- Fish oil. Omega-3 fatty acids, with their anti-inflammatory properties, may offer another low-risk treatment for post-COVID-19-related OD. Several years ago, Zara M. Patel, MD, director of endoscopic skull base surgery at Stanford University, ran a randomized controlled trial using omega-3 in her endoscopic skull base surgery patient population (Neurosurgery. 2020;87:E91-E98). “In this patient group, almost a quarter of patients were having some form of long-term decrease in smelling ability,” she said. “With omega-3 supplementation, this dropped precipitously in comparison to the control group.” While Dr. Patel added that it would be an extrapolation to use this technique in post-viral smell loss cases, she does tell her patients that the risks associated with omega-3 are quite low and rare if they don’t have an underlying bleeding disorder or prostate cancer, and that there appears to be very little downside to taking it, even though it hasn’t been studied in their particular etiology of loss. (There may be hope for clinical data regarding omega-3 use soon: A double-blind, placebo-controlled study of omega-3 and post-COVID-19 smell loss, led by Alfred-Marc Iloreta, MD, and David K. Lerner, MD, ended in June 2021 at Mount Sinai Hospital.)
- Theophylline. This known phosphodiesterase inhibitor, currently used to treat asthma, is being studied in a phase II, single-site, double-blinded, placebo-controlled randomized clinical trial to determine its efficacy and safety for post-COVID-19 OD (ClinicalTrials.gov Identifier). Theophylline has shown benefit in similar clinical trials for other forms of post-viral OD.
- Sodium citrate. Treatment using sodium citrate has been studied in both quantitative and qualitative OD, though not COVID-19-related OD. A paper published in January 2021 on a controlled trial of prolonged use of intranasal sodium citrate in quantitative and qualitative OD in 60 patients showed that there may be some benefit in treating phantosmia with the substance (Eur Arch Otorhinolaryngol. 2021;278:2891-2897). The treatment, however, did not appear to improve smell loss in patients whose impairment was caused by infection. The study recommended further research to investigate this treatment’s effect on qualitative OD resulting from a variety of causes.
- Stem cell therapy. Dr. Goldstein, whose research includes studying the restoration of olfactory function in animal models using stem cell therapy, says this is a treatment that had shown some promise in animal models prior to COVID-19 (J Neurosci. 1996;16:4005-16; Chem Senses. 2020;45:493-502). “We used a tissue-specific purified rodent olfactory epithelial basal stem cell—a bona fide olfactory neuronal progenitor—in those studies,” he said. “There are a lot of barriers to translating this to humans that would require more research.”
- Platelet-rich plasma. Before the pandemic, Dr. Patel took an interest in platelet-rich plasma (PRP) because of its burgeoning use in other medical specialties. “It was being used in aesthetic clinics for facial rejuvenation and hair growth, but also in orthopedic clinics for joint cartilage regeneration and in neurology for nerve regeneration,” she said. “This last use caught my interest because that’s really what we want to do with the olfactory system when it’s damaged—we want to harness its inherent regenerative capability and stimulate it to function again.” Dr. Patel did a pilot study in which Dr. Yan was involved as a fellow, looking at PRP injections into the olfactory cleft (Laryngoscope. 2020;5:187-193). “We only enrolled low numbers at that time to confirm the safety of the injections—I wanted to make sure I wouldn’t make anyone worse or cause tumor growth—and we did prove safety,” Dr. Patel said. Without a placebo arm, efficacy wasn’t something the study could conclude, but researchers did see interesting improvement in patients’ threshold for smell, enough for Dr. Patel to want to conduct the randomized, controlled trial that she is currently running (at press time, due to be completed in July 2021). Dr. Yan has gotten UCSD up and running as a second site. “I’m excited we’ll be able to enroll patients more quickly and get to our answer faster as to whether this treatment option is really going to be beneficial for these patients,” Dr. Patel said.
Dr. Holbrook cautions, however, that mixing olfactory training with other therapies makes it challenging to know what’s working and what isn’t. “Even without olfactory training, the body is able to heal and recover and can regenerate new nerves,” Dr. Holbrook said. “In addition, smell recovery can be difficult to study because there’s already an underlying improvement that can occur.”
Explore This IssueAugust 2021
Another challenge in healing post-COVID-19 OD is that some patients don’t realize that they’re having problems. “Patients are notoriously bad at predicting their degree of smell loss. They often underpredict it or fail to recognize it,” said Dr. Yan. “Basically, there’s a discrepancy between subjective, patient-reported smell loss and objective testing.”
Dr. Villwock cited a recent study conducted over the course of one year in patients with post-COVID-19 OD that found a discrepancy between self-assessed and objective sense of smell. “The study noted that this could be due to issues inherent to either self-assessment strategies or a limited ability of the utilized olfactory tests to completely capture subtle differences in olfactory performance that are meaningful in the context of daily life,” she said.
Overall, however, the gentlest option may be to allow the body to heal itself, even if this might be the slowest alternative. “Although there are various treatments, one option is to just give it time,” Dr. Yan said.