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 June 2022
There have been seven new research studies on ME/CFS and thirteen studies on Long Covid this week.
We have seen a large range of studies published, although the majority of studies this week are review articles and not biological studies.
We have highlighted two of the studies below:
After commenting in last weeks roundup, that it’s been a while since we’ve had a study looking at the two overlapping conditions ME/CFS and fibromyalgia (FM). This week we have got two studies, which are paper two (2) and paper six (6).
Paper two (2) goes into the overlap of these two conditions in further detail with a systematic review and a meta-analysis looking at the clinical overlap. Unsurprisingly, the study found a prominent clinical overlap, however, the study is hugely limited by the fact that these two conditions are not well defined (i.e. we do not know the biology or etiology of either condition) as well as there being a large variety in diagnostic criteria. Finding the answers to explain the clinical overlap between ME/CFS and FM is important, but at the moment we do not have the tools to do this as we do not really know what these conditions are.
Paper five (5) is on the molecular mechanisms of neuroinflammation in ME/CFS and Long COVID, again this is a hypothesis and theory study. The authors pull together findings from their previous research and propose that: “following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles.” This theory is explained well in the use of figures in their research paper, showing the proposed pathway of disease.
I think that the proposed theory in this paper is quite sound, as we know that ME/CFS is often triggered by a viral infection. However, the authors do suggest that neuroinflammation, chronic immune activation and dysregulation is well-defined in ME/CFS, again, we need more biological studies to fully prove this. Furthermore, this study is also limited by some of the terms used by the authors, which questions their grasp on ME/CFS, such as: acute and chronic phases of ME, relapse recovery cycle, and recovery periods. The research is very theory heavy to read, but if you are interested in understanding the theories further, there is a talk available here.
You may also be interested in reading paper four (4) which is a preprint paper of the microclot study which has had a lot of interest on social media. We are waiting to get expert opinion on this study before we provide any comment.
In the Long Covid reference section, you may also be interested in reading paper ten (10) on muscle changes in Long Covid, and Dr Charles Shepherd , has provided a comment for here.
ME/CFS Research References and Abstracts
Leong, KH., Yip, HT., Kuo, CF. et al.
J Transl Med 20, 268 (2022).
Abstract
Background: This study aims to provide 12-year nationwide epidemiology data to investigate the epidemiology and comorbidities of and therapeutic options for chronic fatigue syndrome (CFS) by analyzing the National Health Insurance Research Database.
Methods: 6306 patients identified as having CFS during the 2000–2012 period and 6306 controls (with similar distributions of age and sex) were analyzed.
Result: The patients with CFS were predominantly female and aged 35–64 years in Taiwan and presented a higher proportion of depression, anxiety disorder, insomnia, Crohn’s disease, ulcerative colitis, renal disease, type 2 diabetes, gout, dyslipidemia, rheumatoid arthritis, Sjogren syndrome, and herpes zoster.
The use of selective serotonin receptor inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), Serotonin antagonist and reuptake inhibitors (SARIs), Tricyclic antidepressants (TCAs), benzodiazepine (BZD), Norepinephrine-dopamine reuptake inhibitors (NDRIs), muscle relaxants, analgesic drugs, psychotherapies, and exercise therapies was prescribed significantly more frequently in the CFS cohort than in the control group.
Conclusion: This large national study shared the mainstream therapies of CFS in Taiwan, we noticed these treatments reported effective to relieve symptoms in previous studies. Furthermore, our findings indicate that clinicians should have a heightened awareness of the comorbidities of CFS, especially in psychiatric problems.
Ramírez-Morales R, Bermúdez-Benítez E, Martínez-Martínez LA, Martínez-Lavín M.
Autoimmun Rev. 2022 Jun 8:103129. [Epub ahead of print]
Abstract
Introduction: Myalgic encephalomyelitis is an illness characterized by profound malaise after mental or physical effort occurring in patients already suffering from constant fatigue. On the other hand, widespread pain and widespread allodynia are the core fibromyalgia clinical features.
There is controversy on these two syndromes alikeness. Through the years, different diagnostic and/or classification criteria have been put forward to appraise both fibromyalgia and myalgic encephalomyelitis.
The epidemiology of these two illnesses, and their overlap, may vary accordingly to the used definition. The most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria incorporates three myalgic encephalomyelitis features including fatigue, waking unrefreshed and dyscognition. The objective of this meta-analysis was to define the clinical overlap between fibromyalgia and myalgic encephalomyelitis based on a systematic literature review.
Methods: PubMed, Embase, Lilacs, and Cochrane data bases were searched on January 25, 2021 linking the medical subject heading “Fibromyalgia” to the following terms “chronic fatigue syndrome”, “myalgic encephalomyelitis” and “systemic exertion intolerance disease”.
Our review included all original articles in which the clinical overlap between fibromyalgia and myalgic encephalomyelitis could be quantified based on recognized diagnostic or classification criteria. Articles scrutiny and selection followed the PRISMA guidelines. Each study quality was assessed according to GRADE recommendations. The global clinical overlap was calculated using a fixed effect model with inverse variance-weighted average method.
Results: Twenty one publications were included in the meta-analysis. Reviewed studies were highly dissimilar in their design, objectives, sample size, diagnostic criteria, and/or outcomes yielding a 98% heterogeneity index.
Nevertheless, the clinical overlap between fibromyalgia and myalgic encephalomyelitis was a well defined outcome that could be reliably calculated despite the high heterogeneity value.
All reviewed publications had moderate GRADE evidence level. Most evaluated articles used the old 1990 Wolfe et al. fibromyalgia diagnostic criteria. Myalgic encephalomyelitis and fibromyalgia diagnoses overlapped in 47.3% (95% CI: 45.97-48.63) of the reported cases.
Conclusion: This meta-analysis found prominent clinical overlap between fibromyalgia and myalgic encephalomyelitis. It seems likely that this concordance would be even higher when using the most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria.
Wiedbusch E, Jason LA.
Arch Community Med. 2022;4(1):59-63.
Abstract
A core criterion for Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME) is a substantial reduction in functioning from pre-illness levels.
Despite its ubiquity in diagnostic criteria, there is considerable debate regarding how to measure this domain. The current study assesses five distinct methods for measuring substantial reductions.
The analysis used an international, aggregated dataset of patients (N = 2,368) and controls (N=359) to compare the effectiveness of each method. Four methods involved sophisticated analytic approaches using the Medical Outcomes Survey Short Form-36; the fifth method included a single self-report item on the DePaul Symptom Questionnaire (DSQ).
Our main finding was that all methods produced comparable results, though the DSQ item was the most valid in differentiating patients from controls. Having a simple, reliable method to capture a substantial reduction in functioning has considerable advantages for patients and health care workers.
Massimo Nunes, Arneaux Kruger, Amy Proal, Douglas Kell, Etheresia Pretorius
Research Square [Preprint]
Abstract
We have previously demonstrated that platelet poor plasma (PPP) obtained from patients with LongCovid/Post-Acute Sequelae of COVID-19 (PASC) is characterized by a hypercoagulable state reflected in hyperactivated platelets and the presence of considerable numbers of fibrin(ogen) amyloid microclots or fibrinaloid microclots.
Due to substantial overlap in symptoms and aetiology between PASC and ME/CFS, we investigated whether coagulopathies, platelet hyperactivation and/or fibrin amyloid formation differed between individuals exhibiting ME/CFS and gender- and age-matched healthy controls. ME/CFS patients were statistically far more hypercoagulable as judged by thromboelastography of both whole blood and platelet-poor plasma.
The area of plasma images containing fibrinaloid microclots was commonly more than 10-fold greater in untreated platelet-poor plasma from individuals with ME/CFS than in that of healthy controls.
A similar difference was found when the plasma samples were treated with thrombin. Using fluorescently labelled PAC-1, which recognizes glycoprotein IIb/IIIa, and CD62P, which binds P-selectin, we observed massive hyperactivation and spreading of platelets in samples from individuals with ME/CFS.
Using a quantitative scoring system, this was found to have a score of 2.72 ± 1.24 vs 1.00 (activation with pseudopodia formation) for healthy controls. We conclude that ME/CFS is accompanied by substantial and measurable changes in coagulability, platelet hyperactivation, and fibrinaloid microclot formation.
However, fibrinaloid microclot load was not as prevalent as was previously noted in PASC. Fibrinaloid microclots, in particular can provide a ready explanation, via (temporary) blockage of microcapillaries and hence ischaemia, for many of the symptoms, such as fatigue, seen in patients with ME/CFS.
The discovery of these biomarkers pointing to significant and systemic endothelial inflammation, represents an important development in ME/CFS research. It also points at novel treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation.
Tate W, Walker M, Sweetman E, Helliwell A, Peppercorn K, Edgar C, Blair A, Chatterjee A.
Front Neurol. 2022 May 25;13:877772.
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented as having arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events.
Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long.
The severity of the symptoms frequently fluctuates through relapse recovery periods, with brain-centered symptoms of neuroinflammation, loss of homeostatic control, “brain fog” affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address.
We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles.
Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur.
By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2. We believe the ME/CFS-like ongoing effects of Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with some unique signaling, resulting from the pathology of the initial SARS-CoV-2 infection.
The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.
Haider, Saman; Janowski, Adam J; Lesnak, Joseph B; Hayashi, Kazuhiro; Dailey, Dana L; Chimenti, Ruth; Frey-Law, Laura A; Sluka, Kathleen A
PAIN: June 08, 2022 – Volume – Issue – 10.1097/j.pain.0000000000002711
Abstract
A growing number of individuals report prolonged symptoms following acute COVID-19 infection, known as post-COVID-19 condition (post-COVID-19).
While studies have emerged investigating the symptom sequelae of post-COVID-19, there has been limited investigation into the characterization of pain, fatigue, and function in these individuals, despite initial reports of a clinical phenotype similar to fibromyalgia (FMS) and chronic fatigue syndrome/myalgic encephalomyelitis (CFS).
This study aimed to characterize multiple symptom domains in individuals reporting post-COVID-19 and compare its clinical phenotype to those with FMS and CFS.
A total of 707 individuals with a single or comorbid diagnosis of post-COVID-19, FMS, and/or CFS completed multiple surveys assessing self-reported pain, fatigue, physical and cognitive function, catastrophizing, kinesiophobia, anxiety, depression, dyspnea, and sleep quality. In all three diagnoses, elevated pain, fatigue, anxiety, depression, catastrophizing, and kinesiophobia were reported.
Physical and cognitive function were similarly impacted among individuals with post-COVID-19, FMS, and CFS; however, individuals with post-COVID-19 reported lower pain and fatigue than FMS and CFS.
The comorbid diagnosis of post-COVID-19 with FMS and/or CFS further exacerbated pain, fatigue, and psychological domains when compared to post-COVID-19 alone.
In summary, individuals with post-COVID-19 report a symptom phenotype similar to FMS and CFS, negatively impacting cognitive and physical function, but with less severe pain and fatigue overall. These findings may help direct future investigations of the benefit of a biopsychosocial approach to the clinical management of post-COVID-19.
7. Immunogenetic studies in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Riad Hajdarevic
PhD thesis (University of Oslo)
Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that affects about 0.1-0.2% of the general population. The core symptoms are persistent debilitating fatigue, post-exertional malaise (PEM) and cognitive dysfunction. Most symptoms of ME/CFS are not disease specific. Additionally, there is a lack of both biomarkers and diagnostic tests for the disease, which makes accurate diagnosis difficult.
More than 20 different patient classifications and diagnostic criteria have emerged over the last four decades. Due to this, the patient population can be quite heterogeneous in terms of clinical symptoms and the extent to which the disease impacts quality of life.
There are several different theories that aim to explain the disease development of ME/CFS. In this thesis, we have taken as our starting point the growing evidence for an immunological background for ME/CFS pathogenesis. Several studies have pointed to altered NK cells, autoantibodies and T cell abnormalities in ME/CFS patients.
In addition, several genetic studies reported significant associations in various immunologically relevant genes. Most of these previous studies have been suboptimal and included heterogeneous patient populations and/or few patients in total.
Therefore, we aimed to gain a better understanding of the role of immunologically relevant genes and disease development of ME/CFS.
To do this, we employed known strategies from genetic studies in autoimmune disease and applied them to ME/CFS. We used strict quality control and included, to the best of our knowledge, the largest cohort diagnosed with the Canadian consensus criteria.
In paper I, the main goal was to follow up previously performed work by our group that reported associations between ME/CFS and HLA-C: 07: 04 and HLA-DQB1: 03: 03 alleles. The HLA (human leukocyte antigen) region consists a multitude of immunologically relevant genes in addition to the HLA genes, and there is extensive and complex linkage disequilibrium (LD) in the region.
The previously observed association signals in the HLA region were fine-mapped by genotyping five additional classical HLA loci and 5,342 SNPs (single nucleotide variants) in 427 Norwegian ME/CFS patients, diagnosed according to the Canadian consensus criteria, and 480 healthy Norwegian controls. The analysis revealed two independent association signals (p ≤ 0.001) represented by the genetic variants rs4711249 in the HLA class I region and rs9275582 in the HLA class II region.
The primary association signal in the HLA class II region was located in the vicinity of the HLA-DQ genetic region, most likely due to the HLA-DQB1 gene. In particular, amino acid position 57 (aspartic acid / alanine) in the peptide binding pit of HLA-DQB1, or an SNP upstream of HLA-DQB1 seemed to explain the association signal we observed in the HLA class II region.
In the HLA class I region, the putative primary locus was not as clear and could possibly lie outside the classical HLA genes (the association signal spans several genes DDR1, GTF2H4, VARS2, SFTA2 and DPCR1) with expression levels influenced by the ME/CFS associated SNP genotypes.
Interestingly, we also observed that > 60% of the patients who responded to cyclophosphamide treatment for ME/CFS had either the rs4711249 risk allele and/or DQB1* 03:03 versus 12% of the patients who did not respond to the treatment. Our findings suggest the involvement of the HLA region, and in particular the HLA-DQB1 gene, in ME/CFS.
Although our study is the largest to date, it is still a relatively small study in the context of genetic studies. Our findings need to be replicated in much larger, statistically more representative, cohorts.
In particular, it is necessary to investigate the involvement of HLA- 12 DQB1, a gene that contains alleles that increase the risk of several established autoimmune diseases such as celiac disease.
In paper II, we aimed to investigate immunologically relevant genes using a genotyping array (iChip) targeting immunological gene regions previously associated with different autoimmune diseases.
In addition to the Norwegian cohort of 427 ME/CFS patients (the Canadian consensus criteria), we also analyzed data from two replication cohorts, a Danish one of 460 ME/CFS patients (Canadian consensus criteria) and a data set from the UK Biobank of 2105 self-reported CFS patients.
To the best of our knowledge, this is the first ME/CFS genetic association study of this magnitude and it included more than 2,900 patients in total (of whom 887 are diagnosed according to Canadian consensus criteria).
We found no ME/CFS risk variants with a genome wide significance level (p<5×10-8), but we identified six gene regions (TPPP, LINC00333, RIN3. IGFBP/IGFBP3, IZUMO1/MAMSTR and ZBTB46/STMN3) with possible association with ME/CFS which require further follow-up in future studies in order to assess whether they are real findings or not.
Interestingly, these genes are expressed in disease-relevant tissue, e.g. brain, nerve, skeletal muscle and blood, including immune cells (subgroups of T cells, B cells, NK cells and monocytes).
Furthermore, several of the ME/CFS associated SNP genotypes are associated with differential expression levels of these genes. Although we could not identify statistically convincing associations with genetic variants across the three cohorts, we believe that our data sets and analysis represent an important step in the ME/CFS research field.
Our study demonstrated that for the future understanding of the genetic architecture of ME/CFS much larger studies are required to established reliable associations.
In paper III, we wanted to investigate previous findings from a genome wide association study of 42 ME/CFS patients who reported significant association with two SNPs in the T cell receptor alpha (TRA) locus (P-value<5×10-8).
In order to replicate these previously reported findings, we used a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK Biobank (2105 cases and 4786 controls). We examined a number of SNPs in the TRA locus, including the two previous ME/CFS-associated variants, rs11157573 and rs17255510. No statistically significant associations were observed in either the Norwegian cohort or UK biobank cohorts.
Nevertheless, other SNPs in the region showed weak signs of association (P-value <0.05) in the UK Biobank cohort and meta-analyzes of Norwegian and UK Biobank cohorts, but did not remain associated after applying correction for multiple testing. Thus, we could not confirm associations with genetic variants in the TRA locus in this study.
Long-COVID Research References
Dr Katrina Pears,
Research Correspondent.
The ME Association.
