The ‘medically unexplained symptoms’ (MUS) concept, CBT & CFS

Posted on 09/28/2021 by wames

The ‘medically unexplained symptoms’ syndrome concept and the cognitive-behavioural treatment model, by Michael J Scott , Joan S Crawford , Keith J Geraghty , David F Marks in Journal of Health Psychology Sep 2021 [doi:10.1177/13591053211038042]

 

Article abstract:

The American Psychiatric Association’s, 2013 DSM-5 abandoned the use of the term ‘medically unexplained symptoms’ for non-neurological disorders. In the UK, treatments for various medical illnesses with unexplained aetiology, such as chronic fatigue syndrome, irritable bowel syndrome and fibromyalgia, continue to fall under an MUS umbrella with cognitive behavioural therapy promoted as a primary therapeutic approach.

In this editorial, we comment on whether the MUS concept is a viable diagnostic term, the credibility of the cognitive-behavioural MUS treatment model, the necessity of practitioner training and the validity of evidence of effectiveness in routine practice.

As the MUS diagnostic category is alleged to include up to one-third of all patients seen in primary care on a regular basis (Nimnuan et al., 2001), the scale of the artificially created ‘syndrome’ highlights the absurdity of such a conceptualisation.

Excerpt:

Maes and Twisk (2010) provide a predominantly biological model to help explain chronic fatigue syndrome, rescuing it from the ‘unexplained’ category. Their model explains readily why immunological and endocrinological variables better predict outcome in CFS than psychological variables. By contrast, in the Harvey and Wessely (2009) model of CFS there is no specification of any key and lock mechanism that is, what precipitant, acting on which predisposing factor would usher in the said debility, nor which perpetuating factor would be pertinent to which key-lock combination.

Excerpt: 

A recurring theme among practitioners applying the CBM is the claim that dysfunctional illness beliefs (e.g. that ‘symptoms are the result of a virus’) are causally linked to deconditioning and a poor prognosis (e.g. Wessely et al., 1991). Attempting to induce patients into cognitive behaviour therapy (CBT) to change the way they are alleged to habitually think has not proved a successful strategy, as the revised NICE (2020) guidance has concluded.

Conclusions:

The MUS concept can no longer be accepted as a viable diagnostic term. The credibility of the cognitive-behavioural MUS treatment model has reached a nadir and can be given only an auxiliary role in treatment. An urgent necessity to provide practitioner training has been identified and the need for greater awareness of the misleading nature of poor quality evidence for effectiveness of the CBT approach in routine practice.

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Diagnostic test hypothesis: iP stem cells as suitable sensors for FM & ME/CFS

Posted on 09/27/2021 by wames

Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome, by Maria B Monzon-Nomdedeu, Karl J Morten, Elisa Oltra in World Journal of Stem Cells Vol 13, #8, pp 1134-1150 [DOI:10.4252/wjsc.v13.i8.1134] August 26, 2021

 

Core Tip:

Because of the special ability to sense environmental cues we propose that induced pluripotent stem cells (iPSCs) are suitable for use as a sensor system for metabolic disease. As fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome body-fluids have unique metabolic profiles, the applicability of iPSC-based bioassays for those conditions are worth investigating.

We envisage the development of iPSC platforms that allow differential diagnosis and disease-specific high-throughput drug-screening platforms. Using healthy iPSCs and patient body fluids has significant advantages over using cell lines, primary culture of patient cells or iPSCs derived from patients.

A consistent iPSC control-cell line platform will provide a robust metabolic/phenotypic model allowing faster, cost-effective, large cohort screenings.

Review abstract:

Background

Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are devastating metabolic neuroimmune diseases that are difficult to diagnose because of the presence of numerous symptoms and a lack of specific biomarkers. Despite patient heterogeneity linked to patient subgroups and variation in disease severity, anomalies are found in the blood and plasma of these patients when compared with healthy control groups.

Stem cells are the body’s raw materials — cells from which all other cells with specialized functions are generated. Under the right conditions in the body or a laboratory, stem cells divide to form more cells called daughter cells.     Mayo Clinic

The seeming specificity of these ‘plasma factors’, as recently reported by Ron Davis and his group at Stanford University, CA, United States, and observations by our group, have led to the proposal that induced pluripotent stem cells (iPSCs) may be used as metabolic sensors for FM and ME/CFS, a hypothesis that is the basis for this in-depth review.

Aim

To identify metabolic signatures in FM and/or ME/CFS supporting the existence of disease-associated plasma factors to be sensed by iPSCs.

Methods

A PRISMA (Preferred Reported Items for Systematic Reviews and Meta-analysis)-based systematic review of the literature was used to select original studies evaluating the metabolite profiles of FM and ME/CFS body fluids. The MeSH terms ‘metabolomic’ or ‘metabolites’ in combination with FM and ME/CFS disease terms were screened against the PubMed database.

Only original studies applying omics technologies, published in English, were included. The data obtained were tabulated according to the disease and type of body fluid analyzed. Coincidences across studies were searched and P-values reported by the original studies were gathered to document significant differences found in the disease groups.

Results

Eighteen previous studies show that some metabolites are commonly altered in ME/CFS and FM body fluids. In vitro cell-based assays have the potential to be developed as screening platforms, providing evidence for the existence of factors in patient body fluids capable of altering morphology, differentiation state and/or growth patterns. Moreover, they can be further developed using approaches aimed at blocking or reversing the effects of specific plasma/serum factors seen in patients. The documented high sensitivity and effective responses of iPSCs to environmental cues suggests that these pluripotent cells could form robust, reproducible reporter systems of metabolic diseases, including ME/CFS and FM.

Furthermore, culturing iPSCs, or their mesenchymal stem cell counterparts, in patient-conditioned medium may provide valuable information to predict individual outcomes to stem-cell therapy in the context of precision medicine studies.

Conclusion

This opinion review explains our hypothesis that iPSCs could be developed as a screening platform to provide evidence of a metabolic imbalance in FM and ME/CFS.

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Diagnostic test research: C1q as a potential diagnostic tool for ME/CFS subtyping

Posted on 09/23/2021 by wames

Complement Component C1q as a Potential Diagnostic Tool for ME/CFS Subtyping, by Jesús Castro-Marrero, Mario Zacares, Eloy Almenar-Pérez,  José Alegre-Martín and Elisa Oltra in J. Clin. Med. 2021, 10(18), 4171; [doi.org/10.3390/jcm10184171] 15 September 2021

 

Research abstract:

Background:

Routine blood analytics are systematically used in the clinic to diagnose disease or confirm individuals’ healthy status. For myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), a disease relying exclusively on clinical symptoms for its diagnosis, blood analytics only serve to rule out underlying conditions leading to exerting fatigue. However, studies evaluating complete and large blood datasets by combinatorial approaches to evidence ME/CFS condition or detect/identify case subgroups are still scarce.

Methods:

This study used unbiased hierarchical cluster analysis of a large cohort of 250 carefully phenotyped female ME/CFS cases toward exploring this possibility.

Results:

The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms.

Conclusions:

The results obtained have important implications for the research of ME/CFS etiology and, most likely, for the implementation of future diagnosis methods and treatments of ME/CFS in the clinic.

Excerpt from Conclusion:

In conclusion, this study identified a potential new player in the ME/CFS pathology, the C1q component of the complement system, affecting over 40% of cases. This finding paves the way for exploring a C1q-based standard lab assay to detect ME/CFS subtypes with relevant clinical and research implications. The understanding of the underlying pathomechanisms behind this finding is limited at present, granting further exploration of the observation.

Excerpt from Discussion:

Although clustering methods based on case symptoms have been useful in identifying autonomic phenotypes in CFS [25], they failed at detecting robust blood correlations between symptoms and individual blood parameters in our cohort (Figure 2). The approach did, however, show potential for differentiating cases with severe, moderate, or mild affection as defined by the five symptom scores used for clustering (Table 2 and Table 3).

The physiological significance of the findings, including the increased levels of C3 in severe and moderate with respect to mildly affected cases or the increased neutrophil count in severe ME/CFS by itself or in combination with LDL and cholesterol, as well as their involvement in symptom development or maintenance, remains to be elucidated.

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Hypothesis: Broken connections: the evidence for neuroglial failure in ME/CFS

Posted on 09/22/2021 by wames

Broken Connections: The evidence for neuroglial failure in ME/CFS, by Herbert Renz-Polster, MD, Dorothee Bienzle, PhD 31 Aug 2021 [doi:10.31219/osf.io/ef3n4]

 

Review abstract:

In spite of decades of research, the pathobiology of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is still poorly understood. Several pathomechanisms have been identified – including immune abnormalities, inflammatory activation, mitochondrial dysfunction, endothelial dysfunction, muscular dysfunction, cardiovascular dysfunction, and dysfunction of the autonomous nervous system.

Yet, it remains unclear how these pathways are related, which of them may be upstream or downstream, and which ones may be explanatory of the symptomatology of ME/CFS (and thus possibly targets for therapeutic interventions).

A similar uncertainty is currently experienced by thousands of researchers who struggle to understand Postacute Sequelae of Covid (PASC, “Long Covid”), a condition with many similarities to ME/CFS.

In this paper, we present a theoretical strategy that may help clarify the causal chain of pathophysiological events in ME/CFS. We propose to focus on the common final histological pathway of ME/CFS. i.e., we suggest to ask: Which cellular compartment may explain the pathological processes and clinical manifestations observed in ME/CFS? Any functional unit consistently identified through this search may then be a plausible candidate for further exploration.

For this “histological” approach we have compiled a list of 22 undisputed clinical and pathophysiological features of ME/CFS that need to be plausibly and most directly explained by the dysfunctional cellular unit in question. For each feature we have searched the literature for pathophysiological explanations and analyzed if they may point to the same functional cellular unit.

Through this search we have identified the CNS neuroglia – microglia and astroglia – as the one functional unit in the human body which may best explain all and any of the clinical and pathological features, dysfunctions and observations described for ME/CFS. While this points to neuroinflammation as the central hub in ME/CFS, it also points to a novel understanding of the
neuroimmune basis of ME/CFS.

After all, the neuroglial cells are now understood as the functional matrix of the human brain connectome which operates beyond and above specific brain centers, receptor units or neurotransmitter systems and integrates innate immune functions with CNS regulatory functions pertaining to autonomous regulation, cellular metabolism and the stress response.

We feel encouraged in this “histological” concept by recent findings from fibromyalgia research. After 50 years of unsuccessful investigations this “sister disease” of ME/CFS has been unraveled – through a “histological” approach. As ingenious human-mouse transfer experiment have shown, fibromyalgia is based on a neuroimmune process directed against the glial cells in the dorsal root ganglia of the spinal cord.

The theoretical leads that we are presenting in this review point in a
similar direction: the final pathogenetic pathway of ME/CFS is likely to consist of a neuroimmune reaction – directed against the glial cells of the CNS connectome.

‘The neuroglial unit orchestrates the many physiological functions that have so far been implicated in ME/CFS’

Of note, this is not a unifying theory about the etiology, the triggers or the inception process of ME/CFS. This approach is focused solely on finding the final pathogenetic pathway(s) which may underlie the clinical manifestations of ME/CFS. It does not question existing theories about the inception of ME/CFS, be they based on autoimmunity, persistent infection, mitochondrial or metabolic failure or any other assumption.

Conclusion 3
The profound dysregulation underlying ME/CFS is seated in the central nervous system
. Anyone who has worked through this working paper may understand why this is the only plausible assumption for me: ALL the phenomena of ME/CFS can be most directly explained as a consequence of dysfunctions in the central nervous system. There is just no other location in the human body in
which the deep seated, archaic regulatory units affected in ME/CFS are to be found.

For me, ME/CFS is not a dysfunction that ALSO affects the CNS, it is a dysfunction that is DRIVEN by the CNS. For me, this “central” explanation also covers the general mitochondrial dysfunction seen in ME/CFS, the
muscular dysfunction and the “enigmatic cardiovascular situation in ME/CFS – “peripheral” as all these features may appear, they all can be explained as consequences of central regulatory dysfunctions.

Bluntly, in an “Occam’s razor” investigation, there is just no need for a “peripheral” explanation. Also, the “central” hypothesis is also the only explanation that fits with the specific “coupling” of symptoms in ME/CFS (see [2.5]). And it is also the only explanation for the multi-trigger, threshold driven, delayed and prolonged stress response after exercise (see [3.0]).

Here, I need to add a disclaimer: This is a functional description of how the clinical cascade of ME/CFS may be best explained. This does NOT imply that influences outside the CNS may not play a role in ME/CFS or may not be appropriate targets for therapeutic interventions. Similarly, the “central”
argument does also not imply that there may not be more profound, general processes that inaugurate, prime, sustain or otherwise influence this central pathological matrix (to be revisited below).

Conclusion 4
The pathophysiology of ME/CFS affects completely disparate physiological processes. It is a “dauer state” and it is “sustained arousal” – at the same time. It is vagal dysfunction and sympathetic dysfunction – at the same time. It is adrenergic stimulation and adrenergic failure – at the same time.

It is hyperarousal and under arousal – at the same time (for details on the “paradoxical” nature of ME/CFS, see [4.11]). ME/CFS just does not fit into any single regulatory unit. I therefore doubt that what is broken in ME/CFS can be found in a single brain nucleus (like a “fatigue nucleus”) or a single transmitter system or a single receptor system. I rather suggest that the core pathology of ME/CFS is a diffuse one that affects a matrix that contributes to many regulatory units and spans many regulatory levels.

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Research review: The enterovirus theory of disease etiology in ME/CFS

Posted on 09/16/2021 by wames

The enterovirus theory of disease etiology in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: a critical review, by Adam J O’Neal and Maureen R Hanson in Front. Med., 18 June 2021 [doi.org/10.3389/fmed.2021.688486]

 

Research review abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established.

Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle, and heart.

To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fuelled a decline in related studies over the past two decades.

This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen.

We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS.

Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.

Excerpts from Discussion:

Many ME/CFS patients in a variety of studies indicate a viral-like illness immediately preceded their ME/CFS symptoms. However, surveys also indicate that patients ascribe their onset to a variety of other reasons, including emotional stress, life events, recent travel, accidents, toxic substances, or mold. However, some of these events and exposures could merely be coincidental and actually be due to an enteroviral infection that was unnoticed or very mild, given that many enteroviral infections are asymptomatic.

The COVID19 pandemic has made it obvious that persistent symptoms can arise from mild or asymptomatic infections. Were the existence of SARS CoV-2 not known, many of the individuals with long-lasting symptoms of COVID 19 might readily have ascribed their mysterious illness to some other factor than viral infection.

It is evident that more research must be conducted in order to determine whether or not the majority of pre-2020 ME/CFS cases have arisen from EV infection. At the time of this writing, there have been a number of anecdotal reports of individuals experiencing remission of long-term COVID19 symptoms after receiving anti-SARS COV2 vaccines. Such a therapy will not be possible for any ME/CFS patients whose illness is due to chronic infection unless the persistent virus is identified.

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Genetic research: Fine mapping of the major histocompatibility complex (MHC) in ME/CFS

Posted on 09/13/2021 by wames

Fine mapping of the major histocompatibility complex (MHC) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggests involvement of both HLA class I and class II loci, by Riad Hajdarevic, Asgeir Lande, Ingrid Rekeland, Anne Rydland, Elin B Strand, Daisy D Sosa, Lisa E Creary, Olav Mella, Torstein Egeland, Ola D Saugstad, Øystein Fluge, Benedicte A Lie, Marte K Viken in Brain Behav Immun. 2021 Aug 14;S0889-1591(21)00509-2 [doi: 10.1016/j.bbi.2021.08.219]

 

Highlights:

  • By far the largest genetic study in ME/CFS.
  • Multi-level HLA and SNP analysis.
  • Independent HLA class I and II associations.
  • Positive association of HLA-DQB1 amino acid residue 57D.

Abstract:

The etiology of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is unknown, but involvement of the immune system is one of the proposed underlying mechanisms. Human leukocyte antigen (HLA) associations are hallmarks of immune-mediated and autoimmune diseases.

We have previously performed high resolution HLA genotyping and detected associations between ME/CFS and certain HLA class I and class II alleles. However, the HLA complex harbors numerous genes of immunological importance, and there is extensive and complex linkage disequilibrium across the region.

In the current study, we aimed to fine map the association signals in the HLA complex by genotyping five additional classical HLA loci and 5,342 SNPs in 427 Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria, and 480 healthy Norwegian controls.

Crystallographic structure of HLA-DQA1 (cyan) complexed with HLA-DQB1 (green) & HCRT (magenta) based on PDB: 1uvq​.

SNP association analysis revealed two distinct and independent association signals (p≤0.001) tagged by rs4711249 in the HLA class I region and rs9275582 in the HLA class II region. Furthermore, the primary association signal in the HLA class II region was located within the HLA-DQ gene region, most likely due to HLA-DQB1, particularly the amino acid position 57 (aspartic acid/alanine) in the peptide binding groove, or an intergenic SNP upstream of HLA-DQB1.

In the HLA class I region, the putative causal locus might map outside the classical HLA genes as the association signal spans several genes (DDR1, GTF2H4, VARS2, SFTA2 and DPCR1) with expression levels influenced by the ME/CFS associated SNP genotype.

Taken together, our results implicate the involvement of the MHC, and in particular the HLA-DQB1 gene, in ME/CFS. These findings should be replicated in larger cohorts, particularly to verify the putative involvement of HLA-DQB1, a gene important for antigen-presentation to T cells and known to harbor alleles providing the largest risk for well-established autoimmune diseases.

 

Riad Hajdarevic says:

Hello I am the first author of the studies. I want to bring some clarity to the paper to you guys.

Our study was trying to see the involvement of HLA genes in ME/CFS. We observed some genetic changes (SNPs) to be associated with ME/CFS across the immunologically important HLA genes.

The patients we analyzed were diagnosed according to the CCC. As you know the CCC are more stringent than the Fukuda or similar criteria. Our patient population was 427 Norwegian ME/CFS patients. This is the largest ME/CFS cohort diagnosed according to the CCC however we need much more (up to 10 x) to definitely make a correlation between our findings and ME/CFS.

So far, no clinical implications can be made from this. However, it is indicative that those genetic changes (SNPs) influenced gene expression of some relevant genes for the observed ME/CFS clinical picture. Likewise, it seems (from this statistically limited data set) that some of those changes correlate with response to cyclophosphamide treatment in patients with ME/CFS. You have heard, I assume, about our collaborator’s study from Bergen where they reported improved symptoms for some ME/CFS patients taking the drug.

I just have to emphasize that we need much more research with much, much more patients diagnosed with the CCC to make any deeper assumptions.
If you have any extra questions please let me know I am glad to explain the findings in detail to anyone who wants to know the details.

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Research: A map of metabolic phenotypes in patients with ME/CFS

Posted on 09/10/2021 by wames

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/ chronic fatigue syndrome by Fredrik Hoel, August Hoel, Ina Kn Pettersen, Ingrid G Rekeland, Kristin Risa, Kine Alme, Kari Sørland, Alexander Fosså, Katarina Lien, Ingrid Herder, Hanne L Thürmer, Merete E Gotaas, Christoph Schäfer, Rolf K Berge, Kristian Sommerfelt, Hans-Peter Marti, Olav Dahl, Olav Mella, Øystein Fluge, Karl J Tronstad in JCI Insight 2021;6(16):e149217 [doi.org/10.1172/jci.insight.149217]

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established.

Energy metabolism is the general process by which living cells acquire and use the energy needed to stay alive, to grow, and to reproduce.  Da Poian et al

We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls.

Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses.

Metabolic phenotypes are the products of interactions among a variety of factors-dietary, other lifestyle/environmental, gut microbial and genetic.             Holmes et al

In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.

Comment:

Science Norway: ME/CFS may be linked to failure in energy supply to the cells

ME Association blog: Research Summary – A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome 

MEprecisely: John Duncan

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UK Gov CFS research funding – Q&A in parliament

Posted on 09/10/2021 by wames

UK Parliament Written Question & Answers: CFS

1. Question from Alex Norrie MP, Labour, Nottingham North

To ask the Secretary of State for Health and Social Care, how much Government funding has been provided to ME research in each of the last three years. [UIN 38397, tabled on 22 July 2021]

Answer from Edward Argar MP, Minister of State (Department of Health and Social Care)

The following table shows the funding for research into myalgic encephalomyelitis through the National Institute for Health Research and UK Research and Innovation in the last three years.

Financial Year   Pounds
2018-19                   862,212
2019-20                   691,516
2020-21                   907,848

[Source: UK House of Commons, September 6, 2021]

2. Question from Janet Daby MP, Labour, Lewisham East

To ask the Secretary of State for Health and Social Care, whether he has made a recent assessment of the potential merits of increasing funding for research into ME and Chronic Fatigue Syndrome.  [UIN 41247, tabled on 18 August 2021]

Answer from Edward Argar MP, Minister of State (Department of Health and Social Care)

The Government invests in health research through the National Institute for Health Research (NIHR) and the Medical Research Council (MRC), through UK Research and Innovation. The NIHR and MRC both welcome high-quality applications for research into all aspects of myalgic encephalomyelitis (ME), otherwise known as chronic fatigue syndrome (CFS).

No assessment has been made of the merits of increasing funding for research into ME/CFS. While it is not usual practice for the NIHR and MRC to ring-fence funds for particular topics or conditions, the MRC has had a cross-board highlight notice on CFS/ME open since 2003.

[Source: UK House of Commons, September 6, 2021]

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Research: The SARS-CoV-2 receptor ACE2 in ME/CFS

Posted on 09/08/2021 by wames

The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in  Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a meta-analysis of public DNA methylation and gene expression data, by João Malato, Franziska Sotzny, Sandra Bauer, Helma Freitag, André Fonseca, Anna D Grabowska, Luís Graça, Clara Cordeiro, Luís Nacul, Eliana M Lacerda, Jesus Castro-Marrero, Carmen Scheibenbogen, Francisco Westermeier, Nuno Sepúlveda in Heliyon 2021 Jul 29;7(8):e07665 [doi: 10.1016/j.heliyon.2021.e07665]

 

Research abstract: 

Protein_ACE2_PDB_1r42

People with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Since this reporting is in line with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed to explore whether the expression of the human angiotensin-converting enzyme-2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in this neglected clinical population. In particular, a low expression of ACE2 is usually indicative of a high risk of developing COVID-19.

We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients with ME/CFS when compared to healthy controls.

Accordingly, in newly collected data, we found evidence for a higher proportion of samples with an ACE2 expression below the limit of detection in patients with ME/CFS than in healthy controls.

Altogether, patients with ME/CFS could be at a higher COVID-19 risk when infected by SARS-CoV-2. To further support this conclusion, similar research should be conducted for other human cell entry receptors and other cell types, namely, those mainly targeted by the virus.

Comment:

ME Association: Research Summary – Are people with ME/CFS at higher risk of complications from COVID infection?

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Treatment Research: Cortene’s InTime trial of CT38 results in sustained symptom improvement in ME/CFS

Posted on 09/07/2021 by wames

Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Gerard Pereira, Hunter Gillies, Sanjay Chanda, Michael Corbett, Suzanne D. Vernon, Tina Milani and Lucinda Bateman in Front. Syst. Neurosci., 01 Sep 2021 [doi.org/10.3389/fnsys.2021.698240]

 

Research abstract:

Background:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.

Materials and Methods:

This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.

Results:

ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.

Conclusion:

The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.

Comments:

Biospace: Clinical trial provides preliminary evidence of a cure for myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and Long Covid

Cortene believes the CRFR2 pathway is upregulated and therefore overactive, leading to the wide variety of symptoms in ME/CFS.  “The conventional approach would be to block the overactive pathway. Instead, our counterintuitive approach seeks to overstimulate CRFR2, causing it to downregulate, without the need for chronic treatment.”

Health arising: The Cortene drug trial results for ME/CFS are in

Dr. Bateman indicated that many of the participants reported subtle but noticeable improvements of their symptoms over the 1-2 years following the trial.

In an interview, Cortene proposed that partial downregulation of the CRFR2 receptor had indeed occurred, and that further trials would determine if they could fully return it and the stress response system in ME/CFS to a healthy state.

Cortene hopes to embark on a 60-person $4 million trial next.

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