Mixed results for nasal theophylline to treat COVID-related loss of smell

Woman smelling roses
Woman smelling roses

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Two new linked studies on the effectiveness and safe dosing of theophylline nasal irrigation to treat COVID-19–related altered sense of smell have generated inconclusive results.

The research, a phase 2 randomized, controlled clinical trial and a small, phase 1, open-label dose-escalation study, was published yesterday in JAMA Otolaryngology - Head & Neck Surgery.

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.

Inconclusive benefit suggested by subjective findings

Researchers from Washington University in St. Louis, Missouri, led the clinical trial involving 51 adult Missouri or Illinois residents with olfactory dysfunction persisting for 3 to 12 months after COVID-19 infection. The trial was conducted from Mar 15 to Aug 31, 2021.

Participants were mailed saline sinus-rinse kits and identical-appearing capsules containing either 400 milligrams (mg) of theophylline or a placebo consisting of 500 mg of lactose powder. They were told to dissolve the capsule contents in the saline rinse and irrigate their nasal cavities with it morning and night for 6 weeks. Average participant age was 46 years, and 71% were women.

Twenty-six participants were randomly assigned to receive saline nasal irrigation with theophylline, and 25 were assigned to saline nasal irrigation with placebo. Forty-five participants completed the study.

Thirteen theophylline recipients (59%) reported at least slightly better Clinical Global Impression-Improvement scores, compared with 10 (43%) in the placebo group (absolute difference, 15.6%; 95% confidence interval [CI], -13.2% to 44.5%). The median difference in University of Pennsylvania Smell Identification Test (UPSIT) score from baseline to 6 weeks was 3.0 (95% CI, -1.0 to 7.0) for theophylline recipients and 0.0 (95% CI, -2.0 to 6.0) for the placebo group.

The UPSIT is a 40-question odor-identification test in which a score of 34 points or more for males and 35 or more for females indicates a normal sense of smell, and a change of at least 4 points is considered clinically meaningful.

A mixed-model analysis, however, showed that the change in UPSIT scores was not significantly different between the two groups. Among the theophylline group, 11 (50%) had a change of at least four points in their UPSIT scores over the study period. The difference in the rate of response to treatment, as determined by UPSIT scores, was 24% (95% CI, -4% to 52%) in favor of theophylline.

"This randomized clinical trial suggests that the clinical benefit of theophylline nasal irrigations on olfaction in participants with COVID-19–related OD [olfactory dysfunction] is inconclusive, though suggested by subjective assessments," the authors wrote. "Larger studies are warranted to investigate the efficacy of this treatment more fully."

Higher doses safe, well tolerated

The theophylline dose-escalation study, led by the same team, was conducted after the randomized, controlled trial was inconclusive. "The study found no clinically meaningful differences in olfaction, but the theophylline was likely underdosed," they wrote.

The group studied 11 patients from the randomized, controlled trial with post-infection impaired olfaction unrelated to COVID-19 lasting 6 to 36 months to identify the maximum tolerable dose of theophylline given through high-volume, low-pressure nasal saline irrigation. Median participant age was 61 years, and six were female.

Participants began twice-daily irrigation regimens of 100 mg of theophylline for 7 days, with those experiencing no severe adverse effects going on to 200-mg twice-daily doses for the next 7 days. Doses were increased 100 mg in 7-day intervals as tolerated, up to a maximum of 800 mg daily over 1 month. Participants were asked about adverse effects each week.

The researchers noted their expectation that the maximum dose would be well tolerated because it corresponds to a systemic dose of 20 mg, much lower than the recommended starting oral dose of 300 mg.

Median baseline UPSIT and Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) scores were 18 (range, 10 to 31) and 21 (9 to 41) points, respectively. The QOD-NS is a 17-item questionnaire measuring olfaction-related quality of life, with a maximum (worst) score of 51.

Of the participants, nine reported no adverse effects, while one reported transient light-headedness for a day, and another withdrew 3 weeks into the study because of insomnia, tremors, abdominal pain, and rash, all of which resolved on study drug discontinuation. No serious adverse events were reported.

After 4 weeks of theophylline treatment, 4 of 10 participants reported somewhat improved smell, and 6 said their olfaction remained the same. Median posttreatment UPSIT and QOD-NS scores were 18 (range, 8 to 33) and 9 (19 to 35) points, respectively. Two participants saw clinically meaningful improvement in their UPSIT scores.

The researchers said that postviral olfactory impairment is becoming more prevalent, underscoring the need for new effective therapies.

"While nasal theophylline irrigations dosed at 12 mg twice daily showed no meaningful olfactory improvements, we hypothesized that theophylline dosage could be safely and systematically elevated," they wrote. "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."

The challenge of olfactory dysfunction research

In a commentary on the two trials, Lauren Roland, MD, of Washington University, and Joshua Levy, MD, MPH, of Emory University, said that research on olfactory dysfunction is challenging, especially amid the ongoing pandemic.

"COVID-19 variants differ in adverse effect profiles on smell and taste distortion, and patients have variable immunization status records and COVID-19 reinfection rates," they wrote. "Patients may have trialed various treatments prior to presenting for study enrollment."

Ultimately, they said, patient quality of life is most important. "While objective measures are beneficial for research purposes and documentation, subjective measures are most useful for characterizing the patient experience," Roland and Levy wrote. "We believe that the future of OD research is a balance of pragmatic study design and a focus on endotyping or stratification of OD." An endotype is a subtype of an illness defined by a discrete pathophysiological mechanism.

"If the COVID-19 pandemic has taught us anything," they continued, "it is that things are always in flux. As we experience new variations and new knowledge, we must remember that patients are unique and are changing as well."

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