Severe COVID-19 Shares a Common Neutrophil Activation Signature with Other Acute Inflammatory States

Abstract

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

Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome

“…Bergamaschi et al (2021) also identified IL-6 persistence in severe disease, along with the TNF-a. In contrast, other studies have shown that disease severity was related to elevated levels of myeloid chemoattractants and neutrophil activation (Freire et al, 2021;Szabo et al, 2021;Schimke et al, 2022). Possible differences in results (molecular profiles) observed between different studies may be due to differences in methods used for investigation, different times of sample collection during infection, or even due to differences in the immunogenetic background of the investigated population.…”

“…Therefore, understanding the biological basis of long COVID-19 will allow us to identify factors that predispose to the development of long-term complications and guide effective therapies. In this sense, several studies have been developed, such as the REACT-GE study (in partnership with Genomics England) that aims to look for biological signatures that may be linked to the development of long COVID-19 and whether genes affect the severity of the COVID-19 and its long-term progression (Post-COVID-19 syndrome: in it for the long haul, 2021) Some studies have evaluated the molecular signature of acute COVID-19 cytokines by different methodologies (Bergamaschi et al, 2021;Freire et al, 2021;Szabo et al, 2021;Schimke et al, 2022). In our study, IL-6 levels were associated with the severe form of acute COVID-19.…”

“…Some studies have evaluated the molecular signature of acute COVID-19 cytokines by different methodologies ( Bergamaschi et al., 2021 ; Freire et al., 2021 ; Szabo et al., 2021 ; Schimke et al., 2022 ). In our study, IL-6 levels were associated with the severe form of acute COVID-19.…”

Combining Deep Phenotyping of Serum Proteomics and Clinical Data via Machine Learning for COVID-19 Biomarker Discovery

“…From a pathophysiological standpoint, the dysfunction of both the innate and adaptive immune responses characterize patients with severe COVID-19 [ 74 , 75 ]. Although increased neutrophils and neutrophil-to-lymphocyte ratio have been described in cases of severe COVID-19 [ 38 , 76 ], the active role of neutrophils in COVID-19 pathophysiology has been debated [ 77 ].…”

The mosaic of autoimmunity – Finally discussing in person. The 13th international congress on autoimmunity 2022 (AUTO13) Athens

“…Plaça showcased the overlap in immunological signaling pathways between COVID-19 and hemophagocytic lymphohistiocytosis (HLH) [ 77 ]. This reflected on the fact that a common dysregulated neutrophil-associated gene signature reflected a generalized hyperinflammatory states and associated with COVID-19 severity [ 78 ]. Finally, Kasperkiewicz in a systemic literature review emphasized that awareness of rare post-COVID-vaccine autoimmune bullous disease (AIBD) could prove vital to the patients management.…”