Anosmia: COVID-19's mysterious side effect

Charles Greer, PhD, was intrigued when he read in The New York Times that some COVID-19 patients reported losing their sense of smell. A well-known side effect of having one’s nose clogged with mucus after contracting a cold or the flu, anosmia (loss of smell) can be long-lasting or even permanent in a small number of patients.

That COVID-19 patients experience anosmia—by some accounts as many as 30% of the total—gave Greer pause. Professor of neurosurgery and of neuroscience at Yale School of Medicine (YSM), and director of the interdepartmental neuroscience graduate program, Greer immediately wondered which aspect of the virus was causing this side effect, especially given the lack of other relevant symptoms common to rhinovirus infection, also known as the common cold. “Are neurons degenerating? Are cells being blown up by the virus? Also, why these cells? Why isn’t [COVID-19] in the eye or the skin?” Greer remembered asking himself.

Little is known about COVID-19, and even less is understood. Compared unfavorably and inappropriately with flu and with SARS (another coronavirus syndrome), COVID-19 is a virus unlike either because it prefers cells that can be found in the lungs. As it turns out, similar cells can be found in the olfactory epithelium, which is the layer of skin containing the neurons responsible for the sense of smell.

“The public reports describe anosmia before the onset of other symptoms as well as afterwards, with patients regaining their sense of smell very quickly after recovery,” said Greer. “This is interesting because the olfactory epithelium can regenerate quickly: there’s an almost complete turnover in cellular material there every 6–8 weeks.”

Greer, who came to Yale 40 years ago to study the human olfactory system, also finds the phenomenon interesting for a more troubling reason. “The olfactory epithelium is the only sensory system that’s directly connected to the brain,” he said. “Other senses—touch, taste, auditory, sight—are all mediated by additional mechanisms that interpret signals and pass them along through the nervous system to the brain. Smell is processed by the same neurons that extend into the brain.”

While some researchers are scanning the horizon for potential long-term neurological consequences of COVID-19, others are attempting to understand or measure anosmia. Dana Small, PhD, professor of psychiatry and professor of psychology, and director of the modern diet and physiology research center, has started a limited study to measure people’s ability to smell. “Olfactory loss is not uncommon with other viruses,” said Small. “But smell is one of those things we take for granted, and tend not to notice until it’s gone.”

Small and three of her colleagues designed a screening instrument to track smell loss over time, using common items so that the test can be carried out at home. For example, individuals use a scale to rate the strength of the smell of peanut butter; they can do this over several days to see whether the strength changes. According to Small, peanut butter is a good stimulus because it is familiar, available in most homes, and is a relatively pure olfactory stimulus. “There are many molecules that activate other neurons in alcohol, vanilla, mint, coffee, and other items we associate with smell.” Peanut butter, however, is pure—it activates only the olfactory system, and is therefore an ideal stimulus for tracking smell. It has also been used by other researchers to document smell loss in Alzheimer’s disease.

Both Small and Greer emphasize that patients reporting dysgeusia (distortion or loss of taste) were likely describing a common symptom of anosmia rather than the loss of another distinct sense. “When people say they’ve lost their sense of smell and taste, they’re usually describing a loss in retronasal olfactory function, not the inability to distinguish between sweet and bitter,” said Small.

Greer agrees. “If you close your nose up and taste a strawberry, you will be able to distinguish certain elements with your tongue and mouth. When you release the nose and allow air to flow again, your sense of smell will create a new experience that we associate with taste but is in fact distinct.” Greer says he has students perform a related experiment using jelly beans to underscore distinctions between the two senses.

Understanding anosmia could be a key to helping otherwise asymptomatic and healthy COVID-19 carriers self-identify and quarantine. To this end, members of the Association for Chemoreception Sciences (AChemS) have created a working group, the Global Consortium for Chemosensory Research (GCCR), to help pool expertise and resources for other researchers. The American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS) has also developed a tool for clinicians.

“The chemosensory community is doing what we can to help out with the crisis,” said Small.