COVID-19: Longitudinal immunological and multi-omic profiling of haemodialysis patients

COVID-19, caused by infection with SARS-CoV-2 ('coronavirus'), is a global emergency. Although most people suffer only mild symptoms, some people get seriously ill and the disease is deadly in around 1%. Patients with kidney disease are at high risk of developing serious illness. We urgently need new treatments for COVID-19. In order to develop them, we need to understand why some people get so ill. In these people, we think that the virus causes the body's immune system to goes into 'overdrive' and this causes collateral damage to the body. It is likely that this damage is caused by cells, genes and proteins involved in the immune response to the virus. To understand which ones are causing the problem, we have taken blood samples from patients with kidney disease who are receiving dialysis treatment 3 times a week and who have been infected with COVID-19. This means that we can look at blood samples over time to understand which genes are being switched on and which proteins are changing, particularly in patients who develop the most severe form of the disease. This will help us decide which drugs might help patients and improve survival.

A subset of patients with COVID-19 infection develop severe disease characterised by an excessive inflammatory response. The mechanisms underlying this remain poorly characterised. Patients with end-stage renal failure are at high risk of severe disease, accounting for ~10% of COVID-19 hospitalisations. Despite this, they cannot be shielded as they must receive dialysis three times per week. Here we propose to understand the temporal dynamics of the host immune response during COVID-19 infection, leveraging the unique opportunity for longitudinal sampling from early symptoms through hospitalisation afforded by the largest haemodialysis cohort in the UK. This cannot be addressed through existing national studies.

Our proposal combines serial blood sampling with integrative multi-omic approaches. We have already recruited 40 patients with a mild disease course (continued outpatient dialysis) and 80 patients who subsequently required hospitalisation, together with healthy and non-infected dialysis controls. Blood was taken 48-hourly from first symptoms. We will characterise the temporal changes in immune cell transcriptome and plasma proteome and integrate these data with clinical outcomes. These data will reveal biomarkers that predict clinical deterioration and highlight potential therapeutic targets that may be amenable to repurposing of existing immunomodulatory agents.

We will explore the role of i) complement and ii) inflammasome activation. Preliminary data implicates these pathways in severe disease and they are amenable to therapy (e.g. complement inhibitors). Our Centre has specialist expertise in these areas of immunobiology and the longitudinal nature of our study is uniquely powerful in understanding the development of the COVID-19 cytokine storm.