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).
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 March 2023
It’s been another busy week for research with eight new ME/CFS studies but eighteen new Long Covid studies.
We have highlighted one of the ME/CFS studies in more detail below:
Paper three (3) looks at post-exertional malaise (PEM) in Long Covid compared to ME/CFS. Post-exertional malaise occurs after activity and results in the worsening of symptoms; it is often delayed in onset by hours or days (typically 24-48 hours), and has a prolonged recovery time that may last hours, days, weeks or longer. PEM is the hallmark symptom of ME/CFS.
This study used an online questionnaire which asked about triggers, experience, recovery and prevention of PEM in 80 patients with Long Covid and 151 patients with ME/CFS.
The results were staggering, with all but one patient with Long Covid reporting experiencing PEM, providing further evidence of the similarities between the two conditions.
There were differences in the PEM experienced, especially for the triggers of PEM, experience of symptoms during PEM, methods for recovery and how PEM is prevented. However, there was no significant difference found between ME/CFS and Long Covid in the time to onset PEM and the time it takes to recover from PEM.
A few things to note about this study:
- All answers to the questionnaire were self-reported and no biological specimens were taken to verify or compare the results, therefore it is personal interpretation of symptoms.
- Unfortunately, the answers from patients with Long Covid and ME/CFS were collected in different studies and the questions were asked in slightly different ways making the comparisons between the two cohorts not ideal.
- Long Covid patients were selected from one clinic only, so not representative of Long Covid as a whole, with not all patients having had a positive covid test. ME/CFS patients were recruited as part of an ongoing NIH-funded study.
- The questionnaire used in this research has previously been used in a 2021 research study (Hartle et al., 2021) which was found to be problematic and criticised by the ME/CFS community, such as PEM being poorly defined, only single options being selected for questions on what causes PEM and recovery time (see the discussion here). Luckily, some of the problems that were highlighted previously were addressed by the updated questionnaire in this study, allowing multiple selection of answers. Although problems do still exist where the results suggest that PEM is more likely after medium exertion than high exertion, implying that participants selected the lowest activity which triggers PEM.
- The authors themselves say that the results could be down to the newness of Long Covid and patients not knowing what PEM is or how to manage it as it takes time to determine your limits and to effectively pace. I personally think this the reason for any of the differences seen in PEM experienced in the two cohorts.
In conclusion results from this study are unsurprising, there are quite a few flaws in the study design and results are probably due to the duration of illness. The use of some biological measures would probably make the results more interesting.
Following on from this study this week, you may also be interested in reading:
- Paper six (6) which is on the recovery from cardiopulmonary exercise testing (CPET) in ME/CFS, which was used to assess the severity of post-exertional malaise (PEM). This research shows that on average people with ME/CFS take about two weeks to recover from CPET. Dr Charles Shepherd has provided a comment on this study which can be read here.
ME/CFS Research References and Abstracts
Brain Nerve. 2023 Mar;75(3):217-225. [Article in Japanese.]
Myalgic encephalitis/chronic fatigue syndrome, an intractable disease characterized by profound fatigue, sleep disturbance, cognitive impairment, and orthostatic intolerance, among other features, often occurs after infectious episodes.
Patients experience various types of chronic pain; however, post-exertional malaise is the most significant feature, which requires pacing.
In this article, I summarize the current diagnostic and therapeutic approaches and describe recent biological research in this domain.
Tate WP, Walker MOM, Peppercorn K, Blair ALH, Edgar CD.
International Journal of Molecular Sciences. 2023; 24(6):5124
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood.
While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person.
A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options.
Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination.
Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation.
The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.
Suzanne D. Vernona, Megan Hartleb, Karen Sullivana, Jennifer Bella, Saeed Abbaszadeha, Derya Unutmazc,d and Lucinda Bateman.
Work, vol. Pre-press, no. Pre-press, pp. 1-8, 2023.
Background:Long COVID describes a condition with symptoms that linger for months to years following acute COVID-19. Many of these Long COVID symptoms are like those experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Objective: We wanted to determine if people with Long COVID experienced post-exertional malaise (PEM), the hallmark symptom of ME/CFS, and if so, how it compared to PEM experienced by patients with ME/CFS.
Methods: A questionnaire that asked about the domains of PEM including triggers, experience, recovery, and prevention was administered to 80 people seeking care for Long COVID at Bateman Horne Center. Their responses were compared to responses about PEM given by 151 patients with ME/CFS using chi-square tests of independence.
Results: All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS.
Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM.
Conclusion: People with Long COVID experience PEM. There were significant differences in PEM experienced by people with Long COVID compared to patients with ME/CFS. This may be due to the newness of Long COVID, not knowing what exertional intolerance is or how to manage it.
Johnson, Madeline; Torres, Chelsea; Watts-Rich, Halli; Jason, Leonard.
Work 1 Jan. 2023 : 1 – 11.
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness that impacts pediatric populations.
Objective: The current study aimed to better understand adult perceptions of their experiences leading up to their diagnosis of ME/CFS.
Method: Patients provided data regarding symptoms of ME/CFS they may have experienced during childhood through a popular community blog forum, with participants interacting via blog comments in real-time and across various geographical locations.
Results: Descriptive analyses indicated that roughly 43% of adult survey participants reported having developed ME/CFS prior to age 18. A standard content analysis of patient blog commentary revealed several themes, such as poor mental health, family pattern/history, healthy childhood preceding sick adulthood, feeling misunderstood, lack of clarity until adulthood, sharing of resources, poor school functioning, isolation/poor social supports, and coping mechanisms.
Conclusion: There are unique benefits and insights that can be used by investigators who collaborate with patient organizations as a means of better understanding ME/CFS illness severity, presentation, and lived experiences.
Abdalla Z. Mohamed, Thu Andersen, Sanja Radovic, Peter Del Fante, Richard Kwiatek, Vince Calhoun, Sandeep Bhuta, Daniel F. Hermens, Jim Lagopoulos, Zack Shan.
Sleep Medicine Reviews, 2023, 101771.
Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms. However, the nature and magnitude of sleep architecture alteration in ME/CFS is not known, with studies using objective sleep measures in ME/CFS generating contradictory results.
The current manuscript aimed to review and meta-analyse of case-control studies with objective sleep measures in ME/CSF. A search was conducted in PubMed, Scopus, Medline, Google Scholar, and Psychoinfo databases.
After review, 24 studies were included in the meta-analysis, including 20 studies with 801 adults (ME/CFS = 426; controls = 375), and 4 studies with 477 adolescents (ME/CFS = 242; controls = 235), who underwent objective measurement of sleep.
Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, decreased sleep efficiency, decreased stage 2 sleep, increased Stage 3, and longer rapid eye movement sleep latency.
However, adolescent ME/CFS patients had longer time in bed, longer total sleep time, longer sleep onset latency, and reduced sleep efficiency.
The meta-analysis results demonstrate that sleep is altered in ME/CFS, with changes seeming to differ between adolescent and adults, and suggesting sympathetic and parasympathetic nervous system alterations in ME/CFS.
Moore GE, Keller BA, Stevens J, Mao X, Stevens SR, Chia JK, Levine SM, Franconi CJ, Hanson MR.
Medicina. 2023; 59(3):571.
Background and Objectives: Post-exertional malaise (PEM) is the hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but there has been little effort to quantitate the duration of PEM symptoms following a known exertional stressor.
Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS, we sought to characterize the duration and severity of PEM symptoms following two cardiopulmonary exercise tests separated by 24 h (2-day CPET).
Materials and Methods: Eighty persons with ME/CFS and 64 controls (CTL) underwent a 2-day CPET. ME/CFS subjects met the Canadian Clinical Criteria for diagnosis of ME/CFS; controls were healthy but not participating in regular physical activity. All subjects who met maximal effort criteria on both CPETs were included.
SSS scores were obtained at baseline, immediately prior to both CPETs, the day after the second CPET, and every two days after the CPET-1 for 10 days.
Results: There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001).
The range of ME/CFS patient recovery was 1–64 days, while the range in CTL was 1–10 days; one subject with ME/CFS had not recovered after one year and was not included in the analysis.
Less than 10% of subjects with ME/CFS took more than three weeks to recover. There was no difference in recovery time based on the level of pre-test symptoms prior to CPET-1 (F = 1.12, p = 0.33).
Mean SSS scores at baseline were significantly higher than at pre-CPET-1 (5.70 ± 0.16 vs. 4.02 ± 0.18, p < 0.0001). Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET.
Conclusions: ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. These data quantitate the prolonged recovery time in ME/CFS and improve the ability to obtain well-informed consent prior to doing exercise testing in persons with ME/CFS. Quantitative monitoring of PEM symptoms may provide a method to help manage PEM.
PhD Thesis. University of Otago, New Zealand.
This thesis illustrates the development of a neuroinflammatory paradigm for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), applicable to Long-COVID related “Post-COVID-19 Fatigue Syndrome” (PCFS).
The brain being devoid of nociceptors, in combination with neuroimaging technology lacking sufficient sensitivity, helps to explain why the chronic but low-level neuroinflammation purported to be present in the brains of ME/CFS (and PCFS) sufferers has gone unreported by patients, and has been largely undetected by scientists, until more recently. Over-activation of microglia and astrocytes is increasingly being proposed to be at the heart of ME/CFS (and PCFS) pathophysiology.
A key Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) study (2014) provided evidence of glial-cell over-activity, implicating neuroinflammation within the brain’s limbic system, of ME/CFS patients. Other cerebral spinal fluid and neuroimaging studies, including a more recent Magnetic Resonance Spectroscopy (MRS)/MRI Thermometry study (2019), have added support to this concept.
Resultant dysfunction of the limbic system and its closely-connected hypothalamus, which in turn leads to a disturbed autonomic nervous system (ANS) and dysfunctional hypothalamic-pituitary-adrenal-axis (HPA-axis) could then account for the diverse range of symptoms reported in ME/CFS (and PCFS). These symptoms include chronic fatigue, flu-like malaise, mood, memory and cognitive problems (limbic system), sleep, taste, visual and thermostatic-control problems (hypothalamus), gastro-intestinal disturbance, cardiovascular problems and hypotension (ANS), as well as increased frequency of urination and lower blood cortisol levels (HPA-axis).
A dysfunctional hypothalamic paraventricular nucleus (PVN), a potentially vulnerable site, within the brains of genetically susceptible people, which functions normally as a stress-control integrator, is proposed to be at the core of ME/CFS (and PCFS) aetiology and pathophysiology.
It is proposed that all triggers of ME/CFS, be they viral (Epstein-Barr Virus is the most common trigger), or non-viral; including other infectious diseases, multiple vaccinations, emotional trauma or chemical toxin shock, share a common triggering mechanism. They are each proposed to manifest themselves as severe physiological stressors, which by a combination of humoral and neural routes, target, the hypothalamic PVN, of genetically susceptible individuals. By exceeding an intrinsic stress-threshold pertaining to the complex neurological circuitry, within the hypothalamic PVN, the triggering stressor is proposed to overload it into a (permanently) iii dysfunctional state.
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19), in common with the triggering stressors of ME/CFS, also manifests itself as a severe physiological stressor, due to a cytokine surge at the site of the primary infection (the lungs). This particular stressor is, also, proposed to target the hypothalamic PVN, in genetically susceptible people, thus triggering PCFS. Life’s ongoing physiological stressors, such as physical, mental overexercise, chemical toxin exposure, emotional and financial stress, all of which are known to exacerbate and perpetuate ME/CFS (as well as PCFS) could do so by then targeting a now “compromised” (possibly inflamed) stress-sensitive hypothalamic PVN, by similar routes.
Then if an alternative, but variable (according to fluctuating neuroinflammation of the hypothalamic PVN, itself) stress threshold was exceeded, commonly reported post-exertional malaise (PEM) episodes, more problematic flare-ups, and even more severe prolonged and characteristic relapses could ensue.
It is proposed that a dysfunctional hypothalamic PVN, thereby, acts as an epicentre to a radiating neuroinflammatory response within the brains of ME/CFS (and PCFS) sufferers. A neuroinflammatory pathway, as proposed to be shared by the early-onset stages of several progressive neuroinflammatory (neurodegenerative) diseases could also be shared by ME/CFS, and PCFS. Indeed, this pathway could be shared by other potentially nonprogressive neuroinflammatory disorders, such as the closely-related fibromyalgia, mental health disorders, epilepsy, and migraines.
Might then the “drivers” of the inflammatory process, which sustain glial-cell activation (and neuroinflammation), in ME/CFS (and PCFS), be the perpetuating stressors, themselves, acting in combination with a now “compromised” and stress-sensitive hypothalamic PVN? If so, what then might be the mechanistic detail linking a stressor-targeted hypothalamic PVN and microglial activation in ME/CFS (and PCFS)?
One attractive scenario requiring further investigation involves the release of corticotrophin releasing hormone (CRH), which is released naturally by the hypothalamic PVN due to stress. The chronic release of CRH from a stress-sensitive, dysfunctional hypothalamic PVN might induce microglia activation, leading to chronic neuroinflammation, via the stimulation of mast-cells.
Two papers were published in relation to this neuroinflammatory paradigm for ME/CFS (2018, 2019), followed by another paper (2021), in which a paradigm was presented to explain the more recently emergent, but equally perplexing, Long-COVID related “PostCOVID-19 Fatigue Syndrome” (PCFS).
The neuroinflammatory model presented is both iv coherent and unifying for all triggering stressors and perpetuating stressors of ME/CFS (& PCFS), without the need for subtypes (as many other models require), but it does require validation. To this effect, it is hoped that this neuroinflammatory model will be both thought-provoking, as well as providing a framework for scientific researchers to test, critique, modify, and develop, into the future.
More brain-focussed research, using increasingly sophisticated neuroimaging technology (especially enhanced PET/MRI) is recommended. Then, a brain-signature for both ME/CFS (and PCFS) might even become attainable, within the next decade, perhaps.
Long-COVID related PCFS, affecting millions of people worldwide, presents a golden opportunity for in-depth longitudinal neuroimaging studies (following patients through relapse-recovery cycles) to develop a better understanding of PCFS (and ME/CFS) pathophysiology.
Work 1 Jan. 2023 : 1 – 7.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, debilitating health condition characterized by overwhelming fatigue and post-exertional malaise, or exacerbation of symptoms following physical, mental, or emotional exertion.
ME/CFS often impacts every aspect of an individual’s life, and one’s new reality may be much different from the daily life experienced before the onset of the condition.
Though the long-term effects of COVID-19 have brought increased attention to chronic fatigue and related disorders, ME/CFS is still vastly understudied and frequently misunderstood. People with ME/CFS are often passed between various healthcare providers as evidence-based treatments remain scarce.
These patients are sometimes sent to rehabilitation professionals, who often lack appropriate education and experience with this patient population.
This article describes the experience of a young woman and physical therapist with ME/CFS following COVID-19 infection, as well as potential implications for rehabilitation professionals and those who care for those with this condition.
Long-COVID Research References
- Prevalence and risk factor for long COVID in children and adolescents: A meta-analysis and systematic review
- Epidemiology, Symptomatology, and Risk Factors for Long COVID Symptoms: Population-Based, Multicenter Study
- Ambient air pollution exposure linked to long COVID among young adults: a nested survey in a population-based cohort in Sweden
- Effects of l-Arginine Plus Vitamin C Supplementation on l-Arginine Metabolism in Adults with Long COVID: Secondary Analysis of a Randomized Clinical Trial
- Long COVID-six months of prospective follow-up of changes in symptom profiles of non-hospitalised children and young people after SARS-CoV-2 testing: A national matched cohort study (The CLoCk) study
- Increased insulin resistance due to Long COVID is associated with depressive symptoms and partly predicted by the inflammatory response during acute infection
Dr Katrina Pears,
The ME Association.