Awareness Fuels Olfactory Advances: Treating and Managing Smell Loss

More than 13 million U.S adults live with measurable smell dysfunction, according to the National Institute on Deafness and Other Communication Disorders (NIDCD. https://tinyurl.com/2jy4vdv7).

That’s one in eight adults over the age of 40—and that’s likely a low estimate because it’s based on a 2016 report that was released well before the COVID-19
pandemic affected the olfactory capabilities of millions, raising global awareness about the morbidity of smell and taste dysfunction (Rev Endocr Metab Disord. doi:10.1007/s11154-016-9364-1).

That awareness is fueling scientific advances.

“One of the consequences of so many people losing their sense of smell during the pandemic is that there is a renewed interest in developing treatments for patients with smell disorders,” said Bradley Goldstein, MD, PhD, a professor of head and neck surgery, cell biology, and neurobiology at Duke University in Durham, N.C.

Scientists know less about our senses of smell and taste than the senses of hearing, vision, and touch. That’s in part because the location of the olfactory bulbs makes them difficult to access and in part due to the complexity of the olfactory system.

“I would say we’re still in the infancy of really understanding the disease processes underlying smell and taste dysfunction, and therefore in the infancy of coming up with treatment options,” said Zara Patel, MD, professor of otolaryngology–head and neck surgery at Stanford Medicine in Stanford, Calif.

Although researchers have made significant strides in understanding the basics of olfaction, they are still working to untangle the pathophysiology that drives olfactory dysfunction.

We still don’t understand mechanistically why smell loss happens…It’s much harder to come up with a fix when we’re still trying to figure out exactly where it got broken. — Justin Turner, MD, PhD

“We still don’t understand mechanistically why smell loss happens,” said Justin Turner, MD, PhD, chair of the department of otolaryngology at the University of Alabama–Birmingham Marnix E. Heersink School of Medicine. “In the case of post-viral infection smell loss, is it the virus itself that kills cells, or is it the secondary inflammation that occurs due to the viral infection that causes loss of olfactory neurons? Or is it the inability of those neurons to regenerate themselves after their loss?”

This lack of understanding has hampered the development of effective treatments for anosmia, parosmia, and phantosmia. “It’s much harder to come up with a fix when we’re still trying to figure out exactly where it got broken,” Dr. Turner said.

Patients and clinicians alike may experience frustration with persistent, seemingly intractable smell alterations. But although “there’s this sense that there is not a lot we can do for these patients, we can do a fair amount now to help people who have problems with their sense of smell,” Dr. Goldstein said. “The science may not be advancing as quickly as we would like, but there have been some significant advances.”

Advances in Diagnostic Approaches

It is important not to ignore, discount, or minimize patients’ concerns regarding their senses of smell and taste. It’s true that many people eventually regain olfactory function over time, particularly if their smell or taste dysfunction was triggered by a time-limited illness, such as a viral infection. But “when a patient comes in and says, ‘I can’t smell,’ that’s deserving of further evaluation and investigation,” Dr. Turner said. “Typically, if a patient is mentioning it, it’s having a negative impact on their quality of life.”

The assessment and diagnostic process should include a thorough history, both to determine possible etiologies of olfactory dysfunction and to understand how patients’ altered sense of taste or smell is affecting their nutrition, socialization, and safety. Objective smell testing is also recommended, even though private insurance and Medicare don’t reimburse for smell tests or pay for the time and expertise it takes to administer the test and educate patients about smell testing (WHYY. https://tinyurl.com/ybvupwh7).

A variety of smell tests are currently available. Sniffin’ Sticks, a standardized olfactory function test, was developed in Germany in 1997 (Eur Ann Otorhinolaryngol Head Neck Dis. doi.org/10.1016/j.anorl.2015.08.004); it has since been validated in many countries and settings, but it’s impractical for routine use, as testing takes approximately 45 minutes (Chem Percept. doi.org/10.1007/s12078-021-09287-2). Two newer tests include SCENTinel 1.1, developed by researchers at the Monell Chemical Senses Center, and U Smell It, a test developed by Derek Toomre, PhD, a Yale professor of cell biology (usmellit.com). Both tests can be self-administered in minutes. The SCENTinel test card contains three “Lift’nSmell” patches and measures an individual’s ability to detect an odor, estimate the odor’s intensity, and identify it. Research to date suggests that SCENTinel is reliable and accurate in a variety of settings—and can detect parosmia (Chem Senses. doi.org/10.1093/chemse/bjab004). U Smell It has two parts: U Smell It training and test cards, with defined scratch-and-sniff areas, and an associated digital app, which individuals use to enter their responses and receive their scores. U Smell It is U.S. Department of Food and Drug Administration certified as a Class 2 exempt medical device.

Objective smell tests are helpful for both patients and clinicians. “Many times, when folks come in reporting really severe smell loss, objective testing may show that their sense of smell isn’t that bad,” Dr. Turner said. “That information may alleviate some of their concerns and give them hope that, over time, their senses will return to normal.”

People typically think their sense of smell is better than it is, particularly in the geriatric population. — Carol Yan, MD

On the flip side, objective smell testing may reveal dysfunction that patients have yet to detect. “People typically think that their sense of smell is better than it is, particularly in the geriatric population,” said Carol Yan, MD, associate professor of otolaryngology at the University of California San Diego.

The goal of your diagnostic workup should be to identify both the degree and severity of olfactory dysfunction and to determine its etiology, as treatment will vary depending on the causative factor.

Note: Although COVID-19 infections have indeed caused a lot of cases of olfactory dysfunction, don’t assume an infection is the likely cause of smell loss. “Before COVID-19, patients with smell loss would come to me with multiple scans already completed—CT scans, MRI brain scans. Nowadays, it’s not uncommon to come across a patient with smell loss that hasn’t been carefully assessed because people think it’s COVID-19-related,” Dr. Goldstein said. “Always make sure that a really thorough evaluation is done.”

Current Best Practices in Treatment

Although olfactory dysfunction can have many causes—including head trauma, neurodegenerative disease, and infection—research has confirmed that “inflammation is a common feature of many types of smell loss,” Dr. Goldstein said. Treating and managing inflammation in appropriate patients can significantly improve olfaction in affected patients.

Chronic rhinosinusitis (CRS) is an inflammatory condition that causes smell and taste alterations in nearly 80% of patients (Cureus. doi:10.7759/cureus.53523). Intranasal corticosteroids and nasal irrigation continue to be mainstays of treatment, with one small study suggesting that corticosteroid drops administered when the patient is in the Kaiteki position are more effective in reaching the olfactory cleft than steroids delivered via a nasal spray or exhalation delivery system (Cureus. doi:10.7759/cureus.53523). Systemic steroids may also be used to treat and manage inflammation.

When steroids are not sufficient to control inflammation, treatment with biologic medication that targets type 2 inflammation signaling pathways can be very useful. “One of the newer biologics, dupilumab, blocks IL-4 and IL-13 signaling and is very effective at restoring the sense of smell in appropriate patients with smell loss due to chronic sinusitis,” Dr. Goldstein said. These targeted medications are one of the biggest advances in the treatment of smell loss in recent years.

“They weren’t available three or four years ago and have really been incredibly beneficial for some patients whose chief complaint is their lack of sense of smell,” Dr. Turner said.

It’s important to note, though, that biologic therapy must be given consistently—typically, once every two weeks (Int Forum Allergy Rhinol. doi: 10.1002/alr.22944)—to maintain efficacy.

“Studies have shown that once you stop doing these injections, smell loss will return as inflammation returns,” Dr. Yan said.

Additionally, steroids, biologic therapy, and endoscopic surgery do not provide relief or improved sense of smell in all patients with chronic rhinosinusitis. “Those are often the most frustrated patients,” Dr. Yan said. “When we look into their noses endoscopically, it looks nice and clean, yet they still have persistent smell loss.”

Researchers hypothesize that these patients likely have chronic inflammation that suppresses neurogenesis of olfactory sensory neurons. Although many patients with well-treated but stubbornly persistent CRS don’t have visible evidence of inflammation, animal studies support the idea that chronic inflammation may still be present.

“Most of these experiments are done in mice, and when you biopsy their olfactory mucosa, you see signs of persistent inflammation,” Dr. Yan said. Ongoing research studies may elucidate the pathophysiology of this persistent inflammation, pointing the way toward additional treatment options.

Olfactory dysfunction that is not related to inflammation may respond to olfactory training. While smell training remains a first-line treatment for all etiologies of smell loss, its efficacy varies greatly.

“Smell training is probably not going to be effective in people who have no sense of smell,” Dr. Yan said. “I also counsel people that smell training efficacy is very limited; not all patients will benefit.” However, because olfactory training is low-risk, inexpensive, and can be performed by patients at home, it may be worth a try.

Experimental and Emerging Therapies

Currently, there is a lot of interest in regenerative medicine.

“The olfactory epithelium is well known to maintain neurogenesis under normal conditions throughout life, and there’s some evidence that for certain conditions—for instance, aging-related smell loss—neurogenesis is exhausted. So, potentially new treatment strategies to stimulate regeneration have been thought to hold promise,” Dr. Goldstein said.

At present, this is an area of active research; no regenerative treatments have been approved to treat olfactory dysfunction.

Platelet-rich plasma (PRP) injections are one of the most explored regenerative treatments. A multi-institutional, randomized controlled trial found that patients with COVID-19-related smell loss who received PRP injections into the olfactory cleft experienced greater improvement in olfaction than patients who received saline injections (Int Forum Allergy Rhinol. doi:10.1002/alr.23116).

“The PRP arm had a greater than 12 times odds of improvement in smell compared to the control group,” said Dr. Patel, one of the researchers involved in the study. She has since offered PRP as a treatment option to smell loss patients with varying etiologies.

“Although it does not help everyone, it has helped the majority of patients we tried it on,” Dr. Patel said. “Those patients not only sustained improvement at one year, compared to their three-month function, but they had continued increases in improvement compared to control group patients who did not receive any injection (Int Forum Allergy Rhinol. doi:10.1002/alr.23505).”

One patient’s improvement was particularly striking: A man with a 45-year history of post-traumatic smell loss regained his sense of smell after a series of three PRP injections, Dr. Patel said.

“He came in crying, with a whole list of things he was able to smell, that he hadn’t smelled in 45 years,” Dr. Patel said. “I made him take another psychophysical smell test, and his score almost doubled the minimal clinically important difference of improvement.” (Note: This has been accepted for publication as a case report.)

Dr. Patel is currently embarking on a clinical trial to see if PRP can help people with parosmia. Other scientists are working to understand how PRP injections may stimulate the sense of smell.

“I really want to research the mechanisms of platelet-rich plasma,” said Dr. Yan, who worked with Dr. Patel on the initial COVID-19/PRP study. “I’d like to learn more about which component of PRP would make it a more effective treatment. Although it’s shown some potential, I think PRP as a treatment modality can be improved.”

Neurostimulation of the olfactory system is another active area of research. “We know from neurology and neurosurgery that using electrical stimulation can help with nerve regeneration,” Dr. Patel said. Theoretically, electrically stimulating damaged olfactory nerves may aid in their recovery. Specific patterns of electrical stimulation may also be able to improve patients’ sense of smell—or even induce the perception of particular scents, in the same way that cochlear implants help individuals hear by delivering sound signals directly to the auditory nerve (ENTtoday. https://tinyurl.com/wuw46cm6).

Researchers are also investigating the use of stem cells to restore olfaction. As noted in a 2024 Heliyon journal article, stem cell therapy to regenerate olfactory neurons “represents a promising and innovative strategy for addressing olfactory dysfunction (Heliyon. doi:10.1016/j.heliyon.2024.e29948). Stem cells have not yet been tested in humans with olfactory dysfunction, however (HNO. doi.org/10.1007/s00106-022-01249-8).

Additional research is needed before regenerative treatments are incorporated into the clinical management of olfactory disorders. “So often, certain interventions are trialed for smell loss, and we’ll have some promising initial results. Then, subsequent, better-controlled studies show a lack of efficacy. We’ve seen that many, many times,” Dr. Turner said.

Clinicians can refer to the 2022 International Consensus Statement on Allergy and Rhinology: Olfaction for an overview of the evidence base for olfactory diagnostic techniques and treatment options (Int Forum Allergy Rhinol. doi: 10.1002/alr.22929.).

Advancing the Science of Smell

In July 2024, NIDCD launched the National Smell and Taste Center (NTSC), a collaborative effort to advance understanding of smell, taste, and smell- and taste-related disorders through research, patient care, education, and outreach.

“By combining interdisciplinary research with insights gained from clinical practice, NSTC is advancing patient-centered approaches that will improve quality of life for millions of Americans impacted by smell and taste disorders,” said Joshua M. Levy, MD, MPH, MS, NIDCD clinical director, and NSTC co-director. “Over the next five years, our goals include the establishment of a smell and taste clinic at the NIH Clinical Center, increased training opportunities in smell and taste research, collaborations with academia and industry to evaluate innovative devices and therapeutics, and improved understanding of smell and taste dysfunction in neurodegenerative disorders.”

At present, there is still a “big gap” between understanding the mechanisms of olfactory dysfunction, translating findings from animal models, and developing effective, human-focused treatments, Dr. Yan said. Otolaryngologist involvement will be critical to advancing the science of smell.    

Jennifer Fink is a freelance medical writer based in Wisconsin.