Key points:
- ME Research UK attended, virtually, the “1st International Conference on Clinical and Scientific Advances in ME/CFS and Long COVID” which took place in April 2024.
- In a brief overview of the meeting, 5 key themes which emerged from the speakers talks were identified:
- History of ME/CFS.
- Challenges determining prevalence.
- Biological abnormalities.
- Disease heterogeneity.
- Need for comprehensive clinical assessment.
- The following article discusses three of these themes in more detail.
In summary:
- Disease heterogeneity – how a disease can differ from person to person complicates research into ME/CFS – and into long COVID, and means that analysis of distinct subgroups of the disease – such as those with differing severity of disease, may need to be analysed separately.
- Estimating the proportion of people (prevalence) with ME/CFS in the population is complex, and although estimates exist they are limited by a number of different factors including method of ME/CFS diagnosis, and the specific ME/CFS criteria used.
- Biological abnormalities discussed at the conference related to the pulmonary and cardiovascular systems in people with ME/CFS, and those with long COVID including peripheral limitation, pre-load failure, small fibre neuropathy, and mitochondrial dysfunction.
- Disease heterogeneity in both ME/CFS, and in long COVID, poses a major challenge for researchers – one that must be delt with in the planning, execution, and write up of research studies.
- More research is needed to estimate the prevalence of ME/CFS, especially in populations with reduced access to health and social care (underserved communities), and in different ethnic groups.
Conference Discussion
On the 3rd and 4th April this year, ME Research UK attended, virtually, the “1st International Conference on Clinical and Scientific Advances in ME/CFS and Long COVID” held in Portugal.
In a brief overview of the conference, ME Research UK identify 5 key themes which emerged – this article will discuss three of these themes in more detail:
- Disease heterogeneity – how a disease can differ from person to person.
- Challenges in determining prevalence – the proportion of a population with a disease, or characteristic.
- Biological abnormalities.
Part 2 of this article series is to follow, and will discuss the remaining two themes; history of ME/CFS, and the need for comprehensive clinical assessment in detail, it will also consider further information on biological abnormalities presented at the conference.
Disease heterogeneity
In his talk, Dr. Nuno Sepúlveda discussed disease heterogeneity in ME/CFS relating to the following five factors:
- Disease symptoms: Symptoms of ME/CFS can differ between individuals with the disease.
- Disease triggers: Although the exact cause(s) of ME/CFS remains unclear, research suggests that ME/CFS can develop following an infection by a pathogen – most commonly a virus, but also by bacterial, and fungal infections. Additionally, problems with the immune system, hormonal imbalance, and genetics are all noted by the NHS as potential triggers of the disease.
- Co-morbidities: Conditions or diseases that someone is diagnosed with in addition to ME/CFS can also vary – for example, the International Consensus Criteria (ICC) for ME (2011) list fibromyalgia, myofascial pain syndrome, temporomandibular joint syndrome, and irritable bowel syndrome as conditions which can be present alongside ME.
- Disease stage: Both how long someone has ME/CFS, and the severity of the disease can vary.
- Pathophysiology: While research has suggested that there are commonalities in the processes in the body associated with the ME/CFS (pathophysiology) between people with the disease, it has also identified some differences. For example, each of the following are only observed in some – rather than all – people with ME/CFS: Immunodeficiencies, Joint hypermobility, and Differences in metabolic phenotype – a profile of the products of energy metabolism which reflects interactions among a variety of factors-dietary, other lifestyle/environmental, gut microbial and genetic.
Importantly, research suggests that heterogeneity can also be observed between people with long COVID for each of the five factors listed above. For example; although less heterogeneous than reported triggers for ME/CFS, long COVID can develop following COVID-19 infection or following a COVID-19 vaccination. In addition, research has identified that the symptoms of long covid – and the methods used to assess them in research, are “extremely heterogeneous”. There may also be differences in pathophysiology of the disease – one study found that only some people with long COVID have evidence of human endogenous retrovirus protein in their blood.
How does disease heterogeneity complicate research?
Where a disease of interest has high heterogeneity – as seen in particularly in ME/CFS, but also in long COVID – reproducibility of research findings is more challenging.
Reproducibility refers to the ability of independent researchers to arrive at the same results using their own data and methods – regrettably, low reproducibility is an issue seen across many areas of research, not just that investigating ME/CFS and/or long COVID.
Low reproducibility can occur due to a number of different factors, but is often seen where cases of a disease are not well defined, or are not comparable with each other due to high heterogeneity between participants.
In his talk, Dr Sepúlveda discussed how the lack of reproducibility in ME/CFS studies slows down research progress, and can also lead to disbelief in the research, scientists, and patients with the disease being researched – as is the case with ME/CFS. Nuno commented that another implication of this is decreased research funding which in turn means fewer researchers are drawn to the field of ME/CFS research. Dr Sepúlveda recommended that subgroup analysis – what he called “sub-typing”, should be used to deal with heterogeneous populations for example, grouping by different symptoms, different disease triggers, different stages of disease, and “other factors”. For Nuno, lack of reproducibility is the biggest challenge in ME/CFS research.
We need to be able to compare apples with apples – not apples with pears
Dr Nuno Sepúlveda
Challenges determining prevalence of ME/CFS
Amongst the topics highlighted at the conference was the lack of knowledge about ME/CFS prevalence – the proportion of the population with the disease.
According to Dr. Susane Levine, there is little research available relating to prevalence of ME/CFS in the general population, and even less in populations who are harder to reach, or for those with reduced access to health and social care (underserved communities), and in different ethnic groups.
Obtaining an accurate prevalence estimate for ME/CFS is complicated by both the heterogeneity of ME/CFS, and by the mislabelling of the disease as psychological – not only do these factors lead to mis-diagnosis, but they also increased the stigma associated with ME/CFS which may mean that some people – particularly men, are less likely to seek medical care and, consequently, receive a diagnosis.
While some estimates for the prevalence of ME/CFS do exist, they are limited by a number of different factors including:
- The methods used to collect information on diagnosis of ME/CFS: Some studies use self-reported ME/CFS diagnoses, others use medical records to obtain information about a diagnosis, and others assess participants against ME/CFS diagnostic criteria.
- Differing ME/CFS diagnostic criteria: There are several different criteria which can be used to diagnose ME/CFS – some including the Fukuda criteria which have been developed for research purposes only, some such as the International Consensus Criteria (ICC), the Canadian Consensus Criteria (CCC), and Revised CCC which are for both research and clinical purposes, and others – such as the 2021 NICE guidelines, guide diagnosis in clinical practice. Notably, the different criteria require varying symptoms to be present for a diagnosis of the disease to be made.
- For example, the Fukuda (for CFS) criteria do not require post exertional malaise – often referred to as the main symptom of ME/CFS, for a diagnosis to be made, while the CCC and ICC (for ME/CFS, and ME, respectively), both do – of note is a study, funded by ME Research UK, which identified that differences in communication between different areas of the brain could distinguish between people diagnosed with CFS using the Fukuda criteria, and those diagnosed with ME under the ICC.
- Location: Due to differences in population structure – such as the number of people in certain age, or ethnic groups, prevalence estimates for one country may not be applicable to another.
An additional complication in estimating the prevalence of ME/CFS is the emergence of long COVID. Whilst it is clear that many of the symptoms of long COVID overlap with ME/CFS, not everyone with a diagnosis of long COVID meets ME/CFS criteria – and not all symptoms of long COVID are experienced by those with ME/CFS. For example Dr Levine described that the “cardiac involvement in long COVID is not seen in ME/CFS”.
Biological abnormalities in people with ME/CFS, and those with long COVID – peripheral limitation, pre-load failure, and small fibre neuropathy.
A number of the talks at the conference were from Dr David Systrom, and his research team. These talks, although slightly different in content, all related to the biological abnormalities that have been observed in people with ME/CFS – and those with long COVID, during invasive cardiopulmonary exercise tests.
Highlighted by Dr Systrom was a paper which reviews research relating to the mechanisms underlying exercise intolerance in people with ME/CFS, and those with long COVID. In the paper the following biological abnormalities related to the pulmonary and cardiovascular systems in people with ME/CFS were described – these biological abnormalities have also been observed in people with long COVID:
- Peripheral limitation – characterised by “Impaired systemic oxygen extraction” or decreased ability of exercising muscles to extract and utilise oxygen from the blood.
- Pre-load failure – low filling pressure in both chambers of the heart (also known as low biventricular filling pressure).
- Small fibre neuropathy in muscle biopsies – damage to small nerve fibres in samples of muscle tissue.
- Mitochondrial dysfunction – or “mitochondrial myopathy” where the energy powerhouses in cells – mitochondria, are not functioning as they should.
In this research paper, it is stated that:
Invasive cardiopulmonary exercise test (iCPET) data suggest that similar exercise pathophysiology underlies both PASC (post-acute sequelae of SARS CoV-2 infection – another name given to long COVID) and ME/CFS and argue against deconditioning as the sole explanation for exertional intolerance
Dr Systrom
This is something that Dr Systrom also highlighted at the Invest in ME Research Conference which took place in June 2023.
Interestingly, Dr Systrom also noted that his research team had observed hyperventilation – rapid breathing (“over breathing”) which leads to an imbalance between inhaling oxygen and exhaling carbon dioxide – particularly in those with long COVID. Although it is unclear exactly why hyperventilation occurs, Dr Systrom proposed it may be related to damage to the small nerve fibres in the receptors which help to control our breathing.
Summary
Research presented at the conference provided clear evidence of biological abnormalities in both people with ME/CFS, and those with long COVID. It was also evident from the talks that disease heterogeneity in both ME/CFS, and in long COVID, poses a major challenge for researchers – one that must be dealt with in the planning, execution, and write up of research studies. Not only is sub-group analysis essential in taking into account disease heterogeneity – alongside the appropriate statistical methods and transparent reporting, but the use of clear and consistent definition(s) for ME/CFS, and for long COVID, is imperative to increase the reproducibility of research. In addition, more research is needed to estimate the prevalence of ME/CFS following COVID-19, especially in underserved communities, and in different ethnic groups.
Read Part 2 of ME Research UK’s Lisbon Conference coverage.
Watch individual presentations.
