New research from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, and Weill Cornell Medicine, New York City, has identified three key inflammatory proteins which are lower in individuals at risk of severe COVID-19.
The study, published today in Clinical & Translational Immunology, aimed to understand whether levels of inflammation in the blood differed amongst individuals susceptible to severe COVID-19, before they were exposed to SARS-CoV-2. This was important as previous work had demonstrated very high levels of inflammation in the blood of severe COVID-19 patients versus healthy controls, but few studies had considered whether this also differed amongst susceptible individuals prior to infection.
While it is still difficult to predict who will go on to develop severe COVID-19 once infected, recent studies have identified genetic risk factors, which allowed the authors to rank who in a given population might be at highest or lowest risk.
The team studied how this genetic predisposition to severe COVID-19 correlated with blood levels of 35 inflammatory markers in 406 individuals from South East London, all of whom were SARS-CoV-2-negative. Those at highest genetic risk had lower levels of interferon gamma (IFN-γ), vascular endothelial growth factor D (VEGF-D) and tumor necrosis factor alpha (TNF-α) in their blood. While these immune proteins have previously been shown to be higher amongst COVID-19 patients relative to controls, this study suggests they may be lower amongst susceptible individuals prior to infection, meaning the change in levels of these proteins from pre- to post-infection might be greater than originally expected amongst the most severely affected.
The researchers propose that the severe symptoms experienced by some might be a consequence of the body’s immune system experiencing a delayed reaction to the virus, resulting in a sudden and rapid release of inflammatory proteins, known as the “cytokine storm” or “inflammatory storm”.
Genetic risk for severe COVID-19 correlates with lower inflammatory marker levels in a SARS-CoV-2- negative cohort (doi: 10.1002/cti2.1292) Timothy R Powell, Matthew Hotopf, Stephani L Hatch, Gerome Breen, Rodrigo RR Duarte & Douglas F Nixon was published in Clinical and Translational Immunology
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“Inflammatory cytokines are immune messengers that play many important roles, including helping our blood cells to identify threats and eliminate them. However, there seems to be a middle ground in relation to cytokine levels - while very low levels probably predispose individuals to infection, very high levels have been linked to inflammatory diseases, such as rheumatoid arthritis. In the case of severe COVID-19, symptoms such as fever might be the result of levels going from low to high, very rapidly, as the immune system attempts to compensate for an insufficient first-line response to SARS-CoV-2 infection.”– Dr Timothy Powell, Research Fellow and Head of the Psychiatric Biogerontology & Translational Medicine Lab at King's IoPPN
The study also explored how genetic susceptibility interacts with previously established risk factors like age and body mass index (BMI). In both instances, those at highest genetic risk were found to have lower levels of inflammatory proteins relative to their peers of a similar age or BMI.
In a previous study, Dr Powell demonstrated positive associations between age and inflammation, suggesting that it is a natural part of the ageing process. However, this age-associated rise in inflammation is not seen in individuals at genetic risk of severe COVID-19, suggesting their immune profiles increasingly differ from their peers as they age, which might explain their increased susceptibility to severe infection.
Dr Powell adds “While the results from this study are still preliminary and require replication in larger, longitudinal cohorts, they point towards possible innate immune differences amongst those most susceptible to severe COVID-19. Further studies will be needed to better understand whether the identified immune correlations are causal, or whether other biological mechanisms are more important in explaining severe COVID-19 risk.”
This study was possible thanks to funding from the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre and the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health (NIH).