Severe COVID-19 shares a common neutrophil activa-2 tion signature with other acute inflammatory states 3

Severe COVID-19 patients present a clinical and laboratory overlap with other hyperin43 flammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the under44 lying mechanisms of these conditions remain to be explored. Here, we investigated the transcrip45 tome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, 46 other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], 47 Kawasaky disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bac48 terial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cyto49 kine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures 50 that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU 51 patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of 52 neutrophil-associated genes that reflects a generalized hyperinflamatory state since it is also dysreg53 ulated in patients with KD and bacterial pneumonia. These genes are dysregulated at protein level 54 across several COVID-19 studies and form an interconnected network with differentially expressed 55 plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the in56 tensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across 57 different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial 58 intelligence modeling confirmed the strong association of these genes with COVID-19 severity. 59 Thus, our work indicates putative therapeutic pathways for intervention. 60