Eosinophilic GI Disease

 Eosinophilic GI Disease (EGID) is a group of conditions that occur when there are elevated levels of eosinophils in segments of the GI tract, either the esophagus, stomach, small intestines or colon.  These conditions are called Eosinophilic Esophagitis (EoE), Eosinophilic Gastritis or Gastroenteritis (EoG), Eosinophilic Enteritis (EoN), and Eosinophilic Colitis (EC or EoC).  I have heard reference to Eosinophilic Duodenitis Eosinophilic Rectitis but I don't think either are official conditions.  The esophagus is the one part of the GI tract that doesn't normally have eosinophils, whereas the rest of the GI tract does.  This has led some to speculate that EoE is a different entity than the other EGIDs.  

EGIDs are diagnosed by biopsy.  Tissue samples are collected during endoscopy or colonoscopy, and then sent to a pathologist who looks at the samples under a microscope to identify the presence of eosinophils.  If the numbers are too high, a diagnosis is made.  Symptoms vary depending on the form of EGID a person has, and can be mild to severe.  In EoE, a common symptom, the one that often leads to diagnosis, are food impactions in the esophagus that require medical care to remove.  Symptoms of lower EGIDs tend to be vague such as cramping and pain, vomiting, nausea, diarrhea, food intolerances and a severely restricted diet, malnutrition, and bone pain (usually in the legs).  

Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis

Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study

Molecular analysis of duodenal eosinophilia

Elimination diets are often used by doctors to identify problem foods, as there are no tests to identify eosinophilic triggers.  Treatment often begins by having the patient avoid identified (or suspected) triggers.  If this doesn't adequately control symptoms, various medications can be used, including topical steroids such as Budesonide or Fluticasone (steroids that is swallowed), a PPI (Protono Pump Inhibitor), Singulair, or oral steroids to control flares.  A type of medication called biologics are starting to be used for some EGIDs, in particular Dupilumab (brand name Dupixent).  Eosinophils are the same cells that tend to be responsible for asthma so many of the same medications are used.  Some people describe EGIDs as "like asthma but in your GI tract".  If those treatments fail, it is not uncommon for people with EGIDs to require artificial nutrition such as elemental formula, a feeding tube, or even TPN (IV nutrition).  People with EoE can develop strictures in the esophagus, areas where the tissue has scarring which narrows the width of the esophagus.  This can be treated with dilations, a procedure in which the area is mechanically stretched.

Crafting a Therapeutic Pyramid for Eosinophilic Esophagitis in the Age of Biologics

The leading center for diagnosis and treatment of EGIDs, especially EoE, is Cincinnati Children's Hospital (they also work with adults with EGIDs) 

Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE

Food-specific IgG4 is associated with eosinophilic esophagitis

Common and disparate clinical presentations and mechanisms in different eosinophilic gastrointestinal diseases

Histopathology of Eosinophilic Gastrointestinal Diseases Beyond Eosinophilic Esophagitis
"EoG and eosinophilic duodenitis (EoD) are strongly associated with food allergen triggers and TH2 inflammation, whereas EoC shows minimal transcriptomic overlap with other EGIDs. The level of expression of certain genes associated with TH2 immune response is associated with certain histopathologic findings of EoG, EoD, and EoC. Current immune therapy for EoG depletes tissue eosinophilia with persistence of other histopathologic features of disease."

The Dual Lens of Endoscopy and Histology in the Diagnosis and Management of Eosinophilic Gastrointestinal Disorders—A Comprehensive Review
"Eosinophils, a specific type of leukocyte derived from CD34+ CD125+ stem cells in the bone marrow, are crucial in defending against pathogens, such as bacteria and parasites. Additionally, they play a pivotal role in modulating humoral immune IgA and cellular T-cell responses, and in maintaining tissue homeostasis.

In the context of EGIDs, the abnormal accumulation of eosinophils is primarily driven by interleukin-5 (IL-5), interleukin-4 (IL-4), and interleukin-13 (IL-13). These cytokines are primarily produced by type 2 helper lymphocytes (Th2) in response to exposure to aeroallergens and food allergens. The overproduction of interleukins is further amplified by dysregulated cells in the innate immune system, including Group 2 innate lymphoid cells (ILC2s) that mature directly in tissues like the GI tract or lungs, plasma cells, and mast cells.  Pathogenesis of Th2 inflammatory drive in Eosinophilic Gastrointestinal Disorders (EGIDs), especially EoE. Exposure to initial food antigens triggers lymphocyte-Th2 activation, resulting in the accumulation of eosinophils in the esophagus. Following stimulation with Eotaxin 3, eosinophil degranulation promotes acute damage to the esophageal epithelium, followed by subsequent chronic fibrotic remodeling of the esophagus, which is dependent on TGF-beta.

Th2 cytokines, particularly IL-13, along with other inflammatory mediators such as Tumor Necrosis Factor Alpha (TNF-α) and other chemokines, play a direct role in the activation and degranulation of eosinophils. Eotaxin-3 serves as the primary chemokine involved in these processes and contributes significantly to eosinophilic chemotaxis and accumulation in GI tissues. The release of proteins from eosinophilic granules, including eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and major basic protein (MBP), leads to acute cytotoxic and oxidative damage to the tissue. This acute damage results in compromised barrier function through the downregulation of Desmoglein 1 (DSG1), Filaggrin (FGN), and the Epidermal Differentiation Complex (EDC).
The course of acute eosinophilic Th2 inflammation is typically self-sustained and progressive, often leading to chronic damage. This chronic state is often driven by T regulatory lymphocytes’ activation, accompanied by the recruitment of other cell types, including mast cells and basophils [26]. The persistent inflammatory insult can result in sub-mucosal fibrotic tissue deposition and muscular hypertrophy, primarily induced by Transforming Growth Factor beta (TGF-beta). 

A recent study on colonic biopsies conducted by Shoda et al. revealed that EoC is distinct from other EGIDs, with pathophysiological mechanisms that are not completely dependent on allergic inflammatory reactions [186]. The study identified 987 differentially expressed genes that were overexpressed in EoC tissues, thereby defining the “EoC transcriptome”.  Interestingly, the pathogenesis of EoC seems to have only a weak correlation with Th2-related allergic pathogenesis.  (A)dults typically experience chronic abdominal pain and watery diarrhea [25,179,180]. Additional symptoms can include nausea, vomiting, and weight loss. The presence of atopy history in EoC patients often complicates the clinical picture with conditions like asthma, food allergies, rhinitis, or eczema.

The depth of eosinophilic infiltration in the colonic wall allows for the identification of three disease patterns [147].

The mucosal involvement (type 1), defined as eosinophil infiltration of the mucosa, is the most common. This type often follows a continuous disease course (>6 months) without remission, with patients exhibiting symptoms such as bloody diarrhea, microcytic iron-deficiency anemia, and protein-losing enteropathy [5].

Transmural involvement (type 2) occurs when eosinophils infiltrate the muscular layer. It is associated with symptoms like abdominal spasms, pain, and a possible impact on intestinal motility. Complications such as intestinal obstructions, strictures, volvulus, and perforations may occur. The course of the disease in this form is typically recurrent [5].

The serosal subtype (type 3) is the rarest and occurs when eosinophilic infiltration reaches the serosa. This form can be associated with more severe symptoms, including eosinophilic ascites and intense abdominal pain [5].

Radiological signs include intestinal wall and mucosal fold thickening and submucosal edema [150,153]. Mucosal thickening, stenosis, and sub-mucosal edema form the basis of the “halo sign,” characteristic of EoC. The “arachnoid limb-like sign” may also be observed via radiological imaging [150]. In cases of transmural involvement, stenosis, particularly at the cecum, may be observed.

 

In approximately 70% of EoC cases, no alterations in the colonic mucosa are observed during endoscopic evaluation [183,187,188]. However, when abnormalities are present, they typically involve the colon segmentally, with only about 10% of patients presenting with pancolitis [14,25,183]. The endoscopic findings of EoC are often non-specific and do not correlate with the severity of symptoms [7].

 

Drug-induced colitis, triggered by antiplatelet drugs (clopidogrel, aspirin, and ticlopidine), Non-Steroidal Anti-Inflammatory Drug (NSAIDs) (especially ibuprofen), and estrogenic-progestogen agents is another cause of colonic hypereosinophilia [194,195].  Among connective tissue diseases, rheumatoid arthritis uniquely exhibits patterns of colonic eosinophilia [200]. 

 

In addition to hypereosinophilia, other microscopic characteristics that typify EoC histology include extensive degranulation, eosinophilic micro-abscesses, architectural distortion, fibrosis with mucosal atrophy, loss of mucin, and follicular lymphoid hyperplasia, often accompanied by lymphocytes and plasma cells [187,188].

 

According to the strongest evidence, a PEC with more than 50 eosinophils per HPF in the right colon, more than 35 eos/HPF in the transverse colon, or more than 25 eos/HPF in the left colon, along with a consistent clinical and symptomatic profile, indicates a diagnosis of EoC [14] 

 

adults typically receive steroid anti-inflammatory therapy, such as prednisone or budesonide, as the initial treatment [170,180]. If adults experience a relapse after discontinuing prednisone, indicating steroid-dependent disease, Budesonide Controlled Ileal Release (CIR) can be an effective maintenance therapy. Budesonide CIR has the advantage of primarily topical activity, minimizing the long-term adverse effects associated with steroids [202].

Immunomodulators like azathioprine and methotrexate also represent alternatives to maintenance therapy for EoC. Additionally, Montelukast, a leukotriene receptor antagonist, is beneficial in maintenance therapy due to its ability to block eosinophil homeostasis and prevent their infiltration into the intestinal wall [131]. Fecal microbiota transplantation has been suggested as a rescue strategy in EoC, though this evidence is limited to case reports [203]. Emerging therapies for EoC have mainly been tested in animal models. Studies evaluating the efficacy of anti-Siglec-F antibodies (targeting a sialic acid-binding immunoglobulin superfamily receptor) and anti-CCR3 (cysteine–cysteine chemokine receptor 3) antibodies have shown promising results [204,205]. Future therapeutic options are anticipated with the validation of biological drugs like dupilumab, reslizumab, and mepolizumab, which are currently undergoing testing.

 

 

 

 

Yale Study About Post-Vaccine Syndrome

(This is a pre-print, I will update this post as more information becomes available)

Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination
"To explore potential pathobiological features associated with PVS (Post-Vaccine Syndrome), we conducted a decentralized, cross-sectional study involving 42 PVS participants and 22 healthy controls enrolled in the Yale LISTEN study. Compared with controls, PVS participants exhibited differences in immune profiles, including reduced circulating memory and effector CD4 T cells (type 1 and type 2) and an increase in TNFα+ CD8 T cells. PVS participants also had lower anti-spike antibody titers, primarily due to fewer vaccine doses. Serological evidence of recent Epstein-Barr virus (EBV) reactivation was observed more frequently in PVS participants. Further, individuals with PVS exhibited elevated levels of circulating spike protein compared to healthy controls. These findings reveal potential immune differences in individuals with PVS that merit further investigation to better understand this condition and inform future research into diagnostic and therapeutic approaches."

Protocol for Vaccine Injury Management (from Dr Been, based on Yale study)

Dr Been's video about this study

New and Experimental Treatments for Mast Cell Disease and Allergy

Nanoparticles Targeting Mast Cells Prevent Allergic Reactions in Mice
Researchers at Northwestern University successfully used a new treatment to prevent anaphylaxis in allergic mice using nanoparticles that targeted the mice' mast cells.  These nanoparticles were coated with molecules meant to function as allergens, and another molecule- called Siglec-6 that- that signals mast cells not to react.  The result was that the targeted mast cells were deactivated, which protected the mice and kept them from experiencing anaphylaxis.  "In one final experiment, mice sensitized to an IgE allergen were given the nanoparticle infusions with the two antibodies, and exposed to their allergen. None experienced signs of an allergic reaction."

Mast Cells, MCAS, and Psychiatric Symptoms

Brain mast cells link the immune system to anxiety-like behavior
"Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior."

"Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links."

Prevalence and treatment response of neuropsychiatric disorders in mast cell activation syndrome
"MCAS subjects have significantly elevated odds ratios for many neuropsychiatric disorders and may see improvement of symptoms using MCAS-targeted therapies, suggesting that mast cell dysregulation affects the brain and peripheral nervous systems and contributes to neuropsychiatric symptoms."

Mast Cell Activation & Inflammation in Brain Disorders: How to Calm Things Down
"Though our culture is only starting to consider psychiatric conditions as inflammation of the brain, if you or someone you know has panic attacks, depression, mood swings, ADHD, brain fog, chronic fatigue, PTSD, autism, cognitive issues or even dementia, then you know the destruction neuroinflammation plays in people’s lives.

Tweaking neurotransmitter functioning, the primary role of modern conventional psychiatry, isn’t the same as treating inflammation in the brain.  While psychotropic medications may help lessen symptoms (and can be life saving), they don’t address root causes including inflammation. In those with high immune reactivity, they may even trigger an inflammatory response themselves."

Brain inflammation has a lot to do with the interactions between mast cells, microglial cells, and CRH (corticotropin releasing hormone), which both triggers these cells and is released by them under stress.  This can be either physiological or emotional stress.  Examples of things can alter our stress response and contribute to chronic inflammation in the brain include toxic metals, chronic infections such as viruses and yeast overgrowth, mold exposure, trauma, and early disruption of healthy attachment.  Stress calls for cortisol, so CRH is released to signal the adrenal glands to release mroe cortisol, which also activates mast cells and microglial cells, leading to chronic brain inflammation, which in turn can damage the brain and lead to neurodegeneration.  

Research is also showing the role of mast cells in traumatic brain injury, multiple sclerosis, Parkinson’s disease, dementia, Alzheimer’s disease, stress conditions, sleep disorders, migraine, pain, ADHD and autism.  When mast cells are stimulated they disrupt and release mediators that increase the permeability of what we call the Blood Brain Barrier (BBB) and Gut Blood Barrier (GBB).  If microglia are overstimulated, "they will release their own inflammatory mediators causing local inflammation and disrupted connections between neurons.  If this goes on too long, nearby neurons will die which leads to neurodegeneration which can equate to the beginning of dementia."

Mast Cells, Stress, Fear and Autism Spectrum Disorder
“Prenatal stress has been associated with higher risk of developing ASD in the offspring. Moreover, children with ASD cannot handle anxiety and respond disproportionately even to otherwise benign triggers. Stress and environmental stimuli trigger the unique immune cells, mast cells, which could then trigger microglia leading to abnormal synaptic pruning and dysfunctional neuronal connectivity. This process could alter the “fear threshold” in the amygdala and lead to an exaggerated “fight-or-flight” reaction. The combination of corticotropin-releasing hormone (CRH), secreted under stress, together with environmental stimuli could be major contributors to the pathogenesis of ASD. Recognizing these associations and preventing stimulation of mast cells and/or microglia could greatly benefit ASD patients.”

Mast Cells and Stress- a psychoneuroimmunological perspective

Mast cells regulate blood-brain-barrier permeability from acute stress 

Mast cells can cause permeability of the blood-brain-barrier and contribute to neurological disorders  

Microglia and mast cells: two tracks on the road to neuroinflammation.

Neural circuitry engaged by prostaglandins during the sickness syndrome

Mast cell activation disease: an underappreciated cause of neurologic and psychiatric symptoms and diseases

 
Mast cell disease causes neurological and psychiatric symptoms and diseases

 

Mast Cells Affect Brain Physiology and Behavior

 
Mast Cell Disease can manifest as Mixed Organic Brain Syndrome (psychiatric symptoms)

 
Neuropsychiatric Manifestations of Mast Cell Activation Syndrome and Response to Mast-Cell-Directed Treatment: A Case Series

 
The Role of Mast Cells in Alzheimer's Disease.

 
Mast cells and migraine pathways

 

 

 

 

Dietary Fats and Oils

 (in progress)

Is Saturated Fat Bad For You?
Ketogenic diet therapy doesn't have to include any saturated fat; many people eat a vegan keto diet or one that is vegetarian without dairy, or some other specialized form of keto.  It's possible to make a keto diet that is compliant with almost any other restriction, such as vegan, vegetarian, Mediterranean, carnivore, and others.

Saturated fat, the estimated absolute risk and certainty of risk for mortality and major cancer and cardiometabolic outcomes: an overview of systematic reviews
Absolute risk is much more informative than relative risk- relative risk sounds more catchy but doesn't actually tell you as much.  When thinking about what a study means for you, whether its conclusion means you need to make changes, depends on the quality of evidence and not just the presence or absence of evidence.  This paper found that the evidence supporting a risk from consuming saturated fat was low or critically low quality.  When looking at the results of reducing or replacing saturated fat in terms of cancer mortality, the authors found that the evidence showed a range of 8 fewer deaths to 3 additional deaths per 1,000 people, and the certainty of evidence (quality) was low to very low.  So no clear-cut link between saturated fat consumption and risk of death from cancer.  When considering the impact of saturated fat in the diet and cardiac deaths, they found a rate of two deaths per 1,000 people with low to moderate certainty.  This does not support the strength of the message we get through doctors and public health to avoid saturated fat.

There are other factors to consider when seeing if the results of a study means anything for you individually.  To illustrate this point, consider one study that was included in this meta-analysis (with moderate quality evidence) that found 24 fewer deaths per 1,000 people from all-cause mortality in a treatment group that reduced saturated fat intake.  We need to look at the details to see what the implications are.  Most people being studied are eating the standard American diet, high in ultra-processed foods, and get their saturated fat from sandwiches, desserts and sweet snacks like cookies, cakes, ice cream, pastries; and rice and grain-based dishes like pasta and pizza, and milk and yogurt which is usually sweetened and flavored.  These foods are all high in sugars and simple starches.  Natural foods, including plain meats, cheeses, butter, etc are lower on the list.  The question then is how do you eat- if you eat lots of junk food, fast food, and processed food, then this study might apply to you.  If you already eat a diet primarily of whole foods and low processed foods then these results probably have no relevance for you.

"Nutrition science is full of low quality evidence that applies to a general population eating a low quality diet".  As a patient, we all deserve to have care providers who treat us as individuals.

A short history of saturated fat: the making and unmaking of a scientific consensus 

Dietary Saturated Fats and Health: Are the U.S. Guidelines Evidence-Based?

Mast Cell Disease and Long COVID (aka PACS)

Long COVID and MCAS
Post-COVID Conditions: Information for Healthcare Providers
This is the CDC's current guidelines for treating Long COVID and they specifically mention MCAS as a possible cause of Long COVID symptoms that should be addressed.  They do not give information about diagnosing and treating MCAS however (here is the site they link to for more info about MCAS).

Missouri doctors make discovery about possible cause of long COVID
"Dr. Leonard Weinstock, a gastroenterologist at Missouri Baptist Medical Center, and others found that mast cell activation symptoms were increased in long COVID-19 patients.  Weinstock and his team hypothesized that the mast cell activation could cause long COVID-19 symptoms. They also believe that long COVID-19 symptoms could be mitigated by preventing mast cell activation."
The study referenced in this article can be found here.

Immunological dysfunction and mast cell activation syndrome in long COVID
"Long COVID-19 is the consequence of multiple immune system dysregulation, such as T-cell depletion, innate immune cell hyperactivity, lack of naive T and B cells, and elevated signature of pro-inflammatory cytokines, together with persistent severe acute respiratory syndrome-coronavirus 2 reservoir and other consequences of acute infection. There is an activated condition of mast cells in long COVID-19, with abnormal granulation and excessive inflammatory cytokine release. A study by Weinstock et al. indicates that patients with long COVID-19 suffer the same clinical syndrome as patients with mast cell activation syndrome (MCAS). Diagnosis and treatment of MCAS in patients with long COVID-19 will provide further symptomatic relief, and manage mast cell-mediated hyperinflammation states, which could be useful in the long-term control and recovery of such patients."

Mast cell activation symptoms are prevalent in Long-COVID
"In the present study, there was a high prevalence of MCA symptoms in LC patients prior to MCAS treatment. The symptom data and spider web plots illustrated that LC patients’ symptoms are virtually identical to those experienced by MCAS patients. These results support, but do not provide definitive proof of, our earlier hypothesis that LC might often arise out of a SARS-CoV-2-driven provocation of primary or secondary MCAS. Theories to explain promotion of MCA in LC include: 1) complex interactions of stressor-induced cytokine storms with epigenetic-variant-induced states of genomic fragility to induce additional somatic mutations in stem cells or other mast cell progenitors; 2) cytokine or SARS-CoV-2 coronavirus activation of mast cells and microglia; 3) dysregulation of genes by SARS-CoV-2 coronavirus leading to loss of genetic regulation of mast cells;  4) development of autoantibodies which react with immunoglobulin receptors on mast cells,  and 5) increase in Toll-like receptor activity by the coronavirus.  

In this study, MCA symptoms were significantly increased in LC. Uncontrolled, aberrant mast cells may in part underlie the pathophysiology of LC. Inflammation caused by COVID-19 is complicated, and other immune disturbances that have been seen in the acute infection such as excess dysfunction of the macrophage and serotonin release from platelets might or might not play roles in LC"

MCAS activated by Long COVID or PACS or by MIS-C or PIMS and MCAS activated by Vaccines or by Post Vaccine Syndrome: CRITERIA FOR CLINICAL DIAGNOSIS
"In Long COVID or Post-Acute COVID Syndrome (PACS), in Multisystem Inflammatory Syndrome in children (MIS-C or PIMS) and in Post Vaccine Syndrome, in addition to the symptoms of Hypoperfusion, Hyper-coagulability and Microclots (HHM), it is very important to identify the symptoms associated with Hypersensitivity (HS), Allergies, Histaminosis and Mast Cell Activation Syndrome (MCAS) which are also a frequent cause of persistent symptoms. But, several of the patients who present persistent symptoms after having COVID or MIS-C are not diagnosed in a timely manner for Histaminosis, Tryptasemia, , mast cell activation disorder (MCAD), MCAS, and several years may pass and they may even be admitted to a hospital or psychiatric center. with a treatment that does not correspond, so we have considered it convenient to disseminate for free the criteria that we have developed, which have taken as reference the current International Consensus Criteria for MCAS, which gives a high level of support for your application. The references of the scientific publications taken into account are available in the document at the following link: https://www.researchgate.net/publication/376047625 In a similar way to what occurs in Long COVID or PACS and in MIS-C or PIMS, vaccination against COVID can cause the activation of an MCAS in a patient who did not have it, or the enhancement of an already existing MCAS, therefore we have included the diagnosis of MCAS activated by COVID Vaccines or by Post-Vaccine COVID Syndrome, and we must mention that there is a significant number of these cases without, to date, having agreed upon and disseminated criteria for their adequate diagnosis and treatment."

 

How to Treat Long COVID

 Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study

Evaluation of nutrition risk and its association with mortality risk in severely and critically ill COVID-19 patients
"Most severely and critically ill patients infected with SARS CoV-2 are at nutrition risk.  The patients with higher nutrition risk have worse outcome and require nutrition therapy."

Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey
"Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms.  Our survey indicates that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of attenuating its typical symptoms and improving effort perception."

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial
"Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis.  l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population."

Alleviation of Post-COVID-19 Cognitive Deficits by Treatment with EGb 761®: A Case Series
"In many studies, EGb 761 has been demonstrated to protect endothelial cells, to have potent anti-inflammatory effects, and to enhance neuroplasticity. CASE REPORT Here, we report for the first time the application of EGb 761 in the therapy of post-COVID-19-related cognitive deficits. Three women and 2 men, aged 26 to 59 years (average age 34.6 years), presented with concentration and attention deficits, cognitive deficiencies, and/or fatigue 9-35 weeks after infection. A daily dose of 2×80 mg of EGb 761 did not cause any detectable adverse effects, and it substantially improved or completely restored cognitive deficits and, when initially present, also other symptoms, such as fatigue and hyposmia, within an observation period of up to 6 months."

NAD+ in COVID-19 and viral infections
"NAD+, as an emerging regulator of immune responses during viral infections, may be a promising therapeutic target for coronavirus disease 2019 (COVID-19). In this Opinion, we suggest that interventions that boost NAD+ levels might promote antiviral defense and suppress uncontrolled inflammation. We discuss the association between low NAD+ concentrations and risk factors for poor COVID-19 outcomes, including aging and common comorbidities. Mechanistically, we outline how viral infections can further deplete NAD+ and its roles in antiviral defense and inflammation. We also describe how coronaviruses can subvert NAD+-mediated actions via genes that remove NAD+ modifications and activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Finally, we explore ongoing approaches to boost NAD+ concentrations in the clinic to putatively increase antiviral responses while curtailing hyperinflammation."

Evaluation of thiamine as adjunctive therapy in COVID-19 critically ill patients: a two-center propensity score matched study
"Thiamine is a precursor of the essential coenzyme thiamine pyrophosphate required for glucose metabolism; it improves the immune system function and has shown to reduce the risk of several diseases. The role of thiamine in critically ill septic patient has been addressed in multiple studies.

Thiamine also works as a carbonic anhydrase isoenzyme inhibitor; thus, high doses of thiamine given to patients at the early stages of COVID-19 could limit hypoxia and decrease hospitalization [16]. Additionally, an in-vitro study found that high-dose thiamine lowers the T-helper cells (Th-17) cell pro-inflammatory response believed to be associated with the COVID-19 cytokine storm [17]"

Therapeutic Prospects for Th-17 Cell Immune Storm Syndrome and Neurological Symptoms in COVID-19: Thiamine Efficacy and Safety, In-vitro Evidence and Pharmacokinetic Profile
"Three-week of 200 mg daily thiamine treatment significantly lowered the baseline IL-17 levels while increased IL-22 levels (anti-inflammatory response)."