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Archive for the ‘SARS-CoV-2’ Category


How Are Cancer Researchers Fighting COVID-19? Lectures from Koch Institute @MIT

WATCH RECORDING, below

 

Reporter: Aviva Lev-Ari, PhD, RN

  • I attended Jun 29, 2020 11:30 AM Eastern Time the five presentations on

    How Are Cancer Researchers Fighting COVID-19? Lectures from Koch Institute @MIT

 

From: Koch Institute at MIT <no-reply@zoom.us>

Reply-To: <no-reply@zoom.us>

Date: Wednesday, July 1, 2020 at 11:20 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Thank you for attending SOLUTIONS with/in/sight:

How Are Cancer Researchers Fighting COVID-19? (Part II)

 

Hi Aviva Lev-Ari,

Thank you for attending SOLUTIONS with/in/sight: How Are Cancer Researchers Fighting COVID-19? (Part II). We hope you enjoyed our event.

Please submit your questions or comments to: kievents@mit.edu.

You may view a recording of the webinar here: https://ki.mit.edu/news/events/withinsight/jun-2020

Learn more about Koch Institute cancer research and events by signing up for our mailing list here: https://ki.mit.edu/subscribe

Thank you and be safe.

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

Reporter: Stephen J. Williams, PhD.

 

From CNN at https://www.cnn.com/2020/06/27/health/coronavirus-treatment-fajgenbaum-drug-review-scn-wellness/index.html

Updated 8:17 AM ET, Sat June 27, 2020

(CNN)Every morning, Dr. David Fajgenbaum takes three life-saving pills. He wakes up his 21-month-old daughter Amelia to help feed her. He usually grabs some Greek yogurt to eat quickly before sitting down in his home office. Then he spends most of the next 14 hours leading dozens of fellow researchers and volunteers in a systematic review of all the drugs that physicians and researchers have used so far to treat Covid-19. His team has already pored over more than 8,000 papers on how to treat coronavirus patients.

The 35-year-old associate professor at the University of Pennsylvania Perelman School of Medicine leads the school’s Center for Cytokine Storm Treatment & Laboratory. For the last few years, he has dedicated his life to studying Castleman disease, a rare condition that nearly claimed his life. Against epic odds, he found a drug that saved his own life six years ago, by creating a collaborative method for organizing medical research that could be applicable to thousands of human diseases. But after seeing how the same types of flares of immune-signaling cells, called cytokine storms, kill both Castleman and Covid-19 patients alike, his lab has devoted nearly all of its resources to aiding doctors fighting the pandemic.

A global repository for Covid-19 treatment data

Researchers working with his lab have reviewed published data on more than 150 drugs doctors around the world have to treat nearly 50,000 patients diagnosed with Covid-19. They’ve made their analysis public in a database called the Covid-19 Registry of Off-label & New Agents (or CORONA for short).
It’s a central repository of all available data in scientific journals on all the therapies used so far to curb the pandemic. This information can help doctors treat patients and tell researchers how to build clinical trials.The team’s process resembles that of the coordination Fajgenbaum used as a medical student to discover that he could repurpose Sirolimus, an immunosuppressant drug approved for kidney transplant patients, to prevent his body from producing deadly flares of immune-signaling cells called cytokines.The 13 members of Fajgenbaum’s lab recruited dozens of other scientific colleagues to join their coronavirus effort. And what this group is finding has ramifications for scientists globally.
This effort by Dr. Fajgenbaum’s lab and the resultant collaborative effort shows the power and speed at which a coordinated open science effort can achieve goals. Below is the description of the phased efforts planned and completed from the CORONA website.

CORONA (COvid19 Registry of Off-label & New Agents)

Drug Repurposing for COVID-19

Our overarching vision:  A world where data on all treatments that have been used against COVID19 are maintained in a central repository and analyzed so that physicians currently treating COVID19 patients know what treatments are most likely to help their patients and so that clinical trials can be appropriately prioritized.

Phase 1: COMPLETED

Our team reviewed 2500+ papers & extracted data on over 9,000 COVID19 patients. We found 115 repurposed drugs that have been used to treat COVID19 patients and analyzed data on which ones seem most promising for clinical trials. This data is open source and can be used by physicians to treat patients and prioritize drugs for trials. The CDCN will keep this database updated as a resource for this global fight. Repurposed drugs give us the best chance to help COVID19 as quickly as possible! As disease hunters who have identified and repurposed drugs for Castleman disease, we’re applying our ChasingMyCure approach to COVID19.

Read our systematic literature review published in Infectious Diseases and Therapy at the following link: Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review

From Fajgenbaum, D.C., Khor, J.S., Gorzewski, A. et al. Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review. Infect Dis Ther (2020). https://doi.org/10.1007/s40121-020-00303-8

The following is the Abstract and link to the metastudy.  This study was a systematic review of literature with strict inclusion criteria.  Data was curated from these published studies and a total of 9152 patients were evaluated for treatment regimens for COVID19 complications and clinical response was curated for therapies in these curated studies.  Main insights from this study were as follows:

Key Summary Points

Why carry out this study?
  • Data on drugs that have been used to treat COVID-19 worldwide are currently spread throughout disparate publications.
  • We performed a systematic review of the literature to identify drugs that have been tried in COVID-19 patients and to explore clinically meaningful response time.
What was learned from the study?
  • We identified 115 uniquely referenced treatments administered to COVID-19 patients. Antivirals were the most frequently administered class; combination lopinavir/ritonavir was the most frequently used treatment.
  • This study presents the latest status of off-label and experimental treatments for COVID-19. Studies such as this are important for all diseases, especially those that do not currently have definitive evidence from randomized controlled trials or approved therapies.

Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review

Abstract

The emergence of SARS-CoV-2/2019 novel coronavirus (COVID-19) has created a global pandemic with no approved treatments or vaccines. Many treatments have already been administered to COVID-19 patients but have not been systematically evaluated. We performed a systematic literature review to identify all treatments reported to be administered to COVID-19 patients and to assess time to clinically meaningful response for treatments with sufficient data. We searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles reporting treatments for COVID-19 patients published between 1 December 2019 and 27 March 2020. Data were analyzed descriptively. Of the 2706 articles identified, 155 studies met the inclusion criteria, comprising 9152 patients. The cohort was 45.4% female and 98.3% hospitalized, and mean (SD) age was 44.4 years (SD 21.0). The most frequently administered drug classes were antivirals, antibiotics, and corticosteroids, and of the 115 reported drugs, the most frequently administered was combination lopinavir/ritonavir, which was associated with a time to clinically meaningful response (complete symptom resolution or hospital discharge) of 11.7 (1.09) days. There were insufficient data to compare across treatments. Many treatments have been administered to the first 9152 reported cases of COVID-19. These data serve as the basis for an open-source registry of all reported treatments given to COVID-19 patients at www.CDCN.org/CORONA. Further work is needed to prioritize drugs for investigation in well-controlled clinical trials and treatment protocols.

Read the Press Release from PennMedicine at the following link: PennMedicine Press Release

Phase 2: Continue to update CORONA

Our team continues to work diligently to maintain an updated listing of all treatments reported to be used in COVID19 patients from papers in PubMed. We are also re-analyzing publicly available COVID19 single cell transcriptomic data alongside our iMCD data to search for novel insights and therapeutic targets.

You can visit the following link to access a database viewer built and managed by Matt Chadsey, owner of Nonlinear Ventures.

If you are a physician treating COVID19 patients, please visit the FDA’s CURE ID app to report de-identified information about drugs you’ve used to treat COVID19 in just a couple minutes.

For more information on COVID19 on this Open Access Journal please see our Coronavirus Portal at

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

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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

 

UPDATED on 6/28/2020

https://public.tableau.com/profile/matt.chadsey#!/vizhome/Corona_15895153725490/TreatmentSummary

Corona – COVID19 Treatment Registry

Viz Author: Matt Chadsey

CORONA is the COVID19 Registry of Off-Label & New Agents. A project of the Center for Cytokine Storm Treatment & Laboratory (CSTL) and the Castleman Disease Collaborative Network (CDCN).

10,553 Views  4

Inspiration:

Originally Published:

May 15, 2020

Last Updated:

Jun 27, 2020

Workbook Details:

11 Sheets

Metadata:

https://public.tableau.com/profile/matt.chadsey#!/vizhome/Corona_15895153725490/TreatmentSummary

SOURCE

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/

Paul Sax
@PaulSaxMD

If you’re wondering whether to use dexamethasone for patients presenting with COVID19 who need oxygen as we await the publication of the RECOVERY trial, here’s one opinion (mine): Yes. Latest post: blogs.jwatch.org/hiv-id-observa

Dexamethasone Improves Survival in COVID-19 – Why This Should Be Practice-Changing Even Before the…
When the news broke last week that the dexamethasone component of the RECOVERY randomized clinical trial was halted because those receiving the drug were significantly more likely to survive, I…
blogs.jwatch.org
8
104
239

Paul Sax
@PaulSaxMD

The favorable dexamethasone data for covid19 will likely amplify the already apparent increased risk for aspergillosis among these critically ill people. Plenty of work for experts like

and others.

Image

Paul Sax
@PaulSaxMD
– Very welcome news, dex is cheap, widely available! – Demonstrates the power of RCTs vs obs studies, which were conflicting – How will the numerous ongoing studies of immunomodulators be modified? – Rx guidelines — act now or wait for more info?
Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe…
Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on dexamethasone, 16 June 2020
recoverytrial.net

Note my last point, about “guidelines”. These committees have a responsibility to get what they recommend right, and might be slower than clinicians to recommend an intervention with limited information — even if it is potentially life-saving.

But my assumption was that clinical practice would change quickly, awaiting the updating of guidelines. After all, this is what we’ve been waiting for — data from a randomized trial demonstrating a clear benefit. Even better, it’s a readily available, inexpensive strategy — a course of corticosteroids — familiar to us all.

I confess the responses to my post, and comments elsewhere, surprised me. Lots of skepticism. Wow.

The comments fell into several interrelated categories:

Let’s wait for the study to be peer-reviewed and published in an established medical journal before changing clinical practice.

Really? Even when the sickest patients — those requiring oxygen or ventilatory support — were more likely to survive?

(Yes, I keep italicizing that endpoint. Emphasis, you know.)

For the record, here are the results:

Dexamethasone reduced deaths by

  • one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by
  • one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021).

When a study stops because of a survival benefit for a life-threatening disease, take note. It’s because continuing the study as originally designed is unethical — those randomized to receive “usual care” would be deprived of a potentially life-saving treatment.

The steering committee has a responsibility of ensuring the safety of trial participants. And remember, they have access to all the study data, even if we don’t. Credit: NIAID

It’s critical that this information be made available as soon as possible. Patients are being treated today who might benefit, and writing papers and subsequent peer review take time — typically weeks, even with the “warp speed” of COVID-19.

To quote one of the investigators: “Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.”

Well said.

Why are we getting critical information via press release? I’m inherently distrustful. A press release doesn’t represent actual data.

It’s reasonable to be skeptical of clinical trial press releases, especially when issued by private pharmaceutical companies with multi-million dollar marketing divisions.

These notoriously exaggerate the importance of study results, especially when focused on surrogate markers of disease that may or may not predict clinical outcome.

But consider — this isn’t a press release by a giant company, citing a minor change in an inflammatory cytokine or quality-of-life metric in an open-label study. It’s a respected clinical trials group, funded by the government of Great Britain, and they are reporting a survival benefit from their clinical trial.

To their credit, they early on started doing randomized trials of various COVID-19 interventions while the rest of the globe practiced the therapeutic equivalent of throwing drugs against the wall hoping some of them would stick.

  • Lopinavir-ritonavir!
  • Interferons!
  • Oseltamivir!
  • Hydroxychloroquine!
  • Azithromycin!
  • Ivermectin!

And it’s not just antimicrobials — virtually every immunomodulator under the sun, some extremely expensive, has found its way to off-label use for critically ill patients with COVID-19.

  • Tocilizumab!
  • Sarilumab!
  • Anakinra!
  • Ruxolitinib!
  • Eculizumab!
  • Any-other-mab! And more …

Yes, it’s hard to keep up — see Table 1 in this recent review for all the various anti-inflammatory approaches tried off-label, with many of these now under study.

If we’re using some of these unproven therapies — and many of us have — why not dexamethasone, which in the RECOVERY trial improved survival?

Here we go again! Haven’t we been burned already multiple times with research on COVID-19, only later to have this information questioned, or retracted?

Quite reasonable to be cautious in this very fast-moving area.

But the infamous research that has “burned” us involved much weaker levels of evidence — little more than anecdotal observations at one extreme and observational studies with likely falsified data at the other.

None has been a randomized clinical trial with a survival benefit.

(Have I noted that result enough times already? Nah.)

I need more details about the study. What were the primary endpoints? The specifics of the intervention? What were the patient characteristics of those enrolled? Did some subgroups benefit more than others? What were the toxicities? 

All very reasonable questions! But good news — we have the full protocol available for review. This can answer some of these queries, including the endpoints and description of the exact interventions studied.

https://blogs.jwatch.org/hiv-id-observations/index.php/dexamethasone-improves-survival-in-covid-19-why-this-should-be-practice-changing-even-before-the-paper-is-published/2020/06/21/?query=C19

 

RRFERENCES

Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on dexamethasone, 16 June 2020

https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19

SOURCE

https://blogs.jwatch.org/hiv-id-observations/index.php/dexamethasone-improves-survival-in-covid-19-why-this-should-be-practice-changing-even-before-the-paper-is-published/2020/06/21/?query=C19

Other Related Studies

Countermeasures to COVID-19: Are immunomodulators rational treatment options — a critical review of the evidence 

Open Forum Infectious Diseases, ofaa219, https://doi.org/10.1093/ofid/ofaa219
Published:
05 June 2020

Article history

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with higher concentrations of pro-inflammatory cytokines which leads to lung damage, respiratory failure, and resultant increased mortality. Immunomodulatory therapy has the potential to inhibit cytokines and quell the immune dysregulation. Controversial data found improved oxygenation after treatment with tocilizumab, an IL-6 inhibitor, sparking a wave of interest and resultant clinical trials evaluating immunomodulatory therapies. The purpose of this article is to assess potential pro-inflammatory targets and review the safety and efficacy of immunomodulatory therapies in managing patients with acute respiratory distress syndrome associated with COVID-19.

Conclusions from PDF Full Article Version

SARS-CoV-2 leads to ALI and ARDS with increased mortality. Immunomodulatory therapies have the potential to inhibit cytokines, but the role of elevated cytokines with lung pathology is unclear. The overall lack of evidence and recommendations has forced practitioners to use their own judgment regarding use of immunomodulatory therapy. We are hopeful that as clinical trial data become available their role in managing patients with COVID-19 will emerge. For now, available evidence suggests these treatment options be reserved for use in critically ill COVID-19 patients enrolled in clinical trials. Due to the potential adverse effects, risks and benefits must be weighed and proper screening completed prior to use.

This content is only available as a PDF.

About the RECOVERY trial

The RECOVERY trial is a large, randomised controlled trial of possible treatments for patients admitted to hospital with COVID-19. Over 11,500 patients have been randomised to the following treatment arms, or no additional treatment:

  • Lopinavir-Ritonavir (commonly used to treat HIV)
  • Low-dose Dexamethasone (a type of steroid, which typically used to reduce inflammation)
  • Hydroxychloroquine (which has now been stopped due to lack of efficacy)
  • Azithromycin (a commonly used antibiotic)
  • Tocilizumab (an anti-inflammatory treatment given by injection)
  • Convalescent plasma (collected from donors who have recovered from COVID-19 and contains antibodies against the SARS-CoV-2 virus).

Overall dexamethasone reduced the 28-day mortality rate by 17% (0.83 [0.74 to 0.92]; P=0.0007) with a highly significant trend showing greatest benefit among those patients requiring ventilation (test for trend p<0.001). But it is important to recognise that we found no evidence of benefit for patients who did not require oxygen and we did not study patients outside the hospital setting. Follow-up is complete for over 94% of participants.

The RECOVERY Trial is conducted by the registered clinical trials units with the Nuffield Department of Population Health in partnership with the Nuffield Department of Medicine. The trial is supported by a grant to the University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR) and by core funding provided by NIHR Oxford Biomedical Research CentreWellcome, the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit, and NIHR Clinical Trials Unit Support Funding.

The RECOVERY trial involves many thousands of doctors, nurses, pharmacists, and research administrators at over 175 hospitals across the whole of the UK, supported by staff at the NIHR Clinical Research Network, NHS DigiTrials, Public Health England, Public Health Scotland, Department of Health & Social Care, and the NHS in England, Scotland, Wales and Northern Ireland.

About Oxford University

Oxford University has been placed number 1 in the Times Higher Education World University Rankings for the third year running, and at the heart of this success is our ground-breaking research and innovation.

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Updates on the Oxford, AstraZeneca COVID-19 Vaccine

Reporter: Stephen J. Williams, PhD

AstraZeneca’s CEO states that their COVID-19 vaccine, codeveloped with Oxford University, should provide protection for a year.

AstraZeneca’s potential coronavirus vaccine is likely to provide protection against contracting Covid-19 for about a year, the company’s chief executive told a Belgian radio station on Tuesday.

The British drugmaker has already begun human trials of the vaccine developed by the University of Oxford, with a phase I trial in Britain due to end soon and a phase III trial already begun, Pascal Soriot told broadcaster Bel RTL.

“We think that it will protect for about a year,” Soriot said.

AstraZeneca said on Saturday that it had signed contracts with France, Germany, Italy and the Netherlands to supply the European Union with up to 400 million doses of the potential vaccine.

It has also agreed deals with Britain and the United States.

“If all goes well, we will have the results of the clinical trials in August/September. We are manufacturing in parallel. We will be ready to deliver from October if all goes well,” Soriot said.

Source: https://www.cnbc.com/2020/06/16/astrazeneca-covid-19-vaccine-likely-to-protect-for-a-year-ceo-says.html

 

 

From In The Pipeline (Derek Lowe’s regular column in Science)

Criticism of the Oxford Coronavirus Vaccine

By Derek Lowe 18 May, 2020

This piece at Forbes by Bill Haseltine has set off a lot of comment – it’s a look at the Oxford group’s vaccine candidate as compared to the SinoVac candidate, and you may recall (background here) that these are the two teams that have separately reported that their vaccines appear to protect rhesus monkeys from infection after exposure to the coronavirus. Haseltine has some criticisms of the Oxford data, and as you will see from that link to his name, his opinions deserve to be taken seriously. So what’s going on? Update: here’s the take on this at BioCentury.

Looking at the preprint on the Oxford results, Haseltine has a problem with the claim that the monkeys were protected from infection by a dose of ChAdOx1 nCoV-19. The key data are in the preprint’s Figure 3. The Oxford team checked for viral RNA several different ways. One was using bronchoaveolar lavage (BAL fluid), a sampling technique that involves running a bronchoscope down into the lungs and washing out aveolar spaces – a pretty darn invasive assay, which is why you don’t hear about it all that much compared to the still-not-so-nonivasive nose swabs. BAL fluid of the virus-exposed unvaccinated animals showed coronavirus genomic RNA throughout the study, and viral subgenomic RNA (more indicative of active replication) at days 3 and 5 after exposure. Meanwhile, the vaccinated animals showed the genomic RNA in only two monkeys, and no subgenomic RNA at all.

So far, so good. But both vaccinated and unvaccinated monkeys showed the same amount of viral genomic RNA from nose swab samples (Figure 3c). That’s the test that’s used out in the human population, and that means that the vaccinated animals would still be declared as positive for the coronavirus after being exposed to it. And the other thing that Haseltine notes is that the amount (the “titer”, in the lingo) of neutralizing antibodies in the blood of the vaccinated animals does not appear to be that high. You’d like to be able to dilute the blood antibody samples down by hundreds of times or even a thousandfold and still see antiviral activity in an in vitro assay, but in the Oxford case the activity started disappearing at about fortyfold dilution (Figure 2b).

On the positive side, 2/3 of the unvaccinated animals showed clear evidence of viral pneumonia at autopsy, but none of the vaccinated ones did. The conclusion is that the vaccinated animals were indeed infected – the vaccine did not protect against that – but that the disease was definitely less severe. But these results mean that the virus might well still be transmissible from people who had been so vaccinated, even if the disease course itself was not as deadly. You’d want to do better than that, if you can. Haseltine’s take is “Time will tell if this is the best approach. I wouldn’t bet on it.

Haseltine compares these results to the SinoVac inactivated virus vaccine, and finds that that one looks better – at its highest dose, no viral RNA was recovered from the tissues of the vaccinated animals, for example. This sort of “sterilizing immunity” is what you’d want to aim for – it gives the virus nowhere to go in the human population if you can vaccinate enough people. But it’s worth noting that the SinoVac results were from three doses of their vaccine (versus one of the Oxford candidate), and the viral exposure challenge was about half as strong (total viral particles) as what the Oxford paper used. The Oxford group also inoculated their monkeys in both the upper and lower respiratory tract, while the SinoVac team used a single inoculation in the trachea. So I agree with that tweet linked from AndyBiotech; I don’t think that a head-to-head comparison is fair. But Haseltine’s point stands, that the results as we have them from the ChAdOx1 nCoV-19 vaccine did not actually protect monkeys from infection.

Source: https://blogs.sciencemag.org/pipeline/archives/2020/05/18/criticism-of-the-oxford-coronavirus-vaccine

 

Please see other Articles on COVID-19 on our Coronavirus Portal Including Late Breaking News at:

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

 

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COVID-19: Pandemic Surgery Guidance published by a Global Consortium initiated effort by Björn L.D.M. Brücher, MD, PhD, Prof. Of Surgery, Carl-Thiem-Klinikum, Cottbus, Germany

Reporter: Aviva Lev-Ari, PhD, RN

This video interview with the corresponding author, Björn L.D.M. Brücher, considers the changing landscape of surgery as a result of COVID-19, and explores the process of creating this guidance in an innovative and collaborative way. A ‘Key Summary’ has also been produced in an easy to understand Q&A format.

Watch the full video: https://bit.ly/2AkEgLm
Read the ‘Key Summary’: https://bit.ly/2MNtK20

 

Issue
4open
Volume 3, 2020
Article Number 1
Number of page(s) 19
DOI https://doi.org/10.1051/fopen/2020002
Published online 10 April 2020

© B.L.M.D. Brücher et al., Published by EDP Sciences, 2020

Licence Creative Commons
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

SOURCE

https://www.4open-sciences.org/articles/fopen/full_html/2020/01/fopen200002s/fopen200002s.html

 

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

EIGHT pages on the Coronavirus Portal:

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

Coronavirus Pandemic: RESEARCH CATEGORIES in JOURNAL ONTOLOGY

  • Population genetics
  •  Population Health Management
    •  U.S. Employment-to-Population Ratio

OPEN TO GUEST AUTHORS

on Seven Selected Topics & Lead Curator for Contact:

BREAKING NEWS CORNER

June 2020

 

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New Coronavirus Passive Vaccine Developed by Israeli Researchers

Reporter: Irina Robu, PhD

Researchers at Bar-Ilan University have identified short amino acid sequences that could help the development of a vaccine against COVID-19 virus. Of the 25 epitopes that were discovered to be 100% identical to SARS, seven are theoretically efficient vaccine candidates. Their research indicate that they could cover as much as 87% of the world population

Their study has identified a set of immunodominant epitopes from the SARS-CoV-2 proteome, which are capable of generating antibody and cell mediated immune responses. The epitopes, known as antigenic determinants, are the part of the antigen that binds to a specific antigen receptor on the surface of B cells or T cells and are able to provoke an immune response.

It is known that immune response occurs within an organism for the purpose of defending against foreign invaders such as viruses, bacteria, parasites and fungi. The immune responses that are based on specific immunodominant epitopes contain the generation of both antibody- and cell-mediated immunity against pathogens. Such immunity can facilitate fast and effective elimination of the pathogen. The end result is a passive vaccine capable of capable of activating both cellular and humoral immune responses in humans.

According to the team at Bar-Ilan University, the mapped coronavirus epitopes with those of the influenza virus. And they found that 85% of the sequence identity with experimentally detected epitopes of Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV).

Additional analysis indicated that the epitopes are non-allergic and non-toxic to humans and have very low risk for generating autoimmune responses. The team is looking to partner with companies to build vaccine constructs and test them in-vitro and on animal trials before starting any clinical trials.

SOURCE

https://www.jpost.com/health-science/israeli-researchers-on-road-to-new-covid-19-passive-vaccine-630988?utm_source=ActiveCampaign

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The Complexity of Estimation of the Economic Impact of an Outbreak | Panel Discussion | BC Woods College

Reporter: Ofer Markman, PhD

Economic Impact of an Outbreak | Panel Discussion | BC Woods College

197 views

May 21, 2020

Prominent economists, all faculty of the Boston College M.S. in Applied Economics degree program in the Woods College of Advancing Studies, presented a virtual panel discussion on the impact of the coronavirus outbreak on the health care system and the global economy. For more information about the M.S. program, visit https://on.bc.edu/MSAppliedEcon

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The Wide Variability in Reported COVID-19 Epidemiologic Data May Suggest That Personalized Omic Testing May Be Needed to Identify At-Risk Populations

Curator: Stephen J. Williams, PhD

I constantly check the Youtube uploads from Dr. John Campbell, who is a wonderful immunologist and gives daily reports on new findings on COVID-19 from the scientific literature.  His reporting is extremely insightful and easily understandable.  This is quite a feat as it seems the scientific field has been inundated with a plethora of papers, mostly reported clinical data from small retrospective studies, and many which are being put on preprint servers, and not peer reviewed.

It has become a challenge for many scientists, already inundated with expanding peer reviewed literature in their own fields, as well as the many requests to review papers, to keep up with all these COVID related literature.  Especially when it is up to the reader to do their own detailed peer review. So many thanks to people like Dr. Campbell who is an expert in his field for doing this.

However the other day he had posted a video which I found a bit disturbing, as a central theme of the video was that many expert committee could not find any reliable epidemiologic study concerning transmission or even incidence of the disease.  In all studies, as Dr. Campell alluded to, there is such a tremendous variability in the reported statistics, whether one is looking at percentage of people testing positive who are symptomatic, the percentage of asymptomatic which may be carriers, the transmission of the disease, and even the percentage of people who recover.

With all the studies being done it would appear that, even if a careful meta analysis were done using all available studies, and assuming their validity before peer review, that there would be a tighter consensus on some of these metrics of disease spread, incidence and prevalence.

Below is the video from Dr. Campbell and the topic is on percentage of asymptomatic carriers of the COVID-19 virus.  This was posted last week but later in this post there will be updated information and views by the WHO on this matter as well as other literature (which still shows to my point that this wide variability in reported data may be adding to the policy confusion with respect to asymptomatic versus symptomatic people and why genetic testing might be needed to further discriminate these cohorts of people.

 

Below is the video: 

From the Oxford Center for Evidence Based Medicine: COVID-19 Portal at https://www.cebm.net/oxford-covid-19-evidence-service/

“There is not a single reliable study to determine the number of asymptomatic infections”

And this is very troubling as this means there is no reliable testing resulting in any meaningful data.

As Dr. Campell says

” This is not good enough.  There needs to be some sort of coordinated research program it seems all ad hoc”

A few other notes from post and Oxford Center for Evidence Based Medicine:

  • Symptom based screening will miss a lot of asymptomatic and presymptomatic cases
  • Some asymptomatic cases will become symptomatic over next week (these people were technically presymptomatic but do we know the %?)
  • We need a population based antibody screening program
  • An Italian study of all 3,000 people in city of Vo’Euganeo revealed that 50-75% of those who tested positive were asymptomatic and authors concluded that asymptomatic represents “a formidable source of infection”; Dr. Campbell feels this was a reliable study
  • Another study from a Washington state nursing facility showed while 56% of positive cases were asymptomatic, 75% of these asymptomatic developed symptoms within a week. Symptom based screening missed half of cases.
  • Other studies do not follow-up on the positive cases to determine in presymptomatic
  • It also appears discrepancies between data from different agencies (like CDC, WHO) on who is shedding virus as different tests used (PCR vs antibody)

 

Recent Studies Conflict Concerning Asymptomatic, Presymtomatic and Viral Transmission

‘We don’t actually have that answer yet’: WHO clarifies comments on asymptomatic spread of Covid-19

From StatNews

A top World Health Organization official clarified on Tuesday that scientists have not determined yet how frequently people with asymptomatic cases of Covid-19 pass the disease on to others, a day after suggesting that such spread is “very rare.”

The clarification comes after the WHO’s original comments incited strong pushback from outside public health experts, who suggested the agency had erred, or at least miscommunicated, when it said people who didn’t show symptoms were unlikely to spread the virus.

Maria Van Kerkhove, the WHO’s technical lead on the Covid-19 pandemic, made it very clear Tuesday that the actual rates of asymptomatic transmission aren’t yet known.

Some of the confusion boiled down to the details of what an asymptomatic infection actually is, and the different ways the term is used. While some cases of Covid-19 are fully asymptomatic, sometimes the word is also used to describe people who haven’t started showing symptoms yet, when they are presymptomatic. Research has shown that people become infectious before they start feeling sick, during that presymptomatic period.

At one of the WHO’s thrice-weekly press briefings Monday, Van Kerkhove noted that when health officials review cases that are initially reported to be asymptomatic, “we find out that many have really mild disease.” There are some infected people who are “truly asymptomatic,” she said, but countries that are doing detailed contact tracing are “not finding secondary transmission onward” from those cases. “It’s very rare,” she said.

Source: https://www.statnews.com/2020/06/09/who-comments-asymptomatic-spread-covid-19/

 

Therefore the problems have been in coordinating the testing results, which types of tests conducted, and the symptomology results.  As Dr. Campbell previously stated it appears more ‘ad hoc’ than coordinated research program.  In addition, defining the presymptomatic and measuring this group have been challenging.

However, an alternative explanation to the wide variability in the data may be we need to redefine the cohorts of patients we are evaluating and the retrospective data we are collecting.  It is feasible that sub groups, potentially defined by genetic background may be identified and data re-evaluated based on personalized omic data, in essence creating new cohorts based on biomarker data.

From a Perspective in The Lancet about a worldwide proteomic effort (COVID-19 MS Coalition) to discover biomarkers related to COVID19 infection risk, by identifying COVID-related antigens.

The COVID-19 MS Coalition is a collective mass spectrometry effort that will provide molecular level information on SARS-CoV-2 in the human host and reveal pathophysiological and structural information to treat and minimise COVID-19 infection. Collaboration with colleagues at pace involves sharing of optimised methods for sample collection and data generation, processing and formatting for maximal information gain. Open datasets will enable ready access to this valuable information by the computational community to help understand antigen response mechanisms, inform vaccine development, and enable antiviral drug design. As countries across the world increase widespread testing to confirm SARS-CoV-2 exposure and assess immunity, mass spectrometry has a significant role in fighting the disease. Through collaborative actions, and the collective efforts of the COVID-19 MS Coalition, a molecular level quantitative understanding of SARS-CoV-2 and its effect will benefit all.

 

In an ACS Perspective below, Morteza Mahmoudi suggests a few possible nanobased technologies (i.e., protein corona sensor array and magnetic levitation) that could discriminate COVID-19-infected people at high risk of death while still in the early stages of infection.

Emerging Biomolecular Testing to Assess the Risk of Mortality from COVID-19 Infection

Morteza Mahmoudi*

Publication Date:May 7, 2020

 

Please see other articles on COVID-19 on our Coronavirus Portal at

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

https://pharmaceuticalintelligence.com/coronavirus-portal/an-epidemiological-approach-stephen-j-williams-phd-and-aviva-lev-ari-phd-rn-lead-curators-e-mail-contacts-sjwilliamspacomcast-net-and-avivalev-arialum-berkeley-edu/

and

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

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COVID-19’s seasonal cycle to be estimated at Lawrence Berkeley National Laboratory (Berkeley Lab) by Artificial Intelligence and Machine Learning Algorithms: Will A Fall and Winter resurgence be Likely??

Reporter: Aviva Lev-Ari, PhD, RN

Using machine learning to estimate COVID-19’s seasonal cycle

Woman walks down empty city street wearing a mask

Credit: Ivan Marc/Shutterstock

Berkeley Lab researchers have launched a project to determine if the novel coronavirus might be seasonal, waning in summer months and resurging in fall and winter.

One of the many unanswered scientific questions about COVID-19 is whether it is seasonal like the flu — waning in warm summer months then resurging in the fall and winter.

Now scientists at Lawrence Berkeley National Laboratory (Berkeley Lab) are launching a project to apply machine-learning methods to a plethora of health and environmental datasets, combined with high-resolution climate models and seasonal forecasts, to tease out the answer.

“Environmental variables, such as temperature, humidity, and UV [ultraviolet radiation] exposure, can have an effect on the virus directly, in terms of its viability. They can also affect the transmission of the virus and the formation of aerosols,” said Berkeley Lab scientist Eoin Brodie, the project lead. “We will use state-of-the-art machine-learning methods to separate the contributions of social factors from the environmental factors to attempt to identify those environmental variables to which disease dynamics are most sensitive.

The research team will take advantage of an abundance of health data available at the county level — such as the severity, distribution and duration of the COVID-19 outbreak, as well as what public health interventions were implemented when — along with demographics, climate and weather factors, and, thanks to smartphone data, population mobility dynamics. The initial goal of the research is to predict — for each county in the United States — how environmental factors influence the transmission of the SARS-CoV-2 virus, which causes COVID-19.

Multidisciplinary team for a complex problem

Untangling environmental factors from social and health factors is a knotty problem with a large number of variables, all interacting in different ways. On top of that, climate and weather affect not only the virus but also human physiology and behavior. For example, people may spend more or less time indoors, depending on the weather; and their immune systems may also change with the seasons.

It’s a complex data problem similar to others tackled by Berkeley Lab’s researchers studying systems like watersheds and agriculture; the challenge involves integrating data across scales to make predictions at the local level. “Downscaling of climate information is something that we routinely do to understand how climate impacts ecosystem processes,” Brodie said. “It involves the same types of variables — temperature, humidity, solar radiation.”

Brodie, deputy director of Berkeley Lab’s Climate and Ecosystem Sciences Division, is leading a cross-disciplinary team of Lab scientists with expertise in climate modeling, data analytics, machine learning, and geospatial analytics. Ben Brown, a computational biologist in Berkeley Lab’s Biosciences Area, is leading the machine-learning analysis. One of their main aims is to understand how climate and weather interact with societal factors.

“We don’t necessarily expect climate to be a massive or dominant effect in and of itself. It’s not going to trump which city shut down when,” Brown said. “But there may be some really important interactions [between the variables]. Looking at New York and California for example, even accounting for the differences between the timing of state-instituted interventions, the death rate in New York may be four times higher than in California — though additional testing on random samples of the population is needed to know for sure. Understanding the environmental interactions may help explain why these patterns appear to be emerging. This is a quintessential problem for machine learning and AI [artificial intelligence].”

The computing work will be conducted at the National Energy Research Scientific Computing Center (NERSC), a DOE Office of Science user facility located at Berkeley Lab.

Signs of climatic influences

map of the worldwide incidence rate of COVID-19
The worldwide incidence rate of COVID-19.
Credit: Center for Systems Science and Engineering at Johns Hopkins University

Already, geographical differences in how the disease behaves have been reported, the researchers point out. Temperature, humidity, and the UV Index have all been statistically associated with rates of COVID-19 transmission — although contact rates are still the dominant influence on the spread of disease. In the southern hemisphere, for example, where it’s currently fall, disease spread has been slower than in the northern hemisphere. “There’s potentially other factors associated with that,” Brodie said. “The question is, when the southern hemisphere moves into winter, will there be an increase in transmission rate, or will fall and winter 2020 lead to a resurgence across the U.S. in the absence of interventions?”

India is another place where COVID-19 does not yet appear to be as virulent. “There are cities where it behaves as if it’s the most infectious disease in recorded history. Then there are cities where it behaves more like influenza,” Brown said. “It is really critical to understand why we see those massive differences.”

Brown notes other experiments suggesting the SARS-CoV-2 virus could be seasonal. In particular, the National Biodefense Analysis and Countermeasures Center (NBACC) assessed the longevity of the virus on various surfaces. “Under sunlight and humidity, they found that the virus loses viability in under 60 minutes,” Brown said. “But in darkness and low temperatures it’s stable for eight days. There’s some really serious differences that need investigating.”

The Berkeley Lab team believes that enough data may now be available to determine what environmental factors may influence the virulence of the virus. “Now we should have enough data from around the world to really make an assessment,” Brown said.

The team hopes to have the first phase of their analysis available by late summer or early fall. The next phase will be to make projections under different scenarios, which could aid in public health decisions.

“We would use models to project forward, with different weather scenarios, different health intervention scenarios — such as continued social distancing or whether there are vaccines or some level of herd immunity — in different parts of the country. For example, we hope to be able to say, if you have kids going back to school under this type of environment, the climate and weather in this zone will influence the potential transmission by this amount,” Brodie explained. “That will be a longer-term task for us to accomplish.”

This research is supported by Berkeley Lab’s Laboratory Directed Research and Development (LDRD) program. Other team members include Dan Feldman, Zhao Hao, Chaincy Kuo, Haruko Wainwright, and Nicola Falco. Berkeley Lab mobilized quickly to provide LDRD funding for several research projects to address the COVID-19 pandemic, including one on text mining scientific literature and another on indoor transmission of the virus.

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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

From: “Dr. Larry Bernstein” <larry.bernstein@gmail.com>

Reply-To: “Dr. Larry Bernstein” <larry.bernstein@gmail.com>

Date: Tuesday, June 2, 2020 at 8:50 AM

To: Aviva Lev-Ari <aviva.lev-ari@comcast.net>

Subject: Re: Coronavirus May Be a Vascular Disease, Which Explains Everything | Elemental

“I don’t think the conclusion is fully validated. I would want to see autopsy reports, like that found in China. It can be done safely, and the tools could be discarded.”

Larry

UPDATED on 6/29/2020

Another duality and paradox in the Treatment of COVID-19 Patients in ICUs was expressed by Mike Yoffe, MD, PhD, David H. Koch Professor of Biology and Biological Engineering, Massachusetts Institute of Technology. Dr. Yaffe has a joint appointment in Acute Care Surgery, Trauma, and Surgical Critical Care, and in Surgical Oncology @BIDMC

on 6/29 at SOLUTIONS with/in/sight at Koch Institute @MIT

How Are Cancer Researchers Fighting COVID-19? (Part II)” Jun 29, 2020 11:30 AM EST

Mike Yoffe, MD, PhD 

In COVID-19 patients: two life threatening conditions are seen in ICUs:

  • Blood Clotting – Hypercoagulability or Thrombophilia
  • Cytokine Storm – immuno-inflammatory response
  • The coexistence of 1 and 2 – HINDERS the ability to use effectively tPA as an anti-clotting agent while the cytokine storm is present.

Mike Yoffe’s related domain of expertise:

Signaling pathways and networks that control cytokine responses and inflammation

Misregulation of cytokine feedback loops, along with inappropriate activation of the blood clotting cascade causes dysregulation of cell signaling pathways in innate immune cells (neutrophils and macrophages), resulting in tissue damage and multiple organ failure following trauma or sepsis. Our research is focused on understanding the role of the p38-MK2 pathway in cytokine control and innate immune function, and on cross-talk between cytokines, clotting factors, and neutrophil NADPH oxidase-derived ROS in tissue damage, coagulopathy, and inflammation, using biochemistry, cell biology, and mouse knock-out/knock-in models.  We recently discovered a particularly important link between abnormal blood clotting and the complement pathway cytokine C5a which causes excessive production of extracellular ROS and organ damage by neutrophils after traumatic injury.

SOURCE

https://www.bidmc.org/research/research-by-department/surgery/acute-care-surgery-trauma-and-surgical-critical-care/michael-b-yaffe

 

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

Mandeep Mehra, MD, medical director of the Brigham and Women’s Hospital Heart and Vascular Center.

“All these Covid-associated complications were a mystery. We see blood clotting, we see kidney damage, we see inflammation of the heart, we see stroke, we see encephalitis [swelling of the brain],” says William Li, MD, president of the Angiogenesis Foundation. “A whole myriad of seemingly unconnected phenomena that you do not normally see with SARS or H1N1 or, frankly, most infectious diseases.”

“If you start to put all of the data together that’s emerging, it turns out that this virus is probably a vasculotropic virus, meaning that it affects the [blood vessels],”

Mehra explains. “Then it starts to infect endothelial cell after endothelial cell, creates a local immune response, and inflames the endothelium.”

Benhur Lee, MD, a professor of microbiology at the Icahn School of Medicine at Mount Sinai:

“In SARS1, the protein that’s required to cleave it is likely present only in the lung environment, so that’s where it can replicate. To my knowledge, it doesn’t really go systemic,” Lee says. “[SARS-CoV-2] is cleaved by a protein called furin, and that’s a big danger because furin is present in all our cells, it’s ubiquitous.”

Sanjum Sethi, MD, MPH, an interventional cardiologist at Columbia University Irving Medical Center:

“The endothelial cell layer is in part responsible for [clot] regulation, it inhibits clot formation through a variety of ways, If that’s disrupted, you could see why that may potentially promote clot formation.” Damage to endothelial cells causes inflammation in the blood vessels, and that can cause any plaque that’s accumulated to rupture, causing a heart attack. “Inflammation and endothelial dysfunction promote plaque rupture. Endothelial dysfunction is linked towards worse heart outcomes, in particular myocardial infarction or heart attack.”

https://elemental.medium.com/coronavirus-may-be-a-blood-vessel-disease-which-explains-everything-2c4032481ab2

Endothelial cell dysfunction: pre-existing conditions like high blood pressure, high cholesterol, diabetes, and heart disease are at a higher risk for severe complications from a virus that’s supposed to just infect the lungs. Why ventilation often isn’t enough to help many Covid-19 patients breathe better. Moving air into the lungs, which ventilators help with, is only one part of the equation. The exchange of oxygen and carbon dioxide in the blood is just as important to provide the rest of the body with oxygen, and that process relies on functioning blood vessels in the lungs.

William Li, MD, president of the Angiogenesis Foundation:

“If you have blood clots within the blood vessels that are required for complete oxygen exchange, even if you’re moving air in and out of the airways, [if] the circulation is blocked, the full benefits of mechanical ventilatory support are somewhat thwarted,” “We were observing virus particles filling up the endothelial cell like filling up a gumball machine. The endothelial cell swells and the cell membrane starts to break down, and now you have a layer of injured endothelium.” “Endothelial cells connect the entire circulation [system], 60,000 miles worth of blood vessels throughout our body,” says Li. “Is this one way that Covid-19 can impact the brain, the heart, the Covid toe? Does SARS-CoV-2 traffic itself through the endothelial cells or get into the bloodstream this way? We don’t know the answer to that.”

https://elemental.medium.com/coronavirus-may-be-a-blood-vessel-disease-which-explains-everything-2c4032481ab2

If Covid-19 is a vascular disease, the best antiviral therapy might not be antiviral therapy

“I suspect from what we see and what our preliminary data show is that this virus has an additional risk factor for blood clots, but I can’t prove that yet,” Sethi says. An alternative theory is that the blood clotting and symptoms in other organs are caused by inflammation in the body due to an over-reactive immune response — the so-called cytokine storm

SARS-CoV-2 virus can infect the endothelial cells that line the inside of blood vessels. Endothelial cells protect the cardiovascular system, and they release proteins that influence everything from blood clotting to the immune response. In the paper, the scientists showed damage to endothelial cells in the lungs, heart, kidneys, liver, and intestines in people with Covid-19.

Treatment Protocol for COVID-19

The good news is that if Covid-19 is a vascular disease, there are existing drugs that can help protect against endothelial cell damage. In another New England Journal of Medicine paper that looked at nearly 9,000 people with Covid-19, Mehra showed that the use of statins and ACE inhibitors were linked to higher rates of survival. Statins reduce the risk of heart attacks not only by lowering cholesterol or preventing plaque, they also stabilize existing plaque, meaning they’re less likely to rupture if someone is on the drugs.

“It turns out that both statins and ACE inhibitors are extremely protective on vascular dysfunction,” Mehra says. “Most of their benefit in the continuum of cardiovascular illness — be it high blood pressure, be it stroke, be it heart attack, be it arrhythmia, be it heart failure — in any situation the mechanism by which they protect the cardiovascular system starts with their ability to stabilize the endothelial cells.”

  • The best therapy might actually be a drug that stabilizes the vascular endothelial.

Endothelial cell infection and endotheliitis in COVID-19

Cardiovascular complications are rapidly emerging as a key threat in coronavirus disease 2019 (COVID-19) in addition to respiratory disease. The mechanisms underlying the disproportionate effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities, however, remain incompletely understood.
SARS-CoV-2 infects the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the lung, heart, kidney, and intestine. ACE2 receptors are also expressed by endothelial cells.
Whether vascular derangements in COVID-19 are due to endothelial cell involvement by the virus is currently unknown. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro.
Here we demonstrate endothelial cell involvement across vascular beds of different organs in a series of patients with COVID-19 (further case details are provided in the appendix).
Patient 1 was a male renal transplant recipient, aged 71 years, with coronary artery disease and arterial hypertension. The patient’s condition deteriorated following COVID-19 diagnosis, and he required mechanical ventilation. Multisystem organ failure occurred, and the patient died on day 8.

Post-mortem analysis of the transplanted kidney by electron microscopy revealed viral inclusion structures in endothelial cells (figure A, B). In histological analyses, we found an accumulation of inflammatory cells associated with endothelium, as well as apoptotic bodies, in the heart, the small bowel (figure C) and lung (figure D). An accumulation of mononuclear cells was found in the lung, and most small lung vessels appeared congested.

See Figures in https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30937-5/fulltext

Findings
We found evidence of direct viral infection of the endothelial cell and diffuse endothelial inflammation. Although the virus uses ACE2 receptor expressed by pneumocytes in the epithelial alveolar lining to infect the host, thereby causing lung injury, the ACE2 receptor is also widely expressed on endothelial cells, which traverse multiple organs.
Recruitment of immune cells, either by direct viral infection of the endothelium or immune-mediated, can result in widespread endothelial dysfunction associated with apoptosis (figure D).
The vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis.
Endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischaemia, inflammation with associated tissue oedema, and a pro-coagulant state.
Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19.
COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins., , , ,
This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.

References

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Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19

List of authors.

  • Mandeep R. Mehra, M.D.,
  • Sapan S. Desai, M.D., Ph.D.,
  • SreyRam Kuy, M.D., M.H.S.,
  • Timothy D. Henry, M.D.,
  • and Amit N. Patel, M.D.

Metrics

Abstract

BACKGROUND

Coronavirus disease 2019 (Covid-19) may disproportionately affect people with cardiovascular disease. Concern has been aroused regarding a potential harmful effect of angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in this clinical context.

METHODS

Using an observational database from 169 hospitals in Asia, Europe, and North America, we evaluated the relationship of cardiovascular disease and drug therapy with in-hospital death among hospitalized patients with Covid-19 who were admitted between December 20, 2019, and March 15, 2020, and were recorded in the Surgical Outcomes Collaborative registry as having either died in the hospital or survived to discharge as of March 28, 2020.

CONCLUSIONS

Our study confirmed previous observations suggesting that underlying cardiovascular disease is associated with an increased risk of in-hospital death among patients hospitalized with Covid-19. Our results did not confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital death in this clinical context. (Funded by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital.)

As the coronavirus disease 2019 (Covid-19) pandemic has spread around the globe, there has been growing recognition that persons with underlying increased cardiovascular risk may be disproportionately affected.1-3 Several studies of case series have noted cardiac arrhythmias, cardiomyopathy, and cardiac arrest as terminal events in patients with Covid-19.1-4 Higher incidences of cardiac arrhythmias, acute coronary syndromes, and heart failure–related events have also been reported during seasonal influenza outbreaks, which suggests that acute respiratory infections may result in activation of coagulation pathways, proinflammatory effects, and endothelial cell dysfunction.5 In addition, however, concern has been expressed that medical therapy for cardiovascular disease might specifically contribute to the severity of illness in patients with Covid-19.6,7

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Covid-19, has been shown to establish itself in the host through the use of angiotensin-converting enzyme 2 (ACE2) as its cellular receptor.8 ACE2 is a membrane-bound monocarboxypeptidase found ubiquitously in humans and expressed predominantly in heart, intestine, kidney, and pulmonary alveolar (type II) cells.7,9 Entry of SARS-CoV-2 into human cells is facilitated by the interaction of a receptor-binding domain in its viral spike glycoprotein ectodomain with the ACE2 receptor.10

ACE2 is counterregulatory to the activity of angiotensin II generated through ACE1 and is protective against detrimental activation of the renin–angiotensin–aldosterone system. Angiotensin II is catalyzed by ACE2 to angiotensin-(1–7), which exerts vasodilatory, antiinflammatory, antifibrotic, and antigrowth effects.11 It has been suggested that ACE inhibitors and angiotensin-receptor blockers (ARBs) may increase the expression of ACE2, which has been shown in the heart in rats,12 and thereby may confer a predisposition to more severe infection and adverse outcomes during Covid-19.6,7 Others have suggested that ACE inhibitors may counter the antiinflammatory effects of ACE2. However, in vitro studies have not shown direct inhibitory activity of ACE inhibitors against ACE2 function.9,13

Despite these uncertainties, some have recommended cessation of treatment with ACE inhibitors and ARBs in patients with Covid-19.6 However, several scientific societies, including the American Heart Association, the American College of Cardiology, the Heart Failure Society of America, and the Council on Hypertension of the European Society of Cardiology, have urged that these important medications should not be discontinued in the absence of clear clinical evidence of harm.14,15 We therefore undertook a study to investigate the relationship between underlying cardiovascular disease and Covid-19 outcomes and to evaluate the association between cardiovascular drug therapy and mortality in this illness.

Discussion

Our investigation confirms previous reports of the independent relationship of older age, underlying cardiovascular disease (coronary artery disease, heart failure, and cardiac arrhythmias), current smoking, and COPD with death in Covid-19. Our results also suggest that women are proportionately more likely than men to survive the infection. Neither harmful nor beneficial associations were noted for antiplatelet therapy, beta-blockers, or hypoglycemic therapy. It is important to note that we were not able to confirm previous concerns regarding a potential harmful association of either ACE inhibitors or ARBs with in-hospital mortality in this clinical context.

In viral infections such as influenza, older age is associated with an increased risk of cardiovascular events and death.5 In the 2003 epidemic of severe acute respiratory syndrome (SARS, caused by SARS-CoV-1 infection), sex differences in the risk of death similar to those we observed were noted.17 Women have stronger innate and adaptive immunity and greater resistance to viral infections than men.18 In animal models of SARS-CoV-1 infection, higher susceptibility of male mice to SARS-CoV-1 and greater accumulation of macrophages and neutrophils in the lungs have been described.19 Ovariectomy or the use of estrogen-receptor antagonists increased mortality from SARS-CoV-1 infection in female animals. Furthermore, the difference in risk between the sexes increased with advancing age.19 These findings may support the observation in our investigation that suggested an association between survival and female sex, independent of older age.

Infection with SARS-CoV-2 is a mild disease in most people, but in some the disease progresses to a severe respiratory illness characterized by a hyperinflammatory syndrome, multiorgan dysfunction, and death.20 In the lung, the viral spike glycoprotein of SARS-CoV-2 interacts with cell-surface ACE2, and the virus is internalized by endocytosis. The endocytic event up-regulates the activity of ADAM metallopeptidase domain 17 (ADAM17), which cleaves ACE2 from the cell membrane, resulting in a loss of ACE2-mediated protection against the effects of activation of the tissue renin–angiotensin–aldosterone system while mediating the release of proinflammatory cytokines into the circulation.21 The stress of critical illness and inflammation may unite in destabilizing preexisting cardiovascular illness. Vascular endothelial cell dysfunction, inflammation-associated myocardial depression, stress cardiomyopathy, direct viral infection of the heart and its vessels, or the host response may cause or worsen heart failure, demand-related ischemia, and arrhythmias.22 These factors may underlie the observed associations between cardiovascular disease and death in Covid-19.

In our analyses, use of either ACE inhibitors or statins was associated with better survival among patients with Covid-19. However, these associations should be considered with extreme caution. Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred. These data also offer no information concerning the potential effect of initiation of ACE inhibitor or statin therapy in patients with Covid-19 who do not have an appropriate indication for these medications. Randomized clinical trials evaluating the role of ACE inhibitors and statins will be necessary before any conclusion can be reached regarding a potential benefit of these agents in patients with Covid-19.

In this multinational observational study involving patients hospitalized with Covid-19, we confirmed previous observations suggesting that underlying cardiovascular disease is independently associated with an increased risk of in-hospital death. We were not able to confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital mortality in this clinical context.

Supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital. The development and maintenance of the Surgical Outcomes Collaborative database was funded by Surgisphere.

This article was published on May 1, 2020, and updated on May 8, 2020, at NEJM.org.

Author Affiliations

From Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, Boston (M.R.M.); Surgisphere, Chicago (S.S.D.); Baylor College of Medicine and Department of Veterans Affairs, Houston (S.K.); Christ Hospital, Cincinnati (T.D.H.); the Department of Biomedical Engineering, University of Utah, Salt Lake City (A.N.P.); and HCA Research Institute, Nashville (A.N.P.).

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