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      Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19

      research-article
      1 , 1 , 1 , 1 , 2 , 3 , 4 , 5 , 3 , 6 , 6 , 6 , 6 , 6 , 6 , 4 , 7 , 8 , 5 , 3 , 6 , 3 , 9 , 4 , 10 , 11 , 12 , * , 7 , 13 , * , 1 , * , on behalf of the ISARIC4C investigators **
      (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab)
      Science Immunology
      American Association for the Advancement of Science

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          Abstract

          GM-CSF is elevated early, scaled with severity, and is central to the inflammatory response in COVID-19, but not severe influenza.

          Abstract

          While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19.

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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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              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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                Author and article information

                Journal
                Sci Immunol
                Sci Immunol
                SciImmunol
                immunology
                Science Immunology
                American Association for the Advancement of Science
                2470-9468
                10 March 2021
                10 March 2021
                : 6
                : 57
                : eabg9873
                Affiliations
                [1 ]National Heart and Lung Institute, Imperial College London, U.K.
                [2 ]University of Edinburgh Centre for Inflammation Research, Edinburgh, U.K.
                [3 ]Dept of Clinical Infection, Microbiology and Immunology, University of Liverpool, U.K.
                [4 ]Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, U.K.
                [5 ]Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, U.K.
                [6 ]Department of Infectious Disease, Faculty of Medicine, Imperial College London, U.K.
                [7 ]Intensive Care Unit, Royal Infirmary Edinburgh, Edinburgh, U.K.
                [8 ]Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, U.K.
                [9 ]Tropical and infectious disease unit, Liverpool University Hospitals NHS Foundation Trust (member of Liverpool Health Partners), U.K.
                [10 ]National Infection Service, Public Health England, London, UK
                [11 ]NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, U.K.
                [12 ]Respiratory Medicine, Alder Hey Children’s Hospital, Liverpool, U.K.
                [13 ]Roslin Institute, University of Edinburgh, Edinburgh, U.K.
                Author notes
                [**]

                ISARIC4C authors are listed in the supplementary material.

                Author information
                http://orcid.org/0000-0003-3052-2793
                http://orcid.org/0000-0002-1979-1805
                http://orcid.org/0000-0003-2504-6518
                http://orcid.org/0000-0002-8736-9198
                http://orcid.org/0000-0002-9873-8243
                http://orcid.org/0000-0001-8610-2806
                http://orcid.org/0000-0001-7635-1868
                http://orcid.org/0000-0001-9438-5623
                http://orcid.org/0000-0002-4974-8824
                http://orcid.org/0000-0003-0914-920X
                http://orcid.org/0000-0001-8277-420X
                http://orcid.org/0000-0003-4230-0207
                http://orcid.org/0000-0002-3773-2390
                http://orcid.org/0000-0002-0778-1693
                http://orcid.org/0000-0002-5018-3066
                http://orcid.org/0000-0002-4035-4562
                http://orcid.org/0000-0001-9700-0418
                http://orcid.org/0000-0001-5258-793X
                http://orcid.org/0000-0002-7220-2555
                Article
                abg9873
                10.1126/sciimmunol.abg9873
                8128298
                33692097
                0aaab8e1-c98b-4bb6-95ef-88d1550ba064
                Copyright © 2021, American Association for the Advancement of Science

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 08 February 2021
                : 05 March 2021
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: OPP1209135
                Funded by: doi http://dx.doi.org/10.13039/100010269, Wellcome;
                Award ID: 215091/Z/18/Z
                Funded by: doi http://dx.doi.org/10.13039/100010269, Wellcome;
                Award ID: 205228/Z/16/Z
                Funded by: doi http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;
                Award ID: CO-CIN-01
                Funded by: doi http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: MC_PC_19059
                Funded by: doi http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;
                Award ID: NIHR Imperial BRC P45058
                Funded by: doi http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;
                Award ID: 200907
                Funded by: doi http://dx.doi.org/10.13039/501100002141, Public Health England;
                Award ID: CO-CIN-01
                Funded by: doi http://dx.doi.org/10.13039/501100002141, Public Health England;
                Award ID: 19059
                Funded by: Liverpool Experimental Cancer Medicine Centre;
                Award ID: C18616/A25153
                Funded by: doi http://dx.doi.org/10.13039/501100002141, Public Health England;
                Award ID: P45058
                Funded by: doi http://dx.doi.org/10.13039/501100002141, Public Health England;
                Award ID: 200907
                Funded by: doi http://dx.doi.org/10.13039/501100002141, Public Health England;
                Award ID: 215091/Z/18/Z
                Funded by: doi http://dx.doi.org/10.13039/501100002141, Public Health England;
                Award ID: OPP1209135
                Funded by: doi http://dx.doi.org/10.13039/501100002141, Public Health England;
                Award ID: C18616/A25153
                Funded by: UK Coronavirus Immunology Consortium;
                Funded by: doi http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;
                Award ID: HPRU in Respiratory Infections, Imperial College
                Funded by: doi http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;
                Award ID: HPRU in Emerging and Zoonotic infections, University of Liverpool
                Funded by: doi http://dx.doi.org/10.13039/501100002141, Public Health England;
                Award ID: 205228/Z/16/Z
                Categories
                Research Articles
                Research Articles
                R-Articles
                Coronavirus

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