Long Covid Weekly #94: Lyme disease gets highlighted by Times, Ron Davis publishes new research
Welcome to the 94th edition of our Long Covid Weekly newsletter! Inching closer to the 100th edition!
This week, we explore current care for individuals with Long Covid in England, investigate the causes and consequences of this condition, and discuss the future of clinical trials. Additionally, we highlight the often-dismissed chronic Lyme disease, and share promising research on treatments such as vagus nerve stimulation. We also examine the link between oxidative stress in ME/CFS and Long Covid, track the incidence of Long Covid in adults and children, and explore inflammatory clusters in Long Covid through plasma biomarker analysis.
Article of the Week:
Oxidative Stress is a Shared Characteristic of ME/CFS and Long COVID | bioRxix. This study aimed to identify shared molecular signatures between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long Covid (LC) by analyzing oxidative stress and bioenergetic characteristics in peripheral blood lymphocytes from 16 healthy controls, 15 ME/CFS patients, and 15 LC patients. Ron Davis is a credited author on this one!
Interesting/Important Sentences:
"By comparing T cell proliferation upon antigen stimulation, we find oxidative stress linearly scales with the proportion of proliferating T cells, meaning a higher fraction of female CFS donor T cells proliferate upon stimulation."
"Combining these differences to capture the balance between mitochondrial ROS drivers and anti-oxidant pathways, we find the ratio of Ca2+ to SOD2 MFI levels is highly elevated in both the ME/CFS and LC donors, compared to healthy controls."
"Our findings suggest that the capacity for an individual ME/CFS T cell to proliferate is tuned differently or is insensitive to higher oxidative stress levels, pointing to a potential functional defect in ME/CFS T cell proliferation."
Media
SUMMARY:
This study aimed to investigate current care for people with Long COVID in England using in-depth, semistructured interviews with 15 healthcare professionals and 21 people living with Long COVID.
The data were analyzed using thematic analysis.
The study highlighted the multifaceted nature of Long COVID, with varied symptoms impacting physical, social, mental, and environmental aspects of individuals' lives. Patients reported barriers in accessing primary care and feeling unheard by general practitioners, although some positive interactions were noted.
Peer support systems were found to be highly valuable.
These services were viewed as validating spaces where patients' voices were heard, offering more than just medical expertise. Despite initial challenges, healthcare providers' growing expertise in diagnosing and treating Long COVID has led to refined care approaches.
People with Long COVID faced difficulties in accessing care, including long wait times and feeling dismissed by healthcare providers. Effective communication and comprehensive support systems are crucial for managing Long COVID in primary care settings.
SUMMARY:
Imperial College London conducted the largest UK study of hospitalized Long COVID patients, aiming to identify biological bases for the varied symptoms of Long COVID.
Led by Professor Peter Openshaw, the research suggests that Long COVID involves different subtypes, requiring tailored treatment approaches.
Key Findings:
The study identified persistent symptoms in 65% of patients six months post-infection, including fatigue, anxiety, and depression, using tools like the Functional Assessment of Chronic Illness Therapy (FACIT) scale and the Montreal Cognitive Assessment (MoCA).
Inflammatory markers and myeloid cell activation were common across subtypes, indicating ongoing inflammation and immune response even after recovery from acute COVID-19.
Openshaw emphasizes the need for future clinical trials to focus on the identified inflammatory pathways and subtypes, rather than a one-size-fits-all approach.
Future trials should aim to identify specific biomarkers to diagnose and monitor Long COVID, potentially leading to targeted therapies.
Openshaw and Shaw propose that immunotherapies, including high-quality antibody administration and combination antivirals, could help clear persistent viruses.
Future research should explore the role of immunotherapy in treating Long COVID and investigate other conditions, like Myalgic Encephalomyelitis (ME), which may have similar mechanisms.
Article: Majority of long Covid insurance claims rejected in Switzerland - SWI swissinfo.ch
DEFINITIONS:
More than 60% of individuals suffering from long Covid in Switzerland have been denied support from invalidity insurance, despite facing consequences from Covid since 2021.
The criteria for receiving support is based on the impact on the ability to work rather than the medical diagnosis, as stated by Thomas Pfiffner.
It is concerning that a large number of individuals with long Covid are not receiving the necessary financial assistance to cope with the long-term consequences of the illness.
My Take:
Article: Long Dismissed, Chronic Lyme Is Finally in the Spotlight | TIME
SUMMARY:
Sue Gray, diagnosed with Lyme disease after two decades of symptoms, represents many who suffer from chronic Lyme disease. Her symptoms included neurological issues, chronic pain, and severe anxiety, which led to significant personal and financial challenges.
Lyme disease, caused by tick bites, can lead to a range of symptoms from fatigue and headaches to severe neurological and cardiac issues. While many recover with antibiotics, up to 10-14% experience persistent symptoms, often referred to as post-treatment Lyme disease syndrome (PTLDS) or chronic Lyme disease.
The medical establishment has historically downplayed chronic Lyme disease due to the lack of definitive diagnostic tests and treatments. This dismissal is partly due to the complexity and uncertainty surrounding the disease.
Recent research has renewed interest in chronic Lyme disease, paralleling the attention given to Long COVID. The U.S. National Institutes of Health (NIH) and other institutions have significantly increased funding for Lyme disease research, aiming to improve diagnostics and treatments.
Patient advocates and documentaries have raised awareness and pushed for more research funding and better recognition of chronic Lyme disease. Efforts are being made to validate patients' experiences and improve care.
Research
Article: Oxidative Stress is a shared characteristic of ME/CFS and Long COVID | bioRxiv
DEFINITIONS:
Oxidative Stress: An imbalance between the production of reactive oxygen species (ROS) and the body's ability to detoxify them, leading to cellular damage.
Peripheral Blood Lymphocytes: White blood cells found in the bloodstream that are crucial for the immune response, including T cells and B cells.
Reactive Oxygen Species (ROS): Chemically reactive molecules containing oxygen, such as superoxide and hydrogen peroxide, which can cause cellular damage.
Flow Cytometry: A laboratory technique used to detect and measure physical and chemical characteristics of cells or particles, often used to analyze immune cells.
RNA-seq Analysis: A method used to analyze the quantity and sequences of RNA in a sample, providing insights into gene expression.
Mass Spectrometry: An analytical technique used to measure the mass-to-charge ratio of ions, useful for identifying and quantifying molecules in a sample.
Glutathione: An antioxidant that helps protect cells from oxidative damage by neutralizing ROS.
Metformin: A medication commonly used to treat type 2 diabetes, shown in this study to reduce T cell hyperproliferation and oxidative stress in ME/CFS patients.
Lipid Peroxidation: The oxidative degradation of lipids, leading to cell membrane damage and production of harmful byproducts.
Mitochondrial Superoxide Dismutase (SOD2): An enzyme that helps break down superoxide radicals in the mitochondria, protecting cells from oxidative stress.
SUMMARY:
This study aimed to identify shared molecular signatures between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) by analyzing oxidative stress and bioenergetic characteristics in peripheral blood lymphocytes from 16 healthy controls, 15 ME/CFS patients, and 15 LC patients. Techniques used included flow cytometry, RNA-seq analysis, mass spectrometry, and systems chemistry analysis.
Both ME/CFS and LC patients exhibited elevated oxidative stress compared to healthy controls, particularly in memory lymphocytes.
Elevated reactive oxygen species (ROS) levels, decreases in mitochondrial superoxide dismutase levels, and increased glutathione levels were noted, indicating oxidative stress and mitochondrial dysfunction.
Sex-Specific Differences: Females with ME/CFS had higher total ROS and mitochondrial calcium levels, leading to hyperproliferation of T cells. Males, while not exhibiting higher ROS levels, showed greater lipid oxidative damage. These findings highlight distinct oxidative stress responses and potential pathophysiological differences between sexes.
Higher ROS levels in females were associated with hyperproliferation of T cells, which can be attenuated by metformin, suggesting a possible treatment.
This hyperproliferation was not observed in males, who showed insensitivity to ROS levels.
The study suggests that both ME/CFS and LC can be diagnosed using quantitative blood cell measurements related to oxidative stress.
Metformin, an FDA-approved drug, was shown to reduce T cell hyperproliferation in ME/CFS female patients, indicating its potential as a tailored treatment.
Elevated glutathione levels were found in both male and female ME/CFS patients, indicating a response to oxidative stress.
Lipid oxidative damage was significant in males, with lower levels of protective lipid droplets in ME/CFS and LC patients compared to healthy controls.
My Take:
These findings suggest potential targets for treatment and further research into personalized therapies based on these pathways.
The sex-specific differences observed highlight the importance of considering gender variations in disease pathogenesis and treatment strategies.
The study's approach to combining flow cytometry, RNA-seq analysis, mass spectrometry, and systems chemistry analysis offers a comprehensive understanding of the biochemical changes associated with ME/CFS and Long COVID.
Article: Brain abnormalities in survivors of COVID-19 after 2-year recovery: a functional MRI study
DEFINITIONS:
Resting-State Functional MRI (rs-fMRI): A type of MRI that measures brain activity by detecting changes in blood flow when a person is not performing any specific task.
Amplitude of Low-Frequency Fluctuation (ALFF): A measure of the amplitude of spontaneous brain activity at low frequencies, reflecting the intensity of regional brain activity.
Fractional Amplitude of Low-Frequency Fluctuations (fALFF): A normalized version of ALFF, which measures the relative contribution of low-frequency fluctuations to the total power of the signal.
Regional Homogeneity (ReHo): A measure of the similarity or synchronization of the time series of a given voxel (a value on a regular grid in 3D space) with its nearest neighbors, indicating local brain activity coherence.
SUMMARY:
Study Objective and Design: This study aimed to investigate long-term brain abnormalities in COVID-19 survivors using resting-state functional MRI (rs-fMRI). Fifty-two COVID-19 survivors (25 mild-moderate, 27 severe-critical) and 35 healthy controls were recruited for fMRI scans and cognitive assessments 27 months post-infection.
COVID-19 survivors reported higher levels of cognitive complaints, such as cognitive failure and mental fatigue, compared to healthy controls. However, there were no significant differences in objective cognitive function tests (MoCA, N-back, SRT) among the groups.
Survivors showed increased ALFF values in the left putamen, right inferior temporal gyrus, and right pallidum, and decreased ALFF values in the right superior parietal gyrus and left superior temporal gyrus.
Additionally, decreased ReHo values were found in the right precentral gyrus, left postcentral gyrus, left calcarine fissure, and left superior temporal gyrus.
Significant negative correlations were observed between ReHo values in the left superior temporal gyrus and cognitive failure and mental fatigue, suggesting that functional alterations in this region may contribute to cognitive complaints in COVID-19 survivors.
DEFINITIONS:
Hazard Ratio (HR): A measure of the effect of an intervention on an outcome over time. An HR less than 1 indicates a reduction in risk.
Charlson Comorbidity Index: A method of predicting mortality by classifying or weighting comorbid conditions.
Standardized Mortality Ratio (SMR) Weights: A statistical method used to balance covariates between treatment groups in observational studies to reduce bias.
Kaplan–Meier Curve: A statistical tool used to estimate the survival function and visualize the time until an event occurs, such as death or the development of a health condition.
Proportional Hazards Assumption: An assumption in Cox regression models that the ratio of hazard rates for different levels of a predictor remains constant over time.
SUMMARY:
The study aimed to examine the effects of nirmatrelvir–ritonavir on post-acute sequelae and mortality in patients hospitalized with COVID-19 in Hong Kong.
It utilized a retrospective cohort design, analyzing inpatient records, vaccination records, and COVID-19 case data from March 2022 to October 2023.
The study included 50,055 patients aged 18 and older who tested positive for SARS-CoV-2 and were admitted to the hospital.
Of these, 15,242 patients were prescribed nirmatrelvir–ritonavir within five days of symptom onset, while 23,756 patients did not receive this treatment and served as controls.
The nirmatrelvir–ritonavir group showed a significantly lower hazard of post-acute inpatient death (HR 0.62) and several post-acute sequelae, including congestive heart failure, atrial fibrillation, coronary artery disease, chronic pulmonary disease, acute respiratory distress syndrome, interstitial lung disease, and end-stage renal disease, compared to the control group.
No significant differences were found between the treatment and control groups for deep vein thrombosis, seizure, anxiety, post-traumatic stress disorder, acute kidney injury, and pancreatitis. The median follow-up duration was 393 days.
DEFINITIONS:
Vagus nerve stimulation: A therapeutic intervention involving the stimulation of the vagus nerve for the treatment of various neurological and psychiatric disorders.
Transcutaneous vagus nerve stimulation (t-VNS): Non-invasive vagus nerve stimulation method that involves applying electric stimulation to the auricular branch of the vagus nerve.
SUMMARY:
This pilot study focused on evaluating the efficacy of transcutaneous vagus nerve stimulation (t-VNS) in improving symptoms of Long COVID in a female cohort.
The study observed significant improvements in cognitive functions, mood (anxiety and depression), sleep, and fatigue post-treatment with t-VNS.
While t-VNS did not lead to significant changes in olfactory performance, other outcomes demonstrated sustained gradual improvements beyond the treatment period.
The study highlighted the potential of t-VNS as a promising non-invasive therapeutic approach for managing persistent symptoms in female patients with Long COVID.
DEFINITIONS:
Fatigue Severity Scale (FSS): A questionnaire that measures the impact of fatigue on daily functioning.
Pittsburgh Sleep Quality Index (PSQI): A self-report questionnaire that assesses sleep quality and disturbances over a one-month period.
Health Visual Analogue Scale (VAS): A tool used to measure subjective characteristics or attitudes that cannot be directly measured, such as pain intensity.
SUMMARY:
The study compared well-being and cognitive function between individuals with long COVID (∼16 months illness duration), those with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS, ∼16 years illness duration), and age-matched healthy controls
Both patient groups reported significantly lower well-being across multiple measures compared to healthy controls.
Similarities Between Long COVID and ME/CFS: Both groups experienced similar levels of impairment in well-being, including higher levels of pain, fatigue, post-exertional malaise, sleep disturbances, breathlessness, neurological symptoms, anxiety, and depression compared to controls.
Cognitive function, assessed through the Single Digit Modalities Test (SDMT), Stroop test, and Trails A and B, showed no significant differences between the long COVID, ME/CFS, and control groups, indicating similar cognitive abilities across all groups.
Well-being was assessed using several questionnaires, including the Health Visual Analogue Scale (VAS), Fatigue Severity Scale (FSS), Post-exertional malaise (PEM), Pittsburgh Sleep Quality Index (PSQI), and others. Cognitive function was evaluated using mobile application-based tests.
DEFINITIONS:
Static Lung Hyperinflation (SLH): An increase in the residual volume (RV) of air in the lungs after full expiration, leading to a higher RV to total lung capacity (TLC) ratio, indicating difficulty in fully exhaling air from the lungs.
Small Airway Dysfunction (SAD): Impairment in the small airways of the lungs, often measured using IOS parameters, which can lead to airflow limitations and respiratory symptoms.
Impulse Oscillometry (IOS): A technique used to measure airway resistance and reactance during breathing, providing information on lung function and the presence of SAD.
CD4/CD8 T-cell Ratio: The ratio of two types of T-cells (CD4+ helper T-cells and CD8+ cytotoxic T-cells) in the blood, used to assess immune function and potential dysregulation.
Residual Volume (RV): The amount of air remaining in the lungs after a full exhalation, used to evaluate lung capacity and function.
Total Lung Capacity (TLC): The total volume of air the lungs can hold, including all the air in the lungs after a full inhalation.
SUMMARY:
The study investigated the prevalence and persistence of static lung hyperinflation (SLH) in 64 patients with post-acute sequelae of COVID-19 (PASC) over eight months.
SLH was found in 53.1% of patients, irrespective of COVID-19 severity, and persisted in 57% of those initially affected.
SLH was significantly associated with small airway dysfunction (SAD), measured by impulse oscillometry (IOS) parameters. SAD and SLH contributed to the development of dyspnea and fatigue in PASC patients.
A decreased serum CD4/CD8 T-cell ratio was correlated with SLH. Specifically, an increase in CD8+ T-cell counts and a decrease in CD4+ T-cell counts were observed, suggesting a dysregulated immune response contributing to SAD and SLH.
Lung function parameters, including FEV1, FVC, and DLCO, improved over eight months, but IOS parameters indicating SAD and the prevalence of dyspnea and fatigue did not significantly change. This suggests that SAD and SLH play a crucial role in the persistence of respiratory symptoms.
SLH was the most significant predictor of dyspnea and fatigue in PASC patients, with IOS parameters R5-R20 and AX being strongly associated with post-COVID breathlessness.
DEFINITIONS:
Dopaminergic (DA) Neurons: Neurons that produce dopamine, a neurotransmitter critical for motor function and implicated in Parkinson's disease.
hESC (Human Embryonic Stem Cell)-Derived Neurons: Neurons developed from human embryonic stem cells, used for research due to their ability to differentiate into various cell types.
Human Preformed Fibrils (hPFFs): Aggregates of α-synuclein protein used to model Parkinson’s disease pathology in experimental settings.
Astrocytes: Glial cells in the brain and spinal cord that support neurons and maintain the blood-brain barrier.
Microglia: Immune cells in the brain that act as the first line of defense in the central nervous system, playing a role in inflammation and repair.
α-Synuclein: A protein that aggregates to form fibrils in the brains of Parkinson's disease patients, contributing to neuronal death.
GFAP (Glial Fibrillary Acidic Protein): A protein expressed by astrocytes, often used as a marker of astrocyte activation in neuroinflammation.
Iba-1 (Ionized Calcium-Binding Adapter Molecule 1): A protein expressed by microglia, used as a marker for microglial activation and neuroinflammation.
SUMMARY:
The study investigates how SARS-CoV-2 infection exacerbates Parkinson’s disease (PD) pathology using human embryonic stem cell-derived dopaminergic neurons and a human ACE2 transgenic mouse model.
The findings show that SARS-CoV-2 infection increases susceptibility and cellular toxicity in neurons pre-treated with human preformed fibrils (hPFFs), a model of PD.
SARS-CoV-2 spreads to the brain via the nasal cavity, causing persistent neuroinflammation, even after the virus is no longer detectable.
This prolonged inflammation, mediated by astrocytes and microglia, contributes to the worsening of PD symptoms and cellular damage.
SARS-CoV-2 infection following hPFF treatment in dopaminergic neurons significantly alters gene expression related to apoptosis, autophagy, and neurodegenerative diseases like PD, ALS, and Alzheimer’s disease.
These changes enhance cell death and dysfunction in dopaminergic neurons.
In hACE2 transgenic mice, SARS-CoV-2 infection increased hPFF-induced PD-like pathology, including increased α-synuclein phosphorylation and reduced expression of dopaminergic markers.
Neuroinflammation markers (GFAP and Iba-1) remained elevated for up to 60 days post-infection, indicating prolonged inflammation.
The study highlights the significant role of glial cells (astrocytes and microglia) in sustaining neuroinflammation and contributing to the progression of PD following SARS-CoV-2 infection.
This inflammation persists even after viral clearance, suggesting a lasting impact on the brain's immune environment.
DEFINITIONS:
Computable Phenotypes: Standardized algorithms used to identify patients with specific conditions (such as PASC) based on EHR data.
Principal Component Analysis (PCA): A statistical method used to reduce the dimensionality of large datasets while preserving as much variability as possible.
Charlson Comorbidity Index (CCI): A method of categorizing comorbidities (existing medical conditions) of patients based on the International Classification of Diseases (ICD) diagnosis codes, used to predict mortality risk and other outcomes.
Hazard Ratios (HR) and Adjusted Hazard Ratios (aHR): Measures used in survival analysis to compare the risk of an event (e.g., developing PASC) between different groups over time. Adjusted hazard ratios account for potential confounding variables.
Multisystem Inflammatory Syndrome in Children (MIS-C): A serious condition where different body parts can become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs, associated with COVID-19 in children.
SUMMARY:
This study aimed to estimate the incidence of post-acute sequelae of SARS-CoV-2 infection (PASC), or Long COVID, in both adults and children using electronic health record (EHR) data from three large research networks participating in the RECOVER Initiative. Different classification algorithms were used to identify PASC cases.
The study found that 7% of children and between 8.5% to 26.4% of adults developed PASC, with excess incidence (compared to non-COVID-19 patients) of 4% in children and 4-7% in adults. Incidence rates varied based on the definition of PASC used.
Temporal patterns of PASC incidence were consistent across networks, with peaks corresponding to the emergence of new COVID-19 variants.
Comparison with COVID-19 negative and historical control groups revealed that PASC-like symptoms also occurred in these groups, albeit at lower rates. This highlights the non-specific nature of PASC symptoms and the importance of considering background rates of similar symptoms.
DEFINITIONS:
Hierarchical Clustering: A method of cluster analysis which seeks to build a hierarchy of clusters by successively merging or splitting existing clusters.
Logistic Regression Models: A statistical method used to predict the outcome of a categorical dependent variable based on one or more predictor variables.
Principal Component Analysis (PCA): A dimensionality-reduction method that is used to reduce the complexity of large datasets by transforming them into a set of orthogonal components.
Multiple Correspondence Analysis (MCA): A method used to analyze and visualize relationships between categorical variables in a dataset.
Euclidean Distance Measure: A metric used to calculate the straight-line distance between two points in Euclidean space.
Mesoscale Discovery (MSD) Kits: Kits used for biomarker analysis that allow for the simultaneous measurement of multiple biomarkers from a single sample.
SUMMARY:
The study aimed to identify immunological patterns in individuals with long COVID by analyzing plasma levels of 42 biomarkers.
Hierarchical clustering and logistic regression models were used to explore associations between biomarker clusters, clinical variables, and symptom phenotypes.
101 individuals with long COVID were enrolled, with demographic and clinical data collected from electronic medical records.
Plasma samples were analyzed for inflammatory biomarkers and antibody levels against SARS-CoV-2 proteins.
Three inflammatory clusters were identified:
Limited immune activation cluster: Characterized by low levels of inflammation and younger age.
Innate immune activation cluster: Characterized by elevated innate immune markers, older age, and higher BMI.
Systemic immune activation cluster: Characterized by high levels of systemic inflammation markers and older age.
Cluster membership was associated with clinical variables such as age, BMI, and vaccination status, but not with individual symptoms or symptom phenotypes.
Higher anti-nucleocapsid antibody levels were observed in the innate and systemic inflammation clusters, potentially indicating persistent viral antigen.
Vaccination status was significantly associated with cluster membership.
Thanks so much for this issue Brandon! What a service you are providing for those of us whose life trajectories have been profoundly altered by this protean, polymorphic condition. Instead of mutely suffering and trying to re-order our lives as best we can under a smothering blanket of ignorance, you provide us ways of understanding what science has learned so we can make better-educated decisions on how to proceed or what the path forward looks like. Gratitude!