people who have been ill for many years and that the pandemic created a unique opportunity to study early-onset post-viral illness.

Dr. Bateman said that there are roughly two main groups within the diagnosis of Long Covid. There are those with a severe infection who required hospitalization and have lingering organ damage afterward. Then there are people with a relatively mild infection who get increasingly worse without signs of organ damage or biological markers. It’s the latter group that resembles ME/CFS and that her research focuses on.

Her team recruited people from the Utah COVID-19 long Hauler Facebook group who had an uncomplicated medical history before their coronavirus infection, did not require hospitalization but were still sick 6 months after COVID-19. They have seen more than 60 Long Covid patients but Dr. Bateman cautions that her cohort may not be representative of Long Covid patients as a whole.

Then she started listing the things her team learned but didn’t know yet when they started studying Long Covid. The first point was that many similar comorbid conditions occur in both ME/CFS and Long Covid such as postural orthostatic tachycardia syndrome (POTS), sleep apnea, small fiber neuropathy, irritable bowel syndrome, etc. The second point was that 92% of the long covid patients reported post-exertional malaise (PEM) and that this seemed similar to the PEM of ME/CFS patients. Thirdly, orthostatic intolerance seems to play an important role in the impaired function of Long Covid patients that meet ME/CFS criteria. Dr. Bateman mentioned one patient with Long Covid who had a 73 beat per minute increase in heart rate during a NASA lean test as an example.

Question and Answer

After the talks, there was an interesting Q&A session where the researchers answered questions from people who had been following along in the chat.

EBV reactivation

Somebody asked about Epstein Barr Virus (EBV) reactivation in ME/CFS patients. Dr. Hanson said that they tested this in 105 patients but didn’t find evidence of this. Dr. Lipkin added that his team did PCR-testing but that there was no difference between patients and controls. Others stressed that even if there are signs of reactivation, it is difficult to determine if this is pathogenic or not. Dr. Bateman, for example, said that reactivation is also found in astronauts after a space flight even if it doesn’t lead to disease.

Mitochondrial mutations

Another question was asked about mitochondrial mutations. Dr. Hanson said that she found none in her cohort but that she only looked at blood cells and that this doesn’t tell us what is happening elsewhere in the body. Dr. Nath explained that he did muscle biopsies but didn’t find anything abnormal (his audio was difficult to understand though). Dr. Lipkin, on the other hand, was convinced that mitochondrial function is impacted in ME/CFS.

Clinical trials

Then there was a short discussion on clinical trials. Dr. Bateman was discussing low-dose naltrexone. She was unsure about its role in ME/CFS but suggested it could be tried given that it is relatively safe and inexpensive. Dr. Lipkin, however, stressed that we need randomized controlled trials (RCTs), even if medications are cheap and safe. Dr. Nath agreed and said that the history of medicine is full of surprises where interventions believed to be safe, turned out to be harmful.* Dr. Bateman agreed about the need for RCTs and said one was ongoing in Canada that might tell us more.

Dr. Hanson added that we also need to be a bit wary about probiotics because in some trials it made people worse. So it’s not completely innocuous. She also clarified that her team detected differences of butyrate in the gut only, not in the plasma. So it’s not obvious if and how one should try to correct this.

Conclusion

That was the end of an interesting conference. We had the impression that the researchers at the NIH-funded ME/CFS centers are doing excellent work but that they haven’t found a breakthrough discovery yet and that they need more money to scale and speed up their projects. Many thanks to the Massachusetts ME/CFS & FM Association for organizing this event. The videos of the presentations are now available on their YouTube channel.

* Dr. Nath gave three examples but his audio was hard to understand at this point. We think he mentioned TNF-alpha blockers in multiple sclerosis.

7 thoughts on “A summary of the Massachusetts ME/CFS conference

  1. Alicia Butcher Ehrhardt says:

    Thank you for the interesting summary.

    I’m curious about something you said: that ‘92% of the long covid patients reported post-exertional malaise (PEM)’ – which I thought was THE indicator for ME/CFS, implying that these long covid patients had gotten ME/CFS from the SARS virus.

    Unless I’m misreading this, and the PEM is THE indicator, but only if you can’t find another reason for it.

    Reply
  2. ME/CFS skeptic says:

    Hi Alicia thanks for your comment.

    I think most researchers see post-exertional malaise (PEM) as a characteristic feature of ME/CFS but that doesn’t mean it doesn’t occur in other illnesses. Unfortunately there hasn’t been much research that tests for PEM in other illnesses so it remains a bit unclear how common this symptoms is outside the ME/CFS community.

    In one of her slides, Dr. Bateman noted that “many Long Covid patients appear to meet the IOM/NAM ME/CFS diagnostic criteria” but she also cautioned that her study suffered from selection bias. They selection criteria they used for example, resembled some of the ME/CFS diagnostic criteria (for example the requirement for an illness duration of 6 months). So although many of these Long Covid patients looked like this might have ME/CFS, it was a selected cohort that may not be representative of Long Covid patients as a whole.

    Hope this helps to answer your question.

    Best wishes,

    Reply
    1. Alicia Butcher Ehrhardt says:

      It does, thanks. But these patients might have been diagnosed with ME/CFS if the SARs virus were not so prevalent.

      It makes a huge cohort of patients which have a common viral trigger to study – I have hopes that we will learn a lot about us from the very specific long-covid patients. The cost is horrendous, of course, and the doubters and deniers will have their day, and we could have been ready to help some of these people had they studied us (etc., etc., etc.). But there is a possibility of a life after ME/CFS, and I might be young enough to benefit (I’m 72), if it doesn’t help only those who are within a short period of getting these diseases, and that feels like a lot more than we’ve had in the thirty-one years I’ve been sick.

      I have hope knowledge will come from this disaster. The hard way, as are many of the lessons of humankind, but maybe.

      Reply
  3. Laura says:

    Thank you SO much for note taking and typing this up. I hope you didn’t suffer from too much PEM afterwards.

    Reply
  4. George Goldstein says:

    They are reinventing the wheel. @20-30 years ago it was discovered that more females have cfs/me because there are more B cells in women than men. DUH. I wish that they would check the old data.

    Reply

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