Analysis of mucosal immune dysregulation and safety and tolerability of endoscopic topical steroid therapy for long-COVID hyposmia: randomized, double-blinded pilot study.

BACKGROUND

Millions of people exhibit olfactory dysfunction years after acute SARS-CoV-2 infection. Evidence suggests unresolved olfactory epithelial inflammation may perturb function. Here, we report (1) data from human olfactory biopsies processed for T cell studies, and (2) outcomes from a pilot clinical trial evaluating endoscopic delivery of beclomethasone to the olfactory cleft for improving olfaction in long-COVID hyposmia.

METHODS

Biopsies from long-COVID hyposmia and control subjects underwent single-cell T-cell receptor (TCR) sequencing. In a separate outpatient cohort (Duke Rhinology Clinics), we conducted a randomized, double-blind, placebo-controlled pilot trial. Eligible adults (≥18 y) had ≥3 months long-COVID smell loss confirmed by Smell Identification Test (SIT). Participants were randomized 1:1 to endoscopic delivery of saline or beclomethasone via dissolvable sponge; repeated at 2 weeks. The primary outcome was SIT improvement ≥4 points at 1 month; secondary at 3 months. Study recruitment ran Sept 15, 2023-June 18, 2024.

RESULTS

Biopsies show no evidence of SARS-CoV-2 or EBV/HHV-6 reactivation and demonstrate clonally expanded, pro-inflammatory T-cell subsets. Fifteen subjects are randomized (beclomethasone n = 7, saline n = 8); 13 are analyzed (6 and 7). At 1 month, SIT improvement occurs in 66.7% (4/6) vs 28.6% (2/7) (risk difference 38.1%, 95% CI 2-97%; risk ratio 2.14, 95% CI 0.73-7.79; p = 0.28). At 3 months, rates are 66.7% vs 42.9% (RD 23.8%, 95% CI 17-80%; RR 1.74, 95% CI 0.52-6.5; p = 0.50). No adverse events are reported.

CONCLUSIONS

Human olfactory TCR-seq implicates local T-cell inflammation without local viral reservoirs. Directed, endoscopic topical steroid therapy is feasible and safe, with a non-significant trend toward improved olfaction, supporting larger trials.

FUNDING: NIH DC020172, American Academy of Otolaryngology-Head and Neck Surgery.