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.
Highlights
During almost two years of the COVID-19 pandemic, caused by the severe acute respiratory syndrome Coronavirus (SARS-CoV)-2, over 396 million cases and 5.7 million deaths have been reported worldwide (8 February 2022, WHO COVID-19 dashboard)
We first performed a cross-tissue analysis of transcriptomic datasets obtained from peripheral blood lymphocytes (PBLs), peripheral blood mononuclear cells (PBMCs), and nasopharyngeal swabs
To identify the common differentially expressed genes (DEG) we divided the datasets into three subgroups based on the type of samples and RNA seq platforms: Overlap 1 (HLH and COVID-19 blood transcriptomes), Overlap 2 (HLH and COVID-19 nasopharyngeal swab transcriptomes), and Overlap 3 (HLH and COVID-19 scRNA seq transcriptomes)
Summary
During almost two years of the COVID-19 pandemic, caused by the severe acute respiratory syndrome Coronavirus (SARS-CoV)-2, over 396 million cases and 5.7 million deaths have been reported worldwide (8 February 2022, WHO COVID-19 dashboard). The clinical presentation ranges from asymptomatic to severe disease manifesting as pneumonia, acute respiratory distress syndrome (ARDS), and a life-threatening hyperinflammatory syndrome associated with excessive cytokine release (hypercytokinemia) [1–3]. Risk factors for severe manifestation and higher mortality include old age as well as hypertension, obesity, and diabetes [4]. COVID-19 continues to spread, new variants of SARSCoV-2 have been reported and the number of infections resulting in the death of young individuals with no comorbidities has increased the mortality rates among the young population [5,6]. Some novel SARS-CoV-2 variants of concern appear to escape neutralization by vaccine-induced humoral immunity [7]. There is a need for a better understanding of the immunopathologic mechanisms associated with severe
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
