In December 2023, ME Research UK attended a two-day conference organised by the National Institutes of Health (NIH) and titled “Advancing ME/CFS Research: Identifying Targets for Intervention and Learning from Long COVID”.
Our reflections on the topics discussed at the conference are presented in this three-part series of articles.
1. Overview | 2. Research topics | 3. Treatment targets
During the conference, several of the speakers discussed biological abnormalities in ME/CFS and long COVID which may act as potential targets for treatment.
These abnormalities included:
- Oxidative stress,
- Abnormalities within the immune system,
- Brain inflammation, and
- Dysregulation of blood vessels and blood supply to the brain (neurovascular dysregulation) during exercise.
Oxidative stress
Professor Mark Davis presented research which suggests that oxidative stress is a shared characteristic of both ME/CFS and long COVID.
Oxidative stress – a state in the body caused by increased number of potentially harmful molecules known as “free radicals” or “reactive oxygen species” (ROS) – has been identified previously in people with ME/CFS. For example, a study funded by ME Research UK found that oxidative stress levels are raised in people with ME/CFS and associated with symptoms of the disease.
Professor Davis spoke in detail about oxidative stress and how it relates to the immune system. Key points from the presentation included:
- ROS levels have been found to be elevated in people with ME/CFS, and those with long COVID – this not only increases immune cell activation, using up more energy, but also damages mitochondria (the energy producing cells of the body).
- Notably, females with ME/CFS and those with long COVID were found to have higher levels of ROS compared with males with either of the two illnesses.
Prof. Davis discussed how metformin – a drug used to treat type 2 diabetes, gestational diabetes and polycystic ovary syndrome – may provide a potential treatment option to reduce the ROS levels in people with ME/CFS and long COVID. Interestingly, research funded by ME Research UK and published in 2018 also identified that metformin could improve glucose uptake in muscle cells from people with ME/CFS.
It is important to remember that both the research discussed in the talk relating to oxidative stress and the study published in 2018 were carried out in vitro, or outside the human body, using laboratory equipment such as test tubes. Therefore, much more research is needed to investigate whether metformin would work in the same way in people with ME/CFS and those with long COVID, and consider the risk of adverse side effects. Based on the information Prof. Davis presented, it would also be important to consider the effectiveness of metformin for ME/CFS and long COVID for males and females separately.
Immune system
Prof. Karl-Johan Tronstad spoke about a hypothesis that ME/CFS is due to an “acquired immune system defect” – at least in a subset of individuals.
Prof. Tronstad discussed the history of this hypothesis which began “around 2007” when Olav Mella and Øystein Fluge – who worked with cancer patients – observed that some individuals who had ME/CFS prior to developing cancer improved following cancer therapy. This indicated the possible involvement of autoimmune mechanisms in ME/CFS, and identified an area for potential treatment by “resetting” part of the immune system.
Two trials were mentioned:
- The RituxME study (2019): No clinical benefit of rituximab – a medication used to treat certain autoimmune diseases and types of cancer – in patients with ME/CFS was discovered.
- The CycloME study (2020): Although more than half of participants with ME/CFS experienced clinical benefits from cyclophosphamide – a chemotherapy and immunosuppressant drug – Prof. Tronstad concluded that further investigations would not be carried out due to the side effects experienced by participants.
Despite the results of these trials, it is possible that the immune system may still provide a potential target for treatment in ME/CFS and long COVID – at least in a sub-group of people.
Brain inflammation
Professor Jarred Younger, who acknowledged ME Research UK as a funder in his presentation, presented his work on brain inflammation, in particular relating to immune system cells in the brain (microglia) in ME/CFS – long COVID was not a focus of this talk.
Microglia usually exist in a non-active state but can become sensitised or “primed” ready to respond under stress; for example, due to an altered gut microbiome, exposure to toxin(s), chronic stress, in the normal process of aging, and – as Prof. Younger proposed – in ME/CFS.
Prof. Younger suggested that in ME/CFS, the microglia are sensitised – possibly due to an infection (or series of infections). Then, once in this sensitised state, the microglia interpret only a small amount of exertion as a new pathogen exposure, which then leads to an immune response in the body and chronic inflammation.
Prof. Younger discussed potential treatment options for ME/CFS, and his hope that there is a “huge push on getting clinical trials going” to assess the safety and efficacy of these drugs. In this section of his talk, Prof. Younger highlighted two drugs which have the potential to reduce microglial excitability in a beneficial way in ME/CFS.
Low-dose naltrexone (LDN) targets a specific receptor on microglia shutting off the flow of pro-inflammatory agents. This helps the microglia to return to their resting state – something which Prof. Younger thought may help to ease pain, fatigue, cognitive issues and other symptoms of ME/CFS. Dextro-Naltrexone has the same effect on the microglia as LDN but acts in a slightly different way.
Prof. Younger stated that, to his knowledge, there are no clinical trials assessing whether LDN or Dextro-Naltrexone work safely and effectively to treat ME/CFS. ME Research UK agrees that much more research is needed, and adds that it would also be important to consider whether these drugs may prove useful in the treatment of long COVID.
Neurovascular dysregulation
David Systrom MD presented findings from a study published in 2022 on neurovascular dysregulation and exercise intolerance in ME/CFS.
The study found that pyridostigmine – a drug which is used to improve muscle weakness in patients with myasthenia gravis – increased the maximum amount of oxygen used during exercise in people with ME/CFS.
Although it is important to note that this was a small study of only 45 people, the authors suggested findings may indicate that “treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS”.
Dr Systrom and his colleagues are now conducting research to investigate the effects of pyridostigmine in people with ME/CFS over a 3-month period. Interestingly, the research team are comparing the effectiveness of pyridostigmine alone, and pyridostigmine with LDN, with a placebo.
This study – the LIFT (Life Improvement Trial) study – is ongoing, but you can watch Dr Systrom talk more about the project in a video recorded for the Open Medicine Foundation.
Summary
While the evidence presented at the conference relating to potential targets for treatment of ME/CFS and long COVID is promising, it is clear that much more research is needed to assess whether or not these drugs work.
If and when drugs are identified as effective in treating ME/CFS and long COVID – or in reducing certain symptoms – it is then important to establish how well they work, and if any benefit outweighs the risk of potential side effects. It is also important that consideration is given to how well any drugs across different populations with ME/CFS and long COVID – such as males and females, those with different disease severity, and varying length of disease.
1. Overview | 2. Research topics | 3. Treatment targets
