Carol H. Yan

Introduction While localized inflammation has been implicated in the pathophysiology of acute coronavirus disease of 2019 (COVID‐19) olfactory dysfunction (OD), persistent COVID‐19 OD remains poorly understood with limited therapeutics. Our prospective study evaluated olfactory cleft (OC) biomarkers as predictors of persistent OD in mucus sampling. Methods COVID‐19 subjects with persistent OD >3 months confirmed by psychophysical olfaction tests were compared to COVID‐19 subjects with no OD and those with no prior infection. OC mucus samples were evaluated for 13 anti‐viral and inflammatory biomarkers. Cohorts were compared using analysis of variance (ANOVA) and Mann–Whitney tests with multi‐comparison adjustment. Viral RNA was assessed through RT‐PCR using the COVID‐19 N2 primer. Results Thirty‐five samples were collected (20 COVID persistent OD, 8 COVID no OD, and 7 non‐COVID no OD). Significant differences in IFN‐λ1 ( p = 0.007) and IFN‐γ ( p = 0.006) expression in OC mucus were found across all three groups, with the highest cytokine concentrations corresponding to COVID OD. IFN‐α2 levels were elevated in COVID OD versus no OD ( p = 0.026). Mean IFN‐γ levels were the highest in COVID OD, but there were higher levels found in COVID no OD compared to non‐COVID no OD ( p = 0.008). No difference was seen in IL6. No N2 gene expression was detected in all cohorts. Conclusion IFN pathway cytokines were found elevated in the olfactory microenvironment of COVID‐19 persistent OD compared to those with no OD and no prior history of COVID‐19 infection.