Natural trajectory of recovery of COVID-19 associated olfactory loss.

IMPORTANCE: Prevalence of post-viral olfactory loss has increased dramatically due to the frequency and severity of olfactory dysfunction associated with infection by the SARS-CoV-2 virus. OBJECTIVE: To determine the trajectory of COVID-19 olfactory loss over a six-month period. A key secondary objective is to assess predictive factors associated with the recovery of olfaction. DESIGN: Longitudinal repeated-measures study that enrolled from May 5, 2020 to February 2, 2021, with the last date of data collection on June 15, 2021. SETTING: Barnes-Jewish HealthCare/Washington University School of Medicine facilities (Saint Louis, Missouri, USA). PARTICIPANTS: Individuals who tested positive for SARS-CoV-2 by real-time polymerase chain reaction on nasopharyngeal swab and indicated olfactory loss on COVID-19 screening questionnaire. Individuals were excluded if they had previously diagnosed history of olfactory loss, neurodegenerative disorders, <18 years of age, admitted to hospital service, unable to read, write, and understand English, or lacked computer or internet access. INTERVENTIONS/EXPOSURES: Watch and wait for spontaneous recovery. MAIN OUTCOME(S) AND MEASURE(S): Participants completed olfactory assessments every 30 days for six months. Each assessment consisted of the University of Pennsylvania Smell Identification Test (UPSIT), an objective "scratch-and-sniff" test, and Clinical Global Impressions (CGI), a subjective Likert rating scale. RESULTS: The mean age was 41 years old (SD = 16). 39 (80 %) were female and 42 (86 %) white. At baseline assessment of objective olfaction, 18 (36 %) participants had anosmia or severe hyposmia. Subjective, complete recovery at six months was 81 % (95 % CI 74 % to 88 %). Likelihood of recovery was associated with age <50 years (aHR = 8.1 (95 % CI 1.1 to 64.1)) and mild olfactory loss at baseline (UPSIT = 30-33 for males and 31-34 for females) (aHR 6.2 (95 % CI 1.2 to 33.0)). CONCLUSIONS AND RELEVANCE: The trajectory of olfactory recovery among adults with COVID-19 olfactory loss illustrated rapid recovery within 2-3 weeks of infection, and by six months 81 % had recovered based on self-report. Age <50 years old and mild severity of olfactory loss at baseline were associated with increased likelihood of recovery of olfaction. These findings can be used to inform shared decision-making with patients.

Efficacy of Combined Visual-Olfactory Training With Patient-Preferred Scents as Treatment for Patients With COVID-19 Resultant Olfactory Loss: A Randomized Clinical Trial.

Importance: The number of olfactory dysfunction cases has increased dramatically because of the COVID-19 pandemic. Identifying therapies that aid and accelerate recovery is essential. Objective: To determine the efficacy of bimodal visual-olfactory training and patient-preferred scents vs unimodal olfactory training and physician-assigned scents in COVID-19 olfactory loss. Design, Setting, and Participants: This was a randomized, single-blinded trial with a 2-by-2 factorial design (bimodal, patient preferred; unimodal, physician assigned; bimodal, physician assigned; unimodal, patient preferred) and an independent control group. Enrollment occurred from February 1 to May 27, 2021. Participants were adults 18 to 71 years old with current olfactory loss defined as University of Pennsylvania Smell Identification Test (UPSIT) score less than 34 for men and less than 35 for women and duration of 3 months or longer. Olfactory loss was initially diagnosed within 2 weeks of COVID-19 infection. Interventions: Participants sniffed 4 essential oils for 15 seconds with a 30-second rest in between odors for 3 months. Participants in the physician-assigned odor arms trained with rose, lemon, eucalyptus, and clove. Participants randomized to the patient-preferred arms chose 4 of 24 available scents. If assigned to the bimodal arm, participants were shown digital images of the essential oil they were smelling. Main Outcomes and Measures: The primary end point was postintervention change in UPSIT score from baseline; measures used were the UPSIT (validated, objective psychometric test of olfaction), Clinical Global Impressions Impression-Improvement (CGI-I; self-report improvement scale), and Olfactory Dysfunction Outcomes Rating (ODOR; olfaction-related quality-of-life questionnaire). Results: Among the 275 enrolled participants, the mean (SD) age was 41 (12) years, and 236 (86%) were female. The change in UPSIT scores preintervention to postintervention was similar between the study arms. The marginal mean difference for change in UPSIT scores preintervention to postintervention between participants randomized to patient-preferred vs physician-assigned olfactory training was 0.73 (95% CI, -1.10 to 2.56), and between participants randomized to bimodal vs unimodal olfactory training was 1.10 (95% CI, -2.92 to 0.74). Five (24%) participants in the control arm had clinically important improvement on UPSIT compared with 18 (53%) in the bimodal, patient-preferred arm for a difference of 29% (95% CI, 4%-54%). Four (19%) participants in the control group self-reported improvement on CGI-I compared with 12 (35%) in the bimodal, patient-preferred arm for a difference of 16% (95% CI, -7% to 39%). The mean change in ODOR score preintervention to postintervention was 11.6 points (95% CI, 9.2-13.9), which was not deemed clinically important nor significantly different between arms. Conclusions and Relevance: Based on the change in UPSIT scores, this randomized clinical trial did not show any difference between intervention arms, but when exploring within-patient change in UPSIT as well as self-reported impression of improvement, active interventions were associated with larger improvement than controls with a potential advantage of bimodal intervention. While not definitive, these results suggest that patients with COVID-19 olfactory loss may benefit from bimodal visual-olfactory training with patient-preferred scents. Trial Registration: ClinicalTrials.gov Identifier: NCT04710394.

Development and Psychometric Validation of the Olfactory Dysfunction Outcomes Rating.

Importance: Olfactory dysfunction (OD) is an increasingly common and morbid condition, especially given the ongoing COVID-19 pandemic. Thus, the ability to reproducibly measure smell loss-associated quality of life (QOL) and its response to treatment is paramount. Objective: To develop and validate a concise and visually appealing smell loss-associated QOL patient-reported outcome measure for OD. Design, Setting, and Participants: A secondary analysis of comments to an online survey by 1000 patients with olfactory dysfunction published in 2013 was used as the primary source to generate items of the Olfactory Dysfunction Outcomes Rating (ODOR). In addition, 30 patients with OD enrolled in 2 clinical studies at a tertiary care medical center (Washington University) were asked to identify their main concerns associated with smell loss. And finally, 4 otolaryngologists reviewed the items generated from the online survey and the patients' interviews to identify any additional items. Prospective study design was used for data collection from the 30 patients and 4 otolaryngologists. Prospective study design was used for survey validation. Validation of the ODOR was performed with 283 patients enrolled in several prospective studies at a single institution that completed the ODOR as an outcome measure. Main Outcomes and Measures: Item generation and selection were the outcomes of ODOR development. The psychometric and clinimetric measures evaluated for validation were internal consistency, test-retest reliability, face and content validity, concurrent validity, and discriminant validity. Minimal clinically important difference was also determined. Results: The ODOR is a 28-item instrument with each item scored as either no difficulty or very rarely bothered (0) to complete difficulty or very frequently bothered (4) with a total instrument score range of 0 to 112 points. Higher scores indicate higher degree of dysfunction and limitation. Validation in the cohort of 283 patients (mean [SD] age, 47.0 [14.4] years; 198 female participants [73%]; 179 White participants [80%]) revealed that the instrument has high internal consistency (Cronbach α = 0.968), test-retest reliability (r = 0.90 [95% CI, 0.81-0.95]), face validity, content validity, concurrent validity (r = 0.87 [95% CI, 0.80-0.91] compared with the Questionnaire of Olfactory Disorders-Negative Statements; ρ = -0.76 [95% CI, -0.81 to -0.71] compared with a patient-reported symptom severity scale), and divergent validity (mean score difference, -33.9 [95% CI, -38.3 to -29.6] between normosmic patients and hyposmic/anosmic patients). The minimal clinically important difference was 15 points. The estimated time for survey completion was approximately 5 minutes. Conclusions and Relevance: In this survey creation and validation study, the ODOR was shown to be a novel, concise, reliable, and valid patient-reported outcome measure of OD-associated QOL. It can be used to measure physical problems, functional limitations, and emotional consequences associated with OD and how they change after a given intervention, which is clinically applicable and particularly pertinent given the growing burden of OD associated with COVID-19.

Development and Validation of a Novel At-home Smell Assessment.

IMPORTANCE: Current tools for diagnosis of olfactory dysfunction (OD) are costly, time-consuming, and often require clinician administration. OBJECTIVE: To develop and validate a simple screening assessment for OD using common household items. DESIGN, SETTING, AND PARTICIPANTS: This fully virtual diagnostic study included adults with self-reported OD from any cause throughout the US. Data were collected from December 2020 to April 2021 and analyzed from May 2021 to July 2021. MAIN OUTCOMES AND MEASURES: Participants with self-reported olfactory dysfunction took a survey assessing smell perception of 45 household items and completed the Clinical Global Impression-Severity (CGI-S) smell questionnaire, the University of Pennsylvania Smell Identification Test (UPSIT), and the 36-item Short Form Survey (SF-36). Psychometric and clinimetric analyses were used to consolidate 45 household items into 2 short Novel Anosmia Screening at Leisure (NASAL) assessments, NASAL-7 (range, 0-14; lower score indicating greater anosmia) and NASAL-3 (range, 0-6; lower score indicating greater anosmia). RESULTS: A total of 115 participants were included in the study, with a median (range) age of 42 (19-70) years, 92 (80%) women, and 97 (84%) White individuals. There was a moderate correlation between the UPSIT and NASAL-7 scores and NASAL-3 scores (NASAL-7: ρ = 0.484; NASAL-3: ρ = 0.404). Both NASAL-7 and NASAL-3 had moderate accuracy in identifying participants with anosmia as defined by UPSIT (NASAL-7 area under the receiver operating curve [AUC], 0.706; 95% CI, 0.551-0.862; NASAL-3 AUC, 0.658; 95% CI, 0.503-0.814). Scoring 7 or less on the NASAL-7 had 70% (95% CI, 48%-86%) sensitivity and 53% (95% CI, 43%-63%) specificity in discriminating participants with anosmia from participants without. Scoring 2 or less on the NASAL-3 had 57% (95% CI, 36%-76%) sensitivity and 78% (95% CI, 69%-85%) specificity in discriminating participants with anosmia from participants without. There was moderate agreement between UPSIT-defined OD categories and those defined by NASAL-7 (weighted κ = 0.496; 95% CI, 0.343-0.649) and those defined by NASAL-3 (weighted κ = 0.365; 95% CI, 0.187-0.543). The agreement with self-reported severity of olfactory dysfunction as measured by CGI-S and the NASAL-7 and NASAL-3 was moderate, with a weighted κ of 0.590 (95% CI, 0.474-0.707) for the NASAL-7 and 0.597 (95% CI, 0.481-0.712) for the NASAL-3. CONCLUSION AND RELEVANCE: The findings of this diagnostic study suggest that NASAL-7 and NASAL-3, inexpensive and brief patient-reported assessments, can be used to identify individuals with OD. As the burden of COVID-19-associated OD increases, these assessments may prove beneficial as screening and diagnostic tools. Future work will explore whether the NASAL assessments are sensitive to change and how much of a change is clinically important.