zaterdag 26 september 2020

Corona en het recht op veilig onderwijs

De ernst van het virus voor kinderen: de stand van de wetenschap
Een uitzonderlijke situatie als een pandemie vraagt om passende maatregelen voor veilig onderwijs. In het geval van COVID, veroorzaakt door het virus SARS-CoV-2, dienen de ernstige gevaren voor de volksgezondheid juist te worden ingeschat. Dat kinderen minder zouden bijdragen aan de verspreiding van het coronavirus is een aanname die géén basis vindt in de wetenschappelijke literatuur. Kinderen kunnen als reservoir fungeren voor transmissie van het virus naar andere kinderen en volwassenen. 

De virulentie van het coronavirus voor kinderen (in welke mate het virus schade aanricht) is een andere kwestie. Het is bekend dat COVID-19 onder kinderen gedurende de infectieperiode of ná herstel van het virus een hyperinflammatoir syndroom kan veroorzaken, dat wordt gekenmerkt door symptomen die gelijkenis hebben met Kawasaki (SARS-CoV-2-Induced Kawasaki-Like Hyperinflammatory Syndrome: A Novel COVID Phenotype in Children, Pediatrics Vol. 146, Issue 2, 1 Augustus 2020; An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study, Lancet Vol. 395, Issue 10239, P1171-1178, 6 Juni 2020).

Internationale studies melden dat bij voordien gezonde kinderen en jongeren Multisystemische Inflammatoire Syndromen met kenmerken van Kawasaki of Toxic Shock Syndrome geassocieerd met COVID-19 worden gerapporteerd (Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City, JAMA 2020;324(3):294-296; zie ook "Autoimmune and inflammatory diseases following COVID-19, Nature Reviews Rheumatology 2020, 4 Juni 2020: 1-2"). Er is een recente, ingrijpende melding dat een driejarig kind dat lymfatische leukemie heeft gekregen door infectie met het coronavirus (Acute lymphoblastic leukemia onset in a 3-year-old-child with COVID-19, Pediatric Blood & Cancer Vol. 67, Issue 11, November 2020). Dit kind heeft géén onderliggend medisch lijden. 

Een Franse studie maakt melding van de dossiers van een zestienjarige jongen en zesjarig kind zonder medisch lijden bij wie COVID-gerelateerde hersendood werd vastgesteld (Severe and fatal forms of COVID-19 in children, Archives de Pédiatrie Vol. 27, Issue 5, Juli 2020, P235-238). Bij systemische aandoeningen, zoals PIMS en MIS-C, kan de schade die door SARS-CoV-2 is aangericht pas op langere termijn naar volle omvang worden vastgesteld. 

Er moeten adequate maatregelen worden getroffen om veilig onderwijs te garanderen
De ernst van het virus maakt duidelijk dat adequate maatregelen moeten worden getroffen om publieke activiteiten veilig te kunnen laten verlopen. Transmissie van het virus vindt in belangrijke mate plaats via de aërogene route (door kleine ademhalingsdruppels of aërogeen geworden fomieten die zich door de lucht verspreiden). Juist in een publieke ruimte waar veel mensen samen komen en 's winters de verwarming volop draait, zoals op scholen, moet alles in het werk worden gesteld om de aërogene transmissie te bestrijden. Daar komt bij dat zowel leerlingen als docenten veelvuldig in contact komen met verschillende groepen mensen. De belangrijkste factor is dat de verspreiding van het coronavirus asymptomatisch of presymptomatisch plaatsvindt: de virale lading in de keelneusholte is het hoogst vóórdat er klachten optreden. Mensen worden besmet door personen die nog geen klachten hebben. Thuisblijven op het moment dat de klachten optreden (hoofdpijn, diarree, benauwdheid en in een deel van de gevallen verwarring/een verdoofd gevoel), is dus te laat. 

Scholen geven aan moeite te hebben met het uitvoeren van de maatregelen ("Tobben met het nieuwe normaal", CNV Onderwijs, 23 september 2020, te raadplegen via https://onderwijs.cnvconnectief.nl/nieuws/tobben-met-het-nieuwe-normaal-op-scholen/.

Hoe kan veilig onderwijs in deze noodsituatie worden gegarandeerd?

1. Het recht van het kind op bescherming van het welzijn (art. 3 lid 1 Verdrag inzake de rechten van het kind)
Bij alle beslissingen die worden genomen of maatregelen die worden getroffen, dienen de belangen van het kind de eerste overweging te vormen. De Nederlandse Staat is verplicht om de bescherming van het welzijn en de gezondheid van het kind te verzekeren (art. 3 lid 2 resp. art. 24 Verdrag inzake de rechten van het kind). 

2. Scholen moeten maatregelen treffen om veilig onderwijs te garanderen
Treft de school geen adequate maatregelen om de verspreiding van het virus tegen te gaan? Spreek de schoolleiding en/of de medezeggenschapsraad of het bestuur schriftelijk aan om de ontoereikendheid van het beleid ter discussie te stellen. Neemt de school niet de verantwoordelijkheid of wordt u het niet eens met de schoolleiding, maak dan melding bij de Onderwijsinspectie. Hiervoor kunt u het formulier op de daartoe aangewezen site invullen.


Met de winter in het vooruitzicht komt er een probleem bij: scholen laten de ramen en deuren niet open en zetten de verwarming hoog, omdat het anders "te koud is" in het klaslokaal. Een warme, bedompte ruimte waar de lucht snel verzadigd raakt, is gunstig voor aërogene verspreiding van het virus. Informeer voordat het zover is, hoe de school omgaat met ventilatie in de herfst/winter. Is het ventilatiebeleid van de school niet veilig? Dien een klacht in bij de Onderwijsinspectie.

Kinderen met medisch lijden of kinderen met gezinsleden met medisch lijden kunnen worden vrijgesteld van fysiek onderwijs, zo meldt de Rijksoverheid op 26 september 2020. Tevens kan een beroep worden gedaan op art. 11 onder g van de Leerplichtwet. Gewichtige omstandigheden vormen een uitzondering die maakt dat géén sprake is van verzuim. De gronden voor het beroep op gewichtige omstandigheden moeten door u worden aangevoerd. Het risico op ernstige gevaren voor de volksgezondheid door de verspreiding van SARS-CoV-2 is in de inleiding besproken. Voor kinderen is er, ongeacht of zij onder een "risicogroep" worden geschaard, kans op de in de wetenschappelijke rapportages gemelde systemische aandoeningen of direct medisch lijden als gevolg van COVID-19.

Maak een kopie van het ingevulde formulier op de site van de Onderwijsinspectie, nog vóórdat u het formulier verzendt. Als het goed is, ontvangt u een bevestiging van uw melding. Reageert de Onderwijsinspectie niet op uw melding, maak hiervan dan notitie die u bij uw klacht bewaart. 



3. Vervangend onderwijs
Thuisonderwijs of onderwijs op afstand kan het fysiek onderwijs vervangen om het hoofd te bieden aan gezondheidscrises, zoals de huidige crisis. De mogelijkheid om onderwijs op school te vervangen door thuisonderwijs of onderwijs op afstand, kan worden gebaseerd op art. 41 van de Wet op het Primair Onderwijs. Om onderwijs op afstand mogelijk te maken, dient de school zich in te spannen om een onderwijsplan op te stellen. Onderwijs op afstand of vervangend onderwijs is géén vrijstelling van de leerplicht.

Vraag de school van uw kind hoe de school de mogelijkheid tot flexibel onderwijs invult. In het thuisonderwijs kan hetzelfde onderwijsprogramma worden afgelegd als in het onderwijs met fysieke aanwezigheid. Bij afstandsonderwijs is van belang dat de thuissituatie veilig is voor de leerling. De scholen hebben een inspanningsverplichting om kwaliteit te bieden. De school hoeft geen 'perfect' onderwijs te bieden om het onderwijs op afstand mogelijk te maken. In het geval van een jongere met medische kwetsbaarheid werd de constructie van "begeleid verzuim" in het leven geroepen, waarbij op de school een inspanningsplicht rustte (ECLI:NL:RBNHO:2017:9909). Dit is geen verzuim in letterlijke zin, maar slechts fysieke afwezigheid.




 


maandag 21 september 2020

Extensive reading recommendations on SARS-CoV-2/ COVID-19: all mechanisms (Part 3)

So much to it! A non-exhaustive overview of factors involved in COVID-19

ARDS-like
Co-aerosolized Pulmonary Surfactant and Ambroxol for COVID-19 ARDS Intervention: What are we waiting for?, Frontiers in Bioengineering and Biotechnology, 25 September 2020;

Asymptomatic transmission

Asymptomatic patients as a source of COVID-19 infections: A systematic review and meta-analysis, International Journal of Infectious Diseases Vol. 98, P180-186, September 01, 2020;

Cardiopulmonary complications caused by COVID-19

The emerging spectrum of cardiopulmonary pathology of COVID-19: Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other US cities, Cardiovascular Pathology 2020 September-October; 48: 107233;

Central Nervous System (CNS)
Interactions between Olfaction and the Trigeminal System: what can be learned from olfactory loss
, Cerebral Cortex (Journal), Vol. 17, Issue 10, October 2007;
Sympathetic Nervous System Activation and its Modulation: Role in Atrial Fibrillation, Frontiers in Neuroscience, 23 January 2019;
Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19, Neurology, September 22, 2020; 95(12);
New onset neurologic events in people with COVID-19 in 3 regions in China, Neurology, September 15, 2020; 95 (11);
Potential of SARS-CoV-2 to Cause CNS Infection: Biological Fundamental and Clinical Experience
, Frontiers Neurology, 18 June 2020;
Neurologic Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China, Jama Neurology 2020; 77 (6):683-690;
Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?, MDPI Viruses, 20 December 2019, Viruses 2020, 12(1), 14;
Neuromechanisms of SARS-CoV-2: A Review, Frontiers Neuroanatomy, 16 June 2020;
COVID-19: A Global Threat to the Nervous System (microthrombi and acute infarctions in the brain), Annals of Neurology Vol. 88, Issue 1, July 2020;
Involvement of the Nervous System in SARS-CoV-2 Infection, Neurotoxicity Research 2020, May 13 :1-7;
The Neurology of COVID-19 revisited: A Proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries, Journal of Neurological Science 2020 July 15; 414: 116884;
Multiple Neuroinvasive Pathways in COVID-19, Molecular Neurobiology 2020 September 29: 1-12;
Coronavirus infection of the central nervous system: host-virus stand-off, Nature Reviews Microbiology 4, 121-132(2006);
Pathophysiology of the COVID-19- entry to the CNS through the nose, Acta Oto-Laryngologica Vol. 140, 2020, Issue 10;
COVID-19 associated acute necrotizing encephalopathy (ANE) succesfully treated with steroids and polyvalent immunoglobulin with unusual IgG targeting the cerebral fibre network, Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, Issue 9, 2020;
COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia, Journal of Neuroimmunology & Neuroinflammation, September 2020; 7(5);
Brain abnormalities in COVID-19 acute/subacute phase: A rapid systematic review, Brain Behavior and Immunology 2020 Oct; 89: 543-554;
Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology, Acta Neuropathologica 2020; 140(1): 1-6;

Coagulation
Anticoagulant treatment in COVID-19: a narrative review (in COVID-19 patients, thrombotic lesions in pulmonary vessels have a prevalence twice higher than in non-COVID-19 patients), Journal of Thrombosis and Thrombolysis 2020, 18 August 2020;
Hypercoagulability of COVID-19 patients in IC Unit: A report of thromboelastography findings and other parameters of hemostasis, Journal of Thrombosis and Haemostasis Vol. 18, Issue 7, July 2020, p1738-1742;

Cytokine storms/cascade/cytokine release syndrome
COVID-19: In the Eye of the Cytokine Storm, Frontiers Immunology, 24 September 2020;
T-Cell Hyperactivation and Paralysis in Severe COVID-19 Infection Revealed by Single-Cell Analysis, Frontiers Immunology, 08 October 2020;

Embolism
Occurrence of pulmonary embolism related to COVID-19, Journal of Thrombosis and Thrombolysis 2020, 06 October 2020;
Acute pulmonary embolism in COVID-19 related hypercoagulability, Journal of Thrombosis and Thrombolysis 2020, 30 May 2020;
Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis (22,7% of ICU patients and non-ICU patients), Research and Practice in Thrombosis and Haemostasis, 25 September 2020;
Left ventricular thrombus and pulmonary embolism: A case series of thrombosis in COVID-19 in Thai patients, Research and Practice in Thrombosis and Haemostasis, 18 September 2020

Endothelium
The Enigma of Endothelium in COVID-19 (and sepsis), Frontiers in Physiology, 04 August 2020;

Long-term complications of COVID-19 and SARS-CoV-2 infection
Anticipating the long-term cardiovascular effects of COVID-19, Journal of Thrombosis and Thrombolysis 50, 512-524(2020);
Long-Haul COVID, Neurology, September 29, 2020, 95 (13);

Markers to assess severity of COVID
Serum Activity of Liver Enzymes is Associated with Higher Mortality in COVID-19: A Systematic Review and Meta-Analysis, Frontiers in Medicine, 22 July 2020;
Specific coagulation markers may provide more therapeutic targets in COVID-19 patients receiving prophylactic anticoagulant (TPA, TAT and PAP), Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020, p2428-2430;

Monocytes
Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology, Frontiers Immunology, 23 September 2020;

Macrophages
Targeting Macrophages as a therapeutic option in COVID-19, Research Article to be published, Frontiers Pharmacology;

Matrix Metalloproteinase (MMPs)

Matrix Metalloproteinase-9 Inhibition Reduces Inflammation and Improves Motility in Murine Models of Post-Operative Ileus, Gastroentology 2011 Oct: 141(4): 1283-1292.e4.;

NETs (Neutrophil Extracellular Traps) and neutrophil profiles
Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19, MDPI Cells 2020, Jun; 9(6)1383;

Pathogenicity and structure of SARS-CoV-2
Free fatty acid binding pocket in the locked structure of SARS-CoV-2 Spike protein, AAAS 21 September 2020;
COVID-19 is Distinct from SARS-CoV-2 Negative Community Acquired Pneumonia (= COVID pneumonia differs from other pneumonias), Frontiers in Cellular and Infection Microbiology, 16 June 2020;
ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19, Frontiers in Immunology, 07 October 2020;
Host/genetic factors associated with COVID-19 call for medicine, Precision Clinical Medicine Vol. 3, Issue 3, September 2020, p228-234;
The unique characteristics of COVID-19 coagulopathy, Critical Care 2020; 24: 360;

Red Blood Cells
Association of Red Blood Cell Distribution Width With Mortality Risk in Hospitalized Adults With SARS-CoV-2 Infection, Jama Critical Care, September 23, 2020;3(9);

Stroke as a frequent feature in COVID-19
Acute Ischemic Stroke and COVID-19: Experience from a Comprehensive Stroke Center in Midwest US, Frontiers in Neurology, 20 August 2020;
Stroke risk, phenotypes and death in COVID-19: Systematic review and newly reported cases, September 15, 2020;
Risk of Acute Cerebrovascular Events in patients with COVID-19 Infection (COVID-19-related stroke is not age or comorbidity related), American Journal of Neuroradiology, August 27, 2020;

T lymphocytes
Decreased T cell populations contribute to the increased severity of COVID-19, Clinica Chimica Acta, Vol. 508, September 2020, p110-114;
Mapping the T cell response to COVID-19, Signal Transduction and Targeted Therapy 5, Art. No. 112(2020);

Treatment of COVID-19
An open-label, randomized trial of the combination of IFN-k plus TFF2 (Treefoil Factor Family member 2) with standard care in the treatment of patients with moderate COVID-19, EClinicalMedicine, September 20, 2020;
Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells, Biomedicines 2020 May; 8(5): 129;
Dupilumab and COVID-19: What should we expect?, Dermatologic Therapy Vol. 33, Issue 4, July/August 2020;
COVID-19-related encephalopathy responsive to high-dose glucocorticoids, Neurology September 22, 2020; 95(12);
How nicotine can inhibit cytokine storm in the lungs and prevent or lessen the severity of COVID-19 infection?, Immunology Letters Vol. 224, August 2020, p28-29;
Nicotine and the nicotinic cholinergic system in COVID-19, The FEBS Journal Vol. 287, Issue 17, September 2020, p3656-3663;
COVID-19 associated acute necrotizing encephalopathy succesfully treated with steroids and polyvalent immunoglobulin with unusual IgG targeting the cerebral fibre network, Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, Issue 9, 2020;
SARS-associated Coronavirus Nucleocapsid Protein Interacts with Smad3 and Modulates Transforming Growth Factor-β (TGF-β) Signaling (and the role of PAI-1 in fibosis), Journal of Biological Chemistry, February 8, 2008, 283; 3772-3280;
Low mortality of hospitalized patients with COVID-19 in a tertiary Danish hospital setting, Internation Journal of Infectious Diseases, October 12, 2020;

Urokinase
Urokinase plasminogen activator independent early experimental thrombus resolution: MMP2 as an alternative mechanism, Thrombosis and Haemostasis 2010 Dec;104(6):1174-83;

Vitamin D Immunomodulation
A Basic Review of the Preliminary Evidence that COVID-19 Risk and Severity is Increased in Vitamin D Deficiency, Frontiers in Public Health, 10 September 2020;

zondag 20 september 2020

Extensive reading recommendations on SARS-CoV-2/ COVID: all mechanisms involved (Part 2)

Mechanisms involved in SARS-CoV-2 / COVID-19

It has been clear since the SARS epidemic of 2003 that coronavirus diseases caused by SARS-CoV infections are thromboinflammatory diseases. As of March 2020, when SARS-CoV-2 was politically (finally) declared a pandemic, COVID-19 was still treated like a main pulmonary disease. Reseachers have been pointing out that the underlying mechanisms are characterized by hyperinflammation, hypercoagulation, complement cascades and dysregulation of the Renin-Angiotensin-Aldosterone System, ultimately leading to thromboembolic events in multiple organs (MOF), stroke and post-COVID systemic diseases, such as Guillain-Barré and cardiomyopathy. 

To provide a view into the complexity of COVID-19, I share with you the most prominent research papers on the mechanisms and pathogenicity of SARS-CoV-2. Some of the research papers of the biggest relevance for COVID-19 complications are as old as 60 years. This is why the paradigm should be that "Lots of the mechanisms causing COVID-19 are well-known, but we have to find the best practices to treat its complications".

I only refer to verified and reviewed research and scientific viewpoint papers citing verified references. If paper has already been peer reviewed but still awaitens the editory process (early release), I will mention this. To retrieve these papers from the PubMed/NCBI and Wiley database, I narrowed my search process to combinations of "SARS-CoV-2", "Thrombosis", "Pulmonary embolism", "Complement" and "Coagulation".

ACE and ACE2
Angiotensin Converting Enzyme defects in shock: implications for future therapy, Critical Care 22, Art. No. 274 (2018);

ADAM17
TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the SARS-Coronavirus Spike Protein, Journal of Virology, January 2014 Vol. 88, No. 2, P1293-1307;

Aquaporins
Aquaporin-mediated transport, Pathway R-HSA-445717, PubChem, 08 July 2020;

ARDS
Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study, Lancet Infectious Diseases Vol. 20, Issue 4, P425-434;
The evolving role of the Renin-angiotensin system in ARDS, Critical Care 21, Art. No. 329 (2017);

Asymptomatic SARS-CoV-2 Infection
Natural History of Asymptomatic SARS-CoV-2 Infection, NEJM 2020; 383:885-886, August 27, 2020;

B- and T-cell immunological memory (CD4+ and CD8+)
COVID-19 and the Path to Immunity, JAMA, September 11, 2020;
Depletion of CD4 and CD8 Positive T Cells Impairs Venous Thrombus Resolution in Mice, MDPI International Journal of Molecular Sciences 2020 March;21(5): 1650;

Call for better screening
Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection, The American Journal of Medicine, August 06, 2020;

Cardiovascular complications
Outcomes of Cardiovascular MRI in Patients Recently Recovered from COVID-19 (coronavirus causes myocardial inflammation independent of preexisting conditions), JAMA Cardiology, July 27, 2020;

Coagulation
Immunothrombotic Dysregulation in COVID-19 Pneumonia is Associated with Respiratory Failure and Coagulopathy, Journal of Circulation, 28 July 2020;
Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19, Journal of Thrombosis and Haemostasis, 17 August 2020;
Coagulation parameters and venous thromboembolism in patients with and without COVID-19 admitted to the Emergency Department for acute respiratory insufficiency, Thrombosis Research Vol. 196, P209-212, December 2020;

Complement
Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis, Nature 2020, 29 July 2020;
COVID-19: A collision of complement, coagulation and inflammatory pathways, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020, P2110-2117;

Comparative tropism and transmission (profiling of SARS-CoV-2)
Distinct conformational states of SARS-CoV-2 Spike protein, Science 21 July 2020;
Coronavirus surprise from cryo-EM data, Wiley Analytical Science, 22 July 2020;
Single-Cell Sequencing of Peripheral Mononuclear Cells Reveals Distinct Immune Response Landscapes of COVID-19 and Influenza Patients, Immunity Vol. 53, Issue 3, 15 September 2020, P685-696;
Enhanced Binding of SARS-CoV-2 Spike Protein Receptor by Distal Polybasic Cleavage Site, ACS Nano 2020, 14, 8, 10616-10623;
Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions, Proceedings of the National Academy of Sciences of the US (PNAS) June 23, 2020 117 (25), 13967-13974;
Pathogenicity, Transmission, Diagnosis and Treatment of COVID-19, JAMA 2020;324(8):782-793;
Risk of Ischemic Strole in Patients with COVID-19 vs. Patients With Influenza, JAMA Neurology, July 2, 2020;

Central Nervous System (CNS) complications
A case of malignant cerebral infarction associated with COVID-19 infection, British Journal of Neurosurgery, 05 August 2020;

Critical Care
Association of Noninvasive Oxygenation Strategies with All-Cause Mortality in Adults with Acute Hypoxemic Respiratory Failure: A Systematic Review and Analysis, JAMA 2020;324(1):57-67;
Anti Xa activity after high dose Low Molecular Weight Heparin (LMWH) thrombosis prophypaxis in COVID-19 patients at the IC Unit, Thrombosis Research Vol. 196, P1-3, December 01, 2020;
Impact of implementation of an individualised thromboprophylaxis protocol in critically ill ICU patients with COVID-19: A longitudinal controlled before and after study, Thrombosis Research Vol. 194, October 2020, P209-215;
Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention and treatment of Venous Thromboembolism (VTE) in hospitalized patients with COVID-19, Journal of Thrombosis and Haemostasis Vol. 18, Issue 8, August 2020, P1859-1865;
Inaccuracy of point-of-care international normalized ratio in Rivaroxaban-treated patients, Annals of Pharmacotherapy Vol. 47, Issue 9, September 1, 2013;
How I treat recurrent Venous Thromboembolism in patients receiving anticoagulant therapy, Blood Vol. 129, Issue 25, June 22, 2017;

Deep Vein Thrombosis (DVT)
Deep vein thrombosis in SARS-CoV-2 pneumonia-affected patients within standard care units: Exploring a submerged portion of the iceberg, Thrombosis Research Vol. 194, October 2020, P216-219;
Incidence of deep vein thrombosis among non-ICU patients hospitalized for COVID-19 despite pharmacological thromboprophylaxis, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020;

DIC (Disseminated Intravascular Coagulopathy) and differentiations of DIC
Clotting abnormalities in critically ill COVID-19 patients are inconsistent with overt Disseminated Intravascular Coagulation, Thrombosis Research Vol. 196, P272-275, December 01, 2020;
Higher procoagulatory potential but lower DIC score in COVID-19 ARDS patients compared to non-COVID-19 ARDS patients, Thrombosis Research Vol. 196, P186-192, December 01, 2020;

Endothelialitis/Endotheliitis
Pulmonary Vascular Endothelialitis, Thrombosis and Angiogenesis in COVID-19, New England Journal of Medicine (NEJM) 2020; 383:120-128, July 9, 2020;

Fibrinolysis
Fibrinolytic abnormalities in ARDS and versatility of thrombolytic drugs to treat COVID-19, Journal of Thrombosis and Haemostasis Vol. 18, Issue 7, July 2020;
Hypofibrinolytic state and high thrombin generation may play a major role in SARS-CoV-2 associated thrombosis, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020;

Interferons (IFN)
Role of IFN-γ responsiveness in CD8 T cell-mediated viral clearance and demyelination in coronavirus-infected mice, Journal of Neuroimmunology 2008 February; 194(1): 18-26;
Type I and Type III Interferons- Induction, Signaling, Evasion and Application to combat COVID-19, Cell Host & Microbe Vol. 27, Issue 6, p870-878, June 10, 2020;

Megakaryocytes
Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series, EClinicalMedicine Vol. 24, 100434, July 01, 2020;

Monocytes
Monocyte activation in systemic COVID-19 infection: Assay and rationale, EBioMedicine Vol. 59, 102964, September 01, 2020;

Neutrophils and NETs (& platelet interaction)
Immunothrombosis in severe COVID-19, EBioMedicine Vol. 59, 102942, September 01, 2020;

Pathogenicity of SARS-CoV-2: PROS1 and PL proteins

Identification of the antithrombotic protein S as a potential target of the SARS-CoV-2 palpain-like protease, Thrombosis Research Vol. 196, P257-259, December 01, 2020;

Pathogenicity of SARS-CoV-2: RNA and Spike protein
Circulating endothelial progenitors are increased in COVID-19 patients and correlate with SARS-CoV-2 RNA in severe cases, Journal of Thrombosis and Haemostasis, 06 August 2020;
Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity, Biochemical and Biophysical Research Communications 2007, July 20; 359(1): 174-179;

Platelets
Intravascular Platelet Aggregation in the Heart Induced by Norepinephrine, Journal of Circulation, 1972;46:698-708;
Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus, Blood Vol. 135, Issue 22, May 28, 2020;

Pulmonary Embolism
Subsegmental Thrombus in COVID-19 Pneumonia: Immunothrombosis or Pulmonary Embolism? Data Analysis of Hospitalized Patients with Coronavirus Disease, Heart, Lung and Circulation, 24 August 2020;
Late Pulmonary Embolism after COVID-19 Pneumonia Despite Adequate Rivaroxaban Treatment, European Journal of Case Reports in Internal Medicine Vol. 7, No. 7, June 18, 2020;

Pyroptosis
Inflammasomes and Pyroptosis as Therapeutic Targets for COVID-19, The Journal of Immunology Vol. 205, Issue 2, 15 July 2020, P307-312;

RAAS (Renin-Angiotensin-Aldosterone) - KKS (Kallikrein-Kinin), Angiotensins and Bradykinin
Involvement of bradykinin B1 and B2 receptors in human PMN elastase release and increase in endothelial cell monolayer permeability, Immunopharmacology, 1996 June;33(1-3):325-9;
The Renin-Angiotensin System: An integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications, Journal of Experimental Medicine (2020) 217 (8):e20201000;
The evolving role of the Renin-angiotensin system in ARDS, Critical Care 21, Art. No. 329 (2017);

Stroke (and prevalence in young people due to SARS-CoV-2 infection)
Acute cerebral stroke with multiple infarctions and COVID-19, France, 2020, CDC Research Vol. 26, No. 9, September 2020;
A case of malignant cerebral infarction associated with COVID-19 infection, British Journal of Neurosurgery, 05 August 2020;
COVID-19 related stroke in young individuals, Lancet Neurology Vol. 19, Issue 9, P713-715, September 01, 2020;
Risk of Ischemic Strole in Patients with COVID-19 vs. Patients With Influenza, JAMA Neurology, July 2, 2020;
Stroke as a complication and prognostic factor of COVID-19, Neurologia Vol. 35, Issue 5, June 2020, P318-322;
Mechanisms of Stroke in COVID-19, Cerebrovascular Diseases Vol. 49, No. 4,  September 2020;

Systemic diseases following SARS-CoV-2 infection
Autoimmune and inflammatory diseases following COVID-19, Nature Reviews Rheumatology 16, 413-414(2020);

Thrombosis
Arterial Mesentric Thrombosis as a Complication of SARS-CoV-2 Infection, European Journal of Case Reports in Internal Medicine 2020; 7(5): 001690;
Multisystemic Infarctions in COVID-19: Focus on the Spleen, European Journal of Case Reports in Internal Medicine 2020; 7(7): 001747;
Clotting abnormalities in critically ill COVID-19 patients are inconsistent with overt Disseminated Intravascular Coagulation, Thrombosis Research Vol. 196, P272-275, December 01, 2020;
Asymptomatic Deep Vein Thrombosis (DVT) in critically ill COVID-19 patients despite therapeutic levels of anti-Xa activity, Thrombosis Research Vol. 196, P268-271, December 01, 2020;
Extensive pulmonary perfusion defects compatible with microthrombosis and thromboembolic disease in severe COVID-19 pneumonia, Thrombosis Research Vol. 196, P135-137, December 01, 2020;
Systemic thromboemboli in patients with COVID-19 may result from paradoxical embolization, Thrombosis Research Vol. 196, P206-208, December 01, 2020;
Circulating endothelial progenitors are increased in COVID-19 patients and correlate with SARS-CoV-2 RNA in severe cases, Journal of Thrombosis and Haemostasis, 06 August 2020;
Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2, International Journal of Laboratory Hematology 2020 June;42:19-20;

Treatment/therapeutic options for treating COVID
Treatment of patients with acute Deep Vein Thrombosis and/or pulmonary embolism: efficacy and safety of non-VKA oral anti-coagulants in selected populations, Thrombosis Research Vol. 134, Issue 2, p227-233, August 01, 2014;
Ig-like ACE2 protein therapeutics: a revival in development during a pandemic, Journal of mAbs (antibodies) Vol. 12, Issue 1, December 2020;
Therapeutic blockade of granulocyte macrophage colony-stimulating factor (GM-CSF) in COVID-19 associated hyperinflammation: challenges and opportunities, Lancet Respiratory Medicine Vol. 8, Issue 8, p822-830, August 2020;
Fibrinolytic abnormalities in ARDS and versatility of thrombolytic drugs to treat COVID-19
, Journal of Thrombosis and Haemostasis Vol. 18, Issue 7, July 2020;
Dynamic changes in fibrinogen and D-dimer levels in COVID-19 patients on nafamostat mesylate, Journal of Thrombosis and Thrombolysis 2020, 12 September 2020 (note: trial from Tokyo Hospital, coagulation dynamics might differ in non-Asian people);
Kallikrein-kinin blockade in patients with COVID-19 to prevent ARDS, Radboud UMC, April 27, 2020;
Accumulating evidence suggests anti-TNF therapy needs to be given trial priority in COVID-19 treatment, Lancet Rheumatology, September 04, 2020;
GM-CSF Blockade during Chimeric Antigen Receptor T Cell Therapy Reduces Cytokine Release Syndrome and Neurotoxicity and May Enhance Their Effector Functions, ASH Blood Vol. 132, November 29, 2018;
GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia: A Case-Control Study, Mayo Clinic Proceedings, 03 September 2020;
Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe ARDS and COVID-19: the CoDEX Randomized Clinical Trial, JAMA, September 2, 2020;
Effect of Hydrocortisone Among Critically Ill Patients With COVID-19: A Randomized Clinial Trial, JAMA, September 2, 2020;
The Role of Anticoagulation in COVID-19 Induced Hypercoagulability, Current Cardiology Reports 22, Art. No. 53(2020);

Viral load and antibody responses

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study, Lancet Infectious Diseases Vol. 20, Issue 5, P565-574;






maandag 14 september 2020

Extensive reading recommendations on SARS-CoV-2/COVID: all mechanisms involved (Part 1)

I this message, I will present you all the research papers on Coronavirus Disease 2019 (COVID) I have bookmarked since January 2020. These are extensive papers on SARS-CoV-1 (2003) and SARS-CoV-2 (2019) I have retrieved from the PubMeb database on NCBI and the Wiley Library.
 
All mechanisms involved in COVID-19

There is a ton of information on the mechanisms underlying SARS-CoV infection and the severity of COVID-19. This is the case because (a) SARS-CoV-2 is not entirely new, but shares great similarities with SARS-CoV-1 (2003) and (b) because not all mechanisms are exclusive to SARS' etiology, but are also seen in infections caused by other pathogens, ór, even common in systemic syndromes (say, for example, aHUS). Scientists do compare diseases and viruses, to reveal patterns in similarities and differences. Rarities can reveal a lot about mechanisms underlying other diseases. In short, thrombosis in pregnancy caused by a deficiency in ADAMTS-13, which leads to failure to cleave Von Willebrand Factor (VWF) and therefore contributes to extensive thrombus formation, is also seen in some severe (juvenile) cases of COVID.

Thus, systemic syndromes, common immunity and thromboinflammatory mechanisms need an in-depth view to find solutions to balance the key factors in COVID-19.

ACE2
ACE2 in the brain: properties and future directions, Journal of Neurochemistry 2008 Dec; 107(6): 1482-1494;
COVID-19 and relative ACE2 deficiency: a role in disease severity and therapeutic response, Open Heart 2020; 7(1): e001302;

ARDS
Pathophysiology of COVID-19 associated Acute Respiratory Distress Syndrome: a multicentre prospective observational study, Lancet Respiratory Medicine, August 27, 2020;
COVID-19 pneumonia: ARDS or not?, Critical Care 24, Art. No. 154 (2020);

Autophagy 
Autophagy during viral infection- a double-edged sword, Nature Reviews Microbiology 16, 341-354(2018);

Cardiovascular complications of SARS-CoV-2/COVID-19
Potential effects of coronaviruses on the cardiovascular system, JAMA Cardiology 2020;5(7):831-840;
SARS-CoV-2 and cardiovascular complications: From molecular mechanisms to pharmaceutical treatment, Biochemical Pharmacology 2020 Aug; 178: 114114;

Central Nervous System (CNS) complications caused by SARS-CoV-2
Cerebral Venous Thrombosis: A typical presentation of COVID-19 in the young, Journal of Stroke Cerebrovascular Disease 2020 August; 29(8): 104989;
Meningoencephalitis without respiratory failure in a young female patient with COVID-19 in Downtown Los Angeles, early April 2020, Brain Behavior and Immunology 2020 July;87: 33;
Pathophysiology of the COVID-19- entry to the CNS through the nose, Acta Oto-Laryngologica, 28 June 2020;
Cerebral Venous Sinus Thrombosis as a Presentation of COVID-19, European Journal of Case Reports in Internal Medicine 2020; 7(5): 001691;
Extensive cerebral venous sinus thrombosis: a potential complication in a patient with COVID-19, BMJ Case Reports 2020; 13(8): e236820;

Coagulation
The role of type 1 Interferons (IFN) in coagulation induced by gram-negative bacteria, Immunobiology and Immunotherapy, Vol. 135, Issue 14, 2 April 2020;
Physiology, coagulation pathways;
Local abnormalities of coagulation and fibrinolytic pathways that promote alveolar fibrin deposition in the lungs of baboons with DAD, Journal of Clinical Investigation, 1989 July; 84(1);
Coagulation abnormalities and thrombosis in patients with COVID-19, Haematology, Vol. 7, Issue 6, E438-E440, June 01, 2020;
Coagulopathy in COVID-19, Journal of Thrombosis and Haemostasis, 2020;18:2103-2109;
In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation, Journal of Thrombosis and Haemostasis, 06 August 2020;
Changes in coagulation and fibrinolysis of post-SARS osteonecrosis in a Chinese population, International Orthopaedics 2006 June; 30(3): 143-146;
The Coagulation Factors Fibrinogen, Thrombin and Factor XII in Inflammatory Disorders- a Systemic Review, Frontiers Immunology, 26 July 2018;
Pulmonary intravascular coagulopathy in COVID-19 pneumonia, Lancet Rheumatology Vol. 2, Issue 8, E458-459, August 01, 2020;

Comparative tropism and transmission (profiling COVID)
Comparative tropism, replication kinetics and cell damage profiling of SARS-CoV-2 and SARS-CoV, Lancet Microbe, Vol. 1, Issue 1;

Cytokine cascade/cytokine release syndromes/cytokine storms
Analysis of cytokine profile and heme metabolism byproducts after hemorrhagic stroke, Critical Care 2013; 17(Suppl. 13), 19 June 2013;
The cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist Tocilizumab may be the key, International Journal of Antimicrobial Agents, Vol. 55, Issue 5, May 2020, 105954;
Cytokine release syndrome in severe COVID-19, Science, Vol. 368, Issue 6490, 01 May 2020;
Expansion of myeloid-derived suppressor cells in patients with severe COVID-19, Cell Death & Differentiation (2020), 08 June 2020;
The cytokine storm of severe influenza and development of immunomodulatory therapy, Cellular & Molecular Immunology 13, 3-10(2016);
SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of  cytokine "storm" and risk factor for damage of hematopoietic stem cells, Leukemia 2020; 34(7): 1726-1729;
Cytokine storm intervention in the early days of COVID-19 pneumonia, Cytokine & Growth Factor Reviews Vol. 53, June 2020, pp 38-42;
Up-regulation of IL-6 and TNF-a induced by SARS-coronavirus spike protein in murine macrophages via NF-kB pathway, Virus Research 2007 September; 128(1): 1-8;

Deficiencies
G6PD deficiency in the COVID-19 pandemic: ghost within a ghost, Hematology, Oncology and Stem Cell Therapy 2020, April 18;

Disseminated Intravascular Coagulation (DIC) and differentiations of DIC (noteworthy!)
DIC in COVID-19: Implications for prognosis and treatment?, Journal of Thrombosis and Haemostasis, Letter, 26 April 2020;
Local hemostasis, immunothrombosis and systemic DIC in trauma and traumatic shock, Critical Care 2015; 19(1):72;
Normal prothrombinase activity, increased systemic thrombin activity and lower antithrombin levels in patients with DIC at an early phase of trauma: comparison with acute coagulopathy of trauma-shock, Surgery Vol. 154, Issue 1, p48-57, July 01, 2013;
Differentiating DIC with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock, Journal of Thrombosis and Haemostasis, 22 March 2013, Vol. 11, Issue 5, May 2013;

Endotheliitis and endotheliopathy
Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study, Lancet Haematology Vol.7, Issue 8, E575-E582, August 01, 2020;
The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection, Critical Care 2020; 24: 353, June 16, 2020;

Enterocytes
SARS-CoV-2 productively infects human gut enterocytes, Science Vol. 369, Issue 6499, 03 July 2020;

Eosinophils
Eosinophil responses during COVID-19 infections and coronavirus vaccination, Journal of Allergy and Clinical Immunology, Vol. 146, Issue 1, July 2020, pp 1-7;
Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study, American Journal of Respiratory and Critical Care Medicine, Vol. 201, Issue 11, 2020;

Fibrosis
Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy, Lancet Respiratory Medicine (viewpoint), Vol. 8 Issue 8, August 1, 2020;
SARS Coronavirus and Lung Fibrosis, Molecular Biology of the SARS-Coronavirus, 2009 July 22;
The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis, Antiviral Research 2017 July; 143;
Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: autocrine mechanisms in fibroblasts and macrophages, Current pharmaceutical design 2007;13(12):1247-56;
SARS Coronavirus and Lung Fibrosis, Zuo et al., Molecular Biology of the SARS-Coronavirus, Chapter 15, 24 October 2009, pp. 247-258;

Hemostasis and fibrinolysis
Serpins in thrombosis, hemostasis and fibrinolysis, Journal of Thrombosis and Haemostasis 2007 July: 5;
Association of Plasminogen Activator Inhibitor 1 (SERPINE1) polymorphisms and aneurysmal subarachnoid hemorrhage, World Neurosurgery, Vol. 105, September 2017;
Fibrinolytic abnormalities in ARDS and versatility of thrombolytic drugs to treat COVID-19, Journal of Thrombosis and Haemostasis 2020;18;
High incidence of VTE (venous thromboembolic events) in anticoagulated severe COVID-19 patients, Journal of Thrombosis and Haemostasis 2020;18;
Hematological findings and complications of COVID-19 (high risk of venous thromboembolism), American Journal of Hematology Vol. 95, Issue 7, July 2020;
Fibrinolytic abnormalities in ARDS and versatility of thrombolytic drugs to treat COVID-19, Journal of Thrombosis and Haemostasis, Vol. 18, Issue 7, July 2020, pp 1548-1555;

HLA Haplotypes 
COVID-19 infection: the perspectives on immune responses (Edt.) (Hyaluronan markers), Cell Death & Differentiation 27, 1451-1454(2020);

Hormone secretion and sex differences
Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients, Andrology, 20 May 2020;
TLR7 is higher in women than in men and its expression leads to higher immune responses, Journal of Biological Regulators and Homeostatic Agents 2020 March-April; 34(2):339-343;

Hyperviscosity 
COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia?, Lancet Correspondence, Vol. 395, Issue 10239, June 06, 2020;

Immunity: T cell profile and prognostic markers
Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients, Cellular & Molecular Immunology 17, 541-543(2020);
T Cell Responses to Whole SARS-Coronaviruses in Humans, Journal of Immunology 2008, October 15, 181(8):5490-5500;
Exacerbated Innate Host Response to SARS-CoV in Aged Non-Human Primates, PLoS Pathogens 2010 February; 6(2): e1000756;
Abnormal immunity of non-survivors with COVID-19: predictors (Outcome: Neutrophilia, lymphocytopenia, low CD4+ cells and decreased Complement C3 are prognostic markers of a worse outcome), Infectious Diseases of Poverty 9, Art. No. 108(2020);
Depletion of CD4 and CD8 Positive T cells Impairs Venous Thrombus Resolution in Mice, International Journal of Molecular Sciences 2020 March; 21(5): 1650

Immunomodulation
Hypothesis for potential pathogenesis of SARS-CoV-2 infection- a review of immune changes in patients with viral pneumonia, Emerging Microbes & Infections 2020; 9(1);
Harnessing adenosine A2A receptors as a strategy for suppressing the lung inflammation and thrombotic complications of COVID-19: Potential of pentoxifylline and dipyridamole, Medical Hypotheses 2020 October; 143: 110051;

Immunoglobulin treatment
High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With COVID-19, Open Forum Infectious Diseases, Vol. 7 Issue 3, March 2020;

Inflammation, Toll-like Receptor (TLR) Signaling and stem cells
Lipopolysaccharides induced inflammatory responses and electrophysiological dysfunctions in human-induced pluripotent stem cell derived cardiomyocytes, Scientific Reports 7, 2935 (2017);
Identification of Oxidative Stress and TLR-4 Signaling as a key pathway of Acute Lung Injury, Cell 2008, April 2008; 133(2);
Attenuation of Innate Immunity by Andrographolide Derivates Through NF-kB Signaling Pathway, Scientific Reports 7, Art. No.: 4738(2017);

Inflammation, regulation
Thy-1 (CD90) regulates the extravasation of leukocytes during inflammation, European Journal of Immunology 2011, 41:645-656;

Inflammatory phenotypes
Prevalence of phenotypes of ARDS in critically ill patients with COVID-19: a prosprective observational study, Lancet Respiratoy Medicine, August 27, 2020;

Inhibition
Potential protective and therapeutic role of immune checkpoint inhibitors against viral infections and COVID-19, Immunotherapy, 29 June 2020
Immunotherapeutic implications of IL-6 blockade for cytokine storm, Immunotherapy, 6 July 2016;

Interferons (IFN-x)
Dysregulation of type I interferon responses in COVID-19, Comment, Nature Reviews Immunology 20, 397-398(2020);
Inhibition of Interferon-γ Signaling in Oligodendroglia Delays Coronavirus Clearance Without Altering Demyelination, American Journal of Pathology 2006 March; 168(3): 796-804;
Gamma Interferon Signaling in Oligodendrocytes is Critical for Protection from Neurotropic Coronavirus Infection, Journal of Virology 2010 March;84(6);
Type I and Type III Interferons- Induction, Signaling, Evasion and Application to Combat COVID-19

Long-term complications of SARS-Coronaviruses
Long-term bone and lung consequences associated with hospital-aquired SARS: a 15-year follow-up from a prospective cohort study, Bone Research 8, Art. No. 8 (2020);
Late occurence of pulmonary embolism in SARS-CoV-2 pneumonia: a case series, Giornale Italiano di Cardiologia 2020;21(7):523-525;

Macrophages
SARS Coronavirus-Induced Lung Epithelial Cytokines Exacerbate SARS Pathogenesis by Modulating Intrinsic Funcions of Monocyte-Derived Macrophages and Dendritic Cells, Journal of Virology April 2009, Vol. 83, No. 7;
M2 polarized macrophages induced by CSE promote proliferation, migration and invasion of alveolar basal epithelial cells, International Immunopharmacology, Vol. 28, Issue 1, September 2015;
Macrophages: a Trojan horse in COVID-19?, Nature Reviews Immunology 20, 351(2020);
Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages, Nature Reviews Immunology 20, 355-362(2020);

MMPs
Matrix Metalloproteases in Aberrant Fibrotic Tissue Remodeling, Proceedings of The American Thoracic Society, 2006 June, Vol. 3(4):383-8;
Matrix Metalloproteinase activity in the lung is increased in Hermansky-Pudlak Syndrome, Orphanet Journal of Rare Diseases 14, Art. No. 162 (2019);

Neurotransmitters
Action of Neurotransmitters: Acetylcholine, adrenaline and serotonin on Arterial Thrombosis induced by a laser beam, Thrombosis Research Vol. 84, Issue 3, p189-198, November 01, 1996;

Neutrophils and NETs
Biomarkers in Lung Diseases: Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 Bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration, American Journal of Physiology, Lung Cellular and Molecular Physiology, 2018 January 1;314(1);
In sickness and in health- how neutrophil extracellular traps (NET) works in infections, selected diseases and pregnancy, Journal of Inflammation 16, Art. No. 15 (2019);
NET: Villains and Targets in Arterial, Venous and Cancer-Associated Thrombosis, Journal of Arteriosclerosis, Thrombosis and Vascular Biology (ATVB), Vol. 39, Issue 9, September 2019;
Thrombosis: tangled up in NETs, Blood 2014 May 1, 123(18): 2768-2776;
Excessive Neutrophils and NETs in COVID-19, Frontiers Immunology, 18 August 2020;
Neutrophils and NETs drive Necroinflammation in COVID-19, MDPI Cells, 2 June 2020;

Open Reading Frame (ORF) driving cell death
SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death, Cell Death & Disease 9, Art. No. 904(2018);
The ORF3a protein of SARS-CoV-2 induces apoptosis (programmed cell death) in cells, Cellular & Molecular Immunology 17, 881-883(2020);
SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes, Cell Death Discovery 5, Art. No.: 101(2019);

Pathogenesis of SARS & SARS-CoV-2/COVID
Pathophysiology characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of COVID-19, Cardiovascular Pathology, 2020 July-August; 47:107228;
COVID-19: immunopathology and its implications for therapy, Nature Reviews Immunology 20, 269-270(2020);
Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS, Journal of Pathology, Vol. 210, Issue 3, November 2006;
SARS: The first pandemic of the 21st century, Pediatric Research Vol. 56, No. 1, 2004;

Platelets (and their relation to ADAMTS, thrombi and Von Willebrand Factor (VWF))
Platelet-to-lymphocyte ratio is associated with prognosis in patients with COVID-19, Journal of Medical Virology, 17 March 2020;
Human Platelets Contain and Release an Active ADAMTS-13 Like Metalloprotease, Blood, Vol. 104, Issue 11, November 16, 2004;
What a drag: necrotic platelets induce remote neutrophil thrombi following ischemic gut injury, Journal of Thrombosis and Haemostasis, Vol. 16, Issue 5, May 2018, pp 819-821;
Platelet Interaction with Innate Immune Cells, Transfusion Medicine and Hemotherapy, 2016 March; 43(2): 78-88;
Regulation of Innate Immune Responses by Platelets, Frontiers in Immunology 2019; 10: 1320;

Pyroptosis
Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools, Virologica Sinica 35, 266-271(2020);

Renin-Angiotensin Aldosterone System (RAAS) & Kinin-Kallikrein System (KKS)
A Review of the Role of Bradykinin and Nitric Oxide in the Cardioprotective Action of ACE Inhibitors: Focus on Perindopril, Cardiology and Therapy 8, 179-191(2019);
What have we learned about the Kallikrein-Kinin and Renin-Angiotensin Systems in neurological disorders?, World Journal of Biological Chemistry, 2014 May 26; 5(2): 130-140;
Role of Kallikrein in Blood Pressure Regulation, Hypertensive Cardiovascular Disease: Pathophysiology and Treatment, pp. 68-103;
New agents modulating the RAAS: Will there be a new therapeutic option?, Experimental Biology and Medicine, 2016 Nov;241(17):1888-1899;
ACE2 activity and human atrial fibrillation: increased plasma ACE2 activity is associated with aFib and more advanced left atrial structural remodelling, EP Europace, Vol. 19,  Issue 8, August 2017;
Ang II-induced upregulation of AT1 receptor expression: sequential activation of NF-kB and Ekl-1 in neurons (activation of the RAS in the brain promotes sympathic excitation in heart failure), American Journal of Cell Physiology 2010 September; 299(3): C561-C569;
Ang II revisited: new roles in inflammation, immunology and aging, EMBO Molecular Medicine 2010 July; 2(7): 247-257;
NF-kB and CREB Are Required for Ang II Type 1 Receptor Upregulation in Neurons, PLoS One, November 11, 2013;

Systemic diseases: SIRS,  Kawasaki and MIS-C
Multisystem Inflammatory Syndrome in Children: A systematic review, EClinicalMedicine, September 04, 2020;

Thrombocytopenia
Thrombocytopenia and its association with mortality in COVID-19, Journal of Thrombosis and Haemostasis 2020;18;
Thrombocytopenia is associated with severe COVID-19 infections: a meta-analysis, Clinical Chimica Acta, Vol. 506, July 2020;
Cardiac dysfunction and thrombocytopenia-associated Multiple Organ Failure inflammation phenotype in a severe paediatric case, Lancet Child & Adolescent Health, Vol. 4, Issue 7, July 01, 2020;
Sudden severe thrombocytopenia in a patient in the recovery stage of COVID-19, Haematology Vol. 7, Issue 8, E624, August 01, 2020;

Thrombosis and thromboembolism
Acute limb ischaemia in two young, non-atherosclerotic patients with COVID-19, Vol. 395, Issue 10236, May 16, 2020;
Acute pulmonary embolism in COVID-19 related hypercoagulability, Journal of Thrombosis and Haemostasis 2020 May 30: 1-4;
COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy and Follow-Up, JACC, Vol. 75, Issue 23, June 2020;
Describing the point prevalence and characteristics of Venous Thromboembolism in patients with Thrombotic Thrombocytopenic Purpura (TTP), Journal of Thrombosis and Haemostasis, 23 July 2020;
Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action, British Journal of Haematology 2020;
Arterial Mesentric Thrombosis as a complication of SARS-CoV-2 infection, European Journal of Case Reports in Internal Medicine 2020; 7(5): 001690;
Late Pulmonary Embolism after COVID-19 Pneumonia despite Adequate Rivaroxaban Treatment, European Journal of Case Reports in Internal Medicine 2020; 7(7): 001790;
Multisystemic Infarctions in COVID-19: Focus on the Spleen, European Journal of Case Reports in Internal Medicine 2020; 7(7): 001747;
Deep Venous Thrombosis (DVT) in a non-critically ill patient with COVID-19 infection, Thrombosis Research 2020 August; 192: 27-28;

Treatment options/therapeutics/prophylaxis
Could Ergothioneine Aid in the Treatment of Coronavirus Patients?, Antioxidants, MDPI, 2020 July; 9(7): 595;
CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement, Stem Cell Reviews and Reports 2020 April 20:1-7;
Temporal Relationship of Viral Load, Ribavirin, Interleukin (IL)-6 and IL-8 and Clinical Progression in Patients With SARS, Clinical Infectious Diseases 2004, October 1; 39(7): 1071-1075;
Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in steroid-associated osteonecrotic lesions in rabbits, Scientific Reports 5, Art. No.:8856(2016);
Effective treatment of severe COVID-19 patients with tocilizumab, PNAS May 19, 2020 117(20) 10970-10975;
17β-Estradiol, a potential ally to alleviate SARS-CoV-2 infection, Clinics 2020; 75: e1980; 
Curative anticoagulaton prevents endothelial lesion in COVID-19 patients, Journal of Thrombosis and Haemostasis 2020;18:2391-2399;
Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system, Toxicology Reports 2020;7: 658-663;
Glucocorticoid Therapy for COVID-19 Critically ill Patients with Severe Acute Respiratory Failure, ClinicalTrials.gov;
Interferon-α2b Treatment for COVID-19, Frontiers in Immunology, 15 May 2020;
Lessons learned to date on COVID-19 Hyperinflammatory Syndrome: Considerations for Interventions to Mitigate SARS-CoV-2 Viral Infection and Detrimental Inflammation, Frontiers Immunology, 29 May 2020;
COVID-19/SARS-CoV-2 Infection: Lysosomes and Lysosomotropism Implicate New Treatment Strategies and Personal Risks (Remdesivir, teicoplanin and/or dalbavancin), International Journal of Molecular Sciences 2020 July; 21(14):4953;
Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients, EBioMedicine Vol. 59, 102969, September 01, 2020;
Glycyrrhizin (Liquorice), an active component of liquorice roots, and replication of SARS-associated coronavirus, Lancet 2003 June 14; 361(9374): 2045-2046;
Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities, Lancet Respiratory Medicine Vol. 8, Issue 8, P822-830, August 01, 2020;

Urokinase
Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in COVID-19 pneumonia, Critical Care 24, Art. No.: 187 (2020);
COVID-19 and pneumonia: a role for the uPA/uPAR System, Drug Discovery Today, Vol. 25 Issue 8, August 2020;
Elevated plasminogen as a common risk factor for COVID-19 susceptibility, Physiological Reviews Vol. 100, Issue 3, July 2020;
Multifaceted role of the Urokinase-Type Plasminogen Activator (uPA) and its receptor (uPAR): Diagnostic, Prognostic and Therapeutic Applications, Frontiers Oncology, 12 February 2018;

Von Willebrand Factor
Von Willebrand Factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain inhjury, Thrombosis and Haemostasis, Vol. 132, Issue 10, September 6, 2018;
ADAMTS-13 activity, Von Willebrand Factor, Factor VII and D-dimers in COVID-19 inpatients, Thrombosis Research 2020 August; 192: 174-175;
Involvement of ADAMTS13 and VWF in thromboembolic events in patients infected with SARS-CoV-2, International Journal of Laboratory Hematology 2020 May 22: 10.1111/ijlh.13244;


dinsdag 8 september 2020

Corona en het complementsysteem

Onderliggende mechanismen van de complicaties van SARS-Coronavirussen (2003-2020)
In deze serie ga ik in op de mechanismen die bijdragen aan de ernst van COVID (en het vorige SARS-Coronavirus, SARS-CoV-1 uit 2003). Eerder besprak ik de rol van het RAAS-, trombose en schade aan het centraal zenuwstelsel in gevallen van SARS-CoV-2. Het immuunsysteem, ontstekingsmechanismen en het complementsysteem zijn sterk met elkaar verweven mechanismen. De rol van het complementsysteem is het op gang brengen van een immuniteits- en onstekingsreactie. Zoals ik in dit bericht zal bespreken, zorgt dit mechanisme voor schade aan het endotheel weefsel en obstructie van de bloedvaten.


1 Het complementsysteem: een belangrijke maar 'explosieve' schakel in de immuniteitsreactie
Het complementsysteem verwijst naar de activering van het adaptieve immuunsysteem van de gastheer in reactie op pathogenen, zoals virussen. Een belangrijke functie is lyse door het groepje complementeiwitten C56-9 (C5 tot 9 = C5bC6C7 tot C8 tot C9) dat met "Membrane Attack Complex" (MAC) wordt aangeduid. Een MAC maakt gaten in de ziekteverwekker ('lysing'), om de ziekteverwekker onschadelijk te maken. Opsonisatie is het proces waarbij antilichamen zich binden aan de ziekteverwekker. Fagocyten (witte bloedcellen) sluiten ziekteverwekkers in hun kern in, om zo een isolerend laagje te vormen. Het gezonde weefsel wordt op deze wijze beschermd tegen de ziekteverwekker. Het complementsysteem genereert ook anafylatoxinen. Anafylatoxinen die een heftige ontstekingsreactie op gang brengen, zijn C5a en C3a. Deze complementfactoren zorgen voor een 'explosieve' reactie op infecties. 

 
Het is een normale reactie van het lichaam op ziekteverwekkers om een complementcascade, ofwel een waterval van complementfactoren, op te wekken en zo het immuunsysteem op gang te brengen. De complementcascade kan echter nadelig uitpakken als deze overdreven actief is. In het geval van COVID reageert het complementsysteem hyperactief op de infectie met het virus en raken de gezonde weefsels beschadigd. Specifiek zijn de complementfactoren C5a en C5b-9 (de MAC) betrokken bij beschadiging van de gezonde weefsels van de geïnfecteerde. 

2 Hoe het complementsysteem bijdraagt aan de ernstige complicaties van COVID-19

2.1 Door het complementsysteem geïnduceerde acute longschade (ALI) en ARDS (Acute ademhalingsstoornis
Door het genereren van anafylatoxinen C3a en C5a, de vorming van de amplificatielus waarbij een grote hoeveelheid complementfactoren vrijkomt en de vorming van de MAC via C3- en C5-convertases, ontstaat immuungerelateerde schade. C5a wekt een ontstekingsreactie op door neutrofielen, monocyten, eosinofielen, fagocytische cellen, op granulaat gebaseerde enzymen en T-lymfocyten aan te trekken. 

Wat typerend is voor SARS-Coronavirussen, is een snelle progressie naar ARDS. Zoals het geval is met vogelgriepvirussen, worden veranderingen in het longweefsel 11 dagen na het begin van de symptomen waargenomen, met een snelle ontwikkeling van acuut longletsel (ALI). Verhoogde niveaus van C5a worden gevonden in het vocht in de longblaasjes (BALF). Dit is niet het geval bij seizoensgebonden influenza A (IVA), ofwel de A-variant van het griepvirus. SARS-CoV-1 en SARS-CoV-2 zijn totaal verschillend van griepvirussen. Niet alleen omdat ze geen voorouder delen met griepvirussen, maar ook omdat acuut longletsel geassocieerd met overmatige C5a-activering typerend is voor SARS-Coronavirussen, MERS-Coronavirussen en vogelgriep.

2.2 Aanvulling op anafylatoxine C5a en IL-8 inductie van reactieve zuurstofspecies (ROS)

Zowel C5a als interleukine IL-8 wordt gesynthetiseerd door longepitheelcellen, macrofagen, endotheelcellen en neutrofielen. C5a is in staat om IL-8 te versterken om de longdysfunctie te verhogen. Na activering van neutrofielen en monocyten door C5a, wordt een oxidatieve uitbarsting gegenereerd, gevolgd door het vrijkomen van Reactive Oxygen Species (ROS). Grote hoeveelheden ROS worden waargenomen in fibrotische longen.


2.3 Wisselwerking tussen het complementsysteem en de NETs

C5a is in combinatie met granulocyt-macrofaag kolonie-stimulerende factor (GM CSF) in staat om de afgifte van NET's (neutrofiele extracellulaire vallen) te induceren en om macrofagen en endotheelcellen te activeren om vaatlekkage en de afgifte van NETs te bevorderen. NETs verhogen de doorlaatbaarheid van de longvaatjes. NETs en hypoxie dragen verder bij aan de ontsteking van het endotheel weefsel. Terwijl component-opsonisatie NETs bevordert, remt blokkade van complementreceptoren CR1 en CR3 NETosis (geprogrammeerde celdood). Neutrofielen en NETs bevatten C3, Factor B en Factor P (Properdin), die essentieel zijn voor het genereren en stabiliseren van C3 en de complementcascade. NETs activeren het stollingsproces. 


3 Complementgerelateerde schade bij SARS-CoV-2-patiënten

Afzettingen van MAC (C5b-9), C4d en MASP-2 werden waargenomen in het vaatstelsel bij SARS-CoV-2-patiënten. Patiënt 1 vertoonde ernstige hemorragische pneumonitis (longontsteking met bloedingen) met afzetting van fibrine in het vaatweefsel, celnecrose en trombotisch nectrotiserend letsel-syndroom. Naast fibrine werd C3d in het vaatweefsel aangetroffen. Uitgebreide C4d- en MAC-afzetting werd waargenomen in het vaatweefsel van de longblaasjes. MAC-afzetting werd ook gezien in normaal lijkende huidvaatjes. Patiënt 2 vertoonde een vergelijkbaar letsel, hemorragische pneumonitis, afzetting van fibrine en dominante afzetting van MAC-formaties in het fijne vaatweefsel. Opmerkelijk is dat MAC-afzettingen werden gevonden in normaal ogend longweefsel, terwijl C4d alleen werd gevonden in de beschadigde vaten. Patiënt 1 en 2 vertoonden geen diffuse alveolaire schade (DAD); er werden geen hyalinemembranen aangetroffen.

Patiënt 3 had blauwpaarse billen, trombogene vaatonsteking met necrose, afbraak van witte bloedcellen en uitgebreide MAC-afzettingen in het vaatweefsel. Bij patiënt 4 werden paarse plekken gezien op voetzolen en handpalmen. Occlusieve trombi werden gevonden in een slagader, inclusief uitgebreide afzettingen van MAC-formaties, C3d en C4d. Op CT werden herseninfarcten gezien. Net als patiënt 3 en 4 vertoonde patiënt 5 blauwpaarse plekken over het lichaam. Lymfocytische infiltraten en trombi gingen gepaard met MAC en C4d
(Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: A report of five cases, Translational Research, June 2020, Vol. 220).

4 Farmaceutische interventie gericht tegen de complementcascade in COVID-19
Therapeutische opties voor remming van de complementcascade zijn:

Narsoplimab - menselijk antilichaam gericht tegen MASP-2;
Avdoralimab - monoklonaal antilichaam voorkomt de binding van C5a aan zijn receptor C5aR
Eculizumab - anti-C5 monoklonaal antilichaam dat splitsing van C5 in C5a voorkomt
Ravulizumab-antilichaam tegen C5
C1-INH- C1 klassieke pathway-remmer, goedgekeurd voor de behandeling van erfelijk angio-oedeem
IFX - monoklonaal antilichaam gericht tegen C5a
AMY-101- C3-remmer, voorkomt splitsing van C3, vorming van C3 en C5 en vervolgens voorkomt vorming van C3a, C5a en MAC
 
(Complement Inhibition in COVID-19: A neglected therapeutic option, Frontiers in Immunology, July 2020, Volume 11, Article 1661; see also Complement System I: molecular mechanisms of activation and regulation, Frontiers in Immunology, June 2015, Volume 6 Article 262).