Persistent COVID-19 parosmia and olfactory loss post olfactory training: randomized clinical trial comparing central and peripheral-acting therapeutics

Abstract

Purpose: Although COVID-19 anosmia is often transient, patients with persistent olfactory dysfunction (pOD) can experience refractory parosmia and diminished smell. This study evaluated four putative therapies for parosmia in patients with chronic COVID-19 olfactory impairment.

Methods: After screening nasal endoscopy, 85 patients (49 female, 58%) with pOD and treatment-refractory parosmia were randomized to: (1) ultramicronized palmitoylethanolamide and luteolin + olfactory training (OT) (umPEALUT group, n = 17), (2) alpha-lipoic acid + OT (ALA group, n = 21), (3) umPEALUT + ALA + OT (combination group, n = 28), or 4) olfactory training (OT) alone (control group, n = 23). Olfactory function was assessed at baseline (T₀) and 6 months (T₁) using a parosmia questionnaire and Sniffin' Sticks test of odor threshold, detection, and identification (TDI). Analyses included one-way ANOVA for numeric data and Chi-Square analyses for nominal data on parosmia.

Results: The umPEALUT group had the largest improvement in TDI scores (21.8 ± 9.4 to 29.7 ± 7.5) followed by the combination group (19.6 ± 6.29 to 27.5 ± 2.7), both p < 0.01. The control and ALA groups had no significant change. Patients in the combination and umPEALUT groups had significantly improved TDI scores compared to ALA and control groups (p < 0.001). Rates of parosmia resolution after 6 months were reported at 96% for combination, 65% for control, 53% for umPEALUT and 29% for ALA (p < 0.001). All treatment regimens were well-tolerated.

Conclusions: umPEALUT and OT, with or without ALA, was associated with improvement in TDI scores and parosmia, whereas OT alone or OT with ALA were associated with little benefit.

Keywords: Alpha lipoic acid; Anosmia; Coronavirus long-COVID; Palmitoylethanolamide; Parosmia.

Fig. 1

Figure plot shows the steps of the study, including patients’ allocation to the different groups at the enrollment and the final number after attrition, which included only those patients who completed three months of treatment and included in the data analyses

Fig. 2

Comparison of the TDI between the four analyzed groups before (T₀) and after 6 months of treatment (T₁). A statistically significant improvement (**p < 0.01) was observed in the patients treated with OT and umPEALUT

Fig. 3

Details about the TDI recovery among the 4 groups. The higher recovery (> 5 points) was observed in the patients who used umPEALUT. The combination of umPEALUT plus ALA resulted in lower TDI scores than umPEALUT without ALA in some patients

Fig. 4

Difference in the persistence of parosmia after 6 months in the four study groups. The best recovery was obtained with the combination of umPEALUT with ALA, followed by umPEALUT alone and ALA. Olfactory training alone (control group) did not result in improvement in parosmia