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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Pierre Bay,
  • Laure Boizeau,
  • Sébastien Préau,
  • Raphaël Favory,
  • Aurélie Guigon,
  • Nicholas Heming,
  • Elyanne Gault,
  • Tài Pham,
  • Amal Chaghouri,
  • Matthieu Turpin,
  • Laurence Morand-Joubert,
  • Sébastien Jochmans,
  • Aurélia Pitsch,
  • Adrien Joseph,
  • Damien Contou,
  • Amandine Henry,
  • Damien Roux,
  • Quentin Le Hingrat,
  • Antoine Guillon,
  • Lynda Handala,
  • Stefano Caruso,
  • Mohamed Ader,
  • Alexandre Soulier,
  • Jean-Michel Pawlotsky,
  • Christophe Rodriguez,
  • Nicolas de Prost,
  • Slim Fourati

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.