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      Immunity, endothelial injury and complement-induced coagulopathy in COVID-19

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          Abstract

          In December 2019, a novel coronavirus was isolated from the respiratory epithelium of patients with unexplained pneumonia in Wuhan, China. This pathogen, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a pathogenic condition that has been termed coronavirus disease 2019 (COVID-19) and has reached pandemic proportions. As of 17 September 2020, more than 30 million confirmed SARS-CoV-2 infections have been reported in 204 different countries, claiming more than 1 million lives worldwide. Accumulating evidence suggests that SARS-CoV-2 infection can lead to a variety of clinical conditions, ranging from asymptomatic to life-threatening cases. In the early stages of the disease, most patients experience mild clinical symptoms, including a high fever and dry cough. However, 20% of patients rapidly progress to severe illness characterized by atypical interstitial bilateral pneumonia, acute respiratory distress syndrome and multiorgan dysfunction. Almost 10% of these critically ill patients subsequently die. Insights into the pathogenic mechanisms underlying SARS-CoV-2 infection and COVID-19 progression are emerging and highlight the critical role of the immunological hyper-response — characterized by widespread endothelial damage, complement-induced blood clotting and systemic microangiopathy — in disease exacerbation. These insights may aid the identification of new or existing therapeutic interventions to limit the progression of early disease and treat severe cases.

          Abstract

          This Review describes our current understanding of the pathogenic mechanisms involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the progression of coronavirus disease 2019 (COVID-19), focusing on the immunological hyper-response and the induction of widespread endothelial damage, complement-associated blood clotting and systemic microangiopathy, as well as the effects of these processes on the kidney. The authors also discuss therapeutic interventions that currently hold most promise.

          Key points

          • Although most patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience mild to moderate symptoms that resolve after 6–10 days, almost 20% of patients develop severe illness characterized by atypical interstitial bilateral pneumonia and acute respiratory distress syndrome, with a high fatality rate.

          • Accumulating evidence suggests that an unbalanced and unrestrained innate immune response, which comes at the expense of effective adaptive immunity, underpins the progression of coronavirus disease 2019 (COVID-19).

          • In severe cases of COVID-19, massive endothelial dysfunction, widespread coagulopathy and complement-induced thrombosis can lead to the development of systemic microangiopathy and thromboembolism; these complications can be life-threatening and ultimately lead to multi-organ failure.

          • The kidney is one of the main targets of COVID-19 complications, and abnormal kidney function is associated with a significantly increased risk of death in severely ill patients.

          • Most repurposed anti-viral drugs have failed to improve clinical outcomes in COVID-19; by contrast, therapeutic interventions that target the host response, including the hyper-immune response, complement activation and systemic thrombosis, seem to be more promising approaches to the treatment of severe COVID-19.

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          Most cited references240

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

            In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.
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              Is Open Access

              A pneumonia outbreak associated with a new coronavirus of probable bat origin

              Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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                Author and article information

                Contributors
                giuseppe.remuzzi@marionegri.it
                Journal
                Nat Rev Nephrol
                Nat Rev Nephrol
                Nature Reviews. Nephrology
                Nature Publishing Group UK (London )
                1759-5061
                1759-507X
                19 October 2020
                : 1-19
                Affiliations
                [1 ]GRID grid.4527.4, ISNI 0000000106678902, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, ; Bergamo, Italy
                [2 ]GRID grid.185448.4, ISNI 0000 0004 0637 0221, Infectious Diseases Horizontal Technology Centre (ID HTC), Agency for Science, Technology and Research (A*STAR), ; Singapore, Singapore
                [3 ]GRID grid.185448.4, ISNI 0000 0004 0637 0221, Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), ; Singapore, Singapore
                [4 ]GRID grid.10025.36, ISNI 0000 0004 1936 8470, Institute of Infection, Veterinary and Ecological Sciences, , University of Liverpool, ; Liverpool, UK
                [5 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, Department of Biomedical and Clinical Sciences, , University of Milan, ; Milan, Italy
                Author information
                http://orcid.org/0000-0003-3470-1721
                http://orcid.org/0000-0003-4071-5222
                http://orcid.org/0000-0003-0349-1557
                http://orcid.org/0000-0002-6194-3446
                Article
                357
                10.1038/s41581-020-00357-4
                7570423
                33077917
                8908f0bd-6fa6-4966-bd9e-c8941ca96102
                © Springer Nature Limited 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 18 September 2020
                Categories
                Review Article

                kidney diseases,infectious diseases,sars-cov-2,kidney
                kidney diseases, infectious diseases, sars-cov-2, kidney

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