Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients

BACKGROUND: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. METHODS: In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. RESULTS: Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host. CONCLUSIONS: Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity

Lipid peroxidation in Gram-negative bacteremia modulates the risk for septic shock and infections by resistant Klebsiella pneumoniae

Controversies in outcomes with the parenteral administration of antioxidants as adjuvant therapies led to the measurement of malondialdehyde (MDA), a product of lipid peroxidation, in serum collected from 120 patients with primary Gram-negative bacteremia during the first 24 h from sepsis onset. MDA was measured by the thiobarbiturate assay, followed by high-performance liquid chromatography (HPLC) analysis. After receiver operator characteristic (ROC) curve analysis, patients were divided into those with high levels of MDA and low levels of MDA. The primary endpoint was the association of the level of MDA with septic shock. The level of MDA as an index of neutrophil function and associations with outcome and with infections by carbapenem-resistant Klebsiella pneumoniae were the secondary endpoints. In total, 63 patients had high and 57 had low MDA levels; 27% and 49.1%, respectively, had septic shock (p = 0.015). The rate of the concentration of MDA to the total neutrophil count was used as an expression of neutrophil function; this was lower among patients with septic shock. The odds ratio (OR) for death among patients without septic shock and low level of MDA was 4.00; this was 0.48 for patients with septic shock (p = 0.020 between the two ORs). The OR for resistance to carbapenems among patients with bacteremia by K. pneumoniae and low level of MDA was 7.50 (p = 0.011 compared to patients with bacteremia by other pathogens). Low level of circulating MDA is associated with susceptibility to septic shock and infections by carbapenem-resistant K. pneumoniae. © 2017, Springer-Verlag GmbH Germany

Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients

BACKGROUND: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. METHODS: In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. RESULTS: Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host. CONCLUSIONS: Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity