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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月29日

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  • Sarah Kim,
  • Vincent M. D’Anniballe,
  • John B. Finlay,
  • Tiffany Ko,
  • Michael Wang,
  • David W. Jang,
  • Ralph Abi-Hachem,
  • Bradley J. Goldstein

摘要

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.