In this study, the critical role of the epipharynx in managing long-term coronavirus disease 2019 (COVID-19), and in particular, how residual SARS-CoV-2 RNA affects signalling pathways in the epipharynx were investigated via spatial gene expression analysis (Visium HD). Moreover, we hypothesize that epipharyngeal abrasive therapy (EAT) targeting the epipharynx could improve long COVID symptoms by modulating local inflammation and gene expression. We conducted a comparative analysis of the gene expression profiles of three patients with long COVID and two control individuals without COVID-19. Residual SARS-CoV-2 RNA was detected in the epipharynx of patients with long COVID, along with the activation of signalling pathways in epithelial and immune cells. After EAT, the viral RNA was either completely cleared or significantly reduced. T-cell receptor signalling pathways were suppressed
the levels of proinflammatory cytokines, such as interleukin-6 and tumour necrosis factor-α, were reduced
and excessive antibody production was mitigated. Histology showed that EAT effectively eliminated the inflamed, dysfunctional ciliated epithelium. This study clarifies that SARS-CoV-2 has long-term effects on the immune response in the epipharynx, emphasizing the need to focus on chronic epipharyngitis as a potential cause of long COVID. Furthermore, EAT may offer a promising approach to alleviating persistent long COVID symptoms.