Hi Everyone,
As you may have noticed, this newsletter has started going out on Tuesdays instead of Mondays. This has been experimental in past newsletters but is likely the permanent schedule as we move forward. I wanted to avoid the influx of newsletters that are usually sent on Mondays.
In this edition, we delve into the prevalence of Long Covid among adults in the United States, explore the biological hallmarks of ME/CFS, investigate the quality of sleep among Covid-19 survivors, and much more.
The NIH paper on ME/CFS is a big deal and has been in the works for many years. As a result, this paper is chalk full of interesting findings, among them:
32–74% of the variance in time to grip failure for the PI-ME/CFS participants correlated with effort preference, which was not seen in HVs." "This difference in performance correlated with decreased activity of the right temporal-parietal junction, a part of the brain that is focused on determining mismatch between willed action and resultant movement.
Peak power , peak respiratory rate, peak heart rate , and peak VO2 were all lower in the PI-ME/CFS participants, a difference of approximately 3.3 metabolic equivalent of task units (METs). These peak measures did not correlate with effort preference in PI-ME/CFS. PI-ME/CFS participants performed at a lower percentage of their predicted VO2peak as determined by the Wasserman-Hansen cycling equation and at a lower percentage of their age-predicted maximal heart rate.?
It is quite frankly a must-read!
Media
Article: Solving the puzzle of Long Covid
SUMMARY:
Long Covid is a complex, multisystem disease with a range of persistent symptoms and organ damage that affects people of all ages and backgrounds after COVID-19 infection. Even mild initial infections can lead to Long Covid.
Putative mechanisms include viral persistence, autoimmunity, mitochondrial dysfunction, inflammation, and microbiome disruption, but more research is needed. Multiple subtypes likely exist with different mechanisms.
Vaccines can reduce Long Covid risk by 15-75% (mean 40%). Early antiviral treatment may also help prevent Long Covid but more studies are needed on safety and efficacy. Reinfections further increase Long Covid risk.
Despite growing evidence on Long Covid, major challenges remain around meeting care needs, reaching consensus on definitions/endpoints, understanding long-term trajectories, developing models and biomarkers, addressing denialism, and reinventing data systems.
Economic, healthcare, and societal impacts will be widespread and long-lasting. Finding effective treatments through large, rapid trials is an urgent priority.
Article: Notes from the Field: Long COVID Prevalence Among Adults — United States, 2022 | MMWR
DEFINITIONS:
Behavioral Risk Factor Surveillance System (BRFSS): A population-based cross-sectional survey used to gather data on health-related behaviors.
SUMMARY:
The prevalence of reporting ever having experienced Long COVID among U.S. adults ranged from 1.9% to 10.6% in different states.
Data from the Behavioral Risk Factor Surveillance System (BRFSS) was analyzed to estimate the prevalence of Long COVID.The study highlights the need for ongoing assessment of state-specific Long COVID prevalence for public health action and support.
Understanding the prevalence of Long COVID can guide policy, planning, and programming to assist U.S. adults dealing with this condition.
Article: NIH study of ME/CFS points to clear biological hallmarks - STAT
DEFINITIONS:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A debilitating condition characterized by persistent fatigue, body pain, headaches, dizziness, and exacerbated symptoms following exertion.
T cells: A type of white blood cell that plays a critical role in the body's immune response.
Antigen: A molecule or substance that triggers an immune response, potentially leading to inflammation and symptoms of illness.
SUMMARY:
The NIH study revealed clear biological markers of illness, such as a prolonged immune response, exhausting T cells.
The study also highlighted abnormalities in the functioning of the brain in ME/CFS patients, affecting their tolerance for exertion and perception of fatigue.
Researchers found that inflammation plays a key role in the ongoing battle patients feel, akin to fighting a persistent flu.
Despite the study's milestone achievement, the small sample size limits broader generalizations or therapeutic target identifications in ME/CFS.
The puzzle of what causes ME/CFS and how it can be effectively treated remains unanswered, underscoring the urgent need for further research and understanding in this field.
My Take:
From what I have learned, this is the culmination of multiple years worth of work conducted by the NIH
See longer summary in Research section below
Article: UCSF Launces Tissue Bank to help solve mysteries of long COVID
SUMMARY:
UCSF researchers have launched the world's first bank of tissue specimens from individuals with long COVID to advance understanding of the persistent illness.
The decision to collect these tissue samples acknowledges the presence of viral reservoirs and prolonged active virus remnants that may contribute to long COVID symptoms.
The long COVID tissue bank aims to comprehensively study biological processes across various bodily tissues to unravel the mysteries of this condition and develop effective treatments.
Research
DEFINITIONS:
Insomnia: Difficulty falling asleep, staying asleep, or feeling rested after sleep, which can impact overall health and functioning.
SUMMARY:
The study focused on assessing the prevalence of insomnia among non-hospitalized COVID-19 survivors within 6 months of their infection.
Results showed that a high percentage of participants experienced insomnia, with significant associations with depression, anxiety, and pre-existing chronic conditions.
Insomnia was found to be more common among participants with depressive or anxiety symptoms and those with chronic diseases in this population of COVID-19 survivors.
DEFINITIONS:
Interferon-gamma (IFN-γ): A cytokine secreted by immune cells that has antiviral, immunomodulatory and inflammatory effects.
Peripheral blood mononuclear cells (PBMCs): Immune cells such as T cells and monocytes isolated from blood samples.
MHC class I: Cell surface proteins that display peptides to CD8+ T cells.
CD14+: A receptor expressed at high levels on monocytes.
SUMMARY:
This study investigated the immune mechanisms underlying long COVID to identify potential biomarkers and therapeutic targets.
Blood samples were collected from Long Covid patients (with persistent symptoms >12 weeks after COVID-19 infection), recovering COVID-19 patients, and healthy controls.
Levels of interferon-gamma (IFN-γ) and other cytokines secreted by immune cells were measured without stimulation. Cell depletion assays and flow cytometry were also used.
The key findings were that long COVID patients showed high, spontaneous secretion of IFN-γ from peripheral blood mononuclear cells (PBMCs), unlike recovering patients.
This IFN-γ was secreted by CD8+ T cells when presented antigen by CD14+ monocytes in an MHC class I-dependent manner.
Some Long Covid patients had decreased IFN-γ secretion over time, correlating with symptom improvement post-vaccination.
In summary, persistent IFN-γ production is a potential mechanism and biomarker for fatigue and other symptoms in some long COVID patients. This may be triggered by viral antigens persisting after infection and presented by monocytes to T cells. Resolving high IFN-γ levels could indicate recovery from Long Covid.
DEFINITIONS:
Sequelae: Disorders that persist after initial infection has resolved.
Dysautonomia: Malfunction of nervous system regulation of bodily functions like heart rate and blood pressure.
Postexertional malaise: Severe exhaustion/symptom flare-ups after physical/mental activity.
Multisystemic: Affecting many body systems simultaneously.
Nonmonolithic: Not a single uniform disease process.
Dysbiosis: Imbalance in microbiome populations.
SUMMARY:
Inprevious reports, investigators found increased cognitive complaints in PI-ME/CFS (Post-Infectious ME/CFS)participants but no differences in neuropsychological test performance.
This suggests that documented cognitive complaints are indeed present but do not translate into objective differences in cognitive performance.
The cognitive complaints may be due to brain dysfunction or altered catechol metabolism as evidenced by altered levels of catechols in the cerebrospinal fluid.
Our results identified a differential brain activation pattern in PI-ME/CFS participants during performance tasks, as well as alterations in catechol levels that may contribute to cognitive symptoms.
Immune profiling revealed chronic antigenic stimulation and alterations in B-cell populations in PI-ME/CFS participants, consistent with previous reports of immune dysregulation in this population.
The sex-based immune differences identified in our study suggest unique immune responses in male and female PI-ME/CFS participants.
The gene expression profiles in peripheral blood mononuclear cells also differed between male and female PI-ME/CFS participants, highlighting the importance of considering sex-specific differences in understanding the pathophysiology of this condition.
Overall, our deep phenotyping study provides a comprehensive characterization of the clinical, physiological, and immune abnormalities in PI-ME/CFS participants.
The identification of altered effort preference, dysfunctional integrative brain regions, immune dysregulation, and sex-based differences in gene expression and immune responses sheds light on the complex pathophysiology of PI-ME/CFS.
These findings have important implications for future research and potential targeted interventions for this debilitating condition.
DEFINITIONS:
IL-6: Interleukin-6 is a cytokine involved in inflammation and immune response.Genetic variations can affect IL-6 production.
IL-10: Interleukin-10 is an anti-inflammatory cytokine that regulates immune responses.Genetic variations can impact IL-10 levels.
TNF-α: Tumor necrosis factor-alpha is a pro-inflammatory cytokine involved in immune response regulation.
Polymorphisms can influence TNF-α production.
IFITM3: Interferon-induced transmembrane protein 3 is involved in viral infection defense.Genetic variants in IFITM3 can affect viral susceptibility and response.
SUMMARY:
The study aimed to investigate if specific inflammatory genetic variations were associated with long-term post-COVID symptoms in hospitalized COVID-19 survivors.
No differences were found in post-COVID symptoms based on IL-6, IL-10, TNF-α, and IFITM3 genotypes.
Results suggest that these inflammatory polymorphisms do not predispose individuals to developing post-COVID symptoms after severe SARS-CoV-2 infection.
Article: Microorganisms | Free Full-Text | Dermatologic Changes in Experimental Model of Long COVID
SUMMARY:
The study investigates dermatologic changes in a mouse model of long COVID following infection with MHV-1.
Acute skin findings post-MHV-1 infection include destruction of the epidermal layer, increased hair follicles, and collagen deposition in the dermal layer.
Long-term skin alterations post-MHV-1 infection involve loss of hair follicles, adipose tissue destruction, and further damage to the epidermal layer.
Treatment with a synthetic peptide, SPK, shows promise in preventing and mitigating skin changes induced by MHV-1 infection, offering potential therapeutic benefits.
These findings shed light on the skin manifestations of long COVID and propose a novel treatment approach to address skin alterations following SARS-CoV-2 infection.
DEFINITIONS:
Precapillary cardiovascular disturbances: Various cardiovascular abnormalities including hypovolemia, low stroke volume, and high vasoconstrictor tone that lower capillary perfusion pressure.
Capillary disturbances: Impairment of capillary blood flow caused by pathological blood components, changes in the vascular wall, and endothelial dysfunction, leading to capillary stasis.
Mitochondrial dysfunction: Impairment of mitochondrial function that can result from capillary ischemia/reperfusion, sodium, and calcium overload in skeletal muscles, and generation of reactive oxygen species.
SUMMARY:
ME/CFS shows symptom overlap with the Post-COVID-19 Syndrome.
Pathological blood components in PCS patients impair capillary blood flow.
Precapillary cardiovascular disturbances in ME/CFS and PCS lead to low capillary perfusion pressure.
The interaction of these disturbances severely affects tissue perfusion and can cause mitochondrial dysfunction.
The detrimental interactions contribute to capillary stasis and worsen organ perfusion.
My Take:
The interaction of precapillary cardiovascular and capillary disturbances in ME/CFS and PCS highlights a potential key mechanism underlying these conditions.
Understanding these interactions could lead to new therapeutic strategies for treating these debilitating syndromes.
DEFINITIONS:
Alanine aminotransferase (ALT): Liver enzyme whose elevation indicates liver injury.
Aspartate aminotransferase (AST): Enzyme made in liver and other tissues; can indicate liver or tissue damage.
Alkaline phosphatase (ALP): Liver enzyme which rises with bile duct obstruction or liver disease.
Gamma-glutamyl transpeptidase (GGT): Liver enzyme marker of bile duct injury and heavy alcohol use.
Coagulation: Blood clotting process. PT and APTT measure time for clot formation.
SUMMARY:
This study provides crucial insights into the distinctive post-acute sequelae of SARS-CoV-2 infection and liver injury in elderly patients in Romania.
The study explores liver injury and post-acute COVID-19 sequelae (PASC) in elderly Romanian patients over 6 months. It hypothesizes more severe manifestations are influenced by demographic, clinical and healthcare factors.
Elderly patients were hospitalized for an average 16 days, longer than younger groups (p<0.001).
Markedly elevated liver enzymes, ALP, GGT, and bilirubin in the elderly Long COVID group indicate the range of liver injury.
Persistent high fasting glucose suggests ongoing metabolic disruption.
Sustained coagulation changes and high fibrosis risk scores flag potential chronic liver conditions.
Age, cardiovascular disease, and ICU stay associated with worsened liver injury.
Liver enzymes, glucose, coagulation profiles, fibrosis risk scores improved but remained abnormal at 6 months.
My Take:
This is a pretty understudied segment of LC.
DEFINTIONS:
Blood-brain barrier (BBB): A protective barrier formed by cells lining the brain's blood vessels that regulates transport of molecules between blood and brain.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI): A technique used to assess microvasculature and permeability of tissue by tracking the uptake of a contrast agent over time.
SUMMARY:
This study demonstrates that long COVID-associated brain fog is linked to blood-brain barrier disruption and sustained systemic inflammation.
The article examines whether blood-brain barrier (BBB) disruption and inflammation are associated with "brain fog" (cognitive impairment) in patients recovering from COVID-19 infection. Patients hospitalized with acute COVID-19 who reported "brain fog" had higher blood levels of S100B (a marker of BBB disruption) and inflammatory cytokines like IL-6, compared to patients without brain fog.
Using MRI scans that detect subtle BBB leakage, patients with persistent cognitive impairment at 6-12 months after COVID-19 infection ("long COVID brain fog") showed BBB disruption in temporal and frontal brain regions compared to recovered patients. BBB disruption correlated with decreased brain gray matter volume and enlarged ventricles.
Blood samples from long COVID patients with brain fog showed immune cell gene expression patterns consistent with T cell activation and lower activity of pathways involved in platelet activation and coagulation compared to other groups. The cytokine TGF-beta was uniquely elevated and correlated with BBB disruption.
Spike protein from SARS-CoV-2 activated inflammatory and adhesion molecule genes in lab-grown human brain endothelial cells, suggesting viral components may directly alter BBB permeability.
A few thoughts...
My worst bout of insomnia was right after my second bout of Covid. My brain would not shut off at night. It lasted about a month before my brain recalibrated itself.
Inflammation is a major player in all of this. I remember when I finally broke down and took some ibuprofen for some pain I could not stand for another minute - and within the hour, the "brain fog" had cleared out of my head for the first time in a long time! I don't take ibuprofen daily, but it's definitely in my toolbox.
I would say the biggest obstacle right now is denial - the "it's all in your head" pushback is real, and that's if you get past the "Covid is no big deal" denial. (Insert huge eyeroll here)
Thanks so much for this. I'm excited to see papers talking about skin changes and high liver enzymes, which are two of the things I've heard a lot about. Also, insomnia is such a hallmark of folks with long covid thank goodness that's being acknowledged via a paper. Thanks for your summaries, they keep me updated as I can't go searching for and reading papers. Thanks 🙏