The turning point of COVID‐19 severity is associated with a unique circulating neutrophil gene signature

COVID‐19 has a broad spectrum of clinical manifestations associated with the host immune response heterogeneity. Despite the advances in COVID‐19 research, it is still crucial to seek a panel of molecular markers that enable accurate stratification of COVID‐19 patients. Here, we performed a study that combined analysis of blood transcriptome, demographic data, clinical aspects and laboratory findings from 66 participants classified into different degrees of COVID‐19 severity and healthy subjects. We identified a perturbation in blood‐leukocyte transcriptional profile associated with COVID‐19 aggravation, which was mainly related to processes that disfavoured lymphocyte activation and favoured neutrophil activation. This transcriptional profile stratified patients according to COVID‐19 severity. Hence, it enabled identification of a turning point in transcriptional dynamics that distinguished disease outcomes and non‐hospitalized from hospitalized moderate patients. Central genes of this unique neutrophil signature were S100A9, ANXA3, CEACAM6, VNN1, OLFM4, IL1R2, TCN1 and CD177. Our study indicates the molecular changes that are linked with the differing clinical aspects presented by humans when suffering from COVID‐19, which involve neutrophil activation. COVID‐19 aggravation is linked to distinct transcriptional profiles of blood leukocytes. The turning point in transcriptional dynamics is associated with a unique signature of neutrophils and COVID‐19 severity.