Hi everyone,
The biggest news this week was the Senate Hearing held on Long Covid last Thursday! For the full recording, please see here. I had the opportunity to tune in for the first hour or so of the hearing and it did not disappoint! Senators seem quite engaged and knowledgeable on the subject ( see here, here), I am optimistic we may be seeing a set budget coming to LC soon. It was made quite evident the dire situation people with LC have so hopefully this moves quickly.
You will also notice in this edition, we are highlighting a paper published in Science! This is the first time I can remember highlighting any LC research in Science. Highlighting Long Covid in such a prominent platform not only educates the scientific and medical communities but also raises public awareness. It encourages further research and funding, leading to a better understanding and potentially more effective strategies for prevention and treatment. The tide is turning!
Off topic but I am trying to get a better understanding of how allergies develop, especially later in life. Does anyone have any research articles or books they would be willing to point me too?
Media
Article: Long-COVID signatures identified in huge analysis of blood proteins: Nature
DEFINITIONS:
Biomarkers: Measurable substances or indicators in the body that can be used to diagnose or monitor a disease or condition.
SUMMARY:
Researchers have developed a computational model that predicts how likely a person is to develop long COVID based on an analysis of more than 6,500 proteins found in blood.
The study found notable differences in the composition of proteins in people with long COVID, those who recovered, and those who were never infected.
Proteins involved in immune responses, blood clotting, and inflammation could be key biomarkers in diagnosing and monitoring long COVID.
The condition affects an estimated 65 million people worldwide and is characterized by symptoms such as fatigue, brain fog, chest pain, and breathlessness.
The study's findings could pave the way for further studies and the development of therapies for long COVID.
My Take:
Developing a biomarker is one of the most important priorities in the entire space.
Article: Immune damage in Long Covid | Science
DEFINITIONS::
Complement: The complement system is crucial for innate immune defense by effecting lytic destruction of invading microorganisms, but when uncontrolled, it causes cell and vascular damage.
Thrombosis: The formation of blood clots within blood vessels.
Pentraxin 3: Pentraxins, which include serum amyloid proteins, serve humoral immunity by destroying and opsonizing pathogens for rapid clearance by innate immune cells.
SUMMARY:
Acute infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause a respiratory illness that can be associated with systemic immune cell activation and inflammation, widespread multiorgan dysfunction, and thrombosis.
Patients with Long Covid display signs of immune dysfunction and exhaustion.
The blood antimicrobial defense systems of complement and pentraxin 3 stood out as being significantly associated with Long Covid development.
During acute COVID-19, the complement and coagulation systems can become activated and remain locally activated in various tissues in Long Covid patients.
Together, these feedback loops can maintain local complement activation and inflammation, as well as generating microclots that could underlie some of the features of Long Covid.
My Take:
Also linked the actual research article in the section below
This is the first article highlighted in this newsletter I can remember being published in Science!
Article: Senators push for more investment in long COVID research | The Hill
SUMMARY:
Senate Committee Hearing: During a Senate Committee on Health, Education, Labor, and Pensions hearing, it was agreed that the government needs to enhance its involvement in long COVID research. This is to support the growing number of Americans suffering from prolonged symptoms post-COVID-19 infection.
Sen. Bernie Sanders, Chair of the Committee, expressed concern that long COVID has not received sufficient attention from the community, media, or Congress.
Sen. Tim Kaine shared his personal struggle with long COVID symptoms for four years and addressed the challenges faced by people of color and women in being believed and receiving treatment.
Long COVID, as defined by the CDC, encompasses various medical issues post-COVID-19 infection. Dr. Ziyad Al-Aly noted that it affects at least 20 million Americans and emphasized the lack of FDA-approved treatments, making it difficult for patients to find and afford care.
Sanders cited a study from The Brookings Institution showing that long COVID could be causing significant economic loss due to millions of people being unable to work. The estimated annual earnings loss ranges from $168 billion to $230 billion.
Al-Aly stressed the importance of preventing COVID-19 infections and investing in large-scale research to better understand and treat long COVID, which has low recovery rates and is likely to increase with more COVID-19 reinfections.
SUMMARY:
A billboard has been placed in Ardrossan to bring attention to the long-term impacts of the Covid-19 virus.
The billboard is part of a campaign by Not Recovered UK, a group made up of individuals affected by long Covid or ME/CFS.
Long Covid refers to the condition where symptoms of Covid-19 last longer than the typical recovery period of a few weeks.
ME/CFS is a chronic illness that currently has no cure and can only be treated symptomatically.
My Take:
How does one put up a billboard? How much does it cost?
Also check out this recent article in The Sick Times about billboard advocacy: Long Covid Advocates face challenges/potential discrimination with billboard campaigns
Article: Long Covid: NHS legal action launched by family of girl
DEFINITIONS:
NHS Grampian: The health board responsible for providing healthcare services in the Grampian region of Scotland.
SUMMARY:
The mother of an 11-year-old Aberdeenshire girl with long Covid has launched a legal action against their health board, in what lawyers claim is the first case of its kind in Scotland.
The action claims the health board is responsible for "multiple failings" in Anna's treatment and care.
Anna became unwell after contracting Covid in 2020 and has not been able to return to school, needs the use of a wheelchair, and is often confined to her bed.
The action includes claims that requests for Anna to be referred to the specialist paediatric services of immunology and neurology were refused.
It also claims no further help was offered after Anna was diagnosed with Chronic Fatigue Syndrome (CFS) and Paediatric Acute-onset Neuropsychiatric Syndrome (PANS).
Article: Exercise causes muscle damage and energy depletion in Long Covid: Healthrising
SUMMARY:
This deep-dive breakdown of the recent study in Nature, “Muscle abnormalities worsen after post-exertional malaise in long COVID“, discusses how the study “did something simple but brilliant that we haven’t seen in ME/CFS or FM before...tested how the muscles responded to an exercise challenge.”
The near-infrared spectroscopy readings in the long COVID study indicated a reduction in “peripheral O2 extraction” was present; i.e. the muscles of the long COVID patients weren’t taking up as much oxygen (read energy) as were the muscles of the healthy controls (recovered COVID-19 patients).
The authors proposed that the lower exercise capacity found in long COVID was in part due to a relative overabundance of “highly fatigable” glycolytic (fast-twitch) muscle fibers and reduced mitochondrial activity, possibly in concert with reduced blood flows to the muscles and hyperventilation during exercise.
Two major muscle studies by the Open Medicine Foundation, one of which includes a 2-day cardiopulmonary exercise test (CPET), will tell us even more about this potentially key area of ME/CFS pathophysiology.
My Take (Amy):
This article helpfully discusses the findings from the Nature article and highlights the tie to ME/CFS.
Research
[Article from Science highlighted above, with a little more detail]
DEFINITIONS:
Complement activation: The activation of the complement system, a part of the innate immune response, which targets pathogens and damaged cells.
Terminal complement complex (TCC): A complex formed by the complement components C5b-9, which can integrate into cell membranes and induce cell activation or lysis.
Thromboinflammation: A state of simultaneous activation of coagulation and inflammation, characterized by endothelial activation, platelet activation, and red blood cell lysis.
SUMMARY:
Patients with active Long Covid at 6-month follow-up showed dysregulation of the complement system, a part of the immune system involved in pathogen defense and cell debris clearance.
Specifically, they had increased levels of early complement components like C5bC6 but decreased levels of later components like C7 complexes, indicating excessive complement activation and possible tissue damage.
Long Covid patients also showed signs of increased blood clotting (thrombosis) and red blood cell damage (hemolysis), suggesting a pro-inflammatory and pro-thrombotic state termed "thromboinflammation."
Markers included increased von Willebrand factor, thrombospondin-1, and free heme along with decreased antithrombin III.
Some Long Covid patients had increased levels of antibodies against cytomegalovirus (CMV) and Epstein-Barr virus (EBV).
This was associated with increased complement component C2, suggesting these viral antibodies may be stimulating the classical complement activation pathway.
Machine learning models were able to predict Long Covid with reasonable accuracy based on complement and thromboinflammation protein biomarkers in combination with clinical data. This suggests potential for diagnostic tests.
SUMMARY:
The study aimed to investigate the causal relationship between COVID-19 and chronic pain using a Mendelian randomization study design.
Based on the results of the analysis, hospitalized COVID-19 patients showed a higher risk of experiencing lower leg joint pain compared to the normal population, while the associations between COVID-19 hospitalization and back pain, headache, and pain all over the body were suggestive of increased risk.
COVID-19 patients requiring hospitalization were found to have a higher risk of experiencing neck or shoulder pain and pain all over the body compared to those who did not require hospitalization.
Patients with severe respiratory-confirmed COVID-19 showed a higher risk of experiencing pain all over the body compared to the normal population.
DEFINITIONS:
Molecular mimicry: a phenomenon whereby viral or bacterial antigens share structural similarities with self-antigens, leading to the activation of autoreactive immune cells and the development of autoimmune diseases.
Bystander activation: the activation of immune cells in response to nearby inflammatory signals, even without direct recognition of a specific antigen.
SUMMARY:
Type 1 diabetes (T1D) is caused by an autoimmune process that leads to the destruction of insulin-producing beta cells in the pancreas.
Viral infections, especially enteroviruses, appear to accelerate the autoimmune process and are often seen as a precipitator of clinical diagnosis.
The use of anti-viral drugs has shown efficacy in preserving beta cell function after the onset of diabetes.
There are three key mechanisms linking viral infections to beta-cell death: direct infection of islets by viruses, modulation of the immune system, and increased stress on beta cells by interferon-mediated increase of insulin resistance.
The impact of the recent global coronavirus-2019 (COVID-19) pandemic on the development of autoimmune disease, including T1D, is a subject of concern.
My Take:
Not necessarily LC related but an interesting article.
Understanding the mechanisms by which viral infections accelerate autoimmune processes is crucial for developing targeted therapeutic interventions to preserve beta cell function.
SUMMARY:
The study found that SARS-CoV-2 was not detected in human breast milk.
Anti-SARS-CoV-2 antibodies, specifically IgA, were consistently detected in colostrum (day of birth until day 4 postpartum) samples.
The presence of antibodies in colostrum did not vary significantly based on the time of infection during pregnancy.
The concentration of IgA antibodies in breast milk decreased significantly in mature milk samples (day 7 postpartum until 6 weeks postpartum) compared to colostrum.
The study concludes that breastfeeding is safe during maternal SARS-CoV-2 infection, as the virus is not detected in breast milk and antibodies are present.
DEFINITIONS:
Dopaminergic (DA) neurons: A type of neuron in the brain that produces the neurotransmitter dopamine. Degeneration of DA neurons is associated with Parkinson's disease.
SUMMARY:
The researchers derived DA neurons from human pluripotent stem cells (hPSCs) and showed that these neurons can be infected by SARS-CoV-2.
About 5-8% of the DA neurons were infected after 48-72 hours.
The infected neurons exhibited signs of cellular senescence, which is a state of irreversible growth arrest that is associated with the secretion of proinflammatory proteins (senescence-associated secretory phenotype or SASP).
This can disrupt tissue function and contribute to inflammation throughout the body.
The researchers also identified 3 FDA-approved drugs - riluzole, metformin, and imatinib - that could prevent the SARS-CoV-2-induced senescence in DA neurons by inhibiting viral infection.
Analysis of postmortem substantia brain tissue from COVID-19 patients showed similar inflammatory and senescence signatures as seen in the infected DA neuron cultures.
The findings indicate that DA neurons may be vulnerable to SARS-CoV-2 infection, which could trigger inflammation and senescence.
Although only a small percentage of neurons appear to be infected, this could contribute to neurological symptoms in some COVID-19 patients.
The results suggest a need to monitor recovering COVID-19 patients for potential increased risk of developing Parkinson's disease.
Article: Frontiers | T4 apoptosis in the acute phase of SARS-CoV-2 infection predicts long COVID
DEFINITIONS:
T4 lymphocyte: A type of white blood cell that is part of the adaptive immune system. Also called helper T cell or CD4 T cell. These cells help activate other immune cells like B cells to mount an immune response against pathogens.
Apoptosis: A form of regulated cell death in which cells essentially commit suicide. It is a normal process the body uses to get rid of old, damaged or infected cells.
SUMMARY:
T4 lymphocytes from participants who later presented with long COVID were more apoptotic in culture than those of sequelae-free participants at Month 12.
None of the measured inflammatory markers in plasma and PBMC supernatant were predictive for long COVID.
The intensity of programmed T4 cell death in the acute phase of SARS-CoV-2 infection was able to differentiate between patients who developed long COVID and those who did not.
T4 cell death during the acute phase of SARS-CoV-2 infection might contribute to long COVID by facilitating viral persistence, reactivation of other viruses, and immune dysregulation.
Inhibiting T cell apoptosis, such as through caspase inhibitors, could potentially prevent long COVID.
My Take:
This is a super interesting hypothesis!
DEFINITIONS:
Single-cell RNA sequencing (scRNA-seq): A technique used to profile gene expression at the single-cell level, allowing for the identification of gene expression patterns specific to individual cells.
Classical monocytes: A subset of monocytes that are a key component of the innate immune system and play a role in inflammatory responses.
SUMMARY:
To understand immune dysregulation in ME/CFS, researchers used single-cell RNA sequencing (scRNA-seq) to examine immune cells in patient and control cohorts.
Monocytes, particularly classical monocytes, in ME/CFS patients display dysregulation in gene expression indicative of inappropriate differentiation, migration to tissue, and activation of pro-inflammatory and anti-inflammatory pathways.
Platelets in ME/CFS patients also show dysregulation in gene expression, particularly in relation to platelet activation, but this dysregulation is resolved after symptom provocation.
The findings suggest that immune dysregulation, specifically in monocytes and platelets, may play a role in the pathogenesis of ME/CFS.
My Take:
This study provides valuable insights into immune dysregulation in ME/CFS, specifically highlighting the role of monocytes and platelets.
The resolution of platelet dysregulation following symptom provocation suggests that platelets may be actively involved in the symptomatology of ME/CFS.
SUMMARY:
This open-label randomized controlled clinical trial of 62 participants aimed to investigate the effect of Amantadine on patients with post-COVID-19 fatigue using the Fatigue Severity Scale [FSS] as well as Visual Analog Fatigue Scale (VAFS). The intervention group received Amantadine for two weeks, while the control group received no treatment.
Study results showed a significant difference in the improvement of fatigue in patients receiving Amantadine compared to the control group. This improvement was evident in the FSS and the VAFS scores since the average of both reached less than half of the initial value after two weeks of treatment with Amantadine.
Authors conclude that the study demonstrated that consuming Amantadine has a favorable effect on relieving post-COVID-19 fatigue. Their results reveal the safety and tolerability of two-weeks treatment with Amantadine in post-COVID-19 patients. They recommend well-designed double-blind, randomized studies with placebo and larger sample sizes to validate their results.
SUMMARY:
This prospective cohort study aimed to identify characteristics of long COVID and any potential mitigating effects of COVID-19 vaccinations in patients 24 months following COVID-19 infection.
The study analysis found no difference in the incidence of long COVID based on vaccination status or the number of vaccine doses, supporting a previous systematic review that found the impact of vaccination in people with pre-existing long COVID symptoms to be negligible.
However, due to the small number of unvaccinated patients, a study with a higher proportion of unvaccinated patients will be required to determine the effectiveness of vaccination on long COVID.
Article: Vaccine effectiveness against long COVID in children: Pediatrics
SUMMARY:
Vaccination reduces the risk of acute Covid-19 in children, but it is less clear whether it protects against long Covid. This study estimated vaccine effectiveness (VE) against long Covid in children ages 5-17.
This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data.
My Take (Amy):
We all know that the sure way to not get long Covid is to not get Covid. And we also know that vaccination prevents us (to a certain degree) from getting Covid. It would be helpful to know if this study represents how much vaccination decreases our risk for long Covid in real world terms - combining the decreased risk of getting Covid with the decreased risk of getting Long Covid if you do get Covid. I don’t think this study reflects that, but I couldn’t really tell.
Hi Brandon,
Thanks so much for putting together all of this material.
If you'd like to zoom, I can give you a quick overview of how allergies develop. There are some really wonderful articles that I should be able to dig up for you. Let me know.
Kind regards, Mardi
Excellent information. Just catching up after a flare that lasted over a month. Regarding Science article, I saved it to send to my cardiologist who says not to worry about blood clots. She says all my chest pain/dyspanea is dysautonomia. “No need for follow up”. And on another topic, I was mandated to get 3 vaccines. Didn’t save me. What does the research show about noravax? Is that also harmful to some? I want to avoid vaccine injury.