Hi everyone,
Still figuring out the giveaway details but will keep everyone in the loop as I do. I will only open the pledges when this finalized.
Also just as a reminder, the newsletter will be on break next week. One of our readers shared The Sick Times, which is a journalist-founded website chronicling the Long Covid crisis. This seems like a solid other option while we are on break. I hope everyone enjoys the holidays!
Highlights in this edition include a powerful first-person narrative on three years of living with long COVID symptoms, as well as a review of genetic variants associated with increased risks. We also analyze recent studies pointing to a strong connection between long COVID and ME/CFS, with potential for shared treatment targets. For the latest on persistent symptoms after Omicron infection, don’t miss our roundup of emerging brain imaging and respiratory data. And given growing interest in different long COVID subtypes, we share insights from proteomics and clinical biomarkers currently under exploration.
Media
Article: Opinion | My Life With Long Covid - The New York Times
This is a really insightful piece. Please give it a read if you have time.
There are also some really compelling visuals scattered throughout that make it a unique reading experience
HIGHLIGHTS:
Every morning, I wake up in my Brooklyn apartment, and for two seconds, I can remember the old me.
These sensations have been a daily occurrence, with few exceptions, for the past three years and nine months.
I’ve come to realize that “long Covid” is a deceptive term for a condition that can trigger a diverse swarm of debilitating symptoms with no end in sight.
Article: The first major set of genetic associations found in long COVID
DEFINITIONS:
Combinatorial analysis: An approach that identifies combinations of features associated with a disease phenotype in patient sub-groups, capturing the non-linear effects of interactions between multiple genes.
Genome-wide association study (GWAS): A study that analyzes the entire genome of individuals to identify genetic variants associated with a particular trait or disease.
TLR4 antagonists: Drugs or compounds that inhibit the activity of toll-like receptor 4 (TLR4), which is involved in the immune response to infections.
SUMMARY:
Using combinatorial analysis, genetic variants associated with long COVID have been identified.
TLR4 antagonists have been found to be a potential candidate for repurposing long COVID treatment.
The combinatorial approach is more sensitive than traditional genomic analysis approaches.
Pathway enrichment analyses revealed that the biological pathways most associated with long COVID are neurological and cardiometabolic diseases.
There is genetic overlap between long COVID and ME/CFS, including genes involved in circadian rhythm regulation and insulin regulation.
My Take:
The genetic overlap between long COVID and ME/CFS highlights shared biological mechanisms and provides opportunities for further investigation and understanding of these conditions.
Article: Long Flu Is a Health Risk, New Study Says | Time
SUMMARY:
Statistically, there’s a good chance you know somebody who has experienced Long COVID, the name for chronic symptoms including fatigue, brain fog, and pain following a case of COVID-19.
But many people don’t realize that other viruses, even very common ones, can trigger similarly long-lasting and debilitating symptoms.
That said, previous research shows that even milder illnesses can lead to long-lasting health issues. Influenza, as well as other common viruses like Epstein-Barr (which causes mononucleosis), have long been thought to trigger myalgic encephalomyelitis/chronic fatigue syndrome, a post-infectious illness that shares many symptoms with Long COVID.
My Take:
I think it is important for it to become common knowledge that post-viral syndromes can arise from all viruses, not just Covid.
SUMMARY:
A pilot study examined the proteome of immune cells in patients with long COVID and found changes in physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
The study aimed to investigate the pathophysiology of long COVID and determine if there is a close relationship between long COVID and ME/CFS.
Changes in immune system proteins were observed in the long COVID patients, suggesting a chronic dysfunctional state that had not resolved after the initial SARS-CoV-2 infection.
The proteomic analysis also identified overlapping protein clusters and enriched molecular pathways related to immune functions in both long COVID and ME/CFS.
My Take:
The identification of overlapping protein clusters and enriched molecular pathways related to immune functions further supports this connection.
Definitions:
Epigenetic changes: Changes that alter how genes are expressed without changing the DNA sequence; includes DNA methylation and histone modifications.
Myelopoiesis: Process by which bone marrow stem cells differentiate into mature myeloid immune cells like monocytes and granulocytes.
Hematopoietic stem and progenitor cells (HSPCs): Stem cells in the bone marrow that give rise to all blood and immune cell types.
SUMMARY:
A recent study by Cheong et al. found that COVID-19 causes lasting epigenetic changes in human immune stem cells, specifically increased activity of interleukin-6 (IL-6).
This reprograms these stem cells, leading to altered composition and heightened inflammatory responses in circulating immune cells that persist for at least 12 months after infection.
The authors developed a new method to isolate rare hematopoietic stem and progenitor cells (HSPCs) from blood to show they harbor similar epigenetic changes as circulating mature immune cells post-COVID.
This suggests these altered programs in HSPCs are inherited by mature immune cell progeny.
Blocking IL-6 with an antibody during mouse COVID-19 infection prevented HSPC reprogramming and downstream effects on myeloid cells and tissues, implicating IL-6 as a causal factor. This may explain benefits of IL-6 blockade seen for other inflammatory diseases.
Research
[Since all articles are related to Downstream implications of Covid infection no breakdown by category this week]
DEFINITIONS:
Capillaries: Tiny blood vessels that connect arteries and veins, allowing for the exchange of oxygen and nutrients with surrounding tissues.
Macrophages: Immune cells that play a role in tissue repair and inflammation.
SUMMARY:
The study examined skeletal muscle biopsies from eleven patients with post-COVID syndrome, characterized by enduring fatigue and post-exertional malaise.
The patients had fewer capillaries, thicker capillary basement membranes, and increased numbers of macrophages compared to control cohorts.
No SARS-CoV-2 RNA was detected in the muscle tissues, suggesting that the symptoms were not due to ongoing infection.
The researchers hypothesized that the initial viral infection may have caused immune-mediated structural changes in the microvasculature, leading to exercise-dependent fatigue and muscle pain.
My Take:
REALLY IMPORTANT PIECE
Now we need to figure out how the initial viral infection did this
DEFINITIONS:
HSPCs: Haematopoietic stem/progenitor cells are a subtype of white blood cells involved in maintaining haematopoiesis, regulating immune surveillance, and aiding tissue repair.
SUMMARY:
100 hospitalized COVID-19 patients had HSPC levels measured at admission and were followed for 1 year. 20 died and 36 developed long-COVID.
Lower HSPC levels, especially CD34+ cells, at admission were strongly associated with higher 1 year mortality, independently of age and disease severity.
1 year mortality was also associated with older age, coronary disease, chronic kidney disease, and need for oxygen/ventilation support during initial hospitalization.
Younger patients and those with more severe initial pneumonia were more likely to develop long-COVID. However, HSPC levels did not predict risk of long-COVID.
The mechanisms linking lower HSPCs to mortality are unclear but may involve impaired tissue repair functions. Further research into HSPC changes over time is needed to clarify their role in long-COVID.
My Take:
This study suggests that lower levels of circulating HSPCs at the time of hospital admission for COVID-19 may indicate a higher mortality risk .
DEFINITIONS:
Ages & Stages Questionnaire (ASQ-3): A screening tool used to assess the developmental progress of infants and young children.
Neurodevelopmental impairment: Delays or deficiencies in the development of cognitive, motor, communication, social, and adaptive skills.
SUMMARY:
In a prospective cohort study conducted in Brazil, researchers found that infants exposed to maternal SARS-CoV-2 infection during pregnancy had an increased risk of neurodevelopmental impairment.
The study followed 127 children for one year, with 69 children in the COVID-19 exposed group and 68 in the control group.
The prevalence of neurodevelopmental impairment using the Ages & Stages Questionnaire (ASQ-3) was 35.7% at 4 months, 7% at 6 months, and 32.1% at 12 months in the exposed group.
Maternal depression scores were significantly higher among mothers infected with COVID-19 during pregnancy, but there was no association between maternal depression and developmental delay in the offspring.
The study highlights the need for specific guidelines and interventions to support the development of high-risk children exposed to maternal SARS-CoV-2 infection during pregnancy.
My Take:
This study adds to the growing body of evidence suggesting that infants exposed to maternal SARS-CoV-2 infection during pregnancy may be at increased risk of neurodevelopmental impairment.
The findings highlight the importance of early detection and intervention to support the developmental needs of these children.
DEFINITIONS:
Gray matter thickness: Refers to the thickness or volume of the gray matter, which is the outermost layer of the brain responsible for processing and coordinating information.
Subcortical nuclei: Refers to a collection of structures located below the cerebral cortex in the brain, which are involved in various functions such as movement control, emotions, and memory.
Beck Anxiety Inventory (BAI): A questionnaire used to assess the severity of anxiety symptoms.
SUMMARY:
The study investigated the clinical manifestations and brain microstructural changes associated with the SARS-CoV-2 Omicron variant in male patients.
Changes in gray matter thickness and subcortical nuclear volume were observed in the acute post-Omicron period.
Symptoms in multiple systems, including respiratory, neurological, and digestive symptoms, were reported during the post-Omicron follow-up.
Gray matter thickness and subcortical nuclear volume injury were significantly associated with anxiety and cognitive function.
My Take:
The findings of this study suggest that infection with the SARS-CoV-2 Omicron variant can lead to changes in brain structure and function.
DEFINITIONS:
Toll-like receptor 7 (TLR7): an endosomal receptor involved in the detection of single-stranded RNA viruses such as SARS-CoV-2 and initiation of an immune response.
TLR7 deficiency: a genetic risk factor for severe COVID-19 infection and long-term complications.
Frameshift null variant: a genetic mutation that results in a truncated or non-functional protein.
SUMMARY:
The article discusses a case report of a pediatric patient who experienced severe long-term neurological deterioration following a COVID-19 infection.
The patient developed episodic dystonia and finger spasticity, which rapidly progressed to a significant decrease in the Glasgow Coma Scale (GCS).
Whole genome sequencing identified a novel frameshift null variant of the X chromosomal TLR7 gene, suggesting a role for TLR7 in long-term COVID-19 complications.
DEFINITIONS:
Fractional exhaled nitric oxide (FeNO): a non-invasive test that measures the amount of nitric oxide in the breath, which is used as a marker of airway inflammation.
Eosinophil counts: a measurement of the number of eosinophils, a type of white blood cell involved in allergic responses and asthma, in the blood.
Immunoglobulin E (IgE): an antibody produced by the immune system in response to allergens, often elevated in allergic diseases.
SUMMARY:
This retrospective cross-sectional study compared the clinical and investigative parameters between post-COVID patients and asthmatic patients presenting with asthma-like symptoms.
The study found that post-COVID patients without a history of asthma showed similar symptoms to known asthmatic patients, including cough, chest tightness, and shortness of breath.
Symptoms of wheeze were significantly different between the two groups, and there were differences in inflammatory markers such as fractional exhaled nitric oxide (FeNO) levels and eosinophil counts.
Post-COVID patients showed improvement in symptoms after being treated with a bronchodilator therapy of inhaled corticosteroids and long-acting beta-agonists.
My Take:
Anecdotally, I go through bouts of breathlessness with my LC, and was tested for Asthma but is likely caused by autonomic issues.
DEFINITIONS:
Serological markers : Measurable substances in blood whose levels indicate certain disease states
Confounders: Factors that distort the true relationship between variables under study
Heterogeneity: High variability between studies in populations, methods etc. that prevents pooling of results
Pathophysiological mechanisms: refers to the physiological processes and mechanisms that underlie the development and manifestation of a disease or condition.
Etiology: refers to the cause or origin of a disease or condition.
SUMMARY:
This systematic review examined 29 studies comparing antibody/serological markers between adults with and without long COVID symptoms persisting ≥12 weeks. The main antibodies assessed were:
Anti-nucleocapsid (N) IgG: Targets the nucleocapsid protein inside the virus
Anti-Spike IgG: Targets the Spike protein on the virus surface
Neutralizing antibodies: Antibodies that can block virus infection
Key results:
No clear differences in anti-N IgG levels by long COVID status
Evidence on anti-Spike IgG was very inconsistent between studies
No consensus for neutralizing antibodies; few studies assessed
The authors identified substantial heterogeneity between studies in terms of populations, methods, definitions of long COVID, and adjustment for potential confounders. Most did not account for acute COVID-19 severity.
In conclusion, current evidence on serological markers of long COVID remains inconclusive and inconsistent due to significant study limitations. Collaborative efforts to harmonize research methods and reporting would strengthen this growing body of literature.
Hi Brandon
Thanks for the updates.
Re your headline "Long Covid Weekly #74: PEM cause discovered…"Article: Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles | Acta Neuropathologica Communications
The authors hypothesize "... that the initial viral infection may have caused immune-mediated structural changes in the microvasculature, leading to exercise-dependent fatigue and muscle pain."
I offer a different interpretation. This may be vascular remodeling developed in a low ATP environment. It would seem likely that mitochondrial dysfunction, which is increasingly being shown by research studies to play an important role in Long COVID, would inherently result in low energy levels in muscle tissues.
There is an interesting pre-print (a non-peer reviewed article) that reviews treatment of mitochondria with Coenzyme Q-10 in post viral syndromes. https://www.preprints.org/manuscript/202311.1554/v1
Post Exertional Fatigue outcomes are included in the body of the article.
Below are the quotes from your article. As always, thank you!
DEFINITIONS:
Capillaries: Tiny blood vessels that connect arteries and veins, allowing for the exchange of oxygen and nutrients with surrounding tissues.
Macrophages: Immune cells that play a role in tissue repair and inflammation.
SUMMARY:
The study examined skeletal muscle biopsies from eleven patients with post-COVID syndrome, characterized by enduring fatigue and post-exertional malaise.
The patients had fewer capillaries, thicker capillary basement membranes, and increased numbers of macrophages compared to control cohorts.
No SARS-CoV-2 RNA was detected in the muscle tissues, suggesting that the symptoms were not due to ongoing infection.
The researchers hypothesized that the initial viral infection may have caused immune-mediated structural changes in the microvasculature, leading to exercise-dependent fatigue and muscle pain.
My Take:
REALLY IMPORTANT PIECE
Now we need to figure out how the initial viral infection did this
I wish that the research community would look at the following:
Is there evidence of periodicity in the waxing/waning, appearance/disappearance/re-appearance of LC symptoms as experienced by patients? If so, what correlations can be made with relevant externalities, such as original variant, subsequent medical treatment, patient demographics etc.?
I was diagnosed in April 2020 and kept careful charting of recurring, new, vanished and permanent symptoms for the next three years, at which point all symptoms except neurological and cardio had either disappeared or had weakened to the point of insignificance.
My takeaway was that in my own case there was a definite rhythmicity in many of the symptoms and the waves did not operate in synchrony. Why, what variables were governing? An interesting area of LC study with implications beyond that field.