Upper Airway Immune Dysfunction in Childhood Otitis Media with Effusion

Abstract

Introduction: Otitis media with effusion (OME) is the most common reversible cause of hearing loss in children. It is frequently treated with insertion of ventilation tubes with or without adjuvant adenoidectomy. The mechanism by which adenoidectomy resolves OME remains unknown. Understanding this may reveal biological insights for the development of novel therapeutics which could obviate the need for surgical intervention in young patients. Methods: I have obtained clinical specimens of adenoid tissue from children with and without OME across early childhood. These have been analysed using suspension-based and spatial highthroughput genomics, providing a cell and gene library across key microanatomical compartments at the resolutions of single cells. I have validated the transcriptomic findings using multiplexed imaging and tested them functionally using B cell immunoassays. Results: I have generated the first ‘cell atlas’ of the human adenoid; comprising 45,000 cells and 30,000 genes. I have identified specific immune dysfunction in patients with OME, including arrested B cell maturation in germinal centres, with consequently reduced abundance and function of IgA secreting plasma cells. Gene set enrichment analysis revealed impairments in cellular homeostasis, mechanisms of B cell class-switching, and cell-to-cell communication

programmes. The in-situ profiling of cells showed that dysfunctional populations sit close to the mucosal surface and may be amenable to modulation with intranasal topical agents. Conclusion: I have shown that OME is associated with a mucosal immunodeficiency in the nasopharynx. Future research should focus on augmenting IgA production in the upper airway mucosa, potentially via mucosal vaccinations, and evaluating this in laboratory models of OME.