In this study, we focused on the differences between COVID-19 severe and mild disease, and identified six hub genes (FPR1, FCGR2A, TLR4, S100A12, CXCL1, and LTF) for COVID-19 severe disease based on mRNA-seq data, explored the immune pathways involved in COVID-19 severe disease, and found that neutrophils and neutrophil extracellular traps (NETs) may play important roles in COVID-19 severe disease. This evidence concerns the gene S100A12 and COVID-19.