Respiratory Virus or Something More Sinister?
Below is the well documented perspective of an anonymous group of researchers. The full document can be found at ICENI Bulletin with complete list of sources.
What is COVID-19?
Excerpted from ICENI Bulletin
COVID-19 is the disease caused by SARS-CoV-2, a close relative of SARS-CoV, the causative agent of Severe Acute Respiratory Syndrome, also known as SARS. SARS-CoV-2 is a coronavirus of the betacoronavirus genus, which it shares with SARS-CoV and MERS-CoV.
The healthcare establishment and the media have misrepresented COVID-19 as a lower respiratory disease, as a form of pneumonia. They have done so consistently for the past two years.
This time, Cavuto said he had a “far, far more serious strand” because his “very compromised immune system” simply hasn’t benefited in the same way from the vaccines as those with healthy immune systems.
Cavuto said that his most recent case of Covid-19 had led to pneumonia and landed him “in intensive care for quite a while.”
While it is certainly true that COVID-19 can cause pneumonia, it would be inaccurate to describe COVID-19 as a pneumonia per se. Due to the significant expression of ACE2 in vascular endothelial cells and pericytes as part of the Renin-Angiotensin-Aldosterone System (RAAS), SARS-CoV-2 preferentially attacks the lining of blood vessels and small capillaries, severely inflaming them, leading to sepsis, capillary leak, pulmonary edema, and yes, pneumonia.
However, therein lies the crucial distinction: SARS-CoV-2 injures the lungs by infecting the blood vessels that supply the alveoli and triggering sepsis and ARDS. It would be more accurate, therefore, to describe COVID-19 not as a pneumonia, but as a disease of the circulatory system.
This has been known since April of 2020, when University Hospital Zurich proclaimed that COVID-19 was, in actuality, a vascular endotheliitis.
During analyses of tissue samples taken from deceased COVID-19 patients taken following an autopsy, pathologists at University Hospital Zurich have now discovered that patients are not just suffering from an inflammation of the lungs, but also from an inflammation of all endothelial tissue in a wide range of organs. In addition, pathologist Prof. Zsuzsanna Varga has been able to use an electron microscope to verify for the first time that SARS-CoV-2 is present and causes cell necrosis in endothelial tissue.
The nature of COVID-19 as a vascular endotheliitis is now well-established in the primary literature.
Post-mortem analysis of the transplanted kidney by electron microscopy revealed viral inclusion structures in endothelial cells (figure A, B). In histological analyses, we found an accumulation of inflammatory cells associated with endothelium, as well as apoptotic bodies, in the heart, the small bowel (figure C) and lung (figure D). An accumulation of mononuclear cells was found in the lung, and most small lung vessels appeared congested.
Inflammatory activation of endothelial cells can disrupt VE-cadherin largely responsible for the integrity of the endothelial barrier function.62 Activated endothelial cells can also express matrix metalloproteinases that can degrade the basement membrane and further interrupt endothelial barrier function. In small vessels, such as those that embrace alveoli in the lung, this impaired barrier function can lead to capillary leak.
What these papers are essentially describing is endothelial dysfunction and endothelial injury in the context of acute sepsis. Researchers have stated that severe COVID-19 is a form of sepsis. Why is this important? Because it has serious implications for how COVID-19 may be successfully treated. It also explains why many current treatments fail to rescue critically-ill patients.
Acute sepsis does a number of terrible things to the circulatory system and vital organs. One thing it does is severely disrupt the balance of oxidation and reduction reactions in the body.
Sepsis is a clinical syndrome characterized by systemic inflammation, usually in response to infection. The signs and symptoms are very similar to Systemic Inflammatory Response Syndrome (SIRS), which typically occur consequent to trauma and auto-immune diseases. Common treatments of sepsis include administration of antibiotics and oxygen. Oxygen is administered due to ischemia in tissues, which results in the production of free radicals. Poor utilization of oxygen by the mitochondrial electron transport chain can increase oxidative stress during ischemia and exacerbate the severity and outcome in septic patients. This course of treatment virtually mimics the conditions seen in ischemia–reperfusion disorders. Therefore, this review proposes that the mechanism of free radical production seen in sepsis and SIRS is identical to the oxidative stress seen in ischemia–reperfusion injury. Specifically, this is due to a biochemical mechanism within the mitochondria where the oxidation of succinate to fumarate by succinate dehydrogenase (complex II) is reversed in sepsis (hypoxia), leading to succinate accumulation. Oxygen administration (equivalent to reperfusion) rapidly oxidizes the accumulated succinate, leading to the generation of large amounts of superoxide radical and other free radical species. Organ damage possibly leading to multi-organ failure could result from this oxidative burst seen in sepsis and SIRS. Accordingly, we postulate that temporal administration with anti-oxidants targeting the mitochondria and/or succinate dehydrogenase inhibitors could be beneficial in sepsis and SIRS patients.
Another thing it does is promote endothelial dysfunction.
Sepsis produces endothelial dysfunction, forcing a pro-adhesive, procoagulant and antifibrinolytic state in endothelial cells, thus altering the hemostasis, leucocyte trafficking, inflammation, barrier function and microcirculation .
We know this is occurring in COVID-19, because COVID-19 sufferers have elevated levels of both inflammatory cytokines such as TNF-a and IL-6, and oxidative and nitrosative stress biomarkers such as nitrotyrosine, coupled with low nitric oxide bioavailability. This has led some to hypothesize that, ultimately, severe COVID-19 is “death by neutrophilia”.
Multi-system involvement and rapid clinical deterioration are hallmarks of coronavirus disease 2019 (COVID-19) related mortality. The unique clinical phenomena in severe COVID-19 can be perplexing, and they include disproportionately severe hypoxemia relative to lung alveolar-parenchymal pathology and rapid clinical deterioration, with poor response to O2 supplementation, despite preserved lung mechanics. Factors such as microvascular injury, thromboembolism, pulmonary hypertension, and alteration in hemoglobin structure and function could play important roles. Overwhelming immune response associated with “cytokine storms” could activate reactive oxygen species (ROS), which may result in consumption of nitric oxide (NO), a critical vasodilation regulator. In other inflammatory infections, activated neutrophils are known to release myeloperoxidase (MPO) in a natural immune response, which contributes to production of hypochlorous acid (HOCl). However, during overwhelming inflammation, HOCl competes with O2 at heme binding sites, decreasing O2 saturation. Moreover, HOCl contributes to several oxidative reactions, including hemoglobin-heme iron oxidation, heme destruction, and subsequent release of free iron, which mediates toxic tissue injury through additional generation of ROS and NO consumption. Connecting these reactions in a multi-hit model can explain generalized tissue damage, vasoconstriction, severe hypoxia, and precipitous clinical deterioration in critically ill COVID-19 patients. Understanding these mechanisms is critical to develop therapeutic strategies to combat COVID-19.
This is also known as respiratory burst, or neutrophil degranulation, or, in extreme cases, neutrophil extracellular trap formation:
Neutrophils use enzymes such as superoxide dismutase (SOD) and myeloperoxidase (MPO) to produce hydrogen peroxide and hypochlorous acid (peroxide and bleach, essentially) in order to destroy bacteria and other pathogens by attacking their membranes with powerful oxidants.
Normally, our cells, which are made of essentially the same stuff as bacteria, survive this by using powerful antioxidant enzymes such as glutathione peroxidase (GPX) to break down hydrogen peroxide into water and reduce harmful lipid hydroperoxides to their corresponding alcohols.
Unfortunately, this virus has a very nasty trick up its sleeve. SARS-CoV-2 can directly inhibit the Nrf2 pathway, blocking endogenous antioxidant enzymes from functioning correctly.
To identify host factors or pathways important in the control of SARS-CoV2 infection, publicly available transcriptome data sets including transcriptome analysis of lung biopsies from COVID-19 patients were analyzed using differential expression analysis14. Here, genes linked with inflammatory and antiviral pathways, including RIG-I receptor and Toll-like receptor signaling, were enriched in COVID-19 patient samples, whereas genes associated with the NRF2 dependent antioxidant response were suppressed in the same patients (Fig. 1a–c). That NRF2-induced genes are repressed during SARS-CoV2 infections was supported by reanalysis of another data-set building on transcriptome analysis of lung autopsies obtained from five individual COVID-19 patients (Desai et al.15) (Fig. 1d). Furthermore, that the NRF2-pathway is repressed during infection with SARS-CoV2 was supported by in vitro experiments where the expression of NRF2-inducible proteins Heme Oxygenase 1 (HO-1) and NAD(P)H quinone oxydoreducatse 1 (NqO1) was repressed in SARS-CoV2 infected Vero hTMPRSS2 cells while the expression of canonical antiviral transcription factors such as STAT1 and IRF3 were unaffected (Supplementary Fig. 1). These data indicate that SARS-CoV2 targets the NRF2 antioxidant pathway and thus suggests that the NRF2 pathway restricts SARS-CoV2 replication.
The Nrf2 pathway directly regulates the function of glutathione peroxidase.
Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is the primary transcription factor protecting cells from oxidative stress by regulating cytoprotective genes, including the antioxidant glutathione (GSH) pathway. GSH maintains cellular redox status and affects redox signaling, cell proliferation, and death. GSH homeostasis is regulated by de novo synthesis as well as GSH redox state; previous studies have demonstrated that Nrf2 regulates GSH homeostasis by affecting de novo synthesis.
This is, of course, why severely ill COVID-19 patients are noted to have glutathione deficiencies.
Humanity is battling a respiratory pandemic pneumonia named COVID-19 which has resulted in millions of hospitalizations and deaths. COVID-19 exacerbations occur in waves that continually challenge healthcare systems globally. Therefore, there is an urgent need to understand all mechanisms by which COVID-19 results in health deterioration to facilitate the development of protective strategies. Oxidative stress (OxS) is a harmful condition caused by excess reactive-oxygen species (ROS) and is normally neutralized by antioxidants among which Glutathione (GSH) is the most abundant. GSH deficiency results in amplified OxS due to compromised antioxidant defenses. Because little is known about GSH or OxS in COVID-19 infection, we measured GSH, TBARS (a marker of OxS) and F2-isoprostane (marker of oxidant damage) concentrations in 60 adult patients hospitalized with COVID-19. Compared to uninfected controls, COVID-19 patients of all age groups had severe GSH deficiency, increased OxS and elevated oxidant damage which worsened with advancing age. These defects were also present in younger age groups, where they do not normally occur. Because GlyNAC (combination of glycine and N-acetylcysteine) supplementation has been shown in clinical trials to rapidly improve GSH deficiency, OxS and oxidant damage, GlyNAC supplementation has implications for combating these defects in COVID-19 infected patients and warrants urgent investigation.
Glutathione deficiencies, endothelial dysfunction, and chronic oxidative stress all point essentially to the same thing: untreated chronic malnutrition brought on by consumption of an energy-rich, micronutrient-poor diet. This is also known as Metabolic Syndrome, and has a close association with endothelial dysfunction and, indeed, premature aging of the blood vessels. It is, of course, why COVID-19 causes more severe illness in those with diabetes, high blood pressure, obesity, and old age. All of these conditions involve pre-existing endothelial dysfunction that renders one more vulnerable to sepsis.
There is, in fact, a close association between the severity of COVID-19 and the quality of one’s diet.
Over 3 886 274 person-months of follow-up, 31 815 COVID-19 cases were documented. Compared with individuals in the lowest quartile of the diet score, high diet quality was associated with lower risk of COVID-19 (HR 0.91; 95% CI 0.88 to 0.94) and severe COVID-19 (HR 0.59; 95% CI 0.47 to 0.74). The joint association of low diet quality and increased deprivation on COVID-19 risk was higher than the sum of the risk associated with each factor alone (Pinteraction=0.005). The corresponding absolute excess rate per 10 000 person/months for lowest vs highest quartile of diet score was 22.5 (95% CI 18.8 to 26.3) among persons living in areas with low deprivation and 40.8 (95% CI 31.7 to 49.8) among persons living in areas with high deprivation.
It is plausible, though not conclusively proven, that COVID-19 could be warded off by simple changes to diet and exercise habits, especially the inclusion of antioxidant-rich foods high in Vitamin D, cysteine, dietary nitrate, and selenium in one’s diet.
Rather than suggesting that people eat better and go on jogs, the authorities have spent the past two years locking people down, which has made them both more obese and more vulnerable to the virus.
A total of 26 studies met inclusion criteria (n = 3399, 85.7% female). The pooled prevalence of symptomatic deterioration in EDs was 65% (95% CI[48,81], k = 10). The pooled prevalence of increased weight in obesity was 52% (95% CI[25,78], k = 4). More than half of the participants experienced depression and anxiety. Moreover, at least 75% of the individuals with EDs reported shape and eating concerns, and increased thinking about exercising.
What is actually happening in COVID-19 that causes all this oxidative damage? First, superoxide reacts with nitric oxide to form peroxynitrite, a damaging nitrogen radical. Then, peroxynitrite reacts with tetrahydrobiopterin in endothelial nitric oxide synthase, leading to those enzymes becoming “uncoupled”, which makes them recursively produce superoxide in a damaging biological feedback loop. Dr. Martin L. Pall refers to this phenomenon by the moniker “NO/ONOO- Disease”.
The NO/ONOO-cycle is a primarily local, biochemical vicious cycle mechanism, centered on elevated peroxynitrite and oxidative stress, but also involving 10 additional elements: NF-κB, inflammatory cytokines, iNOS, nitric oxide (NO), superoxide, mitochondrial dysfunction (lowered energy charge, ATP), NMDA activity, intracellular Ca2+, TRP receptors and tetrahydrobiopterin depletion. All 12 of these elements have causal roles in heart failure (HF) and each is linked through a total of 87 studies to specific correlates of HF. Two apparent causal factors of HF, RhoA and endothelin-1, each act as tissue-limited cycle elements. Nineteen stressors that initiate cases of HF, each act to raise multiple cycle elements, potentially initiating the cycle in this way. Different types of HF, left vs. right ventricular HF, with or without arrhythmia, etc., may differ from one another in the regions of the myocardium most impacted by the cycle. None of the elements of the cycle or the mechanisms linking them are original, but they collectively produce the robust nature of the NO/ONOO-cycle which creates a major challenge for treatment of HF or other proposed NO/ONOO-cycle diseases. Elevated peroxynitrite/NO ratio and consequent oxidative stress are essential to both HF and the NO/ONOO-cycle.
As nitric oxide levels decrease and superoxide predominates (a textbook phenomenon in endothelial dysfunction), superoxide dismutase makes hydrogen peroxide, and then myeloperoxidase makes hypochlorous acid. Hypochlorous acid strips iron from heme. Then, free unliganded iron, hydrogen peroxide, and superoxide react in the Haber-Weiss and Fenton reactions to form damaging hydroxyl radicals.
It is difficult for most people to comprehend just how damaging hydroxyl radicals can be. Hydroxyl radicals occur naturally in the upper atmosphere, where they destroy pollutants. When they occur in the body, they oxidize lipids and DNA instantaneously, within nanoseconds, and no enzyme exists that can detoxify them. Hydroxyl radicals are often produced on purpose with hydrogen peroxide and iron catalyst in hydroxyl generators to create a powerful oxidant concoction that decontaminates and bleaches wastewater streams and HVAC systems by rapidly destroying biological material.
Why are COVID-19 patients dying in droves when they’re intubated, with mortality from mechanical ventilation approaching 97% in some cases? It’s because intubation mimics the physiology of ischemia-reperfusion injury. Under the acute sepsis triggered by COVID-19, cells experience hypoxia. They become stressed and switch to anaerobic metabolism and glycolysis to make ATP as a desperate last resort. Then, these cells are suddenly fed with O2 by a ventilator, which causes them to switch back to aerobic metabolism. As this happens, hypoxanthine and succinate breakdown produces superoxide radicals in very large amounts.
Superoxide is a precursor to many other types of radicals, as described above. There’s even a name for it; the “kindling radical/bonfire hypothesis”.
Many diseases and drug-induced complications are associated with – or even caused by – an imbalance between the formation of reactive oxygen and nitrogen species (RONS) and antioxidant enzymes catalyzing the breakdown of these harmful oxidants. According to the “kindling radical” hypothesis, initial formation of RONS may trigger the activation of additional sources of RONS in certain pathological conditions.
This process of ROS release greatly accelerates the damage caused by the virus, promoting lipid peroxidation and the formation of damage-associated molecular patterns and oxidation-specific epitopes. The DAMPs summon more neutrophils by their interaction with PRRs, which release more damaging enzymes. The OSEs cause the body to form autoantibodies against oxidized lipids, somewhat similar to some aspects of the pathophysiology of Lupus.
Oxidation reactions are vital parts of metabolism and signal transduction. However, they also produce reactive oxygen species, which damage lipids, proteins and DNA, generating “oxidation-specific” epitopes. In this review, we will discuss the hypothesis that such common oxidation-specific epitopes are a major target of innate immunity, recognized by a variety of “pattern recognition receptors” (PRRs). By analogy with microbial “pathogen associated molecular patterns” (PAMPs), we postulate that host-derived, oxidation-specific epitopes can be considered to represent “danger (or damage) associated molecular patterns” (DAMPs). We also argue that oxidation-specific epitopes present on apoptotic cells and their cellular debris provided the primary evolutionary pressure for the selection of such PRRs. Further, because many PAMPs on microbes share molecular identity and/or mimicry with oxidation-specific epitopes, such PAMPs provided a strong secondary selecting pressure for the same set of oxidation-specific PRRs as well.
This severe oxidative stress promotes steroid insensitivity. Suddenly, the corticosteroids stop working and the patient experiences inflammatory rebound.
Reactive oxygen and nitrogen species (RONS) promote corticosteroid insensitivity by disrupting glucocorticoid receptor (GR) signaling, leading to the sustained activation of pro-inflammatory pathways in immune and airway structural cells.
A total of 319 COVID-19 patients were admitted to our hospital and 113 patients met inclusion criteria. The success group had 83 patients (73.5%), the rebound group had nine patients (8.0%), and the refractory group had 21 patients (18.6%). Compared with the success group, the rebound group received corticosteroids earlier, for a shorter duration, and stopped them sooner. The median time from symptom onset to rebound was 12 days. There was no rebound after 20 days. Compared with the success group, the hazard ratio for the number of days from corticosteroid onset to an improvement of two points on a seven-point ordinal scale was 0.29 (95% confidence interval [CI], 0.14–0.60, P < .001) for the rebound group versus 0.13 (95% CI, 0.07–0.25, P < .001) for the refractory group.
Antivirals such as Remdesivir, Kaletra, Ivermectin, and Hydroxychloroquine do nothing to stop this, because by the time someone is in the ER complaining of severe COVID-19 symptoms (which are actually acute sepsis brought on by a deranged, overreacting innate immune system), the virus is already gone.
Similarly to IAV infection, the highest viral load and infectivity for SARS-CoV-2 are observed +/−1 day around the day of symptom onset . Both the amount of infectious virus as well as the amount of viral RNA as measured by qRT-PCR decrease rapidly thereafter. Accordingly, the number of cells within the patient’s respiratory tract that are newly infected with SARS-CoV-2 declines sharply within a few days of disease onset. It is now well accepted that immunopathology plays a key role in severe COVID-19 . Accordingly, treatment with corticosteroids, such as dexamethasone, improves survival in critically ill COVID-19 patients in the later stages of the disease .
Ultimately, the afflicted cells begin dying of ferroptosis and parthanatos.
As GPX4 is the major PLOOH-neutralizing enzyme, a general mechanism underlying erastin/RSL3-induced ferroptosis emerged: both compounds inactivate GPX4 – RSL3 does so directly, and erastin does so indirectly by inhibiting cystine import, thus depriving cells of cysteine, an essential cellular antioxidant and a building block of GSH. Consequently, PLOOHs accumulate, possibly causing rapid and unrepairable damage of plasma membrane, leading to cell death (Fig. 2A). Conceptually, these findings establish ferroptosis as a cell death modality with mechanisms distinct from other known death processes. The pharmacological and genetic tools developed herein enable, and have become indispensable for, ferroptosis research.
In the context of the CNS, which is highlighted in this review to illustrate PARP-1-mediated cell death mechanisms that are shared in most cases by non-neuronal systems, stimuli that induce pathological activation of PARP-1 in in vitro and in vivo studies include oxidative stress by reactive oxygen species (ROS), such as hydrogen peroxide (H2O2) or hydroxyl radical, nitrosative stress from NO or peroxynitrite (ONOO−), inflammation, ischaemia (or ischaemic reperfusion), hypoxia, hypoglycaemia and DNA-alkylating agents, such as N-methyl-N’-nitro-N-nitrosoguanidine (MNNG).
That, in a nutshell, is the central pathophysiology of COVID-19. The virus has many other aspects. It can promote hypercoagulability and attack numerous vital organs throughout the body, including the brain, olfactory system, gastrointestinal system, pancreas, kidneys, liver, and even fat cells. However, all of these things occur in the context of acute sepsis and endothelial injury.
In short, COVID-19 is not the disease people have been told it is, and, as per ostracized physicians such as Dr. Peter McCullough, Dr. Paul E. Marik, and Dr. Vladimir Zelenko, it is not being treated correctly.
The medical establishment has shunned those pushing for time-sensitive early outpatient treatment of COVID-19 sepsis. The standard of care for COVID-19 is to send people home without a prescription for anything; no antivirals, no antioxidants. Either their infection resolves without incident, or they get sicker, come back, and are intubated and proned, their diaphragm paralyzed with drugs so they can’t fight the ventilator, a drip of steroids running into their arm.
This is state-sponsored medical murder.