Analysis of mucosal immune dysregulation and safety and tolerability of endoscopic topical steroid therapy for [LC] hyposmia: [DBRCT], 2025, Kim et al

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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

Spoiler: Authors

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

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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.

Web | DOI | PDF | Communications Medicine | Open Access

 

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Characterizing T cells in the olfactory epithelium of people with hyposmia:

No TCRs matched known epitopes for SARS-CoV-2, EBV, or HHV6 antigens (Fig. 1d). Of interest, in a COVID-hyposmic sample we identified a T cell clone recognizing the Homo sapiens BST2 antiviral defense protein (Bone Marrow Stromal Antigen 2, also known as Tetherin), consistent with potential autoimmune mechanisms.

Our samples contained no detectable SARS-CoV-2, HHV4 or HHV6 transcripts, suggesting that local viral reservoirs or reactivation are unlikely.

Specifically, there was a significantly increased proportion of IL-17-producing CD8+ T cells (Tc17) and natural killer T cells (NK T), accompanied by a greater diversity and expansion of unique clones within these subsets (Fig. 1f,h, Supplemental Fig. 2).

To compare functional differences across all T cells between hyposmic and normosmic individuals, we performed differential expression analysis and mapped the results to canonical biological pathways. T cells from COVID-hyposmics displayed a mixed inflammatory profile, characterized by significant upregulation of pro-inflammatory (IL-1, TLR1/2, and NF-κB signaling) as well as a T helper-2 (Th2) pathway (IL-4, IL-13) relative to normosmic subjects (Fig. 1g).

Together, these analyses suggest a complex, ongoing inflammatory T cell response in the OE of long COVID hyposmics, in the absence of active local virus activity.

 

[Utsikt]

The MCID for the SIT score was 4. The between group difference was 1.74 at 3 months.

Yet another trial where they use a responder threshold instead of comparing the groups directly.

I can’t see anything about if the blinding was successful either.