Blended outcomes for nasal theophylline to deal with COVID-related lack of odor

Two new linked research on the effectiveness and protected dosing of theophylline nasal irrigation to deal with COVID-19–associated altered sense of odor have generated inconclusive outcomes.

The analysis, a part 2 randomized, managed medical trial and a small, part 1, open-label dose-escalation research, was revealed yesterday in JAMA Otolaryngology – Head & Neck Surgical procedure.

Theophylline relaxes and opens respiratory passages within the lungs and is used to stop and deal with shortness of breath, wheezing, and chest discomfort brought on by bronchial asthma, emphysema, persistent bronchitis, and different situations. It could additionally promote neural olfactory signaling.

Inconclusive profit steered by subjective findings

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

Contributors had been mailed saline sinus-rinse kits and identical-appearing capsules containing both 400 milligrams (mg) of theophylline or a placebo consisting of 500 mg of lactose powder. They had been advised to dissolve the capsule contents within the saline rinse and irrigate their nasal cavities with it morning and evening for six weeks. Common participant age was 46 years, and 71% had been girls.

Twenty-six contributors had been randomly assigned to obtain saline nasal irrigation with theophylline, and 25 had been assigned to saline nasal irrigation with placebo. Forty-five contributors accomplished the research.

13 theophylline recipients (59%) reported a minimum of barely higher Medical World Impression-Enchancment scores, in contrast with 10 (43%) within the placebo group (absolute distinction, 15.6%; 95% confidence interval [CI], -13.2% to 44.5%). The median distinction in College of Pennsylvania Odor Identification Take a look at (UPSIT) rating from baseline to six weeks was 3.0 (95% CI, -1.0 to 7.0) for theophylline recipients and 0.0 (95% CI, -2.0 to six.0) for the placebo group.

The UPSIT is a 40-question odor-identification take a look at wherein a rating of 34 factors or extra for males and 35 or extra for females signifies a traditional sense of odor, and a change of a minimum of 4 factors is taken into account clinically significant.

A mixed-model evaluation, nonetheless, confirmed that the change in UPSIT scores was not considerably completely different between the 2 teams. Among the many theophylline group, 11 (50%) had a change of a minimum of 4 factors of their UPSIT scores over the research interval. The distinction within the fee of response to therapy, as decided by UPSIT scores, was 24% (95% CI, -4% to 52%) in favor of theophylline.

“This randomized medical trial means that the medical good thing about theophylline nasal irrigations on olfaction in contributors with COVID-19–associated OD [olfactory dysfunction] is inconclusive, although steered by subjective assessments,” the authors wrote. “Bigger research are warranted to research the efficacy of this therapy extra totally.”

Greater doses protected, nicely tolerated

The theophylline dose-escalation research, led by the identical crew, was performed after the randomized, managed trial was inconclusive. “The research discovered no clinically significant variations in olfaction, however the theophylline was probably underdosed,” they wrote.

The group studied 11 sufferers from the randomized, managed trial with post-infection impaired olfaction unrelated to COVID-19 lasting 6 to 36 months to determine the utmost tolerable dose of theophylline given by way of high-volume, low-pressure nasal saline irrigation. Median participant age was 61 years, and 6 had been feminine.

Contributors started twice-daily irrigation regimens of 100 mg of theophylline for 7 days, with these experiencing no extreme adversarial results happening to 200-mg twice-daily doses for the subsequent 7 days. Doses had been elevated 100 mg in 7-day intervals as tolerated, as much as a most of 800 mg each day over 1 month. Contributors had been requested about adversarial results every week.

The researchers famous their expectation that the utmost dose could be nicely tolerated as a result of it corresponds to a systemic dose of 20 mg, a lot decrease than the advisable beginning oral dose of 300 mg.

Median baseline UPSIT and Questionnaire of Olfactory Issues-Destructive Statements (QOD-NS) scores had been 18 (vary, 10 to 31) and 21 (9 to 41) factors, respectively. The QOD-NS is a 17-item questionnaire measuring olfaction-related high quality of life, with a most (worst) rating of 51.

Of the contributors, 9 reported no adversarial results, whereas one reported transient light-headedness for a day, and one other withdrew 3 weeks into the research due to insomnia, tremors, belly ache, and rash, all of which resolved on research drug discontinuation. No critical adversarial occasions had been reported.

After 4 weeks of theophylline therapy, 4 of 10 contributors reported considerably improved odor, and 6 stated their olfaction remained the identical. Median posttreatment UPSIT and QOD-NS scores had been 18 (vary, 8 to 33) and 9 (19 to 35) factors, respectively. Two contributors noticed clinically significant enchancment of their UPSIT scores.

The researchers stated that postviral olfactory impairment is changing into extra prevalent, underscoring the necessity for brand new efficient therapies.

“Whereas nasal theophylline irrigations dosed at 12 mg twice each day confirmed no significant olfactory enhancements, we hypothesized that theophylline dosage may very well be safely and systematically elevated,” they wrote. “Whereas the low pattern dimension and lack of controls restrict complete evaluation of olfactory outcomes, this research did inform a part 2 RCT of nasal theophylline irrigation delivered at these larger doses.”

The problem of olfactory dysfunction analysis

In a commentary on the 2 trials, Lauren Roland, MD, of Washington College, and Joshua Levy, MD, MPH, of Emory College, stated that analysis on olfactory dysfunction is difficult, particularly amid the continuing pandemic.

“COVID-19 variants differ in adversarial impact profiles on odor and style distortion, and sufferers have variable immunization standing data and COVID-19 reinfection charges,” they wrote. “Sufferers might have trialed numerous therapies previous to presenting for research enrollment.”

In the end, they stated, affected person high quality of life is most vital. “Whereas goal measures are useful for analysis functions and documentation, subjective measures are most helpful for characterizing the affected person expertise,” Roland and Levy wrote. “We imagine that the way forward for OD analysis is a steadiness of pragmatic research design and a give attention to endotyping or stratification of OD.” An endotype is a subtype of an sickness outlined by a discrete pathophysiological mechanism.

“If the COVID-19 pandemic has taught us something,” they continued, “it’s that issues are all the time in flux. As we expertise new variations and new data, we should keep in mind that sufferers are distinctive and are altering as nicely.”


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