Category: Pathophysiology

The Potential Role of Ocular and Otolaryngological Mucus Proteins in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness associated with a constellation of other symptoms. While the most common symptom is unrelenting fatigue, many individuals also report suffering from rhinitis, dry eyes and a sore throat.

Mucin proteins are responsible for contributing to the formation of mucosal membranes throughout the body. These mucosal pathways contribute to the body’s defense mechanisms involving pathogenic onset. When compromised by pathogens the epithelium releases numerous cytokines and enters a prolonged state of inflammation to eradicate any particular infection.

Based on genetic analysis, and computational theory and modeling we hypothesize that mucin protein dysfunction may contribute to ME/CFS symptoms due to the inability to form adequate mucosal layers throughout the body, especially in the ocular and otolaryngological pathways leading to low grade chronic inflammation and the exacerbation of symptoms.

Source: Kaylin Huitsing, Tara Tritsch, Francisco J. Carrera Arias et al. The Potential Role of Ocular and Otolaryngological Mucus Proteins in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, 24 July 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3171709/v1] https://www.researchsquare.com/article/rs-3171709/v1 (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)

Hypothesis: Astrocyte dysregulation of sympathetic nervous system causes metabolic dysfunction in subset of Long COVID and ME/CFS patients

Abstract:

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.

Hypothesis: 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.

Underlying mechanisms of the SNS overactivation subtype: Theoretically, patients with this subtype already have a genetic dysregulation of neuronal norepinephrine (NE) release/clearance or noradrenergic receptor sensitivity2. This latent genetic dysfunction of NE signaling may not cause significant problems unless there is a trigger that causes excess NE release.

As NE affects immune cell signaling, this could result in an over-activation or prolonged activation of the immune system in response to infection with SARS-CoV-2, the virus that causes COVID-193 . This subtype could explain why ME/CFS is often triggered by a virus or brain injury, as these occurrences can trigger noradrenergic signaling3.

Possible mechanisms for the SNS overactivation subtype include viral reservoirs, antibody reaction, and dysregulation of noradrenergic receptor expression. In Long COVID patients, viral antigens and reservoirs that remain in the body long after the initial infection may keep the overactive immune system in an inflammatory state4,5. A healthy person may not react to these SARS-CoV-2 reservoirs, as their functional immune cells should develop immune tolerance. Another possibility is that the immune system is reacting to SARS-CoV-2 antibodies.

Finally, it is possible that excess extracellular NE could keep the SNS and noradrenergic systems in the brain stuck in an overactive state. A prolonged period of increased levels of extracellular NE could lead to dysregulation of noradrenergic receptor expression. The excess extracellular NE may be due to a prolonged release of excess NE during the initial infection, or a failure of the negative feedback mechanisms that should reduce NE release.

Symptoms of an overactive SNS: An overactive SNS explains many of the symptoms found in Long COVID patients, such as IBS/gastrointestinal symptoms6, heart palpitations7, and sleep disturbance8. Additionally, in orthostatic intolerance, which is common in Long COVID and ME/CFS, the release of NE causes pronounced tachycardia. This rapid heart rate may cause palpitations, breathlessness, and chest pain.

Dysfunctional energy metabolism causes fatigue and cognitive dysfunction: An important piece of the puzzle is to explain how a dysregulated SNS could lead to chronic fatigue and brain fog (cognitive dysfunction). The most likely explanation is a dysregulation of metabolic function. There are many ways excess NE could affect metabolism, including enhancing aerobic glycolysis and depleting glycogen stores.

Source: Carnac, T. (2023). Hypothesis: Astrocyte dysregulation of sympathetic nervous system causes metabolic dysfunction in subset of Long COVID and ME/CFS patients. Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 36-43 https://patientresearchcovid19.com/hypothesis-astrocyte-dysregulation-of-sympathetic-nervous-system-causes-metabolic-dysfunction-in-subset-of-long-covid-and-me-cfs-patients-pghj-issue1-may2023/ (Full text)

MTHFR and LC, CFS, POTS, MCAS, SIBO, EDS: Methylating the Alphabet

Abstract:

Long Covid (LC), Chronic Fatigue Syndrome (CFS), Postural Orthostatic Tachycardia Syndrome (POTS), Mast Cell Activation Syndrome (MCAS), Small Intestine Bacterial Overgrowth (SIBO), and Ehlers-Danlos Syndrome (EDS) are all loosely connected, some poorly defined, some with overlapping symptoms.

The female preponderance, the prominence of fatigue and chronic inflammation, and methylenetetrahydrofolate reductase (MTHFR) abnormalities may connect them all. Indeed differential methylation may lie at the root. Two – EDS and MTHFR – are genetic. But epigenetic factors may ultimately determine their phenotypic expression.

Oxidative stress, overloaded mitochondria, an antioxidant and nutrient shortfall, and suboptimal gut microbiome appear to be the primary determinants. A deep dive into the folate and methionine cycles is undertaken in an attempt to connect these syndromes.

The active forms of vitamin D and vitamins B2,3,6,9,12 are shown to be biochemically integral to optimal methylation and control of the epigenome. Their status largely determines the symptoms of abnormal MTHFR in all its phenotypes. The wider implications for aging, cancer, cardiovascular disease, neurodegenerative disease, and autoimmune disease are briefly explored.

Source: Chambers P. MTHFR and LC, CFS, POTS, MCAS, SIBO, EDS: Methylating the Alphabet. Preprint from Qeios, 30 Jun 2023. https://www.qeios.com/read/ZPYS4F (Full text)

Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystemic condition. The pathomechanism of ME/CFS remains unestablished; however, impaired natural killer (NK) cell cytotoxicity is a consistent feature of this condition. Calcium (Ca2+) is crucial for NK cell effector functions.
Growing research recognises Ca2+ signalling dysregulation in ME/CFS patients and implicates transient receptor potential ion channel dysfunction. TRPM7 (melastatin) was recently considered in the pathoaetiology of ME/CFS as it participates in several Ca2+-dependent processes that are central to NK cell cytotoxicity which may be compromised in ME/CFS. TRPM7-dependent Ca2+ influx was assessed in NK cells isolated from n = 9 ME/CFS patients and n = 9 age- and sex-matched healthy controls (HCs) using live cell fluorescent imaging techniques.
Slope (p < 0.05) was significantly reduced in ME/CFS patients compared with HCs following TRPM7 activation. Half-time of maximal response (p < 0.05) and amplitude (p < 0.001) were significantly reduced in the HCs compared with the ME/CFS patients following TRPM7 desensitisation.
Findings from this investigation suggest that TRPM7-dependent Ca2+ influx is reduced with agonism and increased with antagonism in ME/CFS patients relative to the age- and sex-matched HCs. The outcomes reported here potentially reflect TRPM3 dysfunction identified in this condition suggesting that ME/CFS is a TRP ion channelopathy.
Source: Du Preez S, Eaton-Fitch N, Smith PK, Marshall-Gradisnik S. Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Biomolecules. 2023; 13(7):1039. https://doi.org/10.3390/biom13071039 https://www.mdpi.com/2218-273X/13/7/1039 (Full text)

Serum from Myalgic encephalomyelitis/chronic fatigue syndrome patients causes loss of coherence in cellular circadian rhythms

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling disorder characterized by disrupted daily patterns of activity, sleep, and physiology. Past studies in ME/CFS patients have examined circadian rhythms, suggested that desynchronization between central and peripheral rhythms may be an important pathological feature, and identified associated changes in post-inflammatory cytokines such as transforming growth factor beta (TGFB). However, no previous studies have examined circadian rhythms in ME/CFS using cellular models or studied the role of cytokines on circadian rhythms.

In this study, we used serum samples previously collected from ME/CFS patients (n = 20) selected for the presence of insomnia symptoms and matched controls (n = 20) to determine the effects of serum factors and TGFB on circadian rhythms in NIH3T3 mouse immortalized fibroblasts stably transfected with the Per2-luc bioluminescent circadian reporter.

Compared to control serum, ME/CFS serum caused a significant loss of rhythm robustness (decreased goodness of fit) and nominally increased the rate of damping of cellular rhythms. Damping rate was associated with insomnia severity in ME/CFS patients using the Pittsburgh Sleep Quality Index (PSQI). Recombinant TGFB1 peptide applied to cells reduced rhythm amplitude, caused phase delay and decreased robustness of rhythms.

However, there was no difference in TGFB1 levels between ME/CFS and control serum indicating the effects of serum on cellular rhythms cannot be explained by levels of this cytokine. Future studies will be required to identify additional serum factors in ME/CFS patients that alter circadian rhythms in cells.

Source: Heather Wei, Zoe Adelsheim, Rita Fischer, Michael J. McCarthy. Serum from Myalgic encephalomyelitis/chronic fatigue syndrome patients causes loss of coherence in cellular circadian rhythms. Journal of Neuroimmunology. Available online 24 June 2023, 578142. https://doi.org/10.1016/j.jneuroim.2023.578142 https://www.sciencedirect.com/science/article/abs/pii/S0165572823001285

Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID

Abstract:

Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN). The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID.

In the present study, we measured serum TRY, TRYCATs, insulin resistance (using the Homeostatic Model Assessment Index 2-insulin resistance, HOMA2-IR), C-reactive protein (CRP), physiosomatic, depression, and anxiety symptoms in 90 Long COVID patients, 3–10 months after remission of acute infection.

We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains. One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome.

Three Long COVID biomarkers (CRP, KYN/TRY, and IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection. One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, and IR (Long COVID), and PBT and SpO2 (acute COVID-19).

In conclusion, the physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID, and lowered plasma tryptophan and increased kynurenine may contribute to these effects.

Source: Al-Hakeim HK, Khairi Abed A, Rouf Moustafa S, Almulla AF, Maes M. Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID. Front Mol Neurosci. 2023 Jun 2;16:1194769. doi: 10.3389/fnmol.2023.1194769. PMID: 37333619; PMCID: PMC10272345. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272345/ (Full text)

Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease (ME/CFS/SEID) is a condition diagnosed primarily based on clinical symptoms, including prolonged fatigue and post-exertional malaise; however, there is no specific test for the disease. Additionally, diagnosis can be challenging since healthcare professionals may lack sufficient knowledge about the disease. Prior studies have shown that patients with ME/CFS/SEID have low serum acylcarnitine levels, which may serve as a surrogate test for patients suspected of having this disease. This systematic review and meta-analysis aimed to investigate the differences in serum acylcarnitine levels between patients with ME/CFS/SEID and healthy controls.

Methods: This systematic review was conducted using PubMed and Ichushi-Web databases. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, we included all studies from the databases’ inception until February 17, 2023, that evaluated blood tests in both patients with ME/CFS/SEID and healthy control groups. The primary endpoint was the difference in serum acylcarnitine levels between the two groups.

Results: The electronic search identified 276 studies. Among them, seven met the eligibility criteria. The serum acylcarnitine levels were analyzed in 403 patients with ME/CFS/SEID. The patient group had significantly lower serum acylcarnitine levels when compared with the control group, and the statistical heterogeneity was high.

Conclusion: The patient group had significantly lower serum acylcarnitine levels when compared with the control group. In the future, the measurement of serum acylcarnitine levels, in addition to clinical symptoms, may prove to be a valuable diagnostic tool for this condition.

Source: Jinushi R, Masuda S, Tanisaka Y, Nishiguchi S, Shionoya K, Sato R, Sugimoto K, Shin T, Shiomi R, Fujita A, Mizuide M, Ryozawa S. Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis. J Transl Med. 2023 Jun 19;21(1):398. doi: 10.1186/s12967-023-04226-z. PMID: 37337273; PMCID: PMC10280864. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10280864/ (Full text)

Major Depressive Disorder and Chronic Fatigue Syndrome Show Characteristic Heart Rate Variability Profiles Reflecting Autonomic Dysregulations: Differentiation by Linear Discriminant Analysis

Abstract:

Major depressive disorder (MDD) and chronic fatigue syndrome (CFS) have overlapping symptoms, and differentiation is important to administer the proper treatment.

The present study aimed to assess the usefulness of heart rate variability (HRV) indices.

Frequency-domain HRV indices, including high-frequency (HF) and low-frequency (LF) components, their sum (LF+HF), and their ratio (LF/HF), were measured in a three-behavioral-state paradigm composed of initial rest (Rest), task load (Task), and post-task rest (After) periods to examine autonomic regulation.

It was found that HF was low at Rest in both disorders, but was lower in MDD than in CFS. LF and LF+HF at Rest were low only in MDD. Attenuated responses of LF, HF, LF+HF, and LF/HF to task load and an excessive increase in HF at After were found in both disorders.

The results indicate that an overall HRV reduction at Rest may support a diagnosis of MDD. HF reduction was found in CFS, but with a lesser severity.

Response disturbances of HRV to Task were observed in both disorders, and would suggest the presence of CFS when the baseline HRV has not been reduced.

Linear discriminant analysis using HRV indices was able to differentiate MDD from CFS, with a sensitivity and specificity of 91.8% and 100%, respectively. HRV indices in MDD and CFS show both common and different profiles, and can be useful for the differential diagnosis.

Source: Shinba T, Kuratsune D, Shinba S, Shinba Y, Sun G, Matsui T, Kuratsune H. Major Depressive Disorder and Chronic Fatigue Syndrome Show Characteristic Heart Rate Variability Profiles Reflecting Autonomic Dysregulations: Differentiation by Linear Discriminant Analysis. Sensors. 2023; 23(11):5330. https://doi.org/10.3390/s23115330 https://www.mdpi.com/1424-8220/23/11/5330 (Full text)

Altered Lipid, Energy Metabolism and Oxidative Stress Are Common Features in a Range of Chronic Conditions

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS) and Fibromyalgia are chronic illnesses that, despite their prevalence in society, are still of unknown aetiology. All three conditions present similar clinical symptoms and are difficult to diagnose due to a lack of appropriate biomarkers. Currently, diagnosis consists of satisfying clinical criteria and eliminating other conditions, a lengthy and often costly process for patients. The discovery of biomarkers would significantly speed up patient diagnosis and allow the development of pharmacological therapies that target the underlying metabolic causes of these diseases.

Metabolomics is an emerging research area used to characterise the metabolites present within biological specimens. Developments within this field now allow the analysis of thousands of metabolites within different samples and model systems, and have the potential to aid in unravelling the metabolic phenotypes that underpin complex metabolic diseases. ME/CFS, GWS and Fibromyalgia are three conditions that could benefit from a plasma/tissue metabolomics analysis, allowing a greater understanding of their aetiology and identify common pathways. An analysis of the literature in these conditions reveals alterations within pathways associated with energy and lipid metabolism with alterations in key metabolites associated with elevated oxidative stress. Understanding what might drive the elevated oxidative stress within all three illnesses will not only be important in future research but could also be a potential therapeutic target for antioxidant medications which could be implemented to reduce the symptom burden in these illnesses.

Source: MORTEN, Karl Jonathan and Davis, Leah and Lodge, Tiffany A. and Strong, James and Espejo-Oltra, José Andrés and Zalewski, Pawel and Pretorius, Etheresia, Altered Lipid, Energy Metabolism and Oxidative Stress Are Common Features in a Range of Chronic Conditions. Available at SSRN: https://ssrn.com/abstract=4455366 or http://dx.doi.org/10.2139/ssrn.4455366 (Full text available as PDF file)