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Archive for the ‘Immune-Mediation (independent immunopathology: lung and reticuloendothelial system)’ Category


Bradykinin Hypothesis: Potential Explanation for COVID-19

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 9/14/2020

First Randomized Trial Backs Safety of ACE and ARB Heart Drugs in COVID-19 Patients

BRACE CORONA trial presented in a Hot Line Session at ESC Congress 2020

September 8, 2020 – Heart patients hospitalized with COVID-19 (SARS-CoV-2) can safely continue taking angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), according to the BRACE CORONA trial presented in a Hot Line session at the virtual European Society of Cardiology (ESC) Congress 2020.[1]

ACE inhibitors and ARBs are commonly taken by heart patients to reduce blood pressure and to treat heart failure. There is conflicting observational evidence about the potential clinical impact of ACE inhibitors and ARBs on patients with COVID-19.[2] Select preclinical investigations have raised concerns about their safety in patients with COVID-19. Preliminary data hypothesize that renin-angiotensin-aldosterone system (RAAS) inhibitors could benefit patients with COVID-19 by decreasing acute lung damage and preventing angiotensin-II-mediated pulmonary inflammation.

Given the frequent use of these agents worldwide, randomized clinical trial evidence is urgently needed to guide the management of patients with COVID-19.

SOURCE

https://www.dicardiology.com/content/first-randomized-trial-backs-safety-ace-and-arb-heart-drugs-covid-19-patients

Related ACE and ARB Content Related to COVID-19:

ESC Council on Hypertension Says ACE-I and ARBs Do Not Increase COVID-19 Mortality

AHA Explains Severe COVID-19 is Closely Associated With Heart Issues

 

The Voice of Dr. Justin D. Pearlman, MD, PhD, FACC

Justin D. Pearlman, MD, PhD, FACC – Scientific Expert & Key Opinion Leader on Cardiovascular Diseases, Cardiac Imaging & Complex Diagnosis in Cardiology: Senior Editor & Author

The BRACE CORONA TRIAL compared outcomes for COVID19 patients previously on ACE inhibitor or ARB of holding the medication for a month, or not, and saw no significant benefit from withholding either class of medication. The basis for specific concern is the fact that the COVID19 virus utilizes ACE2 receptors for its invasion, and that disturbances in the renin-angiotensin and bradykinin levels and capillary leak have been observed with COVID19 infections. ACEI and ARB medications both modulate the renin angiotensin system, but with different impact on bradykinin levels. Changes in bradykinin levels cause for dry cough seen with ACE inhibitors like lisinopril that are not seen with angiotensin receptor blockers (ARB) such as Losartan. The absence of significant differences in outcome measures by holding either drug weakens the Jacobson’s bradykinin hypothesis based on a cascade of observations related to the ACE2 receptor and downstream effects. The new observations on safety of both ACEI and ARB weaken Jacobson’s hypothesis of a primary importance of renin angiotensin and bradykinin changes in the course and complications of COVID19 infection.

The ACE gene product degrades bradykinin. Jacobson’s bradykinin hypothesis suggested that the observations of capillary leak and disturbances in the renal angiotensin system may be prime factors rather than bystanders. Jacobson made strong statements from associations, but the lack of impact of stoppage of either ACE inhibitors or Angiotensin Receptor Blockers (ARB) argues that his observations are not major in determination of outcomes.

Bradykinin Hypothesis: Potential Explanation for COVID-19

The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2.

critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomesexplain many of the symptoms being observed in COVID-19.

Jacobson says, “What we’ve found is that the imbalance in the renin-angiotensin system (RAS) pathway that appeared to be present in Covid-19 patients could be responsible for constantly resensitizing bradykinin receptors. So, this imbalance in the RAS pathways will take the brakes off the bottom of the bradykinin pathway at the receptor level. In addition, the downregulation of the ACE gene in Covid-19 patients, which usually degrades bradykinin, is another key imbalance in the regulation of bradykinin levels. We have also observed that the key negative regulator at the top of the bradykinin pathway is dramatically down-regulated. Thus, you likely have an increase in bradykin production as well, stopping many of the braking mechanisms usually in place, so the bradykinin signal spirals out of control.”

The bradykinin hypothesis also extends to many of Covid-19’s effects on the heart. About one in five hospitalized Covid-19 patients have damage to their hearts, even if they never had cardiac issues before. Some of this is likely due to the virus infecting the heart directly through its ACE2 receptors. But the RAS also controls aspects of cardiac contractions and blood pressure. According to the researchers, bradykinin storms could create arrhythmias and low blood pressure, which are often seen in Covid-19 patients.

“the pathology of Covid-19 is likely the result of Bradykinin Storms rather than cytokine storms,” which had been previously identified in Covid-19 patients, but that “the two may be intricately linked.”

According to Jacobson and his team, MRI studies in France revealed that many Covid-19 patients have evidence of leaky blood vessels in their brains.

bradykinin would indeed be likely to increase the permeability of the blood-brain barrier. In addition, similar neurological symptoms have been observed in other diseases that result from an excess of bradykinin.”

Increased bradykinin levels could also account for other common Covid-19 symptoms. ACE inhibitors — a class of drugs used to treat high blood pressure — have a similar effect on the RAS system as Covid-19, increasing bradykinin levels. In fact, Jacobson and his team note in their paper that “the virus… acts pharmacologically as an ACE inhibitor” — almost directly mirroring the actions of these drugs.

SOURCE

https://elifesciences.org/articles/59177?utm_source=Unknown+List&utm_campaign=7a5785d58d-EMAIL_CAMPAIGN_2020_07_27_02_37&utm_medium=email&utm_term=0_-7a5785d58d-

Potential therapeutic development path is to

  • repurpose existing FDA approved drugs such as Danazol, Stanasolol, Icatibant, Ecallantide, Berinert, Cynryze, Haegarda, etc.. to reduce the amount of bradykinin signaling to prevent the escalation of the bradykinin storm.
  • Partnerships with pharmaceutical companies and clinical research are needed to design and implement the right clinical trials to see how these types of treatments can be applied.
  • Systems biology perspective and think that attempts to inhibit the virus itself will also probably require a combinatorial strategy it’s possible that we will need a combinatorial approach to therapies both on the human side and on the viral side
  • Other compounds could treat symptoms associated with bradykinin storms. Hymecromone, for example, could reduce hyaluronic acid levels, potentially stopping deadly hydrogels from forming in the lungs. And timbetasin could mimic the mechanism that the researchers believe protects women from more severe Covid-19 infections

https://www.forbes.com/sites/cognitiveworld/2020/08/05/your-lungs-can-fill-up-with-jell-o-scientists-discover-a-new-pathway-for-covid-19-inflammatory-response/#7a80ff4c24be

 

A Supercomputer Analyzed Covid-19 — and an Interesting New Theory Has Emerged

A closer look at the Bradykinin hypothesis

Thomas Smith Sep 1, 2020

Earlier this summer, the Summit supercomputer at Oak Ridge National Lab in Tennessee set about crunching data on more than 40,000 genes from 17,000 genetic samples in an effort to better understand Covid-19. Summit is the second-fastest computer in the world, but the process — which involved analyzing 2.5 billion genetic combinations — still took more than a week.

When Summit was done, researchers analyzed the results. It was, in the words of Dr. Daniel Jacobson, lead researcher and chief scientist for computational systems biology at Oak Ridge, a “eureka moment.” The computer had revealed a new theory about how Covid-19 impacts the body: the bradykinin hypothesis. The hypothesis provides a model that explains many aspects of Covid-19, including some of its most bizarre symptoms. It also suggests 10-plus potential treatments, many of which are already FDA approved. Jacobson’s group published their results in a paper in the journal eLife in early July.

According to the team’s findings, a Covid-19 infection generally begins when the virus enters the body through ACE2 receptors in the nose, (The receptors, which the virus is known to target, are abundant there.) The virus then proceeds through the body, entering cells in other places where ACE2 is also present: the intestines, kidneys, and heart. This likely accounts for at least some of the disease’s cardiac and GI symptoms.

https://elemental.medium.com/a-supercomputer-analyzed-covid-19-and-an-interesting-new-theory-has-emerged-31cb8eba9d63

Researchers Use Supercomputers To Discover New Pathway For Covid-19 Inflammation

COGNITIVE WORLD

A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

  1. Michael R Garvin
  2. Christiane Alvarez
  3. J Izaak Miller
  4. Erica T Prates
  5. Angelica M Walker
  6. B Kirtley Amos
  7. Alan E Mast
  8. Amy Justice
  9. Bruce Aronow
  10. Daniel JacobsonIs a corresponding author
  1. Oak Ridge National Laboratory, Biosciences Division, United States
  2. University of Tennessee Knoxville, The Bredesen Center for Interdisciplinary Research and Graduate Education, United States
  3. University of Kentucky, Department of Horticulture, United States
  4. Versiti Blood Research Institute, Medical College of Wisconsin, United States
  5. VA Connecticut Healthcare/General Internal Medicine, Yale University School of Medicine, United States
  6. University of Cincinnati, United States
  7. Biomedical Informatics, Cincinnati Children’s Hospital Research Foundation, United States
  8. University of Tennessee Knoxville, Department of Psychology, Austin Peay Building, United States

Abstract

Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2.Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.

https://elifesciences.org/articles/59177?utm_source=Unknown+List&utm_campaign=7a5785d58d-EMAIL_CAMPAIGN_2020_07_27_02_37&utm_medium=email&utm_term=0_-7a5785d58d-

Short Report 

https://www.forbes.com/sites/cognitiveworld/2020/08/05/your-lungs-can-fill-up-with-jell-o-scientists-discover-a-new-pathway-for-covid-19-inflammatory-response/#7a80ff4c24be

A hypothesized role for dysregulated bradykinin signaling in COVID‐19 respiratory complications

1 Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit MI, USA,
2 College of Health and Human Services, Eastern Michigan University, Ypsilanti MI, USA,
Joseph A. Roche, ude.enyaw@ehcor.hpesoj.
corresponding authorCorresponding author.
*Correspondence
Joseph A. Roche, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA.
Email: ude.enyaw@ehcor.hpesoj,

Abstract

As of April 20, 2020, over time, the COVID‐19 pandemic has resulted in 157 970 deaths out of 2 319 066 confirmed cases, at a Case Fatality Rate of ~6.8%. With the pandemic rapidly spreading, and health delivery systems being overwhelmed, it is imperative that safe and effective pharmacotherapeutic strategies are rapidly explored to improve survival. In this paper, we use established and emerging evidence to propose a testable hypothesis that, a vicious positive feedback loop of des‐Arg(9)‐bradykinin‐ and bradykinin‐mediated inflammation → injury → inflammation, likely precipitates life threatening respiratory complications in COVID‐19. Through our hypothesis, we make the prediction that the FDA‐approved molecule, icatibant, might be able to interrupt this feedback loop and, thereby, improve the clinical outcomes. This hypothesis could lead to basic, translational, and clinical studies aimed at reducing COVID‐19 morbidity and mortality.

Keywords: bradykinin, bradykinin receptor, coronavirus, icatibant, inflammation, injury

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267506/

 

 

Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome

Frank L van de Veerdonk1*, Mihai G Netea1,2, Marcel van Deuren1,

Jos WM van der Meer1, Quirijn de Mast1, Roger J Bru¨ggemann3,

Hans van der Hoeven4

van de Veerdonk et al. eLife 2020;9:e57555. DOI: https://doi.org/10.7554/eLife.57555 1 of 9

Abstract

COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.

 

Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach

Frank L. van de Veerdonk1*, Mihai G. Netea1,2, Marcel van Deuren1, Jos W.M. van der Meer1, Quirijn de Mast1, Roger J. Brüggemann3, Hans van der Hoeven4

doi:10.20944/preprints202004.0023.v1

Abstract

Most striking observations in COVID-19 patients are the hints on pulmonary edema (also seen on CT scans as ground glass opacities), dry cough, fluid restrictions to prevent more severe hypoxia, the huge PEEP that is needed while lungs are compliant, and the fact that antiinflammatory therapies are not powerful enough to counter the severity of the disease. We propose that the severity of the disease and many deaths are due to a local vascular problem due to activation of B1 receptors on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2, a cell membrane bound molecule with enzymatic activity that next to its role in RAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). In contrast to bradykinin receptor 2 (B2), the B1 receptor on endothelial cells is upregulated by proinflammatory cytokines. Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Angioedema is likely a feature already early in disease, and might explain the typical CT scans and the feeling of people that they drown. In some patients, this is followed by a clinical worsening of disease around day 9 due to the formation antibodies directed against the spike (S)-antigen of the corona-virus that binds to ACE2 that could contribute to disease by enhancement of local immune cell influx and proinflammatory cytokines leading to damage. In parallel, inflammation induces more B1 expression, and possibly via antibody-dependent enhancement of viral infection leading to continued ACE2 dysfunction in the lung because of persistence of the virus. In this viewpoint we propose that a bradykinin-dependent local lung angioedema via B1 and B2 receptors is an important feature of COVID-19, resulting in a very high number of ICU admissions. We propose that blocking the B1 and B2 receptors might have an ameliorating effect on disease caused by COVID-19. This kinin-dependent pulmonary edema is resistant to corticosteroids or adrenaline and should be targeted as long as the virus is present. In addition, this pathway might indirectly be responsive to anti-inflammatory agents or neutralizing strategies for the anti-S-antibody induced effects, but by itself is likely to be insufficient to reverse all the pulmonary edema. Moreover, we provide a suggestion of how to ventilate in the ICU in the context of this hypothesis.

 

Emerging Pandemic Diseases: How We Got to COVID-19

David M. Morens1,* and Anthony S. Fauci1

1Office of the Director, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

*Correspondence: dm270q@nih.gov

https://doi.org/10.1016/j.cell.2020.08.021

SUMMARY

Infectious diseases prevalent in humans and animals are caused by pathogens that once emerged from other animal hosts. In addition to these established infections, new infectious diseases periodically emerge. In extreme cases they may cause pandemics such as COVID-19; in other cases, dead-end infections or smaller epidemics result. Established diseases may also re-emerge, for example by extending geographically or by becoming more transmissible or more pathogenic. Disease emergence reflects dynamic balances and imbalances, within complex globally distributed ecosystems comprising humans, animals, pathogens, and the environment. Understanding these variables is a necessary step in controlling future devastating disease emergences.

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Why Blood Clots Are a Major Problem in Severe COVID-19

Reporter: Aviva Lev-Ari, PhD, RN

 

  • Clotting in uninjured blood vessels is a common occurrence in hospital patients, especially those in the intensive care unit.

  • In a July report in the journal Blood, Al-Samkari and colleagues found that nearly 10 percent of 400 people hospitalized for Covid-19 developed clots. In a February report by researchers in China, about 70 percent of people who died of Covid-19 had widespread clotting, while few survivors did.
  • people who died of Covid-19 were nine times as likely to be speckled with tiny clots as those of people who died of influenza
  • SARS-CoV-2 infects and damages the cells lining blood vessels, it could expose the tissue underneath
  • clotting results from inflammation. And here, many experts are eyeing a set of proteins called the complement system
  • These proteins, known collectively as complement, attack invaders and call in other parts of the immune system to assist. They also can activate platelets and promote clotting.
  • Claudia Kemper1,2,3 said “complementologists think that this is a massive part of the disease”  signs of complement activity in the lungs and livers of people who died from Covid-19
  • Laurence found several active complement proteins in the skin and blood vessels of his early Covid-19 clotting cases
  • a New York team found that patients were more likely to become very ill and die if they had a history of clotting or bleeding, or if they had macular degeneration, which can indicate complement problems.
  • Genes involved in complement and clotting responses were more active when the virus was present in patients’ nasal swabs.
  • immune element may promote clotting in severe Covid-19 cases: an overreaction called a cytokine storm, in which the body releases an excess of inflammation-promoting cytokine molecules.
  • Body’s response in need of control: (1) control the clotting, (2) control the inflammation, (2) control the complement pathway in tandem with antiviral Remdesivir that controls the viral replication thus the viral load.
  • Balance the risk of clotting with the danger of bleeding (bleeds into the digestive system for these patients, but they may also hemorrhage in the lungs, brain or spots where medical devices pierce the skin)
  • Dosage of blood thinners is debated – 40 Studies found for: anticoagulation | Covid19
    Also searched for COVID and SARS-CoV-2See Search Details
  • there is no evidence that people with less severe Covid-19, who do not require hospitalization, should take blood thinners or aspirin to ward off clots.
  • Management of Clotting: Argatroban, for example, is a Food and Drug Administration-approved anticoagulant that interferes with thrombin, an element of the clotting cascade. Eculizumab, which blocks one of the complement proteins, is approved for certain inflammatory conditions.
  • Clinical judgement is used in light of lack of evidence

 

SOURCES

Why Blood Clots Are a Major Problem in Severe Covid-19

SMITHSONIANMAG.COM

https://www.smithsonianmag.com/science-nature/why-blood-clots-are-major-problem-severe-covid-19-180975678/

Complement and the Regulation of T Cell Responses

Annual Review of Immunology

Vol. 36:309-338 (Volume publication date April 2018)
https://doi.org/10.1146/annurev-immunol-042617-053245

Complement Dysregulation and Disease: Insights from Contemporary Genetics

M. Kathryn Liszewski,1 Anuja Java,2

Elizabeth C. Schramm,3 and John P. Atkinson1

1Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110; email: j.p.atkinson@wustl.edu

2Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

3Serion Inc., St. Louis, Missouri 63108

 

Keywords

atypical hemolytic uremic syndrome, age-related macular degeneration,

alternative complement pathway, C3 glomerulopathies, factor H, CD46,

factor I, C3, factor B

Abstract

The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system’s components are engaged in its regulation. An emerging theme over the past decade is that variations in these inhibitors predispose to two scourges of modern humans. One, occurring most often in childhood, is a rare but deadly thrombomicroangiopathy called atypical hemolytic uremic syndrome. The other, age-related macular degeneration, is the most common form of blindness in the elderly. Their seemingly unrelated clinical presentations and pathologies share the common theme of overactivity of the complement system’s alternative pathway. This review summarizes insights gained from contemporary genetics for understanding how dysregulation of this powerful innate immune system leads to these human diseases.

CONCLUSIONS AND PERSPECTIVES

Over the last decade, a remarkable advance has been the elucidation of the role of mutations in complement regulators and components in aHUS, AMD, and C3G. Next-generation sequencing has led theway to these discoveries, but functional assessments are the critical factors in definitively associating pathogenesis with genetic variants.

Most exciting has been the development and approval by the FDA of the monoclonal antibody, eculizumab, as the new standard of care for treatment of aHUS. Challenges remain, however because eculizumab is costly and the duration of treatment remains uncertain and warrants further prospective studies. The use of eculizumab in C3G should also be prospectively addressed.

Furthermore, given the increasing number of mutations in the complement regulatory proteins identified in aHUS and C3G and the heterogeneity in the mechanisms leading to dysregulation of the AP, there is a need for further assessment of the genetic variants of unknown significance. As yet, no complement inhibitor has been approved to treat AMD.

These analyses coupled with the anticipated new developments of complement therapeutics will help establish patient-tailored therapies based on each patient’s specific alteration. The future holds much promise for the further delineation of complement-disease associations and for novel complement-targeted therapeutic agents.

SOURCE

Annu. Rev. Pathol. Mech. Dis. 2017. 12:25–52

https://www.annualreviews.org/doi/10.1146/annurev-pathol-012615-044145

 

 

Other related articles published in this Open Access Online Scientific Journal include the following: 

 

Is SARS-COV2 Hijacking the Complement and Coagulation Systems?

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/08/04/is-sars-cov2-hijacking-the-complement-and-coagulation-systems/

 

New Etiology for COVID-19: Death results from Immune-Mediation (virus-independent immunopathology: lung and reticuloendothelial system) vs Pathogen-Mediation causing Organ Dysfunction & Hyper-Inflammation – Immunomodulatory Therapeutic Approaches (dexamethasone)

Curators: Stephen J. Williams and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/07/12/new-etiology-for-covid-19-death-results-from-immune-mediation-virus-independent-immunopathology-lung-and-reticuloendothelial-system-vs-pathogen-mediation-causing-organ-dysfunction-hyper-infl/

Corticosteroid, Dexamethasone Improves Survival in COVID-19: Deaths reduction by 1/3 in ventilated patients and by 1/5 in other patients receiving oxygen only

Reporter: Aviva Lev-Ari, PhD, RN – bold face and color fonts added

https://pharmaceuticalintelligence.com/2020/06/27/corticosteroid-dexamethasone-improves-survival-in-covid-19-deaths-reduction-by-1-3-in-ventilated-patients-and-by-1-5-in-other-patients-receiving-oxygen-only/

SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19

Reporter: Aviva Lev-Ari, PhD, RN – Bold face and colors are my addition

https://pharmaceuticalintelligence.com/2020/06/01/sar-cov-2-is-probably-a-vasculotropic-rna-virus-affecting-the-blood-vessels-endothelial-cell-infection-and-endotheliitis-in-covid-19/

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Thymic Dysfunction and Atrophy in COVID-19 Disease Complicated by Inflammation, Malnutrition and Cachexia

Reporter: Aviva Lev-Ari, PhD, RN

Kate Chiang

Charak Foundation; Applied Medical Technologies LLC

Kamyar Kalantar-Zadeh

University of California Irvine

Ajay Gupta

University of California Irvine

Date Written: July 13, 2020

Abstract

The current COVID-19 pandemic sweeping across developing countries is putting millions at risk of protein-energy malnutrition by pushing them into poverty and disrupting the global food supply chain. COVID-19 disease and protein-energy malnutrition are both known to cause immune dysfunction. The objective of this review is to highlight the known pathogenetic mechanisms underlying immune dysfunction in COVID-19 disease and malnutrition, and thereby identify preventive and therapeutic interventions that would help limit and contain the global health impact of this pandemic. Severe COVID-19 disease is characterized by dysregulation of myeloid compartments and lymphopenia. Lymphopenia is often protracted and outlasts the cytokine storm, suggesting underlying thymic dysfunction or involution. The thymus is considered a barometer of malnutrition, and leptin deficiency induced by protein-energy malnutrition can lead to thymic dysfunction and atrophy. Immune dysfunction in COVID-19 disease and malnutrition may be further increased by comorbidities including zinc and vitamin deficiencies, hyperinflammation, and stress. Thymic dysfunction or involution, especially in children, can potentially slow the recovery from COVID-19 disease and increase the risk of other infections. National governments and international organizations including WHO, World Food Program, and UNICEF should institute measures to ensure provision of food including micronutrients for the poor, thereby mitigating the health impact of the COVID-19 pandemic, especially amongst children in developing countries.

 

Note: Conflict of Interest: AG has filed provisional patents for use of Ramatroban as an immunotherapy to treat COVID-19 infection. (Gupta, A. Use of Ramatroban as a therapeutic agent for prevention and treatment of viral infections including COVID-Application no. 63/003,286 filed on March 31, 2020; and Gupta A. Use of a DP2 antagonist such as Ramatroban as a therapeutic agent for treatment of adults with viral infection including COVID-19 Provisional Patent Application no. 63/005,205 filed on April 3, 2020). Other authors have not declared conflict of interest.

Funding: None to declare

Keywords: COVID-19, protein-calorie malnutrition, thymic atrophy, inflammation, zinc, cachexia, lymphopenia, leptin, stress, glucocorticoids

 Suggested Citation

Chiang, Kate and Kalantar-Zadeh, Kamyar and Gupta, Ajay, Thymic Dysfunction and Atrophy in COVID-19 Disease Complicated by Inflammation, Malnutrition and Cachexia (July 13, 2020). Available at SSRN: https://ssrn.com/abstract=3649836 or http://dx.doi.org/10.2139/ssrn.3649836

Kate Chiang

Charak Foundation ( email )

12551 Downey Ave
Downey, CA 90242
United States
5627020617 (Phone)

Applied Medical Technologies LLC ( email )

2505 Seascape Drive
Las Vegas, NV NV 89128
United States
5624126259 (Phone)
89128 (Fax)

Kamyar Kalantar-Zadeh

University of California Irvine ( email )

Division of Nephrology, University of California I
101 City Drive South, City Tower, Suite 400-ZOT;40
Orange, CA California 92868-3217
United States
7144565142 (Phone)

Ajay Gupta (Contact Author)

University of California Irvine ( email )

Division of Nephrology, University of California I
101 City Drive South, City Tower, Suite 400-ZOT;40
Orange, CA California 92868-3217
United States
5624197029 (Phone)
92868-3217 (Fax)

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Contagious

We are in the midst of a pandemic that is impacting people and society in ways that are hard to grasp. The most apparent impact is on physical health. It also effects our attitudes in society, our economy and our cultural life. Throughout history, humanity has had to face the challenge of understanding, managing and fighting viruses.

In the exhibition Contagious we are highlighting Nobel Prize-awarded researchers who have expanded our knowledge about viruses, mapped our immune system and developed vaccines. We also examine the perspectives from Literature and Economics Laureates about the impact of epidemics on life and society. Visit us at the museum or on these pages.

Museums have an important role to play in times of crisis, since they can help people tackle existential questions and provide a broader context. The Nobel Museum is about ideas that have changed the world. The Nobel Prize points to the ability of humans to find solutions to difficult challenges that we face time and time again. It is a source of hope, even in the midst of the crisis.

SOURCE

Nobel Prize Museum

https://nobelprizemuseum.se/en/whats-on/contagious/?utm_content=contagious_text

Coronavirus

On March 11 this year, the World Health Organization announced that the spread of the coronavirus should be classified as a pandemic, that is “an infectious disease that spreads to large parts of the world and affects a large proportion of the population of each country”. Today, nobody knows how many will die in this pandemic, or when, or if, we can have a vaccine against the disease.

SARS-CoV-2, or Severe acute respiratory syndrome coronavirus 2, is an RNA virus from the family coronavirus that causes the respiratory disease covid-19.

The virus was detected at the end of last year in the Wuhan sub-province of China, and in most cases causes milder disease symptoms that disappear within two weeks. But sometimes, especially in certain groups such as the elderly and people with certain other underlying illnesses, the infection becomes more severe and can in some cases lead to death.

The virus is believed to have zoonotic origin, that is, it has been transmitted to humans from another animal. Where the origin of the disease comes from, that is to say from which host animal the virus originates, is still unknown. However, the virus has close genetic similarity to a corona virus carried by some bats, which might indicate where the virus comes from.

This model shows the SARS-CoV-2 virus, which causes the illness covid-19. The globe-shaped envelope has a membrane of fat-like substances. Inside the envelope are proteins bound to RNA molecules, that contain the virus’s genes. Short spikes of proteins and longer spikes of glycoprotein stick out of the envelope and attach to receptors on the surface of attacked cells. The spikes, which are bigger at the top, give the virus its appearance reminiscent of the Sun’s corona. This where the coronavirus’s name comes from.

Testing is an important tool for tracking and preventing the spread of infection during an epidemic.

One type of test looks at if a person is infected by looking for traces of the virus’s RNA genetic material. The test is taken using a swab stick inserted into the throat. The small amounts of RNA or DNA that attach to the swab are analyzed using the PCR technique, which was invented by Kary Mullis in 1983. Ten years later he was awarded the Nobel Prize in Chemistry.

Another type of test looks for antibodies to the virus in the blood. This indicates that the person has had the disease.

https://nobelprizemuseum.se/en/coronavirus/

The first virus ever discovered

We have understood since the 19th century that many diseases are caused by microscopic bacteria that cannot be seen by the naked eye. It turned out that there were even smaller contagions: viruses. Research on viruses has been recognized with several Nobel Prizes.

https://nobelprizemuseum.se/en/the-first-virus-ever-discovered/

Spanish flu

The worst pandemic of the 20th century was the Spanish flu, which swept across the world 1918–1920.

The Spanish flu was caused by an influenza virus. American soldiers at military facilities at the end of World War I were likely an important source of its spread in Europe. The war had just ended, and the pandemic claimed even more lives than the war. Between 50 and 100 million people died in the pandemic.

The Red Cross, an international aid organization, which received the Nobel Peace Prize for its efforts during the war, also took part in fighting the Spanish flu. International Committee of the Red Cross received the prize in 1917, 1944 and 1963.

This photo shows personnel from the Red Cross providing transportation for people suffering from the Spanish flu in St. Louis, Missouri in the United States.

https://nobelprizemuseum.se/en/spanish-flu/

Polio

Polio is an illness that often affects children and young people and that can lead to permanent paralysis.

Polio is a highly infectious RNA virus belonging to the genus Enterovirus. The virus only infects humans and enters the body via droplets such as sneezing and coughing, or through contact with infected people’s feces. Usually, polio infects our respiratory and intestinal tract, but sometimes the virus spreads to the spinal cord and can then cause paralysis. The virus mainly affects children, but most of those infected show no or very mild symptoms.

Vaccines are a way to help our immune system fight viruses. The immune system is the body’s defence mechanism against attacks from viruses and bacteria. A number of Nobel Laureates have researched the immune system and contributed to the development of vaccines.

Hepatitis B

The virus can infect people without them becoming sick. Discoveries in the 1960s enabled both vaccines and tests to prevent the spread.

Hepatitis B can infect humans and apes, and is most common in West Africa and in sub-Saharan Africa. The disease also occurs in the rest of Africa, as well as in areas from the Caspian Sea through to China and Korea and further down to Southeast Asia.

Baruch Blumberg discovered the virus behind hepatitis B and developed a vaccine against the disease.

There are many varieties of hepatitis, or jaundice, that cause inflammation in the liver. When studying blood proteins from people from different parts of the world at the end of the 1960s, Baruch Blumberg unexpectedly discovered an infectious agent for hepatitis B. He showed that the infectious agent was linked to a virus of previously unknown type. The virus can infect people without them becoming sick. The discoveries enabled both vaccines and tests to prevent the spread through blood transfusions.

Baruch Blumberg was awarded the Nobel Prize in Physiology or Medicine 1976. He has summarized what the Nobel Prize meant to him.

https://nobelprizemuseum.se/en/hepatitis-b/

Yellow fever

Each year, Yellow fever causes about 30,000 deaths. The vaccine against yellow fever was produced in the 1930s. A work awarded the Nobel Prize.

Yellow fever is a serious disease caused by a virus that is spread by mosquitos in tropical areas of Africa and South America.

Each year, Yellow fever causes about 200,000 infections and 30,000 deaths. About 90% of the cases occur in Africa. The disease is common in warm, tropical climates such as South America and Africa, but it is not found in Asia.

You may think that the number of people infected would be decreasing, but since the 1980s the number of yellow fever cases has unfortunately increased. This is believed to be due to the fact that more and more people are living in cities, that we are traveling more than before, and an increased climate impact.

Since there is no cure for the disease, preventive vaccination is a very important measure. Max Theiler successfully infected mice with a virus in the 1930s, which opened the door to more in-depth studies. When the virus was transferred between mice, a weakened form of the virus was created that gave monkeys immunity. In 1937, Theiler was able to develop an even weaker version of the virus. This version could be used as a vaccine for people.

Max Theiler was awarded the Nobel Prize in Physiology or Medicine in 1951.

https://nobelprizemuseum.se/en/yellow-fever/

HIV/AIDS

In the early 1980s, reports began to emerge about young men that suffered from unusual infections and cancers that normally only affect patients with weakened immune systems. It turned out to be a previously unknown epidemic, HIV, which spread rapidly across the world.

HIV, which is an abbreviation of human immunodeficiency virus, is a sexually transmitted retrovirus that attacks our immune system. An untreated infection eventually leads to AIDS, or acquired immune deficiency syndrome. In 2008, French scientists Luc Montagnier and Françoise Barré-Sinoussi were awarded the Nobel Prize in Physiology or Medicine for the detection of human immunodeficiency virus.

Watch the interview where Françoise Barré-Sinoussi talks about what it is like to meet patients affected by the virus she discovered.

https://nobelprizemuseum.se/en/hiv-aids/

 

Viruses captured in photos

Viruses are incredibly small and cannot be seen in normal microscopes.

The electron microscope, which was invented by Ernst Ruska and Max Knoll in 1933, made it possible to take pictures of much smaller objects than was previously possible. Ernst Ruska’s brother, Helmut Ruska, was a doctor and biologist, and used early electron microscopes to make images of viruses and other small objects. The tobacco mosaic virus was the first virus captured on film. The development of the electron microscope has enabled increasingly better images to be taken.

Ernst Ruska was awarded the 1986 Nobel Prize in Physics together with Gerd Binnig and Heinrich Röhrer, who developed the scanning electron microscope.

Read more about Ernst Ruska – his life and research. https://www.nobelprize.org/prizes/physics/1986/ruska/facts/

https://nobelprizemuseum.se/en/viruses-captured-in-photos/

 

Epidemics and literature

When epidemics and pandemics strike the world, it isn’t just the physical health of people that are impacted but also ways of life, thoughts and feelings. Nobel Laureates in literature have been effected by epidemics and written about life under real and fictive epidemics.

The coronavirus crisis has had a dramatic impact on our lives and our view of our lives. Olga Tokarczuk is one of the authors who has reflected on this.

Tokarczuk argues that the coronavirus has swept away the illusion that we are the masters of creation and that we can do anything since the world belongs to us. She wonders if the pandemic has forced us into a slower, more natural rhythm in life, but also worries about how it may increase distrust of strangers and worsen inequality among people.

Orhan Pamuk has worked for many years on a novel about a bubonic plague epidemic that struck primarily Asia in 1901. The coronavirus crisis has caused him to consider the similarities between the ongoing pandemic and past epidemics throughout history.

He sees several recurring behaviors when epidemics strike: denial and false information, distrust of individuals belonging to other groups, and theories about a malicious intent behind the pandemic. But epidemics also remind us that we are not alone and allow us to rediscover a sense of solidarity. He writes in The New York Times.

https://nobelprizemuseum.se/en/epidemics-and-literature/

Economics Laureates on the current pandemic

Pandemics have wide-ranging impacts on the economy. Paul Romer and Paul Krugman are two economists who have been active in the public discourse during the coronavirus crisis.

Paul Romer has expressed concerns about the pandemic’s effects on the economy but is optimistic about the possibilities of technology. He supports widespread testing. Those who are infected have to stay home for two weeks while others can work and take part in other ways in society.

Paul Romer was awarded the prize “for integrating technological innovations into long-run macroeconomic analysis.” Paul Romer has demonstrated how knowledge can function as a driver of long-term economic growth. He showed how economic forces govern the willingness of firms to produce new ideas.

His thoughts are developed in his lecture during the Nobel Week 2018.

https://nobelprizemuseum.se/en/economics-laureates-on-the-current-pandemic/

 

Other SOURCE

https://www.nobelprize.org/

 

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Study with important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection

Reporter: Aviva Lev-Ari, PhD, RN

Serological Testing WordCloud

Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection

Jeffrey SeowCarl GrahamBlair MerrickSam AcorsKathryn J.A. SteelOliver HemmingsAoife O’BryneNeophytos KouphouSuzanne PickeringRui GalaoGilberto BetancorHarry D WilsonAdrian W SignellHelena WinstoneClaire KerridgeNigel TempertonLuke SnellKaren BisnauthsingAmelia MooreAdrian GreenLauren MartinezBrielle StokesJohanna HoneyAlba Izquierdo-BarrasGill ArbaneAmita PatelLorcan OConnellGeraldine O HaraEithne MacMahonSam DouthwaiteGaia NebbiaRahul BatraRocio Martinez-NunezJonathan D. EdgeworthStuart J.D. NeilMichael H. MalimKatie Doores

Abstract

Antibody (Ab) responses to SARS-CoV-2 can be detected in most infected individuals 10-15 days following the onset of COVID-19 symptoms. However, due to the recent emergence of this virus in the human population it is not yet known how long these Ab responses will be maintained or whether they will provide protection from re-infection. Using sequential serum samples collected up to 94 days post onset of symptoms (POS) from 65 RT-qPCR confirmed SARS-CoV-2-infected individuals, we show seroconversion in >95% of cases and neutralizing antibody (nAb) responses when sampled beyond 8 days POS. We demonstrate that the magnitude of the nAb response is dependent upon the disease severity, but this does not affect the kinetics of the nAb response. Declining nAb titres were observed during the follow up period. Whilst some individuals with high peak ID50 (>10,000) maintained titres >1,000 at >60 days POS, some with lower peak ID50 had titres approaching baseline within the follow up period. A similar decline in nAb titres was also observed in a cohort of seropositive healthcare workers from Guy′s and St Thomas′ Hospitals. We suggest that this transient nAb response is a feature shared by both a SARS-CoV-2 infection that causes low disease severity and the circulating seasonal coronaviruses that are associated with common colds. This study has important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection.

SOURCE

https://www.medrxiv.org/content/10.1101/2020.07.09.20148429v1

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New Etiology for COVID-19: Death results from Immune-Mediation (virus-independent immunopathology: lung and reticuloendothelial system) vs Pathogen-Mediation causing Organ Dysfunction & Hyper-Inflammation – Immunomodulatory Therapeutic Approaches (dexamethasone)

Curators: Stephen J. Williams and Aviva Lev-Ari, PhD, RN

 

  • State of Science on 7/21/2020

New Etiology for COVID-19: Death results from Immune-Mediation (virus-independent immunopathology: lung and reticuloendothelial system) vs Pathogen-Mediation causing Organ Dysfunction & Hyper-Inflammation – Immunomodulatory Therapeutic Approaches (dexamethasone)

Curators: Stephen J. Williams and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/07/12/new-etiology-for-covid-19-death-results-from-immune-mediation-virus-independent-immunopathology-lung-and-reticuloendothelial-system-vs-pathogen-mediation-causing-organ-dysfunction-hyper-infl/

  • State of Science on 5/19/2020

RNA from the SARS-CoV-2 virus taking over the cells it infects: Virulence – Pathogen’s ability to infect a Resistant Host: The Imbalance between Controlling Virus Replication versus Activation of the Adaptive Immune Response

Curator: Aviva Lev-Ari, PhD, RN – I added colors and bold face

Highlights

  • SARS-CoV-2 infection induces low IFN-I and -III levels with a moderate ISG response
  • Strong chemokine expression is consistent across in vitroex vivo, and in vivo models
  • Low innate antiviral defenses and high pro-inflammatory cues contribute to COVID-19

Highlights

  • ORF3b of SARS-CoV-2 and related bat and pangolin viruses is a potent IFN antagonist
  • SARS-CoV-2 ORF3b suppresses IFN induction more efficiently than SARS-CoV ortholog
  • The anti-IFN activity of ORF3b depends on the length of its C-terminus
  • An ORF3b with increased IFN antagonism was isolated from two severe COVID-19 cases

    https://pharmaceuticalintelligence.com/2020/05/23/rna-from-the-sars-cov-2-virus-taking-over-the-cells-it-infects-virulence-pathogens-ability-to-infect-a-resistant-host-the-imbalance-between-controlling-virus-replication-versus-activation-of-the/

    Immunomodulatory Therapeutic Approaches (dexamethasone): COVID-19 Death results from Immune-Mediation (virus-independent immunopathology: lung and reticuloendothelial system) vs Pathogen-Mediation causing Organ Dysfunction & Hyper-Inflammation

     

    Highlights

    1. Dissociation between viral tropism and tissue-spesific immune/inflammatory response
    2. Inflammatory response only seen in the lungs and reticuloenthothelial system, and not necessarity with viral presence
    3. No correlation of severity with viral load of RNA fragments and protein presence in serum

    Tissue-specific tolerance in fatal Covid-19

    David A DorwardClark D RussellIn Hwa UmMustafa ElshaniStuart D ArmstrongRebekah Penrice-RandalTracey MillarChris EB LerpiniereGiulia TagliaviniCatherine S HartleyNadine P RandallNaomi N GachanjaPhilippe MD PoteyAlison M AndersonVictoria L CampbellAlasdair J DuguidWael Al QsousRalph BouHaidarJ Kenneth BaillieKevin DhaliwalWilliam A WallaceChristopher OC BellamySandrine ProstColin SmithJulian A HiscoxDavid J HarrisonChristopher D LucasICECAP

    Abstract

    Successful host defence against a pathogen can involve resistance or tolerance, with implications for prioritising either antimicrobial or immunomodulatory therapeutic approaches. Hyper-inflammation occurs in Covid-19 and is associated with worse outcomes. The efficacy of dexamethasone in preventing mortality in critical Covid-19 suggests that inflammation has a causal role in death. Whether this deleterious inflammation is primarily a direct response to the presence of SARS-CoV-2 requiring enhanced resistance, or an independent immunopathologic process necessitating enhanced tolerance, is unknown. Here we report an aberrant immune response in fatal Covid-19, principally involving the lung and reticuloendothelial system, that is not clearly topologically associated with the virus, indicating tissue-specific tolerance of SARS-CoV-2. We found that

    • inflammation and organ dysfunction in fatal Covid-19 did not map to the widespread tissue and cellular distribution of SARS-CoV-2 RNA and protein, both between and within tissues.
    • A monocyte/myeloid-rich vasculitis was identified in the lung, along with an influx of macrophages/monocytes into the parenchyma. In addition,
    • stereotyped abnormal reticulo-endothelial responses (reactive plasmacytosis and iron-laden macrophages) were present and dissociated from the presence of virus in lymphoid tissues. Our results support
    • virus-independent immunopathology being one of the primary mechanisms underlying fatal Covid-19.
    • This supports prioritising pathogen tolerance as a therapeutic strategy in Covid-19, by better understanding
    • non-injurious organ-specific viral tolerance mechanisms and targeting aberrant macrophage and plasma cell responses.

    SOURCE 

    https://www.medrxiv.org/content/10.1101/2020.07.02.20145003v1

    Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report

    Peter HorbyWei Shen LimJonathan EmbersonMarion MafhamJennifer BellLouise LinsellNatalie StaplinChristopher BrightlingAndrew UstianowskiEinas ElmahiBenjamin PrudonChristopher GreenTimothy FeltonDavid ChadwickKanchan RegeChristopher FeganLucy C ChappellSaul N FaustThomas JakiKatie JefferyAlan MontgomeryKathryn RowanEdmund JuszczakJ Kenneth BaillieRichard HaynesMartin J LandrayRECOVERY Collaborative Group

    Abstract

    Background: Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death.

    Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results: 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14).

    Conclusions: In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support.

     SOURCE

    https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1

    Other Etiologies Explained

    SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19

    Reporter: Aviva Lev-Ari, PhD, RN

    https://pharmaceuticalintelligence.com/2020/06/01/sar-cov-2-is-probably-a-vasculotropic-rna-virus-affecting-the-blood-vessels-endothelial-cell-infection-and-endotheliitis-in-covid-19/

    A mysterious blood-clotting complication is killing coronavirus patients

    Once thought a relatively straightforward respiratory virus, covid-19 is proving to be much more frightening

    SOURCE

    https://www.washingtonpost.com/health/2020/04/22/coronavirus-blood-clots/

    Mechanism of thrombocytopenia in COVID-19 patients

    Abstract

    Since December 2019, a novel coronavirus has spread throughout China and across the world, causing a continuous increase in confirmed cases within a short period of time. Some studies reported cases of thrombocytopenia, but hardly any studies mentioned how the virus causes thrombocytopenia. We propose several mechanisms by which coronavirus disease 2019 causes thrombocytopenia to better understand this disease and provide more clinical treatment options.

    Keywords: Severe acute respiratory syndrome coronavirus 2, Coronavirus disease 2019, Thrombocytopenia, Platelet
    SOURCE

    SAR-Cov-2 is neuro-invasive. Is CNS regulation of peripheral catacholamine outflow disrupted in susceptible patients, CAT leads to platelet aggregation

    Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain

    Abstract

    Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has caused a global pandemic in only 3 months. In addition to major respiratory distress, characteristic neurological manifestations are also described, indicating that SARS-CoV-2 may be an underestimated opportunistic pathogen of the brain. Based on previous studies of neuroinvasive human respiratory coronaviruses, it is proposed that after physical contact with the nasal mucosa, laryngopharynx, trachea, lower respiratory tract, alveoli epithelium, or gastrointestinal mucosa, SARS-CoV-2 can induce intrinsic and innate immune responses in the host involving increased cytokine release, tissue damage, and high neurosusceptibility to COVID-19, especially in the hypoxic conditions caused by lung injury. In some immune-compromised individuals, the virus may invade the brain through multiple routes, such as the vasculature and peripheral nerves. Therefore, in addition to drug treatments, such as pharmaceuticals and traditional Chinese medicine, non-pharmaceutical precautions, including facemasks and hand hygiene, are critically important.

    Keywords: coronavirus disease 2019 (COVID-19), SARS-CoV-2, neurological manifestations, neuroinvasion, brain
    SOURCE

    The neuroinvasive potential of SARS‐CoV2 may play a role in the respiratory failure of COVID‐19 patients

    First published: 27 February 2020
    Citations: 139

    [Correction added on March 17, 2020 after first online publication: Manuscript has been revised with author’s latest changes]

    Abstract

    Following the severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), another highly pathogenic coronavirus named SARS‐CoV‐2 (previously known as 2019‐nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS‐CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID‐19) with clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV. The most characteristic symptom of patients with COVID‐19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse‐connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Considering the high similarity between SARS‐CoV and SARS‐CoV2, it remains to make clear whether the potential invasion of SARS‐CoV2 is partially responsible for the acute respiratory failure of patients with COVID‐19. Awareness of this may have a guiding significance for the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.

    Research Highlights

    • SARS‐CoV2 causes epidemic pneumonia characterized by acute respiratory distress.
    • This novel coronavirus is similar to SARS‐CoV in sequence, pathogenesis, and cellular entry.
    • Some coronaviruses can invade brainstem via a synapse‐connected route from the lung and airways.
    • The potential invasion of SARS‐CoV2 may be one reason for the acute respiratory failure.
    • Awareness of this will have guiding significance for the prevention and treatment.

    Intravascular Platelet Aggregation in the Heart Induced by Norepinephrine

    Microscopic Studies
    Originally publishedhttps://doi.org/10.1161/01.CIR.46.4.698Circulation. 1972;46:698–708

    Aggregated platelets and occlusive platelet thrombi were found in small myocardial vessels of dogs on electron-microscope examination after prolonged infusion of norepinephrine. The etiology of the myocardial necrosis and fibrosis induced by catecholamines in experimental animals and seen in patients with pheochromocytoma and patients after norepinephrine treatment for shock may be related to this intravascular platelet-aggregating effect of catecholamines. The link between stress and acute myocardial infarction may be via catecholamine-induced intravascular platelet thrombosis. If the thrombogenic theory of atherosclerosis is valid, platelet aggregation induced by catecholamines may be the mechanism whereby arteriosclerotic heart disease is related to stress.

    SOURCE

    https://www.ahajournals.org/doi/abs/10.1161/01.cir.46.4.698

     

    Ramatroban (Baynas®) for the Treatment of COVID-19

    Ajay Gupta, MBBS, MD

    Department of Medicine,

    University of California, Irvine

    President & Chief Scientific Officer,

    Charak LLC

    E-mails:

    ajayg1@hs.uci.edu

    charaklabs@outlook.com

    Off.: 1 (562) 419 7029

    Cell: 1 (562) 412 6259

    Fax: 1 (702) 974 1001

     

    Multi-Functional Anti-Inflammatory Drugs (MFAIDs) for the Treatment of COVID-19 Patients

    Professor Saul Yedgar

    Walter & Greta Stiel Chair in Heart Studies

    Department of Biochemistry

    Hebrew University-Hadassah Medical School

    Jerusalem, Israel 91120

    Tel:   00972-2-643-9218 (office)

             00972-2-652-0159 (home)

    Fax: 00972-2-675-7291

    Email: yedgar@md.huji.ac.il

     

    Other articles related to the etiology of COVID-19 published in this Open Access Online Scientific Journal include the following:

     

    CORONAVIRUS, SARS-CoV-2 PORTAL @LPBI

    http://lnkd.in/ePwTDxm

    Launched on 3/14/2020

    Eight Pages of LPBI Group’s Coronavirus PORTAL

    https://pharmaceuticalintelligence.com/coronavirus-portal/

     

    Lead Curators are:

    1. Breakthrough News Corner
    2. Development of Medical Counter-measures for 2019-nCoV, CoVid19, Coronavirus
    3. An Epidemiological Approach Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN Lead Curators – e–mail Contacts: sjwilliamspa@comcast.net and avivalev-ari@alum.berkeley.edu
    4. Community Impact Stephen J. Williams, PhD and Irina Robu, PhD Lead Curators – e–mail Contacts: irina.stefania@gmail.com and sjwilliamspa@comcast.net
    5. Economic Impact of The Coronavirus Pandemic Dr. Joel Shertok, PhD Lead Curator – e–mail Contact: jshertok@processindconsultants.com
    6. Voices of Global Citizens: Impact of The Coronavirus Pandemic, Gail S. Thornton, M.A. Lead Curator – e–mail Contact: gailsthornton@yahoo.com
    7. Diagnosis of Coronavirus Infection by Medical Imaging and Cardiovascular Impacts of Viral Infection, Aviva Lev-Ari, PhD, RN Lead Curator e-mail contact: avivalev-ari@alum.berkeley.edu
    8. Key Opinion Leaders Followed by LPBI Aviva Lev-Ari, PhD, RN and Dr. Ofer Markman, PhD Lead Curators e-mail contacts: oferm2015@gmail.com and avivalev-ari@alum.berkeley.edu

     

    The Castleman Disease Research Network publishes Phase 1 Results of Drug Repurposing Database for COVID-19

    Reporter: Stephen J. Williams, PhD.

    https://pharmaceuticalintelligence.com/2020/06/27/the-castleman-disease-research-network-publishes-phase-1-results-of-drug-repurposing-database-for-covid-19/

    Corticosteroid, Dexamethasone Improves Survival in COVID-19: Deaths reduction by 1/3 in ventilated patients and by 1/5 in other patients receiving oxygen only

    Reporter: Aviva Lev-Ari, PhD, RN – bold face and color fonts added

    https://pharmaceuticalintelligence.com/2020/06/27/corticosteroid-dexamethasone-improves-survival-in-covid-19-deaths-reduction-by-1-3-in-ventilated-patients-and-by-1-5-in-other-patients-receiving-oxygen-only/

     

    SARS-CoV-2 is pre-adapted to Human Transmission, branches of evolution stemming from a less well-adapted human SARS-CoV-2-like virus have been found: The Role of SARS-CoV-2 Virus Progenitors for Future Virus Disease Transmission and Pandemic Re-Emergence

    Reporter and Curator: Aviva Lev-Ari, PhD, RN – all bold face and colors are my additions

    https://pharmaceuticalintelligence.com/2020/05/31/sars-cov-2-is-pre-adapted-to-human-transmission-branches-of-evolution-stemming-from-a-less-well-adapted-human-sars-cov-2-like-virus-have-been-found-the-role-of-sars-cov-2-virus-progenitors-for-futur/

     

    COVID-19: Novel Treatment Protocols using Approved drugs vs Standard of Care vs Vaccine and Antiviral new drug discovery and development – An LPBI Group Response and An LPBI Group & Affiliates Response

    Curator: Aviva Lev-Ari, PhD, RN

    https://pharmaceuticalintelligence.com/2020/05/29/covid-19-novel-treatment-protocols-using-approved-drugs-vs-standard-of-care-vs-vaccine-and-antiviral-new-drug-discovery-and-development-an-lpbi-group-response-and-an-lpbi-group-affiliates-res/

     

    T cells found in COVID-19 patients ‘bode well’ for long-term immunity | Science | AAAS

    https://www.sciencemag.org/news/2020/05/t-cells-found-covid-19-patients-bode-well-long-term-immunity

    Clinical Trial for the Use of Nitric Oxide to Treat Severe COVID-19 Infection 

    https://pharmaceuticalintelligence.com/2020/04/14/clinical-trial-for-the-use-of-nitric-oxide-to-treat-severe-covid-19/

     

    RNA from the SARS-CoV-2 virus taking over the cells it infects: Virulence – Pathogen’s ability to infect a Resistant Host: The Imbalance between Controlling Virus Replication versus Activation of the Adaptive Immune Response

    Curator: Aviva Lev-Ari, PhD, RN – I added colors and bold face

    https://pharmaceuticalintelligence.com/2020/05/23/rna-from-the-sars-cov-2-virus-taking-over-the-cells-it-infects-virulence-pathogens-ability-to-infect-a-resistant-host-the-imbalance-between-controlling-virus-replication-versus-activation-of-the/

     

    A Series of Recently Published Papers Report the Development of SARS-CoV2 Neutralizing Antibodies and Passive Immunity toward COVID19

    Curator: Stephen J. Williams, Ph.D.

    https://pharmaceuticalintelligence.com/2020/05/19/a-series-of-recently-published-papers-report-the-development-of-sars-cov2-neutralizing-antibodies-and-passive-immunity-toward-covid19/

     

    Updated listing of COVID-19 vaccine and therapeutic trials from NIH Clinical Trials.gov

    Curator: Stephen J. Williams, PhD

    https://pharmaceuticalintelligence.com/2020/04/16/updated-listing-of-covid-19-vaccine-and-therapeutic-trials-from-nih-clinical-trials-gov/

     

    Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients

    Reporter: Aviva Lev-Ari, PhD, RN

    https://pharmaceuticalintelligence.com/2020/04/14/actemra-immunosuppressive-which-was-designed-to-treat-rheumatoid-arthritis-but-also-approved-in-2017-to-treat-cytokine-storms-in-cancer-patients-saved-the-sickest-of-all-covid-19-patients/

     

    Structure-guided Drug Discovery: (1) The Coronavirus 3CL hydrolase (Mpro) enzyme (main protease) essential for proteolytic maturation of the virus and (2) viral protease, the RNA polymerase, the viral spike protein, a viral RNA as promising two targets for discovery of cleavage inhibitors of the viral spike polyprotein preventing the Coronavirus Virion the spread of infection____________________________ Curators and Reporters: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

    https://pharmaceuticalintelligence.com/2020/03/12/structure-guided-drug-discovery-1-the-coronavirus-3cl-hydrolase-mpro-enzyme-main-protease-essential-for-proteolytic-maturation-of-the-virus-and-2-viral-protease-the-rna-polymerase-the-viral/

    Group of Researchers @ University of California, Riverside, the University of Chicago, the U.S. Department of Energy’s Argonne National Laboratory, and Northwestern University solve COVID-19 Structure and Map Potential Therapeutics____________________________ Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

    https://pharmaceuticalintelligence.com/2020/03/06/group-of-researchers-solve-covid-19-structure-and-map-potential-therapeutic/

     

    Predicting the Protein Structure of Coronavirus: Inhibition of Nsp15 can slow viral replication and Cryo-EM – Spike protein structure (experimentally verified) vs AI-predicted protein structures (not experimentally verified) of DeepMind (Parent: Google) aka AlphaFold____________________________ Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

    https://pharmaceuticalintelligence.com/2020/03/08/predicting-the-protein-structure-of-coronavirus-inhibition-of-nsp15-can-slow-viral-replication-and-cryo-em-spike-protein-structure-experimentally-verified-vs-ai-predicted-protein-structures-not/

     

     

    Different Drug development efforts

    https://www.clinicaltrialsarena.com/analysis/coronavirus-mers-cov-drugs/

    https://www.pharmaceutical-technology.com/news/vir-biotechnology-nih-biogen-coronavirus-antibodies/

    https://www.genengnews.com/a-lists/how-to-conquer-coronavirus-top-35-treatments-in-development/

    https://www.biospace.com/article/mobilizing-drug-development-efforts-against-the-novel-coronavirus/

    https://www.statnews.com/2020/03/10/125m-effort-to-find-coronavirus-drugs-started-by-gates-foundation-wellcome-and-mastercard/

    Coronavirus puts drug repurposing on the fast track

    https://www.nature.com/articles/d41587-020-00003-

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