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.