Southampton researchers have identified a blood profile that could help identify COVID-19 patients at greatest risk of deterioration and direct them towards trials of specific treatments that could modify their immune systems’ responses.
A new study jointly led by Professor Tom Wilkinson and Dr Tristan Clark of the University of Southampton, has shown a blood test for five cytokines could help predict those at risk of life-threating overstimulation of immune defences by COVID-19, and potentially tailor their treatment to tackle this.
‘Preventing a cytokine storm’
Cytokines are cell signalling molecules with many associated with inflammation released into the bloodstream after an infection, helping to drive protective immune responses.
In patients with severe COVID-19, the immune system can overreact leading to massively increased cytokine levels in the blood – a ‘cytokine storm’. Instead of helping the body fight the virus, this overreaction is extremely damaging to the cells and tissues of the body itself and can be fatal.
Identifying those more prone to this response, and tackling the hyperinflammation could be a key route to reducing the severity of COVID-19 and deaths.
‘Identifying patients most at risk’
The study, published in Respiratory Research, analysed blood samples from 100 COVID-19 positive patients admitted to University Hospital Southampton NHS Foundation Trust (UHS) between 20 March and 29 April 2020, during the first phase of the pandemic.
They found that high levels of cytokines IL-6, IL-8, TNF, IL-1β and IL-33 in the patients’ blood on admission were associated with greater chance of needing intensive care, artificial ventilation and of dying. IL-1β and IL-33 showed the biggest effect.
This study formed part of the CoV-19POC study – a trial led by Dr Clark looking at the clinical impact of molecular point-of-care testing in patients at UHS with suspected COVID-19, including tests that dramatically cut the time taken to diagnose COVID-19.
Combining this cytokine test with a clinical assessment of the patients’ condition could help doctors identify and treat those most at risk of deteriorating.
Dr Anna Freeman and Dr Hannah Burke, Respiratory Clinical Research Fellows and joint first authors commented: “This project was a great opportunity for collaboration within the Faculty of Medicine, using resource from both the respiratory and infectious diseases teams.
“As early career researchers this study provided us with a valuable learning opportunity about how to deliver academic impact within the evolving COVID-19 pandemic.”
‘Investigating new treatments’
Two treatments for those hospitalised with COVID-19 have been found so far, with the steroid dexamethasone shown to reduce deaths by up to a third, in patients needing oxygen. The mechanism for Dexamethasone’s protective effects isn’t known, but as a non-specific anti-inflammatory it points to the potential benefit of controlling the inflammatory immune response.
The Southampton team hope that by accurately identifying which cytokines are driving hyperinflammation in each COVID-19 patient, doctors could target them (such as with an IL-33 blocker current in UK trials), yielding the biggest benefits for individual patients- an approach known as ‘precision medicine’.
Professor Tom Wilkinson said: “These findings, from the ongoing COVID research programme in Southampton, have identified important inflammatory signals which will help steer the development of treatment strategies for this new disease.
“It is increasingly apparent that COVID is highly heterogeneous. Only by applying these techniques to stratify the condition will we be able to target the key mechanisms of disease with the best treatment for that individual.”
Dr Tristan Clark said: “Our findings suggest that testing for both COVID-19 and cytokines at the point-of-care is feasible and in the future may identify infected patients and the most appropriate treatment for them, in near real-time.”
The COVID-19 pandemic has led to more than 760,000 deaths worldwide (correct as of 16th August 2020). Studies suggest a hyperinflammatory response is a major cause of disease severity and death. Identitfying COVID-19 patients with hyperinflammation may identify subgroups who could benefit from targeted immunomodulatory treatments. Analysis of cytokine levels at the point of diagnosis of SARS-CoV-2 infection can identify patients at risk of deterioration.
We used a multiplex cytokine assay to measure serum IL-6, IL-8, TNF, IL-1β, GM-CSF, IL-10, IL-33 and IFN-γ in 100 hospitalised patients with confirmed COVID-19 at admission to University Hospital Southampton (UK). Demographic, clinical and outcome data were collected for analysis.
Age > 70 years was the strongest predictor of death (OR 28, 95% CI 5.94, 139.45). IL-6, IL-8, TNF, IL-1β and IL-33 were significantly associated with adverse outcome. Clinical parameters were predictive of poor outcome (AUROC 0.71), addition of a combined cytokine panel significantly improved the predictability (AUROC 0.85). In those ≤70 years, IL-33 and TNF were predictive of poor outcome (AUROC 0.83 and 0.84), addition of a combined cytokine panel demonstrated greater predictability of poor outcome than clinical parameters alone (AUROC 0.92 vs 0.77).
A combined cytokine panel improves the accuracy of the predictive value for adverse outcome beyond standard clinical data alone. Identification of specific cytokines may help to stratify patients towards trials of specific immunomodulatory treatments to improve outcomes in COVID-19.