Profiling the Inflammatory Cascade of COVID-19

Overview

COVID-19 is a new and poorly understood virus. It is imperative that the scientific community develops an understanding of the viral mechanisms and human immunological response in order to develop effective therapies and assess their efficacy. This research study is being initiated in response to the ongoing COVID-19 pandemic and will provide much needed insight into the temporal immune response which can lead to rapid respiratory failure in infected patients.

The immuno-inflammatory cascade is essential to define in COVID-19 patients to develop an intervention strategy to abrogate respiratory failure. For this study, four groups of patients have been identified to inform disease characterisation: * Patients in the community * Patients at hospital admission * Rapidly deteriorating patients * Ventilated, critically ill patients There is an urgent need to elucidate the dynamic peripheral blood signature including neutrophil, monocyte, lymphocyte and soluble mediators. Indeed recent data suggest that activation and subsequent exhaustion of cytotoxic T cells and emergence of GM-CSF+ CD4+ T cells and inflammatory monocytes and macrophages (in blood and BAL(1,2,3)) are associated with severe pathology in COVID-19 patients, however the fine kinetics of changes in these populations relative to disease progression are unknown. In this study, samples will be obtained from NHS Lothian patients (in both primary care and hospital settings) who have tested positive for COVID-19 infection. Once consented, blood samples and (where possible) surplus clinical samples will be obtained from participants at defined time-points through the duration of their disease. Participants who rapidly deteriorate during their hospital admission will provide smaller, more frequent blood samples to permit profiling of the immunological/inflammatory response during deterioration. Patients without COVID-19 but of comparable age and comorbid status will act as controls. In-house assays will be used to measure and phenotype circulating immune cells, their activation status and cytokine production (focusing primarily on polymorphonuclear leukocytes, mononuclear phagocytes and lymphocytes) from peripheral blood samples obtained from participants at different stages of COVID-19 disease. Blood and other clinical samples (including but not limited to Bronchoalveolar Lavage (BAL), bronchoabsorption) will undergo laboratory analysis, including but not limited to; whole blood cytokine release assays, inflammatory biomarkers and cell numbers, measurement of cytokines, flow cytometric cell analysis and staining of cells for markers. Results will inform the identification of optimized biomarkers, timing of interventions and lead prioritisation of pharmaceutical assets for experimental medicine studies or assays for use in high throughput automated screens of compound libraries to modulate observed phenotypes and profile the inflammatory pathway. It will build from and complement emerging data from other national or international studies e.g. ISARIC 4C but will be distinct since it informs a specific translational study platform which requires greater depth of phenotyping and more precise kinetic analysis to inform design of early clinical studies of repurposed immunomodulating therapeutics. It is intended this will accelerate the linking of basic mechanistic information with drug targets for development and assessment of COVID-19 therapies. Research materials and results will be also be used to develop novel diagnostics and prognostic approaches that can help identify high risk patients who need higher level of monitoring or care and more fully define susceptibility and risk.

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