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Archive for the ‘SARS-CoV-2’ Category


COVID concern in Cardiology: Asymptomatic patients who have been previously infected demonstrating evidence on MRI of scarring or myocarditis

Reporters: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

 

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

Indeed, many viruses can cause inflammation and weakening of the heart.

So far there is no established action to take for prevention, and management is based on clinical manifestations of heart failure: shortness of breath, particularly if worse laying flat or worse with exertion, leg swelling (edema), blood tests showing elevated brain natriuretic peptide (BNP or proBNP, a marker of heart muscle strain), and a basic metabolic panel that may show “pre-renal azotemia” (elevation of BUN and Creatinine, typically in a ratio >20:1) and/or hyponatremia (sodium concentration below 135 mEq/dL). If any of the above are suspected, it is reasonable to get transthoracic echocardiography for systolic and diastolic function. If either systolic or diastolic function by ultrasound show significant impairment not improved by usual therapy (diuretic, ACEI/ARB/ARNI, blocker, aldosterone inhibitor e.g. spironolactone) then an MRI scar map may be considered (MRI scar maps show retention of gadolinium contrast agent by injured heart muscle, first demonstrated by Dr. Justin Pearlman during angiogenesis research MRI studies).

There is no controversy in the above, the controversy is a rush to expanded referral for cardiac MRI without clear clinical evidence of heart impairment, at a stage when there is no established therapy for possible detection of myocarditis (cardiac inflammation). General unproven measures for inflammation may include taking ginger and tumeric supplements if well tolerated by the stomach, drinking 2 cups/day of Rooibos Tea if well tolerated by the liver.

Canakinumab was recommended by one research group to treat inflammation and risk to the heart if the blood test hsCRP is elevated (in addition to potential weakening of muscle, inflammation activates complement, makes atherosclerosis lesions unstable, and thus may elevate risk of heart attack, stroke, renal failure or limb loss from blocked blood delivery). The canakinumab studies were published in NEJM and LANCET with claims of significant improvement in outcomes, but that was not approved by FDA or confirmed by other groups, even though it has biologic plausibility. https://www.thelancet.com/journals/lancet/article/PIIS0140-67361732247-X/fulltext

 

Some Heart Societies Agree on Cautions for COVID-Myocarditis Screening

— Official response has been modest, though

Such evidence of myocardial injury and inflammation on CMR turned up in a German study among people who recovered from largely mild or moderate cases of COVID-19 compared with healthy controls and risk factor-matched controls.

Then an Ohio State University study showed CMR findings suggestive of myocarditis in 15% of collegiate athletes after asymptomatic or mild SARS-CoV-2 infection.

But an open letter from some 50 medical professionals across disciplines emphasized that “prevalence, clinical significance and long-term implications” of such findings aren’t known. The letter called on the 18 professional societies to which it was sent on Tuesday to release clear guidance against CMR screening in the general population to look for post-COVID heart damage in the absence of symptoms.

The Society for Cardiac Magnetic Resonance quickly responded with a brief statement from its chief executive officer, Chiara Bucciarelli-Ducci, MD, PhD, agreeing that routine CMR in asymptomatic patients after COVID-19 “is currently not justified… and it should not be encouraged.”

She referred clinicians to the multisociety guidelines on clinical indications of CMR when deciding whether to scan COVID-19 patients. “While CMR is an excellent imaging tool for diagnosing myocarditis in patients with suspected disease, we do not recommend its use in patients without symptoms,” she added.

The American Heart Association didn’t put out any written statement but offered spokesperson Manesh Patel, MD, chair of its Diagnostic and Interventional Cath Committee.

“The American Heart Association’s position on this is that in general we agree that routine cardiac MRI should not be conducted unless in the course of a study” for COVID-19 patients, he said. “There’s a lot of evolving information around people with COVID, and certainly asymptomatic status, whether it’s recent or prior, it’s not clearly known what the MRI findings will mean or what the long-term implications are without both a control group and an understanding around population.”

The ACC opted against taking a stand. It provided MedPage Today with the following statement from ACC President Athena Poppas, MD:

“We appreciate the authors’ concerns about the potential mischaracterization of the long-term impact of myocarditis after a COVID-19 diagnosis and the need for well-designed clinical trials and careful, long term follow-up. The pandemic is requiring everyone make real-time decisions on how to best care for heart disease patients who may be impacted by COVID-19. The ACC is committed to helping synthesize and provide the most up-to-date, high quality information possible to the cardiovascular care team. We will continue to review and assess the scientific data surrounding cardiac health and COVID-19 and issue guidance to help our care team.”

While the open letter noted that some post-COVID patients have been asking for CMR, Walsh noted that primary care would likely see the brunt of any such influx. She personally has not had any patients ask to be screened.

SOURCE

https://www.medpagetoday.com/infectiousdisease/covid19/88704?xid=nl_covidupdate_2020-09-21

Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial

Summary

Background

Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence.

Methods

We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose–response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.govNCT01327846. The trial is closed (the last patient visit was in June, 2017).

Findings

Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26–41% and of interleukin 6 of 25–43% (p<0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31–0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39–0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18–0·59]; p<0·0001; p<0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10–0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83–1·06]; p=0·31).

Interpretation

Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required.

Funding

Novartis Pharmaceuticals.

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Coronavirus damages the Human Heart Muscle: Disrupting Sarcomeres and Displacing DNA

Reporters: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

 

‘Carnage’ in a lab dish shows how the coronavirus may damage the heart

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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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Sex Differences in Immune Responses that underlie COVID-19 Disease Outcomes

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

 

This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our authors and readers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Sex differences in immune responses that underlie COVID-19 disease outcomes

Abstract

A growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)1–5. However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in

  • viral loads,
  • SARS-CoV-2-specific antibody titers,
  • plasma cytokines, as well as
  • blood cell phenotyping in COVID-19 patients.

By focusing our analysis on patients with moderate disease who had not received immunomodulatory medications, our results revealed that

  • male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. In contrast,
  • female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age.
  • Importantly, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients.
  • Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients.
  • These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide an important basis for the development of
  • a sex-based approach to the treatment and care of men and women with COVID-19.

Author information

Affiliations

Consortia

Corresponding author

Correspondence to Akiko Iwasaki.

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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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Clustering of Country-Based Data in COVID-19 Infections by Coronavirus outbreak features – First wave, Data up to date 28/5/2020

Authors: Akad Doha, Markman Ofer and Lefkort Jared

 

This study investigated connections between the infection cycles of countries around the world. Utilizing factors such as the Day of Maximum Infections, the Total Infections and the Day of Maximum Infections, and Deaths and Recoveries per Million. In addition, countries that have completed the infection cycle were compared to understand similarities and differences amongst the aforementioned factors and others.

Note: All variables are reportedly up to date 28/5.

The variables:

Country

State / status – The state of the outbreak

Daily_peak – Maximum number of new daily infections

Total_at_daily_peak – The number of infections from the beginning of the outbreak to the maximum day of the new infections.

Death_per_m – The deaths per million people

Recovered_per_m – The recovery cases per million people

Continent – Continent

Time_to_peak- Time from day to the maximum day of new infections.

Break_time – Time in days from the maximum day for new infections until fading (only in countries that have significantly decreased the number of infections, which means that they can be considered in the end)

Total_time- Time from the day of first outbreak to the end.

 

 

Clustering:

Figure 1. Classification 1, Clustering Based on the variables – the number of new daily infections , the number of infections from the beginning of the outbreak to the maximum day of infections , the deaths per million people , the recoveries per million people , the time to the maximum day for new infections.

Cluster 1 – red – characterized by:

  • The number of new daily maximum infections below average
  • The number of infections from the beginning of the outbreak to the maximum daily infections below average
  • Deaths per million persons below average
  • Recoveries per million less than the number of deaths and below average.

Cluster 2 – blue – characterized by:

  • The number of new daily infections usually above average Deaths per million people above average
  • Recoveries per million above average yet less than deaths
  • Time to the maximum day for new infections less than average.

 

Figure 2. Classification 2, Clustering Based on the variables – the number of new daily infections, the number of infections from the beginning of the outbreak to the maximum day of infections, the deaths per million people , the recovery cases per million people.

Cluster 1 (red): The number of new daily infections is less than average, the number of infections from the beginning of the outbreak to the maximum day of the new infections is almost average, deaths to one million people on average, recovery cases per million people above average

Cluster 2 ( green): the number of new daily maximum infections above average, the number of infections from the beginning of the outbreak to the maximum daily infections most often above average, yet less than the maximum daily new infections, the deaths per million above average, the recoveries per million above average, but less than deaths.

Cluster 3 (blue): maximum number of new daily infections smaller than average and smaller than cluster 1 , the number of infections since the beginning of the outbreak to the maximum new infections below the average, deaths per million people below average, recoveries per million people under the average and lower than deaths.

 

Figure 3. Classification 3, Cluster (clustering) Based on all variables for countries that have already completed the outbreak cycle.

Cluster 1 (red): maximum number of daily new infections above average, number of infections from the initial outbreak to the maximum day of new infections above average, recoveries per million people below average, the fading time below average, and total time to completion of outbreak circle below average.

Cluster 2 ( blue ): maximum number of daily new infections below average, number of infections from the initial outbreak to the maximum day of new infections less than average, fading time usually above average and not necessarily over cluster 1, and the total time to the end of the outbreak cycle above average.

This classification is done based on a small number of countries since there are a lack of countries who have completed the outbreak circle, so we will use it only to understand what kinds of classifications we receive if there is a fading time and total time.

Figure 4. World map by classification 1:

The map shows that the countries of Asia, Northeastern Europe, Africa, Central America and South America, and some of North America are classified by Cluster 1, which means that they have Cluster 1 characteristics.

Western Europe, Eastern South America, part of North America belongs to Cluster 2. (Please refer to Cluster properties in explanation of Figure 3)

 

Figure 5. World Map by Classification 2:

Northern North America, South America, the Middle East, parts of Europe, and North Asia are classified as Cluster 3.

Western Europe, Southeastern America, and some of North America are classified as Cluster 2.

East Asia, Africa, parts of Northern Europe, parts of South America and Central America are classified into Cluster 3. (Please refer to Cluster properties in explanation of Figure 2).

 

Figure 6. Summary Classification – Combining the two classifications 1 and 2:

Cluster 1 (red) is characterized by a maximum number of new infections larger than average (highest number of maximum daily infections), the number of infections since the beginning of the outbreak to the day of maximum new daily infections more than or equal to the average, deaths above average and above cluster 4, recoveries per million people over the average, yet less than deaths.

Cluster 2 (green) is characterized by the maximum number of daily new infections close to average and tends to be above average in most cases, the number of infections since the beginning of the outbreak to the day of maximum new daily infections almost average, deaths mostly at or above average, but below cluster 1, recoveries per million above average and greater than the deaths.

Cluster 3 (blue) is characterized by a maximum number of new infections below average, the number of infections since the beginning of the outbreak to the day of maximum new daily infections less than or equal to the average, deaths below average (lowest deaths) , recoveries per million people below average and less than deaths.

Cluster 4 (Purple) is characterized by a maximum number of new infections below average, the number of infections since the beginning of the outbreak to the day of maximum new daily infections below average, deaths above average and above clusters 2 and 3, recoveries per million above average and above deaths (greatest amount of recoveries)

 

Figure 7. Distribution of time until the maximum day of New infections by the summary classification.

Cluster 3 has the highest average time up to the maximum day for new infections, followed by Cluster 1, then Cluster 2 and Cluster 4 with the lowest average.

 

Figure 8. The world map is classified according to the summery classification:

Southern South America, parts of North America, and Western Europe are classified as Cluster 1.

Table 1. countries in first cluster:

Status Country
Ongoing USA
Subsiding Belgium
Subsiding UK
Subsiding Italy
Ongoing Brazil
Subsiding France
Subsiding Spain

 

Western South America, parts of North America, the Middle East, North Asia and some parts of Europe are classified as Cluster 2.

Table 2. countries in second cluster:

status country status country
ongoing Panama ongoing Russia
completed Norway subsiding Turkey
subsiding Germany reemerged Iran
ongoing Peru ongoing Canada
subsiding Netherlands ongoing Saudi Arabia
ongoing Sweden ongoing Chile
completed Israel subsiding Portugal
completed Austria subsiding Ecuador
    subsiding Denmark

 

Parts of America, Africa, East Asia and parts of Europe are classified into Cluster 3.

Table 3. countries in second cluster:

status country status country
ongoing South Africa ongoing Poland
ongoing Philippines ongoing Mexico
ongoing Dominican Republic ongoing India
ongoing Egypt ongoing Pakistan
completed South Korea ongoing Bangladesh
subsiding Czechia ongoing Ukraine
ongoing Argentina ongoing Indonesia
ongoing Algeria subsiding Romania
subsiding Finland completed Japan
subsiding Hungary ongoing Colombia
    completed China

 

Small parts of Western Europe are classified into Cluster 4. (Please refer to Cluster properties in explanation of Figures 6 and 7)

Table 4. countries in second cluster:

status country
completed Switzerland
completed Ireland

 

Interesting discovery:

While searching the variables that contribute to a clearer picture of the world situation, some countries were found to have a day that repeats every week, characterized by the minimum number of deceased from coronavirus. These countries include: The United States, Brazil, the Netherlands, Sweden, and Israel.

In addition, India had a day characterized by a maximum number of new infections that repeats every week.

Peru had a devoted day that repeats every week characterized by a minimum number of new infections.

Statistical insights appendix:

 

Figure 9. The quantum of the quantitative variables

We can see that:

  1. The maximum number of new daily infections in most countries is less than 10000 people. In individual cases over 10000.
  2. The number of deaths from the virus in most countries is less than 200 people per million.
  3. The number of people who have recovered from the virus in most countries are under 2000 people per million.
  4. The maximum time to date for new infections varies by country and there is no common reservation for a number of days, but from the chart it can be assumed that most countries are below 80 days for maximum full outbreak.
  5. The number of infections from the beginning of the outbreak to the maximum day for new infections in most countries does not exceed 250000 infections.

 

Relationships and adjustments between variables:

 

Figure 10. Correlation between the different variables

The most prominent correlations between the variables are:

  1. The number of new daily infections in the maximum day for new infections and the number of infections from the beginning of the outbreak to the maximum day for new infections. Indicates a strong positive correlation.
  2. Between the number of deaths and the number of recoveries a moderate positive correlation exists.
  3. Between the number recoveries per million and the time to maximum day of new infections a moderate negative correlation exists.

 

Figure 11. Correlation of all variables Countries that completed the outbreak cycle:

The most prominent correlations between the variables are:

  1. The number of new daily infections in the maximum day for new infections and the number of infections from the beginning of the outbreak to the maximum day for new infections. Indicates a very strong positive correlation.
  2. Between the number of deaths and the number of recoveries correlates strong positive.
  3. The number of infections that have healed, the maximum number of new daily cases and the number of infections from the beginning of the outbreak to the maximum day of new infections has a negative medium correlation.
  4. Between the time of the outbreak fading and the time of the complete outbreak cycle there is a very strong positive correlation.
  5. The maximum number of daily new infections and outbreak fading time and all the time of outbreak cycle has a strong negative correlation.
  6. Between the number of infections from the onset of the outbreak to the maximum day for new infections, the time of outbreak fading and the whole time of the complete outbreak cycle has a very strong negative correlation.

* consider that the correlations are based on a small number of countries, so there may be biases in the correctness of adjustment with the true situation. If there were more countries that have completed the outbreak cycle would have been more precise – recommends future research.

 

Figure 12. Diagram of the correlation between variables by PCA analysis (For all countries)

 

The diagram shows the relationships between all variables, they can be interpreted as follows:

  • As the total number of infections from the onset of the outbreak to the maximum day for new infections increases, the number of maximum new daily infections increases.
  • As the number of deaths increases, the number of recovered patients also increases.
  • As the time to the maximum day for new infections decreases, the number of recovered patients increases.
  • The variables depicted in red represent those that are significant to understanding the world data, and conversely, the variables in blue are less significant, but are also necessary in understanding the data. Therefore, subsequently, one analysis was performed including the maximum day for new infections variable, and one was performed without it.

 

Figure 13. Diagram of the correlation between variables by PCA analysis (Countries that have completed the outbreak cycle)

Chart is prepared to show the connections of the variables with two variables that were found only in countries that have completed the outbreak cycle, 1. Fading time 2. The total time to completion.

  • As the time between the reduction of infection rates and the day of maximum infections increases, so does the total length of the infection cycle. And it seems that a negative relationship exists between this relationship and time to the maximum day of new infections.
  • As the fading time and time to end decreases, the total number of infections in the maximum day of new infections and new daily infections number increases (very interesting).

Reference:

The data was collected from:

https://ourworldindata.org/covid-deaths

 

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Dmitry Korkin is a professor of bioinformatics and computational biology at Worcester Polytechnic Institute, where he specializes in bioinformatics of complex disease, computational genomics, systems biology, and biomedical data analytics. I came across Dmitry’s work when in February his group used the viral genome of the COVID-19 to reconstruct the 3D structure of its major viral proteins and their interactions with human proteins, in effect creating a structural genomics map of the coronavirus and making this data open and available to researchers everywhere. We talked about the biology of COVID-19, SARS, and viruses in general, and how computational methods can help us understand their structure and function in order to develop antiviral drugs and vaccines.
This conversation is part of the Artificial Intelligence podcast.
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OUTLINE: 0:00 – Introduction 2:33 – Viruses are terrifying and fascinating 6:02 – How hard is it to engineer a virus? 10:48 – What makes a virus contagious? 29:52 – Figuring out the function of a protein 53:27 – Functional regions of viral proteins 1:19:09 – Biology of a coronavirus treatment 1:34:46 – Is a virus alive? 1:37:05 – Epidemiological modeling 1:55:27 – Russia 2:02:31 – Science bobbleheads 2:06:31 – Meaning of life
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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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Inflammation BioMarker C-Reactive Protein Guides Use of Systemic Glucocorticoids in Patients with COVID-19: The Effects on Mortality or Use of Mechanical Ventilation – (CRP) ≥20 mg/dL was associated with significantly reduced risk of Mortality or Mechanical Ventilation Efficacy

Reporter: Aviva Lev-Ari, PhD, RN

 

In patients with high levels of inflammation — at least 20 mg/dL — steroid treatment was associated with a 77% reduction in the risk of needing mechanical ventilation or dying (odds ratio [OR], 0.23).

Importantly, treating with steroids when CRP levels were less than 10 mg/dL was associated with an almost threefold increased risk of going on mechanical ventilation or dying (OR, 2.64).

“The laboratory test could potentially be very helpful,” Keller told Medscape Medical News.

https://www.medscape.com/viewarticle/934571

Effect of Systemic Glucocorticoids on Mortality or Mechanical Ventilation in Patients With COVID-19

Article has an altmetric score of 299

Abstract

The efficacy of glucocorticoids in COVID-19 is unclear. This study was designed to determine whether systemic glucocorticoid treatment in COVID-19 patients is associated with reduced mortality or mechanical ventilation. This observational study included 1,806 hospitalized COVID-19 patients; 140 were treated with glucocorticoids within 48 hours of admission. Early use of glucocorticoids was not associated with mortality or mechanical ventilation. However, glucocorticoid treatment of patients with initial C-reactive protein (CRP) ≥20 mg/dL was associated with significantly reduced risk of mortality or mechanical ventilation (odds ratio, 0.23; 95% CI, 0.08-0.70), while glucocorticoid treatment of patients with CRP <10 mg/dL was associated with significantly increased risk of mortality or mechanical ventilation (OR, 2.64; 95% CI, 1.39-5.03). Whether glucocorticoid treatment is associated with changes in mortality or mechanical ventilation in patients with high or low CRP needs study in prospective, randomized clinical trials.

Glucocorticoids are useful as adjunctive treatment for some infections with inflammatory responses, but their efficacy in COVID-19 is unclear. Prior experience with influenza and other coronaviruses may be relevant. A recent meta-analysis of influenza pneumonia showed increased mortality and a higher rate of secondary infections in patients who were administered glucocorticoids.3 For Middle East respiratory syndrome, severe acute respiratory syndrome, and influenza, some studies have demonstrated an association between glucocorticoid use and delayed viral clearance.4-7 However, a recent retrospective series of patients with COVID-19 and ARDS demonstrated a decrease in mortality with glucocorticoid use.8 Glucocorticoids are easily obtained and familiar to providers caring for COVID-19 patients. Hence their empiric use is widespread.8,9

The primary goal of this study was to determine whether early glucocorticoid treatment is associated with reduced mortality or need for MV in COVID-19 patients.

DISCUSSION

The results of this study indicate that early treatment with glucocorticoids is not associated with mortality or need for MV in unselected patients with COVID-19. Subgroup analyses suggest that glucocorticoid-treated patients with markedly elevated CRP may benefit from glucocorticoid treatment, whereas those patients with lower CRP may be harmed. Our findings were consistent after adjustment for clinical characteristics. The public health implications of these findings are hard to overestimate. Given the global growth of the pandemic and that glucocorticoids are widely available and inexpensive, glucocorticoid therapy may save many thousands of lives. Equally important because we have been able to identify a group that may be harmed, some patients may be saved because glucocorticoids will not be given.

Our study reaffirms the finding of the as yet unpublished Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial that there is a subset of patients with COVID-19 who benefit from treatment with glucocorticoids.10 Our study extends the findings of the RECOVERY trial in two important ways. First, in addition to finding some patients who may benefit, we also have identified patient groups that may experience harm from treatment with glucocorticoids. This finding suggests choosing the right patients for glucocorticoid treatment is critical to maximize the likelihood of benefit and minimize the risk of harm. Second, we have identified patient groups who are likely to benefit (or be harmed) on the basis of a widely available lab test (CRP).

Our results are also consistent with previous studies of patients with SARS-CoV and MERS-CoV, in which no associations between glucocorticoid treatment and mortality were found.7 However, the results of studies examining the effect of glucocorticoids in patients with COVID-19 are less consistent.8,11,12

Few of the previous studies examined the effects of glucocorticoids in subgroups of patients. In our study, the improved outcomes associated with glucocorticoid use in patients with elevated CRPs is intriguing and may be clinically important. Proinflammatory cytokines, especially interleukin-6, acutely increase CRP levels. Cytokine storm syndrome (CSS) is a hyperinflammatory condition that occurs in a subset of COVID-19 patients, often resulting in multiorgan dysfunction.13 CRP is markedly elevated in CSS,14 and improved outcomes with glucocorticoid therapy in this subgroup may indicate benefit in this inflammatory phenotype. Patients with lower CRP are less likely to have CSS and may experience more harm than benefit associated with glucocorticoid treatment.

Several limitations are inherent to this study. Since it was done at a single center, the results may not be generalizable. As a retrospective analysis, it is subject to confounding and bias. In addition, because patients were included only if they had reached the outcome of death/MV or hospital discharge, the sample size was truncated. We believe glucocorticoid use in hospitalized patients excluded from the study reflects increased use with time because of a growing belief in their effectiveness.

Preliminary analysis from the RECOVERY study showed a reduced rate of mortality in patients randomized to dexamethasone, compared with those who received standard of care.10 These results led to the National Institutes for Health COVID-19 Treatment Guidelines Panel recommendation for dexamethasone treatment in patients with COVID-19 who require supplemental oxygen or MV.15 Our findings suggest a role for CRP to identify patients who may benefit from glucocorticoid therapy, as well as those in whom it may be harmful. Additional studies to further elucidate the role of CRP in guiding glucocorticoid therapy and to predict clinical response are needed.

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