Over 100 million people globally are suffering from Long Covid. A new paper soon to be published in the Lancet estimates that following an acute Covid-19 infection the risk of developing Long Covid is 15% per individual per infection. No formal training exists for health professionals to assist patents with Long Covid, leaving millions of people to cope on their own with an illness which in many ways resembles ME. This ‘escalating global health crisis’ presents a huge challenge to health systems across the world.
There appears to be a growing number of scientists whose research into Long Covid also overlaps with their research into ME. We can hope that insights gained from research into Long Covid will benefit people with ME and vice versa. A good example of a scientist conducting research into both illnesses is Professor Resia Pretorious.
Professor Resia Pretorious is a Distinguished Research Professor in the Physiological Sciences Department, Faculty of Science, Stellenbosch University, South Africa and is an honorary professor at the University of Liverpool. Her scientific work is focused on research into microclots in a range of chronic, inflammatory diseases including Long Covid and ME. She is collaborating with researchers from Harvard, Yale, Mount Sinai and MIT, as well as scientists and clinicians in the UK, France, Germany, Italy, Australia on the issue of Long Covid and has had many papers published examining different aspects of Long Covid. Professor Pretorious is a member of the WHO’s Long Covid Expert Advisory Group.
Professor Pretorious took time out from her busy schedule to talk to us about her research into ME.
In June of 2024 you and a group of colleagues had a paper published in the journal Frontiers In Immunology titled: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Most academic papers often have quite dry dull titles yet the title of your paper can be said to be rather thought provoking. Some in the more conservative circles of the medical establishment might say it is a controversial title. What was the thinking behind the title of your paper?
RP: All credit must be given to my fantastic PhD student, Hayley Arron, who is the first author of the paper you refer to. The title was chosen deliberately to emphasize the historical neglect of ME/CFS in biomedical research and clinical practice. Despite its prevalence and debilitating nature, the disease has long been misunderstood, dismissed, or under-researched. The aim was to provoke thought and draw attention to the need for systemic change in how the scientific and medical communities approach ME/CFS. While the title may be seen as controversial in conservative circles, it reflects the urgency of addressing the unmet needs of patients.
In your paper you provide a comprehensive overview of the different factors which may be causing the many symptoms of ME. These range from neuroinflammation to gut dysbiosis. One area you touch is that of micro-clotting. I find this very interesting as some scientists during the Covid pandemic asserted that micro-clots were causing some of the problems facing people who caught the Sar-Cov2 virus. Some doctors used the anticoagulant (Heparin) to limit the microvascular and macrovascular clotting, and supplemental oxygen to help overcome the hypoxia (insufficient oxygen in body tissues). In your research you have discovered how circulating inflammatory molecules in systemic inflammatory diseases lead to blood clotting which can cause cell death in red blood cells. You have further observed that interactions between circulating inflammatory molecules and fibrinogen (a protein which helps with blood clotting) can lead to both hypercoagulation (a condition in which blood clots too easily) and hypofibrinolysis (a breakdown of blood clots). Can you explain in layman’s terms how blood micro-clots might be causing some of the symptoms of ME?
RP: Fibrin(ogen) amyloid microclots are tiny clumps of plasma proteins that contain fibrin(ogen) (the main clotting protein in circulation), and various inflammatory molecules entrapped in them. These microclots form abnormally in the bloodstream in the presence of circulating inflammagens originating from viruses, bacteria, their particles and other inflammatory molecules originating from the disease pathways. In ME/CFS, these microclots are also present, albeit not as large in numbers as in Long COVID. They might also impact on the smallest blood vessels, called capillaries, reducing blood flow and oxygen delivery to tissues. This can contribute to symptoms like fatigue, brain fog, and muscle pain. The underlying problem may involve inflammatory molecules interacting with fibrinogen (a clotting protein), leading to excessive clotting and reduced clot breakdown, compounding circulation issues.
What further research is needed in this area?
RP: Future research should focus on:
RP: The paper highlights the importance of:
RP: Combatting stigma requires widespread education of healthcare professionals to ensure ME/CFS is recognized as a legitimate and serious medical condition. Increased support can come from:
We have been conducting various analyses on ME/CFS, including micro clot imaging using flow cytometry, microscopy, and proteomics, and also in collaboration with international teams. We anticipate publishing several data papers in 2025.
The Kanro Research Foundation has also provided a three-year postdoctoral grant for Massimo Nunes, who recently completed his PhD. Massimo and has published extensively on ME/CFS and I am extremely happy to have him in our lab for another three years. Our work will include comparative analyses between Long COVID and ME/CFS, supported by several data and material sharing agreements with collaborators. If any researchers reading this have well-characterized stored samples of ME/CFS and control groups, we encourage you to reach out to us. We would greatly appreciate the opportunity to receive additional well-characterized samples to further research.
There appears to be a growing number of scientists whose research into Long Covid also overlaps with their research into ME. We can hope that insights gained from research into Long Covid will benefit people with ME and vice versa. A good example of a scientist conducting research into both illnesses is Professor Resia Pretorious.
Professor Resia Pretorious is a Distinguished Research Professor in the Physiological Sciences Department, Faculty of Science, Stellenbosch University, South Africa and is an honorary professor at the University of Liverpool. Her scientific work is focused on research into microclots in a range of chronic, inflammatory diseases including Long Covid and ME. She is collaborating with researchers from Harvard, Yale, Mount Sinai and MIT, as well as scientists and clinicians in the UK, France, Germany, Italy, Australia on the issue of Long Covid and has had many papers published examining different aspects of Long Covid. Professor Pretorious is a member of the WHO’s Long Covid Expert Advisory Group.
Professor Pretorious took time out from her busy schedule to talk to us about her research into ME.
- How did you get involved in the field of ME research?
RP: My entry into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) research stemmed from my broader interest in understanding systemic inflammation and its role in chronic diseases, followed by our work on acute COVID-19 and Long COVID. The research was done by me and my long-standing collaborator Doug Kell from University of Liverpool. Our earlier work, focusing on the interplay between circulating inflammatory molecules and pathological blood clotting, revealed mechanisms that overlapped significantly with the symptoms of ME/CFS. The multifaceted nature of the disease, its significant global burden, the lack of effective diagnostics or treatments, and the spread of misconceptions, propagated by a small but influential group, motivates me to contribute to unravelling its biology.
In June of 2024 you and a group of colleagues had a paper published in the journal Frontiers In Immunology titled: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Most academic papers often have quite dry dull titles yet the title of your paper can be said to be rather thought provoking. Some in the more conservative circles of the medical establishment might say it is a controversial title. What was the thinking behind the title of your paper?
RP: All credit must be given to my fantastic PhD student, Hayley Arron, who is the first author of the paper you refer to. The title was chosen deliberately to emphasize the historical neglect of ME/CFS in biomedical research and clinical practice. Despite its prevalence and debilitating nature, the disease has long been misunderstood, dismissed, or under-researched. The aim was to provoke thought and draw attention to the need for systemic change in how the scientific and medical communities approach ME/CFS. While the title may be seen as controversial in conservative circles, it reflects the urgency of addressing the unmet needs of patients.
In your paper you provide a comprehensive overview of the different factors which may be causing the many symptoms of ME. These range from neuroinflammation to gut dysbiosis. One area you touch is that of micro-clotting. I find this very interesting as some scientists during the Covid pandemic asserted that micro-clots were causing some of the problems facing people who caught the Sar-Cov2 virus. Some doctors used the anticoagulant (Heparin) to limit the microvascular and macrovascular clotting, and supplemental oxygen to help overcome the hypoxia (insufficient oxygen in body tissues). In your research you have discovered how circulating inflammatory molecules in systemic inflammatory diseases lead to blood clotting which can cause cell death in red blood cells. You have further observed that interactions between circulating inflammatory molecules and fibrinogen (a protein which helps with blood clotting) can lead to both hypercoagulation (a condition in which blood clots too easily) and hypofibrinolysis (a breakdown of blood clots). Can you explain in layman’s terms how blood micro-clots might be causing some of the symptoms of ME?
RP: Fibrin(ogen) amyloid microclots are tiny clumps of plasma proteins that contain fibrin(ogen) (the main clotting protein in circulation), and various inflammatory molecules entrapped in them. These microclots form abnormally in the bloodstream in the presence of circulating inflammagens originating from viruses, bacteria, their particles and other inflammatory molecules originating from the disease pathways. In ME/CFS, these microclots are also present, albeit not as large in numbers as in Long COVID. They might also impact on the smallest blood vessels, called capillaries, reducing blood flow and oxygen delivery to tissues. This can contribute to symptoms like fatigue, brain fog, and muscle pain. The underlying problem may involve inflammatory molecules interacting with fibrinogen (a clotting protein), leading to excessive clotting and reduced clot breakdown, compounding circulation issues.
What further research is needed in this area?
RP: Future research should focus on:
- Developing advanced diagnostic tools to detect microclots and related abnormalities. We have started to do so, using florescence microscopy, imaging flow cytometry and conventional flow cytometry.
- Understanding how microclots interact with immune and vascular systems in ME/CFS, and which biochemical pathways specifically in ME/CFS drive the formation of these microclots.
- Identifying effective treatments to prevent or dissolve microclots.
- Exploring links between viral triggers, gut dysbiosis, and clotting patholog
- One of the main problems people with ME is the lack of any kind of treatments for their illness. In your paper you talk about potential therapies that could be beneficial in the treatment of ME and break them down into five categories: lowering inflammatory responses, targeting mitochondrial dysfunction, promoting the immune system, reducing autoimmune responses and lowering oxidative stress. In your opinion which of these potential therapies seem most promising? What action needs to be taken by public health authorities to speed up the discovery of potential therapies?
- Increase funding for large-scale, multi-centre clinical trials.
- Support the development of diagnostic tools to better stratify ME/CFS subgroups to determine various pathological phenotypes within the broader ME/CFS population. We need targeted treatments for phenotypes within ME/CFS, as one treatment definitely will not be the answer, as we have seen over the years.
- Foster collaborations between researchers, clinicians, and patient groups to accelerate translational research.
RP: The paper highlights the importance of:
- Using consistent diagnostic criteria and biomarkers to define ME/CFS subgroups.
- Conducting larger, well-controlled studies to address variability and dropout rates.
- Including diverse populations to ensure findings are broadly applicable.
- Integrating interdisciplinary approaches to capture the multifactorial nature of the disease.
RP: Combatting stigma requires widespread education of healthcare professionals to ensure ME/CFS is recognized as a legitimate and serious medical condition. Increased support can come from:
- Establishing dedicated ME/CFS clinics.
- Providing financial and care giving assistance to patients and families.
- Encouraging patient advocacy groups to collaborate with researchers and policymakers.
- We urgently need an action plan to counter years of misinformation that has perpetuated the misconception of this condition as primarily psychosocial, leading to the promotion of graded exercise therapy (GET) and psychological interventions. These approaches have been championed by a small group of influential individuals who appear to have their own agenda.
We have been conducting various analyses on ME/CFS, including micro clot imaging using flow cytometry, microscopy, and proteomics, and also in collaboration with international teams. We anticipate publishing several data papers in 2025.
The Kanro Research Foundation has also provided a three-year postdoctoral grant for Massimo Nunes, who recently completed his PhD. Massimo and has published extensively on ME/CFS and I am extremely happy to have him in our lab for another three years. Our work will include comparative analyses between Long COVID and ME/CFS, supported by several data and material sharing agreements with collaborators. If any researchers reading this have well-characterized stored samples of ME/CFS and control groups, we encourage you to reach out to us. We would greatly appreciate the opportunity to receive additional well-characterized samples to further research.