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Mechanism of thrombosis with AstraZeneca and J & J vaccines: Expert Opinion by Kate Chander Chiang & Ajay Gupta, MD

UPDATED on 4/15/2021


Atul Gawande@Atul_Gawande
·

Why wait for more info? A new case of cerebral sinus venus thrombosis was reported in a 25 year old man who became critically ill from a cerebral hemorrhage. And for women age 20-50, CSVT occurred in 1 in 13,000, or 4-15X higher than background.

UPDATED on 4/14/2021

How UK doctor linked rare blood-clotting to AstraZeneca Covid jab

https://www.theguardian.com/society/2021/apr/13/how-uk-doctor-marie-scully-blood-clotting-link-astrazeneca-covid-jab-university-college-london-hospital

From: “Gupta, Ajay” <ajayg1@hs.uci.edu>

Date: Wednesday, April 14, 2021 at 10:33 AM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

Cc: Kate Chiang <kcscience777@gmail.com>

Subject: Mechanism of thrombosis with AstraZeneca and J & J vaccines

https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine

We have put together the following mechanism for thrombosis including central vein sinus thrombosis as a complication of both J&J and the AstraZeneca vaccines. This unifying mechanism explains the predilection of cerebral veins and higher risk in younger women. Please share your thoughts on the proposed mechanism.

We have submitted the attached manuscript to SSRN.  Sharing this promptly considering the public health significance.

Thanks

Figure 1. AstraZeneca or Janssen COVID-19 vaccine induced thromboinflammation and cerebral venous sinus thrombosis (CVST)-Proposed Mechanisms: Adenovirus carrier delivers SARS-CoV-2 DNA encoding the Spike (S) protein to the lung megakaryocytes via the coxsackie-adenovirus receptor (CAR). Spike protein induces COX-2 expression in megakaryocytes leading to megakaryocyte activation, biogenesis of activated platelets that express COX-2 and generate thromboxane A2 (TxA2). Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to release of extracellular vesicles, thereby promoting CLEC5A and TLR2 mediated neutrophil activation, thromboinflammation, CVST, and thromboembolism in other vascular beds. Young age and female gender are associated with increased TxA2 generation and platelet activation respectively, and hence increased risk of thromboembolic complications following vaccination.

Best regards,

Ajay

Ajay Gupta, M.B.,B.S., M.D.

Clinical Professor,

Division of Nephrology, Hypertension and Kidney Transplantation

University of California Irvine  

President & CSO, KARE Biosciences (www.karebio.com)

E-mail:     ajayg1@hs.uci.edu

Cell:         1 (562) 412-6259

Office:     1 (562) 419-7029

PERSPECTIVE 

Title: SARS-CoV-2 vaccination induced thrombosis: Is chemoprophylaxis with antiplatelet agents warranted? 

Guest Authors: 

Kate Chander Chiang1 

Ajay Gupta, MBBS, MD1,2 

Affiliations 

(1) KARE Biosciences, Orange, CA 92869 

(2) Department of Medicine, University of California Irvine (UCI) School of Medicine, Orange, CA 92868 

*Corresponding author: 

Ajay Gupta, MBBS, MD 

Clinical Professor of Medicine, 

Division of Nephrology, Hypertension and Kidney Transplantation 

University of California Irvine (UCI) School of Medicine, 

Orange, CA 92868 

Tel: +1 (562) 412-6259 

E-mail: ajayg1@hs.uci.edu 

Word Count 

Abstract: 359 

Main Body: 1,648 

Funding: No funding was required. 

Conflict of Interest: AG and KCC have filed a patent for use of Ramatroban as an anti-thrombotic and immune modulator in SARS-CoV-2 infection. The patents have been licensed to KARE Biosciences. KCC is an employee of KARE Biosciences. 

Author Contributions: AG and KCC conceptualized, created the framework, wrote and reviewed the manuscript. 

Abbreviations: TxA2, thromboxane A2; DIC, disseminated intravascular coagulopathy; COX, cyclooxygenase; TTP, thrombotic thrombocytopenic purpura; CVST, cerebral venous sinus thrombosis; CLEC, C-type lectin-like receptor; TLR, toll-like receptor; CAR, coxsackievirus and adenovirus receptor; COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 2 

ABSTRACT 

The COVID-19 vaccines, Vaxzevria® (AstraZeneca) and the Janssen vaccine (Johnson & Johnson) are highly effective but associated with rare thrombotic complications. These vaccines are comprised of recombinant, replication incompetent, chimpanzee adenoviral vectors encoding the Spike (S) glycoprotein of SARS-CoV-2. The adenovirus vector infects epithelial cells expressing the coxsackievirus and adenovirus receptor (CAR). The S glycoprotein of SARS-CoV-2 is expressed locally stimulating neutralizing antibody and cellular immune responses, which protect against COVID-19. The immune responses are highly effective in preventing symptomatic disease in adults irrespective of age, gender or ethnicity. However, both vaccines have been associated with thromboembolic events including cerebral venous sinus thrombosis (CVST). Megakaryocytes also express CAR, leading us to postulate adenovirus vector uptake and expression of spike glycoprotein by megakaryocytes. Spike glycoprotein induces expression of cyclooxygenase -2 (COX-2), leading to generation of thromboxane A2 (TxA2). TxA2 promotes megakaryocyte activation, biogenesis of activated platelets and thereby increased thrombogenicity. Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to CVST. The mechanisms proposed are consistent with the following clinical observations. First, a massive increase in TxA2 generation promotes platelet activation and thromboinflammation in COVID-19 patients. Second, TxA2 generation and platelet activation is increased in healthy women compared to men, and in younger mice compared to older mice; and, younger age and female gender appear to be associated with increased risk of thromboembolism as a complication of adenoviral vector based COVID-19 vaccine. The roll out of both AstraZeneca and Janssen vaccines has been halted for adults under 30-60 years of age in many countries. We propose that antiplatelet agents targeting TxA2 receptor signaling should be considered for chemoprophylaxis when administering the adenovirus based COVID-19 vaccines to adults under 30-60 years of age. In many Asian and African countries, only adenovirus-based COVID-19 vaccines are available at present. A short course of an antiplatelet agent such as aspirin could allow millions to avail of the benefits of the AstraZeneca and Janssen COVID-19 vaccines which could be otherwise either denied to them or put them at undue risk of thromboembolic complications. 

Keywords: SARS-CoV-2, COVID-19, Vaxzevria, COVISHIELD, Janssen COVID-19 vaccine, Johnson & Johnson vaccine, AstraZeneca vaccine, AZD1222, thrombosis, cerebral venous sinus thrombosis, thromboembolism, aspirin, antiplatelet agents, thromboxane, COX-2, disseminated intravascular coagulation, thrombocytopenia, thrombotic thrombocytopenia, CLEC2, megakaryocyte 3 

COVID-19 disease is caused by a novel positive-strand RNA coronavirus (SARS-CoV-2), which belongs to the Coronaviridae family, along with the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) coronaviruses.1 The genome of these viruses encodes several non-structural and structural proteins, including spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins.2 The majority of the vaccines for COVID-19 that employ administration of viral antigens or viral gene sequences aim to induce neutralizing antibodies against the viral spike protein (S), preventing uptake through the ACE2 receptor, and thereby blocking infection.3 

The Janssen COVID-19 vaccine (Johnson & Johnson) is comprised of a recombinant, replication- incompetent Ad26 vector, encoding a stabilized variant of the SARS-CoV-2 Spike (S) protein. The ChAdOx1 nCoV-19 vaccine (AZD1222, Vaxzevria®) was developed at Oxford University and consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, encoding the S protein.4 In US Phase III trials, Vaxzevria has been demonstrated to have 79% efficacy at preventing symptomatic COVID-19, and 100% efficacy against severe or critical disease and hospitalization, with comparable efficacy across ethnicity, gender and age.5 However, Vaxzevria has been associated with thrombotic and embolic events including disseminated intravascular coagulation (DIC) and cerebral venous sinus thrombosis (CVST), occurring within 14 days after vaccination, mostly in people under 55 years of age, the majority of whom have been women.6 Data from Europe suggests that the event rate for thromboembolic events may be about 10 per million vaccinated. Antibodies to platelet factor 4/heparin complexes have been recently reported in a few patients.7 However, the significance of this finding remains to be established. As of April 12, 2021, about 6.8 million doses of the Janssen vaccine have been administered in the U.S.8 CDC and FDA are reviewing data involving six reported U.S. cases of CVST in combination with thrombocytopenia.8 All six cases occurred among women between the ages of 18 and 48, and symptoms occurred 6 to 13 days after vaccination.8 

SARS-CoV-2 is known to cause thromboinflammation leading to thrombotic microangiopathy, pulmonary thrombosis, pedal acro-ischemia (“COVID-toes”), arterial clots, strokes, cardiomyopathy, coronary and systemic vasculitis, deep venous thrombosis, pulmonary embolism, and microvascular thrombosis in renal, cardiac and brain vasculature.9-14 Cerebral venous sinus thrombosis (CVST) has also been reported in COVID-19 patients.15 Amongst 34,331 hospitalized COVID-19 patients, CVST was diagnosed in 28.16 In a multicenter, multinational, cross sectional, retrospective study of 8 patients diagnosed with CVST and COVID-19, seven were women.17 In another series of 41 patients with COVID-19 and CVST, the average age was about 50 years (SD, 16.5 years).17 The pathobiology of thrombotic events associated with the AstraZeneca vaccine should be viewed in the context of mechanisms underlying thromboinflammation that complicates SARS-CoV-2 infection and COVID-19 disease. 

A. Role of COX-2 and thromboxane A2 in thromboinflammation complicating adenovirus based COVID-19 vaccine encoding the Spike protein of SARS-CoV-2 

Thromboinflammation in COVID-19 seems to be primarily caused by endothelial, platelet and neutrophil activation, platelet-neutrophil aggregates and release of neutrophil extracellular traps (NETs).13,18 Platelet activation in COVID-19 is fueled by a lipid storm characterized by massive increases in thromboxane A2 (TxA2) levels in the blood and bronchoalveolar lavage fluid.19,20 Cyclooxygenase (COX) enzymes catalyze the first step in the biosynthesis of TxA2 from arachidonic acid, and COX-2 expression is induced by the spike (S) protein of coronaviruses.21 We postulate that an aberrant increase in TxA2 generation induced by the spike protein expression from the AstraZeneca vaccine leads to thromboinflammation, thromboembolism and CVST. 4 

The support for the above proposed mechanism comes from the following observations. First, when mice of different age groups were infected with SARS-CoV virus, the generation of TxA2 was markedly increased in younger mice compared to middle aged mice.22 Furthermore, in children with asymptomatic or mildly symptomatic SARS-CoV-2 infection, microvascular thrombosis and thrombotic microangiopathy occur early in infection.20 These observations are consistent with the higher risk for thrombosis in adults under 60 years of age, compared with the older age group.6,7 Second, platelets from female mice are much more reactive than from male mice.23 Furthermore, TxA2 generation, TxA2-platelet interaction and activation is increased in women compared to men.24,25 These observations are consistent with disproportionately increased risk of thrombosis in women following AstraZeneca and Janssen COVID-19 vaccines. 

The adenoviral vector ChAdOx1, containing nCoV-19 spike protein gene, infects host cells through the coxsackievirus and adenovirus receptor (CAR).26 CAR-dependent cell entry of the viral vector allows insertion of the SARS-CoV-2 spike protein gene and expression of Spike protein by host cells (Figure 1). CAR is primarily expressed on epithelial tight junctions.27 CAR expression has also been reported in platelets,28 and since platelets are anucleate cells CAR expression by megakaryocytes can be inferred. Therefore, AstraZeneca and Janssen vaccines would be expected to induce expression of Spike protein in megakaryocytes and platelets (Figure 1). 

Spike protein of coronaviruses in known to induce COX-2 gene expression.21,29 COX-2 expression is induced during normal human megakaryopoiesis and characterizes newly formed platelets.30 While in healthy controls <10% of circulating platelets express COX-2, in patients with high platelet generation, up to 60% of platelets express COX-2.30 Generation of TxA2 by platelets is markedly suppressed by COX-2 inhibition in patients with increased megakaryopoiesis versus healthy subjects.30 Therefore, we postulate that expression of Spike protein induces COX-2 expression and generation of thromboxane A2 by megakaryocytes. TxA2 promotes biogenesis of activated platelets expressing COX-2. Platelet TxA2 generation leads to platelet activation and aggregation, and thereby thromboinflammation (Figure 1). 

Extravascular spaces of the lungs comprise populations of mature and immature megakaryocytes that originate from the bone marrow, such that lungs are a major site of platelet biogenesis, accounting for approximately 50% of total platelet production or about 10 million platelets per hour.31 More than 1 million extravascular megakaryocytes have been observed in each lung of transplant mice.31 Following intramuscular injection of the AstraZeneca and Janssen vaccines, the adenovirus vector will traverse the veins and lymphatics to be delivered to the pulmonary circulation thereby exposing lung megakaryocytes in the first pass. Interestingly, under thrombocytopenic conditions, haematopoietic progenitors migrate out of the lung to repopulate the bone marrow and completely reconstitute blood platelet counts.31 

B. Predilection of cerebral venous sinuses for thrombosis following vaccination 

Recent studies have demonstrated that arterial, venous and sinusoidal endothelial cells in the brain uniquely express markers of the lymphatic endothelium including podoplanin.32 Podoplanin serves as a ligand for CLEC2 receptors on platelets.33 Thromboxane A2 dependent CLEC2 signaling leads to platelet activation (Figure 1), while a TxA2 receptor antagonist nearly abolish CLEC2 signaling and platelet activation.33 TxA2 dependent CLEC2 signaling promotes release of exosomes and microvesicles from platelets, leading to activation of CLEC5A and TLR2 receptors respectively on neutrophils, neutrophil activation and release of neutrophil extracellular traps (NETs) (Figure 1).34 Neutrophil activation, more than platelet activation, is associated with thrombotic complications in COVID-19.13,18,35 As proposed above, the expression of podoplanin, a unique molecular signature of cerebral endothelial cells, may be responsible for the predilection of brain vascular bed to thromboinflammation and CVST as a complication of COVID-19 vaccines. 5 

C. Chemoprophylaxis with antiplatelet agents 

In animal models of endotoxin mediated endothelial injury and thromboinflammation, antagonism of TxA2 signaling prevents ARDS, reduces myocardial damage and increases survival.36-38 

Considering the key role played by platelets in thromboinflammation, we propose consideration of antiplatelet agents, either aspirin or TxA2 receptor antagonists, as chemoprophylactic agents when the AstraZeneca vaccine is administered to adults between 18 and 60 years of age.39 High bleeding risk because of another medical condition or medication would be contraindications to use of antiplatelet agents.39 Medical conditions that increase bleeding risk include previous gastrointestinal bleeding, peptic ulcer disease, blood clotting problems, and kidney disease.39 Medications that increase bleeding risk include nonsteroidal anti-inflammatory drugs, steroids, and other anticoagulants or anti-platelet agents.39 Aspirin appears to be safe in COVID-19. In a retrospective observational study in hospitalized patients with COVID-19, low-dose aspirin was found to be effective in reducing morbidity and mortality; and was not associated with any safety issues including major bleeding.40 Therefore, aspirin is likely to be safe as an adjunct to COVID-19 vaccines even in the event of a subsequent infection with SARS-CoV-2 virus. 

Can aspirin influence the host immune response to the COVID-19 vaccines? This issue merits further investigation. When healthy adults > 65 years of age were given influenza vaccine and randomized to receive 300 mg aspirin or placebo on days 1, 2, 3, 5 and 7, the aspirin group showed 4-fold or greater rise in influenza specific antibodies.41 The risk-benefit analysis, based on above information, suggests that a one to three week course of low-dose aspirin merits consideration in order to prevent the thromboembolic events associated with the AstraZeneca vaccine. 

SUMMARY 

Thromboembolic disease including disseminated intravascular coagulation and cerebral venous sinus thrombosis have been reported in association with AstraZeneca and Janssen COVID-19 vaccines. Many countries have halted use of these vaccines either entirely or for adults under 30 to 60 years of age. European and North American countries generally have access to mRNA vaccines. However, in Asian and African countries the choices are limited to adenovirus based COVID-19 vaccines. The governments in such countries are forging ahead with vaccinating all adults, including those under 60 years of age, with Vaxzevria, Covishield (the version of Vaxzevria manufactured by the Serum Institute of India) or the Janssen vaccines. This has led to grave concern and anxiety amongst the citizens and medical professionals. Considering the profound global public health implications of limiting the use of these vaccines, it is critical to understand the pathobiology of vaccination induced thrombotic events in order to guide strategies aimed at prevention. In this regard, studies are urgently needed to examine lipid mediators and thromboxane A2 – platelet axis following vaccination with these vaccines, compared with mRNA vaccines. The risk-benefit analysis based on information presented here suggests that chemoprophylaxis using a short course of low-dose aspirin in adults under 60 years of age may be justified in conjunction with adenovirus based COVID-19 vaccines in order to prevent thromboembolic events and enhance safety. 6 

Figure 1. AstraZeneca or Janssen COVID-19 vaccine induced thromboinflammation and cerebral venous sinus thrombosis (CVST)-Proposed Mechanisms: Adenovirus carrier delivers SARS-CoV-2 DNA encoding the Spike (S) protein to the lung megakaryocytes via the coxsackie-adenovirus receptor (CAR). Spike protein induces COX-2 expression in megakaryocytes leading to megakaryocyte activation, biogenesis of activated platelets that express COX-2 and generate thromboxane A2 (TxA2). Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to release of extracellular vesicles, thereby promoting CLEC5A and TLR2 mediated neutrophil activation, thromboinflammation, CVST, and thromboembolism in other vascular beds. Young age and female gender are associated with increased TxA2 generation and platelet activation respectively, and hence increased risk of thromboembolic complications following vaccination. 

REFERENCES 

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3. Kyriakidis NC, López-Cortés A, González EV, Grimaldos AB, Prado EO. SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. npj Vaccines. 2021;6(1). 

4. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet. 2021;397(10269):99-111. 

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16. Baldini T, Asioli GM, Romoli M, et al. Cerebral venous thrombosis and severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis. Eur J Neurol. 2021. 

17. Abdalkader M, Shaikh SP, Siegler JE, et al. Cerebral Venous Sinus Thrombosis in COVID-19 Patients: A Multicenter Study and Review of Literature. J Stroke Cerebrovasc Dis. 2021;30(6):105733. 

18. Petito E, Falcinelli E, Paliani U, et al. Association of Neutrophil Activation, More Than Platelet Activation, With Thrombotic Complications in Coronavirus Disease 2019. The Journal of Infectious Diseases. 2020. 8 

19. Archambault A-S, Zaid Y, Rakotoarivelo V, et al. Lipid storm within the lungs of severe COVID-19 patients: Extensive levels of cyclooxygenase and lipoxygenase-derived inflammatory metabolites. medRxiv. 2020:2020.2012.2004.20242115. 

20. Diorio C, McNerney KO, Lambert M, et al. Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations. Blood Advances. 2020;4(23):6051-6063. 

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22. Vijay R, Hua X, Meyerholz DK, et al. Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome-CoV infection. J Exp Med. 2015;212(11):1851-1868. 

23. Leng X-H, Hong SY, Larrucea S, et al. Platelets of Female Mice Are Intrinsically More Sensitive to Agonists Than Are Platelets of Males. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24(2):376-381. 

24. Kim BS, Auerbach DA, Sadhra H, et al. A Sex-Specific Switch in Platelet Receptor Signaling Following Myocardial Infarction. In: Cold Spring Harbor Laboratory; 2019. 

25. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002;105(14):1650-1655. 

26. Cohen CJ, Xiang ZQ, Gao G-P, Ertl HCJ, Wilson JM, Bergelson JM. Chimpanzee adenovirus CV-68 adapted as a gene delivery vector interacts with the coxsackievirus and adenovirus receptor. Journal of General Virology. 2002;83(1):151-155. 

27. Cohen CJ, Shieh JT, Pickles RJ, Okegawa T, Hsieh JT, Bergelson JM. The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc Natl Acad Sci U S A. 2001;98(26):15191-15196. 

28. Assinger A. Platelets and infection – an emerging role of platelets in viral infection. Front Immunol. 2014;5:649. 

29. Yan X, Hao Q, Mu Y, et al. Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein. Int J Biochem Cell Biol. 2006;38(8):1417-1428. 

30. Rocca B, Secchiero P, Ciabattoni G, et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci U S A. 2002;99(11):7634-7639. 

31. Lefrançais E, Ortiz-Muñoz G, Caudrillier A, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017;544(7648):105-109. 

32. Mezey É, Szalayova I, Hogden CT, et al. An immunohistochemical study of lymphatic elements in the human brain. Proceedings of the National Academy of Sciences. 2021;118(3):e2002574118. 

33. Badolia R, Inamdar V, Manne BK, Dangelmaier C, Eble JA, Kunapuli SP. G(q) pathway regulates proximal C-type lectin-like receptor-2 (CLEC-2) signaling in platelets. J Biol Chem. 2017;292(35):14516-14531. 9 

34. Sung P-S, Huang T-F, Hsieh S-L. Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2. Nature Communications. 2019;10(1). 

35. Ng H, Havervall S, Rosell A, et al. Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19. Arteriosclerosis, Thrombosis, and Vascular Biology. 2021;41(2):988-994. 

36. Carey MA, Bradbury JA, Seubert JM, Langenbach R, Zeldin DC, Germolec DR. Contrasting Effects of Cyclooxygenase-1 (COX-1) and COX-2 Deficiency on the Host Response to Influenza A Viral Infection. The Journal of Immunology. 2005;175(10):6878-6884. 

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39. Peters AT, Mutharasan RK. Aspirin for Prevention of Cardiovascular Disease. JAMA. 2020;323(7):676. 

40. Chow JH, Khanna AK, Kethireddy S, et al. Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019. Anesthesia & Analgesia. 2021;132(4). 

41. Saleh E, Moody MA, Walter EB. Effect of antipyretic analgesics on immune responses to vaccination. Human Vaccines & Immunotherapeutics. 2016;12(9):2391-2402. 

SOURCE

From: “Gupta, Ajay” <ajayg1@hs.uci.edu>

Date: Wednesday, April 14, 2021 at 10:33 AM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

This EXPERT OPINION is in response to:

From: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Date: Tuesday, April 13, 2021 at 9:03 AM
To: “Joel Shertok, PhD” <jshertok@yahoo.com>, “Stephen Williams, PhD” <sjwilliamspa@comcast.net>, “Prof. Marcus W Feldman” <mfeldman@stanford.edu>, “Irina Robu, PhD” <irina.stefania@gmail.com>, “Dr. Sudipta Saha” <sudiptasaha1977@gmail.com>, Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>, “Dr. Larry Bernstein” <larry.bernstein@gmail.com>, “Ofer Markman, PhD” <oferm2020@gmail.com>, “Daniel Menzin (gmail)” <dmenzin@gmail.com>, Pnina Abir-Am <pnina.abiram@gmail.com>, Alan <alanalanf@gmail.com>, Justin MDMEPhD <jdpmdphd@gmail.com>, Inbar Ofer <ofer.i@northeastern.edu>, Aviva Lev-Ari <aviva.lev-ari@comcast.net>, Madison Davis <madisond2302@gmail.com>, Danielle Smolyar <dsmolyar@syr.edu>, “Adina Hazan, PhD” <adinathazan@gmail.com>, Gail Thornton <gailsthornton@yahoo.com>, Amandeep kaur <662amandeep@gmail.com>, Premalata Pati <premalata09@gmail.com>, “Ajay Gupta, MD” <charaklabs@outlook.com>, Saul Yedgar <saulye@ekmd.huji.ac.il>, Yigal Blum <yigalblum@gmail.com>, a el <AElRoeiy@gmail.com>, “Dr. Raphael Nir” <rnir@sbhsciences.com>, “George Tetz, MD, PhD” <gtetz@clstherapeutics.com>, “Dr. Martin R Schiller (CEO, Heligenics)” <heligenics@gmail.com>, “Jea Asio (Heligenics)” <JAsio@Heligenics.com>, Yakov Kogan <ykogan@tgv-biomed.com>, Haim Levkowitz <haim@cs.UML.edu>

Subject: APRIL 13. 2021 – J&J Statement – Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine. ->> Are there relations between these FINDINGS?

Johnson & Johnson Statement on COVID-19 Vaccine

NEW BRUNSWICK, N.J., April 13, 2021– The safety and well-being of the people who use our products is our number one priority. We are aware of an extremely rare disorder involving people with blood clots in combination with low platelets in a small number of individuals who have received our COVID-19 vaccine. The United States Centers for Disease Control (CDC) and Food and Drug Administration (FDA) are reviewing data involving six reported U.S. cases out of more than 6.8 million doses administered. Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine.

In addition, we have been reviewing these cases with European health authorities. We have made the decision to proactively delay the rollout of our vaccine in Europe.

We have been working closely with medical experts and health authorities, and we strongly support the open communication of this information to healthcare professionals and the public.

The CDC and FDA have made information available about proper recognition and management due to the unique treatment required with this type of blood clot. The health authorities advise that people who have received our COVID-19 vaccine and develop severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after vaccination should contact their health care provider.

For more information on the Janssen COVID-19 vaccine, click here.

Please All send me your Expert Opinion on the relations between these FINDINGS?

Linking Thrombotic Thrombocytopenia to ChAdOx1 nCov-19 Vaccination, AstraZeneca | Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/04/12/linking-thrombotic-thrombocytopenia-to-chadox1-ncov-19-vaccination-astrazeneca/

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/

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/

THANK YOU

Best regards,

Aviva

Aviva Lev-Ari, PhD, RN

Director & Founder

https://lnkd.in/eEyn69r

Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston, MA, NJ, CA, PA, ME, DE, India, Israel & Canada

Editor-in-Chief

http://pharmaceuticalintelligence.com 

e-Mail: avivalev-ari@alum.berkeley.edu

(M) 617-775-0451

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Linking Thrombotic Thrombocytopenia to ChAdOx1 nCov-19 Vaccination, AstraZeneca

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 4/13/2021

“Right now, these adverse events appear to be extremely rare,” Anne Schuchat, MD, principal deputy director of the CDC, and Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a joint statement from the two agencies. “COVID-19 vaccine safety is a top priority for the federal government, and we take all reports of health problems following COVID-19 vaccination very seriously.”

STATEMENT BY J&J

Johnson & Johnson Statement on COVID-19 Vaccine

NEW BRUNSWICK, N.J., April 13, 2021The safety and well-being of the people who use our products is our number one priority. We are aware of an extremely rare disorder involving people with blood clots in combination with low platelets in a small number of individuals who have received our COVID-19 vaccine. The United States Centers for Disease Control (CDC) and Food and Drug Administration (FDA) are reviewing data involving six reported U.S. cases out of more than 6.8 million doses administered. Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine.

In addition, we have been reviewing these cases with European health authorities. We have made the decision to proactively delay the rollout of our vaccine in Europe.

We have been working closely with medical experts and health authorities, and we strongly support the open communication of this information to healthcare professionals and the public.

The CDC and FDA have made information available about proper recognition and management due to the unique treatment required with this type of blood clot. The health authorities advise that people who have received our COVID-19 vaccine and develop severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after vaccination should contact their health care provider.

For more information on the Janssen COVID-19 vaccine, click here.

SOURCE

https://endpts.com/us-pauses-jj-vaccinations-amid-new-reports-of-rare-serious-blood-clots/

Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination, AstraZeneca

Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca).

This study found that vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia (aHIT).

This study also found that the addition of immune globulin in doses that are readily achieved clinically was effective in inhibiting platelet activation by patients’ antibodies.

Clinician reluctance to start anticoagulation may be tempered by administering high-dose intravenous immune globulin to raise the platelet count, especially when a patient presents with severe thrombocytopenia and thrombosis, such as cerebral venous thrombosis.

Given the parallels with autoimmune heparininduced thrombocytopenia, anticoagulant options should include nonheparin anticoagulants used for the management of heparin-induced thrombocytopenia, unless a functional test has excluded heparin-dependent enhancement of platelet activation.

Finally, this paper suggest naming this novel entity vaccine-induced immune thrombotic thrombocytopenia (VITT) to avoid confusion with heparin-induced thrombocytopenia.

SOURCE

From: “Prof. Marcus W Feldman” <mfeldman@stanford.edu>

Date: Monday, April 12, 2021 at 1:10 PM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

Subject: Fwd: Vaccination thrombotic events clinically mimics Heparin-induced thrombocytopenia | CD8+ Memory T Cell Responses against Viral Variants

Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination

This article was published on April 9, 2021, at NEJM.org. DOI: 10.1056/NEJMoa2104840

BACKGROUND Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder. METHODS We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)–heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4–heparin immunoassay. RESULTS Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4–heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor–blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4–heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation. CONCLUSIONS Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.)

SOURCE

Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination

Andreas Greinacher, M.D., Thomas Thiele, M.D., Theodore E. Warkentin, M.D., Karin Weisser, Ph.D., Paul A. Kyrle, M.D., and Sabine Eichinger, M.D.

Author Affiliations

From Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald (A.G., T.T.), and the Division of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen (K.W.) — both in Germany; the Departments of Pathology and Molecular Medicine and of Medicine, McMaster University, Hamilton, ON, Canada (T.E.W.); and the Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna (P.A.K., S.E.).

Address reprint requests to Dr. Greinacher at Institut für Immunologie und Transfusionsmedizin, Abteilung Transfusionsmedizin, Sauerbruchstrasse, 17487 Greifswald, Germany.

NEJM.org. DOI: 10.1056/NEJMoa2104840

https://files.constantcontact.com/6edd32c5501/a5408883-7fbd-4509-b11d-8d52c6b807fc.pdf

Other related articles published in this Open Access Online Scientific Journal included 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/

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/

Read Full Post »


COVID-19 Sequel: Neurological Impact of Social isolation been linked to poorer physical and mental health

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 4/13/2021

Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19

 

Abstract

Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in an enormous worldwide burden of infection and mortality. However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection, representing in the broadest sense a failure to return to a baseline state of health after acute SARS-CoV-2 infection. On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps regarding this condition.

Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in more than 113 million persons infected and 2.5 million deaths (1). However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection. Although a standardized case definition does not yet exist for these manifestations, in the broadest sense they represent a failure to return to a baseline state of health after acute SARS-CoV-2 infection. The various terms used to describe this condition have included postacute (or late) sequelae of COVID-19, post-COVID condition or syndrome, long COVID, and long-haul COVID. In this article, we use the general umbrella term of “postacute COVID-19” to refer to multiple disease processes that may have varying degrees of overlap (including but not limited to sequelae of critical illness and hospitalization in persons with COVID-19) and the entity of long COVID, which refers to prolonged health abnormalities in persons previously infected with SARS-CoV-2 who may or may not have required hospitalization. Of note, there is not yet a consensus on terminology, which will likely evolve with a better understanding of this condition.

Reported symptoms are wide-ranging and may involve nearly all organ systems, with fatigue, dyspnea, cognitive dysfunction, anxiety, and depression often described (2–5). Although abnormalities in imaging studies and functional testing have been reported, the long-term clinical significance of some of these findings is not yet clear (367). Postacute manifestations of COVID-19 have been seen in persons of all demographic groups and include reports of multisystem inflammatory syndrome in children (89). Although the epidemiology of the diverse manifestations of postacute COVID-19 is not yet known, the expansive global burden of SARS-CoV-2 infection suggests that the potential public health effects of postacute COVID-19 are significant if even a small proportion of persons with SARS-CoV-2 infection have prolonged recovery or do not return to their baseline health.

On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop (available via videocast at https://videocast.nih.gov/watch=38878 and https://videocast.nih.gov/watch=38879) to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps. The speakers and participants included epidemiologists, clinicians, clinical and basic scientists, and members of the affected community. The videocast was open to the general public and had more than 1200 registered participants.

SOURCE

UPDATED on 4/7/2021

‘Beyond a Reasonable Doubt’: COVID-19 Brain Health Fallout Is Real, Severe

Sarah Edmonds

April 07, 2021

Editor’s note: Find the latest COVID-19 news and guidance in Medscape’s Coronavirus Resource Center.

START QUOTE

COVID-19 survivors face a sharply elevated risk of developing psychiatric or neurologic disorders in the six months after they contract the virus — a danger that mounts with symptom severity, new research shows.

In what is purported to be the largest study of its kind to-date, results showed that among 236,379 COVID-19 patients, one third were diagnosed with at least one of 14 psychiatric or neurologic disorders within a 6-month span.

The rate of illnesses, which ranged from depression to stroke, rose sharply among those with COVID-19 symptoms acute enough to require hospitalization.  

“If we look at patients who were hospitalized, that rate increased to 39%, and then increased to about just under 1 in 2 patients who needed ICU admission at the time of the COVID-19 diagnosis,” Maxime Taquet, PhD, University of Oxford Department of Psychiatry, Oxford, United Kingdom, told a media briefing.

Incidence jumps to almost two thirds in patients with encephalopathy at the time of COVID-19 diagnosis, he added.

The study, which examined the brain health of 236,379 survivors of COVID-19 via a US database of 81 million electronic health records, was published online April 6 in The Lancet Psychiatry.

High Rate of Neurologic, Psychiatric Disorders

The research team looked at the first-time diagnosis or recurrence of 14 neurologic and psychiatric outcomes in patients with confirmed SARS-CoV-2 infections. They also compared the brain health of this cohort with a control group of those with influenza or with non-COVID respiratory infections over the same period. 

SOURCE

The Effects of Loneliness and Our Brain function: poorer physical and mental health

One review of the science of loneliness found that people with stronger social relationships have a 50 per cent increased likelihood of survival over a set period of time compared with those with weaker social connections. Other studies have linked loneliness to cardiovascular disease, inflammation, and depression.

For loneliness researchers the pandemic has provided an unprecedented natural experiment in the impact that social isolation might have on our brains. As millions of people across the world emerge from months of reduced social contact, a new neuroscience of loneliness is starting to figure out why social relationships are so crucial to our health.

Neural basis of Emotion

Desire for Social Interaction

Are there neurological differences between people who experience short-term isolation and those who have been isolated for long stretches of time? What kinds of social interactions satisfy our social cravings? Is a video call enough to quell our need for social contact, or do some people require an in-person connection to really feel satiated?

START QUOTE

Julianne Holt-Lunstad, a psychology professor at Brigham Young University in the US and the author of two major studies on social isolation and health. “We have a lot of data that very robustly shows that both isolation and loneliness put us at increased risk for premature mortality—and conversely, that being socially connected is protective and reduces our risk,” she says.

START QUOTE

“Trying to investigate isolation or loneliness is not as straightforward in humans. In humans, being lonely is not necessarily correlated with how many people are around you,” says Tomova. She is particularly interested in the impact that the pandemic might have had on young people whose cognitive and social skills are still developing. “I think we will see potentially some differences in how their social behavior developed or things like that,” she says. But as is always the case in the uncertain world of loneliness research, the opposite could be true. “It could also be that most people are fine, because maybe social media does fulfill our social needs really well.”

SOURCE

https://www.wired.co.uk/article/lockdown-loneliness-neuroscience

The Weird Science of Loneliness and Our Brains – Social isolation as been linked to poorer physical and mental health, but scientists are finally starting to understand its neurological impact

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T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants 

Andrew D ReddAlessandra NardinHassen KaredEvan M BlochAndrew PekoszOliver LaeyendeckerBrian AbelMichael FehlingsThomas C QuinnAaron A R TobianOpen Forum Infectious Diseases, ofab143, https://doi.org/10.1093/ofid/ofab143Published: 30 March 2021 Article history

Abstract

This study examined whether CD8+ T-cell responses from COVID-19 convalescent individuals (n=30) potentially maintain recognition of the major SARS-CoV-2 variants (n=45 mutations assessed). Only one mutation found in B.1.351-Spike overlapped with a previously identified epitope (1/52), suggesting that virtually all anti-SARS-CoV-2 CD8+ T-cell responses should recognize these newly described variants.

Key words:

CD8+ T cellSARS-CoV-2COVID-19Convalescent patients

Topic: 

SOURCE

https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab143/6189113

Original paper:

Andrew D Redd, Alessandra Nardin, Hassen Kared, Evan M Bloch, Andrew Pekosz, Oliver Laeyendecker, Brian Abel, Michael Fehlings, Thomas C Quinn, Aaron A R Tobian, CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants, Open Forum Infectious Diseases, 2021;, ofab143, https://doi.org/10.1093/ofid/ofab143

Tuesday, March 30, 2021

T cells recognize recent SARS-CoV-2 variants

Healthy Human T CellScanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. NIAID

What

When variants of SARS-CoV-2 (the virus that causes COVID-19) emerged in late 2020, concern arose that they might elude protective immune responses generated by prior infection or vaccination, potentially making re-infection more likely or vaccination less effective. To investigate this possibility, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and colleagues analyzed blood cell samples from 30 people who had contracted and recovered from COVID-19 prior to the emergence of virus variants. They found that one key player in the immune response to SARS-CoV-2—the CD8+ T cell—remained active against the virus.

The research team was led by NIAID’s Andrew Redd, Ph.D., and included scientists from Johns Hopkins University School of Medicine, Johns Hopkins Bloomberg School of Public Health and the Immunomics-focused company, ImmunoScape.

The investigators asked whether CD8+ T cells in the blood of recovered COVID-19 patients, infected with the initial virus, could still recognize three SARS-CoV-2 variants: B.1.1.7, which was first detected in the United Kingdom; B.1.351, originally found in the Republic of South Africa; and B.1.1.248, first seen in Brazil. Each variant has mutations throughout the virus, and, in particular, in the region of the virus’ spike protein that it uses to attach to and enter cells. Mutations in this spike protein region could make it less recognizable to T cells and neutralizing antibodies, which are made by the immune system’s B cells following infection or vaccination.

Although details about the exact levels and composition of antibody and T-cell responses needed to achieve immunity to SARS-CoV-2 are still unknown, scientists assume that strong and broad responses from both antibodies and T cells are required to mount an effective immune response.  CD8+ T cells limit infection by recognizing parts of the virus protein presented on the surface of infected cells and killing those cells.

In their study of recovered COVID-19 patients, the researchers determined that SARS-CoV-2-specific CD8+ T-cell responses remained largely intact and could recognize virtually all mutations in the variants studied. While larger studies are needed, the researchers note that their findings suggest that the T cell response in convalescent individuals, and most likely in vaccinees, are largely not affected by the mutations found in these three variants, and should offer protection against emerging variants.   

Optimal immunity to SARS-Cov-2 likely requires strong multivalent T-cell responses in addition to neutralizing antibodies and other responses to protect against current SARS-CoV-2 strains and emerging variants, the authors indicate. They stress the importance of monitoring the breadth, magnitude and durability of the anti-SARS-CoV-2 T-cell responses in recovered and vaccinated individuals as part of any assessment to determine if booster vaccinations are needed. 

SOURCE

https://www.nih.gov/news-events/news-releases/t-cells-recognize-recent-sars-cov-2-variants

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COVID-related financial losses at Mass General Brigham

Reporter: Aviva Lev-Ari, PhD, RN

Based on

Mass General Brigham reports COVID-related financial losses not as bad as expected

By Priyanka Dayal McCluskey Globe Staff,Updated December 11, 2020, 3:02 p.m.

START QUOTE

The state’s largest hospital system on Friday reported the worst financial loss in its history while fighting the COVID-19 pandemic — but still ended the fiscal year in better shape than expected.

Mass General Brigham, formerly known as Partners HealthCare, lost $351 million on operations in the fiscal year that ended Sept. 30. In 2019, the system recorded a gain of $382 million.

The loss, however, is not as great as projected, thanks in part to an infusion of federal aid and patients returning to hospitals in large numbers after the first COVID surge receded.

“2020 is like no other year,” said Peter Markell, chief financial officer at Mass General Brigham, which includes Massachusetts General Hospital, Brigham and Women’s Hospital, and several community hospitals. “At the end of the day, we came out of this better than we thought we might.”

Total revenue for the year remained relatively stable at about $14 billion.

When the pandemic first hit Massachusetts in March, hospitals across the state suddenly experienced sharp drops in revenue because they canceled so much non-COVID care to respond to the crisis at hand. They also faced new costs related to COVID, including the personal protective equipment needed to keep health care workers safe from infection.

Federal aid helped to make up much of the losses, including $546 million in grant money that went to Mass General Brigham. The nonprofit health system also slashed capital expenses in half, by about $550 million, and temporarily froze employee wages and cut their retirement benefits.

Among the unusual new costs for Mass General Brigham this year was the expense of building a field hospital, Boston Hope, at the Boston Convention and Exhibition Center. The project cost $15 million to $20 million, Markell said, and Mass General Brigham is working to recoup those costs from government agencies.

The second surge of COVID, now underway, could hit hospitals’ bottom lines again, though Markell expects a smaller impact this time. One reason is because hospitals are trying to treat most of the patients who need care for conditions other than COVID even while treating growing numbers of COVID patients. In the spring, hospitals canceled vastly more appointments and procedures in anticipation of the first wave of COVID.

Mass General Brigham hospitals were treating more than 300 COVID patients on Friday, among the more than 1,600 hospitalized across the state.

Steve Walsh, president of the Massachusetts Health & Hospital Association, said hospitals across the state will need more federal aid as they continue battling COVID into the new year.

“The financial toll of COVID-19 has been felt by every hospital and health care organization in the Commonwealth,” he said. “Those challenges will continue during 2021.”


Priyanka Dayal McCluskey can be reached at priyanka.mccluskey@globe.com. Follow her on Twitter @priyanka_dayal.

END QUOTE

SOURCE

https://www.bostonglobe.com/2020/12/11/business/mass-general-brigham-reports-covid-related-financial-losses-better-than-expected/?p1=Article_Inline_Related_Box

Integration of Mass General Hospital and Brigham Women’s Hospital was accelerated by the COVID-19 pandemic

Reporter: Aviva Lev-Ari, PhD, RN

BASED on

At Mass General Brigham, a sweeping effort to unify hospitals and shed old rivalries

Executives say greater cooperation is necessary to stay relevant in a dynamic and competitive health care industry. But the aggressive push to integrate is stirring tensions and sowing discontent among doctors and hospital leaders.

By Priyanka Dayal McCluskey and Larry Edelman Globe Staff and Globe Columnist,Updated March 27, 2021, 6:15 p.m.125

https://www.bostonglobe.com/2021/03/27/business/mass-general-brigham-sweeping-effort-unify-hospitals-shed-old-rivalries/?s_campaign=breakingnews:newsletter

START QUOTE

The work of integration was accelerated by the COVID-19 pandemic. As patients flooded hospitals last spring, Mass General Brigham — not each of its individual hospitals — set pandemic policies, from what kind of personal protective equipment health care providers should wear, to which visitors were allowed inside hospitals, to how employees would be paid if they were out sick with the virus.

During the winter surge of COVID, Mass General Brigham officials closely tracked beds across their system and transferred patients daily from one hospital to another to ensure that no one facility became overwhelmed.

And, in the early months of the pandemic, the company dropped the name Partners, which meant little to patients, and unveiled a new brand to reflect the strength of its greatest assets, MGH and the Brigham.

Officials at the nonprofit health system have instructeddepartment heads across their hospitals to coordinate better, so, for example, if a patient needs surgery at the Brigham but is facing a long wait, they can refer that patient to another site within Mass General Brigham.

Some executives want patients, eventually, to be able to go online and book appointments at any Mass General Brigham facility, as easily as they make reservations for dinner or a hotel.

Walls described it like this: “How do we put things together that make things better and easier for patients, and leave alone things that are better where they are?

“We’re not going to push things together that don’t fit together,” he said.

And yet the aggressive pursuit of “systemness,” as executives call it, is taking a toll. Physicians and hospital leaders are struggling with the loss of control over their institutions and worried that the new era of top-down management threatens to homogenize a group of hospitals with different cultures and identities.

Veteran physicians and leaders have been surprised and upset by the power shift that is stripping them of the ability to make key decisions and unhappy with abrupt changes they feel are occurring with little discussion. Most are uncomfortable sharing their concerns publicly.

“If you’re not on the train, you’re getting run over by the train,” said one former Mass General Brigham executive who requested anonymity in orderto speak openly. “It’s not an environment to invite debate.”

Amid the restructuring, senior executives are departing in droves. They include the CEO of the MGH physicians group, Dr. Timothy Ferris; Brigham and Women’s president Dr. Elizabeth Nabel; chief financial officer of the system, Peter Markell; Cooley Dickinson Hospital president Joanne Marqusee; and president of Spaulding Rehabilitation Network, David Storto.

Some also fear the internal discord could hinder Mass General Brigham’s ability to attract talented leaders.

Top executives acknowledge there is angst — “Change is hard,” Klibanski said — but are pushing ahead.

MORE

https://www.bostonglobe.com/2021/03/27/business/mass-general-brigham-sweeping-effort-unify-hospitals-shed-old-rivalries/?s_campaign=breakingnews:newsletter

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The WHO team is expected to soon publish a 300-page final report on its investigation, after scrapping plans for an interim report on the origins of SARS-CoV-2 — the new coronavirus responsible for killing 2.7 million people globally

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 4/1/2021

Coronavirus: More work needed to rule out China lab leak theory says WHO

START QUOTE

The head of the World Health Organization (WHO) has said further investigation is needed to conclusively rule out that Covid-19 emerged from a laboratory in China.

Tedros Adhanom Ghebreyesus said that although a lab leak was the least likely cause, more research was needed.

The US and other countries have criticised China for failing to provide the WHO with sufficient data.

Beijing has always dismissed the allegations of a virus leak.

A report by WHO and Chinese experts released on Tuesday, said the lab leak explanation was highly unlikely and the virus had probably jumped from bats to humans via another intermediary animal.

China has yet to respond to the WHO’s latest statement.

‘All hypothesis on the table’

However the theory that the virus might have come from a leak in a laboratory “requires further investigation, potential with additional missions involving specialist experts,” Dr Tedros said on Tuesday.

“Let me say clearly that as far as WHO is concerned, all hypothesis remain on the table,” he added.

The virus was first detected in Wuhan, in China’s Hubei province in late 2019. An international team of experts travelled to to the city in January to probe the origins of the virus.

The team investigated all possibilities, including one theory that the virus had originated at the Wuhan Institute of Virology. The institute is the world’s leading authority on the collection, storage and study of bat coronaviruses.

International criticism

In response to the WHO report, the US and 13 allies including South Korea, Australia and the UK voiced concern over the findings and urged China to provide “full access” to experts.

The statement said the mission to Wuhan was “significantly delayed and lacked access to complete, original data and samples”.

“Scientific missions like these should be able to do their work under conditions that produce independent and objective recommendations and findings.”

The group pledged to work together with the WHO.

Former US President Donald Trump was among those who supported the theory that the virus might have escaped from a lab.

WHO investigation team leader, Peter Ben Embarek said on Tuesday his team had felt under political pressure, including from outside China but said he was never pressed to remove anything from the team’s final report.

He also confirmed his team had found no evidence that any laboratories in Wuhan were involved in the outbreak.

MORE …

SOURCE

https://www.bbc.com/news/world-asia-china-56581246

@@@@

Ex-CDC Director Robert Redfield believes COVID-19 came from Wuhan lab

By Lia Eustachewich

March 26, 2021 | 10:03am | Updated

START QUOTE

The former director of the Centers for Disease Control and Prevention believes the virus that causes COVID-19 escaped from a lab in Wuhan, China, according to a new interview.

Robert Redfield told CNN on Friday that it was his “opinion” that SARS-CoV-2 — the new coronavirus responsible for killing 2.7 million people globally — did not evolve naturally.

“I’m of the point of view that I still think the most likely etiology of this pathology in Wuhan was from a laboratory — escaped,” said Redfield, who led the CDC during the height of the pandemic. “Other people don’t believe that. That’s fine. Science will eventually figure it out.”

Researchers believe the deadly and highly transmissible strain of coronavirus behind the global pandemic mutated from a virus that infects animals — namely, bats — to one that sickens humans.

But some believe the virus was somehow released from the Wuhan Institute of Virology — which is the only lab in China authorized to study the most dangerous known pathogens, according to Axios.

“It’s not unusual for respiratory pathogens that are being worked on in a laboratory to infect the laboratory worker. … That’s not implying any intentionality,” Redfield said. “It’s my opinion, right? But I am a virologist. I have spent my life in virology.

“I do not believe this somehow came from a bat to a human and at that moment in time, that the virus came to the human, became one of the most infectious viruses that we know in humanity for human-to-human transmission.”

Redfield said usually when a virus jumps from animals to humans, “it takes a while for it to figure out how to become more and more efficient in human-to-human transmission.”

SOURCE

START QUOTE

What they’re saying: “I’m of the point of view that I still think the most likely etiology of this pathology in Wuhan was from a laboratory. Escaped. Other people don’t believe that. That’s fine. Science will eventually figure it out,” Redfield told CNN’s Sanjay Gupta.

  • “It’s not unusual for respiratory pathogens that are being worked on in a laboratory to infect the laboratory worker. … That’s not implying any intentionality. It’s my opinion, right? But I am a virologist. I have spent my life in virology,” he continued.
  • “I do not believe this somehow came from a bat to a human and at that moment in time that the virus came to the human, became one of the most infectious viruses that we know in humanity for human-to-human transmission.”

Between the lines: Lab accidents in the U.S. are not especially rare, as USA Today’s Alison Young noted in a recent opinion piece arguing why the Wuhan lab theory cannot be ruled out. The CDC itself experienced a possible contamination in a lab where it was making COVID-19 test kits early in the pandemic.

What to watch: The WHO team is expected to soon publish a 300-page final report on its investigation, after scrapping plans for an interim report amid mounting tensions between the U.S. and China.

SOURCE

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FDA emergency use authorization would bring the public a third vaccine for the novel coronavirus – J&J single vaccine – Authorized on 2/28/2021

 

Reporter: Aviva Lev-Ari, PhD, RN

 

J&J’s Covid-19 vaccine gets vote of confidence from FDA advisory panel

The committee voted 22-0 on the question of whether the benefits of Johnson & Johnson’s Covid-19 vaccine outweigh its risks. FDA emergency use authorization would bring the public a third vaccine for the novel coronavirus.

The U.S. is one step closer to making available another Covid-19 vaccine after a panel of experts voted unanimously Friday to recommend emergency use authorization for a shot developed by Johnson & Johnson.

The independent panel, comprised of mostly physicians, voted 22-0 to support the vaccine with no one abstaining. These votes aren’t binding on the FDA, but the agency often follows the recommendations of its panels. A decision could come as early as this weekend. The two Covid vaccines currently cleared for emergency use received their authorizations the day after their respective advisory panel meetings.

Top ArticlesFDA authorizes third Covid-19 vaccine; J&J pledges 20M shots by month’s end

The Johnson & Johnson vaccine would offer an alternative to the ones currently available from the Pfizer and BioNtech alliance, and Moderna. Those messenger RNA vaccines must be distributed and stored at ultra-cold temperatures, then thawed before use. Those shots are given as two doses, weeks apart. The J&J vaccine can be kept at refrigerator temperatures. Another key difference is that the J&J jab requires a single shot. Together, those features will make the J&J vaccine easier to distribute to more people in more places through distribution channels that are already in place.

Panel members expressed support for the J&J vaccine, saying that the safety and efficacy data supported its authorization. But panelists also cautioned the public against picking vaccine favorites.

“It’s important that people do not think one vaccine is better than another,” said Cody Meissner, an infectious disease expert and professor of pediatrics at the Tufts University School of Medicine. “There is no preference for one vaccine over another and all vaccines work with what appears to be equal safety and equal efficacy as of this time.”

 

GUIDANCE DOCUMENT

Emergency Use Authorization for Vaccines to Prevent COVID-19 Guidance for Industry FEBRUARY 2021

Final
Docket Number:
FDA-2020-D-1137
Issued by:
Center for Biologics Evaluation and Research

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

FDA is issuing this guidance to provide sponsors of requests for Emergency Use Authorization (EUA) for COVID-19 vaccines with recommendations regarding the data and information needed to support the issuance of an EUA under section 564 of the FD&C Act (21 U.S.C. 360bbb-3) for an investigational vaccine to prevent COVID-19 for the duration of the COVID-19 public health emergency.

SOURCE

 

FDA Statement on Vaccines and Related Biological Products Advisory Committee Meeting

The following is attributed to Acting Commissioner Janet Woodcock, M.D. and Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research


NEWS PROVIDED BY

U.S. Food and Drug Administration 

Feb 26, 2021, 18:50 ET


SILVER SPRING, Md.Feb. 26, 2021 /PRNewswire/ — Following today’s positive advisory committee meeting outcome regarding the Janssen Biotech Inc. COVID-19 Vaccine, the U.S. Food and Drug Administration has informed the sponsor that it will rapidly work toward finalization and issuance of an emergency use authorization. The agency has also notified our federal partners involved in vaccine allocation and distribution so they can execute their plans for timely vaccine distribution.

Additional Resources:

Media Contact: FDA Office of Media Affairs, 301-796-4540
Consumer InquiriesEmail or 888-INFO-FDA

SOURCE

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Rise of a trio of mutated viruses hints at an increase in transmissibility, speeding the virus’ leaps from one host to the next

Reporter: Aviva Lev-Ari, PhD, RN

“We have uncontrolled viral spread in much of the world,” says Adam Lauring, an infectious disease physician and virologist at the University of Michigan. “So the virus has a lot of opportunity to evolve.”

“The variants may be more transmissible, but physics has not changed,” says Müge Çevik, an infectious disease physician at the University of St. Andrews in Scotland.

Many changes don’t affect the virus’ function, and some even harm SARS-CoV-2’s ability to multiply, but they keep happening. “Viruses mutate; that’s what they do,” says Akiko Iwasaki, an immunologist at Yale School of Medicine in Connecticut.

U.K., Brazil, and South Africa. In the United Kingdom, variant B.1.1.7 likely drove the region’s record-setting spike of COVID-19 cases in January. The variant is now circulating in more than 60 countries, including the United States—and projections suggest it will become the most common virus variety in the U.S. by mid-March.

An independently arising lineage called P.1 might also be driving a wave of cases in Manaus, Brazil, where it accounted for nearly half of new COVID-19 infections in December. On January 26, Minnesotan officials reported the first U.S. case of P.1 in a resident who previously traveled to Brazil. And a third lineage raising alarms, known as B.1.351, was first spotted amid a December wave of infections in South Africa. On January 28, the first known U.S. cases of the variant were reported in South Carolina.

One specific mutation, known as N501Y, popped up independently in all three variants, suggesting it could provide an advantage to the virus. “That’s a sign that there is natural selection going on,” Lauring says. The N501Y mutation affects the virus’ spike protein, which is the key it uses to unlock entry into its host’s cells.

Another possibility is that new variants cause people who are infected to harbor more copies of the virus. This results in greater viral “shedding” in airborne droplets spewed when people talk, sing, cough, and breath.

mutations in 501Y.V2 could diminish the effectiveness of antibodies in the blood of people previously infected with the virus. But understanding whether that could lead to more re-infections, or if it could affect vaccine efficacy.

Dramatically scale up production of high-filtration masks for the general public.

Based on:

Why some coronavirus variants are more contagious‹and how we can stop them

https://www.nationalgeographic.com/science/2021/01/why-some-coronavirus-variants-are-more-contagious/?cmpid=org=ngp::mc=crm-email::src=ngp::cmp=editorial::add=SpecialEdition_20210129

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A Platform called VirtualFlow: Discovery of Pan-coronavirus Drugs help prepare the US for the Next Coronavirus Pandemic

Reporter: Aviva Lev-Ari, PhD, RN

 

ARTICLE|ONLINE NOW, 102021

A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening

Open AccessPublished:January 04, 2021DOI:https://doi.org/10.1016/j.isci.2020.102021

 

The work was made possible in large part by about $1 million in cloud computing hours awarded by Google through a COVID-19 research grant program.

The work reported, below was sponsored by

  • a Google Cloud COVID-19 research grant. Funding was also provided by the
  • Fondation Aclon,
  • National Institutes of Health (GM136859),
  • Claudia Adams Barr Program for Innovative Basic Cancer Research,
  • Math+ Berlin Mathematics Research Center,
  • Templeton Religion Trust (TRT 0159),
  • U.S. Army Research Office (W911NF1910302), and
  • Chleck Family Foundation

 

Harvard University, AbbVie form research alliance to address emergent viral diseases

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

Harvard University and AbbVie today announced a $30 million collaborative research alliance, launching a multi-pronged effort at Harvard Medical School to study and develop therapies against emergent viral infections, with a focus on those caused by coronaviruses and by viruses that lead to hemorrhagic fever.

The collaboration aims to rapidly integrate fundamental biology into the preclinical and clinical development of new therapies for viral diseases that address a variety of therapeutic modalities. HMS has led several large-scale, coordinated research efforts launched at the beginning of the COVID-19 pandemic.

“A key element of having a strong R&D organization is collaboration with top academic institutions, like Harvard Medical School, to develop therapies for patients who need them most,” said Michael Severino, vice chairman and president of AbbVie. “There is much to learn about viral diseases and the best way to treat them. By harnessing the power of collaboration, we can develop new therapeutics sooner to ensure the world is better prepared for future potential outbreaks.”

“The cataclysmic nature of the COVID-19 pandemic reminds us how vital it is to be prepared for the next public health crisis and how critical collaboration is on every level—across disciplines, across institutions and across national boundaries,” said George Q. Daley, dean of Harvard Medical School. “Harvard Medical School, as the nucleus of an ecosystem of fundamental discovery and therapeutic translation, is uniquely positioned to propel this transformative research alongside allies like AbbVie.”

AbbVie will provide $30 million over three years and additional in-kind support leveraging AbbVie’s scientists, expertise and facilities to advance collaborative research and early-stage development efforts across five program areas that address a variety of therapeutic modalities:

  • Immunity and immunopathology—Study of the fundamental processes that impact the body’s critical immune responses to viruses and identification of opportunities for therapeutic intervention.

Led by Ulirich Von Andrian, the Edward Mallinckrodt Jr. Professor of Immunopathology in the Blavatnik Institute at HMS and program leader of basic immunology at the Ragon Institute of MGH, MIT and Harvard, and Jochen Salfeld, vice president of immunology and virology discovery at AbbVie.

  • Host targeting for antiviral therapies—Development of approaches that modulate host proteins in an effort to disrupt the life cycle of emergent viral pathogens.

Led by Pamela Silver, the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology in the Blavatnik Institute at HMS, and Steve Elmore, vice president of drug discovery science and technology at AbbVie.

  • Antibody therapeutics—Rapid development of therapeutic antibodies or biologics against emergent pathogens, including SARS-CoV-2, to a preclinical or early clinical stage.

Led by Jonathan Abraham, assistant professor of microbiology in the Blavatnik Institute at HMS, and by Jochen Salfeld, vice president of immunology and virology discovery at AbbVie.

  • Small molecules—Discovery and early-stage development of small-molecule drugs that would act to prevent replication of known coronaviruses and emergent pathogens.

Led by Mark Namchuk, executive director of therapeutics translation at HMS and senior lecturer on biological chemistry and molecular pharmacology in the Blavatnik Institute at HMS, and Steve Elmore, vice president of drug discovery science and technology at AbbVie.

  • Translational development—Preclinical validation, pharmacological testing, and optimization of leading approaches, in collaboration with Harvard-affiliated hospitals, with program leads to be determined.

SOURCE

https://hms.harvard.edu/news/joining-forces

 

 

A Screen Door Opens

Virtual screen finds compounds that could combat SARS-CoV-2

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education, and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

Less than a year ago, Harvard Medical School researchers and international colleagues unveiled a platform called VirtualFlow that could swiftly sift through more than 1 billion chemical compounds and identify those with the greatest promise to become disease-specific treatments, providing researchers with invaluable guidance before they embark on expensive and time-consuming lab experiments and clinical trials.

Propelled by the urgent needs of the pandemic, the team has now pushed VirtualFlow even further, conducting 45 screens of more than 1 billion compounds each and ranking the compounds with the greatest potential for fighting COVID-19—including some that are already approved by the FDA for other diseases.

“This was the largest virtual screening effort ever done,” said VirtualFlow co-developer Christoph Gorgulla, research fellow in biological chemistry and molecular pharmacology in the labs of Haribabu Arthanari and Gerhard Wagner in the Blavatnik Institute at HMS.

The results were published in January in the open-access journal iScience.

The team searched for compounds that bind to any of 15 proteins on SARS-CoV-2 or two human proteins, ACE2 and TMPRSS2, known to interact with the virus and enable infection.

Researchers can now explore on an interactive website the 1,000 most promising compounds from each screen and start testing in the lab any ones they choose.

The urgency of the pandemic and the sheer number of candidate compounds inspired the team to release the early results to the scientific community.

“No one group can validate all the compounds as quickly as the pandemic demands,” said Gorgulla, who is also an associate of the Department of Physics at Harvard University. “We hope that our colleagues can collectively use our results to identify potent inhibitors of SARS-CoV-2.

In most cases, it will take years to find out whether a compound is safe and effective in humans. For some of the compounds, however, researchers have a head start.

Hundreds of the most promising compounds that VirtualFlow flagged are already FDA approved or being studied in clinical or preclinical trials for other diseases. If researchers find that one of those compounds proves effective against SARS-CoV-2 in lab experiments, the data their colleagues have already collected could save time establishing safety in humans.

Other compounds among VirtualFlow’s top hits are currently being assessed in clinical trials for COVID-19, including several drugs in the steroid family. In those cases, researchers could build on the software findings to investigate how those drug candidates work at the molecular level—something that’s not always clear even when a drug works well.

It shows what we’re capable of computationally during a pandemic.

Hari Arthanari

SOURCE

https://hms.harvard.edu/news/screen-door-opens?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_1&utm_content=HMNews02012021

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Inflammation and potential links with the microbiome: Mechanisms of infection by SARS-CoV-2

Reporter: Aviva Lev-Ari, PhD, RN

Mechanisms of infection by SARS-CoV-2, inflammation and potential links with the microbiome

Published Online:https://doi.org/10.2217/fvl-2020-0310

Human coronaviruses (HCoVs) were first isolated from patients with the common cold in the 1960s [1–3]. Seven HCoVs known to cause disease in humans have since been identified: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, the SARS coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus and the novel SARS-CoV-2 [4]. The latter was identified after a spike in cases of pneumonia of unknown etiology in Wuhan, Hubei Province, China during December 2019 and was initially named novel coronavirus (2019-nCoV) [5,6]. The virus was renamed SARS-CoV-2 according to the International Committee on Taxonomy of Viruses classification criteria due to its genomic closeness to SARS-CoV; the disease caused by this virus was named coronavirus disease (COVID-19) according to the WHO criteria for naming emerging diseases [7]. SARS-CoV-2 belongs to the genera Betacoronavirus and shares a different degree of genomic similarity with the other two epidemic coronaviruses: SARS-CoV (∼79%) and Middle East respiratory syndrome coronavirus (∼50%) [8].

COVID-19 has caused considerable morbidity and mortality worldwide and has become the central phenomenon that is shaping our current societies. Human-to-human transmission is the main route of spread of the virus, mainly through direct contact, respiratory droplets and aerosols [9–12]. Management of COVID-19 has been extremely challenging due to its high infectivity, lack of effective therapeutics and potentially small groups of individuals (i.e., asymptomatic or mild disease) rapidly spreading the disease [13–17]. Although research describing COVID-19 and the mechanisms of infection by SARS-CoV-2 and its pathogenesis has expanded rapidly, there is still much to be learnt. Important gaps in knowledge which remain to be elucidated are the dynamic and complex interactions between the virus and the host’s immune system, as well as the potential interspecies communications occurring between ecological niches encompassing distinct microorganisms in both healthy individuals and persons living with chronic diseases, and how these interactions could determine or modulate disease progression and outcomes.

In this review, we describe recent insights into these topics, as well as remaining questions whose answers will allow us to understand how interactions between the virus, the immune system and microbial components could possibly be related to disease states in patients with COVID-19, as well as existing studies of the microbiome in patients with COVID-19.

SOURCE

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