Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19-Related Olfactory Dysfunction: The SCENT2 Phase 2 Randomized Clinical Trial.

Importance: Recent studies suggest that theophylline added to saline nasal irrigation (SNI) can be an effective treatment for postviral olfactory dysfunction (OD), a growing public health concern during the COVID-19 pandemic. Objective: To evaluate the efficacy and safety of theophylline added to SNI compared with placebo for COVID-19-related OD. Design, Setting, and Participants: This triple-blinded, placebo-controlled, phase 2 randomized clinical trial was conducted virtually between March 15 and August 31, 2021. Adults residing in Missouri or Illinois were recruited during this time period if they had OD persisting for 3 to 12 months following suspected COVID-19 infection. Data analysis was conducted from October to December 2021. Interventions: Saline sinus rinse kits and bottles of identical-appearing capsules with either 400 mg of theophylline (treatment) or 500 mg of lactose powder (control) were mailed to consenting study participants. Participants were instructed to dissolve the capsule contents into the saline rinse and use the solution to irrigate their nasal cavities in the morning and at night for 6 weeks. Main Outcomes and Measures: The primary outcome was the difference in the rate of responders between the treatment and the control arms, defined as a response of at least slightly better improvement in the Clinical Global Impression-Improvement scale posttreatment. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT), the Questionnaire for Olfactory Disorders, the 36-Item Short Form Health Survey on general health, and COVID-19-related questions. Results: A total of 51 participants were enrolled in the study; the mean (SD) age was 46.0 (13.1) years, and 36 (71%) participants were women. Participants were randomized to SNI with theophylline (n = 26) or to SNI with placebo (n = 25). Forty-five participants completed the study. At the end of treatment, 13 (59%) participants in the theophylline arm reported at least slight improvement in the Clinical Global Impression-Improvement scale (responders) compared with 10 (43%) in the placebo arm (absolute difference, 15.6%; 95% CI, -13.2% to 44.5%). The median difference for the UPSIT change between baseline and 6 weeks was 3.0 (95% CI, -1.0 to 7.0) for participants in the theophylline arm and 0.0 (95% CI, -2.0 to 6.0) for participants in the placebo arm. Mixed-model analysis revealed that the change in UPSIT scores through study assessments was not statistically significantly different between the 2 study arms. Eleven (50%) participants in the theophylline arm and 6 (26%) in the placebo arm had a change of 4 or more points in UPSIT scores from baseline to 6 weeks. The difference in the rate of responders as measured by the UPSIT was 24% (95% CI, -4% to 52%) in favor of theophylline. Conclusions and Relevance: This randomized clinical trial suggests that the clinical benefit of theophylline nasal irrigations on olfaction in participants with COVID-19-related OD is inconclusive, though suggested by subjective assessments. Larger studies are warranted to investigate the efficacy of this treatment more fully. Trial Registration: ClinicalTrials.gov Identifier: NCT04789499.

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.