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Archive for the ‘SARS-COV2 Hijacking the Complement and Coagulation Systems’ Category


The Impact of COVID-19 on the Human Heart

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

The Voice of Dr. Pearlman:

 

 

Editorial

September 22/29, 2020

The COVID-19 Pandemic and the JAMA Network

In 13 Viewpoints in this issue,214 JAMA Network editors reflect on the clinical, public health, operational, and workforce issues related to COVID-19 in each of their specialties. Questions and concerns they identify in their clinical communities include the following:

  • Benefits and harms of treatments and identifying mortality risk markers beyond age and comorbidities

  • Cardiovascular consequences of COVID-19 infection, including risks to those with comorbid hypertension and risks for myocardial injury

  • Risk for direct central nervous system invasion and COVID-19 encephalitis and for long-term neuropsychiatric manifestations in a post–COVID-19 syndrome

  • Risks related to SARS-CoV-2 infection for patients with compromised immunity, such as those receiving treatment for cancer

  • Challenges unique to patients with acute kidney injury and chronic kidney disease

  • Risks of viral transmission from aerosol-generating procedures, including most minimally invasive surgeries, and the need for eye protection as well as personal protective equipment as part of universal precautions

  • The prevalence and pathophysiology of skin findings in patients with COVID-19, determining if they are primary or secondary cutaneous manifestations of infection, and how best to manage them

  • The prevalence and significance of eye findings in patients with COVID-19 and the risk of transmission and infection through ocular surfaces

  • The role of anticoagulation for managing the endotheliopathy and coagulopathy characteristic of the infection in some patients

  • Developmental effects on children of the loss of family routines, finances, older loved ones, school and education, and social-based activities and milestone events

  • Effects of the pandemic, mitigation efforts, and economic downturn on the mental health of patients and frontline clinicians

  • Seasonality of transmission as the pandemic enters its third season

  • How to implement reliable seroprevalence surveys to document progression of the pandemic and effects of public health measures

  • Effects of the pandemic on access to care and the rise of telehealth

  • Consequences of COVID-19 for clinical capabilities, such as workforce availability in several specialties, delays in performing procedures and operations, and implications for medical education and resident recruitment.

Additional important questions that require careful observation and research include

  • Randomized evaluations of treatment: what is effective and safe, and what timing of which drug will reduce morbidity and mortality? Will a combination of therapies be more effective than any single drug?
  • Randomized evaluations of preventive interventions, including convalescent plasma, monoclonal antibodies, and vaccines. Which are effective and safe enough to prevent COVID-19 at a population level?
  • How can COVID-19 vaccines and therapeutics be distributed and paid for in ways that are fair and equitable?
  • Is immunity complete or partial, permanent or temporary, what is its mechanism, and how best is it measured? Can the virus mutate around host defenses?
  • How important are preadolescent children to the spread of infection to older family members and adult communities, and what are the implications for parent, caregiver, and teacher personal risk and disease transmission?
  • Is SARS-CoV-2 like influenza (continually circulating without or with seasonality), measles (transmissible but containable beneath threshold limits), or smallpox and polio (eradicable, or nearly so)?
  • Has the pandemic fundamentally altered the way health care is financed and delivered? By shining a spotlight on health inequities, can the pandemic motivate changes in health care finance, organization, and delivery to reduce those inequities?
  • Cardiology and COVID-19

Cardiology and COVID-19 – Original Article

Bonow  RO, O’Gara  PT, Yancy  CW.  Cardiology and COVID-19.   JAMA. Published online September 22, 2020. doi:10.1001/jama.2020.15088
Article Google Scholar

The initial reports on the epidemiology of coronavirus disease 2019 (COVID-19) emanating from Wuhan, China, offered an ominous forewarning of the risks of severe complications in elderly patients and those with underlying cardiovascular disease, including the development of acute respiratory distress syndrome, cardiogenic shock, thromboembolic events, and death. These observations have been confirmed subsequently in numerous reports from around the globe, including studies from Europe and the US. The mechanisms responsible for this vulnerability have not been fully elucidated, but there are several possibilities. Some of these adverse consequences could reflect the basic fragility of older individuals with chronic conditions subjected to the stress of severe pneumonia similar to influenza infections. In addition, development of type 2 myocardial infarction related to increased myocardial oxygen demand in the setting of hypoxia may be a predominant concern, and among patients with chronic coronary artery disease, an episode of acute systemic inflammation might also contribute to plaque instability, thus precipitating acute coronary syndromes, as has also been reported during influenza outbreaks.

However, in the brief timeline of the current pandemic, numerous publications highlighting the constellation of observed cardiovascular consequences have emphasized certain distinctions that appear unique to COVID-19.1 Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains entry via the upper respiratory tract, its affinity and selective binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is abundant in the endothelium of arteries and veins as well as in the respiratory tract epithelium, create a scenario in which COVID-19 is as much a vascular infection as it is a respiratory infection with the potential for serious vascular-related complications. This may explain why hypertension is one of the cardiovascular conditions associated with adverse outcomes. In the early stages of the pandemic, the involvement of the ACE2 receptor as the target for viral entry into cells created concerns regarding the initiation or continuation of treatment with ACE inhibitors and angiotensin receptor antagonists in patients with hypertension, left ventricular dysfunction, or other cardiac conditions. Subsequently, many studies have shown that these drugs do not increase susceptibility to infection or increase disease severity in those who contract the disease,2 thus supporting recommendations from academic societies that these drugs should not be discontinued in patients who develop COVID-19 infections.

Thrombosis, arterial or venous, is a hallmark of severe COVID-19 infections, related both to vascular injury and the prothrombotic cytokines released during the intense systemic inflammatory and immune responses.3 This sets the stage for serious thrombotic complications including acute coronary syndromes, ischemic strokes, pulmonary embolism, and ischemic damage to multiple other organ systems. Such events can complicate the course of any patient with COVID-19 but would be particularly devasting to individuals with preexisting cardiovascular disease.

Another unique aspect of COVID-19 infections that is not encountered by patients with influenza is myocardial injury, manifested by elevated levels of circulating troponin, creatinine kinase-MB, and myoglobin. Hospitalized patients with severe COVID-19 infections and consequent evidence of myocardial injury have a high risk of in-hospital mortality.4 Troponin elevations are most concerning, and when accompanied by elevations of brain natriuretic peptide, the risk is further accentuated. Although myocardial injury could reflect a COVID-19–related acute coronary event, most patients with troponin elevations who undergo angiography do not have epicardial coronary artery obstruction. Rather, those with myocardial injury have a high incidence of acute respiratory distress syndrome, elevation of D-dimer levels, and markedly elevated inflammatory biomarkers such as C-reactive protein and procalcitonin, suggesting that the combination of hypoxia, microvascular thrombosis, and systemic inflammation contributes to myocardial injury. Myocarditis is a candidate explanation for myocardial injury but has been difficult to confirm consistently. However, features of myocarditis have been reported in case reports5 based on clinical presentation and results of noninvasive imaging, but thus far confirmation of myocarditis based on myocardial biopsy or autopsy examinations has been a rare finding.6 Instead, myocardial tissue samples more typically show vascular or perivascular inflammation (endothelialitis) without leukocytic infiltration or myocyte damage.

There remain important unknowns regarding the intermediate and long-term sequelae of COVID-19 infection among hospital survivors. In an autopsy series of patients who died from confirmed COVID-19 without clinical or histological evidence of fulminant myocarditis,7 viral RNA was identified in myocardial tissue in 24 of 39 cases, with viral load of more than 1000 copies/μg of RNA in 16 cases. A cytokine response panel demonstrated upregulation of 6 proinflammatory genes (tumor necrosis factor, interferon γ, CCL4, and interleukin 6, 8, and 18) in the 16 myocardial samples with the high viral RNA levels.

Whether a subclinical viral load and associated cytokine response such as this in survivors of COVID-19 could translate into subsequent myocardial dysfunction and clinical heart failure require further investigation. However, the results of a recent biomarker and cardiac magnetic resonance (CMR) imaging study provide evidence to support this concern.6 Among 100 patients who were studied by CMR after recovery from confirmed COVID-19 infection, of whom 67 did not require hospitalization during the acute phase, left ventricular volume was greater and ejection fraction was lower than that of a control group. Furthermore, 78 patients had abnormal myocardial tissue characterization by CMR, with elevated T1 and T2 signals and myocardial hyperenhancement consistent with myocardial edema and inflammation, and 71 patients had elevated levels of high-sensitivity troponin T. Three patients with the most severe CMR abnormalities underwent myocardial biopsy, with evidence of active lymphocytic infiltration.6 It is noteworthy that all 100 patients in this series had negative COVID-19 test results at the time of CMR study (median, 71 days; interquartile range [IQR], 64-92 days after acute infection). The results of these relatively small series should be interpreted cautiously until confirmed by larger series with longer follow-up and with confirmed clinical outcomes. But the findings do underscore the uncertainty regarding the long-term cardiovascular consequences of COVID-19 in patients who have ostensibly recovered. Of note, a randomized clinical trial of anticoagulation to reduce the risk of thrombotic complications in the posthospital phase of COVID-19 infection is under development through the National Institutes of Health’s set of ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) initiatives.

In addition, the indirect effects of COVID-19 have become a major concern. Multiple observations during the COVID-19 pandemic confirm a sudden and inexplicable decline in rates of hospital admissions for ST–segment elevation myocardial infarction and other acute coronary syndromes beginning in March and April 2020. This has been a universal experience, with similar findings reported from multiple countries around the world in single-center observations, multicenter registries, and national databases. A concerning increase in out-of-hospital cardiac arrests has also been reported.8 These data suggest that COVID-19 has influenced health care–seeking behavior resulting in fewer presentations of acute coronary syndromes in emergency departments and more out-of-hospital events. Failure to seek appropriate emergency cardiac care could contribute to the observations of increased number of deaths and cardiac arrests, more than the anticipated average during this period8,9 with worse outcomes among those who ultimately do seek care.10 Recent data suggest that admission rates for myocardial infarction may be returning to baseline,10 but outcomes will improve only if patients seek care promptly and hospital systems are not overwhelmed by COVID-19 surges.

Given the ongoing activity of COVID-19, very clear messaging to the public and patients should include the following: heed the warning signs of heart attack, act promptly to initiate emergency medical services, and seek immediate care in hospitals, which have taken every step needed to be safe places. And especially, the messaging should continuously underscore the most important considerations that have been extant since this crisis began—wear a mask and practice physical distancing. In the meantime, the generation of rigorous evidence to inform best practices for diagnosis and management of COVID-19–related cardiovascular disease is a global imperative.

Corresponding Author: Robert O. Bonow, MD, MS, Division of Cardiology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Ste 600, Chicago, IL 60611 (r-bonow@northwestern.edu)

SOURCE

https://jamanetwork.com/journals/jama/fullarticle/2770858

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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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Did FDA Reverse Course on Convalescent Plasma Therapy for COVID-19?

Reporter: Stephen J. Williams, PhD

 

Starting with a timeline of recent announcements by the FDA on convalescent plasma therapy

April 16, 2020

FDA STATEMENT

Coronavirus (COVID-19) Update: FDA Encourages Recovered Patients to Donate Plasma for Development of Blood-Related Therapies

 

As part of the all-of-America approach to fighting the COVID-19 pandemic, the U.S. Food and Drug Administration has been working with partners across the U.S. government, academia and industry to expedite the development and availability of critical medical products to treat this novel virus. Today, we are providing an update on one potential treatment called convalescent plasma and encouraging those who have recovered from COVID-19 to donate plasma to help others fight this disease.

Convalescent plasma is an antibody-rich product made from blood donated by people who have recovered from the disease caused by the virus. Prior experience with respiratory viruses and limited data that have emerged from China suggest that convalescent plasma has the potential to lessen the severity or shorten the length of illness caused by COVID-19. It is important that we evaluate this potential therapy in the context of clinical trials, through expanded access, as well as facilitate emergency access for individual patients, as appropriate.

The response to the agency’s recently announced national efforts to facilitate the development of and access to convalescent plasma has been tremendous. More than 1,040 sites and 950 physician investigators nationwide have signed on to participate in the Mayo Clinic-led expanded access protocol. A number of clinical trials are also taking place to evaluate the safety and efficacy of convalescent plasma and the FDA has granted numerous single patient emergency investigational new drug (eIND) applications as well.

Source: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-encourages-recovered-patients-donate-plasma-development-blood

August 23, 2020

 

Recommendations for Investigational COVID-19 Convalescent Plasma

 

  • FDA issues guidelines on clinical trials and obtaining emergency enrollment concerning convalescent plasma

FDA has issued guidance to provide recommendations to health care providers and investigators on the administration and study of investigational convalescent plasma collected from individuals who have recovered from COVID-19 (COVID-19 convalescent plasma) during the public health emergency.

The guidance provides recommendations on the following:

Because COVID-19 convalescent plasma has not yet been approved for use by FDA, it is regulated as an investigational product.  A health care provider must participate in one of the pathways described below.  FDA does not collect COVID-19 convalescent plasma or provide COVID-19 convalescent plasma.  Health care providers or acute care facilities should instead obtain COVID-19 convalescent plasma from an FDA-registered blood establishment.

Excerpts from the guidance document are provided below.

Background

The Food and Drug Administration (FDA or Agency) plays a critical role in protecting the United States (U.S.) from threats including emerging infectious diseases, such as the Coronavirus Disease 2019 (COVID-19) pandemic.  FDA is committed to providing timely guidance to support response efforts to this pandemic.

One investigational treatment being explored for COVID-19 is the use of convalescent plasma collected from individuals who have recovered from COVID-19.  Convalescent plasma that contains antibodies to severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 (the virus that causes COVID-19) is being studied for administration to patients with COVID-19. Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2003 SARS-CoV-1 epidemic, the 2009-2010 H1N1 influenza virus pandemic, and the 2012 MERS-CoV epidemic.

Although promising, convalescent plasma has not yet been shown to be safe and effective as a treatment for COVID-19. Therefore, it is important to study the safety and efficacy of COVID-19 convalescent plasma in clinical trials.

Pathways for Use of Investigational COVID-19 Convalescent Plasma

The following pathways are available for administering or studying the use of COVID-19 convalescent plasma:

  1. Clinical Trials

Investigators wishing to study the use of convalescent plasma in a clinical trial should submit requests to FDA for investigational use under the traditional IND regulatory pathway (21 CFR Part 312). CBER’s Office of Blood Research and Review is committed to engaging with sponsors and reviewing such requests expeditiously. During the COVID-19 pandemic, INDs may be submitted via email to CBERDCC_eMailSub@fda.hhs.gov.

  1. Expanded Access

An IND application for expanded access is an alternative for use of COVID-19 convalescent plasma for patients with serious or immediately life-threatening COVID-19 disease who are not eligible or who are unable to participate in randomized clinical trials (21 CFR 312.305). FDA has worked with multiple federal partners and academia to open an expanded access protocol to facilitate access to COVID-19 convalescent plasma across the nation. Access to this investigational product may be available through participation of acute care facilities in an investigational expanded access protocol under an IND that is already in place.

Currently, the following protocol is in place: National Expanded Access Treatment Protocol

  1. Single Patient Emergency IND

Although participation in clinical trials or an expanded access program are ways for patients to obtain access to convalescent plasma, for various reasons these may not be readily available to all patients in potential need. Therefore, given the public health emergency that the COVID-19 pandemic presents, and while clinical trials are being conducted and a national expanded access protocol is available, FDA also is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of the patient’s physician requesting a single patient emergency IND (eIND) for the individual patient under 21 CFR 312.310. This process allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization, if the applicable regulatory criteria are met.  Note, in such case, a licensed physician seeking to administer COVID-19 convalescent plasma to an individual patient must request the eIND (see 21 CFR 312.310(b)).

To Obtain a Single Patient Emergency IND  

The requesting physician may contact FDA by completing Form FDA 3926 (https://www.fda.gov/media/98616/download) and submitting the form by email to CBER_eIND_Covid-19@FDA.HHS.gov.

FACT SHEET FOR PATIENTS AND PARENTS/CAREGIVERS EMERGENCY USE AUTHORIZATION (EUA) OF COVID-19 CONVALESCENT PLASMA FOR TREATMENT OF COVID-19 IN HOSPITALIZED PATIENTS

  • FDA issues fact sheet for patients on donating plasma

August 23, 2020

 

FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment, Another Achievement in Administration’s Fight Against Pandemic

 

Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for investigational convalescent plasma for the treatment of COVID-19 in hospitalized patients as part of the agency’s ongoing efforts to fight COVID-19. Based on scientific evidence available, the FDA concluded, as outlined in its decision memorandum, this product may be effective in treating COVID-19 and that the known and potential benefits of the product outweigh the known and potential risks of the product.

Today’s action follows the FDA’s extensive review of the science and data generated over the past several months stemming from efforts to facilitate emergency access to convalescent plasma for patients as clinical trials to definitively demonstrate safety and efficacy remain ongoing.

The EUA authorizes the distribution of COVID-19 convalescent plasma in the U.S. and its administration by health care providers, as appropriate, to treat suspected or laboratory-confirmed COVID-19 in hospitalized patients with COVID-19.

Alex Azar, Health and Human Services Secretary:
“The FDA’s emergency authorization for convalescent plasma is a milestone achievement in President Trump’s efforts to save lives from COVID-19,” said Secretary Azar. “The Trump Administration recognized the potential of convalescent plasma early on. Months ago, the FDA, BARDA, and private partners began work on making this product available across the country while continuing to evaluate data through clinical trials. Our work on convalescent plasma has delivered broader access to the product than is available in any other country and reached more than 70,000 American patients so far. We are deeply grateful to Americans who have already donated and encourage individuals who have recovered from COVID-19 to consider donating convalescent plasma.”

Stephen M. Hahn, M.D., FDA Commissioner:
“I am committed to releasing safe and potentially helpful treatments for COVID-19 as quickly as possible in order to save lives. We’re encouraged by the early promising data that we’ve seen about convalescent plasma. The data from studies conducted this year shows that plasma from patients who’ve recovered from COVID-19 has the potential to help treat those who are suffering from the effects of getting this terrible virus,” said Dr. Hahn. “At the same time, we will continue to work with researchers to continue randomized clinical trials to study the safety and effectiveness of convalescent plasma in treating patients infected with the novel coronavirus.”

Scientific Evidence on Convalescent Plasma

Based on an evaluation of the EUA criteria and the totality of the available scientific evidence, the FDA’s Center for Biologics Evaluation and Research determined that the statutory criteria for issuing an EUA criteria were met.

The FDA determined that it is reasonable to believe that COVID-19 convalescent plasma may be effective in lessening the severity or shortening the length of COVID-19 illness in some hospitalized patients. The agency also determined that the known and potential benefits of the product, when used to treat COVID-19, outweigh the known and potential risks of the product and that that there are no adequate, approved, and available alternative treatments.

 

August 24, 2020

Donate COVID-19 Plasma

 

  • FDA posts video and blog about how to donate plasms if you had been infected with COVID

 

https://youtu.be/PlX15rWdBbY

 

 

Please go to https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/donate-covid-19-plasma

to read more from FDA

 

 

August 25, 2020

 

CLINICAL MEMORANDUM From: , OBRR/DBCD/CRS To: , OBRR Through: , OBRR/DBCD , OBRR/DBCD , OBRR/DBCD/CRS Re: EUA 26382: Emergency Use Authorization (EUA) Request (original request 8/12/20; amended request 8/23/20) Product: COVID-19 Convalescent Plasma Items reviewed: EUA request Fact Sheet for Health Care Providers Fact Sheet for Recipients Sponsor: Robert Kadlec, M.D. Assistant Secretary for Preparedness and Response (ASPR) Office of Assistant Secretary for Preparedness and Response (ASPR) U.S. Department of Health and Human Services (HHS) EXECUTIVE SUMMARY COVID-19 Convalescent Plasma (CCP), an unapproved biological product, is proposed for use under an Emergency Use Authorization (EUA) under section 564 of the Federal Food, Drug, and Cosmetic Act (the Act),(21 USC 360bbb-3) as a passive immune therapy for the treatment of hospitalized patients with COVID-19, a serious or life-threatening disease. There currently is no adequate, approved, and available alternative to CCP for treating COVID-19. The sponsor has pointed to four lines of evidence to support that CCP may be effective in the treatment of hospitalized patients with COVID-19: 1) History of convalescent plasma for respiratory coronaviruses; 2) Evidence of preclinical safety and efficacy in animal models; 3) Published studies of the safety and efficacy of CCP; and 4) Data on safety and efficacy from the National Expanded Access Treatment Protocol (EAP) sponsored by the Mayo Clinic. Considering the totality of the scientific evidence presented in the EUA, I conclude that current data for the use of CCP in adult hospitalized patients with COVID-19 supports the conclusion that CCP meets the “may be effective” criterion for issuance of an EUA from section 564(c)(2)(A) of the Act. It is reasonable to conclude that the known and potential benefits of CCP outweigh the known and potential risks of CCP for the proposed EUA. Current data suggest the largest clinical benefit is associated with high-titer units of CCP administered early course of the disease.

Source: https://www.fda.gov/media/141480/download

 

And Today August 26, 2020

  • A letter, from Senator Warren, to Commissioner Hahn from Senate Committee asking for documentation for any communication between FDA and White House

August 25, 2020 Dr. Stephen M. Hahn, M.D. Commissioner of Food and Drugs U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 Dear Commissioner Hahn: We write regarding the U.S. Food and Drug Administration’s (FDA) troubling decision earlier this week to issue an Emergency Use Authorization (EUA) for convalescent plasma as a treatment for coronavirus disease 2019 (COVID-19).1 Reports suggests that the FDA granted the EUA amid intense political pressure from President Trump and other Administration officials, despite limited evidence of convalescent plasma’s effectiveness as a COVID-19 treatment.2 To help us better understand whether the issuance of the blood plasma EUA was motivated by politics, we request copies of any and all communications between FDA and White House officials regarding the blood plasma EUA.

Source: https://www.warren.senate.gov/imo/media/doc/2020.08.25%20Letter%20to%20FDA%20re%20Blood%20Plasma%20EUA.pdf

…….. which may have been a response to this article

FDA chief walks back comments on effectiveness of coronavirus plasma treatment

 

From CNBC: https://www.cnbc.com/2020/08/25/fda-chief-walks-back-comments-on-effectiveness-of-coronavirus-plasma-treatment.html

PUBLISHED TUE, AUG 25 202010:45 AM EDTUPDATED TUE, AUG 25 20204:12 PM EDT

Berkeley Lovelace Jr.@BERKELEYJR

Will Feuer@WILLFOIA

KEY POINTS

  • The authorization will allow health-care providers in the U.S. to use the plasma to treat hospitalized patients with Covid-19.
  • The FDA’s emergency use authorization came a day after President Trump accused the agency of delaying enrollment in clinical trials for vaccines or therapeutics.
  • The criticism from Trump and action from the FDA led some scientists to believe the authorization, which came on the eve of the GOP national convention, was politically motivated.

FDA Commissioner Dr. Stephen Hahn is walking back comments on the benefits of convalescent plasma, saying he could have done a better job of explaining the data on its effectiveness against the coronavirus after authorizing it for emergency use over the weekend.

Commisioners responses over Twitter

https://twitter.com/SteveFDA/status/1298071603675373569?s=20

https://twitter.com/SteveFDA/status/1298071619236245504?s=20

August 26, 2020

In an interview with Bloomberg’s , FDA Commissioner Hahn reiterates that his decision was based on hard evidence and scientific fact, not political pressure.  The whole interview is at the link below:

https://www.bloomberg.com/news/articles/2020-08-25/fda-s-hahn-vows-to-stick-to-the-science-amid-vaccine-pressure?sref=yLCixKPR

Some key points:

  • Dr. Hahn corrected his initial statement about 35% of people would be cured by convalescent plasma. In the interview he stated:

I was trying to do what I do with patients, because patients often understand things in absolute terms versus relative terms. And I should’ve been more careful, there’s no question about it. What I was trying to get to is that if you look at a hundred patients who receive high titre, and a hundred patients who received low titre, the difference between those two particular subset of patients who had these specific criteria was a 35% reduction in mortality. So I frankly did not do a good job of explaining that.

  • FDA colleagues had frank discussion after the statement was made.  He is not asking for other people in HHS to retract their statements, only is concerned that FDA has correct information for physicians and patients
  • Hahn is worried that people will not enroll due to chance they may be given placebo
  • He gave no opinion when asked if FDA should be an independent agency

 

For more articles on COVID19 please go to our Coronavirus Portal at

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

 

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Online Event: Vaccine matters: Can we cure coronavirus? An AAAS Webinar on COVID19: 8/12/2020

Reporter: Stephen J. Williams. PhD

Source: Online Event

Top on the world’s want list right now is a coronavirus vaccine. There is plenty of speculation about how and when this might become a reality, but clear answers are scarce.Science/AAAS, the world’s leading scientific organization and publisher of the Science family of journals, brings together experts in the field of coronavirus vaccine research to answer the public’s most pressing questions: What vaccines are being developed? When are we likely to get them? Are they safe? And most importantly, will they work?

link: https://view6.workcast.net/AuditoriumAuthenticator.aspx?cpak=1836435787247718&pak=8073702641735492

Presenters

Presenter
Speaker: Sarah Gilbert, Ph.D.

University of Oxford
Oxford, UK
View Bio

Presenter
Speaker: Kizzmekia Corbett, Ph.D.

National Institute of Allergy and Infectious Diseases, NIH
Bethesda, MD
View Bio

Presenter
Speaker: Kathryn M. Edwards, M.D.

Vanderbilt Vaccine Research Program
Nashville, TN
View Bio

Presenter
Speaker: Jon Cohen

Science/AAAS
San Diego, CA
View Bio

Presenter
Moderator: Sean Sanders, Ph.D.

Science/AAAS
Washington, DC
View Moderator Bio

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Recent Grim COVID-19 Statistics in U.S. and Explanation from Dr. John Campbell: Why We Need to be More Proactive

Reporter: Stephen J. Williams, Ph.D.

In case you have not been following the excellent daily YouTube sessions on COVID-19 by Dr. John Campbell I am posting his latest video on how grim the statistics have become and the importance of using proactive measures (like consistent use of facial masks, proper social distancing) instead of relying on reactive measures (e.g. lockdowns after infection spikes).  In addition, below the video are some notes from his presentation and some links to sites discussed within the video.

 

Notes from the video:

  • approaching 5 million confirmed cases in US however is probably an underestimation
  • 160,00 deaths as of 8/08/2020

From the University of Washington Institute for Health Metrics and Evaluation in Seattle WA

  • 295,000 US COVID-19 related deaths estimated by December 1, 2020
  • however if 95% of people in US consistently and properly wear masks could save 66,000 lives
  • however this will mean a remaining 228,271 deaths which is a depressing statistic
  • Dr. John Campbell agrees with Dr. Christopher Murray, director of the Institute for Health Metrics that “people’s inconsistent use of these measures (face masks, social distancing) is a serious problem”
  • States with increasing transmission like Colorado, Idaho, Kansas, Kentucky, Mississippi, Missouri, Ohio, Oklahoma, Oregon, and Virginia are suggested to have a lockdown when death rate reaches 8 deaths per million population however it seems we should be also focusing on population densities rather than geographic states
  • Dr. Campbell and Dr. Murray stress more proactive measures than reactive ones like lockdowns
  • if mask usage were to increase to 95% usage reimposition to shutdown could be delayed 6 to 8 weeks

 

New IHME COVID-19 Forecasts See Nearly 300,000 Deaths by December 1

SEATTLE (August 6, 2020) – America’s COVID-19 death toll is expected to reach nearly 300,000 by December 1; however, consistent mask-wearing beginning today could save about 70,000 lives, according to new data from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington’s School of Medicine.The US forecast totals 295,011 deaths by December. As of today, when, thus far, 158,000 have died, IHME is projecting approximately 137,000 more deaths. However, starting today, if 95% of the people in the US were to wear masks when leaving their homes, that total number would decrease to 228,271 deaths, a drop of 49%. And more than 66,000 lives would be saved.Masks and other protective measures against transmission of the virus are essential to staying COVID-free, but people’s inconsistent use of those measures is a serious problem, said IHME Director Dr. Christopher Murray.

“We’re seeing a rollercoaster in the United States,” Murray said. “It appears that people are wearing masks and socially distancing more frequently as infections increase, then after a while as infections drop, people let their guard down and stop taking these measures to protect themselves and others – which, of course, leads to more infections. And the potentially deadly cycle starts over again.”

Murray noted that there appear to be fewer transmissions of the virus in Arizona, California, Florida, and Texas, but deaths are rising and will continue to rise for the next week or two. The drop in infections appears to be driven by the combination of local mandates for mask use, bar and restaurant closures, and more responsible behavior by the public.

“The public’s behavior had a direct correlation to the transmission of the virus and, in turn, the numbers of deaths,” Murray said. “Such efforts to act more cautiously and responsibly will be an important aspect of COVID-19 forecasting and the up-and-down patterns in individual states throughout the coming months and into next year.”

Murray said that based on cases, hospitalizations, and deaths, several states are seeing increases in the transmission of COVID-19, including Colorado, Idaho, Kansas, Kentucky, Mississippi, Missouri, Ohio, Oklahoma, Oregon, and Virginia.

“These states may experience increasing cases for several weeks and then may see a response toward more responsible behavior,” Murray said.

In addition, since July 15, several states have added mask mandates. IHME’s statistical analysis suggests that mandates with no penalties increase mask wearing by 8 percentage points. But mandates with penalties increase mask wearing by 15 percentage points.

“These efforts, along with media coverage and public information efforts by state and local health agencies and others, have led to an increase in the US rate of mask wearing by about 5 percentage points since mid-July,” Murray said. Mask-wearing increases have been larger in states with larger epidemics, he said.

IHME’s model assumes that states will reimpose a series of mandates, including non-essential business closures and stay-at-home orders, when the daily death rate reaches 8 per million. This threshold is based on data regarding when states and/or communities imposed mandates in March and April, and implies that many states will have to reimpose mandates.

As a result, the model suggests which states will need to reimpose mandates and when:

  • August – Arizona, Florida, Mississippi, and South Carolina
  • September – Georgia and Texas
  • October – Colorado, Kansas, Louisiana, Missouri, Nevada, North Carolina, and Oregon.
  • November – Alabama, Arkansas, California, Iowa, New Mexico, Oklahoma, Utah, Washington, and Wisconsin.

However, if mask use is increased to 95%, the re-imposition of stricter mandates could be delayed 6 to 8 weeks on average.

Source: http://www.healthdata.org/news-release/new-ihme-covid-19-forecasts-see-nearly-300000-deaths-december-1

 

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Is SARS-COV2 Hijacking the Complement and Coagulation Systems?

Reporter: Stephen J. Williams, PhD

In a recent Nature Medicine paper “Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection” Ramlall et al. demonstrate, in a retrospective study, that a significant number of patients presenting SARS-CoV2 complications had prior incidences of macular degeneration and coagulation disorders and these previous indications are risk factors for COVID-related complications.

 

Abstract

Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral–host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses. To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality—effects that are independent of age, sex or history of smoking. Transcriptional profiling of nasopharyngeal swabs demonstrated that in addition to type-I interferon and interleukin-6-dependent inflammatory responses, infection results in robust engagement of the complement and coagulation pathways. Finally, in a candidate-driven genetic association study of severe SARS-CoV-2 disease, we identified putative complement and coagulation-associated loci including missense, eQTL and sQTL variants of critical complement and coagulation regulators. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multimodal analytical approach to reveal determinants and predictors of immunity, susceptibility and clinical outcome associated with infection.

Introduction

As part of a separate study, the authors mapped over 140 cellular proteins that are structurally mimicked by coronaviruses (CoVs) and identified complement and coagulation pathways as targets of this strategy across all CoV strains4. The complement system is a critical defense against pathogens, including viruses5 and when dysregulated (by germline variants or acquired through age-related effects or excessive tissue damage) can contribute to pathologies mediated by inflammation5,6,7.

“So, virally encoded structural mimics of complement and coagulation factors may contribute to CoV-associated immune-mediated pathology and indicate sensitivities in antiviral defenses.”

 

Methods and Results

  • Between 1 February 2020 and 25 April 2020, 11,116 patients presented to New York-Presbyterian/Columbia University Irving Medical Center with suspected SARS-CoV-2 infection, of which 6,398 tested positive
  • Electronic health records (EHRs) were used to define sex, age and smoking history status as well as histories of macular degeneration, coagulatory disorders (thrombocytopenia, thrombosis and hemorrhage), hypertension, type 2 diabetes (T2D), coronary artery disease (CAD) and obesity (see Methods). A Python algorithm was used to analyze all confounders.
  • identified 88 patients with history of macular degeneration, 4 with complement deficiency disorders and 1,179 with coagulatory disorders).
  • observed a 35% mortality rate among patients that were put on mechanical ventilation and that 31% of deceased patients had been on mechanical respiration.
  • patients with AMD (a proxy for complement activation disorders) and coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) were at significantly increased risk of adverse clinical outcomes (including mechanical respiration and death) following SARS-CoV-2 infection
  • 650 NP swabs from control and SARS-CoV-2-infected patients who presented to Weill-Cornell Medical Center were evaluated by RNA-Seq. Gene set enrichment analysis (GSEA) of Hallmark gene sets found that SARS-CoV-2 infection (as defined by presence of SARS-CoV-2 RNA and stratified into ‘positive’, ‘low’, ‘medium’ or ‘high’ based on viral load; induces genes related to pathways with known immune modulatory functions (Fig. 2a). Moreover, among the most enriched gene sets, SARS-CoV-2 infection induces robust activation of the complement cascade (false discovery rate (FDR) P < 0.001), with increasing enrichment and significance with viral load (FDR P < 0.0001).
  • KEGG Pathway Analysis revealed KEGG_Complement_and_Coagulation_Cascades’, ‘GO_Coagulation’ and ‘Reactome_initial_triggering_of_complement’ to be significantly enriched in expression profiles of SARS-CoV-2-infected samples
  • conducted a candidate-driven study to evaluate whether genetic variation within a 60-Kb window around 102 genes with known roles in regulating complement or coagulation cascades (2,888 genetic variants fulfill this criteria of the 805,426 profiled in the UK Biobank) is associated with poor SARS-CoV-2 clinical outcome
  • identified 11 loci representing seven genes with study-wide significance. A variant of coagulation factor III (F3), variant rs72729504, was found to be associated with increased risk of adverse clinical outcome associated with SARS-CoV-2 infection. The analysis also identified that four variants previously reported to be associated with AMD (rs45574833, rs61821114, rs61821041 and rs12064775)15predispose carriers to hospitalization following SARS-CoV-2 infection

As authors state:

“Among the implications, the data warrant heightened public health awareness for the most vulnerable individuals and further investigation into an existing menu of complement and coagulation targeting therapies that were recently shown to be beneficial in a small cohort of patients with SARS-CoV-2 infection.” 26,27.

 

References

Ramlall, V., Thangaraj, P.M., Meydan, C. et al. Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat Med (2020). https://doi.org/10.1038/s41591-020-1021-2

 

4.

Lasso, G., Honig, B. & Shapira, S. D. A sweep of earth’s virome reveals host-guided viral protein structural mimicry; with implications for human disease. Preprint at bioRxiv https://doi.org/10.1101/2020.06.18.159467 (2020).

 

SUMMARY

Viruses deploy an array of genetically encoded strategies to coopt host machinery and support viral replicative cycles. Molecular mimicry, manifested by structural similarity between viral and endogenous host proteins, allow viruses to harness or disrupt cellular functions including nucleic acid metabolism and modulation of immune responses. Here, we use protein structure similarity to scan for virally encoded structure mimics across thousands of catalogued viruses and hosts spanning broad ecological niches and taxonomic range, including bacteria, plants and fungi, invertebrates and vertebrates. Our survey identified over 6,000,000 instances of structural mimicry, the vast majority of which (>70%) cannot be discerned through protein sequence. The results point to molecular mimicry as a pervasive strategy employed by viruses and indicate that the protein structure space used by a given virus is dictated by the host proteome. Interrogation of proteins mimicked by human-infecting viruses points to broad diversification of cellular pathways targeted via structural mimicry, identifies biological processes that may underly autoimmune disorders, and reveals virally encoded mimics that may be leveraged to engineer synthetic metabolic circuits or may serve as targets for therapeutics. Moreover, the manner and degree to which viruses exploit molecular mimicry varies by genome size and nucleic acid type, with ssRNA viruses circumventing limitations of their small genomes by mimicking human proteins to a greater extent than their large dsDNA counterparts. Finally, we identified over 140 cellular proteins that are mimicked by CoV, providing clues about cellular processes driving the pathogenesis of the ongoing COVID-19 pandemic.

 

26.

Risitano, A. M. Complement as a target in COVID-19?. Nat. Rev. Immunol. 20, 343–344 (2020).

 

27.

Mastaglio, S. et al. The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin. Immunol. 215, 108450 (2020).

 

28.

Polubriaginof, F. C. G. et al. Challenges with quality of race and ethnicity data in observational databases. J. Am. Med. Inf. Assoc. 26, 730–736 (2019).

 

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

Curator: Stephen J. Williams, Ph.D.

 

Passive Immunity and Treatment of Infectious Diseases

The ability of one person to pass on immunity to another person (passive immunity) is one of the chief methods we develop immunity to many antigens.  For instance, maternal antibodies are passed to the offspring in the neonatal setting as well as in a mother’s milk during breast feeding.  In the clinical setting this is achieved by transferring antibodies from one patient who has been exposed to an antigen (like a virus) to the another individual.   However, the process of purifying the most efficacious antibody as well as its mass production is limiting due to its complexity and cost and can be prohibitively long delay during a pandemic outbreak, when therapies are few and needed immediately.  Regardless, the benefits of developing neutralizing antibodies to confer passive immunity versus development of a vaccine are evident, as the former takes considerable less time than development of a safe and effective vaccine.  For a good review on the development and use of neutralizing antibodies and the use of passive immunity to treat infectious diseases please read the following review:

Margaret A. Keller1,* and E. Richard Stiehm. Passive Immunity in Prevention and Treatment of Infectious Diseases. Clin Microbiol Rev. 2000 Oct; 13(4): 602–614. doi: 10.1128/cmr.13.4.602-614.2000

ABSTRACT

Antibodies have been used for over a century in the prevention and treatment of infectious disease. They are used most commonly for the prevention of measles, hepatitis A, hepatitis B, tetanus, varicella, rabies, and vaccinia. Although their use in the treatment of bacterial infection has largely been supplanted by antibiotics, antibodies remain a critical component of the treatment of diptheria, tetanus, and botulism. High-dose intravenous immunoglobulin can be used to treat certain viral infections in immunocompromised patients (e.g., cytomegalovirus, parvovirus B19, and enterovirus infections). Antibodies may also be of value in toxic shock syndrome, Ebola virus, and refractory staphylococcal infections. Palivizumab, the first monoclonal antibody licensed (in 1998) for an infectious disease, can prevent respiratory syncytial virus infection in high-risk infants. The development and use of additional monoclonal antibodies to key epitopes of microbial pathogens may further define protective humoral responses and lead to new approaches for the prevention and treatment of infectious diseases.

TABLE 1

Summary of the efficacy of antibody in the prevention and treatment of infectious diseases

Infection
Bacterial infections
 Respiratory infections (streptococcus, Streptococcus pneumoniaeNeisseria meningitisHaemophilus influenzae)
 Diphtheria
 Pertussis
 Tetanus
 Other clostridial infections
  C. botulinum
  C. difficile
 Staphylococcal infections
  Toxic shock syndrome
  Antibiotic resistance
  S. epidermidis in newborns
 Invasive streptococcal disease (toxic shock syndrome)
 High-risk newborns
 Shock, intensive care, and trauma
Pseudomonas infection
  Cystic Fibrosis
  Burns
Viral diseases
 Hepatitis A
 Hepatitis B
 Hepatitis C
 HIV infection
 RSV infection
 Herpesvirus infections
  CMV
  EBV
  HSV
  VZV
 Parvovirus infection
 Enterovirus infection
  In newborns
 Ebola
 Rabies
 Measles
 Rubella
 Mumps
 Tick-borne encephalitis
 Vaccinia

Go to:

A Great Explanation of Active versus Passive Immunity by Dr. John Campbell, one of the pioneers in the field of immunology:Antibodies have been used for over a century in the prevention and treatment of infectious disease. They are used most commonly for the prevention of measles, hepatitis A, hepatitis B, tetanus, varicella, rabies, and vaccinia. Although their use in the treatment of bacterial infection has largely been supplanted by antibiotics, antibodies remain a critical component of the treatment of diptheria, tetanus, and botulism. High-dose intravenous immunoglobulin can be used to treat certain viral infections in immunocompromised patients (e.g., cytomegalovirus, parvovirus B19, and enterovirus infections). Antibodies may also be of value in toxic shock syndrome, Ebola virus, and refractory staphylococcal infections. Palivizumab, the first monoclonal antibody licensed (in 1998) for an infectious disease, can prevent respiratory syncytial virus infection in high-risk infants. The development and use of additional monoclonal antibodies to key epitopes of microbial pathogens may further define protective humoral responses and lead to new approaches for the prevention and treatment of infectious diseases.

 

However, developing successful neutralizing antibodies can still be difficult but with the latest monoclonal antibody technology, as highlighted by the following papers, this process has made much more efficient.  In addition, it is not feasable to isolate antibodies from the plasma of covalescent patients in a scale that is needed for a worldwide outbreak.

A good explanation of the need can be found is Dr. Irina Robu’s post Race to develop antibody drugs for COVID-19 where:

When fighting off foreign invaders, our bodies make antibodies precisely produced for the task. The reason vaccines offer such long-lasting protection is they train the immune system to identify a pathogen, so immune cells remember and are ready to attack the virus when it appears. Monoclonal antibodies for coronavirus would take the place of the ones our bodies might produce to fight the disease. The manufactured antibodies would be infused into the body to either tamp down an existing infection, or to protect someone who has been exposed to the virus. However, these drugs are synthetic versions of the convalescent plasma treatments that rely on antibodies from people who have recovered from infection. But the engineered versions are easier to scale because they’re manufactured in rats, rather than from plasma donors.

The following papers represent the latest published work on development of therapeutic and prophylactic neutralizing antibodies to the coronavirus SARS-CoV2

1.  Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody.

Pinto, D., Park, Y., Beltramello, M. et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature (2020).                                                                            https://doi.org/10.1038/s41586-020-2349-y

Abstract

SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-19 pandemic that has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 20201,2. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe multiple monoclonal antibodies targeting SARS-CoV-2 S identified from memory B cells of an individual who was infected with SARS-CoV in 2003. One antibody, named S309, potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 by engaging the S receptor-binding domain. Using cryo-electron microscopy and binding assays, we show that S309 recognizes a glycan-containing epitope that is conserved within the sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails including S309 along with other antibodies identified here further enhanced SARS-CoV-2 neutralization and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309- and S309-containing antibody cocktails for prophylaxis in individuals at high risk of exposure or as a post-exposure therapy to limit or treat severe disease.

 

2.  Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells

Yunlong Cao et al.  Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell (2020).

https://doi.org/10.1016/j.cell.2020.05.025

Summary

The COVID-19 pandemic urgently needs therapeutic and prophylactic interventions. Here we report the rapid identification of SARS-CoV-2 neutralizing antibodies by high-throughput single-cell RNA and VDJ sequencing of antigen-enriched B cells from 60 convalescent patients. From 8,558 antigen-binding IgG1+ clonotypes, 14 potent neutralizing antibodies were identified with the most potent one, BD-368-2, exhibiting an IC50 of 1.2 ng/mL and 15 ng/mL against pseudotyped and authentic SARS-CoV-2, respectively. BD-368-2 also displayed strong therapeutic and prophylactic efficacy in SARS-CoV-2-infected hACE2-transgenic mice. Additionally, the 3.8Å Cryo-EM structure of a neutralizing antibody in complex with the spike-ectodomain trimer revealed the antibody’s epitope overlaps with the ACE2 binding site. Moreover, we demonstrated that SARS-CoV-2 neutralizing antibodies could be directly selected based on similarities of their predicted CDR3H structures to those of SARS-CoV neutralizing antibodies. Altogether, we showed that human neutralizing antibodies could be efficiently discovered by high-throughput single B-cell sequencing in response to pandemic infectious diseases.

3. A human monoclonal antibody blocking SARS-CoV-2 infection

Wang, C., Li, W., Drabek, D. et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun 11, 2251 (2020). https://doi.org/10.1038/s41467-020-16256-y

Abstract

The emergence of the novel human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this disease are currently lacking. Here we report a human monoclonal antibody that neutralizes SARS-CoV-2 (and SARS-CoV) in cell culture. This cross-neutralizing antibody targets a communal epitope on these viruses and may offer potential for prevention and treatment of COVID-19.

Extra References on Development of Neutralizing antibodies for COVID19 {Sars-CoV2} published this year (2020)  [1-4]

  1. Fan P, Chi X, Liu G, Zhang G, Chen Z, Liu Y, Fang T, Li J, Banadyga L, He S et al: Potent neutralizing monoclonal antibodies against Ebola virus isolated from vaccinated donors. mAbs 2020, 12(1):1742457.
  2. Dussupt V, Sankhala RS, Gromowski GD, Donofrio G, De La Barrera RA, Larocca RA, Zaky W, Mendez-Rivera L, Choe M, Davidson E et al: Potent Zika and dengue cross-neutralizing antibodies induced by Zika vaccination in a dengue-experienced donor. Nature medicine 2020, 26(2):228-235.
  3. Young CL, Lyons AC, Hsu WW, Vanlandingham DL, Park SL, Bilyeu AN, Ayers VB, Hettenbach SM, Zelenka AM, Cool KR et al: Protection of swine by potent neutralizing anti-Japanese encephalitis virus monoclonal antibodies derived from vaccination. Antiviral research 2020, 174:104675.
  4. Sautto GA, Kirchenbaum GA, Abreu RB, Ecker JW, Pierce SR, Kleanthous H, Ross TM: A Computationally Optimized Broadly Reactive Antigen Subtype-Specific Influenza Vaccine Strategy Elicits Unique Potent Broadly Neutralizing Antibodies against Hemagglutinin. J Immunol 2020, 204(2):375-385.

 

For More Articles on COVID-19 Please see Our Coronavirus Portal on this Open Access Scientific Journal at:

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

and the following Articles on  Immunity at

Race to develop antibody drugs for COVID-19
Bispecific and Trispecific Engagers: NK-T Cells and Cancer Therapy
Issues Need to be Resolved With ImmunoModulatory Therapies: NK cells, mAbs, and adoptive T cells
Antibody-bound Viral Antigens

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Crowdsourcing Difficult-to-Collect Epidemiological Data in Pandemics: Lessons from Ebola to the current COVID-19 Pandemic

 

Curator: Stephen J. Williams, Ph.D.

 

At the onset of the COVID-19 pandemic, epidemiological data from the origin of the Sars-Cov2 outbreak, notably from the Wuhan region in China, was sparse.  In fact, official individual patient data rarely become available early on in an outbreak, when that data is needed most. Epidemiological data was just emerging from China as countries like Italy, Spain, and the United States started to experience a rapid emergence of the outbreak in their respective countries.  China, made of 31 geographical provinces, is a vast and complex country, with both large urban and rural areas.

 

 

 

As a result of this geographical diversity and differences in healthcare coverage across the country, epidemiological data can be challenging.  For instance, cancer incidence data for regions and whole country is difficult to calculate as there are not many regional cancer data collection efforts, contrasted with the cancer statistics collected in the United States, which is meticulously collected by cancer registries in each region, state and municipality.  Therefore, countries like China must depend on hospital record data and autopsy reports in order to back-extrapolate cancer incidence data.  This is the case in some developed countries like Italy where cancer registry is administered by a local government and may not be as extensive (for example in the Napoli region of Italy).

 

 

 

 

 

 

Population density China by province. Source https://www.unicef.cn/en/figure-13-population-density-province-2017

 

 

 

Epidemiologists, in areas in which data collection may be challenging, are relying on alternate means of data collection such as using devices connected to the internet-of-things such as mobile devices, or in some cases, social media is becoming useful to obtain health related data.  Such as effort to acquire pharmacovigilance data, patient engagement, and oral chemotherapeutic adherence using the social media site Twitter has been discussed in earlier posts: (see below)

Twitter is Becoming a Powerful Tool in Science and Medicine at https://pharmaceuticalintelligence.com/2014/11/06/twitter-is-becoming-a-powerful-tool-in-science-and-medicine/

 

 

 

 

 

Now epidemiologists are finding crowd-sourced data from social media and social networks becoming useful in collecting COVID-19 related data in those countries where health data collection efforts may be sub-optimal.  In a recent paper in The Lancet Digital Health [1], authors Kaiyuan Sun, Jenny Chen, and Cecile Viboud present data from the COVID-19 outbreak in China using information collected over social network sites as well as public news outlets and find strong correlations with later-released government statistics, showing the usefulness in such social and crowd-sourcing strategies to collect pertinent time-sensitive data.  In particular, the authors aim was to investigate this strategy of data collection to reduce the time delays between infection and detection, isolation and reporting of cases.

The paper is summarized below:

Kaiyuan Sun, PhD Jenny Chen, BScn Cécile Viboud, PhD . (2020).  Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study.  The Lancet: Digital Health; Volume 2, Issue 4, E201-E208.

Summary

Background

As the outbreak of coronavirus disease 2019 (COVID-19) progresses, epidemiological data are needed to guide situational awareness and intervention strategies. Here we describe efforts to compile and disseminate epidemiological information on COVID-19 from news media and social networks.

Methods

In this population-level observational study, we searched DXY.cn, a health-care-oriented social network that is currently streaming news reports on COVID-19 from local and national Chinese health agencies. We compiled a list of individual patients with COVID-19 and daily province-level case counts between Jan 13 and Jan 31, 2020, in China. We also compiled a list of internationally exported cases of COVID-19 from global news media sources (Kyodo News, The Straits Times, and CNN), national governments, and health authorities. We assessed trends in the epidemiology of COVID-19 and studied the outbreak progression across China, assessing delays between symptom onset, seeking care at a hospital or clinic, and reporting, before and after Jan 18, 2020, as awareness of the outbreak increased. All data were made publicly available in real time.

Findings

We collected data for 507 patients with COVID-19 reported between Jan 13 and Jan 31, 2020, including 364 from mainland China and 143 from outside of China. 281 (55%) patients were male and the median age was 46 years (IQR 35–60). Few patients (13 [3%]) were younger than 15 years and the age profile of Chinese patients adjusted for baseline demographics confirmed a deficit of infections among children. Across the analysed period, delays between symptom onset and seeking care at a hospital or clinic were longer in Hubei province than in other provinces in mainland China and internationally. In mainland China, these delays decreased from 5 days before Jan 18, 2020, to 2 days thereafter until Jan 31, 2020 (p=0·0009). Although our sample captures only 507 (5·2%) of 9826 patients with COVID-19 reported by official sources during the analysed period, our data align with an official report published by Chinese authorities on Jan 28, 2020.

Interpretation

News reports and social media can help reconstruct the progression of an outbreak and provide detailed patient-level data in the context of a health emergency. The availability of a central physician-oriented social network facilitated the compilation of publicly available COVID-19 data in China. As the outbreak progresses, social media and news reports will probably capture a diminishing fraction of COVID-19 cases globally due to reporting fatigue and overwhelmed health-care systems. In the early stages of an outbreak, availability of public datasets is important to encourage analytical efforts by independent teams and provide robust evidence to guide interventions.

A Few notes on Methodology:

  • The authors used crowd-sourced reports from DXY.cn, a social network for Chinese physicians, health-care professionals, pharmacies and health-care facilities. This online platform provides real time coverage of the COVID-19 outbreak in China
  • More data was curated from news media, television and includes time-stamped information on COVID-19 cases
  • These reports are publicly available, de-identified patient data
  • No patient consent was needed and no ethics approval was required
  • Data was collected between January 20, 2020 and January 31,2020
  • Sex, age, province of identification, travel history, dates of symptom development was collected
  • Additional data was collected for other international sites of the pandemic including Cambodia, Canada, France, Germany, Hong Kong, India, Italy, Japan, Malaysia, Nepal, Russia, Singapore, UK, and USA
  • All patients in database had laboratory confirmation of infection

 

Results

  • 507 patient data was collected with 153 visited and 152 resident of Wuhan
  • Reported cases were skewed toward males however the overall population curve is skewed toward males in China
  • Most cases (26%) were from Beijing (urban area) while an equal amount were from rural areas combined (Shaanzi and Yunnan)
  • Age distribution of COVID cases were skewed toward older age groups with median age of 45 HOWEVER there were surprisingly a statistically high amount of cases less than 5 years of age
  • Outbreak progression based on the crowd-sourced patient line was consistent with the data published by the China Center for Disease Control
  • Median reporting delay in the authors crowd-sourcing data was 5 days
  • Crowd-sourced data was able to detect apparent rapid growth of newly reported cases during the collection period in several provinces outside of Hubei province, which is consistent with local government data

The following graphs show age distribution for China in 2017 and predicted for 2050.

projected age distribution China 2050. Source https://chinapower.csis.org/aging-problem/

 

 

 

 

 

 

 

 

 

 

 

 

The authors have previously used this curation of news methodology to analyze the Ebola outbreak[2].

A further use of the crowd-sourced database was availability of travel histories for patients returning from Wuhan and onset of symptoms, allowing for estimation of incubation periods.

The following published literature has also used these datasets:

Backer JA, Klinkenberg D, Wallinga J: Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2020, 25(5).

Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, Azman AS, Reich NG, Lessler J: The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Annals of internal medicine 2020, 172(9):577-582.

Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY et al: Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. The New England journal of medicine 2020, 382(13):1199-1207.

Dataset is available on the Laboratory for the Modeling of Biological and Socio-technical systems website of Northeastern University at https://www.mobs-lab.org/.

References

  1. Sun K, Chen J, Viboud C: Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study. The Lancet Digital health 2020, 2(4):e201-e208.
  2. Cleaton JM, Viboud C, Simonsen L, Hurtado AM, Chowell G: Characterizing Ebola Transmission Patterns Based on Internet News Reports. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2016, 62(1):24-31.

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Powerful AI Tools Being Developed for the COVID-19 Fight

Curator: Stephen J. Williams, Ph.D.

 

Source: https://www.ibm.com/blogs/research/2020/04/ai-powered-technologies-accelerate-discovery-covid-19/

IBM Releases Novel AI-Powered Technologies to Help Health and Research Community Accelerate the Discovery of Medical Insights and Treatments for COVID-19

April 3, 2020 | Written by: 

IBM Research has been actively developing new cloud and AI-powered technologies that can help researchers across a variety of scientific disciplines accelerate the process of discovery. As the COVID-19 pandemic unfolds, we continue to ask how these technologies and our scientific knowledge can help in the global battle against coronavirus.

Today, we are making available multiple novel, free resources from across IBM to help healthcare researchers, doctors and scientists around the world accelerate COVID-19 drug discovery: from gathering insights, to applying the latest virus genomic information and identifying potential targets for treatments, to creating new drug molecule candidates.

Though some of the resources are still in exploratory stages, IBM is making them available to qualifying researchers at no charge to aid the international scientific investigation of COVID-19.

Today’s announcement follows our recent leadership in launching the U.S. COVID-19 High Performance Computing Consortium, which is harnessing massive computing power in the effort to help confront the coronavirus.

Streamlining the Search for Information

Healthcare agencies and governments around the world have quickly amassed medical and other relevant data about the pandemic. And, there are already vast troves of medical research that could prove relevant to COVID-19. Yet, as with any large volume of disparate data sources, it is difficult to efficiently aggregate and analyze that data in ways that can yield scientific insights.

To help researchers access structured and unstructured data quickly, we are offering a cloud-based AI research resource that has been trained on a corpus of thousands of scientific papers contained in the COVID-19 Open Research Dataset (CORD-19), prepared by the White House and a coalition of research groups, and licensed databases from the DrugBankClinicaltrials.gov and GenBank. This tool uses our advanced AI and allows researchers to pose specific queries to the collections of papers and to extract critical COVID-19 knowledge quickly. Please note, access to this resource will be granted only to qualified researchers. To learn more and request access, please click here.

Aiding the Hunt for Treatments

The traditional drug discovery pipeline relies on a library of compounds that are screened, improved, and tested to determine safety and efficacy. In dealing with new pathogens such as SARS-CoV-2, there is the potential to enhance the compound libraries with additional novel compounds. To help address this need, IBM Research has recently created a new, AI-generative framework which can rapidly identify novel peptides, proteins, drug candidates and materials.

We have applied this AI technology against three COVID-19 targets to identify 3,000 new small molecules as potential COVID-19 therapeutic candidates. IBM is releasing these molecules under an open license, and researchers can study them via a new interactive molecular explorer tool to understand their characteristics and relationship to COVID-19 and identify candidates that might have desirable properties to be further pursued in drug development.

To streamline efforts to identify new treatments for COVID-19, we are also making the IBM Functional Genomics Platform available for free for the duration of the pandemic. Built to discover the molecular features in viral and bacterial genomes, this cloud-based repository and research tool includes genes, proteins and other molecular targets from sequenced viral and bacterial organisms in one place with connections pre-computed to help accelerate discovery of molecular targets required for drug design, test development and treatment.

Select IBM collaborators from government agencies, academic institutions and other organizations already use this platform for bacterial genomic study. And now, those working on COVID-19 can request the IBM Functional Genomics Platform interface to explore the genomic features of the virus. Access to the IBM Functional Genomics Platform will be prioritized for those conducting COVID-19 research. To learn more and request access, please click here.

Drug and Disease Information

Clinicians and healthcare professionals on the frontlines of care will also have free access to hundreds of pieces of evidence-based, curated COVID-19 and infectious disease content from IBM Micromedex and EBSCO DynaMed. Using these two rich decision support solutions, users will have access to drug and disease information in a single and comprehensive search. Clinicians can also provide patients with consumer-friendly patient education handouts with relevant, actionable medical information. IBM Micromedex is one of the largest online reference databases for medication information and is used by more than 4,500 hospitals and health systems worldwide. EBSCO DynaMed provides peer-reviewed clinical content, including systematic literature reviews in 28 specialties for comprehensive disease topics, health conditions and abnormal findings, to highly focused topics on evaluation, differential diagnosis and management.

The scientific community is working hard to make important new discoveries relevant to the treatment of COVID-19, and we’re hopeful that releasing these novel tools will help accelerate this global effort. This work also outlines our long-term vision for the future of accelerated discovery, where multi-disciplinary scientists and clinicians work together to rapidly and effectively create next generation therapeutics, aided by novel AI-powered technologies.

Learn more about IBM’s response to COVID-19: IBM.com/COVID19.

Source: https://www.ibm.com/blogs/research/2020/04/ai-powered-technologies-accelerate-discovery-covid-19/

DiA Imaging Analysis Receives Grant to Accelerate Global Access to its AI Ultrasound Solutions in the Fight Against COVID-19

Source: https://www.grantnews.com/news-articles/?rkey=20200512UN05506&filter=12337

Grant will allow company to accelerate access to its AI solutions and use of ultrasound in COVID-19 emergency settings

TEL AVIV, IsraelMay 12, 2020 /PRNewswire-PRWeb/ — DiA Imaging Analysis, a leading provider of AI based ultrasound analysis solutions, today announced that it has received a government grant from the Israel Innovation Authority (IIA) to develop solutions for ultrasound imaging analysis of COVID-19 patients using Artificial Intelligence (AI).Using ultrasound in point of care emergency settings has gained momentum since the outbreak of COVID-19 pandemic. In these settings, which include makeshift hospital COVID-19 departments and triage “tents,” portable ultrasound offers clinicians diagnostic decision support, with the added advantage of being easier to disinfect and eliminating the need to transport patients from one room to another.However, analyzing ultrasound images is a process that it is still mostly done visually, leading to a growing market need for automated solutions and decision support.As the leading provider of AI solutions for ultrasound analysis and backed by Connecticut Innovations, DiA makes ultrasound analysis smarter and accessible to both new and expert ultrasound users with various levels of experience. The company’s flagship LVivo Cardio Toolbox for AI-based cardiac ultrasound analysis enables clinicians to automatically generate objective clinical analysis, with increased accuracy and efficiency to support decisions about patient treatment and care.

The IIA grant provides a budget of millions NIS to increase access to DiA’s solutions for users in Israel and globally, and accelerate R&D with a focus on new AI solutions for COVID-19 patient management. DiA solutions are vendor-neutral and platform agnostic, as well as powered to run in low processing, mobile environments like handheld ultrasound.Recent data highlights the importance of looking at the heart during the progression of COVID-19, with one study citing 20% of patients hospitalized with COVID-19 showing signs of heart damage and increased mortality rates in those patients. DiA’s LVivo cardiac analysis solutions automatically generate objective, quantified cardiac ultrasound results to enable point-of-care clinicians to assess cardiac function on the spot, near patients’ bedside.

According to Dr. Ami Applebaum, the Chairman of the Board of the IIA, “The purpose of IIA’s call was to bring solutions to global markets for fighting COVID-19, with an emphasis on relevancy, fast time to market and collaborations promising continuity of the Israeli economy. DiA meets these requirements with AI innovation for ultrasound.”DiA has received several FDA/CE clearances and established distribution partnerships with industry leading companies including GE Healthcare, IBM Watson and Konica Minolta, currently serving thousands of end users worldwide.”We see growing use of ultrasound in point of care settings, and an urgent need for automated, objective solutions that provide decision support in real time,” said Hila Goldman-Aslan, CEO and Co-founder of DiA Imaging Analysis, “Our AI solutions meet this need by immediately helping clinicians on the frontlines to quickly and easily assess COVID-19 patients’ hearts to help guide care delivery.”

About DiA Imaging Analysis:
DiA Imaging Analysis provides advanced AI-based ultrasound analysis technology that makes ultrasound accessible to all. DiA’s automated tools deliver fast and accurate clinical indications to support the decision-making process and offer better patient care. DiA’s AI-based technology uses advanced pattern recognition and machine-learning algorithms to automatically imitate the way the human eye detects image borders and identifies motion. Using DiA’s tools provides automated and objective AI tools, helps reduce variability among users, and increases efficiency. It allows clinicians with various levels of experience to quickly and easily analyze ultrasound images.

For additional information, please visit http://www.dia-analysis.com.

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