Study Highlights

• This randomized, single-blinded trial with 2-by-2 factorial design (bimodal, patient preferred; unimodal, physician assigned; bimodal, physician assigned; unimodal, patient preferred) included an independent control group.
• From February 1 to May 27, 2021, 275 participants aged 18 to 71 years (mean, 41±12 years; 86% female) were enrolled.
• Olfactory loss criteria were University of Pennsylvania Smell Identification Test score lower than 34 for men and lower than 35 for women, duration at least 3 months (mean, 6±+3 months), and initially diagnosed within 2 weeks of COVID-19 infection.
• 68% of participants reported concurrent symptoms of phantosmia or parosmia.
• Participants sniffed 4 essential oils for 15 seconds, separated by a 30-second rest, for 3 months.
• Participants in the physician-assigned odor groups trained with rose, lemon, eucalyptus, and clove; those in the patient-preferred groups chose 4 of 24 available scents; and those in the bimodal group viewed digital images of the essential oil they were smelling.
• The primary end point of change in objective University of Pennsylvania Smell Identification Test scores preintervention to postintervention was similar among the study groups.
• Marginal mean difference for change in University of Pennsylvania Smell Identification Test scores preintervention to postintervention between participants randomly assigned to patient-preferred vs physician-assigned scents was 0.73, and between participants randomly assigned to bimodal visual-olfactory training vs unimodal olfactory training it was 1.10, both of which were insignificant differences.
• Five (24%) participants in the control group had clinically important improvement on the University of Pennsylvania Smell Identification Test, as did 18 (53%) in the bimodal, patient-preferred group (difference, 29%; 95% CI, 4%-54%).
• Self-reported improvement on Clinical Global Impressions-Improvement occurred in 4 control participants (19%) compared with 12 (35%) in the bimodal, patient-preferred group (difference, 16%; 95% CI, −7% to 39%).
• Mean change in the quality-of-life questionnaire Olfactory Dysfunction Outcomes Rating (ODOR) score preintervention to postintervention was 11.6 points (85% CI, 9.2-13.9), which was not considered clinically important nor significantly different between groups.
• Reported adverse effects during the intervention included 2 (0.8%) reports of headaches and 1 (0.4%) report of worsening parosmia associated with olfactory training.
• The investigators concluded that there was improvement over time in olfactory function in the control and intervention groups, with no clinically meaningful improvement in University of Pennsylvania Smell Identification Test score among individuals given olfactory training and no added benefit from bimodal visual-olfactory training or patient-preferred scents.
• However, when exploring within-patient change in University of Pennsylvania Smell Identification Test and self-reported impression of improvement, active interventions were associated with larger improvement than controls, with a potential advantage of bimodal intervention.
• The finding of possible benefit of olfactory training is consistent with the published literature.
• Although the findings are not definitive, they suggest that patients with COVID-19 olfactory loss may benefit from adding a visual component to olfactory training and using patient-preferred scents.
• Although natural improvement does occur, the low-cost, noninvasive nature and minimal risk for olfactory training suggests that clinicians should recommend this treatment to patients with postviral olfactory dysfunction, as it may provide incremental benefit.
• Future studies should focus on identifying subgroups for whom olfactory training is likely to benefit, alone or in combination with other potential treatments.
• Multiple studies suggest that the olfactory pathway has neuroplasticity for peripheral and central recovery.
• The optimal olfactory training delivery method is unknown, with previous studies assessing total duration of intervention from 3 to 14 months, varying odor concentrations, and supplementing training with adjuvant pharmacotherapy.
• Dual-sensory stimulation training may enhance auditory adaption and various other sensory and cognitive processes.
• Study limitations include study cohort comprising mostly White patients, with a large proportion reporting concurrent dysosmia, and significant attrition across all study groups, resulting in a smaller sample with complete data.
• In addition, the intervention was limited to 3 months, but some data suggest that patients may derive benefit for up to 6 months, and the control group could not be blinded because of the difficulty of administering placebo olfactory training.
• An accompanying commentary suggests that the improvements in some patients with belief and satisfaction in their therapeutic plan may have been a placebo effect, which should be considered for treatment plans for patients with postviral olfactory dysfunction from COVID-19.
• Allowing patients to select their own odorants may improve cost-effectiveness and increase adherence, and adding visual cues to olfactory training may improve engagement in some patients while increasing the burden on others.