COVID-19 is one of the most significant global public health challenges of the 21st century, affecting millions of individuals worldwide. Chronic chemosensory dysfunction (CSD) is prominent manifestation of SARS-CoV-2 infection and remains significant concern for clinicians and patients. 

90 participants with history of chronic-CSD associated with Covid-19 (representing 27 of 50 states) were recruited. Participants self-administered olfactory testing over a 6-week interval that measured odor intensity, identification, confidence, and discrimination. Samples were collected via endoscope-guided nasal brushing of olfactory epithelium. [Recovered-CSD (n=2), Persistent-CSD (n=2), healthy controls (n=2)]. We used regression models to predict olfactory function from clinical history and CSD status. Single-cell transcriptomic analyses were performed on OE samples to investigate cellular composition, gene expression, and intercellular signaling

Comparisons of olfactory function in the Persistent-CSD group showed deficits across all olfactory measures relative to Recovered-CSD group. The observed deficits were stably maintained after repeat testing 6 weeks later. Comparisons of olfactory function between Recovered-CSD vs healthy participants showed no statistically significant differences. Single-cell analysis revealed significantly reduced ratio of olfactory sensory neurons to sustentacular support cells in persistent CSD, indicating neuronal loss. Transcriptomic analyses in persistent CSD groups identified elevated type-I interferon (IFN-α) signaling in epithelial cells and heightened IFN-γ and cytotoxic programs in T-cells. Gene set enrichment analysis further implicated pro-inflammatory pathways, including TNF–NFκB and IL6–JAK–STAT3.

Subjective reporting of persistent chemosensory dysfunction in patients with COVID-19 associated CSD are validated by objective psychophysical olfactory testing. Single-cell profiling implicates convergent neuronal loss and persistent, interferon-linked epithelial–immune crosstalk as key drivers of chronic post-COVID smell loss. Molecular analyses of the epithelial cells obtained through nasal brushing demonstrate promising insights about mechanism of chronic CSD and may guide future diagnostic strategies and therapeutic trials.