Hi everyone,
Another jam packed edition this week! From a nationwide survey in France revealing that up to 13.4% of the general adult population may suffer from long COVID, depending on the definition used, to groundbreaking research identifying abzymes that could explain the persistent symptoms experienced by some patients. This newsletter will explore the multifaceted nature of long COVID, including its higher prevalence among certain demographic groups and the critical need for a unified definition to advance research and patient care. We'll also highlight innovative approaches to treatment, such as targeting specific antibodies and exploring the efficacy of existing medications for relieving symptoms. And a new project helps people with Long Covid find clinical trials and participate in research.
I'm highlighting this paper, "Article: A Prospective Study on Neural Biom.arkers in Patients with Long COVID Symptoms | Journal of Personalized Medicine" By examining neural biomarkers like GFAP, s100b, and total Tau, the study contributes to a deeper understanding of Long Covid's neurological implications. GFAP, or glial fibrillary acidic protein, plays a pivotal rolea a key intermediate filament protein in astrocytes, GFAP is crucial for maintaining the structural integrity and support of the central nervous system. Here are some interesting quotes:
"The levels of GFAP were significantly higher in the long-COVID patients than in the age and sex-matched controls [4.62 (0.22–20.23) ng/mL vs. 0.65 (0.08–5.20) ng/mL, p = 0.031]."
This significant elevation of GFAP among long-COVID patients underscores a potential marker for assessing the neurological impact of the condition.
Despite the increase in GFAP levels, "There were no significant associations between biomarker levels and CNS-related symptoms (p > 0.05)”
Elevated levels of GFAP do not translate to symptom severity?
Media
SUMMARY:
A patient-researcher named Ezra Spier has developed a project called Long Covid Studies, which provides information about clinical trials in an accessible way for people who may want to participate in research. It launched on March 26.
‘“Clinical trials are the currency in research that pushes things forward. Trials are how consensus is built within medicine,” Spier said. He was inspired to develop Long Covid Studies after participating in a Long Covid trial at Stanford University and seeing discussions from people with Long Covid who wanted to learn about new trials, he told The Sick Times.’
“To build the new website, Spier used data from ClinicalTrials.gov, a database run by the National Institutes of Health (NIH) that lists registered trials in the U.S. and elsewhere in the world.”
Article: Failure to Define Long Covid Will Impede Research Progress | Undark
SUMMARY:
This opinion piece by Leonard A. Jason discusses the challenges in defining and researching long COVID, highlighting the need for a unified case definition and the shortcomings of current symptom surveys. Here's a summary:
Accurate case definitions are vital for identifying patients, estimating prevalence rates, discovering biomarkers, and finding effective treatments. Long COVID suffers from multiple, differing definitions, impacting research and patient care.
Current surveys assessing long COVID symptoms are criticized for their simplistic yes-or-no approach, which fails to capture the frequency and severity of symptoms, crucial for distinguishing long COVID from other conditions or healthy states.
The National Institutes of Health’s RECOVER consortium's definition of long COVID heavily relied on the symptom of "loss of or change in smell or taste," which, while discriminative, may overlook other critical symptoms due to its infrequency and lesser severity.
Jason argues against conflating symptom measurement with functionality assessment in case definitions, pointing out that physical illnesses generally do not require demonstrated functional impairment for diagnosis, unlike mental disorders.
The failure to agree on a clear long COVID case definition not only hinders scientific progress but also potentially stigmatizes patients. A valid, comprehensive case definition should accurately describe patients' symptoms and functional limitations without necessitating demonstrated impairment.
Article: COVID-19 Antibody Discovery Could Explain Long COVID | UVA Health Newsroom
DEFINITIONS:
Abzymes: Antibodies that act like enzymes, potentially causing harmful effects in the body.
ACE2: Angiotensin Converting Enzyme 2, a protein responsible for regulating blood pressure.
Complement: A system in the body responsible for helping the immune system clear pathogens.
SUMMARY:
Researchers at UVA Health led by Steven L. Zeichner, MD, PhD, have discovered potential abzymes in some COVID-19 patients that may explain long COVID symptoms.
These abzymes mimic the activity of important enzymes like ACE2, which regulate blood pressure, blood clotting, and inflammation.
The findings suggest that targeting these rogue abzymes could lead to new treatments for both acute COVID-19 effects and long COVID symptoms.
Article: UN humanitarian chief Martin Griffiths is stepping down for health reasons | PBS Newshour
SUMMARY:
Martin Griffiths, the U.N. humanitarian chief, is resigning due to health reasons after nearly three years in the role, during which he addressed significant humanitarian crises in Ukraine, Gaza, and Africa.
His resignation follows a severe case of COVID-19 in October, from which he is still experiencing long-term effects. Griffiths, 72, has had a distinguished career, serving as the U.N. special envoy for Yemen before his current position and has been praised by U.N. Secretary-General António Guterres for his leadership in humanitarian advocacy and resource mobilization.
Research
!Case Study so not a large sample size
DEFINITIONS:
Hyperadrenergic POTS: A subtype of POTS where the patient experiences a significant increase in heart rate and blood pressure upon standing, often with elevated levels of norepinephrine.
Histamine Blocker: Medication that inhibits the action of histamine, a chemical mediator released by mast cells, used in treating allergic reactions and conditions like MCAS.
Autonomic Dysfunction: A condition where the autonomic nervous system, which controls bodily functions like heart rate and blood pressure, does not work properly.
Dysautonomia: A term encompassing various conditions of autonomic nervous system dysfunction, including POTS and orthostatic intolerance.
SUMMARY:
Postural Orthostatic Tachycardia Syndrome (POTS), especially its hyperadrenergic subtype, has been linked to Long Covid, characterized by a significant increase in heart rate upon standing without a corresponding drop in blood pressure.
Hyperadrenergic POTS, associated with increased serum norepinephrine levels and blood pressure upon standing, is proposed to have a connection with mast cell activation syndrome (MCAS), a condition marked by excessive mast cell degranulation leading to a variety of symptoms including rash and gastrointestinal discomfort.
Both conditions have been observed post-viral infections.
A case of a 26-year-old man showing complete remission of intractable hyperadrenergic POTS symptoms after COVID-19 using a histamine blocker, suggests a direct link between POTS, MCAS, and PCC (post-COVID condition).
This case underscores the potential effectiveness of targeting mast cell activation in treating certain post-COVID complications.
Mast cells, due to their wide distribution and ability to release various mediators, play a key role in the pathophysiology of POTS and PCC. Their activation can lead to symptoms ranging from dermatological to cardiovascular.
SUMMARY:
The prevalence of long COVID in the French adult population ranged from 1.2% to 13.4% depending on the specific definition used for assessment.
Agreement between different definitions of long COVID was modest, with distinct prevalence estimates and variations across sociodemographic and infection characteristics.
Regardless of the definition, long COVID remains a significant burden in the general adult population, affecting up to 13.4% of individuals.
The study highlighted higher prevalence rates of long COVID in women, unemployed individuals, and those with a history of hospitalization for acute COVID-19.
Perceived long COVID prevalence was notably higher in women, self-employed individuals, and those infected during the Omicron variant waves.
SUMMARY:
This was a large-scale, prospective community-based cohort examining the long-term risks of psychiatric disorder and psychotropic prescription after infection with SARS-CoV-2.
The study found that participants with SARS-CoV-2 infection were at increased risks of subsequent incident psychiatric diagnoses, and had higher risk of related prescriptions for psychotropic medications.
Diagnoses included psychotic disorders, mood disorders, anxiety disorders, alcohol use disorders and sleep disorders.
Related prescriptions included antipsychotics, antidepressants, benzodiazepines, mood stabilizers and opioids.
These increased risks were evident even in those who tested positive in the community setting, usually people with mild symptoms or asymptomatic COVID-19.
Fully vaccinated participants with breakthrough infection were at lower risk of mental health outcomes compared with those who were unvaccinated or partially vaccinated when they got infected.
Identification and treatment of psychiatric disorders among survivors of SARS-CoV-2 infection should be a priority in the long-term management of COVID-19, especially for those with severe infection and those who were not fully vaccinated at the time of infection.
SUMMARY:
This was a case-series, prospective, observational cohort study that evaluated 105 patients at 18 months from hospital discharge. The study investigated health-related quality of life (HR-QoL), physical functioning, fatigue, and cognitive outcomes in COVID-19 patients who received invasive mechanical ventilation (IMV).
After 18 months from ICU discharge, survivors of severe COVID-19 respiratory failure experience a moderate reduction in HR-QoL, and a severe reduction in physical functioning.
In the fatigue area, the patients had a moderately high frequency of tiredness, weakness, and feeling of low energy with a minority of participants reporting some degree of impairment in everyday occupations. Fatigue prevalence was higher in younger patients and in females.
The most affected areas were pain and discomfort and anxiety and depression, with 60 (58.2%) and 45 (43.6%) patients reporting some sort of impairment, respectively.
Study authors observed a moderate to severe reduction in physical functioning, with most patients performing worse than predicted for their age and gender in the 6MWT (6 minute walk test).
Cognitive impairment was present at a low frequency.
DEFINITIONS:
CRP (C-Reactive Protein): A protein found in the blood, levels of which rise in response to inflammation.
IL6 (Interleukin 6): A cytokine involved in inflammation and the immune response. Elevated levels can indicate severe infection or inflammation.
BAU/ml (Binding Antibody Units per Milliliter): A unit of measurement used to quantify the level of specific antibodies in the blood.
aOR (Adjusted Odds Ratio): A measure of the association between an exposure and an outcome, adjusted for other variables.
aHR (Adjusted Hazard Ratio): A measure of how often a particular event happens in one group compared to another, adjusted for other variables, over time.
SUMMARY:
This study highlights a significant relationship between inflammatory markers (CRP and IL6) and anti-SARS-CoV-2 spike antibodies in hospitalized COVID-19 patients.
Notably, lower levels of CRP and IL6 were observed in patients with antibody levels above 1200 BAU/ml, suggesting that higher antibody levels are associated with reduced inflammation.
The combination of inflammatory markers and antibody levels proved to be a superior predictor of mortality among COVID-19 patients.
Specifically, patients with high levels of inflammatory markers and low antibody levels faced approximately 8 to 9 times higher mortality risk than those with low inflammatory responses and high antibody levels.
The study stratified patients into four categories based on their levels of CRP or IL6 and anti-SARS-CoV-2 spike antibodies.
Patients with high inflammatory markers and low antibody levels showed the highest mortality risk, while those with low inflammatory markers and high antibody levels had the lowest risk.
These findings underscore the importance of measuring anti-SARS-CoV-2 spike antibody levels in hospitalized patients, particularly those at risk of severe COVID-19. The data support the recommendation for regular booster vaccinations to mitigate COVID-19 related mortality by maintaining sufficient antibody levels.
DEFINITIONS:
Inflammatory Bowel Disease (IBD): A term for two conditions (Crohn's disease and ulcerative colitis) that are characterized by chronic inflammation of the gastrointestinal (GI) tract.
Erythrocyte Sedimentation Rate (ESR): A blood test that measures the rate at which red blood cells sediment in a period of one hour, used to assess inflammation in the body.
SUMMARY:
About 30% of IBD patients with non-severe COVID-19 experienced exacerbated gastrointestinal symptoms (EGS), and 38.1% developed long COVID, suggesting a significant impact of the virus on these patients despite vaccination.
Higher levels of erythrocyte sedimentation rate (ESR) were predictive of EGS during COVID-19, indicating inflammation as a contributing factor to symptom exacerbation.
A longer IBD duration and the experience of EGS during COVID-19 were significantly associated with the development of long COVID, suggesting that chronic IBD and acute EGS might predispose patients to prolonged COVID-19 complications.
DEFINITIONS:
HDL-Cholesterol (HDL-C): A type of cholesterol known for its protective role against cardiovascular diseases, often referred to as "good" cholesterol.
Ferritin: A blood protein that contains iron; high levels can indicate inflammation or iron overload, potentially contributing to oxidative stress.
Insulin Resistance (HOMA-IR): A condition in which cells in muscles, fat, and the liver start resisting or ignoring the signal that the hormone insulin is trying to send out—to grab glucose out of the bloodstream and put it into our cells. It is a precursor to several metabolic conditions, including type 2 diabetes.
SUMMARY:
Significant metabolic shifts were observed in severe Long-COVID-19 cases (referring to a severe initial infection), notably a marked reduction in HDL-cholesterol (HDL-C) levels and a significant increase in ferritin levels and insulin resistance, compared to mild cases and controls.
Both HDL-C and ferritin levels were identified as primary factors influenced by the severity of the initial COVID-19 infection, suggesting their potential role in the persistence and progression of Long-COVID-19 symptoms.
Patients with Long-COVID-19 exhibited persistent symptoms and metabolic changes, with severe cases showing significant alterations resembling metabolic syndrome, which is characterized by reduced HDL-C levels and poses a risk to cardiovascular health.
DEFINITIONS:
IFN-α2 (Interferon alpha-2): A type of interferon, a group of signaling proteins made and released by host cells in response to the presence of viruses. IFN-α2 is particularly important for the immune response against viral infections.
Handgrip Strength: A measure of muscle strength in the hands and forearms, often used as an indicator of overall muscle strength and function.
Timed Up-and-Go Test: A simple test used to assess a person's mobility and requires both static and dynamic balance. It measures the time taken for an individual to rise from a chair, walk a short distance, turn around, walk back to the chair, and sit down.
SUMMARY:
Participants with Long Covid were categorized into those with self-reported symptoms (SR) and those with both self-reported symptoms and decreased pulmonary function (SRPF). Both groups exhibited persistent symptoms and inflammatory dysregulation, with SRPF showing a more pro-inflammatory cytokine profile.
The study reveals sex-specific variations in Post-Covid Condition (PCC) manifestations. Female participants in the SR group demonstrated lower grip strength compared to females in the SRPF group. Males in the SR and SRPF needed more time to complete functional tests than those in the control group.
Lower muscle function was observed in individuals with PCC, with significant findings such as reduced handgrip strength and slower timed up-and-go test performance. These impairments are concerning due to their potential long-lasting health consequences.
The study found that serum cytokine levels, particularly lower IFN-α2, moderately predict the total number of self-reported symptoms in PCC, indicating a link between specific cytokines and the severity of persistent symptoms.
DEFINITIONS:
Caspase: A family of protease enzymes playing a key role in programmed cell death (apoptosis) and inflammation.
NHE-1 (Sodium–Hydrogen Exchanger 1): A membrane protein involved in regulating intracellular pH by exchanging sodium ions for hydrogen ions.
Polyphenolic Compounds: A group of naturally occurring compounds found in plants, known for their antioxidant properties and potential health benefits.
Thromboxane: A compound formed in platelets that causes blood clotting and constriction of blood vessels, playing a role in thrombosis.
SUMMARY:
The article examines several small molecules with potential therapeutic benefits for long COVID related conditions.
These include ramatroban, a thromboxane receptor antagonist; emricasan, a pan-caspase inhibitor; rimeporide, an NHE-1 inhibitor; and natural polyphenolic compounds.
These molecules target various aspects of the disease process, including inflammation, blood clotting, and endothelial dysfunction.
The discussion suggests that combining anti-inflammatory and anticoagulant therapies could be beneficial for treating the interconnected proinflammatory and prothrombotic processes in long COVID.
DEFINITIONS:
Glial Fibrillary Acidic Protein (GFAP): A protein expressed by various cell types in the CNS, playing a role in maintaining astrocyte mechanical strength and cellular structure. It's used as a biomarker for acute brain injuries.
S100b: A protein found primarily in brain astrocytes involved in calcium homeostasis and signal transmission. It’s levels can indicate brain damage but may also be elevated due to extracerebral sources.
Total Tau (t-Tau): A protein that stabilizes microtubules in neurons, with hyperphosphorylated forms leading to tauopathies like Alzheimer’s disease. Its levels in plasma can be predictive of dementia.
SUMMARY:
The study found that GFAP levels were significantly higher in long COVID patients compared to controls, indicating CNS involvement in long COVID.
However, this elevation did not correlate with the presence of long COVID symptoms or impacts on cognitive function, mental health, or quality of life.
Serum levels of S100b and total Tau did not show significant differences between long COVID patients and healthy controls.
Nearly half of the patients reported symptoms related to the nervous system, with high rates of cognitive decline, depression, anxiety, and post-traumatic stress disorder, highlighting the substantial impact of long-COVID on mental health and cognitive functions.
The study revealed that over 80% of participants scored below normative cutoffs for the SF-36 questionnaire, indicating a significant impact of long COVID on patients' quality of life.
DEFINITIONS:
α-ketoamide: A peptidomimetic inhibitor containing an α-ketoamide group that binds to the catalytic site of the SARS-CoV-2 main protease.
Mpro: The main protease of SARS-CoV-2, also known as Mpro or 3CLpro, plays a crucial role in viral replication and is a primary target for antiviral drug development.
Pharmacokinetics: The study of how drugs are absorbed, distributed, metabolized, and excreted in the body over time.
SUMMARY:
Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared to nirmatrelvir, suggesting its potential as an antiviral drug for COVID-19 treatment.
RAY1216 inhibits the SARS-CoV-2 main protease with high specificity and forms a stable complex with the enzyme.
In vitro and in vivo studies demonstrate that RAY1216 exhibits antiviral activities against SARS-CoV-2 variants comparable to nirmatrelvir, with improved pharmacokinetic profiles in mice and rats.
Interesting! My POTS/dysautonomia seemed to improve with antihistamines- Benadryl, Pepcid and Zyrtec. But ALL my LC symptoms , including the extreme fatigue and PEM, resolved completely after taking the 5 day course of paxlovid !