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Fat Anon's September COVID-19 File

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  1. I hope this message finds you all in good health. I've sent all of this info to a virologist I know in the US, but I figured I'd forward it to you guys, as well (I agree with the Vitamin D and bradykinin stuff; the info I've found backs it up).
  2.  
  3. I’ve continued studying the papers that have been published regarding COVID-19 and its pathology. I have looked over the review papers that have described many aspects of the pathology in detail, as well as some of the newer hypotheses.
  4.  
  5. COVID-19 appears to be an airborne vasculotropic disease that primarily infects and injures pulmonary microvasculature, but is by no means restricted to those tissues alone.
  6.  
  7. These are the manifestations of COVID-19 that researchers have been able to identify so far:
  8. Bilateral Viral Pneumonia
  9. Cytokine Release Syndrome
  10. Pulmonary Edema
  11. Pulmonary Fibrosis
  12. Pulmonary Embolism
  13. ARDS
  14. Vascular Endotheliitis
  15. Viremia
  16. Systemic Capillary Leak Syndrome (rare)
  17. Antiphospholipid Syndrome
  18. Coagulopathy
  19. Shock
  20. Kawasaki Disease (in pediatric cases, especially)
  21. Acro-ischemia/Purpura (in toes)
  22. Dyslipidemia
  23. Urea Cycle Disorder
  24. Ammonemia (features in some cases with liver involvement)
  25. Hyperferritinemia
  26. Mild Hepatitis
  27. Hypokalemia (from hyperaldosteronism)
  28. Encephalitis/Meningitis
  29. Mental Issues/Impaired Consciousness
  30. Skeletal Muscle Injury
  31. Cerebrovascular Disease
  32. Guillain-Barre Syndrome
  33. Dysautonomia
  34. Anosmia
  35. Dysgeusia
  36. Seizure
  37. Stroke
  38. Myocarditis
  39. Pericarditis
  40. Heart Attack
  41. Arrhythmia
  42. Acute Kidney Injury
  43. Gastrointestinal Inflammation
  44. Diarrhea
  45. Nausea/Vomiting
  46. Abdominal Pain
  47. Testicular Inflammation
  48. Conjunctivitis
  49. Rash
  50. Transient Livedo Reticularis
  51. Bacterial Co-infections
  52. The general ER presentation of a severe or critical COVID-19 patient looks something like this:
  53. Fever
  54. Dry cough
  55. Hemoptysis
  56. Shortness of breath
  57. Body aches
  58. Abdominal pain
  59. Loss of sense of smell and/or taste
  60. Low blood O2 sat (<90%)
  61. Hypokalemia
  62. Abnormal AST/ALT
  63. High C-reactive Protein
  64. Elevated troponin
  65. Elevated D-dimer
  66. Elevated ferritin
  67. Lymphopenia
  68. Thrombocytopenia
  69. Albuminuria
  70. Hematuria
  71. The sequelae of a serious COVID-19 infection are very similar to SARS and include damage to the lungs from fibrosis and loss of as much as 30% of lung capacity, myalgic encephalomyelitis (chronic fatigue syndrome), and mental issues like brain fog, depression, difficulty concentrating, and so on.
  72.  
  73. https://www.icd10monitor.com/what-we-currently-know-about-the-sequela-effects-of-covid-19
  74.  
  75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324652/
  76.  
  77. https://www.medpagetoday.com/infectiousdisease/covid19/86482
  78.  
  79. SARS-CoV-2 preferentially infects cells through ACE2 receptors. There was some early pre-print research indicating that it could also infect cells CD147/Basigin receptors, as well, but this has since been contradicted by further research.
  80.  
  81. https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03120-0
  82.  
  83. https://www.biorxiv.org/content/10.1101/2020.03.14.988345v1
  84.  
  85. https://www.biorxiv.org/content/10.1101/2020.07.25.221036v1
  86.  
  87. The virus is airborne in aerosols and can travel a good 15 feet or so; it is present in the oral and nasal mucosa and can be readily aerosolized by high speech volume. Singing or shouting can enhance the aerosolization of the virus. One way to reduce transmission may be to reduce the volume of one's speech.
  88.  
  89. https://www.nytimes.com/2020/08/11/health/coronavirus-aerosols-indoors.html
  90.  
  91. https://www.cdc.gov/mmwr/volumes/69/wr/mm6919e6.htm
  92.  
  93. SARS-CoV-2 can enter the body in a number of ways.
  94.  
  95. It can be inhaled and infect the respiratory tract, of course. Airborne respiratory transmission appears to be the dominant route.
  96.  
  97. https://www.pnas.org/content/117/26/14857
  98.  
  99. It can potentially land in the eyes, cause an eye infection, and spread systemically from there.
  100.  
  101. https://www.tandfonline.com/doi/full/10.1080/09273948.2020.1772313
  102.  
  103. It can possibly enter the nose, infect the olfactory nerve, and enter the brain through the olfactory bulb.
  104.  
  105. https://www.biorxiv.org/content/10.1101/2020.06.04.135012v1
  106.  
  107. It can potentially be transmitted via the oral-fecal route and infect the GI tract, as well.
  108.  
  109. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332911/
  110.  
  111. In the brain, it's possible that the virus homes in on the parts of the brain with the highest concentrations of ACE2; the cardiorespiratory center of the medulla (the Bötzinger complex), as well as the vasculature of the brain and the endothelial lining of the blood-brain barrier itself. These neurological manifestations of COVID-19 can occasionally lead to quite severe encephalitis and even rare seizures.
  112.  
  113. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199725/
  114.  
  115. https://pubs.acs.org/doi/10.1021/acschemneuro.0c00217
  116.  
  117. https://www.sciencedirect.com/science/article/pii/S0889159120306760?via%3Dihub
  118.  
  119. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346808/
  120.  
  121. https://hub.jhu.edu/2020/07/01/covid-19-mini-brain-models/
  122.  
  123. https://www.nature.com/articles/s41582-020-0398-3
  124.  
  125. https://www.biorxiv.org/content/10.1101/2020.06.15.150912v1
  126.  
  127. In the lungs, the disease attacks the blood vessels and the small capillaries of the alveoli, leading to inflammation of the small vessels of the lungs, pulmonary edema, and diffusion problems. It appears that this endotheliitis is the primary manifestation of a SARS-CoV-2 infection. The vascular endothelium is assaulted by a combination of severe inflammation and oxidative stress. This progresses to fibrosis and neutrophil infiltration of the lungs, and can even lead to hemorrhagic necrosis of the parenchyma of the lungs, multinucleated giant cell formation, coagulopathy, platelet depletion, migration of megakaryocytes into the tissues, and so forth. The furin cleavage sites on the S protein of SARS-CoV-2 promote a lot of cell-to-cell fusion, leading to tissues becoming basically unrecognizable.
  128.  
  129. https://academic.oup.com/eurheartj/article/41/32/3038/5901158
  130.  
  131. https://erj.ersjournals.com/content/55/4/2000607
  132.  
  133. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273129/
  134.  
  135. The pathology of COVID-19 itself is a mind-bending cascade of metabolic and hormonal factors. The interactome of all the related proteins would make for one very, very large flowchart. At its most basic level, the virus down-regulates ACE2 receptors while using them as its entry receptor. This, in turn, prevents Angiotensin II from being converted into Angiotensin 1-7, but it also prevents the inactivation of des-Arg9-bradykinin. It is similar to the effect of an ACE inhibitor drug, right down to the dry cough characteristic of long-term ACEi use.
  136.  
  137. This leads to a number of very undesirable phenomena in the vasculature of the lungs. Angiotensin II, in excess, activates a number of inflammatory and oxidative pathways:
  138.  
  139. https://www.nature.com/articles/1002101
  140.  
  141. NF-κB, NADPH oxidase, TNF-α, IL-6, MCP-1/CCL2, ICAM-1, VCAM-1, CD142, and PAI-1 are all stimulated by the over-activation of Angiotensin II Receptor Type 1 (AT1R). Also, the loss of ACE2 receptors leads to an excess of bradykinin and dysregulation of the Kallikrein-Kinin system. This, in turn, promotes a number of different things that contribute to the overall pathology of COVID-19.
  142.  
  143. https://www.nature.com/articles/s41577-020-0343-0
  144.  
  145. The excess Angiotensin II promotes RAAS dysregulation, aldosterone secretion, and hypokalemia. The subject loses much of their potassium through their kidneys.
  146.  
  147. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290402/
  148.  
  149. Excessive bradykinin release and inflammatory cytokines cause the endothelium to separate, exposing the basement membrane.
  150.  
  151. https://www.thailandmedical.news/news/covid-19-bradykinin-storm-hypothesis-gaining-stronghold-among-medical-community-and-offers-new-avenues-for-treatments-using-already-approved-drugs
  152.  
  153. https://www.the-scientist.com/news-opinion/is-a-bradykinin-storm-brewing-in-covid-19--67876
  154.  
  155. https://www.newscientist.com/article/2253987-we-are-finally-unravelling-the-mystery-of-what-causes-severe-covid-19/
  156.  
  157. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC408867/
  158.  
  159. The subject's blood enters a hypercoagulable state. The body tries desperately to wall-off the damage to the vascular endothelium. Many patients have D-dimer levels in excess of 2000 ng/ml, and some have D-dimer levels in excess of 20,000 ng/ml. Antiphospholipid syndrome and release of von Willebrand Factor have also been noted. Many ICU patients are meeting the criteria for disseminated intravascular coagulation, right before death.
  160.  
  161. https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30216-7/fulltext
  162.  
  163. https://www.hematologyadvisor.com/home/topics/thrombotic-disorders/multiple-organ-thrombi-present-in-covid19-autopsy-series/
  164.  
  165. https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30216-7/fulltext
  166.  
  167. https://www.nejm.org/doi/full/10.1056/NEJMc2007575
  168.  
  169. Superoxide free radicals are produced in very large amounts. Endothelial nitric oxide synthase (eNOS) function is reduced by a number of factors, such as the depletion of nicotinamide adenine dinucleotide phosphate and the virus's disruption of carbamoyl phosphate production and the urea cycle, leading to a paucity of the precursors to gaseous-state nitric oxide, which is necessary for many types of biological signaling and potentially has an antiviral effect on SARS-CoV-2 on its own (NO was noted to prevent the palmitoylation of the S protein of SARS-CoV, and this may also be true for SARS-CoV-2; NO down-regulation triggered by AT1R over-activation may allow SARS-CoV-2 to replicate with impunity, and restoring the normal balance of eNOS function may prevent this). Also, the superoxide that is produced can react with any available nitric oxide to form peroxynitrite, which is cytotoxic. See also; NO/ONOO- cycle disease, and eNOS uncoupling.
  170.  
  171. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229726/
  172.  
  173. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111989/
  174.  
  175. https://www.clinicaleducation.org/resources/reviews/how-can-we-cure-noonoo-cycle-diseases-a-review/
  176.  
  177. The lungs fill up with phagocytes. Neutrophils and monocyte-derived alveolar macrophages, attracted to the alveoli and its vasculature by all the chemoattractant release, begin fibrosing the lungs. Hyaline membrane formation occurs. Oxygen diffusion through the alveoli becomes very difficult.
  178.  
  179. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161085/
  180.  
  181. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102614/
  182.  
  183. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164679/
  184.  
  185. There is a possible disruption of iron metabolism. This may be caused by inflammation, but it is also possible that a loss of nitric oxide signaling plays a role.
  186.  
  187. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264936/
  188.  
  189. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC42500/
  190.  
  191. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC45567/
  192.  
  193. Viremia can spread SARS-CoV-2 through the bloodstream to other organs in the body, where it inflames the endothelial lining of blood vessels and starves organs of oxygen, eventually leading to sepsis, shock, multiple organ failure, and death.
  194.  
  195. https://www.medrxiv.org/content/10.1101/2020.08.25.20154252v2
  196.  
  197. COVID-19 has been observed to be more severe in people of Hispanic or especially African-American descent. African-Americans are hospitalized with COVID-19 at 4.7x the rate of caucasians. When one examines the action of the virus, a hypothesis presents itself. There are two related factors in play, and both of them have to do with oxidative stress.
  198.  
  199. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-race-ethnicity.html
  200.  
  201. First, COVID-19 morbidity and mortality is highly correlated with hypovitaminosis D, and hypovitaminosis D is more prevalent in people with higher melanin content in their skin (lower cholecalciferol production from UV light exposure).
  202.  
  203. https://www.uchicagomedicine.org/forefront/coronavirus-disease-covid-19/vitamin-d-deficiency-may-raise-risk-of-getting-covid19
  204.  
  205. https://www.medpagetoday.com/infectiousdisease/covid19/88456
  206.  
  207. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30268-0/fulltext
  208.  
  209. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376522/
  210.  
  211. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30183-2/fulltext
  212.  
  213. 41% of Americans have a Vitamin D deficiency, but over 80% of African-Americans are Vitamin D deficient.
  214.  
  215. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075634/
  216.  
  217. Higher circulating OH(25)D levels have a strong antioxidant effect, reducing the activity of NADPH oxidase. They also help regulate inflammation.
  218.  
  219. https://res.mdpi.com/d_attachment/nutrients/nutrients-12-00575/article_deploy/nutrients-12-00575.pdf
  220.  
  221. Second, African-Americans in particular have genetic differences in endothelial function that lead to lower levels of L-arginine available for eNOS, leading to a lower baseline level of nitric oxide production, which, in turn, may lead to more highly accelerated nitric oxide bioavailability depletion in COVID-19.
  222.  
  223. https://www.ahajournals.org/doi/10.1161/01.CIR.0000129087.81352.7A?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
  224.  
  225. These observations point to treatment possibilities that involve the modulation of NADPH oxidase or eNOS activity. For instance, one possibility that has not yet been explored is the use of apocynin to block NADPH oxidase activity and scavenge free radicals.
  226.  
  227. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812778/
  228.  
  229. https://www.hindawi.com/journals/jir/2019/9015292/
  230.  
  231. COVID-19 preys on people who have Metabolic Syndrome. Hypertension, diabetes, obesity, and chronic malnutrition from a high-fat, high-sucrose diet are all risk factors. The common characteristic that these conditions all possess is that the body tries to dilate blood vessels to reduce blood pressure to within the normal range, and it does this by increasing ACE2 protein expression. These conditions also cause a high baseline level of inflammation and oxidative stress that may be tipped into a lethal domain by the addition of the virus and its pathological processes.
  232.  
  233. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext
  234.  
  235. My assessment is that this pandemic and its effects appear to be as much the result of nutritional issues in industrialized nations as they are a failure of mitigation strategies. Diet, exercise, and supplementation with Vitamin D, NAC, NAD+, Citrulline, and Arginine may greatly enhance one's chances of survival, but this would require further study to test and verify the hypothesis. I, personally, have been topping off on my vitamins, just in case. If 40% of Americans are Vitamin D deficient, then a little supplementation can't hurt (although we don't want people panicking and gulping down whole bottles of Vitamin D and developing hypervitaminosis and hypercalcemia, obviously).
  236.  
  237. One of the main sources of Vitamin D in the American diet is fortified milk, and in a cruel twist of fate, the racial variations in lactose-intolerance mean that a large number of people cannot take advantage of this valuable source of vitamins without discomfort or illness. This disparity only amplifies the severity of the nutritional problem and makes the need for Vitamin D supplementation obvious.
  238.  
  239. https://intermountainhealthcare.org/blogs/topics/live-well/2017/07/lactose-intolerance/#:~:text=Estimates%20for%20lactose%20intolerance%20vary,they%20need%20for%20the%20day.
  240.  
  241. If it is true that nitric oxide has antiviral effects against SARS-CoV-2, and that Vitamin D helps reduce ROS and loss of NO bioavailability in patients, then there's a plausible mechanism whereby simple Vitamin D supplementation could reduce the morbidity and mortality of COVID-19. Accordingly, evidence is mounting that hypovitaminosis D increases the severity of COVID-19 by an order of magnitude.
  242.  
  243. https://www.homeceuconnection.com/blog/vitamin-d-levels-impact-covid-19-mortality-rates/
  244.  
  245. https://www.sciencedaily.com/releases/2020/05/200507121353.htm
  246.  
  247. https://www.youtube.com/watch?v=V8Ks9fUh2k8
  248.  
  249. SARS-CoV-2 is insidious. The virus suppresses the immune system quite profoundly, damaging both the innate and adaptive immune responses.
  250.  
  251. https://www.nature.com/articles/s41467-020-17665-9
  252.  
  253. https://www.nature.com/articles/s41423-020-0514-8
  254.  
  255. https://www.nature.com/articles/s41590-020-0782-6
  256.  
  257. https://www.medrxiv.org/content/10.1101/2020.03.27.20045427v1
  258.  
  259. There is also the possibility that SARS-CoV-2 has ADE, like Dengue, which would complicate the process of developing a safe, effective vaccine.
  260.  
  261. https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa518/5891764
  262.  
  263. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311339/
  264.  
  265. Even after the emergence of the bradykinin hypothesis of endothelial injury in COVID-19, there yet remain a few unanswered questions, such as the high serum ferritin levels and their precise cause (the iron troubles I mentioned earlier). High serum ferritin is correlated with inflammation. Nitric oxide levels and Endothelin-1 may play a role.
  266.  
  267. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194813/
  268.  
  269. https://www.tandfonline.com/doi/abs/10.1080/08880010601166447?scroll=top&needAccess=true&journalCode=ipho20
  270.  
  271. https://pubmed.ncbi.nlm.nih.gov/24549403/#:~:text=Serum%20ferritin%20is%20also%20a,a%20marker%20of%20cellular%20damage.
  272.  
  273. Excessive nitric oxide can also be counterproductive (it's a bit of a tightrope act):
  274.  
  275. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388708/
  276.  
  277. In summary, if someone has a diet rich in Vitamin D and dietary nitrate, and they don't have any underlying problems that up-regulate ACE2 like hypertension or diabetes, their chances of surviving COVID-19 appear to be very good. The CDC's guidance should be for people to exercise, lose weight, and incorporate more fish and vegetables into their diet to reduce their risk of death or severe injury from COVID-19, but given the widespread deficiencies in Vitamin D, supplementation wouldn't hurt, either. The widespread nutritional deficiencies in the US are partly due to a diet high in processed grains and other empty carbohydrates that are rich in energy but lacking in nutrients. The Russians were definitely onto something when they noted glutathione deficiency and uncontrolled production of ROS as a major pathological factor.
  278.  
  279. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263077/
  280.  
  281. The solution to this problem is a healthy metabolism and an antioxidant-rich diet.
  282.  
  283. Many of the puzzle pieces have fallen into place. The scientific community's understanding of this disease is far more advanced than it was at the outset. The course of COVID-19 is somewhat predictable, but the initial manifestations are highly variable. The typical course of the disease is about 5 days of incubation, followed by around 7 days of flu-like symptoms, and then about 10 to 12 days of hyper-inflammation, ARDS, and recovery or death. Some of those infected experience only flu-like symptoms and no hyper-inflammation. Others experience no symptoms at all.
  284.  
  285. There are a few antivirals that have been proposed. Remdesivir, Hydroxychloroquine, Kaletra, and Interferon beta, to name a few. Based on the data I've seen, Remdesivir is not very effective and potentially accelerates kidney failure in COVID-19, HCQ has issues with QT prolongation/arrhythmias and needs to be given very early to have any beneficial effects, and Kaletra is very hard on the liver. Interferon appears to be the most effective treatment.
  286.  
  287. https://www.synairgen.com/wp-content/uploads/2020/07/200720-Synairgen-announces-positive-results-from-trial-of-SNG001-in-hospitalised-COVID-19-patients.pdf
  288.  
  289. All antivirals need to be given to patients pretty much the moment they become symptomatic in order to be effective. The viral load tapers off to nothing by the end of the flu-like phase. Unfortunately, in practice, most patients are becoming hospitalized after they've been symptomatic for a week already (i.e. they're not seeking prompt medical care for what they assume is an ordinary flu). After that point, doctors are stuck using steroids like dexamethasone and monoclonal antibodies like tocilizumab to try and knock down the cytokine storm. Many of the severe and critical patients receive heparin for coagulopathy, but it's not very effective (the buildup of Angiotensin II promotes the release of a lot of Plasminogen Activator Inhibitor-1, for one thing, helping to sustain clotting). Many of the severe and critical patients end up having kidney trouble and requiring dialysis, but the filters clog up with clots. Also, cytokine reduction strategies using devices like CytoSorb are ineffective for the same reason; the device fills up with clots almost instantly, rendering it useless.
  290.  
  291. Early detection and screening, and the administering of antivirals at the first sign of symptoms, would greatly reduce the morbidity and mortality of COVID-19. Ultimately, I think this disease is actually quite treatable, with the appropriate protocols. Avoidance of intubation and treating the endotheliitis directly to try and restore diffusion of oxygen through the alveoli is paramount, but it can be difficult to accomplish this satisfactorily. Medical science has never really encountered an airborne vascular disease like this before. Some doctors aren't even sure whether or not COVID-19 causes pneumonia, or whether the ground-glass opacities visible on CT are a sign of wedge pulmonary embolism.
  292.  
  293. https://pubs.rsna.org/doi/full/10.1148/ryct.2020200277
  294.  
  295. You can't really treat endotheliitis very well with a ventilator. In fact, endotheliitis may weaken pulmonary blood vessels to such a degree that they become more susceptible to VILI. Ventilator-induced lung injury.
  296.  
  297. https://science.thewire.in/health/coronavirus-covid-19-ards-ventilators-vili-icu-high-flow-nasal-cannula/
  298.  
  299. The clinical trial situation is a mess. Very few proper placebo-controlled trials and very small sample sizes.
  300.  
  301. https://www.fiercebiotech.com/cro/bmj-nature-warn-against-sabotaging-covid-19-response-poor-and-chaotic-trials
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