Nasal theophylline, an apt treatment for COVID-related loss of smell? Studies yield mixed results
USA: Two linked studies investigating the effectiveness and safe dosing of theophylline nasal irrigation for the treatment of COVID-19–related altered sense of smell have yielded inconclusive results. The findings from the small, phase 1, open-label dose-escalation study and a phase 2 randomized, controlled clinical trial were published in JAMA Otolaryngology-Head & Neck Surgery.
Theophylline is used for the prevention and treatment of wheezing, shortness of breath, and chest discomfort caused by asthma, emphysema, chronic bronchitis, and other conditions, and may also promote olfactory signaling. It does so by relaxing and opening respiratory passages in the lungs.
Theophylline relaxes and opens respiratory passages in the lungs and is used to prevent and treat shortness of breath, wheezing, and chest discomfort caused by asthma, emphysema, chronic bronchitis, and other conditions. It may also promote neural olfactory signaling.
Dose-Escalation Study
Jake J. Lee, Washington University School of Medicine in St Louis, St Louis, Missouri, and colleagues conducted a phase 1, open-label, dose-escalation trial of patients with non-COVID-19–related postviral olfactory dysfunction (PVOD) of 6 to 36 months' duration to determine the maximum tolerable dose of theophylline delivered via high-volume, low-pressure nasal saline irrigation.
Of the 11 patients enrolled, the median age was 61 years, and 6 patients were female.
Following were the findings from the study:
- All patients reported hyposmia/anosmia, which was confirmed via UPSIT score.
- Baseline median (range) UPSIT and QOD-NS scores were 18 (10-31) and 21 (9-41) points, respectively.
- Nine of 11 patients reported no adverse effects throughout treatment.
- One patient reported transient light-headedness for a day while another withdrew after 3 weeks owing to insomnia, tremors, abdominal pain, and rash, which resolved on discontinuation.
- After treatment, 4 of 10 patients who completed their 4-week course reported some smell improvement while 6 patients reported unchanged smell.
- Median posttreatment UPSIT and QOD-NS scores were 18 and 9 points, respectively.
- Two patients had a clinically meaningful improvement in UPSIT score.
The authors concluded their study by saying, "We hypothesized that theophylline dosage could be safely and systematically elevated. While the low sample size and lack of controls limit comprehensive assessment of olfactory outcomes, this study did inform a phase 2 RCT of nasal theophylline irrigation delivered at these higher doses."
SCENT2 Phase 2 Randomized Clinical Trial
Shruti Gupta, Medical College of Georgia, Augusta University, Augusta, and colleagues conducted the triple-blinded, placebo-controlled, phase 2 randomized clinical trial to evaluate the efficacy and safety of theophylline added to SNI compared with placebo for COVID-19–related olfactory dysfunction.
The trial was conducted virtually between March 15 and August 31, 2021. The researchers recruited adults residing in Missouri or Illinois 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.
A total of 51 participants were enrolled in the study; the mean age was 46.0 years, and 71% of participants were women. Participants were randomized to saline nasal irrigation (SNI) with theophylline (n = 26) or to SNI with placebo (n = 25). Forty-five participants completed the study.
The findings of the study were as follows:
- At the end of treatment, 59% of participants in the theophylline arm reported at least slight improvement in the Clinical Global Impression-Improvement scale (responders) compared with 43% in the placebo arm.
- The median difference for the UPSIT change between baseline and 6 weeks was 3.0 for participants in the theophylline arm and 0.0 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.
- 50% of participants in the theophylline arm and 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% in favor of theophylline.
This led researchers to conclude, "Trial findings suggest 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."
Reference:
1) Lee JJ, Gupta S, Kallogjeri D, Piccirillo JF. Safety of High-Dose Nasal Theophylline Irrigation in the Treatment of Postviral Olfactory Dysfunction: a Dose-Escalation Study. JAMA Otolaryngol Head Neck Surg. Published online July 07, 2022. doi:10.1001/jamaoto.2022.1574
2) Gupta S, Lee JJ, Perrin A, et al. Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19–Related Olfactory Dysfunction: The SCENT2 Phase 2 Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. Published online July 07, 2022. doi:10.1001/jamaoto.2022.1573
