Prospective multicentre study of upper respiratory mucosal transcriptomics reveals two major endotypes of critically ill COVID-19 patients

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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. Severe forms of COVID-19 are associated with an immune response that behaves irregularly. While previous studies have demonstrated that this response can vary significantly between patients, most of this research was conducted prior to the emergence of the Omicron variant. The aim of this study was to explore whether this diversity in immune responses also exists in critically ill patients infected with Omicron. We analysed the immune systems in samples taken from the upper airways of critically ill patients and grouped them based on similarities in their immune response. Two distinct categories of immune response were identified. One group showed a stronger immune response and more inflammation, but no clear differences were observed in how symptoms or disease progression presented between the two groups. These findings emphasise the diversity of immune responses in critically ill patients infected with the Omicron variant, highlighting the need for more personalised treatment strategies. Bay et al. investigate upper respiratory mucosal transcriptomic profiles in critically ill COVID-19 patients infected with Omicron using an unsupervised clustering approach. Their study identifies two distinct immune response profiles, one characterised by enhanced innate and inflammatory activation compared with the other, highlighting the immune heterogeneity in severe COVID-19.