Two studies in this issue of JAMA Otolaryngology–Head & Neck Surgery evaluate the use of nasal theophylline, a phosphodiesterase inhibitor that may promote neural olfactory signaling and recovery for postviral olfactory dysfunction (OD). The first, a dose-modification Research Letter by Lee et al was conducted in patients with non-COVID-19–related hyposmia or anosmia secondary to viral infection and confirmed by the objective University of Pennsylvania Smell Identification Test. This open-label, dose-escalation trial provides an educ ational description of how to evaluate the appropriate dose for an emerging pharmacologic intervention. Specifically, the authors identified 400 mg of theophylline twice daily as a tolerated dosage. This was calculated as an equivalent oral dose of 20 mg. A phase 2 pilot study by Gupta et al was designed using this valuable information. Patients with suspected COVID-19–related OD completed the University of Pennsylvania Smell Identification Test and were randomized to either theophylline or placebo nasal irrigations for 6 weeks. This study was inconclusive regarding the clinical benefit of theophylline nasal irrigations, although there was suggested improvement by subjective assessments. The authors acknowledge several limitations, including small sample size, the virtual nature of the study design and subsequent inability to conduct endoscopic nasal examinations, lack of information regarding participant COVID-19 vaccination status, lack of polymerase chain reaction–confirmed C OVID-19 infection, and short-term participant follow-up. These acknowledgments are justified, and many can be overcome in subsequent studies with adequate funding and time. However, the heterogeneous nature of COVID-19 and associated research make this area of work particularly challenging. Herein, we propose several approaches to improve the rigor of OD research in the COVID-19 era.
