Numerous Post-acute COVID-19 survivors develop a clinical syndrome that causes considerable disability regardless of the severity of the acute disease. This “Long-Hauler Syndrome” is due to immune system malfunctions. A similar situation can occur after receiving the “COVID Shot” (which is NOT a vaccine and which has not only been associated with the deaths of many of those who have received it but also been shown to not work very reliably at preventing COVID.
Chronic Inflammatory Response Syndrome (CIRS) has been described at length by Richie Shoemaker MD[i]. There is a genetic tendency for certain people to be susceptible to this syndrome in which, essentially, the “off-switch” of the immune system malfunctions leading to continued immune system activation after the threat (infection, etc) is gone—resulting in “auto-immunity”. CIRS can progress to Mast Cell Activation Syndrome, Multiple Chemical Sensitivity, ElectroMagnetic Field Sensitivity and other physiologic problems/illnesses that have a variety of symptoms and clinical manifestations.
COVID19 “recovery” is unfortunately, the “illusion of recovery” far to often.
Table of Contents
There are a wide range of recurring symptoms regardless of whether or not the acute disease required hospitalization. These symptoms may manifest in the respiratory system, brain, cardiovascular system, kidneys, gut, liver and skin. Symptoms range in intensity, duration and are non-sequential[ii].
COVID patients who develop chronic symptoms (not related to intensive care complications) are often physically fit, younger people who had relatively mild disease. They may have persistent exercise intolerance, breathlessness, cough, anxiety, palpitations, poor concentration, intense fatigue, mood swings, muscle and joint pains, headaches and a poorly defined cerebral sensation known as ‘brain fog’[iii] [iv].
Symptom profile and time course in 3762 patients with Long COVID, along with its impact on daily life, work, and return to baseline health using an international web-based survey design of suspected and confirmed COVID-19 cases with illness lasting from 28 days to 6 months from mid- to late 2020. The most likely symptoms to persist were fatigue, post-exertional malaise, cognitive dysfunction (“brain fog”), neurologic sensations (neuralgias, weakness, coldness, electric shock sensations, facial paralysis/pressure/numbness), headaches, insomnia, shortness of breath, postural dizziness, lightheadedness, and tachycardia suggesting tandem central, peripheral, and autonomic nervous system (CNS, PNS and ANS) involvement.
The symptoms that had been present for ≥2 months were most commonly anosmia, fatigue, ageusia and dyspnea and, compared with seronegative participants[v].
How the Disease Works;
There may be an association with the extent of the inflammatory response, cytokine-mediated cellular injury and cellular energy depletion, which may account for some of the symptoms; however, not all patients who develop this syndrome experience severe symptoms during the acute phase[vi]. A deficiency of nicotinamide adenine dinucleotide (NAD+) (the primary building block being nicotinic acid), which along with zinc is essential for the activation of the silent information regulator (SIRT 1), an immunomodulatory molecule suppressing the production of pro-inflammatory cytokines, may be a factor involved in acute COVID infection and also in its chronic manifestations[vii] [viii] [ix]. NAD+ deficiency is present in most of the comorbid conditions associated with Long-Haulers.
Role of NAD+
Where Nicotinamide adenine dinucleotide (NAD(+)) is a central metabolic coenzyme/co-substrate involved in cellular energy metabolism and energy production is depleted and exogenous sources are not available, tryptophan is utilized via the kynurenine pathway to enhance production which, in addition to its role in SIRT activation, is an essential cofactor for cell survival and even more so in metabolically active tissues[x].
NAD+ levels are maintained by three pathways. The most common is the Preiss–Handler pathway in which nicotinic acid is the substrate. If nicotinic acid is insufficient, NAD+ is synthesized from tryptophan with an excessive accumulation of the metabolites kynurenine and quinolinic acid. The NAD+ salvage pathway recycles the nicotinamide generated as a by-product of the enzymatic activities of NAD+-consuming enzymes[xi].
Cytokines & Lab Testing
Increase in proinflammatory cytokines such as
TNFα LabCorp Test# 140673, CPT 83520 and
Tryptophan/Amino Acid Profile LabCorp 700068 CPT 82139
Serotonin LabCorp Test 120204 CPT 84260
Metabolites of tryptophan catabolism so produced are implicated in many disease processes and may explain various symptoms of PACS, including autonomic dysfunction[xii] [xiii] [xiv] [xv]. Similarly, quinolinic acid, a precursor of nicotinic acid mononucleotide, is increased by an upregulation of the kynurenine pathway and increased levels have been implicated in the clinical manifestations of many diseases [xvi] [xvii] [xviii] [xix]. Quinolinic acid also activates NMDA receptors with the release of glutamate and the resultant calcium influx increases protein kinases, phospholipases, nitric oxide synthetase and proteases which may contribute to the neurological manifestations
Toxic encephalopathy (poisoned-brain disease) also occurs as a result of these metabolic problems.
Immune System Modulators
Large doses of steroids and potentially administration of Tocilizumab may be needed to dampen the inflammatory process[xx] [xxi]. It is possible that other anti-inflammatory agents such as colchicine may reduce the propensity to form mature collagen; however, there are no clinical studies to confirm this treatment as yet.
Pirfenidone is an antifibrotic and anti-inflammatory agent used in the treatment of idiopathic pulmonary fibrosis and there are a few case reports emerging suggesting some efficacy in patients with ‘COVID-associated pulmonary fibrosis’. The drug, however, remains very expensive in most settings and would be used as an off-label indication[xxii] [xxiii] [xxiv].
Those with at least one underlying medical condition are likely to suffer worse complications with COVD19 issues[xxv].
Children with established pediatric autoimmune neuropsychiatric disease associated with Group A beta hemolytic streptococcus (PANDAS) and the closely related disorder PANS, triggered by other microbial agents, notably autoantibody-positive and seronegative autoimmune encephalitides (AE)[xxvi] may be vulnerable to post-infectious SARS- CoV-2 hyperimmunity. Clinicians treating severe hospitalized COVID-19 may administer monthly high-dose intravenous immune globulin (IVIg-HD) therapy at doses of 1 – 2 grams per kilogram (g/kg) over 3 to 5 days to delay progression and improve mortality of SARS-CoV-2-related illness[xxvii]. However, IVIg-HD therapy may be safely administered and well-tolerated at higher total monthly doses with careful monitoring of serum IgG levels, and renal, liver, bone marrow and clotting parameters. More recently, IVIg-HD has been used in the empiric treatment of post-acute sequela of COVID-19 post-acute syndrome[xxviii].
Such an empiric approach has been extrapolated to AE, PANDAS/PANS and other autoimmune encephalopathies wherein remission status relates to baseline IgG deficiency , and the risk-benefit ratio may favor the timely administration of one or more induction IVIg-HDs in a single dose with careful monitoring before commencing maintenance IVIg therapy of 1 g/kg every 3-4 weeks[xxix].
Immune Regulation P38 MAPK
The P38 MAPK pathway relays, amplifies and integrates signals from a diverse range of stimuli and elicit an appropriate physiological response including cellular proliferation, differentiation, development, inflammatory responses and apoptosis in mammalian cells.
- Long COVID patients include millions of people worldwide, and persistent symptoms following COVID-19 can continue for months.
- Varied and relapsing symptoms of Long Covid can be attributed to elevated peripheral and central cytokines, generated by an abnormal immune response.
- CNS effects may be due to direct viral invasion or an indirect immune response.
- Dysregulated activation of brain microglia, due to neuroinflammation, can cause centrally mediated symptoms.
- Upregulation of the p38 MAPK pathway by SARS-Cov-2 can be a possible mechanism by which the virus increases cytokine production.
- Progression to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may be possible and could involve development of autoimmunity.
Dysregulated immune-inflammatory response with elevated peripheral and central cytokines can explain Long COVID symptoms. Hyperreactive brain microglia can modulate a host of CNS-mediated symptoms.
The Long Haul COVID group includes patients with mild-to-moderate symptoms, in whom recovery is prolonged, lasting months.
A model exists for the pathophysiology of the Long Haul COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with “brain fog,” arthralgias, paresthesias, and GI and ophthalmic problems can all be attributed to elevated peripheral and central cytokines.
There are abundant similarities between symptoms in Long COVID and CIRS, & myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
A post-infectious ME/CFS model involving a dysfunctional peripheral and central cytokine inflammatory response and autoimmunity is emerging.
DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS[xxx].
Graphene Oxide Toxicity
Is there anything else that may contribute to the COVID after-effects? We know that graphene oxide is present in “the shot”, we know that it is not harmless[xxxi].
Due to their unique physicochemical properties, graphene-family nanomaterials (GFNs) are widely used in many fields, especially in biomedical applications. Currently, many studies have investigated the biocompatibility and toxicity of GFNs in vivo and in intro. Generally, GFNs may exert different degrees of toxicity in animals or cell models by following with different administration routes and penetrating through physiological barriers, subsequently being distributed in tissues or located in cells, eventually being excreted out of the bodies. This review collects studies on the toxic effects of GFNs in several organs and cell models. We also point out that various factors determine the toxicity of GFNs including the lateral size, surface structure, functionalization, charge, impurities, aggregations, and corona effect etc.
Several typical mechanisms underlying GFN toxicity have been revealed, for instance, physical destruction, oxidative stress,
In these mechanisms, (toll-like receptors-) TLR-, transforming growth factor β- (TGF-β-) and tumor necrosis factor-alpha (TNF-α) dependent-pathways are involved in the signaling pathway network, and oxidative stress plays a crucial role in these pathways[xxxii].
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