A report by Dr Louise Crozier, our Science and Engagement Director.
The 13th international scientific conference of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) was held on August 21st by Zoom, having been postponed from being held in Stony Brook University in June due to COVID-19. Seventeen oral presentations were given over five sessions in total, beginning with a discussion on several projects related to COVID-19 and tracking the development of ME/CFS after infection. Other sessions were dedicated to immunology, metabolism, heart rate variability, research/clinical networks and treatments, followed by questions and answers from the conference attendees. Over 270 delegates were present, with 20% of being early stage researchers. A short summary of each of the five sessions is below.
Session 1: COVID-19
Due to the current pandemic, there has been much focus in the ME/CFS research community about the impact of SARS-COV-2 (COVID-19) on both those with and those without ME/CFS. The session began with a talk by Dr Moldofsky (University of Toronto), who had studied the development of long-term complications following the previous SARS-COV-1 epidemic in 2003. His studied centred on front-line nurses that fell ill during the 2003 epidemic who were still suffering one year after initial infection. Symptoms included profound fatigue, difficulty thinking/concentrating and disturbed sleep, among others. Dr Moldofsky was interested as he saw similarities with fibromyalgia, which he had been studying for some years. Unfortunately, when asked about longer-term follow-up studies, he stated that he had difficulty securing the funding for this, as long-term complications were not seen to be a high research priority at the time.
The development of long-term post-viral complications is receiving more media attention due to the number of people reporting “long COVID”, which in turn is helping to raise awareness of ME/CFS in general. The pandemic is an opportunity for researchers to study risk factors which may lead to someone developing long COVID or perhaps ME/CFS. Dr Jason from DePaul University had previously carried out a large study looking at the potential development of ME/CFS in approximately 4,500 college students after infection with infectious mononucleosis (Epstein-Barr Virus). They are now reusing this data to track candidates at a 6-year follow up to see who may have developed COVID-19. Dr Jason explained that this pandemic represents a unique opportunity to track how various factors may lead to post-infectious fatigue.
Dr Whittaker from the Solve ME/CFS Initiative provided details about the You + ME registry, collecting data on the lived experience and genetics of people with ME/CFS. Due to the timing of making the registry live as the pandemic started, they have been able to track the impact of COVID-19 on people with ME/CFS, to see if the illness makes symptoms worse for example. She also stated that they are hoping to open the registry up globally to ME/CFS patients in the next few months.
Dr Tompkins of the Open Medicine Foundation (OMF) described three phases of research they have planned to track the development of ME/CFS from hospitalised COVID-19 patients, in projects which they aim to carry out for up to 24 months after initial infection. Finally, Dr Nacul of the London School of Hygiene and Tropical Medicine detailed projects in which he is involved in the UK and Canada. These projects aim to track whether COVID-19 develops into post-viral fatigue syndrome from both community and hospitalised patients. He is also planning a study on symptom outcomes in people with ME/CFS after COVID-19 infection.
Overall, the session was very informative and showed real promise in the number of projects aiming to understand factors which may lead to the development of ME/CFS or on how the current pandemic may affect those who already have ME/CFS.
Session 2: Immunology/Metabolism/Heart Rate Variability
The next session was on immunology, metabolism and heart rate variability, with some of the most interesting results shown. First to present was Dr Sato from the National Institute of Neuroscience in Japan on a possible treatment for ME/CFS – B cell depletion therapy. B cells form an important part of the immune system and some patients with ME/CFS have responded positively to this treatment, for reasons that are, as yet, not clear. In their studies, Dr Sato and colleagues found that both a specific immunology gene and certain short-lived antibody-secreting cells (known as plasmablasts – which B cells can develop into) were increased in ME/CFS, with the possibility of specific plasmablasts being an indicator of severe ME. Dr Sato proposed that infection may trigger plasmablast activation, along with the activation of specific B cell receptors, which may lead to autonomic dysfunction through autoimmune mechanisms.
Dr Pettersen from the University of Bergen (Norway) whose area of research was focused on metabolism, mitochondria and ATP (energy) levels presented next. Dr Pettersen hypothesised that there are impaired cellular energetics in ME/CFS. Interestingly, this is similar to research from Julia Newton’s lab in a previously ME Research UK-funded project (see Tomas et al, “The effect of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) severity on cellular bioenergetic function”, published in PLOS ONE, 2020). The Norwegian study found that a key enzyme in the main pathway for energy production, PDH, was impaired in ME/CFS, suggesting that less energy and more lactate is produced. Her work is ongoing but her takeaway message was that there appears to be subgroups with different metabolic profiles within the ME/CFS groups, which is important for taking into account for future research in the ME/CFS field in general.
The final two presentations were on heart rate variability – the time from one heartbeat to the next. Dr Friedberg (Stony Brook University) presented data showing that for people with ME/CFS studied for activity patterns (pacing and crashes), heart rate variability and major life events over 6 months, the most significant factor for those that improved in their symptoms, was a higher heart rate variability and increased positive “uplifts” (positive experiences). Dr Baraniuk from George Washington University detailed the relevance of heart rate variability in POTS during exercise. He studied exertional exhaustion in ME/CFS patients and Gulf War Illness veterans. His team measured patients’ heart rate laying down, then standing up, subjected them to a submaximal bicycle exercise then carry out serial orthostatic tests and heart rate variability. From the patients’ heart rate variability tests, the team defined three groups: the STOPP group (control – normal response), the POTS group (postural orthostatic tachycardia syndrome) and the START group (stress test activated reversible tachycardia). The team found significant differences between the START group and the POTS group when the patients were lying down. However, when patients were standing up, the STOPP group and the POTS group were significantly different. They are still trying to understand these differences but it was clear that Dr Baraniuk had three different subgroups within the patient cohort, purely on the basis of heart rate variability. This warrants further investigation.
Session 3: Treatment
There were three presentations given in the treatment session. The first was from Dr Renesca (Nova Southeastern University), who detailed the program her group were running for treatment of ME/CFS. Each patient would attend four sessions. The first, covering the ME/CFS diagnosis, discussing pacing, patterns that may lead to push/crash cycles and introducing activity logs. The second concentrating on emotion and behaviour, with the introduction of CBT (in the context of pacing), meditation and mindfulness. The third session addressed pain and sleep to identify solutions for these symptoms where possible; and the final session was on nutrition, providing information on using food as a source of energy and medicine. It was not until the one month follow-up after the final session that any significant changes were seen in the 26 patients studied. Positive changes were observed in reduced fatigue, anxiety, depression, pain, sleep disturbances and health distress. Dr Renesca would like to implement the program in the future, with the addition of virtual options to reach housebound and long-distance patients. Whilst this will not treat the main cause of ME/CFS, she hopes that it will help increase the quality of life of these patients.
The next presentation was from Dr Medow, New York Medical College, on the benefits of oral rehydration on orthostatic intolerance in children with POTS. Reduction in total blood volume is common in acute and chronic orthostatic intolerance (OI). Previous work had shown the isosmotic saline reduces OI; however, conventional oral hydration fails to provide the same benefit. In their study, they tested whether equal amounts of oral rehydration solution (ORS) or IV saline provided similar improvements in OI in POTS patients with OI. This was evaluated using the lower body negative pressure (LBNP) test. The LBNP was repeated on three separate days before which randomly: 1) either no fluids were administered; 2) subjects were asked to drink 1 litre of ORS over 30 minutes; or 3) subjects had 1 litre of IV normal saline administered over 30 minutes. The team then waited an hour and carried out the test. They tested 10 patients with a history of POTS and chronic, daily occurances of OI. They found that the patients had significantly reduced tolerance to LBNP compared with the controls – the test was able to be completed at 45mm Hg pressure, but the patients could not tolerate the 60mm Hg pressure during the test. In POTS, following oral rehydration solution but not saline infusion, cerebral blood flow velocity was significantly higher than with no treatment. Although fluid loading did not confer any advantage in controls, subjects with POTS experienced a significant improvement in orthostatic tolerance following both saline infusion and oral rehydration solution.
Finally, Dr Mckay gave a presentation with an appeal for the research community to carry out a randomised controlled trial of low dose naldextrone (LDN) on ME/CFS. Dr Mckay works in the Complex Chronic Diseases Program at the University of British Columbia in Canada, where she has prescribed LDN for some of her ME/CFS patients. Dr Mckay explained that in Canada they can prescribe off label drugs but patients need to be monitored for side effects. For the 97 cases of ME/CFS, fibromyalgia and chronic Lyme Disease in their clinic, LDN was used in more than a third. In the end, they found 12% had increased energy and 10% had decreased pain and improved sleep.
Overall, the scientific literature on naldextrone and ME/CFS is sparse, with only one paper quoted in the presentation which showed a response rate of 73.9% in 218 ME/CFS patients. The previous study saw improved vigilence, less fever, pain relief and improvement in more than one symptom – however, it included side effects such as insomnia, nausea, dizziness and gastrointestinal issues. The results from Dr Mckay’s clinic do not appear to show a statistically significant improvement in the majority of patients, or specifically to the ME/CFS patients, and there are still questions as to how LDN works, with one of the main theories being that it modulates the immune system. More work is clearly needed to see if this will be a suitable treatment option in the future.
Session 4: Research and Clinical Networks
The fourth session was on research and clinical networks, offering advice and new tools for researchers/clinicians working in ME/CFS research. The first presentation was by Ms Caroline Kingdon from the London School of Hygiene and Tropical Medicine, covering her latest paper she published on guidance for visiting severely affected ME/CFS patients at home. Ms Kingdon is a research nurse; a research fellow; and is responsible for sample distribution from the UK ME/CFS Biobank. During her time at the UK ME/CFS Biobank, she has met with over 80 people with severe ME/CFS, in some cases visiting them up to 5 times at home as part of sample collection/projects. She explained that people with ME/CFS have been found to be more functionally impaired than people with MS or cancer and as result, the 6Cs for compassion in practice must be used – namely compassion, care, competence, communication, courage and commitment. As there is a real need to involve severely affected patients in ME/CFS research, this served as a useful and touching guide for the wider ME/CFs and research community.
Dr Schu from RTI International presented a paper on a new tool developed from MECFSnet called mapMECFS. This is a result of a collaboration with several clinical research centres, including Cornell University, ICanCME, Solve ME/CFS Initiative and with #MEAction, with an aim to develop a tool for easy access for researchers to large datasets from various studies.
For many large studies in metabolomics, proteomics or genomics, typicaly they have results for thousands of factors – however, there is limited discoverability beyond reading the top results in papers. This is because manuscripts are only able to discuss a subset of the data (for example, changes in 300 genes out of 39,000). Full data is deposited in data type-specific repositories (not ME/CFS focused – this is standard across research in general). It is also challenging to compare results across different studies due to differences in the experimental designs (e.g. number of patients, definitions, methodology used). As a result, the team developed the mapMECFS tool, a database for these large datasets specifically for ME/CFS with smart search capabilities, allowing researchers to look for genes/proteins/metabolites of interest across studies quickly and easily. They have now added 30 datasets since January and are planning an expanded launch to the research community soon. Once this is fully established, this could be incredibly useful for driving research forward and could prove to be an invaluable tool for researchers.
The final presentation in this session was from Dr Lacerda of the London School of Hygiene and Tropical Medicine with updates from the UK ME/CFS Biobank. To date, they have 601 consenting participants: 249 mild/moderately affected patients; 57 severely affected; 90 with multiple sclerosis and 153 with no disease (controls). She detailed the process for sample collection, along with questionnaire-based assessments. They have found statistical differences between healthy controls, MS, ME/CFS (mild/moderate) and severe ME/CFS cohorts in different symptoms, including hand-grip strength, upon which they recently published a paper. This is a simple test they have standardised and they suggest that hand grip strength could be used as a clinical biomarker for ME/CFS and disease severity. She also detailed an unexpected finding of reduction in creatine phosphokinase (CPK) in severe ME/CFS, which merits further investigation.
Session 5: Immunology/Metabolism
The final two presentations covered immunology and metabolism once more, with talks from Mr Whelan of the Simmaron Research Institute and Dr Missailidis of La Trobe University.
Mr Whelan discussed autoantibodies (antibodies directed against our own cells) in ME/CFS. These have been implicated in numerous scientific papers in recent years. They wanted to determine if specific autoantibodies were detected in their patient population. They collected serum from 61 ME/CFS patients and quantified the presence of autoantibodies in the serum. They found that 52% of patients tested positive for at least one autoantibodies, with 47% positive for the Chol-4 autoantibody. He suggested that the evidence supports the theory that these autoantibodies may bind to receptor sites, blocking ligands from reaching these receptors. Disturbance of adrenergic receptors and cholinergic receptor by autoantibodies may lead to these symptoms seen in ME/CFS.
He also detailed another autoimmune disorder which has been suggested to play a role in ME/CFS – small fibre neuropathy (SFN). SFN shares many symptoms with ME/CFS, such as pain, sensory loss, autonomic dysfunction, post-exertional malaise and gastrointestinal complaints.
SFN is characterised by widespread damage to the small-diameter somatic and autonomic unmyelinited C-fibers and/or thinly myelinated A-delta nerve fibres. It is very undiagnosed. Diagnosis is currently carried out by a skin biopsy (88 – 90% diagnostic value). The team wanted to determine if their ME/CFS patients had SFN. When they carried out the diagnostic test, they found that 33% of their ME/CFS patients met the criteria for SFN. From of this group, 93% of them had POTS or orthostatic intolerance. Of the group which was positive for the Chol-4 autoantibody, 70% qualified for a diagnosis of SFN.
Clearly, there is work to be done in this area, but this could open up the possibilities of new treatments for a subset of ME/CFS patients. One of the team’s future aims is to assess symptoms and autoantibody levels following an intravenous immunoglobulin (IVIg) treatment in more patients. It will be interesting to see how this work progresses.
Finally, Dr Missailidis covered his PhD work from La Trobe University, where he had studied mitrochondrial function and energy utilisation in ME/CFS lymphoblasts (immature white blood cells) by studying protein and gene expression changes. There are two major pathways that regulate energy supply – APMK and OXPHOS. During his PhD studies, he found several differences in the metabolic pathways for energy production in lymphoblasts. He found that ME/CFS lymphoblasts exhibit inefficient ATP synthesis by complex v (part of respiration), a chronic activation of TORC1 (an important regulator) and increased levels of enzymes involved in using fatty acids and amino acids of fuels.
Overall, the conference had some very interesting presentations and it was encouraging to see new researchers presenting in the field. One can but hope that the IACFS/ME conference will be able to go ahead in person next year, but the committee did an excellent job of adapting in the current circumstances, with worldwide participation and the ability for those housebound to attend for the first time. ME Research UK looks forward to seeing how these projects will progress in the future.