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Archive for the ‘Treatment Protocols for COVID-19’ Category


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

Reporter: Aviva Lev-Ari, PhD, RN

 

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

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

 

SOURCES

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

SMITHSONIANMAG.COM

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

Complement and the Regulation of T Cell Responses

Annual Review of Immunology

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

Complement Dysregulation and Disease: Insights from Contemporary Genetics

M. Kathryn Liszewski,1 Anuja Java,2

Elizabeth C. Schramm,3 and John P. Atkinson1

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

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

3Serion Inc., St. Louis, Missouri 63108

 

Keywords

atypical hemolytic uremic syndrome, age-related macular degeneration,

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

factor I, C3, factor B

Abstract

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

CONCLUSIONS AND PERSPECTIVES

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

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

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

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

SOURCE

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

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

 

 

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

 

Is SARS-COV2 Hijacking the Complement and Coagulation Systems?

Reporter: Stephen J. Williams, PhD

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

 

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

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

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

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

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

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

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

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

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

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

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

 

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

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

Abstract

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

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

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

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

Author information

Affiliations

Consortia

Corresponding author

Correspondence to Akiko Iwasaki.

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

Reporter: Aviva Lev-Ari, PhD, RN

Kate Chiang

Charak Foundation; Applied Medical Technologies LLC

Kamyar Kalantar-Zadeh

University of California Irvine

Ajay Gupta

University of California Irvine

Date Written: July 13, 2020

Abstract

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

 

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

Funding: None to declare

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

 Suggested Citation

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

Kate Chiang

Charak Foundation ( email )

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

Applied Medical Technologies LLC ( email )

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

Kamyar Kalantar-Zadeh

University of California Irvine ( email )

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

Ajay Gupta (Contact Author)

University of California Irvine ( email )

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

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Inflammation BioMarker C-Reactive Protein Guides Use of Systemic Glucocorticoids in Patients with COVID-19: The Effects on Mortality or Use of Mechanical Ventilation – (CRP) ≥20 mg/dL was associated with significantly reduced risk of Mortality or Mechanical Ventilation Efficacy

Reporter: Aviva Lev-Ari, PhD, RN

 

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

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

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

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

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

Article has an altmetric score of 299

Abstract

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

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

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

DISCUSSION

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

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

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

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

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

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

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Severe COVID-19 in Patients experiencing Cytokine Storm: Positive Outcomes (faster respiratory recovery, a lower likelihood of mechanical ventilation, and fewer in-hospital deaths) of high dose methylprednisolone plus tocilizumab (Actemra, Genentech) vs Supportive Care Alone

Reporter: Aviva Lev-Ari, PhD, RN

 

“COVID-19-associated cytokine storm syndrome [CSS] is an important complication of severe acute respiratory syndrome coronavirus-2 infection in up to 25% of the patients,” lead author Sofia Ramiro, MD, PhD, told Medscape Medical News.

The researchers assessed outcomes of 86 individuals with COVID-19-associated CSS treated with high-dose methylprednisolone plus/minus tocilizumab, an anti-interleukin-6 receptor monoclonal antibody. They compared them with another 86 patients with COVID-19 treated with supportive care before initiation of the combination therapy protocol.

Participants with CSS had an oxygen saturation of 94% or lower at rest or tachypnea exceeding 30 breaths per minute.

They also had at least two of the following:

  • C-reactive protein > 100 mg/L;
  • serum ferritin > 900 μg/L at one occasion or
  • a twofold increase at admission within 48 hours; or
  • D-dimer levels > 1500 μg/L.

https://www.medscape.com/viewarticle/934567

Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study

  1. Sofia Ramiro1,2,
  2. Rémy L M Mostard3,
  3. César Magro-Checa1,
  4. Christel M P van Dongen1,
  5. Tom Dormans4,
  6. Jacqueline Buijs5,
  7. Michiel Gronenschild3,
  8. Martijn D de Kruif3,
  9. Eric H J van Haren3,
  10. Tom van Kraaij3,
  11. Mathie P G Leers6,
  12. Ralph Peeters1,
  13. Dennis R Wong7,
  14. Robert B M Landewé1,8

Author affiliations

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 10 million people, including pregnant women. To date, no consistent evidence for the vertical transmission of SARS-CoV-2 has been found. The placenta serves as the lungs, gut, kidneys, and liver of the fetus. This fetal organ also has major endocrine actions that modulate maternal physiology and, importantly, together with the extraplacental chorioamniotic membranes shield the fetus against microbes from hematogenous dissemination and from invading the amniotic cavity.

 

Most pathogens that cause hematogenous infections in the mother are not able to reach the fetus, which is largely due to the potent protective mechanisms provided by placental cells (i.e. trophoblast cells: syncytiotrophoblasts and cytotrophoblasts). Yet, some of these pathogens such as Toxoplasma gondii, Rubella virus, herpesvirus (HSV), cytomegalovirus (CMV), and Zika virus (ZIKV), among others, are capable of crossing the placenta and infecting the fetus, causing congenital disease.

 

The placental membranes that contain the fetus and amniotic fluid lack the messenger RNA (mRNA) molecule required to manufacture the ACE2 receptor, the main cell surface receptor used by the SARS-CoV-2 virus to cause infection. These placental tissues also lack mRNA needed to make an enzyme, called TMPRSS2, that SARS-CoV-2 uses to enter a cell. Both the receptor and enzyme are present in only miniscule amounts in the placenta, suggesting a possible explanation for why SARS-CoV-2 has only rarely been found in fetuses or newborns of women infected with the virus, according to the study authors.

 

The single-cell transcriptomic analysis presented by the researchers provides evidence that SARS-CoV-2 is unlikely to infect the placenta and fetus since its canonical receptor and protease, ACE2 and TRMPSS2, are only minimally expressed by the human placenta throughout pregnancy. In addition, it was shown that the SARS-CoV-2 receptors are not expressed by the chorioamniotic membranes in the third trimester. However, viral receptors utilized by CMV, ZIKV, and others are highly expressed by the human placental tissues.

 

Transcript levels do not always correlate with protein expression, but the data of the present study indicates a low likelihood of placental infection and vertical transmission of SARS-CoV-2. However, it is still possible that the expression of these proteins is much higher in individuals with pregnancy complications related with the renin-angiotensin-aldosterone system, which can alter the expression of ACE2. The cellular receptors and mechanisms that could be exploited by SARS-CoV-2 are still under investigation.

 

References:

 

https://www.nih.gov/news-events/news-releases/placenta-lacks-major-molecules-used-sars-cov-2-virus-cause-infection

 

https://pubmed.ncbi.nlm.nih.gov/32662421/

 

https://pubmed.ncbi.nlm.nih.gov/32217113/

 

https://pubmed.ncbi.nlm.nih.gov/32161408/

 

https://pubmed.ncbi.nlm.nih.gov/32335053/

 

https://pubmed.ncbi.nlm.nih.gov/32298273/

 

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

Reporter: Aviva Lev-Ari, PhD, RN

Serological Testing WordCloud

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

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

Abstract

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

SOURCE

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

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

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

 

  • State of Science on 7/21/2020

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

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

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

  • State of Science on 5/19/2020

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

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

Highlights

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

Highlights

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

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

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

     

    Highlights

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

    Tissue-specific tolerance in fatal Covid-19

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

    Abstract

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

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

    SOURCE 

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

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

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

    Abstract

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

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

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

     SOURCE

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

    Other Etiologies Explained

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

    Reporter: Aviva Lev-Ari, PhD, RN

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

    A mysterious blood-clotting complication is killing coronavirus patients

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

    SOURCE

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

    Mechanism of thrombocytopenia in COVID-19 patients

    Abstract

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

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

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

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

    Abstract

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

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

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

    First published: 27 February 2020
    Citations: 139

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

    Abstract

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

    Research Highlights

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

    Intravascular Platelet Aggregation in the Heart Induced by Norepinephrine

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

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

    SOURCE

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

     

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

    Ajay Gupta, MBBS, MD

    Department of Medicine,

    University of California, Irvine

    President & Chief Scientific Officer,

    Charak LLC

    E-mails:

    ajayg1@hs.uci.edu

    charaklabs@outlook.com

    Off.: 1 (562) 419 7029

    Cell: 1 (562) 412 6259

    Fax: 1 (702) 974 1001

     

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

    Professor Saul Yedgar

    Walter & Greta Stiel Chair in Heart Studies

    Department of Biochemistry

    Hebrew University-Hadassah Medical School

    Jerusalem, Israel 91120

    Tel:   00972-2-643-9218 (office)

             00972-2-652-0159 (home)

    Fax: 00972-2-675-7291

    Email: yedgar@md.huji.ac.il

     

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

     

    CORONAVIRUS, SARS-CoV-2 PORTAL @LPBI

    http://lnkd.in/ePwTDxm

    Launched on 3/14/2020

    Eight Pages of LPBI Group’s Coronavirus PORTAL

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

     

    Lead Curators are:

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

     

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

    Reporter: Stephen J. Williams, PhD.

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

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

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

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

     

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

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

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

     

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

    Curator: Aviva Lev-Ari, PhD, RN

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

     

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

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

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

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

     

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

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

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

     

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

    Curator: Stephen J. Williams, Ph.D.

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

     

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

    Curator: Stephen J. Williams, PhD

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

     

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

    Reporter: Aviva Lev-Ari, PhD, RN

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

     

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

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

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

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

     

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

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

     

     

    Different Drug development efforts

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

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

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

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

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

    Coronavirus puts drug repurposing on the fast track

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

    Read Full Post »


    Setting The Price for Remdesivir @Gilead Sciences – The first medicine shown to work against Covid-19, it does not save lives

     

    Reporter: Aviva Lev-Ari, PhD, RN

     

    UPDATED ON 6/29/2020

    Gilead’s long-awaited remdesivir price is $3,120, in line with watchdog estimates

    Will Gilead be able to make a profit out of remdeisivr at the current price? It looks like it.

    At the $2,340 government purchase price, Gilead could collect revenue of about $2.3 billion from selling around 1.5 million remdeisivr treatment course in 2020, RBC Capital analyst Brian Abrahams wrote in a Monday note to clients. Gilead expects to spend about $1 billion developing and distributing remdesivir this year alone. That would imply around $1.3 billion in profit.

    However, Abrahams figured there wouldn’t be much room for growth left afterward “given the likelihood of ultimate development of a vaccine (or herd immunity), the likelihood other therapies will produce similar or greater benefits perhaps with more convenient administration.”

    Right now, Gilead’s planning to test an inhaled formulation of the drug for potential use in patients with earlier stages of the disease. It’s also exploring combinations with anti-inflammatory agents, including Roche’s Actemra and Eli Lilly’s Olumiant, both FDA-approved arthritis treatments.

    During a Monday interview with CNBC’s “Squawk Box,” O’Day pointed to those second wave of clinical development investments as part of Gilead’s “dual responsibility” alongside access.

    In the developing world, Gilead has penned nine deals with generic makers to offer remdesivir at low cost. For example, India’s Cipla and Hetero Labs have launched generic versions in their home country at around $70 per vial.

    Remdesivir gets a price

    After a long wait, Gilead Sciences has set a price for remdesivir, the first medicine shown to work against Covid-19. Now the debate over whether that price is fair can begin.

    For all governments in the developed world, including the U.S. government’s Medicaid program and the Department of Veterans Affairs, Gilead will charge $2,340 for a five-day course. U.S. insurers will pay 33% more, or $3,120. Countries in the developing world will get the drug at greatly reduced prices through generic manufacturers to which Gilead has licensed production.

    There has been speculation about the price for months, with the Institute for Clinical and Economic Review offering up arguments for a price anywhere between $10 and $5,080, and some Wall Street analysts making their own estimates.

    “We spent a lot of time and considerable care and discussion about how to approach the pricing of this medicine,” Gilead CEO Daniel O’Day told STAT. “At this price it’s significantly below the value it brings to patients and to society. There is no doubt of that in my mind.”

    SOURCE

    From: STAT | The Readout <damian.garde@statnews.com>

    Reply-To: STAT | The Readout <damian.garde@statnews.com>

    Date: Monday, June 29, 2020 at 7:18 AM

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

    Subject: Gilead announces remdesivir price, novel antibiotics get $1 billion, & patients die in gene therapy trial

     

    Gilead announces long-awaited price for Covid-19 drug remdesivir

    Read Full Post »


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

    Reporter: Stephen J. Williams, PhD.

     

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

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

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

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

    A global repository for Covid-19 treatment data

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

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

    Drug Repurposing for COVID-19

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

     

    Phase 1: COMPLETED

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

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

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

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

    Key Summary Points

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

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

    Abstract

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

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

    Phase 2: Continue to update CORONA

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

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

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

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

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

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