Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction

Perrin

et al. 2022

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IMPORTANCERecent 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 PARTICIPANTSThis 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 MEASURESThe 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 asses...

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19–Related Olfactory Dysfunction

Gupta

Perrin

et al. 2022

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“…Participants from the previous phase 2 RCT were recruited. 4 Institutional review board approval was obtained from Washington University in St Louis. Patients also provided verbal informed consent.…”

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confidence: 99%

“…Considering theophylline's pharmacokinetics and pharmacodynamics, 4 all patients started with twice-daily irrigations of 100 mg of theophylline for 7 days. Participants without severe adverse effects advanced to 200 mg of theophylline twice daily for the following 7 days.…”

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confidence: 99%

Safety of High-Dose Nasal Theophylline Irrigation in the Treatment of Postviral Olfactory Dysfunction: A Dose-Escalation Study

Gupta

Kallogjeri

et al. 2022

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Olfactory dysfunction (OD) is an increasingly prevalent and debilitating condition associated with acute and chronic SARS-CoV-2 infection. 1 Despite the rise in postviral OD (PVOD), to our knowledge, no universally effective treatments exist. 2 Theophylline is a potential, newer treatment for OD. 3 We recently completed a doubleblind, placebo-controlled randomized clinical trial (RCT) of patients who received 6 weeks of nasal theophylline irrigation (12 mg twice daily) vs placebo saline irrigation. 4 The study found no clinically meaningful differences in olfaction, but the theophylline was likely underdosed.

Development and Psychometric Validation of the Olfactory Dysfunction Outcomes Rating

Mahadev

Kallogjeri

et al. 2022

ImportanceOlfactory 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.ObjectiveTo develop and validate a concise and visually appealing smell loss–associated QOL patient-reported outcome measure for OD.Design, Setting, and ParticipantsA 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 MeasuresItem 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.ResultsThe 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 RelevanceIn 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.