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).
There have been nine new ME/CFS studies and twenty-five new Long Covid studies this week.
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
Four of the papers included in this week’s roundup are of a slightly different nature, all of these are patient written hypothesis research (an idea which is suggested as a possible explanation for a particular situation or condition, but which has not yet been proved to be correct). These are all single authored and have been included out of interest.
We have highlighted one of the ME/CFS studies in more detail below:
Paper five (5) is on symptoms and herpesvirus IgG antibody concentrations in ME/CFS and multiple sclerosis (MS). This work reanalysed a previously described data set which looked at the response to six different herpesviruses (CMV – cytomegalovirus; EBV – Epstein-Barr virus; HHV6 – human herpesvirus-6; HSV1 and HSV2 – herpes simplex virus-1 and -2; VZV – varicella-zoster virus). The samples came from the UK ME/CFS biobank, and included 222 with ME/CFS, and 46 with MS.
The aim of this study was to establish if there is a link between underlying symptomology and herpesvirus IgG antibodies using data from four disease-trigger-based subgroups of ME/CFS patients and patients with MS. The four groups were: unknown disease trigger, non-infection trigger, and an infection disease trigger confirmed in the lab at the time of the event and an unconfirmed infection disease.
The secondary aim was to determine whether serological data could distinguish between ME/CFS and MS using machine learning.
The study found:
- In the MS group, a significant negative association between the symptom of temporary eye disturbances and CMV antibody concentrations.
- In the MS group, a significant positive association between the symptom of bladder problems and EBV antibody concentrations.
- In the ME/CFS group, the most significant association was between increasing HSV1 (herpes simplex virus-1) antibody concentration and brain fog. This is in line with the negative impact HSV1 exposure is commonly found to have on cognitive outcomes in healthy and ME/CFS and MS conditions.
- There was evidence for a higher number of significant antibody-symptom associations in MS than ME/CFS. Therefore, IgG antibody data explains more of the symptomology in MS than in ME/CFS.
- However, the ME/CFS overall had more symptoms (of higher frequency) than the MS group.
- Combining all the serological data allowed three of the ME/CFS groups (unknown disease trigger, non-infection trigger, and an infection disease trigger confirmed in the lab at the time of the event) to be distinguished from the MS group.
- The ME/CFS groups which had an unconfirmed infection disease trigger could not be distinguished from the MS group.
This study involved a large international collaboration of researchers, with many well known to the field. The study also has its major strength in using samples from the UK ME/CFS biobank (UK ME/CFS). The UKMEB was launched in August 2011 with funding and input from the ME Association (MEA), Action for M.E. and ME Research UK. The MEA Ramsay Research Fund has continued to provide annual grants since 2011 and now covers all the basic running costs of this vital and unique project.
The UKMEB contains samples from mild to severely affected people aged 18-60, as well as healthy controls and people with multiple sclerosis (MS). Blood samples have been aliquoted into serum, plasma, peripheral blood mononuclear cells (PBMC), red blood cells/granulocyte pellet, whole blood, and RNA. They use the samples in their own research and provide them to research teams from around the world. More information on this ME Association funded project can be found here.
There are a few limitations of this study:
- It is a shame that this study reanalysed previous data and not performed their own analysis which can help to eliminate errors, such as methodological approaches. However, the previous studies which were analysed included many of the same researchers and hopefully this effect would be minimal (Cliff et al., 2019 and Domingues et al., 2021).
- The results only give a single snapshot in time, and ME/CFS is known to have highly fluctuating conditions which change over-time, therefore, results may prove irreproducible. Furthermore, antibody-symptom association could then become significant at later time points, therefore there is a need for longitudinal studies.
- It is also disappointing there is no control group included for comparison and to see whether this could be distinguished from ME/CFS and MS groups.
- The use of IgG antibodies in this research has limited ability to show whether the herpesviruses present are active or latent. This can be improved by combining with IgM antibody results which shows recent activation.
- Lastly, there was a selection bias in the MS patients used which only included those not undergoing immune therapy. This could mean that those with less severe symptoms only were included and may have produced the difference between ME/CFS and MS symptoms seem. However, therapy does modify the disease and make it less comparable when measuring biomedical specimens.
In conclusion, this was a large study providing some new results to the field and highlights future avenues which should be followed up.
(N.B. we have previously written a research summary on the reactivation of human herpesviruses in ME/CFS, which can be found here.)
ME/CFS Research References and Abstracts (13 – 19 June)
Snell GE, Seage CH, Mercer J.
Journal of Health Psychology. 2023;0(0).
Whilst chronic fatigue syndrome (CFS) has been widely researched amongst women, studies investigating how men experience a CFS diagnosis is limited.
This study utilised an interpretative phenomenological approach to interview five men who have a medical diagnosis of CFS.
Six themes emerged to demonstrate the participants’ experiences prior to, during and after obtaining their CFS diagnosis.
Findings revealed that participants were initially reluctant to accept their condition, confounded by their perception that symptoms compromised their sense of masculinity. They also felt that healthcare professionals had limited recognition of CFS leading them to seek social support and legitimisation from other sources.
The struggle to come to terms with a different lifestyle and sense of masculinity prevailed. Such knowledge could be effectively utilised by researchers, practitioners and employers to facilitate an increased understanding of male accounts of the condition and more bespoke interventions where required.
Alberto Olmo Fernández, Sara Martínez Rodríguez, Daniel Martín Fernández, et al.
Authorea. July 11, 2023. [Preprint]
Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/ CFS) is a disabling, chronic, multi-system and complex disease. Currently, there are no specific laboratory tests to directly diagnose ME/CFS.
In this work we study the use of impedance spectroscopy as a potential technique for the diagnosis of this disease. A specific device for the electrical characterization of peripheral blood mononuclear cells was designed and implemented.
Impedance spectroscopy measurements in the range from 1 Hz to 500 MHz were made after osmotic stress of the samples with sodium chloride solution 1M. The evolution in time after the osmotic stress at two specific frequencies (1.36 kHz and 154 kHz) was analysed.
The device showed its sensitivity to the presence of cells and the evolution of the osmotic process. Higher values of impedance were measured for 1.36 kHz in ME/CFS patients compared to control samples. Results help to further understand the relation of bioimpedance measurements with ME/CFS samples physical properties and osmotic processes.
Walker, Max O.M. et al.
Medical Research Archives, [S.l.], v. 11, n. 7.1, july 2023. ISSN 2375-1924
Viral infection in most people results in a transient immune/inflammatory response resulting in elimination of the virus and recovery where the immune system returns to that of the pre-infectious state. In susceptible people by contrast there is a transition from an acute immune response to a chronic state that can lead to an ongoing lifelong complex post-viral illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. This susceptibility is proposed to be genetic or be primed by prior health history.
Complex abnormalities occur in immune cell functions, immune cell metabolism and energy production, and in cytokine immune modulator regulation. The immune system of the brain/central nervous system becomes activated leading to dysfunction in regulation of body physiology and the onset of many neurological symptoms.
A dysfunctional immune system is core to the development of the post-viral condition as shown with diverse strategies of immune profiling. Many studies have shown changes in numbers and activity of immune cells of different phenotypes and their metabolism.
Immune regulating cytokines show complex altered patterns and vary with the stage of the disease, and there are elements of associated autoimmunity. These complex changes are accompanied by an altered molecular homeostasis with immune cell transcripts and proteins no longer produced in a tightly regulated manner, reflected in the instability of the epigenetic code that controls gene expression.
Potential key elements of the altered immune function in this disease needing further exploration are changes to the gut-brain-immune axis as a result of changes in the microbiome of the gut, and viral reactivation from latent elements of the triggering virus or from a prior viral infection.
Long COVID, an Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-like illness, is the post-viral condition that has arisen in large numbers solely from the pandemic virus Severe Acute Respiratory Syndrome Coronovirus-2. With over 760 million cases worldwide, an estimated ~100 million cases of Long COVID have occurred within a short period. This now provides an unprecedented opportunity to understand the progression of these post-viral diseases, and to progress from a research phase mainly documenting the immune changes to considering potential immunotherapies that might improve the overall symptom profile of affected patients, and provide them with a better quality of life.
Ronessa Dass, Mohini Kalia, Jocelyn Harris & Tara Packham.
Canadian Journal of Pain, 7:1.
Introduction: Approximately 15% to 40% of persons with chronic pain as a primary disorder experience brain fog. Prior research has investigated the etiology of “brain fog” in conditions in which pain presents as a key feature (e.g., fibromyalgia). However, it remains understudied in the context of chronic 10 musculoskeletal pain.
Following current scoping review guidelines, we obtained stakeholder input from patient and health care professionals (HCPs) to define this phenomenon. Specific aims of this review were to (1) identify factors contributing to brain fog, (2) identify the functional correlates of brain fog and assessments used to measure them, and (3) establish a definition of brain fog that can be employed by researchers and HCPs to advance research and care.
Methods: A scoping review was conducted using recommendations of the Joanna Briggs Institute methodology of scoping reviews and the Levac et al methodology. Embase, Cinahl, PsycINFO, and Medline was searched to identify relevant sources. Findings were verified with patient and healthcare professionals.
Results: We identified four 15 key features of brain fog: perceived variability, subjective cognitive dysfunction, participation limitations, and changes in functional activities. We developed a model of brain fog illustrating the overlapping categories of contributors to brain fog in chronic musculoskeletal pain: (1) neuroanatomical and neurophysiological, (2) mental health/emotional, and (3) environmental/lifestyle.
Conclusion: The results of this scoping review conclude that the inconsistency in research regarding brain fog in 20 chronic musculoskeletal pain is obstructing a clear understanding of the phenomenon and therefore may be impeding persons with chronic pain and brain fog from receiving optimal care.
Tiago Dias Domingues, João Malato, Anna D. Grabowska, Ji-Sook Lee, Jose Ameijeiras-Alonso, Przemysław Biecek, Luís Graça, Helena Mouriño, Carmen Scheibenbogen, Francisco Westermeier, Luis Nacul, Jacqueline M. Cliff, Eliana Lacerda, Nuno Sepúlveda.
Heliyon, Volume 9, Issue 7, 2023, e18250.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS) are two complex and multifactorial diseases whose patients experience persistent fatigue, cognitive impairment, among other shared symptoms. The onset of these diseases has also been linked to acute herpesvirus infections or their reactivations.
In this work, we re-analyzed a previously-described dataset related to IgG antibody responses to 6 herpesviruses (CMV – cytomegalovirus; EBV – Epstein-Barr virus; HHV6 – human herpesvirus-6; HSV1 and HSV2 – herpes simplex virus-1 and -2, respectively; VZV – varicella-zoster virus) from the United Kingdom ME/CFS biobank.
The primary goal was to report the underlying symptomology and its association with herpesvirus IgG antibodies using data from 4 disease-trigger-based subgroups of ME/CFS patients (n = 222) and patients with MS (n = 46).
The secondary objective was to assess whether serological data could distinguish ME/CFS and its subgroup from MS using a SuperLearner (SL) algorithm.
There was evidence for a significant negative association between temporary eye insight disturbance and CMV antibody concentrations and for a significant positive association between bladder problems and EBV antibody concentrations in the MS group.
In the ME/CFS or its subgroups, the most significant antibody-symptom association was obtained for increasing HSV1 antibody concentration and brain fog, a finding in line with a negative impact of HSV1 exposure on cognitive outcomes in both healthy and disease conditions.
There was also evidence for a higher number of significant antibody-symptom associations in the MS group than in the ME/CFS group.
When we combined all the serological data in an SL algorithm, we could distinguish three ME/CFS subgroups (unknown disease trigger, non-infection trigger, and an infection disease trigger confirmed in the lab at the time of the event) from the MS group. However, we could not find the same for the remaining ME/CFS group (related to an unconfirmed infection disease).
In conclusion, IgG antibody data explains more the symptomology of MS patients than the one of ME/CFS patients. Given the fluctuating nature of symptoms in ME/CFS patients, the clinical implication of these findings remains to be determined with a longitudinal study. This study is likely to ascertain the robustness of the associations during natural disease course.
Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 36-43.
An overactive sympathetic nervous system (SNS) may cause one subtype of Long COVID. People who are genetically at risk for noradrenergic nerve problems may develop an overactive SNS after an infection. Alternatively, genetic or virus-induced dysregulation of astrocytes could lead to overactivation of the SNS. An overactive SNS could disrupt regulation of immune cells, energy metabolism, sleep homeostasis, respiratory rate, gastrointestinal function, and systemic and cerebral blood pressure, causing fatigue and cognitive dysfunction.
Long COVID refers to symptoms that continue for more than four weeks after onset of acute COVID-19 illness. This umbrella term includes a wide variety of symptoms and presentations. Long COVID patients may have different types of biological dysfunction, meaning that there may be distinct subtypes of Long COVID. One possible subtype is sympathetic nervous system (SNS) over-activation. This subtype may exist in both Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)1.
Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 44-48
To date, no single blood lab test exists to diagnose or track ME/CFS or chronic Long COVID. Based on existing literature, this article brings together evidence that a molecule secreted by the immune system called sCD40L tends to become increasingly elevated in ME/CFS, Long COVID, and Multiple Sclerosis. These studies, along with what’s known about the role of sCD40L in health and other diseases, suggest sCD40L may be useful to track over time in ME/CFS and Long COVID patients.
Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 13-20
The ophthalmological condition known as myodesopsia or vitreous floaters results from aggregates of proteins or cellular debris in the vitreous body casting shadows onto the retina that are perceived as objects moving through the visual field. While this is commonly viewed as a benign condition associated with aging, a growing body of research suggests that for some patients it can severely impact visual function and quality of life. Myodesopsia is often caused by posterior vitreous detachment, but can also result from other conditions such as asteroid hyalosis, uveitis, or myopic vitreopathy.
There are strong reasons to suspect that its presence may be indicative of a susceptibility to collagen degradation in response to inflammatory triggers, which may represent a risk factor for the development of Long COVID, ME/CFS, or related chronic illnesses. Evidence for such susceptibility includes the presence of collagen-degrading enzymes in the vitreous, associations with other connective tissue disorders, and links between myodesopsia and infections with various pathogens.
Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 21-29
Nonselective matrix metalloproteinase (MMP) inhibition with FDA approved subantimicrobial dose doxycycline formulations could improve systemic symptoms in at least a subset of patients with Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as compared to those who receive placebo.
Long-COVID Research References
- Post COVID-19 symptoms are common, also among young adults in the general population
- Long COVID as a never-ending puzzle: the experience of primary care physicians
- SARS-CoV-2 post-acute sequelae in previously hospitalised patients: systematic literature review and meta-analysis
- The effect of nirmatrelvir-ritonavir on the long-term risk of neuropsychiatric sequelae following COVID-19
- Circulating Reelin promotes inflammation and modulates disease activity in acute and long COVID-19 cases
- Evaluation of Outpatients in the Post-COVID-19 Period in Terms of Autonomic Dysfunction and Silent Ischemia
- The immunology of long COVID
- Long COVID prevalence and impact on quality of life 2 years after acute COVID-19
- Hematological alterations associated with Long Covid-19
- Cognitive impairment after Long COVID-19: Current Evidence and Perspectives
- Exploring the Complexities of Long Covid: An Analysis of Illness Narratives through Antonovsky’s Sense of Coherence Theory
- Long COVID, linking etiopathogenic theories
- Treatment and outcomes of 95 post-Covid patients with an antidepressant and neurobiological explanations
- Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges
- Understanding the neurological implications of acute and long COVID using brain organoids
- Post-COVID cognitive dysfunction: current status and research recommendations for high risk population
- Exploring potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy
- Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID
- Prevalence of Long COVID Symptoms Related to SARS-CoV-2 Strains
- Preliminary scoping review on long-covid influence on ophthalmological signals
- Health-related quality of life in long COVID-19 in context of symptom type
- Multisystem inflammatory syndrome in children (MIS-C): Implications for long COVID
- Using Data Science and a Health Equity Lens to Identify Long-COVID Sequelae Among Medically Underserved Populations
- Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness
- Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations
Dr Katrina Pears
The ME Association.