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 7 – 13 February 2023
It’s been an extremely busy week for research, with eight new ME/CFS studies and nineteen new Long Covid studies.
We have highlighted one of the ME/CFS studies in detail below:
Paper seven (7) looks into the effect of exercise and maximal exertion on the composition of urine, specifically the metabolomes present (metabolomics is the study of metabolites present within the blood, which are substances needed or produced for metabolism).
This study used 10 ME/CFS patients and 8 sedentary controls. A urine sample was collected at baseline and 24 hours post exercise, with the aim of seeing the effect of a maximal cardiopulmonary exercise test (CPET) on the urine metabolomes present.
In this study a significant quantity of metabolites were anaylsed compared to any previous study conducted, with 1403 in the present study, representing an approximate 30-fold increase. The metabolites included amino acids, carbohydrates, lipids, nucleotides, cofactors, vitamins, and xenobiotics.
The novel finding from this research was the lack of significant changes in the metabolome that occurred following exercise in ME/CFS patients compared to the controls. This demonstrates a lack of adaptation to severe stress (exercise) in ME/CFS.
The findings of this research are very comprehensive, details are given of changes in specific metabolites, for example changes were seen in lipid (steroids, acyl carnitines and acyl glycines) and amino acid subpathways (cysteine, methionine, leucine, isoleucine, urea cycle, arginine and proline). In summary, other key findings from this research were:
- Large-scale changes were found in the urine metabolome for the controls with 255 compounds being significantly altered following exercise. Of these 255, 250 increased in concentration after exercise.
- 110 of these compounds had a significant relationship between disease status (with or without ME/CFS (control)) and time (baseline or post-exercise).
- No significant changes in any compound were found in the ME/CFS group following exercise.
- Pathway analysis was also used to discover what these metabolites were being used for, showing significant alteration in the pathways in controls and not in ME/CFS.
- Predominantly lower metabolite concentrations were found in ME/CFS patients.
- The metabolites that changed differently during recovery in controls compared to ME/CFS patients are seen to be predominantly amino acids and lipids.
- The study also compared results to previous research conducted by this group which used plasma, showing a correlation between metabolites present in urine and plasma. This gives further evidence for metabolic dysregulation following exercise.
Unfortunately, as with many studies in this area, this was a small study. The authors say that this was a pilot study which produced much more interesting results than expected, so there is hope that this will be followed up. These results demonstrate a key component to ME/CFS which is post-exertional malaise but this could also be linked to exercise intolerance that many experience.
This study was also limited by not controlling diet which has a significant effect on the urine metabolites produced as well as only collecting urine at two-time points, therefore, ME/CFS patients may exhibit a delay in the excretion of metabolites just like delayed recovery. Furthermore, a female only population was used, which has advantages and disadvantages due to the high prevalence in the female sex as well as reported differences at a molecular level in other studies, but this is also a drawback as we don’t know if results would vary in males.
This is the third study we have seen of late showing that ME/CFS patients have a different response to exercise which effects their recovery. We have previously covered in our roundup the research by:
- Germain et al., 2022 with previous roundup comment here and IACFS conference coverage. (This research is from the same research group.)
- van Booven et al., 2023– previously covered in our roundup two weeks ago which can be found here.
You may also be interested in reading:
- Paper eight (8) which is on severe ME, and the study demonstrates the importance of listening to patients. The ME Association has leaflets available for adults and children.
- Paper two (2) in the Long Covid reference section, which shows that T cell dysregulation may be another mechanism contributing to Long Covid, there is a new article which breaks this study down which can be read here.
ME/CFS Research References and Abstracts
1. Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases
Gottschalk, C.G., Peterson, D., Armstrong, J. et al.
Infect Agents Cancer 18, 7 (2023).
Abstract
Historically, COVID-19 emerges as one of the most devastating diseases of humankind, which creates an unmanageable health crisis worldwide. Until now, this disease costs millions of lives and continues to paralyze human civilization's economy and social growth, leaving an enduring damage that will take an exceptionally long time to repair.
While a majority of infected patients survive after mild to moderate reactions after two to six weeks, a growing population of patients suffers for months with severe and prolonged symptoms of fatigue, depression, and anxiety. These patients are no less than 10% of total COVID-19 infected individuals with distinctive chronic clinical symptomatology, collectively termed post-acute sequelae of COVID-19 (PASC) or more commonly long-haul COVID.
Interestingly, Long-haul COVID and many debilitating viral diseases display a similar range of clinical symptoms of muscle fatigue, dizziness, depression, and chronic inflammation.
In our current hypothesis-driven review article, we attempt to discuss the molecular mechanism of muscle fatigue in long-haul COVID, and other viral diseases as caused by HHV6, Powassan, Epstein–Barr virus (EBV), and HIV. We also discuss the pathological resemblance of virus-triggered muscle fatigue with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Chen C, Yip HT, Leong KH, Yao WC, Hung CL, Su CH, Kuo CF, Tsai SY.
J Transl Med. 2023 Feb 8;21(1):98.
Abstract
Objective: An increased prevalence of psychiatric comorbidities (including depression and anxiety disorder) has been observed among patients with chronic fatigue syndrome (CFS). However, few studies have examined the presence of depression and anxiety disorder before the diagnosis of CFS. This study aimed to clarify the preexisting comorbidities and treatments associated with patients with subsequent CFS diagnosis in a population-based cohort in Taiwan.
Methods: An analysis utilizing the National Health Insurance Research Database of Taiwan was conducted. Participants included were 6303 patients with CFS newly diagnosed between 2000 and 2010 and 6303 age-/sex-matched controls.
Results: Compared with the control group, the CFS group had a higher prevalence of depression and anxiety disorder before the diagnosis of CFS. Sampled patients who took specific types of antidepressants, namely, selective serotonin reuptake inhibitors (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI] 1.04-1.39), serotonin antagonists and reuptake inhibitors (SARI; aOR = 1.87, 95% CI 1.59-2.19), and tricyclic antidepressants (aOR = 1.46, 95% CI 1.09-1.95), had an increased risk of CFS. CFS risk was also higher among participants taking benzodiazepine, muscle relaxants, and analgesic drugs.
A sub-group analysis revealed that SARI use was related to an increased risk of CFS in the depression, anxiety disorder, male, and female groups. In the depression and anxiety disorder groups, analgesic drug use was associated with an increased CFS risk. Nonpharmacological treatment administration differed between men and women.
Conclusion: This population-based retrospective cohort study revealed an increased risk of CFS among populations with preexisting depression and anxiety disorder, especially those taking SARI and analgesic drugs.
Merethe Eide Gotaas, Tormod Landmark, Anne S. Helvik & Egil A. Fors.
Fatigue: Biomedicine, Health & Behavior.
Abstract
Objective: This study aimed to explore associations at the group level between patient characteristics at baseline and the outcomes of physical functioning and fatigue in patients with chronic fatigue syndrome (CFS) participating in a randomized controlled trial on cognitive behavioural therapy (CBT).
Methods/design: Consecutively, 236 adult participants fulfilling the Centres for Disease Control and Prevention (CDC) 1994 criteria for CFS were randomly allocated to either 16 weeks of standard CBT, 8 weeks of Interpersonal CBT or a treatment as usual control group. In secondary analyses we investigated how gender, age, pain, anxiety, depression, memory and VO2max at baseline were associated with physical function and fatigue before and after treatment, controlling for the CBT-interventions and the baseline levels of the outcome measures.
For the two groups receiving CBT, a 1-year follow-up analysis was also done. Bivariate and multivariable linear regression was used to explore the targeted associations.
Results: At baseline, less pain (p < .001) and higher VO2max (p = 0.014) were associated with better physical function, while better memory (p = 0.001) and fewer depressive symptoms (p = 0.017) were associated with less fatigue. Better memory and physical function at baseline (p = 0.015 and p < .001, respectively) and male gender (p = 0.003) were associated with higher physical function post-intervention.
Male gender (p = 0.010) was associated with higher physical function at 1-year follow-up. Fatigue severity at baseline was the only variable associated with follow up scores for fatigue (p < .001).
Conclusion: Our findings show that fatigue and physical function were associated with different types of characteristics at baseline, indicating a heterogeneity among CFS patients.
Palacios N, Molsberry S, Fitzgerald KC, Komaroff AL.
Sci Rep. 2023 Feb 11;13(1):2469.
Abstract
Fatigue is a common reason that patients seek medical care. Only a fraction of these patients meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
To determine if ME/CFS is just a more extreme form of fatigue, or a qualitatively different condition, we assessed whether risk factors for ME/CFS and for Severe Fatigue were similar.
An email questionnaire that inquired about symptoms of Severe Fatigue and ME/CFS was completed by 41,802 US female nurses from whom detailed medical and lifestyle information had been collected since 1989: 102 met criteria for ME/CFS, 522 had Severe Fatigue, and 41,178 individuals were without significant chronic fatigue.
We used Cox proportional hazards regression to estimate the Hazard Ratio (HR) of Severe Fatigue and of ME/CFS with each of several potential risk factors, according to the level of exposure to each risk factor.
The risk of Severe Fatigue was significantly increased among participants who were older, had a higher BMI in adulthood, used hormone therapy, had increased alcohol intake and decreased caffeine intake. In contrast, these risk factor associations were not seen in people with ME/CFS.
A self-reported past history of acute infectious mononucleosis was associated with a non-significantly increased Hazard Ratio of later ME/CFS (HR 1.77, 0.87-3.61) and, to a lesser extent, of Severe Fatigue (HR 1.28, 0.98-1.66).
The different contribution of various risk factors to Severe Fatigue and ME/CFS suggests that ME/CFS has a qualitatively different underlying biology from the more common state of Severe Fatigue.
Vaes, A.W., Van Herck, M., Deng, Q. et al.
J Transl Med 21, 112 (2023).
Abstract
Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a complex, heterogenous disease. It has been suggested that subgroups of people with ME/CFS exist, displaying a specific cluster of symptoms. Investigating symptom-based clusters may provide a better understanding of ME/CFS. Therefore, this study aimed to identify clusters in people with ME/CFS based on the frequency and severity of symptoms.
Methods: Members of the Dutch ME/CFS Foundation completed an online version of the DePaul Symptom Questionnaire version 2. Self-organizing maps (SOM) were used to generate symptom-based clusters using severity and frequency scores of the 79 measured symptoms. An extra dataset (n = 252) was used to assess the reproducibility of the symptom-based clusters.
Results:Data of 337 participants were analyzed (82% female; median (IQR) age: 55 (44–63) years). 45 clusters were identified, of which 13 clusters included ≥ 10 patients. Fatigue and PEM were reported across all of the symptom-based clusters, but the clusters were defined by a distinct pattern of symptom severity and frequency, as well as differences in clinical characteristics. 11% of the patients could not be classified into one of the 13 largest clusters. Applying the trained SOM to validation sample, resulted in a similar symptom pattern compared the Dutch dataset.
Conclusion: This study demonstrated that in ME/CFS there are subgroups of patients displaying a similar pattern of symptoms. These symptom-based clusters were confirmed in an independent ME/CFS sample. Classification of ME/CFS patients according to severity and symptom patterns might be useful to develop tailored treatment options.
7. Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients
Glass KA, Germain A, Huang YV, Hanson MR.
International Journal of Molecular Sciences. 2023; 24(4):3685.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown etiology or effective treatments. Post-exertional malaise (PEM) is a key symptom that distinguishes ME/CFS patients. Investigating changes in the urine metabolome between ME/CFS patients and healthy subjects following exertion may help us understand PEM.
The aim of this pilot study was to comprehensively characterize the urine metabolomes of eight female healthy sedentary control subjects and ten female ME/CFS patients in response to a maximal cardiopulmonary exercise test (CPET).
Each subject provided urine samples at baseline and 24 h post-exercise. A total of 1403 metabolites were detected via LC-MS/MS by Metabolon® including amino acids, carbohydrates, lipids, nucleotides, cofactors and vitamins, xenobiotics, and unknown compounds.
Using a linear mixed effects model, pathway enrichment analysis, topology analysis, and correlations between urine and plasma metabolite levels, significant differences were discovered between controls and ME/CFS patients in many lipid (steroids, acyl carnitines and acyl glycines) and amino acid subpathways (cysteine, methionine, SAM, and taurine; leucine, isoleucine, and valine; polyamine; tryptophan; and urea cycle, arginine and proline).
Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients.
Sommerfelt K, Schei T, Angelsen A.
Journal of Clinical Medicine. 2023; 12(4):1487.
Abstract
There is a striking lack of systematic knowledge regarding the symptom burden, capacity for activities of daily living, and supportive measures for the most severely ill ME/CFS patients.
The present study seeks to address this through a national, Internet-based survey targeting patients with severe and very severe ME/CFS and their carers.
Responses from 491 patients were included, with 444 having severe and 47 very severe ME/CFS with the classification based on the best estimate from patient responses. In addition, 95 respondents were reclassified from patients’ own classification to moderate and included for comparison.
The onset was before 15 years of age for 45% in the very severe and 32% in the severe group. Disease duration was more than 15 years for 19% in the very severe and 27% in the severe group.
Patient symptom burden was extensive. The most severely affected were totally bedridden, unable to talk, and experienced dramatic worsening of symptoms after minimal activity or sensory stimuli.
Care and assistance from healthcare and social services were often described as insufficient or inadequate, often worsening the symptom load and burden of care. A substantial lack of disease knowledge among healthcare providers in general was reported.
Yet approximately 60% in the severe and very severe groups found services provided by occupational therapists and family doctors (general practitioners) helpful, while a smaller proportion experienced appropriate help from other health personnel groups. This indicates that help and support are highly needed and possible to provide.
On the other hand, this must be approached carefully, as a substantial number of patients experienced deterioration from contact with healthcare personnel.
Family carers described an extensive burden of care with often inadequate help from healthcare providers or municipal authorities. Patient care by family members of very severe ME/CFS patients constituted more than 40 h a week for 71% of this patient group. The carers described a large negative impact on their work and financial situation, and on their mental wellbeing.
We conclude that childhood onset was common, burden of disease was extensive, and support from responsible societal health and social support providers was commonly grossly inadequate.
Long-COVID Research References
Dr Katrina Pears,
Research Correspondent.
The ME Association.
