Prospective multicentre study of upper respiratory mucosal transcriptomics reveals two major endotypes of critically...

Severe COVID-19 is associated with dysregulated immune responses. Immune responses heterogeneity was previously reported during the first waves of the pandemic. We aimed to characterise mucosal transcriptomic profiles in critically-ill patients during the Omicron era.

This prospective multicentre study included 94 critically-ill COVID-19 patients between May 2022 and August 2023. Upper respiratory tract mucosal transcriptomes were obtained from nasopharyngeal swabs and clustered based on KEGG cytokine-cytokine receptor interaction pathways using an unsupervised algorithm. Differential transcript expression, cell population abundance and gene set enrichment analyses were performed.

Here we show that in 56 critically ill COVID-19 patients, transcriptomic clustering reveals two distinct COVID-19 Immune Transcriptomic Respiratory Profiles (CITRP), including CITRP-1 and CITRP-2, characterised by differential expression of cytokine and immune response pathways. Patients in the CITRP-2 group display a more pronounced immune and inflammatory response, involving specific innate immune pathways, neutrophil degranulation and T-helper 2 cytokines (e.g., IL-1, IL-4 and IL-13), and a significantly higher proportion of neutrophils than patients in the CITRP-1 group. No significant differences are observed between the two transcriptomic clusters in clinical, biological and virological characteristics at ICU admission or in patient outcomes.

This study highlights the heterogeneity of the immune response in critically-ill COVID-19 patients in the Omicron era, identifies two endotypes from the analysis of upper airway mucosal transcriptomics. Our findings suggest the existence of two distinct pathogenic mechanisms and the detrimental role of neutrophil and Th2 helper cell-mediated inflammation in a subset of patients with severe disease. They support the need for personalised treatment strategies targeting neutrophil-mediated lung damage and/or specific cytokine production in a subset of critically-ill COVID-19 patients.