Long Covid Weekly #85: LC research repo? Brain Changes and more
In this edition, we cover a range of topics, from the alarming rise in Americans experiencing long Covid symptoms to the impact of vaccination on the association with cardiovascular diseases. We also delve into studies on autonomic nervous system dysfunction, the cost of Long Covid, and the potential effects of long Covid on workers in healthcare settings.
The pace of research being published is staggering. In fact, I started a backlog this week because there were so many pieces I found worth highlighting!
Also just throwing this out there but Amy and I have been discussing the early stages of a repository of all the research ever published through this newsletter! Given, each edition has around 8 research articles and 85 total editions, that is nearly 700 articles! Curious what others in the community think of this initiative and if it is worth the time.
The article I wanted to highlight this week is Article: SARS-CoV2 evokes structural brain changes resulting in declined executive function | Plos One. This is another must read. As the title states the authors found some really interesting (and concerning) insights related to brain changes seen in acute covid patients.
Here are some interesting excerpts:
"We found significantly reduced grey matter in whole-brain analyses in patients with an acute COVID-19 infection in the left inferior frontal gyrus, the insular cortex and the basal ganglia compared to healthy controls. This decline could also be retraced in recovered patients compared to healthy controls in similar regions suggesting persistence of these changes over the period of acute illness."
"A decline in executive function and especially verbal fluency was found in acute patients, partially persisting in recovered. Changes in gray matter volume and white matter tracts included mainly areas involved in networks of executive control and language."
Media
Article: #MEAction's NIH Study Response - #MEAction Network
SUMMARY:
The NIH study on ME/CFS raised concerns within the community due to its limited sample size of n=17 and conclusions that may not represent the broader ME/CFS population.
The study's selection criteria led to the exclusion of many potential participants, potentially creating a selection bias among the participants, impacting the generalizability of the results.
The study reported claims of recovery and alterations in effort preference among ME/CFS patients, which require careful interpretation due to the small sample size and potential biases in participant selection.
Concerns were raised about the study's focus on specific diagnostic criteria, comorbidities, and exclusion of more severely affected patients, leading to questions about the validity and representativeness of the findings.
The study's conclusions and recommendations, including the potential use of immune checkpoint inhibitors for ME/CFS, should be critically assessed in the context of the study's limitations and participant selection issues.
My Take:
This is from a couple of weeks ago, but the points are still very relevant. The flagship NIH study was a great start but the lack of meaningful sample size is concerning.
SUMMARY:
The National Institutes of Health's RECOVER Initiative has begun two phase 2 clinical trials, named RECOVER-AUTONOMIC, to test three treatments for autonomic nervous system dysfunction symptoms in adults who have had COVID-19. This condition, known as long COVID, can lead to symptoms such as rapid heart rate, dizziness, and fatigue.
These trials specifically target adults with Postural Orthostatic Tachycardia Syndrome (POTS).
The trials will evaluate the safety and effectiveness of Gamunex-C (an intravenous immunoglobulin), Ivabradine (a heart rate reducing medication), and a non-drug care approach involving lifestyle adjustments managed by a care coordinator.
RECOVER-AUTONOMIC adopts an adaptive clinical trial model, allowing the integration and testing of additional potential treatments as they become available. This design aims to enroll 380 participants across 50 sites in the U.S., with a focus on recruiting from diverse communities.
The development of the trials benefitted from inputs by patients with long COVID, caregivers, community representatives, clinicians, and scientists, ensuring that the chosen interventions are relevant and potentially beneficial to the affected individuals.
Article: Did ‘long COVID’ increase road deaths in the USA? | Injury Prevention
DEFINITIONS:
Poisson Regression: A statistical approach used to model count data and rates, such as the number of events (road deaths in this case) in a given time period or area.
SUMMARY:
This abstract is from a research study that examined data showing significant association between cumulative COVID-19 cases and a 10 percent increase in U.S. road deaths from 2020 to 2021, highlighting potential impacts of pandemic stress and neurological damage from COVID-19 on road safety.
Utilizing Poisson regression, the study analyzed the correlation between road deaths and several factors, including recent and accumulated COVID-19 cases, maximum temperatures, truck registrations, and gasoline prices, across U.S. states in 2021.
The analysis found that road deaths were correlated with accumulated COVID-19 cases but not with cases from the previous month. Increases in gasoline prices had a counteracting effect, reducing the number of road deaths that might have occurred had fuel costs remained low.
The study posits that neurological changes and long-term symptoms experienced by COVID-19 survivors (long COVID) could be contributing to increased road fatalities, although it calls for more research to distinguish the specific effects of neurological damage and pandemic-related stress on driving behavior.
My Take:
This is a really interesting study…the second order implications of wide-scale LC have been understudied.
Article: Long COVID, with no treatment in sight, took my life as I knew it | USA Today
SUMMARY:
Rachel Beale shares her personal experience of living with long COVID, highlighting the profound impact it has had on her health, job, and quality time with her children.
Despite testing positive for COVID-19 in March 2021 and initially feeling better after two weeks, Rachel's symptoms persisted and evolved into chronic fatigue, pain, and neurological issues that significantly altered her daily life.
The lasting effects of long COVID forced Rachel to adapt to a new reality, including losing her job due to debilitating symptoms and needing to carefully plan activities around her limited energy levels.
DEFINITIONS:
The Office of Disability Employment Policy (ODEP) released a special edition of its News Brief to honor International Long COVID Awareness Day on March 15, focusing on resources to help employers support workers affected by Long COVID.
This guide, titled "Supporting Employees with Long COVID," was developed by ODEP-funded organizations. It provides information on Long COVID, its effects on mental health, and common workplace accommodations, alongside employers' responsibilities under the Americans with Disabilities Act (ADA).
The Job Accommodation Network (JAN) offers a webpage with strategies for supporting workers with Long COVID, including specific accommodation ideas, situations and solutions, and questions for identifying effective accommodations.
Article: ‘Alarming’ rise in Americans with long Covid symptoms | The Guardian
!paywalled
SUMMARY:
The CDC survey revealed an alarming increase in Americans experiencing long Covid symptoms, with an estimated 17.6 million people affected.
Experts note that the rise in long Covid cases is concerning, especially as it limits day-to-day activities for many individuals.
From the article: “The survey results were released on 22 February, more than a week before the CDC updated its Covid isolation recommendations. The CDC says in that guidance that the ‘prevalence of long Covid also appears to be decreasing,’ in contrast to its own survey findings.”
Research
SUMMARY:
COVID-19 impacts the central nervous system, causing structural brain changes, notably in gray and white matter, leading to a decline in executive functions and language abilities.
This study aimed to link these structural changes with neurocognitive testing outcomes to develop a multidimensional disease model.
The study involved three groups: acutely ill COVID-19 patients, recovered COVID-19 patients, and healthy controls.
MRI imaging and comprehensive neurocognitive testing were conducted, revealing significant alterations in gray matter volume and white matter tracts, particularly in areas associated with executive control and language.
Acutely ill COVID-19 patients showed a decrease in gray matter volume and diminution of white matter tracts.
These changes persisted in recovered patients but to a lesser extent, suggesting partial recovery over time.
Neurocognitive testing indicated deficits in attention, executive functions, memory, and language in COVID-19 patients, with these symptoms often outlasting the acute phase of the illness and contributing to long-term impairments known as 'Post-COVID'.
The study found specific networks to be more affected by COVID-19, including the frontal–basal ganglia–thalamic network and the temporal areas.
DEFINITIONS:
Whole genome sequencing: A process that determines the complete DNA sequence of an organism's genome at a single time, providing comprehensive information about all its genetic material.
Real-time RT-PCR: A nuclear-derived method for detecting the presence of specific genetic material in any pathogen, including a virus.
Intrahost evolution: Changes in the genetic makeup of a virus within a single host over time, which can lead to the emergence of new variants.
B-cell dysfunction: Impaired function of B cells, a type of white blood cell crucial for producing antibodies, often resulting from certain diseases or treatments.
Hematopoietic stem-cell transplantation (HSCT): A procedure that restores stem cells in patients who have had theirs destroyed by chemotherapy or radiation therapy, used in the treatment of various blood and bone marrow diseases.
SUMMARY:
This multicentre, prospective analysis aimed to evaluate risk factors for prolonged SARS-CoV-2 infection and associated intrahost evolution among immunocompromised patients during the Omicron period.
Participants, aged 18 or older and tested SARS-CoV-2-positive within the last 14 days, were enrolled from five US medical centers and underwent nasal specimen testing by real-time RT-PCR and whole genome sequencing.
The study included 150 patients with various immunocompromising conditions.
Results showed that 25% remained RT-PCR-positive, and 8% were culture-positive 21 days or longer after initial detection. Patients with B-cell dysfunction, solid organ transplantation or hematopoietic stem-cell transplantation (HSCT), and AIDS had significantly longer infections.
Individuals with infections exceeding 56 days accumulated distinct spike mutations, especially within the receptor-binding domain, differing from global strains.
Despite similar evolutionary rates across patients, prolonged infections led to notable within-host evolution.
The findings underline the importance of monitoring and treating immunocompromised populations to prevent the emergence of antiviral resistance and novel SARS-CoV-2 variants.
DEFINITIONS:
HRV (Heart Rate Variability) - The fluctuation in time intervals between adjacent heartbeats and a way to measure changes in cardiac autonomic function.
SUMMARY:
Autonomic dysfunction is suspected to play a role in long COVID symptoms in children and adolescents following SARS-CoV-2 infection.
This observational case-control study in Italy investigated changes in cardiac autonomic function through heart rate variability parameters in pediatric long COVID patients.
Fifty-six long COVID pediatric patients (mean age 10.3 ± 3.8 y) and 27 healthy controls (mean age 10.4 ± 4.5y) underwent 12-lead ECG and 24-h ECG Holter monitoring. Autonomic cardiac function was assessed by heart rate variability parameters. A comprehensive echocardiographic study was also obtained.
Data analysis showed that pediatric patients with long COVID had significant changes in HRV variables compared to healthy controls. The findings suggest an imbalance towards increased parasympathetic tone, as also seen in adults.
Understanding the autonomic dysfunction in long COVID may pave the way for therapeutic interventions targeting the underlying pathophysiological mechanisms.
DEFINITIONS:
Cardiovascular diseases (CVDs): A class of diseases that involve the heart or blood vessels, including conditions such as coronary artery disease, heart failure, and thrombotic events.
Thrombotic events: Conditions where blood clots form in blood vessels, potentially leading to arterial thrombotic events (e.g., myocardial infarction, ischemic stroke) or venous thrombotic events (e.g., pulmonary embolism, deep vein thrombosis).
Hazard ratio (HR): A measure used in survival analysis to compare the likelihood of an event occurring at any given time in one group to the likelihood of it occurring in another group.
OpenSAFELY: A secure analytics platform for electronic health records in the NHS, developed to support urgent research during the COVID-19 pandemic.
SUMMARY:
This cohort study, conducted using the OpenSAFELY platform, analyzed linked electronic health records of around 40% of the English population to understand the impact of COVID-19 vaccination on the association of COVID-19 with cardiovascular diseases (CVDs).
The pre-vaccination cohort included individuals from the wild-type/Alpha variant eras (January 2020-June 2021), while the vaccinated and unvaccinated cohorts were followed during the Delta variant era (June-December 2021).
The study found that the incidence of arterial and venous thrombotic events was substantially higher in the weeks following a COVID-19 diagnosis but was less pronounced in vaccinated individuals.
Hazard ratios (HRs) for cardiovascular events were significantly higher in the pre-vaccination and unvaccinated cohorts compared to the vaccinated cohort, indicating a protective effect of vaccination.
The elevated risk persisted for at least two years post-COVID-19 in those who were unvaccinated or contracted COVID-19 before vaccination.
SUMMARY:
This study investigates the effectiveness of COVID-19 vaccines against long COVID in children aged 5 to 17, using data from 17 health systems and the RECOVER PCORnet electronic health record program.
Vaccination showed a moderate protective effect against long COVID in children, with an adjusted vaccine effectiveness of 35.4% against probable long COVID and 41.7% against diagnosed long COVID within 12 months post-vaccination.
Vaccine effectiveness was higher for adolescents (12-17 years) than for younger children (5-11 years) and showed a significant decline over time, from 61.4% at 6 months to 10.6% at 18 months.
The study confirms a protective effect of COVID-19 vaccination against long COVID in children and emphasizes the importance of vaccination for this age group.
SUMMARY:
This systematic review of 2 qualitative and 28 quantitative studies highlights the struggles of healthcare workers dealing with long-term COVID-19 symptoms, emphasizing the importance of listening to and supporting these individuals.
The findings shed light on the need for improved communication and multi-disciplinary care to address the diverse symptoms and challenges faced by healthcare professionals with Long COVID.
The study underscores the impact of the dual identity healthcare workers carry and the barriers they encounter in accessing healthcare services.
Having a medical background did not help healthcare professionals make sense of the wide range of debilitating and unpredictable LC symptoms. The dual role of being a patient and a doctor was particularly problematic and they felt dismissed and unheard by their doctors/clinicians.
They reported a variety of persisting symptoms but low levels of sick leave and the need for multidisciplinary care was highlighted.
There was little research on NHS workers and participants were mainly doctors, white and from Western populations.
My Take (Amy):
This review of the literature definitely reflects my experience as a physician with Long Covid. It’s clear, however, that there needs to be more representation in studies of the diverse types and different ethnicities of healthcare workers.
DEFINITIONS:
Compact Portable Plasma Reactor (CPPR): A compact, lightweight, portable device that forms Dielectric Barrier Discharge generating ozone using surrounding atmosphere, eliminating the need for source gas tanks.
Dielectric Barrier Discharge (DBD): A type of cold plasma formed by applying a high alternating voltage across electrodes separated by a dielectric medium, producing reactive oxygen and nitrogen species like ozone.
HCoV-OC43: Human coronavirus OC43, a surrogate for SARS-CoV-2 used in laboratory research due to its similarities in replication and properties.
PFU: Plaque forming unit, a measure of viral concentration based on the formation of visible plaques on cell cultures.
SUMMARY:
The study investigated the effectiveness of a Compact Portable Plasma Reactor (CPPR) in inactivating SARS-CoV-2 and HCoV-OC43 on porous and nonporous surfaces.
Iterative exposure experiments determined minimum exposure times for complete virus inactivation and showed significant reduction in viral load.
Ozone concentrations and energy requirements for virus inactivation using the CPPR were documented, indicating the technology's potential for effective decontamination.
The results suggest that the CPPR can provide a powerful decontamination method to reduce the spread of infectious diseases like COVID-19 on various surfaces, including PPE and medical devices.
DEFINITIONS:
Metabolic phenotyping: Analysis of the molecular content of biological fluids or tissues to identify discriminatory markers, classify individuals, and detect metabolic risk markers.
Tricarboxylic acid (TCA) cycle: A fundamental metabolic pathway occuring in the mitochondria that oxidizes acetyl-CoA and produces energy in the form of ATP.
Bile acids: Bioactive metabolites resulting from the breakdown of cholesterol with roles in lipid metabolism, bile flow modulation, and cholesterol homeostasis regulation.
SUMMARY:
This study evaluated the capability of liquid chromatography-mass spectrometry (LC-MS) assays to validate metabolic phenotypes of SARS-CoV-2 infection using two independent sample sets from Australia (plasma) and Spain (serum).
The assays targeted organic acids, capturing metabolites key in mitochondrial energy metabolism and the tricarboxylic acid (TCA) cycle, as well as metabolites indicative of oxidative stress, and bile acids, providing insights into host cellular energy generation during infection and the host-gut microbial relationship.
Despite different biofluids (plasma vs serum) and geographical locations, the study found consistent metabolic signatures across both cohorts, indicating a systemic metabolic shift following SARS-CoV-2 infection.
A panel of 23 metabolites was consistently perturbed in SARS-CoV-2 positive individuals compared to healthy controls.
The metabolic signatures observed suggest increased systemic oxidative stress and altered mitochondrial metabolism and TCA cycle activity following infection. Elevated concentrations of certain metabolites like 2-hydroxyglutaric acid indicate the presence of hypoxia in acute patients.
The study also highlighted the impact of SARS-CoV-2 infection on host-gut microbial cometabolism, with significant changes in metabolites like hippuric acid and tryptophan. Bile acid metabolism was also affected, suggesting systemic metabolic impacts of the infection beyond the respiratory system.
DEFINITIONS:
Proteoglycan: A protein that is heavily glycosylated (covalently attached with carbohydrate units), playing crucial roles in the structure and function of the extracellular matrix.
Extracellular Matrix (ECM): A complex network of proteins and carbohydrates that provide structural and biochemical support to surrounding cells in tissues.
Collagen Fibrillogenesis: The process of collagen fibers assembling into organized structures, which is essential for the mechanical strength and integrity of tissues.
Hypercoagulative State: A condition characterized by an increased tendency for blood to clot, often observed in various diseases, including infections and inflammatory conditions.
SUMMARY:
Lumican (LUM) is identified as a multifunctional proteoglycan playing a critical role in regulating cellular functions, influencing tissue repair, and acting as a biomarker for tissue pathology and various diseases, including long COVID.
LUM is instrumental in collagen organization essential for tissue structure and clarity, particularly in the cornea.
Animal studies have highlighted its distribution in various tissues and its involvement in bone structure.
Recent research has unveiled LUM's potential as a biomarker for the hypercoagulative state observed in SARS-CoV-2 infections, suggesting its usefulness in diagnosing and prognosticating long COVID disease.
LUM's interaction with cell receptors, cytokines, and chemokines extends its roles to mediating inflammatory responses, inhibiting tumor growth, and facilitating wound healing, showcasing its significance in combating infections and modulating immune responses.
Elevated levels of LUM in certain pathological conditions, including cardiac fibrosis and various forms of cancer, underline its dualistic nature in promoting and inhibiting tumor activities, thus serving as a vital biomarker for disease severity and therapeutic effectiveness.
DEFINITIONS:
Nested case-control study: In this type of study, cases of a disease that occur in a defined cohort are identified and, for each, a specified number of matched controls is selected from among those in the cohort who have not developed the disease by the time of disease occurrence in the case.
CKD G4/5: Chronic Kidney Disease, Stages G4-G5. Stage G4 represents severe impairment of kidney function. Stage G5 represents the most severe impairment, often referred to as End-Stage Renal Failure.
KTR: Kidney Transplant Recipients.
SUMMARY:
This nested case-control study in The Netherlands analyzed the association between COVID-19 and long-lasting symptoms and its burden in a cohort of patients with CKD G4/5, dialysis patients, and KTR who were vaccinated for COVID-19.
Patients who were included in the prospective Long-term Efficacy and Safety of SARS-CoV-2 vaccination (LESS-CoV-2) study were surveyed. 2596 patients (72%) responded to the survey and were included for analysis, of which 853 had prior COVID-19 and 1743 had not.
Long-lasting symptoms were reported in 204 of 853 patients (24%) with prior COVID-19, whereas these were reported in 297 of 1743 (17%) patients without prior COVID-19 (p<0.001). This resulted in an OR of 1.45 ((1.17-1.78), p=0.001) after correction for confounders.
The Post Covid Condition-related disease burden in CKD G4/5, dialysis patients, and KTR was experienced as ‘’much’’ or ‘’very much’’ in 57%, 72%, and 70%, respectively. The most frequent PCC-related symptoms were fatigue (81%), dyspnea (57%), and muscle weakness (47%).
Patients with CKD G4/5, dialysis patients, and KTR who were hospitalized due to COVID-19 had a 4.6 times higher risk of PCC in this cohort. This suggests that a more severe course of COVID-19 predisposed for PCC in these patient groups.
Patients with CKD G4/5, dialysis patients, and KTR are at risk for Post Covid Condition (PCC) with a high symptom burden, especially if antibody levels after SARS-CoV-2 vaccination are low or if they were hospitalized due to COVID-19.
I’d like to say that I totally support an initiative for a repository of long covid research articles! I work for a university library and worked on their repository for several years, it’s very important to have a place that contains all the relevant research, particularly for people like us who are suffering from a new disabling disease and maybe overwhelmed with the research. Most people aren’t trained in research like I am for my job and will have no idea where to start. Having a repository not only preserves this important information, but gives people one place they can go to find the information they so badly need. It’s one way to remove that barrier. I would be more than willing to help if needed! Thank you so much for your continued dedication to this cause!
Re: a repository of all the research, I think that'd be hugely helpful! An Airtable base might be good for this? I'd be willing to volunteer some time helping to compile everything in a csv for upload. Thank you for all you do!