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Theophylline added to saline nasal irrigation showed a hint of promise in treating postviral olfactory dysfunction related to COVID-19, data from the phase II suggested.

In a study of 51 people with persistent olfactory dysfunction after SARS-CoV-2 infection, 13 participants (59%) in the theophylline group reported at least slight improvement in the Clinical Global Impression-Improvement scale, compared with 10 people (43%) in the placebo group (absolute difference 15.6%, 95% CI -13.2% to 44.5%), reported Jay Piccirillo, MD, of Washington University School of Medicine in St. Louis, and co-authors.

Eleven (50%) participants in the theophylline group and 6 (26%) in the placebo cohort had a clinically meaningful change in objective smell identification test score, the researchers reported in .

"We conclude that the use of theophylline added to saline nasal irrigation may result in clinically beneficial improvements in smell function compared to saline irrigation alone," Piccirillo told MedPage Today.

"Unfortunately, due to the small sample size, our estimates of the effect of theophylline are not precise and therefore we cannot definitely conclude that theophylline is beneficial," he added. "Nevertheless, our results suggest benefit and can be used to inform the design of future larger trials."

Olfactory dysfunction has been reported by more than half of people with COVID-19. Acute olfactory dysfunction is more prevalent in mild forms of COVID-19 than moderate-to-critical disease. Most people recover their sense of smell within 6 months, but about 5% do not.

"There is no consensus on the mechanisms of postviral anosmia, parosmia, and phantosmia; however, angiotensin-converting enzyme 2 receptors, which act as a key site of viral entry, are expressed throughout the nervous system and may explain the SARS-CoV-2 neurological manifestations," Piccirillo and co-authors observed.

Theophylline, a phosphodiesterase inhibitor, has been shown to in earlier studies of people with hyposmia. A single-arm established the safety of increased theophylline dosing by saline nasal irrigation in people with postviral olfactory dysfunction not related to COVID-19.

Olfactory dysfunction research is challenging, especially during the COVID-19 pandemic, noted Lauren Roland, MD, MSCI, of Washington University in St. Louis, and Joshua Levy, MD, MPH, MSc, of Emory University in Atlanta, in an .

"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," Roland and Levy pointed out. "Patients may have trialed various treatments prior to presenting for study enrollment."

"Ultimately, patient quality of life is the most important outcome," they wrote. "While objective measures are beneficial for research purposes and documentation, subjective measures are most useful for characterizing the patient experience."

The SCENT2 trial was conducted virtually from March 15 through Aug. 31, 2021. Researchers recruited people residing in Missouri or Illinois who had olfactory dysfunction that persisted for 3 to 12 months after suspected COVID-19 infection.

Baseline olfactory dysfunction was defined as a score of 33 or lower for men and 34 or lower for women on the University of Pennsylvania Smell Identification Test (). Mean age of participants was 46, and 71% were women.

Participants received saline sinus rinse kits and bottles of capsules with either 400 mg of theophylline (treatment) or 500 mg of lactose powder (control) by mail. They were asked to dissolve the capsule contents into the saline rinse and use the solution to irrigate their nasal cavities morning and night for 6 weeks. Overall, 26 people were randomized to theophylline treatment and 25 to placebo.

From baseline to 6 weeks, the median difference for the UPSIT change was 3.0 (95% CI -1.0 to 7.0) for the theophylline group and 0.0 (95% CI -2.0 to 6.0) for placebo. Eleven participants in the theophylline arm and six in the placebo arm had a change of 4 or more points in UPSIT scores from baseline to 6 weeks.

"Mixed-model analysis revealed that the change in UPSIT scores through study assessments was not statistically significantly different between the two study arms," Piccirillo and co-authors noted.

Adverse effects were similar at week 6 for both groups. At week 3, two people in the theophylline group reported insomnia and three people in the placebo group reported tachycardia. There were no severe adverse effects.

The study had several limitations. It was conducted virtually, which meant researchers could not examine nasal cavities and had to rely on participant accounts about whether nasal polyps, septal deviation, or other abnormalities that could contribute to anosmia were present. Vaccination status of participants was unknown. In addition, the 6-week intervention may not have been long enough to observe neural recovery.

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