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      Active Prescription of Low-dose Aspirin During or Prior to Hospitalization and Mortality in COVID-19 — A Systematic Review and Meta-analysis of Adjusted Effect Estimates

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          Abstract

          Background

          This study aims to investigate whether the active prescription of low-dose aspirin during or prior to hospitalization affects mortality in COVID-19 patients. Aspirin is often prescribed for secondary prevention in patients with cardiovascular disease and other comorbidities that might increase mortality, thus, may falsely demonstrate increased mortality. To reduce bias, we only enrolled studies that performed the adjusted analysis.

          Methods

          A systematic literature search was performed using PubMed, Scopus, Embase, and Clinicaltrials.gov from the inception of the database up until 16 April 2021. The exposure was active prescription of low-dose aspirin during or prior to hospitalization. The primary outcome was mortality. The pooled adjusted effect estimate was reported as relative risk (RR).

          Results

          There were 6 eligible studies that were included in this meta-analysis, comprising of 13,993 patients. The studies have a low-moderate risk of bias based on Newcastle-Ottawa Scale. Meta-analysis indicates that low-dose aspirin use was independently associated with reduced mortality (RR 0.46 [0.35, 0.61], p < 0.001; I 2: 36.2%). Subgroup analysis on in-hospital low-dose aspirin administration also showed statistically significant mortality reduction (RR 0.39 [0.16, 0.96], p < 0.001; I 2: 47.0%).

          Conclusion

          Low-dose aspirin use is independently associated with reduced mortality in patients with COVID-19 with a low certainty of evidence.

          PROSPERO

          CRD42021249440.

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          Most cited references55

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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            Autopsy Findings and Venous Thromboembolism in Patients With COVID-19

            Background: The new coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2), has caused more than 210 000 deaths worldwide. However, little is known about the causes of death and the virus's pathologic features. Objective: To validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests. Design: Prospective cohort study. Setting: Autopsies performed at a single academic medical center, as mandated by the German federal state of Hamburg for patients dying with a polymerase chain reaction–confirmed diagnosis of COVID-19. Patients: The first 12 consecutive COVID-19–positive deaths. Measurements: Complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed. Clinical data and medical course were evaluated. Results: Median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital (n = 10) or outpatient sector (n = 2). Coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively). Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients. Postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients. In all patients, SARS–CoV-2 RNA was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral RNA titers in the liver, kidney, or heart. Limitation: Limited sample size. Conclusion: The high incidence of thromboembolic events suggests an important role of COVID-19–induced coagulopathy. Further studies are needed to investigate the molecular mechanism and overall clinical incidence of COVID-19–related death, as well as possible therapeutic interventions to reduce it. Primary Funding Source: University Medical Center Hamburg-Eppendorf.
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              COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives

              Coronavirus disease 2019 (COVID-19), caused by a strain of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic that has affected the lives of billions of individuals. Extensive studies have revealed that SARS-CoV-2 shares many biological features with SARS-CoV, the zoonotic virus that caused the 2002 outbreak of severe acute respiratory syndrome, including the system of cell entry, which is triggered by binding of the viral spike protein to angiotensin-converting enzyme 2. Clinical studies have also reported an association between COVID-19 and cardiovascular disease. Pre-existing cardiovascular disease seems to be linked with worse outcomes and increased risk of death in patients with COVID-19, whereas COVID-19 itself can also induce myocardial injury, arrhythmia, acute coronary syndrome and venous thromboembolism. Potential drug–disease interactions affecting patients with COVID-19 and comorbid cardiovascular diseases are also becoming a serious concern. In this Review, we summarize the current understanding of COVID-19 from basic mechanisms to clinical perspectives, focusing on the interaction between COVID-19 and the cardiovascular system. By combining our knowledge of the biological features of the virus with clinical findings, we can improve our understanding of the potential mechanisms underlying COVID-19, paving the way towards the development of preventative and therapeutic solutions.
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                Author and article information

                Journal
                Int J Infect Dis
                Int J Infect Dis
                International Journal of Infectious Diseases
                The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
                1201-9712
                1878-3511
                15 May 2021
                15 May 2021
                Affiliations
                [a ]Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Padjadjaran, Rumah Sakit Umum Pusat Hasan Sadikin, Bandung, Indonesia
                [b ]Faculty of Medicine, Universitas Pelita Harapan, Tangerang, Indonesia
                Author notes
                [* ]Corresponding author at: Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Padjadjaran, Rumah Sakit Umum Pusat Hasan Sadikin, Jalan Professor Eyckman No.38, Pasteur, Bandung, Jawa Barat 40161, Indonesia.
                Article
                S1201-9712(21)00417-3
                10.1016/j.ijid.2021.05.016
                8123385
                34000418
                3ddb07b0-7c88-436d-8599-c390846874d2
                © 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 19 April 2021
                : 6 May 2021
                : 10 May 2021
                Categories
                Article

                Infectious disease & Microbiology
                aspirin,acetylsalicylic acid,coronavirus,thrombosis,outcome
                Infectious disease & Microbiology
                aspirin, acetylsalicylic acid, coronavirus, thrombosis, outcome

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