The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).
RESEARCH INDEX
The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.
Audio Commentary by Dr Katrina Pears
ME/CFS Research Published 14 – 20 March 2023
It’s been another busy week for research with eight new ME/CFS studies but nineteen new Long Covid studies.
A number of studies this week (and last) are published in a special edition of the journal WORK, which features studies on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID. This includes research on symptoms of post-exertional malaise (PEM), (Paper two (2)) and experiences using heart rate monitors to manage PEM (Paper four (4)). You can read the introduction to this special edition here.
We have highlighted one of the ME/CFS studies in more detail below:
Paper one (1) is a preprint study (meaning it has not been peer-reviewed and the science verified) and is on developing a blood test for diagnosis of ME/CFS. This research is being funded by the ME Association's Ramsay Research Fund (RRF) and has been using blood samples from the ME Biobank for which the ME Association also provides funding for its running costs.
This study used a total of 98 subjects, which included 61 with ME/CFS, 21 with MS (multiple sclerosis) and 16 healthy controls. The ME/CFS cohort was further divided into Severe (n = 21), Moderate (n = 15) and Mild (n = 25). The study used peripheral blood mononuclear cells (PBMCs).
The principal method of this study was the fairly new application of the technique Raman spectroscopy. This technique involves cell imaging, where a light (usually from a laser) shining on a cell results in changed frequencies of photons – due to the energy exchange between the incident light and vibrations of biomolecules in cells – which are then detected and observed in the form of a Raman spectrum, named after Indian Physicist Sir C. V. Raman who earned the 1930 Nobel Prize for the discovery.
Each biomolecule has a unique ‘fingerprint’ on the Raman spectrum (shown as different length bands) and the sum of all biomolecular fingerprints in a cell can be used as a phenotype of the single cell. These fingerprints can be used to indicate changes in cellular metabolism and identify disease related biomarkers.
This non-invasive biochemical analysis technique has an advantage over other biomarker-identifying methods as it can be performed on living cells. Also, compared to other techniques no radio-active labelling is needed so the cells remain close to their natural state, reflecting the intrinsic biochemical profiles of the cells with less manipulation. The initial pilot study which was conducted by this research group back in 2018, can be found in a previous MEA research review.
Results from this study included:
- Healthy individuals, disease controls, and ME/CFS patients to be distinguished between with high accuracy (91%).
- The two disease cohorts differed from each other (with different spectra produced) and the cells in the ME/CFS cohorts differed more than those in the MS cohort in terms of their metabolic profiles, probably because of a higher number of subjects involved and the broad range of symptom severities from mild, moderate and severe.
- Results allowed differentiation between mild, moderate, and severe ME/CFS patients with 84% accuracy.
- Important biomarkers which allowed the differentiation between cohorts was through the quantification of aromatic amino acids (AAAs), namely tryptophan, tyrosine, and phenylalanine. The levels of these three AAAs differed between the cohorts, e.g. intracellular phenylalanine suggested metabolic subtypes exist in the ME/CFS patients, with the moderate and severe groups having significantly reduced phenylalanine and the mild ME and MS having increased levels relative to controls.
- Altered lipid metabolism was also found, with elevated glycerol levels compared to the controls, suggesting different lipidic profiles in the cohorts.
- Energy fuelling biomarkers were also different between cohorts, glycogen levels were significantly reduced in the mild and severe ME (and MS). Glucose quantification showed a decrease in all ME subgroups and the MS cohort had the lowest glucose accumulation.
Results from this study are exciting, as there is a desperate need to develop a diagnostic test. Results are reassuring as the majority of metabolic changes which were found in this study relating to energy strain and lipid metabolism are in agreement with previous research. Furthermore, these results showed clear cellular differences with different ME/CFS severities and allowed different phenotypes to be observed, which could in turn lead to the development of targeted therapies.
The study has a number of strengths as it uses the well-defined ME/CFS cohort from the ME UK Biobank. The research team have a vast amount of experience and knowledge of ME/CFS, with Karl Morten being funded by the MEA.
Unfortunately, there are a few problems with this research currently as this technique is not widely clinically accepted, therefore, the researchers are desperately trying to get others involved to verify results and validate the findings. This needs other research groups to carry out the same research on samples from the ME UK Biobank and also on separate ME/CFS samples, there is hope that this preprint paper will help to bring other researchers together. Additionally, bigger sample numbers are needed.
Furthermore, this research tried but could not replicate the findings that were previously found by Tomas et al. 2017, which showed the inability of ME/CFS patients to fulfil cellular energy demands. This new research found no difference in mitochondrial respiration between groups.
There are a few explanations as to why this was found, firstly this technique is very difficult anyway needing viable cells with intact mitochondria and very low levels being measured anyway (hard to distinguish from the background).
Secondly, this could be due to the samples being frozen, cells and mitochondria are all affected by the time taken to process the blood, time to freeze, time in the freezer, and temperature of the freezer. Therefore, the effect of these variables all have an impact on what is being measured. Unfortunately, this does make it hard to develop diagnostic tests when measurements are so delicate (fresh samples are more reliable but processing and collection of samples would add extra complications).
Fortunately, as shown in this study, the Raman approach measures many other variables (with mitochondria respiration being just one) and this technique so far is proving robust to the variables of freezing. Although further work is needed to compare fresh verus frozen samples using this technique.
ME/CFS Research References and Abstracts
Jiabao Xu, Tiffany Lodge, Caroline Claire Kingdon, James W L Strong, John Maclennan,Eliana Lacerda, Slawomir Kujawski, Pawel Zalewski, Wei Huang, Karl J. Morten.
medRxiv [Preprint]
Abstract
A blood-based diagnostic test for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS) would be of great value in both conditions, facilitating more accurate and earlier diagnosis, helping with current treatment delivery, and supporting the development of new therapeutics.
Here we use Raman micro-spectroscopy to examine differences between the spectral profiles of blood cells of ME/CFS, MS and healthy controls.
We were able to discriminate the three groups using ensemble classification models with high levels of accuracy (91%) with the additional ability to distinguish mild, moderate, and severe ME/CFS patients from each other (84%).
To our knowledge, this is the first research using Raman micro-spectroscopy to discriminate specific subgroups of ME/CFS patients on the basis of their symptom severity. Specific Raman peaks linked with the different disease types with the potential in further investigations to provide insights into biological changes associated with the different conditions.
Davenport, Todd E; Chu, Lily; Stevens, Staci R; Stevens, Jared; Snell, Christopher R; Van Ness, J. Mark.
Work. 1 Jan. 2023 : 1 – 15.
Abstract
Background: Post-exertional malaise (PEM) is the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) yet its diverse manifestations make it difficult to recognize. Brief instruments for detecting PEM are critical for clinical and scientific progress.
Objective: To develop a clinical prediction rule for PEM.
Method: 49 ME/CFS and 10 healthy, sedentary subjects recruited from the community completed two maximal cardiopulmonary exercise tests (CPETs) separated by 24 hours.
At five different times, subjects reported symptoms which were then classified into 19 categories. The frequency of symptom reports between groups at each time point was compared using Fisher’s exact test.
Receiver operating characteristics (ROC) analysis with area under the curve calculation was used to determine the number of different types of symptom reports that were sufficient to differentiate between ME/CFS and sedentary groups. The optimal number of symptoms was determined where sensitivity and specificity of the types of symptom reports were balanced.
Results: At all timepoints, a maximum of two symptoms was optimal to determine differences between groups. Only one symptom was necessary to optimally differentiate between groups at one week following the second CPET. Fatigue, cognitive dysfunction, lack of positive feelings/mood and decrease in function were consistent predictors of ME/CFS group membership across timepoints.
Conclusion: Inquiring about post-exertional cognitive dysfunction, decline in function, and lack of positive feelings/mood may help identify PEM quickly and accurately. These findings should be validated with a larger sample of patients.
3. Development and measurement properties of the PEM/PESE activity questionnaire (PAQ)
Davenport, Todd E; Stevens, Staci R; Stevens, Jared; Snell, Christopher R; Van Ness, J. Mark.
Work, 1-11, 2023.
Abstract
Background: Existing instruments often are inappropriate to measure the effects of post-exertional malaise (PEM) and post-exertional symptom exacerbation (PESE) on activities of daily living (ADLs). A validated questionnaire to measure self-reported ability with ADLs would advance research and clinical practice in conditions like myalgic encephalomyelitis and Long Covid.
Objective: Determine the measurement properties of the PEM/PESE Activity Questionnaire (PAQ).
Methods: The PAQ is adapted from the Patient Specific Functional Scale. Respondents rated three self-selected ADLs on two 0-100 scales, including current performance compared to (1) a ‘good day’ and (2) before illness. Respondents provided a Burden of Functioning rating on a 0-100 scale, anchored at 0 being the activity took “No time, effort, and resources at all” and 10 being “All of my time, effort, and resources.” Respondents took the PAQ twice, completing a demographic questionnaire after the first PAQ and before the second PAQ.
Descriptive statistics and intraclass correlation coefficients were calculated for each scale to assess test-retest reliability. Minimum detectable change outside the 95% confidence interval (MDC95) was calculated. Ceiling and floor effects were determined when the MDC95 for average and function scores crossed 0 and 100, respectively.
Results: n = 981 responses were recorded, including n = 675 complete surveys. Test-retest reliability was generally fair to excellent, depending on function and scale. MDC95 values generally indicated scale responsiveness. Ceiling and floor effects were noted infrequently for specific functions.
Conclusion: The PAQ is valid, reliable, and sensitive. Additional research may explore measurement properties involving functions that were infrequently selected in this sample.
Clague-Baker, Nicola; Davenport, Todd E; Madi, Mohammad; Dickinson, Kathryne; Leslie, Karen; Bull, Michelle; Hilliard, Natalie.
Work, pp. 1-10, 2023.
Abstract
Background: Myalgic encephalomyelitis (ME) is a complex, multi-system neurological condition. The defining feature of ME is post-exertional malaise (PEM) with over 30 symptoms triggered by physical, cognitive, emotional and social activity.
The cause of PEM is unclear but one area of research using cardio-pulmonary exercise tests show a reduced ventilatory anaerobic threshold (VAT) with repeated tests leading to PEM.
Pacing with heart rate monitoring (HRM) provides feedback to maintain activity intensity below the VAT. There is only one piece of research investigating the use of HRM although a number of guidelines recommend it.
Objective: To identify the experiences and attitudes of people with ME towards HRM.
Methods: A 40 question online survey was devised and released on ME websites, Twitter and Facebook pages. People with ME read the information sheet and followed an online link to the survey. The survey was open for three weeks and all answers were anonymous.
Results: 488 people with ME completed the survey. Most participants were female, 35-50 years and with a reported illness of greater than 5 years. Over 100 types of HR monitor used. Over 30 benefits and over 30 negatives identified. HRM reduced severity of ME and severity and duration of PEM.
Conclusion: Although there are limitations, HRM has many benefits including helping PwME to understand and manage their PEM and support them to increase their activities, including work. There is a need for more research and education of healthcare professionals in the safe use of HRM.
5. Management of Post-Viral Postural Orthostatic Tachycardia Syndrome With Craniosacral Therapy
Tafler L, Chaudry A, Cho H, Garcia A.
Cureus 15(2): e35009.
Abstract
Postural Orthostatic Tachycardia Syndrome (POTS) is a rare disorder of the autonomic nervous system. The number of people afflicted with this dysautonomia has increased dramatically in recent years due to the long-term effects of coronavirus disease (COVID-19); however, it is largely underdiagnosed.
This case report is about a patient with post-viral neuropathic POTS.
Neuropathic POTS is believed to be due to the damage of small nerve fibers that regulate the constriction of the blood vessels in the limb and abdomen, which leads to interference with vasoconstriction, and therefore causes tachycardia.
Current literature emphasizes a treatment that is based on lifestyle modifications, such as increasing water and salt intake, and symptomatic pharmacological treatment.
In this case, the 39-year-old male patient was treated with osteopathic manipulative treatment (OMT), specifically the compression of the fourth ventricle (CV4), which has been associated with the production of hyperparasympathetic and anti-inflammatory effects and, hence, helps overcome the small-fiber neuropathy caused by the viral illness.
We found that the CV4 technique led to the successful remission of the patient’s symptoms. Therefore, we propose craniosacral therapy as a successful single management modality in patients with POTS.
Petracek LS, Broussard CA, Swope RL, Rowe PC.
Healthcare. 2023; 11(6):865.
Abstract
Persistent fatigue is one of the most common symptoms of post-COVID conditions, also termed long COVID. At the extreme end of the severity spectrum, some individuals with long COVID also meet the criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), raising the possibility that symptom management approaches for ME/CFS may benefit some long COVID patients.
We describe the long-term outcomes of a 19-year-old male who developed profound impairment consistent with ME/CFS after a SARS-CoV-2 infection early in the pandemic.
We evaluated and treated him using our clinic’s approach to ME/CFS. This included a history and physical examination that ascertained joint hypermobility, pathological reflexes, physical therapy maneuvers to look for a range of motion restrictions in the limbs and spine, orthostatic testing, and screening laboratory studies.
He was found to have profound postural tachycardia syndrome, several ranges of motion restrictions, and mast cell activation syndrome. He was treated according to our clinic’s guidelines for managing ME/CFS, which included manual physical therapy maneuvers and both non-pharmacologic measures and medications directed at postural tachycardia syndrome and mast cell activation.
He experienced significant improvement in his symptoms over 30 months. His case emphasizes how the application of the principles of treating ME/CFS has the potential to provide a direction for treating long COVID.
Jean M. Nunes, Douglas B. Kell, Etheresia Pretorius.
Blood reviews, 20 March 2023, 101075 [Epub ahead of print]
Abstract
ME/CFS is a debilitating chronic condition that often develops after viral or bacterial infection. Insight from the study of Long COVID/Post Acute Sequelae of COVID-19 (PASC), the post-viral syndrome associated with SARS-CoV-2 infection, might prove to be useful for understanding pathophysiological mechanisms of ME/CFS. Disease presentation is similar between the two conditions, and a subset of Long COVID patients meet the diagnostic criteria for ME/CFS.
Since Long COVID is characterized by significant vascular pathology – including endothelial dysfunction, coagulopathy, and vascular dysregulation – the question of whether or not the same biological abnormalities are of significance in ME/CFS arises.
Cardiac abnormalities have for a while now been documented in ME/CFS cohorts, with recent studies demonstrating major deficits in cerebral blood flow, and hence vascular dysregulation. A growing body of research is demonstrating that ME/CFS is accompanied by platelet hyperactivation, anomalous clotting, a procoagulant phenotype, and endothelial dysfunction. Endothelial damage and dysregulated clotting can impair substance exchange between blood and tissues, and result in hypoperfusion, which may contribute to the manifestation of certain ME/CFS symptoms.
Here we review the ME/CFS literature to summarize cardiovascular and haematological findings documented in patients with the condition, and, in this context, briefly discuss the potential role of previously-implicated pathogens.
Overall, cardiac and haematological abnormalities are present within ME/CFS cohorts. While atherosclerotic heart disease is not significantly associated with ME/CFS, suboptimal cardiovascular function defined by reduced cardiac output, impaired cerebral blood flow, and vascular dysregulation are, and these abnormalities do not appear to be influenced by deconditioning. Rather, these cardiac abnormalities may result from dysfunction in the (autonomic) nervous system.
Plenty of recently published studies are demonstrating significant platelet hyperactivity and endothelial dysfunction in ME/CFS, as well as anomalous clotting processes. It is of particular importance to determine to what extent these cardiovascular and haematological abnormalities contribute to symptom severity, and if these two systems can be targeted for therapeutic purposes.
Viral reservoirs of herpesviruses exist in ME/CFS, and most likely contribute to cardiovascular and haematological dysfunction directly or indirectly. This review highlights the potential of studying cardiac functioning, the vasculature, and coagulation system in ME/CFS.
Rodenburg, Sanne.
Master Thesis. Utrecht University, Netherlands
Abstract
Many of the people that get infected with the Coronavirus develop long-lasting complaints and are diagnosed with Long COVID after the acute infection is gone. These complains can last several months or years and include fatigue, cognitive impairment, sleeping problems and post-exertional symptom exacerbation (PESE).
Research shows that COVID-19 patients with an acute infection have abnormalities in their brain, which could potentially lead to long-lasting neurological problems and symptoms. However, although many researchers are trying to uncover the underlying mechanisms, Long COVID is still very new. The underlying mechanisms causing and maintaining the disease are therefore unclear.
A large group of Long COVID patients resembles patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in terms of symptoms and, in many cases, the viral trigger of the disease. A core symptom of ME/CFS is PESE, which is uncommon in other fatiguing illnesses, but frequently seen in Long COVID patients.
PESE involves an abnormal worsening of symptoms and cognitive and physical functions after any type of normal activity. Because of the large symptom overlap and lack of knowledge regarding PESE, underlying brain-mechanisms associated with Long COVID and ME/CFS in general as well as after physical exertion were investigated.
The findings of this review indicate that ME/CFS is associated with several abnormalities in the brain which are also proposed to be present in Long COVID patients. Such abnormalities include inflammation of the brain, shrinkage of the brain and less blood flow to the brain.
After physical exertion, these abnormalities might be exacerbated in ME/CFS patients. This results in a brain that needs to work harder than the healthy brain to complete a task. It is demonstrated by increased brain activity in several brain regions after physical exertion and general symptom exacerbation.
Since the two diseases seem to have a large overlap in symptoms and underlying brain-mechanisms, this finding might apply to patients with long COVID as well.
Importantly, Long COVID seems to consist of different subgroups of which a large part fulfills the criteria for ME/CFS. Treatment and therapy for ME/CFS patients is therefore likely transferable to this subgroup of Long COVID patients, with explicit attention towards the PESE phenomenon.
More research is needed to uncover the underlying mechanisms as well as correct treatment approach of these diseases. Future research should take subgroups of Long COVID into account.
Long-COVID Research References
Dr Katrina Pears,
Research Correspondent.
The ME Association.
