Tag: long covid vs ME/CFS

Long COVID, POTS, CFS and MTHFR: Linked by Biochemistry and Nutrition

Abstract:

The recent pandemic has energized research spotlighting chronic fatigue disorders. The similarities between Long COVID (LC) and Chronic Fatigue Syndrome (CFS), often accompanied by postural orthostatic tachycardia syndrome (POTS) are striking.

Furthermore, the majority afflicted with LC and CFS may be those with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, present in the majority of Americans and characterized by hypomethylation. Elevated homocysteine (Hcy) and depressed B9 and B12 may be links. Speculation about an association between these laboratory analytes and MTHFR abnormalities has been previously reported (Regland et al., 2015).

The absence of a blood-brain barrier (BBB) in CNS circumventricular organs (CVOs) that control autonomic and neuroendocrine functions, problematic in LC, CFS, POTS, and MTHFR, is provocative. Diffusion of CNS Hcy is associated with brain fog, cognitive impairment, and dementia. This provides a distinct link between MTHFR variants and the fog of LC, CFS, and POTS.

Small intestine bacterial overgrowth (SIBO), present in about 17% of Americans, is linked to POTS, mast cell activation syndrome (MCAS), and Ehlers Danlos syndrome (EDS). All exhibit histamine intolerance and female predominance. This may be due to hypomethylation and/or intestinal diamine oxidase (DAO) deficiency.

Metabolism of monoamines and histamine requires methylation. Specific CNS nuclei in CVOs may also provide insight to the POTS paradox. The similar gut microbiomes of LC/CFS (and vitamin D deficiency) may via CVOs trigger an imbalance in glutamate/GABA neurotransmission that translates to neuroendocrine and baroreflex dysfunction. Homozygosity for the MTHFR 677T allele can facilitate hypermethylation via an alternative “rescue” riboflavin pathway triggered by significant Hcy increase.

Hypermethylation predominates in Long Covid. The primary problem in these syndromes is compromised mitochondrial function due to oxidative stress induced by an antioxidant shortfall.

Victims are also frequently deficient in 25(OH)D3 (the storage form of vitamin D), magnesium, and B vitamins, consumed by the persistent chronic inflammatory state. Estrogen increases histamine, norepinephrine, and bradykinin (BKN), which may in part explain the brain fog and its predilection for females.

Source: Patrick W Chambers. Long COVID, POTS, CFS and MTHFR: Linked by Biochemistry and Nutrition. Journal of Orthomolecular Medicine. 38. https://www.researchgate.net/publication/373073968_Long_Covid_POTS_CFS_and_MTHFR_Linked_by_Biochemistry_and_Nutrition#fullTextFileContent (Full text)

Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort

Summary:

Background: Post-COVID-19 syndrome (PCS) is characterised by a wide range of symptoms, primarily fatigue and exertion intolerance. While disease courses in the early months post-infection have been well-described, the long-term health consequences for patients with PCS with disabling fatigue remain unclear.

Methods: In this prospective observational cohort study, we evaluated symptom severity and various biomarkers, including hand grip strength (HGS), cardiovascular function, and laboratory parameters, in 106 patients with PCS with moderate to severe fatigue and exertion intolerance at three time points after infection (3–8, 9–16, and 17–20 months). The study was conducted at the Charité’s Fatigue Centre and the Charité’s outpatient clinic for neuroimmunology at Berlin, Germany from July 16, 2020, to February 18, 2022. A subset of patients (PCS-ME/CFS) met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome according to the Canadian Consensus Criteria (CCC). The aim was to determine differences in the disease course between the two patient groups (i.e., PCS vs PCS-ME/CFS) and identify correlating biomarkers.

Findings: Patients with PCS-ME/CFS reported persistently high severity of most symptoms up to 20 months after infection, while patients with PCS showed overall health improvement. Although fatigue and post-exertional malaise (PEM), hallmarks of post-infectious fatigue syndromes, were still evident in both groups, they remained more pronounced in PCS-ME/CFS. Inflammatory biomarkers decreased in both groups, but not antinuclear antibodies. Lower HGS at onset correlated with symptom persistence, particularly in patients with PCS-ME/CFS.

Interpretation: Our findings suggest that PCS can persist beyond 20 months post-infection and encompass the full scope of post-infectious ME/CFS as defined by the CCC. Sub-classifying patients with PCS based on the CCC can assist in the management and monitoring of patients with PCS-ME/CFS due to their persistently higher symptom severity.

Source: Franziska Legler, Lil Meyer-Arndt, Lukas Mödl, Claudia Kedor, Helma Freitag, Elisa Stein, Uta Hoppmann, Rebekka Rust, Kirsten Wittke, Nadja Siebert, Janina Behrens, Andreas Thiel, Frank Konietschke, Friedemann Paul, Carmen Scheibenbogen, Judith Bellmann-Strobl,
Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort, eClinicalMedicine, Volume 63, 2023, 102146, ISSN 2589-5370, https://doi.org/10.1016/j.eclinm.2023.102146. https://www.sciencedirect.com/science/article/pii/S2589537023003231 (Full text)

Longterm course of neuropsychological symptoms and ME/CFS after SARS-CoV-2-infection: a prospective registry study

Abstract:

A significant proportion of patients after SARS-CoV-2 infection suffer from long-lasting symptoms. Although many different symptoms are described, the majority of patients complains about neuropsychological symptoms. Additionally, a subgroup of patients fulfills diagnostic criteria for ME/CFS. We analyzed a registry of all patients presenting in the out-patients clinic at a German university center. For patients with more than one visit, changes in reported symptoms from first to second visit were analyzed.

A total of 1022 patients were included in the study, 411 of them had more than one visit. 95.5% of the patients reported a polysymptomatic disease. At the first visit 31.3% of the patients fulfilled ME/CFS criteria after a median time of 255 days post infection and and at the second visit after a median of 402 days, 19.4% still suffered from ME/CFS. Self-reported fatigue (83.7-72.7%) and concentration impairment (66.2-57.9%) decreased from first to second visit contrasting non-significant changes in the structured screening.

A significant proportion of SARS-CoV-2 survivors presenting with ongoing symptoms present with ME/CFS. Although the proportion of subjective reported symptoms and their severity reduce over time, a significant proportion of patients suffer from long-lasting symptoms necessitating new therapeutic concepts.

Source: Reuken PA, Besteher B, Finke K, Fischer A, Holl A, Katzer K, Lehmann-Pohl K, Lemhöfer C, Nowka M, Puta C, Walter M, Weißenborn C, Stallmach A. Longterm course of neuropsychological symptoms and ME/CFS after SARS-CoV-2-infection: a prospective registry study. Eur Arch Psychiatry Clin Neurosci. 2023 Aug 16. doi: 10.1007/s00406-023-01661-3. Epub ahead of print. PMID: 37587244. https://link.springer.com/article/10.1007/s00406-023-01661-3 (Full text)

A Scoping Review of Pacing for Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Lessons Learned for the Long COVID Pandemic

Abstract:

Background: Controversy over treatment for people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a barrier to appropriate treatment. Energy management or pacing is a prominent coping strategy for people with ME/CFS that involves regulating activity to avoid post exertional malaise (PEM), the worsening of symptoms after an activity. Until now, characteristics of pacing, and the effects on patients’ symptoms had not been systematically reviewed. This is problematic as the most common approach to pacing, pacing prescription, and the pooled efficacy of pacing was unknown. Collating evidence may help advise those suffering with similar symptoms, including long COVID, as practitioners would be better informed on methodological approaches to adopt, pacing implementation, and expected outcomes.

Objectives: In this scoping review of the literature, we aggregated type of, and outcomes of, pacing in people with ME/CFS. Eligibility criteria: Original investigations concerning pacing were considered in participants with ME/CFS. Sources of evidence: Six electronic databases (PubMed, Scholar, ScienceDirect, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials [CENTRAL]) were searched; and websites MEPedia, Action for ME, and ME Action were also searched for grey literature.

Methods: A scoping review was conducted. Review selection and characterisation was performed by two independent reviewers using pretested forms.

Results: Authors reviewed 177 titles and abstracts, resulting in included 17 studies: three randomised control trials (RCTs); one uncontrolled trial; one interventional case series; one retrospective observational study; two prospective observational studies; four cross-sectional observational studies; and five cross-sectional analytical studies. Studies included variable designs, durations, and outcome measures. In terms of pacing administration, studies used educational sessions and diaries for activity monitoring. Eleven studies reported benefits of pacing, four studies reported no effect, and two studies reported a detrimental effect in comparison to the control group.

Conclusions: Highly variable study designs and outcome measures, allied to poor to fair methodological quality resulted in heterogenous findings and highlights the requirement for more research examining pacing. Looking to the long COVID pandemic, future studies should be RCTs utilising objectively quantified digitised pacing, over a longer duration of examination, using the core outcome set for patient reported outcome measures.

Source: Nilihan Sanal-Hayes, Marie Mclaughlin, Lawrence D D Hayes, Jacqueline Mair, Jane Ormerod, David Carless, Natalie Hilliard, Rachel Meach, Joanne Ingram, Nicholas Sculthorpe. A Scoping Review of Pacing for Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Lessons Learned for the Long COVID Pandemic. medRxiv 2023.08.10.23293935; doi: https://doi.org/10.1101/2023.08.10.23293935 https://www.medrxiv.org/content/10.1101/2023.08.10.23293935v1 (Full text available as PDF file)

Genetic Risk Factors for Severe and Fatigue Dominant Long COVID and Commonalities with ME/CFS Identified by Combinatorial Analysis

Abstract:

Background Long COVID is a debilitating chronic condition that has affected over 100 million people globally. It is characterized by a diverse array of symptoms, including fatigue, cognitive dysfunction and respiratory problems. Studies have so far largely failed to identify genetic associations, the mechanisms behind the disease, or any common pathophysiology with other conditions such as ME/CFS that present with similar symptoms.

Methods We used a combinatorial analysis approach to identify combinations of genetic variants significantly associated with the development of long COVID and to examine the biological mechanisms underpinning its various symptoms. We compared two subpopulations of long COVID patients from Sano Genetics’ Long COVID GOLD study cohort, focusing on patients with severe or fatigue dominant phenotypes. We evaluated the genetic signatures previously identified in an ME/CFS population against this long COVID population to understand similarities with other fatigue disorders that may be triggered by a prior viral infection. Finally, we also compared the output of this long COVID analysis against known genetic associations in other chronic diseases, including a range of metabolic and neurological disorders, to understand the overlap of pathophysiological mechanisms.

Results Combinatorial analysis identified 73 genes that were highly associated with at least one of the long COVID populations included in this analysis. Of these, 9 genes have prior associations with acute COVID-19, and 14 were differentially expressed in a transcriptomic analysis of long COVID patients. A pathway enrichment analysis revealed that the biological pathways most significantly associated with the 73 long COVID genes were mainly aligned with neurological and cardiometabolic diseases.

Expanded genotype analysis suggests that specific SNX9 genotypes are a significant contributor to the risk of or protection against severe long COVID infection, but that the gene-disease relationship is context dependent and mediated by interactions with KLF15 and RYR3.

Comparison of the genes uniquely associated with the Severe and Fatigue Dominant long COVID patients revealed significant differences between the pathways enriched in each subgroup. The genes unique to Severe long COVID patients were associated with immune pathways such as myeloid differentiation and macrophage foam cells. Genes unique to the Fatigue Dominant subgroup were enriched in metabolic pathways such as MAPK/JNK signaling. We also identified overlap in the genes associated with Fatigue Dominant long COVID and ME/CFS, including several involved in circadian rhythm regulation and insulin regulation. Overall, 39 SNPs associated in this study with long COVID can be linked to 9 genes identified in a recent combinatorial analysis of ME/CFS patient from UK Biobank.

Among the 73 genes associated with long COVID, 42 are potentially tractable for novel drug discovery approaches, with 13 of these already targeted by drugs in clinical development pipelines. From this analysis for example, we identified TLR4 antagonists as repurposing candidates with potential to protect against long term cognitive impairment pathology caused by SARS-CoV-2. We are currently evaluating the repurposing potential of these drug targets for use in treating long COVID and/or ME/CFS.

Conclusion This study demonstrates the power of combinatorial analytics for stratifying heterogeneous populations in complex diseases that do not have simple monogenic etiologies. These results build upon the genetic findings from combinatorial analyses of severe acute COVID-19 patients and an ME/CFS population and we expect that access to additional independent, larger patient datasets will further improve the disease insights and validate potential treatment options in long COVID.

Source: Krystyna Taylor, Matthew Pearson, Sayoni Das, Jason Sardell, Karolina Chocian, Steve Gardners. Genetic Risk Factors for Severe and Fatigue Dominant Long COVID and Commonalities with ME/CFS Identified by Combinatorial Analysis. medRxiv 2023.07.13.23292611; doi: https://doi.org/10.1101/2023.07.13.23292611 https://www.medrxiv.org/content/10.1101/2023.07.13.23292611v1.full-text (Full text)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and COVID-19: is there a connection?

Abstract:

Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic systemic disease that leads to neurological, immunological, autonomic, and energy metabolism dysfunction. COVID-19 has been reported to cause similar symptoms to ME/CFS. The study aims to investigate the prevalence of myalgic encephalomyelitis in patients post-COVID-19 infection by assessing acute and long-term COVID-19 symptoms.

Methods: A cross-sectional questionnaire was developed based on the ME/CFS diagnostic criteria, as specified by the IOM clinical diagnostic criteria, and administered to participants with confirmed COVID-19 who are more than 18 years old and have BMI below 40 Kg/m2. Data from 437 participants were completed.

Results: The current study results revealed that 8.1% of the study participants met the ME/CFS diagnostic criteria. Interestingly, 2.8 of the study participants were classified to have COVID-19 related to ME/CFS. While 4.6% of participants were determined to have disease-related fatigue, 0.7% of participants showed ME/CFS that was not related to COVID-19, and 3.7% of participants were considered to have long COVID-19. Almost one-fourth of the study participants had a family history of ME/CFS. The current study demonstrated that the prevalence of ME/CFS is similar to slightly higher than reported in the literature.

Conclusion: The presence of a relationship between ME/CFS and COVID-19 has been supported by the results of our study. Follow-up of COVID-19 patients is strongly recommended to ensure proper management of ME/CFS symptoms.

Source: Muhaissen SA, Abu Libdeh A, ElKhatib Y, Alshayeb R, Jaara A, Bardaweel SK. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and COVID-19: is there a connection? Curr Med Res Opin. 2023 Jul 28:1-24. doi: 10.1080/03007995.2023.2242244. Epub ahead of print. PMID: 37501626. https://pubmed.ncbi.nlm.nih.gov/37501626/

Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness

Abstract:

Despite advances in the treatment and mitigation of critical illness caused by infection with SARS-CoV-2, millions of survivors have a devastating, post-acute infection syndrome known as long COVID. A large proportion of patients with long COVID have nervous system dysfunction, which is also seen in the distinct but overlapping condition of post-intensive care syndrome (PICS), putting survivors of COVID-19-related critical illness at high risk of long-lasting morbidity affecting multiple organ systems and, as a result, engendering measurable deficits in quality of life and productivity.

In this Series paper, we discuss neurological, cognitive, and psychiatric sequelae in patients who have survived critical illness due to COVID-19. We review current knowledge of the epidemiology and pathophysiology of persistent neuropsychological impairments, and outline potential preventive strategies based on safe, evidence-based approaches to the management of pain, agitation, delirium, anticoagulation, and ventilator weaning during critical illness. We highlight priorities for current and future research, including possible therapeutic approaches, and offer considerations for health services to address the escalating health burden of long COVID.

Source: Pandharipande P, Williams Roberson S, Harrison FE, Wilson JE, Bastarache JA, Ely EW. Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness. Lancet Respir Med. 2023 Jul 17:S2213-2600(23)00238-2. doi: 10.1016/S2213-2600(23)00238-2. Epub ahead of print. PMID: 37475124. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00238-2/fulltext (Full text)

People with Long Covid and ME/CFS Exhibit Similarly Impaired Balance and Physical Capacity: A Case-Case-Control Study

Abstract:

Purpose: Postural sway and physical capacity had not previously been compared between people with long COVID and people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Therefore, this study determined postural sway and physical capacity in people with long COVID (∼16 month illness duration; n=21) and ME/CFS (∼16 year illness duration; n=20), versus age-matched healthy controls (n=20).

Methods: Postural sway was during a 30 s static stand test. Physical capacity was determined using the timed up and go test and five times sit to stand test. Throughout, participants wore isoinertial measurement units.

Results: Postural sway was worse (i.e. greater) in people with long COVID and ME/CFS than controls, but not different between long COVID and ME/CFS. Performance of the timed up and go test and five times sit to stand test were worse in long COVID and ME/CFS than controls, but not different between long COVID and ME/CFS. 87% and 13% of long COVID and ME/CFS participants exceeded the threshold for muscle weakness in the five times sit to stand test and timed up and go test, respectively.

Conclusions: These data suggest that both people with long COVID and people with ME/CFS have similarly impaired balance and physical capacity. Therefore, there is an urgent need for interventions to target postural sway and physical capacity in people with ME/CFS, and given the current pandemic, people with long COVID.

Source: Lawrence D. Hayes, PhD, Nilihan E.M. Sanal-Hayes, PhD, Marie Mclaughlin, PhD, Ethan C.J. Berry, BSc (Hons), Nicholas F. Sculthorpe, PhD. People with Long Covid and ME/CFS Exhibit Similarly Impaired Balance and Physical Capacity: A Case-Case-Control Study. The American Journal of Medicine. Published: July 23, 2023 DOI: https://doi.org/10.1016/j.amjmed.2023.06.028 https://www.amjmed.com/article/S0002-9343(23)00465-5/fulltext#%20

Hypothesis: Matrix metalloproteinase inhibition with low-dose doxycycline in Long COVID and ME/CFS

Abstract:

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.

Source: Sanders, E.C. (2023). Hypothesis: Matrix metalloproteinase inhibition with low-dose doxycycline in Long COVID and ME/CFS. Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 21-29 https://patientresearchcovid19.com/hypothesis-matrix-metalloproteinase-inhibition-with-low-dose-doxycycline-in-long-covid-and-me-cfs-pghj-issue1-may2023/ (Full text)

Hypothesis: Symptomatic myodesopsia/vitreous floaters may constitute a risk factor for Long COVID and ME/CFS

Abstract:

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.

Source: Mazewski, M. (2023). Hypothesis: Symptomatic myodesopsia/vitreous floaters may constitute a risk factor for Long COVID and ME/CFS. Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 13-20 https://patientresearchcovid19.com/hypothesis-symptomatic-myodesopsia-vitreous-floaters-may-constitute-a-risk-factor-for-long-covid-and-me-cfs-pghj-issue1-may2023/ (Full text)