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Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review.

ABSTRACT: Severe Acute Respiratory Syndrome related to Coronavirus-2 (SARS-CoV-2), coronavirus disease-2019 (COVID-19) may cause severe illness in 20% of patients. This may be in part due to an uncontrolled immune-response to SARS-CoV-2 infection triggering a systemic hyperinflammatory response, the so-called "cytokine storm". The reduction of this inflammatory immune-response could be considered as a potential therapeutic target against severe COVID-19. The relationship between inflammation and clot activation must also be considered. Furthermore, we must keep in mind that currently, no specific antiviral treatment is available for SARS-CoV-2. While moderate-severe forms need in-hospital surveillance plus antivirals and/or hydroxychloroquine; in severe and life-threating subsets a high intensity anti-inflammatory and immunomodulatory therapy could be a therapeutic option. However, right data on the effectiveness of different immunomodulating drugs are scarce. Herein, we discuss the pathogenesis and the possible role played by drugs such as: antimalarials, anti-IL6, anti-IL-1, calcineurin and JAK inhibitors, corticosteroids, immunoglobulins, heparins, angiotensin-converting enzyme agonists and statins in severe COVID-19.

SUBMITTER: Alijotas-Reig J

PROVIDER: S-EPMC7252146 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review.

Alijotas-Reig Jaume J Esteve-Valverde Enrique E Belizna Cristina C Selva-O'Callaghan Albert A Pardos-Gea Josep J Quintana Angela A Mekinian Arsene A Anunciacion-Llunell Ariadna A Miró-Mur Francesc F

Autoimmunity reviews 20200503 7

Severe Acute Respiratory Syndrome related to Coronavirus-2 (SARS-CoV-2), coronavirus disease-2019 (COVID-19) may cause severe illness in 20% of patients. This may be in part due to an uncontrolled immune-response to SARS-CoV-2 infection triggering a systemic hyperinflammatory response, the so-called "cytokine storm". The reduction of this inflammatory immune-response could be considered as a potential therapeutic target against severe COVID-19. The relationship between inflammation and clot acti ...[more]

PMID: 32376394

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Project description:The severe acute respiratory syndrome coronavirus 2 associated coronavirus disease 2019 (COVID-19) illness is a syndrome of viral replication in concert with a host inflammatory response. The cytokine storm and viral evasion of cellular immune responses may play an equally important role in the pathogenesis, clinical manifestation, and outcomes of COVID-19. Systemic proinflammatory cytokines and biomarkers are elevated as the disease progresses towards its advanced stages, and correlate with worse chances of survival. Immune modulators have the potential to inhibit cytokines and treat the cytokine storm. A literature search using PubMed, Google Scholar, and ClinicalTrials.gov was conducted through 8 July 2020 using the search terms 'coronavirus', 'immunology', 'cytokine storm', 'immunomodulators', 'pharmacology', 'severe acute respiratory syndrome 2', 'SARS-CoV-2', and 'COVID-19'. Specific immune modulators include anti-cytokines such as interleukin (IL)-1 and IL-6 receptor antagonists (e.g. anakinra, tocilizumab, sarilumab, siltuximab), Janus kinase (JAK) inhibitors (e.g. baricitinib, ruxolitinib), anti-tumor necrosis factor-? (e.g. adalimumab, infliximab), granulocyte-macrophage colony-stimulating factors (e.g. gimsilumab, lenzilumab, namilumab), and convalescent plasma, with promising to negative trials and other data. Non-specific immune modulators include human immunoglobulin, corticosteroids such as dexamethasone, interferons, statins, angiotensin pathway modulators, macrolides (e.g. azithromycin, clarithromycin), hydroxychloroquine and chloroquine, colchicine, and prostaglandin D2 modulators such as ramatroban. Dexamethasone 6 mg once daily (either by mouth or by intravenous injection) for 10 days may result in a reduction in mortality in COVID-19 patients by one-third for patients on ventilators, and by one-fifth for those receiving oxygen. Research efforts should focus not only on the most relevant immunomodulatory strategies but also on the optimal timing of such interventions to maximize therapeutic outcomes. In this review, we discuss the potential role and safety of these agents in the management of severe COVID-19, and their impact on survival and clinical symptoms.

Project description:BackgroundCorticosteroids are commonly used as adjuvant therapy for acute respiratory distress syndrome by many clinicians because of their perceived anti-inflammatory effects. However, for patients with severe viral pneumonia, the corticosteroid treatment is highly controversial.ObjectivesThe purpose of this review is to systematically evaluate the effect and potential mechanism of corticosteroid administration in pandemic viral pneumonia.SourcesWe comprehensively searched all manuscripts on corticosteroid therapy for influenza, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and SARS coronavirus 2 (SARS-CoV-2) viral pneumonia from the PubMed, EMBASE, Web of Science and Cochrane Library databases.ContentWe systematically summarized the effects of corticosteroid therapy for pandemic viral pneumonia and the potential mechanism of action for corticosteroids in coronavirus disease 2019 (COVID-19).ImplicationsObservational studies showed that corticosteroid treatment was associated with increased mortality and nosocomial infections for influenza and delayed virus clearance for SARS-CoV and MERS-CoV. Limited data on corticosteroid therapy for COVID-19 were reported. Corticosteroids were used in about a fifth of patients (670/2995, 22.4%). Although clinical observational studies reported the improvement in symptoms and oxygenation for individuals with severe COVID-19 who received corticosteroid therapy, case fatality rate in the corticosteroid group was significantly higher than that in the non-corticosteroid group (69/443, 15.6% versus 56/1310, 4.3%). Compared individuals with non-severe disease, those with severe disease were more likely to receive corticosteroid therapy (201/382, 52.6% versus 201/1310, 15.3%). Although there is no evidence that corticosteroid therapy reduces mortality in people with COVID-19, some improvements in clinical symptoms and oxygenation were reported in some clinical observational studies. Excessive inflammatory response and lymphopenia might be critical factors associated with severity of and mortality from COVID-19. Sufficiently powered randomized controlled trials with rigorous inclusion/exclusion criteria and standardized dose and duration of corticosteroids are needed to verify the effectiveness and safety of corticosteroid therapy.

Project description:The objective of this study was to elucidate the pathophysiology that underlies severe COVID-19 by assessing the histopathology and the in situ detection of infectious SARS-CoV-2 and viral capsid proteins along with the cellular target(s) and host response from twelve autopsies. There were three key findings: 1) high copy infectious virus was limited mostly to the alveolar macrophages and endothelial cells of the septal capillaries; 2) viral spike protein without viral RNA localized to ACE2+ endothelial cells in microvessels that were most abundant in the subcutaneous fat and brain; 3) although both infectious virus and docked viral spike protein was associated with complement activation, only the endocytosed pseudovirions induced a marked up-regulation of the key COVID-19 associated proteins IL6, TNF alpha, IL1 beta, p38, IL8, and caspase 3. Importantly, this microvasculitis was associated with characteristic findings on hematoxylin and eosin examination that included endothelial degeneration and resultant basement membrane zone disruption and reduplication. It is concluded that serious COVID-19 infection has two distinct mechanisms: 1) a microangiopathy of pulmonary capillaries associated with a high infectious viral load where endothelial cell death releases pseudovirions into the circulation, and 2) the pseudovirions dock on ACE2+ endothelial cells most prevalent in the skin/subcutaneous fat and brain that activates the complement pathway/coagulation cascade resulting in a systemic procoagulant state as well as the expression of cytokines that produce the cytokine storm. The data predicts a favorable response to therapies based on either removal of circulating viral proteins and/or blunting of the endothelial-induced response. Highlights • SARS-CoV-2 causes serious disease via two distinct mechanisms• One mechanism is damage to the alveolar wall (microangiopathy) associated with high viral copy numbers• The other mechanism is circulating viral capsid proteins that dock on ACE2+ endothelia• The ACE2+ endothelia are most prominent in the subcutaneous fat and brain• Endocytosis of viral capsid protein by endothelia induces cell death, cytokine expression, and complement activation (endothelialitis)

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Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review.

Publications

Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review.

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