Abstract
This case series aims to determine the maximum tolerable dose of theophylline delivered via high-volume, low-pressure nasal saline irrigation for treatment of postviral olfactory dysfunction.
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 double-blind, 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.
Methods
We conducted a phase 1, open-label, dose-escalation trial of patients with non-COVID-19–related PVOD of 6 to 36 months’ duration to determine the maximum tolerable dose of theophylline delivered via high-volume, low-pressure nasal saline irrigation. 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.
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. Similar increases of 100 mg per dose were instituted in 7-day intervals as tolerated until a maximum daily dose of 800 mg for a 4-week total treatment course (Table 1). Daily theophylline nasal irrigation of 800 mg was expected to be well tolerated because it corresponds to a systemic dose of 20 mg, which is much lower than the starting oral dose of 300 mg. Participants were queried weekly about adverse effects.
Table 1. Equivalent Daily Oral Dosing Conversion per Total Daily Irrigation Dose.
| Theophylline total daily dose in irrigation | Theophylline actual drug exposure |
|---|---|
| 200 mg (initial dose, week 1) | 5 mg |
| 400 mg (week 2) | 10 mg |
| 600 mg (week 3) | 15 mg |
| 800 mg (maximum dose, week 4) | 20 mg |
| 12 000 mg (theoretical dose) | 300 mg (starting oral dose) |
Olfactory outcomes before and after 4 weeks included the (1) Clinical Global Impression-Improvement scale, which asks, “Overall, how would you rate your change in smell after your 4 weeks of irrigations?” with response options of much better, somewhat better, slightly better, neither better nor worse, slightly worse, somewhat worse, or much worse; (2) University of Pennsylvania Smell Identification Test (UPSIT), a 40-question odor identification test where normosmia is considered as a score of 34 or more points for males and 35 or more points for females, and a change in 4 or more points is deemed clinically meaningful; and (3) Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS), a validated 17-item questionnaire measuring smell-related quality of life where the maximum and worst score is 51.
Results
Of the 11 patients enrolled, the median (range) age was 61 (60-68) years, and 6 patients were female. 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 (Table 2). 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.
Table 2. Safety and Olfaction Outcomes.
| Patient No. | Baseline score | Week 1 outcomes | Week 2 outcomes | Week 3 outcomes | Week 4 outcomes | Clinical Global Impression-Improvement | Posttreatment score | ||
|---|---|---|---|---|---|---|---|---|---|
| UPSIT | QOD-NS | UPSIT | QOD-NS | ||||||
| 1 | 15 | 41 | None | None | None | None | Neither better nor worse | 16 | NA |
| 2 | 18 | 19 | Insomnia, sore throat | Insomnia, mild tremors | Insomnia, mild tremors, abdominal pain, rash | Withdrawn | NA | NA | NA |
| 3 | 10 | 26 | None | None | Light-headedness for 1 d | None | Neither better nor worse | 8 | 35 |
| 4 | 18 | 19 | None | None | None | None | Neither better nor worse | 17 | 19 |
| 5 | 18 | 14 | None | None | None | None | Neither better nor worse | 18 | 11 |
| 6 | 17 | 21 | None | None | None | None | Somewhat better | 16 | 19 |
| 7 | 28 | 36 | None | None | None | None | Much better | 28 | 20 |
| 8 | 15 | 19 | None (baseline arrhythmia from atrial fibrillation) | None (baseline arrhythmia from atrial fibrillation) | None (baseline arrhythmia from atrial fibrillation) | None (baseline arrhythmia from atrial fibrillation) | Neither better nor worse | 19 | 17 |
| 9 | 29 | 9 | None | None | None | None | Neither better nor worse | 33 | 9 |
| 10 | 10 | 21 | None | None | None | None | Slightly better | 10 | 16 |
| 11 | 31 | 27 | None | None | None | None | Slightly better | 26 | 21 |
Abbreviations: NA, not available; QOD-NS, Questionnaire of Olfactory Disorders-Negative Statements; UPSIT, University of Pennsylvania Smell Identification Test.
After treatment, 4 of 10 patients who completed their 4-week course reported some smell improvement while 6 patients reported unchanged smell (Table 2). Median (range) posttreatment UPSIT and QOD-NS scores were 18 (8-33) and 9 (19-35) points, respectively. Two patients had a clinically meaningful improvement in UPSIT score.
Discussion
In this open-label, dose-escalation case series, 10 of 11 patients achieved a dose of 400 mg of theophylline delivered via nasal saline irrigation twice daily. Nine patients reported no adverse effects while 1 patient reported sustained adverse effects. There were no severe adverse effects, including seizures and new-onset arrhythmia. Four patients reported smell improvement while 2 had a clinically meaningful improvement in UPSIT score.
As the prevalence of PVOD is rapidly increasing owing to COVID-19, discovering new effective treatments is paramount. While nasal theophylline irrigations dosed at 12 mg twice daily showed no meaningful olfactory improvements,4 we hypothesized that theophylline dosage could be safely and systematically elevated.5 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.6
References
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