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    Increased serum SERO levels of soluble TNF-α receptor is associated with mortality of ICU COVID-19 patients

    Authors: Esmaeil Mortaz; Payam Tabarsi; Hamidreza Jamaati; Neda Dalil Roofchayee; Neda KakaDezfuli; Seyed MohammadReza Hashemian; Afshin Moniri; Majid Marjani; Majid Malekmohammd; Davood Manosuri; Mohammd Varahram; Gert Folkerts; Ian M Adcock

    doi:10.1101/2020.07.12.20152066 Date: 2020-07-15 Source: medRxiv

    Background: Severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) that causes coronavirus disease MESHD 2019 (COVID-19) has spread to almost 100 countries, infected over 10M patients and resulted in 505K deaths worldwide as of 30th June 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute Respiratory Distress HP Respiratory Distress MESHD Syndrome ( ARDS MESHD) with multi-functional failure as a result of a cytokine storm with increased serum SERO levels of cytokines such as TNF- and IL-6 being reported. TNF- levels are increased during the cytokine storm in very ill patients and soluble receptors for IL-6 and IL-2 are present in the blood SERO of COVID-19 patients, Objectives: To elucidate the involvement of serum SERO levels of soluble TNF-Receptor of severe and mild COVID-19 patients to determine for severity of disease. Method: We recruited 16 severe COVID-19 patients in the ICU on ventilator support and 26 milder COVID-19 patients who were hospitalised but not within the intensive care unit (ICU) between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran. After harvesting of whole blood SERO the serum SERO was isolated and soluble TNF-Receptor levels measured by ELISA SERO. Results: Serum SERO levels of the usually inhibitory soluble TNF receptor 1 (sTNFaR1) were significantly elevated in severe COVID-19 patients at admission to ICU. High serum SERO levels of sTNFaR1 were associated with mortality of severe COVID-19 patients treated within ICU. Conclusions: This pilot study demonstrates for role of STNF-aR1 receptor in severity of disease. Future studies should examine whether lower levels of systemic sTNFaR1 at admission may indicate a better disease outcome.

    SARS-CoV-2 assays to detect functional antibody SERO responses that block ACE2 recognition in vaccinated animals and infected MESHD patients

    Authors: Daniel W Kulp; Susanne Walker; Neethu Chokkalingam; Emma L Reuschel; Mansi Purwar; Ziyang Xu; Ebony Y Gary; Kevin Y. Kim; Katherine Schultheis; Jewell Walters; Stephanie Ramos; Trevor R.F. Smith; Kate Broderick; Pablo Tebas; Ami Patel; David B Weiner

    doi:10.1101/2020.06.17.158527 Date: 2020-06-20 Source: bioRxiv

    SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2 MESHD) has caused a global pandemic of COVID-19 resulting in cases of mild to severe respiratory distress HP and significant mortality. The global outbreak of this novel coronavirus has now infected >8 million people worldwide with >2 million cases in the US (June 17th, 2020). There is an urgent need for vaccines and therapeutics to combat the spread of this coronavirus. Similarly, the development of diagnostic and research tools to determine infection MESHD and vaccine efficacy are critically needed. Molecular assays have been developed to determine viral genetic material present in patients. Serological assays SERO have been developed to determine humoral responses to the spike protein or receptor binding domain (RBD). Detection of functional antibodies SERO can be accomplished through neutralization of live SARS-CoV2 virus, but requires significant expertise, an infectible stable cell line, a specialized BioSafety Level 3 (BSL-3) facility. As large numbers of people return from quarantine, it is critical to have rapid diagnostics that can be widely adopted and employed to assess functional antibody SERO levels in the returning workforce. This type of surrogate neutralization diagnostic can also be used to assess humoral immune responses induced in patients from the large number of vaccine and immunotherapy trials currently on-going. Here we describe a rapid serological diagnostic assay for determining antibody SERO receptor blocking and demonstrate the broad utility of the assay by measuring the antibody SERO functionality of sera from small animals and non-human primates immunized with an experimental SARS-CoV-2 vaccine and using sera from infected patients.

    A systems approach to inflammation MESHD identifies therapeutic targets in SARS-CoV-2 infection MESHD

    Authors: Frank L. van de Veerdonk; Nico A.F. Janssen; Inge Grondman; Aline H. de Nooijer; Valerie A.C.M. Koeken; Vasiliki Matzaraki; Collins K. Boahen; Vinod Kumar; Matthijs Kox; Hans J.P.M. Koenen; Ruben L. Smeets; Irma Joosten; Roger J.M. Brüggemann; Ilse J.E. Kouijzer; Hans G. van der Hoeven; Jeroen A. Schouten; Tim Frenzel; Monique Reijers; Wouter Hoefsloot; Anton S.M. Dofferhoff; Angèle P.M. Kerckhoffs; Marc J.T. Blaauw; Karin Veerman; Coen Maas; Arjan H. Schoneveld; Imo E. Hoefer; Lennie P.G. Derde; Loek Willems; Erik Toonen; Marcel van Deuren; Jos W.M. van der Meer; Reinout van Crevel; Evangelos J. Giamarellos-Bourboulis; Leo A.B. Joosten; Michel M. van den Heuvel; Jacobien Hoogerwerf; Quirijn de Mast; Peter Pickkers; Mihai G. Netea

    doi:10.1101/2020.05.23.20110916 Date: 2020-05-24 Source: medRxiv

    Background Infection with SARS-CoV-2 manifests itself as a mild respiratory tract infection HP respiratory tract infection MESHD in the majority of individuals, which progresses to a severe pneumonia HP pneumonia MESHD and acute respiratory distress syndrome MESHD respiratory distress HP syndrome ( ARDS MESHD) in 10-15% of patients. Inflammation plays a crucial role in the pathogenesis of ARDS MESHD, with immune dysregulation HP in severe COVID-19 leading to a hyperinflammatory response. A comprehensive understanding of the inflammatory process in COVID-19 is lacking. Methods In this prospective, multicenter observational study, patients with PCR-proven or clinically presumed COVID-19 admitted to the intensive care unit (ICU) or clinical wards were included. Demographic and clinical data were obtained and plasma SERO was serially collected. Concentrations of IL-6, TNF-, complement components C3a, C3c and the terminal complement complex (TCC) were determined in plasma SERO by ELISA SERO. Additionally, 269 circulating biomarkers were assessed using targeted proteomics. Results were compared between ICU and non ICU patients. Findings A total of 119 (38 ICU and 91 non ICU) patients were included. IL-6 plasma SERO concentrations were elevated in COVID-19 (ICU vs. non ICU, median 174.5 pg/ml [IQR 94.5-376.3 vs. 40.0 pg/ml [16.5-81.0]), whereas TNF- concentrations were relatively low and not different between ICU and non ICU patients (median 24.0 pg/ml [IQR 16.5-33.5] and 21.5 pg/ml [IQR 16.0-33.5], respectively). C3a and terminal complement complex (TCC) concentrations were significantly higher in ICU vs. non ICU patients (median 556.0 ng/ml [IQR 333.3-712.5]) vs. 266.5 ng/ml [IQR 191.5-384.0 for C3a and 4506 mAU/ml [IQR 3661-6595 vs. 3582 mAU/ml [IQR 2947-4300] for TCC) on the first day of blood SERO sampling. Targeted proteomics demonstrated that IL-6 (logFC 2.2), several chemokines and hepatocyte growth factor (logFC 1.4) were significantly upregulated in ICU vs. non ICU patients. In contrast, stem cell factor was significantly downregulated (logFC -1.3) in ICU vs. non ICU patients, as were DPP4 (logFC -0.4) and protein C inhibitor (log FC -1.0), the latter two factors also being involved in the regulation of the kinin-kallikrein pathway. Unsupervised clustering pointed towards a homogeneous pathogenetic mechanism in the majority of patients infected with SARS-CoV-2, with patient clustering mainly based on disease severity. Interpretation We identified important pathways involved in dysregulation of inflammation MESHD in patients with severe COVID-19, including the IL-6, complement system and kinin-kallikrein pathways. Our findings may aid the development of new approaches to host-directed therapy.

    Systemic and mucosal antibody SERO secretion specific to SARS-CoV-2 during mild versus severe COVID-19

    Authors: Carlo Cervia; Jakob Nilsson; Yves Zurbuchen; Alan Valaperti; Jens Schreiner; Aline Wolfensberger; Miro E. Raeber; Sarah Adamo; Marc Emmenegger; Sara Hasler; Philipp P. Bosshard; Elena De Cecco; Esther Baechli; Alain Rudiger; Melina Stuessi-Helbling; Lars C. Huber; Annelies S. Zinkernagel; Dominik J. Schaer; Adriano Aguzzi; Ulrike Held; Elsbeth Probst-Mueller; Silvana K. Rampini; Onur Boyman

    doi:10.1101/2020.05.21.108308 Date: 2020-05-23 Source: bioRxiv

    BackgroundInfection with the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) causes an acute illness termed coronavirus disease MESHD 2019 (COVID-19). Humoral immune responses likely play an important role in containing SARS-CoV-2, however, the determinants of SARS-CoV-2-specific antibody SERO responses are unclear. MethodsUsing immunoassays SERO specific for the SARS-CoV-2 spike protein, we determined SARS-CoV-2-specific immunoglobulin A (IgA) and immunoglobulin G (IgG) in sera and mucosal fluids of two cohorts, including patients with quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR)-confirmed SARS-CoV-2 infection (n = 56; median age TRANS 61 years) with mild versus severe COVID-19, and SARS-CoV-2-exposed healthcare workers (n = 109; median age TRANS 36 years) with or without symptoms and tested negative or positive by RT-qPCR. FindingsOn average, SARS-CoV-2-specific serum SERO IgA titers in mild COVID-19 cases became positive eight days after symptom onset TRANS and were often transient, whereas serum SERO IgG levels remained negative or reached positive values 9-10 days after symptom onset TRANS. Conversely, patients with severe COVID-19 showed a highly significant increase of SARS-CoV-2-specific serum SERO IgA and IgG titers as a function of duration since symptom onset TRANS, independent of patient age TRANS and comorbidities. Very high levels of SARS-CoV-2-specific serum SERO IgA correlated with severe acute respiratory distress HP syndrome (ARDS). Interestingly, some of the SARS-CoV-2-exposed healthcare workers with negative SARS-CoV-2-specific IgA and IgG serum SERO titers had detectable SARS-CoV-2-specific IgA antibodies SERO in their nasal fluids and tears. Moreover, SARS-CoV-2-specific IgA levels in nasal fluids of these healthcare workers were inversely correlated with patient age TRANS. InterpretationThese data show that systemic IgA and IgG production against SARS-CoV-2 develops mainly in severe COVID-19, with very high IgA levels seen in patients with severe ARDS, whereas mild disease may be associated with transient serum SERO titers of SARS-CoV-2-specific antibodies SERO but stimulate mucosal SARS-CoV-2-specific IgA secretion. The findings suggest four grades of antibody SERO responses dependent on COVID-19 severity.

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MeSH Disease
Human Phenotype

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