Hi everyone,
Been a slow news week so we had to pull a couple of articles from the backlog. In this week’s edition we will be covering a couple of interesting articles. Efforts like Colorado's data project are crucial for understanding LC’s impacts. Also - hats off to Akiko Iwasaki, recognized in the TIMES 100. Our marquee article featured in Nature finds that patients showed improvements in immune function and quality of life over a 24-month period. Another study highlights the use of biomarkers to differentiate between ME/CFS and long COVID, which could lead to more precise treatments.
Our article of the week, "Improvement of immune dysregulation in individuals with long COVID at 24-months following SARS-CoV-2 infection," offers significant insights into the long-term immune response and health-related quality of life for people with LC. Notably, the study demonstrates how immune responses initially differ between long Covid patients and recovered COVID-19 controls but tend to converge over a two-year period, suggesting a gradual normalization of immune functions. However, as a personal opinion, I do not think this means LC is completely resolved for everyone in 24 months.
Here are the most interesting points:
From the Results: Single-cell RNA sequencing at the 24 month time point shows similar immune cell proportions and reconstitution of naïve T and B cell subsets in LC and recovered controls.
From the Discussion: By 24-months almost all parameters which had shown striking differences between the LC and MC control groups at 4- and 8-months had resolved, with no significant differences remaining between the two groups.
From the Discussion: "Self-reported health-related quality of life analysis using the EQ-5D-5L score demonstrated that participants with LC reported more problems in mobility, usual activities, and pain/discomfort domains within the first few months after infection, but by 24 months these differences were less and no longer statistically significant.
Media
Article: 4 years in, a sobering look at Long Covid progress | Medscape Medical News
SUMMARY:
Four years into the COVID-19 pandemic, long Covid remains a significant health concern with around 6.4% of Americans reporting persistent symptoms.
The condition can manifest as extreme fatigue, brain fog, tremors, and other troublesome symptoms.
Physicians have refined diagnostic tests and are exploring new treatments for long Covid, including catecholamine testing and vagus nerve stimulation, to alleviate symptoms.
Clinical trials are ongoing to investigate the efficacy of treatments like HIV antivirals and monoclonal antibodies in managing long Covid.
Article: Colorado's long COVID data project pushes for greater access to care | StateScoop
SUMMARY:
Colorado's participation in a university-led data program has allowed insights into the effects of long Covid in the state's population, specifically on employed Coloradans and those experiencing disability due to the illness.
The work undertaken by the Office of Saving People Money on Health Care, in collaboration with Data Labs experts, aims to assess the impact of long Covid on welfare programs and health care systems in Colorado.
The lack of a standardized definition for long Covid poses challenges in data comparison, making it essential for comprehensive data collection and analysis for informed policy-making.
Article: Unruly Gut Fungi Can Make Your Covid Worse | WIRED
SUMMARY:
In a study published in Nature Immunology, certain strains of gut fungi are increased in severe Covid, and trigger a prolonged immune response that could last long after the initial infection.
Iliyan Iliev, one of the study authors, says this research points to the critical role of the gut microbiome in the immune response and could lead to better disease treatments in the future.
Now, Iliev and his co-authors are interested in exploring how fungal overgrowth may appear in long Covid—and how immunity is affected.
According to Alessio Fasano, a gastroenterologist at Massachusetts General Hospital, “The gut is not like Las Vegas,” he says. “What happens in the gut does not stay in the gut.”
Article: Akiko Iwasaki Is on the 2024 TIME100 List | TIME
SUMMARY:
Akiko Iwasaki, a prominent immunologist, has been instrumental in investigating the immune response to COVID-19 and understanding the phenomenon of long Covid.
Her work on innate immunity has provided valuable insights into the lingering effects of the disease, validating patient experiences and guiding treatment approaches.
Iwasaki's dedication to championing diversity in science and her impactful leadership have significantly contributed to the scientific community.
My Take:
This is absolutely fantastic, congrats to Akiko, a researcher who is doing very important work in the world of LC!
Research
DEFINITIONS:
Humoral and Cellular Immune Responses: Humoral response involves antibodies, primarily through B cells, while cellular response involves T cells that target and destroy infected cells.
Nucleocapsid IgG: Antibodies targeted against the nucleocapsid protein of viruses, a common marker in viral infections.
CD4+ and CD8+ T Cells: Types of T lymphocytes; CD4+ cells assist other immune cells, and CD8+ cells directly destroy virus-infected cells.
PTX3, CRP: Proteins that rise in response to inflammation; their levels can indicate the degree of inflammation or damage within the body.
Neutralizing Capacity: The ability of the body's antibodies to neutralize viruses, preventing them from infecting cells.
SUMMARY:
The research assessed immune responses and health-related quality of life in individuals with long Covid (LC) over 24 months compared to recovered COVID-19 controls (MC). It focused on humoral (antibody-mediated) and cellular immune responses at various intervals post-infection.
Initially, LC participants showed elevated immune responses, including higher levels of nucleocapsid IgG and increased T-cell activation.
These immune markers were distinct from controls up to 8 months post-infection.
By the 24-month mark, immune differences between LC and MC participants largely resolved, indicating a normalization of immune function.
Both cohorts showed similar proportions of immune cell types and levels of immune activation.
There was a significant improvement in self-reported health-related quality of life among LC participants, with 62% reporting better outcomes at the 24-month checkpoint.
Certain biomarkers, such as PTX3, CRP levels, and platelet count, were identified as associated with improvements in health-related quality of life.
My Take (Amy):
I think it’s important to note that while the immune differences evaluated here in LC patients appear resolved, inflammatory differences remain, as do a host of other differences as seen in other studies.
Although it was not statistically significant, the proportion with poor health remained higher in the LC group (38% vs 26% for LC and MC, respectively; p = 0.53).
DEFINITIONS:
Endothelial Function: Refers to the endothelium's ability to regulate blood vessel tone and maintenance of vascular homeostasis. Dysfunctions here can lead to various cardiovascular diseases.
Principal Component Analysis (PCA): A statistical technique used to simplify the complexity in high-dimensional data while retaining trends and patterns.
Discriminant Analysis: A statistical method used to distinguish between two or more groups based on their features. It's used here to identify biomarkers that can classify ME/CFS and long Covid distinctly from healthy controls.
SUMMARY:
This research aimed to distinguish ME/CFS and long Covid from healthy controls using circulating biomarkers related to endothelial function and inflammation. Participants underwent cardiovascular testing and were assessed for circulating biomarkers to determine illness severity.
Patients with ME/CFS and long Covid displayed higher levels of endothelial and inflammation markers compared to controls.
ME/CFS patients showed particularly high levels of specific biomarkers like serpin E1 and E-selectin.
Long COVID patients had distinctively lower levels of TSP-1 compared to ME/CFS patients.
Both patient groups exhibited higher endothelial and inflammatory biomarkers than healthy controls.
However, ME/CFS patients showed more pronounced biomarker levels, suggesting more severe endothelial dysfunction and inflammation.
Principal component analysis effectively differentiated patient groups from healthy controls based on biomarkers and self-reported outcomes. Discriminant analysis further helped in distinguishing between ME/CFS and long Covid using a combination of clinical measures and biomarkers.
The study concluded that circulating biomarkers of endothelial dysfunction and inflammation can help differentiate ME/CFS and long COVID from each other and from healthy states. This differentiation supports the development of targeted therapies.
Further investigations are needed to understand the complex pathomechanisms and to confirm these findings in larger cohorts.
DEFINITIONS:
Essential fatty acids (EFAs): Fatty acids that are required for optimal health but cannot be synthesized by the human body and must be obtained through diet.
Serotonin: A neurotransmitter that regulates mood, behavior, and various physiological processes in the body.
SUMMARY:
The paper proposes that post-COVID and post-mRNA COVID-19 manifestations, including long-haul syndrome, could be linked to a deficiency in essential fatty acids (EFAs) and dysregulated metabolism of these fats.
EFAs and their metabolites play critical roles in modulating immune responses, suppressing cytokine release, protecting cells, affecting neurotransmitter production, and influencing gut microbiota, among other functions.
Insufficient EFA intake may lead to altered gut microbiota, serotonin deficiency, excessive inflammation, and impaired wound healing contributing to conditions like long-haul COVID-19.
The administration of EFAs is suggested as a potential therapeutic strategy for preventing and managing post-COVID complications, including long-haul syndrome.
DEFINITIONS:
FDG-PET: Fluorodeoxyglucose positron emission tomography, a molecular imaging technique used to quantify brain metabolism and assess neuroinflammation.
ERK1/2 (Extracellular signal-Regulated Kinases 1 and 2): Proteins involved in transmitting signals from receptors on the cell surface to the DNA in the nucleus, affecting how cells grow and divide.
Calcium Signaling: Involves the use of calcium ions to carry signals within cells, crucial for various cellular processes including muscle contractions and neurotransmitter release in neurons.
SUMMARY:
COVID-19, particularly its long-term effects (long Covid), exacerbates symptoms and progression in patients with neurodegenerative diseases.
This is driven largely by chronic inflammation and abnormal immune responses, which contribute to neuronal damage.
FDG-PET imaging has been useful in assessing the extent of neurodegeneration and neuroinflammation in post-COVID patients, highlighting the relationship between ongoing neuroinflammation and cognitive/psychiatric symptoms.
SARS-CoV-2 can invade the central nervous system (CNS) via multiple routes including the olfactory route, blood-brain barrier, and potentially through the gastrointestinal tract via the vagus nerve, contributing to neurological complications.
The study points to the need for targeted therapies focusing on inflammation control and specific molecular pathways such as ACE2 receptors, ERK1/2, and calcium signaling to mitigate the neurological impacts of COVID-19
DEFINITIONS:
Single Nucleotide Polymorphism (SNP): A variation in a single nucleotide that occurs at a specific position in the genome, which can be common in the population and may affect how diseases develop or the response to medications.
Mendelian Randomization (MR): A method used in genetics to determine if observational associations between a risk factor and an outcome are consistent with a causal effect.
Latent Causal Variable (LCV) Model: A statistical method used to infer causality between traits using genetic data.
Genetic Causality Proportion (GCP): A measure derived from the LCV model indicating the extent to which genetic factors contribute to causality between traits.
SUMMARY:
This study explored the genetic overlap between COVID-19 and multi-site chronic pain, revealing 19 significant single nucleotide polymorphisms (SNPs) that are shared between the conditions.
This suggests a genetic basis for the link between COVID-19 and increased susceptibility to chronic pain.
Analysis identified 482 significant overlapped genes with notable involvement in inflammatory and neurotrophic pathways.
This includes the amygdala and prefrontal cortex, which are important in regulating chronic pain in critical COVID-19 cases.
The gene ANAPC4 was highlighted as a potential drug target for both chronic pain and COVID-19.
This finding supports the potential for targeted therapeutic strategies.
The latent causal variable (LCV) model indicated a genetic component of critical COVID-19 that causally influences multi-site chronic pain, with a genetic causality proportion (GCP) of 0.60.
DEFINITIONS:
Neuropsychological testing: Assessment of cognitive and emotional functioning using standardized tests.
Right frontal lobe: The area of the brain responsible for executive functions, such as decision-making, planning, and problem-solving.
SUMMARY:
The case study involves a high-functioning woman in her late 40s who developed cognitive difficulties after a mild course of acute COVID-19 illness.
Neuropsychological testing revealed impairment in right frontal lobe functioning, impacting executive functions.
Empirical treatment with ADHD medications showed a positive response, but repeat testing a year later still demonstrated dysfunction in executive functioning.
DEFINITIONS:
Small fiber neuropathy (SFN): A condition characterized by damage to small nerve fibers, leading to symptoms such as burning pain, numbness, and autonomic dysfunction.
Invasive cardiopulmonary exercise testing (iCPET): A diagnostic test that provides information about the function of the heart, lungs, and muscles during exercise.
SUMMARY:
This case-control study examines new-onset SFN in patients after COVID-19, demonstrating its association with autonomic dysfunction and neurovascular dysregulation.
Results indicate that SFN may be responsive to treatment with intravenous immunoglobulin (IVIG) and is linked with neurovascular dysregulation and dysautonomia.
The study suggests the potential role of IVIG in treating postinfectious SFN and calls for a larger clinical trial to further demonstrate its clinical utility.
DEFINITIONS:
VA (Veterans Affairs): Refers to the United States Department of Veterans Affairs, a federal agency that provides healthcare and other services to military veterans.
EHR (Electronic Health Records): Digital versions of patients’ paper charts, widely used in healthcare to support treatment by providing comprehensive patient data.
AUD (Alcohol Use Disorder): A medical condition characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences.
Mixed-method approach: A research methodology that combines qualitative (e.g., interviews) and quantitative (e.g., surveys) methods to gather and analyze data.
SUMMARY:
The study aimed to understand sleep experiences and unhealthy alcohol use among Veterans with long Covid, and providers’ perspectives on barriers and facilitators to delivering care.
Researchers used a mixed-method approach, employing VA electronic health records, chart reviews, and interviews with veterans and clinicians at a VA COVID-19 Recovery Clinic.
Veterans with long Covid often had pre-existing sleep disorders that worsened during long Covid.
Both patients and providers recognized the potential benefits of sleep interventions in the recovery clinic setting.
Few vVeterans had a pre-existing alcohol use disorder, and alcohol use was less frequent and less often a topic of discussion.
There was a mixed response from providers regarding the feasibility of addressing alcohol use in the clinic.
There was a consensus on the usefulness of targeted sleep interventions. However, there were mixed feelings about incorporating alcohol-related care due to varying perceptions of its relevance and the potential receptiveness of patients.
DEFINITIONS:
Multiomic profiling: molecular phenomics data across multiple “omics” layers, including genomes, epigenomes, transcriptomes, proteomes and metabolomes, of a sample or set of samples which are fully measured, analyzed and integrated from the same set of samples on a genome scale.
Chemokine ligand (CCL): (aka chemotactic cytokines) A large family of small, secreted proteins that signal through cell surface chemokine receptors. They are important to the development and homeostasis of the immune system.
SUMMARY:
Investigators sought to identify underlying mechanisms for older adults being more susceptible to severe and fatal COVID-19. They studied the immune response to SARS-CoV-2 in a large longitudinal clinical cohort by analyzing 1,031 blood and nasal swab samples from vaccine-naive adults.
Older adults exhibited impaired viral clearance:
Older adults (63 to 96 years old) had a much higher SARS-CoV-2 viral abundance at the time of hospitalization compared with the younger adults (18 to 62 years old) (P = 0.0092).
There were significant differences in viral abundance dynamics, with the oldest adults showing delayed viral clearance compared with the youngest adults (P = 0.0030).
Older adults showed dysregulated immune signaling:
Analysis of statistically significant age-associated genes and age-associated proteins from the blood identified three prominent nodes related to chemokine ligand (CCL) signaling, T cell signaling, and the cell cycle.
Together, the results suggested both greater activation and impaired attenuation of immune signaling with advanced age.
Older adults had persistent and potentially pathologic activation of pro-inflammatory genes and cytokines:
Study authors found evidence of prolonged, potentially pathologic inflammatory responses in the oldest adults from transcriptomics and protein analyses.
For instance, upon hospitalization, pro-inflammatory cytokines and chemokines such as TNF, IL-6, CXCL8, and CXCL9 were higher in the blood of older participants and continued to increase over time.
Together, these findings identify discrete innate and adaptive immune signaling pathways that are altered with age, suggesting potential targets for age-dependent therapeutic intervention.
SUMMARY:
Long Covid and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients experience multiple complex symptoms, potentially linked to imbalances in brain neurochemicals.
This study measured brain neurochemical levels in long Covid and ME/CFS patients as well as healthy controls to investigate associations with severity measures.
Glutamate levels were significantly higher in long Covid (p=0.02) and ME/CFS (p=0.017) than in healthy controls. N-acetyl-aspartate levels were significantly higher in long Covid patients (p=0.012).
Importantly, brain neurochemical levels were associated with self-reported severity measures in long Covid and ME/CFS.
No significant differences in brain neurochemicals were observed between the two patient cohorts, suggesting a potential overlap in their underlying pathology.
These findings suggest that imbalanced neurochemicals contribute to the complex symptoms experienced by long COVID and ME/CFS patients.
Akiko is just as nice a person as she is a brilliant scientist. So happy for her!
I have a hard time distinguishing them(ME/CFS and LC but that may just be my brain fog kicking up!