1. Participants with post-viral olfactory dysfunction (PVOD) who underwent olfactory training (OT) did not have a clinically meaningful improvement when compared to participants who did not undergo OT.
2. There was no clinically meaningful difference between participants who underwent unimodal versus bimodal OT, and there was no clinically meaningful difference between participants who used patient-preferred versus physician-assigned scents for OT.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Post-viral olfactory dysfunction (PVOD) is the most common cause of chronic olfactory loss (OL), and is associated with negative outcomes. Evidence surrounding current pharmacological interventions is weak, with very few controlled studies accounting for spontaneous recovery over time. A proposed beneficial treatment is olfactory training; however, the most beneficial delivery of olfactory training is unknown, and it has not yet been shown to be effective in COVID-related OL. Previous research has shown a connection between olfaction and vision, and multisensory integration may potentiate olfactory neuroplasticity. This randomized controlled trial aimed to determine the efficacy of bimodal versus unimodal training, and the effect of patient-preferred versus physician-assigned scents for COVID-19-related PVOD. This randomized trial had a 2-by-2 factorial design with an independent control group to compare with each intervention arm. Enrollment took place from February 1 to May 27, 2021, and patients were randomly assigned to 1 of 4 intervention arms: bimodal training with patient-preferred scents, bimodal training with physician-assigned scents, unimodal training with patient-preferred scents, and unimodal training with physician-assigned scents. Patients sniffed the scents twice a day for three months total, and in the bimodal training, patients were shown digital images of what they were smelling. The primary endpoint was a clinically meaningful improvement in the University of Pennsylvania Smell Identification Test (UPSIT), defined by a change in score by ≥4 points. Other scales used include the Clinical Global Impressions (CGI) score to measure both the severity of dysfunction (CGI-S) and the perceived degree of improvement (CGI-I). In addition, the ODOR scale was used; it is a patient-reported outcome measure assessing smell loss-related quality of life for OL. Overall, the change in UPSIT scores from preintervention to postintervention was similar between groups, with no significant differences between intervention groups. Compared to the control, all intervention groups had a higher proportion of responders than the control group, but these differences were not statistically significant. Based on the Clinical Global Impressions (CGI) scales, 60 (35%) participants reported a clinically meaningful improvement in their smell, and only 9 (5%) participants only reported slightly worse or much worse smell in the intervention group, compared to 4 (19%) of the controls who reported a clinically meaningful change in CGI-I (Clinical Global Impressions – Improvement). Overall, this randomized controlled trial found that olfactory function improved over time in both intervention and control groups, with no clinically meaningful difference observed in the mean change in the UPSIT score between the intervention arms and when they were compared to the control group. However, even though the difference was not clinically meaningful, the highest proportion of participants experiencing improvement was in the bimodal arms. A major limitation of this study is that the cohort consisted of primarily white women, which would have poor generalizability to the general population. This trial suggests that patients with COVID-19-related OL may benefit from OT, possibly with a bimodal approach. This is an important step for future research that would further study the possible benefit of OT with other potential treatments.
Relevant Reading: Olfactory Dysfunction in COVID-19
In-Depth [randomized controlled trial]: This randomized controlled trial studied the effect of unimodal versus bimodal OT, as well as patient-preferred versus physician-chosen scents used in OT. Participants were enrolled from February 1 to May 27, 2021, and were enrolled in 1 of 4 intervention arms: bimodal training with patient-preferred scents, bimodal training with physician-assigned scents, unimodal training with patient-preferred scents, and unimodal training with physician-assigned scents. Included were patients from 18 to 71 years old with current OL as defined by UPSIT <34 for men, and <35 for women. Excluded were patients with OL due to head trauma, chronic rhinosinusitis, congenital disease, nasal polyps, and neurological disorders. 275 participants were enrolled, and concerning baseline characteristics, the mean (SD) age was 41 (12) years old, and 236 (85%) of the patients were female. The mean (SD) duration of OL at the time of enrollment was 6 (3) months, with 187 (68%) of patients reporting concurrent phantosmia or parosmia. Between study groups, the change in UPSIT scores from preintervention to postintervention was similar. Between participants randomized to patient-preferred and physician-assigned olfactory training, there was no meaningful difference (marginal mean difference, 0.73; 95% CI, -1.10 to 2.56), and there was no meaningful difference between participants randomized to unimodal versus bimodal training (marginal mean difference, 1.10; 95% CI, -2.92 to 0.74). Between the intervention and control groups, there was no significant difference in the change in the UPSIT score. Interestingly, the intervention groups had a higher proportion of responders (defined as a 4-point change or greater on the UPSIT) than the control group, with the strongest evidence for bimodal patient-preferred training, though these differences were not statistically significant. Overall, the findings in this study do not suggest a clinically meaningful difference between olfactory training versus watchful waiting, and also do not suggest a clinically meaningful difference between unimodal and bimodal training, as well as patient-preferred and physician-assigned scents.
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