Metabolic biomarker profiling for identification of susceptibility to severe pneumonia and COVID-19 in the general population

Biomarkers of low-grade inflammation have been associated with susceptibility to a severe infectious disease course, even when measured prior to disease onset. We investigated whether metabolic biomarkers measured by nuclear magnetic resonance (NMR) spectroscopy could be associated with susceptibility to severe pneumonia (2507 hospitalised or fatal cases) and severe COVID-19 (652 hospitalised cases) in 105,146 generally healthy individuals from UK Biobank, with blood samples collected 2007-2010. The overall signature of metabolic biomarker associations was similar for the risk of severe pneumonia and severe COVID-19. A multi-biomarker score, comprised of 25 proteins, fatty acids, amino acids, and lipids, was associated equally strongly with enhanced susceptibility to severe COVID-19 (odds ratio 2.9 [95%CI 2.1-3.8] for highest vs lowest quintile) and severe pneumonia events occurring 7-11 years after blood sampling (2.6 [1.7-3.9]). However, the risk for severe pneumonia occurring during the first 2 years after blood sampling for people with elevated levels of the multi-biomarker score was over four times higher than for long-term risk (8.0 [4.1-15.6]). If these hypothesis generating findings on increased susceptibility to severe pneumonia during the first few years after blood sampling extend to severe COVID-19, metabolic biomarker profiling could potentially complement existing tools for identifying individuals at high risk. These results provide novel molecular understanding on how metabolic biomarkers reflect the susceptibility to severe COVID-19 and other infections in the general population.National policies for mitigating the COVID-19 pandemic include stricter measures for people considered to be at high risk of severe and potentially fatal cases of the disease. Although older age and pre-existing health conditions are strong risk factors, it is poorly understood why susceptibility varies so widely in the population. People with cardiometabolic diseases, such as diabetes and liver diseases, or chronic inflammation are at higher risk of severe COVID-19 and other infections including pneumonia. These conditions alter the molecules circulating in the blood, providing potential ‘biomarkers’ to determine whether a person is more likely to develop a fatal infection. Uncovering these blood biomarkers could help to identify people who are prone to life-threatening infections despite not having ever been diagnosed with a cardiometabolic disease. To find these biomarkers, Julkunen et al. studied blood samples that had been collected from 105,000 healthy individuals in the United Kingdom over ten years ago. The data showed that individuals with biomarkers linked to low-grade inflammation and cardiometabolic disease were more likely to have died or been hospitalised with pneumonia. A score based on 25 of these biomarkers provided the best predictor of severe pneumonia. This biomarker score performed up to four times better within the first few years after blood sampling compared to predicting cases of pneumonia a decade later. The same blood biomarker changes were also linked with developing severe COVID-19 over ten years after the blood samples had been collected. The predictive value of the biomarker score was similar for both severe COVID-19 and the long-term risk of severe pneumonia. Julkunen et al. propose that the metabolic biomarkers reflect inhibited immunity that impairs response to infections. The results from over 100,000 individuals suggest that these blood biomarkers may help to identify people at high risk of severe COVID-19 or other infectious diseases.