Hi everyone,
In this week’s edition we look at research highlighting potential underlying mechanisms, including viral persistence leading to endothelial dysfunction, autoimmunity similarities with multiple sclerosis, and epigenetic reprogramming by viruses like Epstein-Barr virus. Metabolomic studies are identifying potential biomarkers for improved diagnosis, while clinical trials explore promising therapeutic avenues like metformin for reducing viral load and neurological symptoms.
Thank you all for taking the time filling out the LC Database survey! Your responses are invaluable in shaping a resource that will serve as a comprehensive hub for accessing and sharing vital information. The majority of you expressed a need for searchable databases that include detailed summaries of medical research, treatment strategies, and personal experiences related to Long Covid, ME/CFS, POTS, and other related conditions. These resources will be tagged and categorized to facilitate easy access and navigation, aiming to support both personal advocacy and professional discussions. We will hopefully have updates on next steps in the following Newsletter!
This article, "Herpesvirus Infection of Endothelial Cells as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome," is my article of the week due to its exploration into the potential linkage between herpesvirus infections in endothelial cells and the pathophysiology ME/CFS. The paper proposes an interesting perspective - related to other hypotheses. Here are the most interesting quotes:
Results: "We found significant levels of amyloid fibrin(ogen)/microclots—the clotting material that is implicated in Long COVID [38,44,45]—in ME/CFS PPP samples. These microclots have been therapeutically targeted with considerable success in Long COVID patients [46]."
Discussion: "A herpesvirus infection of ECs might be able to explain the persisting nature of ME/CFS symptoms. Firstly, the endothelium has a low turnover, with the entire population being replaced every 6 years in adults [90]."
Discussion: "This ability of herpesviruses to establish latency in (endothelial) host cells, along with the long life span of ECs, means that a herpesvirus-infected endothelium and the resulting complications may persist for months to years. This is a timeline that is in accord with the chronicity of ME/CFS symptoms."
Media
Article: Thousands Believe Covid Vaccines Harmed Them. Is Anyone Listening? - The New York Times
DEFINITIONS:
Many people believe they have suffered serious side effects from the COVID-19 vaccines, though federal health officials insist such cases are extremely rare and their surveillance efforts are sufficient to detect patterns.
Thousands of vaccine-injury compensation claims have been filed with the federal government, but very few have been reviewed or paid out due to stringent requirements for proof and narrow criteria.
Some scientists and experts, including a former FDA leader, believe these potential vaccine injuries should be acknowledged and studied more extensively, as the current research efforts are inadequate.
Patients with suspected vaccine injuries report being dismissed by doctors, labeled as anti-vaccine, and struggling to get their symptoms recognized or officially linked to the vaccines.
The rise of anti-vaccine misinformation has made it difficult for officials to candidly address potential side effects, and there are challenges in detecting rare events in the fragmented U.S. healthcare system.
Article: An incomplete picture: understanding the burden of long Covid - Economist Impact
SUMMARY:
Disparate views continue to inhibit understanding and require further research to comprehend the scale and scope of long COVID.
The physical symptoms of long COVID suggest it represents a range of diseases that can exert a heavy burden on individuals.
The impact of long COVID ranges from mild to debilitating, affecting daily activities, workforce participation, and quality of life.
Reports suggest that between 2% and 7% of the population likely has long COVID, showing a significant impact worldwide.
Encouragingly, some countries have implemented policies to address long COVID, emphasizing holistic, patient-centered care and support for social and economic needs of affected individuals.
DEFINITION:
Bezisterim (NE3107): An anti-inflammatory and insulin sensitizer drug developed by BioVie, with potential therapeutic benefits for neurological symptoms related to Long COVID.
SUMMARY:
BioVie Inc secured $13.1 million funding from the U.S. Department of Defense to evaluate Bezisterim for treating neurological symptoms in long COVID.
The clinical trial aims to assess the safety and efficacy of Bezisterim in reducing neurological symptoms in around 200 patients over a three-month period.
Bezisterim's mechanism of action aligns with the emerging evidence for the underlying pathophysiology of long COVID, providing hope for effective treatment.
Research
DEFINITIONS:
Endothelial cells (ECs): Thin, flat cells that line the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood and the rest of the vessel wall.
Herpesvirus latency: A state in which the virus remains inactive and persists in the host cell without causing active infection, but can reactivate under certain conditions.
Endothelial dysfunction: Impaired functioning of the endothelium, which can lead to various vascular complications, such as impaired blood flow regulation, increased coagulation, and inflammation.
SUMMARY:
This review paper proposes a novel hypothesis that infection of endothelial cells by herpesviruses, particularly through latent infection, may contribute to the pathophysiology and symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Herpesviruses like Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6) have been implicated in ME/CFS and are known to infect and establish latency in endothelial cells, potentially causing endothelial dysfunction.
Endothelial dysfunction can lead to various complications, including impaired blood flow regulation, coagulation abnormalities, and cognitive impairment, which are consistent with the symptoms observed in ME/CFS.
The chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be attributed to the long-lasting effects of herpesvirus-induced endothelial maladaptation, as endothelial cells have a low turnover rate.
DEFINITIONS:
MS (multiple sclerosis): A disabling neurological disease where immune system cells mistakenly attack the protective sheath of nerve fibers (known as the myelin sheath) in the central nervous system (the brain, optic nerves, and spinal cord).
Autoimmunity: an aberration in the body's normal development such that the immune system mounts an attack against its own cells.
Non-invasive brain stimulation: A set of technologies and techniques to stimulate or alter brain activity from the surface of the head without the introduction of instruments inside the body or breaking the skin.
SUMMARY:
Some pathophysiological mechanisms well-known in MS (multiple sclerosis), such as autoimmunity, neuroinflammation and myelin damage, have also been implicated in PCC (post-COVID condition).
This cross-sectional study included 218 patients with PCC and 218 with MS. It compared the cognitive phenotypes of the two cohorts using the same neuropsychological protocol. It also evaluated the relationship between fatigue and cognitive performance.
The study found similar cognitive profiles in PCC and MS, which are mainly characterized by attention and processing speed deficit.
Fatigue was more severe in PCC, but the relationship between fatigue and cognitive function was greater in the case of MS.
The findings suggested that cognitive deficits in PCC are almost as pronounced and prevalent as in MS, and fatigue is even more severe.
This information paves the way to test new therapies for fatigue based on their association with functional brain changes, such as non-invasive brain stimulation, which have shown positive effects in two clinical trials.
SUMMARY:
In order to develop accessible care for people with PCC (post-COVID-19 condition) who have psychiatric symptoms, inclusive estimates of the prevalence of symptoms and an understanding of whether people with symptoms are able to access care is needed.
In this nationally representative cross-sectional study of 25,122 participants, those experiencing PCC were approximately twice as likely to report depression and anxiety symptoms than other US adults.
Compared with other US adults, participants with current PCC were more likely to have depression symptoms (16.8% vs 7.1%; adjusted odds ratio [AOR]), anxiety symptoms (16.7% vs 6.3%; AOR, 2.21;), sleep difficulties (41.5% vs 22.7%; AOR 1.95), cognitive difficulties (35.0% vs 19.5%; AOR, 2.04), and disabling fatigue (4.0% vs 1.6%; AOR, 1.85).
Among individuals with these symptoms, adults with PCC were just as likely to have received mental health treatment but more likely to report cost-related barriers to accessing therapy.
The findings of this study suggest that people with PCC have a higher prevalence of psychiatric symptoms than other adults but are more likely to experience cost-related barriers to accessing therapy. Care pathways for PCC should consider prioritizing mental health screening and affordable treatment.
MY Take (Amy):
Interestingly and of some concern in my opinion, cognitive difficulties and fatigue were lumped together in this study as psychiatric symptoms: “Psychiatric symptoms frequently reported by these individuals have included depression, anxiety, sleep difficulties, fatigue, cognitive difficulties, and posttraumatic stress.”
[PAYWALLED]
DEFINITIONS:
COVID-OUT: A randomized, placebo-controlled, double-blind trial with 999 participants that assessed metformin, fluvoxamine, and ivermectin in outpatient treatment for Covid-19 and Long Covid.
Pleiotropic: Producing more than one effect.
SUMMARY:
In the COVID-OUT randomized trial for COVID-19, Metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%.
As a follow up to these previously published results, the current study focused on the ability of Metformin to reduce viral load.
The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (−0.56 log10 copies/mL; P = .027).
Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72).
Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68).
The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo.
In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology.
DEFINITIONS:
Metabolomics: The systematic study of the unique chemical fingerprints that specific cellular processes leave behind in the form of small molecule metabolites.
Explainable AI (XAI): Artificial intelligence techniques that aim to make the decision-making process of AI systems more transparent and interpretable to humans.
SHAP (SHapley Additive exPlanations): A game theory-based approach to explain the output of machine learning models by assigning an importance value to each feature.
SUMMARY:
The study developed an explainable artificial intelligence (XAI) integrated machine learning (ML) framework to identify and classify potential metabolic biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) using metabolomic data.
Among various ML algorithms tested (XGBoost, random forest, decision tree, support vector machines, naive Bayes, logistic regression), the XGBoost classifier combined with ANOVA feature selection performed best, achieving 98.18% accuracy and 98.85% area under the ROC (receiver operating characteristic) curve.
The SHAP (SHapley Additive exPlanations) method revealed that decreased levels of metabolites like alpha-CEHC sulfate, hypoxanthine, phenylacetylglutamine, and increased levels of N-delta-acetylornithine and oleoyl-linolooyl-glycerol increased the risk of ME/CFS.
The study highlights the potential of using ML and XAI techniques for accurate diagnosis and improved understanding of the underlying mechanisms of ME/CFS based on metabolic biomarkers.
DEFINITIONS:
Hypermobility Spectrum Disorder (HSD): A connective tissue disorder characterized by joint hypermobility and associated symptoms like chronic pain, fatigue, and gastrointestinal issues.
Th2-type cytokines: A subset of cytokines (signaling molecules) produced by helper T cells that promote humoral immunity, allergic responses, and eosinophil recruitment.
Mast cells: Immune cells present in connective tissues that release inflammatory mediators, contributing to allergic reactions and immune responses.
Eosinophils: Type of white blood cell involved in immune responses against parasites and allergic reactions, also found in various tissues.
BCL6 and TP53: Transcription factors (proteins regulating gene expression) identified as potential regulators in ME/CFS etiology.
SUMMARY:
This study focused on longitudinal cytokine profiling and integrating multi-modal health data from an extremely severe ME/CFS patient with hypermobility spectrum disorder (HSD) over 4 years to understand immunopathology, disease severity, and potential treatments.
The results highlighted the significance of dysregulated Th2-type cytokines (e.g., CCL11, IL-5, MCP-1) and synergistic activities between mast cells and eosinophils in skewing the immune response towards Th2, contributing to cognitive impairment, sensory intolerance, and suggesting a shared mechanism with comorbidities like HSD and POTS.
Potential roles of BCL6 and TP53 pathways were identified in ME/CFS etiology, and the importance of investigating adverse reactions to medications and supplements was emphasized.
The study introduced an updated severity assessment platform, a real-time symptom tracking app (ME-CFSTrackerApp), and a text mining application (LexiTime) to facilitate patient-physician communication and evaluate treatment responses.
Findings suggest exploring low-dose drugs with partial agonist activity towards neurotransmitters and mast cell/eosinophil-directed biologic therapies as potential treatment avenues for ME/CFS.
DEFINITIONS:
Iodine-123-metaiodobenzylguanidine (MIBG) Single-Photon Emission Computed Tomography (SPECT): MIBG SPECT is a nuclear imaging technique used to assess sympathetic nerve function in various organs, particularly the heart. It involves the administration of a radioactive tracer (MIBG) that binds to sympathetic nerve endings, allowing visualization of sympathetic nerve activity in the heart.
Arrhythmia: Arrhythmia is an abnormal heart rhythm that may be too fast (tachycardia), too slow (bradycardia), or irregular. It can result from disturbances in the electrical impulses that coordinate heartbeats.
Syncope: Syncope is a temporary loss of consciousness and muscle tone caused by a sudden decrease in blood flow to the brain. It is often referred to as fainting and can be triggered by various factors, including changes in body position, emotional stress, or underlying medical conditions.
Vasodepressor Response: A drop in blood pressure upon standing or during orthostatic challenge. It is a type of abnormal cardiovascular response associated with orthostatic intolerance and dysautonomia.
SUMMARY:
The study aimed to assess dysautonomia in patients with long COVID using iodine-123-metaiodobenzylguanidine (MIBG) single-photon emission computed tomography (SPECT) imaging.
Patients with previous SARS-CoV-2 infection and dysautonomia symptoms were included. MIBG SPECT imaging and tilt table tests were performed to evaluate autonomic function.
A large proportion (75%) of patients showed reduced MIBG uptake, indicating sympathetic denervation in the absence of perfusion abnormalities.
Most (66.7%) patients' symptoms were reproduced during tilt table tests.
MIBG SPECT can be useful for diagnosing dysautonomia symptoms in long COVID patients.
It provides quantitative data aiding prognosis determination and treatment evaluation.
DEFINITIONS:
Epigenetics: Heritable changes in gene expression that do not involve changes to the underlying DNA sequence. Mechanisms include DNA methylation, histone modifications, and non-coding RNAs.
DNA methylation: An epigenetic mechanism involving addition of a methyl group to DNA, often resulting in gene silencing.
Non-coding RNAs: RNAs that are transcribed from DNA but not translated into proteins. Examples include microRNAs and long non-coding RNAs that can regulate gene expression.
Human endogenous retroviruses (HERVs): Remnants of ancient retroviral infections that make up ~8% of the human genome and can influence gene regulation.
SUMMARY:
This article provides an overview of the epigenetic signatures demonstrated in ME/CFS. It also focuses on potential strategies that latent viruses—particularly Epstein–Barr virus—may employ in epigenetic reprogramming in ME/CFS.
Epigenetic studies in ME/CFS patients have revealed alterations in DNA methylation patterns and changes in the expression of non-coding RNAs (e.g. microRNAs, long non-coding RNAs) compared to healthy controls.
These epigenetic changes are associated with dysregulation of immune function, cellular metabolism, mitochondrial dysfunction, and impairment of the central/autonomic nervous systems - reflecting known abnormalities in ME/CFS pathology.
The Epstein-Barr virus (EBV) and other herpesviruses may play a key role by inducing epigenetic changes that enable viral persistence and immune evasion, as well as disrupting host cell metabolism and function.
Epigenetic reprogramming induced by viral infections like EBV could provide a "hit-and-run" mechanism underlying the chronic symptoms in ME/CFS and long COVID, even after clearance of the initial viral trigger.
Studying the epigenetics of host-virus interactions may aid in patient stratification, understanding disease mechanisms, and identifying potential treatment approaches for ME/CFS.
SUMMARY:
The study examines long COVID in children & young individuals after 12 months post-Omicron variant infection.
Symptoms commonly reported include tiredness and sleep difficulties, with 17.4-21.9% fulfilling the long COVID definition at 12 months.
Overall, symptom profiles, severity, and impact did not differ significantly between groups based on infection status.
The research presents data showing similar persistence of symptoms post-infection across CYP (children and young people), irrespective of prior infection or re-infection.
Vaccination status did not significantly impact the number of symptoms or their related health indicators at 12 months.
Article: Cureus | Sinus Tachycardia Following COVID-19 and Its Implications
DEFINITIONS:
Sinus tachycardia: A heart rate greater than 100 bpm (beats per minute) that can occur as a physiological response to various stimuli or as a result of underlying pathology.
Propensity score matching (PSM): A statistical method used to balance covariates between two groups to reduce bias in observational studies.
SUMMARY:
The study investigates the prevalence of sinus tachycardia occurring 12-16 weeks post-diagnosis of COVID-19, its association with intensive care usage, ventilator use, and mortality, considering vaccination status.
The study utilized the TriNetX COVID-19 Research Network, a global health research network providing deidentified electronic medical records. Adult patients with confirmed COVID-19 diagnoses from January 20th, 2020, to February 14th, 2022, were included.
The study population was divided into cohorts based on the presence of sinus tachycardia, with further analysis based on vaccination status.
Of 1,363,907 patients studied, 2.2% developed sinus tachycardia 12-16 weeks post-diagnosis.
Patients with tachycardia had higher mortality, critical care utilization, and ventilator use.
Among patients with persistent tachycardia, those unvaccinated or partially vaccinated had significantly worse outcomes compared to fully vaccinated individuals.
The article about metformin reducing the odds of LC by 42% at 10 months is amazing. More attention needs to be focused on this!
I agree with Amy! My wife and I contracted Covid at the same time. She was taking metformin daily for an ailment. I wasn't. I developed long Covid. She didn't.