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      Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers

      research-article
      1 , 2 , 3 , 4 , 3 , 3 , 5 , 6 , 7 , 5 , 7 , 7 , 8 , 9 , 10 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 7 , 11 , 3 , 1 , 1 , 12 , 13 , 14 , 15 , 15 , 16 , 15 , 17 , 7 , 18 , 7 , 19 , 2 , 8 , 20 , 2 , 7 , 21 , 17 , 22 , 5 , 17 , 23 , 1 , 2 , 11 , 1 , 2 , 11 , 24 , 8 , 24 , 15 , 17 , 3 , 25 , 26 , 27 , 28 ,
      Cell Death & Disease
      Nature Publishing Group UK
      Metabolomics, Viral infection

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          Abstract

          The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient’s plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.

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          Most cited references34

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          Clinical Characteristics of Coronavirus Disease 2019 in China

          Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
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            Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

            Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression suggesting diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A unique phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor NF-κB and characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling. These data suggest that type-I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.
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              An inflammatory cytokine signature predicts COVID-19 severity and survival

              Several studies have revealed that the hyper-inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of disease severity and death. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β in hospitalized patients with coronavirus disease 2019 (COVID-19) upon admission to the Mount Sinai Health System in New York. Patients (n = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected. We found that high serum IL-6, IL-8 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival (P < 0.0001, P = 0.0205 and P = 0.0140, respectively). Notably, when adjusting for disease severity, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. These findings were validated in a second cohort of patients (n = 231). We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of patients with COVID-19 to stratify prospective clinical trials, guide resource allocation and inform therapeutic options.
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                Author and article information

                Contributors
                kroemer@orange.fr
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                11 March 2021
                11 March 2021
                March 2021
                : 12
                : 3
                : 258
                Affiliations
                [1 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, INSERM U1015, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [2 ]Université Paris Saclay, Faculté de Médecine, 94270 Le Kremlin-Bicêtre, France
                [3 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [4 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, INSERM U1138, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [5 ]GRID grid.414106.6, ISNI 0000 0000 8642 9959, Service de Médecine Interne, Hôpital Foch, ; 92150 Suresnes, France
                [6 ]Service d’Accueil des Urgences, AP-HP, Hôpital Hôtel-Dieu, 75004 Paris, France
                [7 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Département d’Oncologie Médicale, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [8 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Département d’Hématologie, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [9 ]GRID grid.414106.6, ISNI 0000 0000 8642 9959, Service de biologie clinique, Hôpital Foch, ; 92150 Suresnes, France
                [10 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Service de virologie, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [11 ]Centre d’Investigation Clinique – Biothérapie, INSERM CICBT1428, 94800 Villejuif, France
                [12 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Département de Biologie Médicale, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [13 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Département de Réanimation, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [14 ]GRID grid.411784.f, ISNI 0000 0001 0274 3893, Service de Virologie, AP-HP. Centre-Université de Paris, Hôpital Cochin, ; Paris, France
                [15 ]GRID grid.411784.f, ISNI 0000 0001 0274 3893, Service d’Hématologie Biologique, AP-HP, , Centre-Université de Paris, Hôpital Cochin, ; 75014 Paris, France
                [16 ]Université de Paris, Innovative Therapies in Haemostasis, INSERM 1140, F-75006 Paris, France
                [17 ]Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, 75006 Paris, France
                [18 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Gustave Roussy, Paris-Saclay University, ; Paris, France
                [19 ]GRID grid.463833.9, ISNI 0000 0004 0572 0656, Aix Marseille University, CNRS, INSERM, CRCM, ; Marseille, France
                [20 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, INSERM U1287, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [21 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, INSERM U981, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [22 ]GRID grid.411784.f, ISNI 0000 0001 0274 3893, Service de Médecine Intensive et Réanimation, AP-HP, Hôpital Cochin, ; 75014 Paris, France
                [23 ]GRID grid.411784.f, ISNI 0000 0001 0274 3893, Service de Médecine Interne, AP-HP, Hôpital Cochin, ; 75014 Paris, France
                [24 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Département d’Innovation Thérapeutique et des Essais Précoces, Gustave Roussy Cancer Campus, ; 94800 Villejuif, France
                [25 ]Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France
                [26 ]GRID grid.414093.b, Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, ; 75015 Paris, France
                [27 ]GRID grid.9227.e, ISNI 0000000119573309, Suzhou Institute for Systems Biology, Chinese Academy of Sciences, ; Suzhou, China
                [28 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Department of Women’s and Children’s Health, Karolinska University Hospital, ; 17176 Stockholm, Sweden
                Author information
                http://orcid.org/0000-0002-7526-0769
                http://orcid.org/0000-0002-8629-1341
                http://orcid.org/0000-0003-1596-0998
                http://orcid.org/0000-0002-5816-3019
                Article
                3540
                10.1038/s41419-021-03540-y
                7948172
                82d94d8c-ce60-4e58-9b84-97f416b2d203
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 24 November 2020
                : 9 February 2021
                : 10 February 2021
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                © The Author(s) 2021

                Cell biology
                metabolomics,viral infection
                Cell biology
                metabolomics, viral infection

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