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Loss of Smell as an Early Symptom of COVID-19: What Research Is Uncovering

What first emerged as a series of anecdotal reports shared on social media has rapidly become a key aspect of COVID-19 research as scientists mobilize to explore whether the deadly respiratory virus can cause people to lose their sense of smell.

Basic scientists and clinical researchers have geared up to try to quantify the extent of anosmia among COVID-19 patients and to understand what, at the cellular level, may explain the coronavirus' possible assault on the olfactory system.

Researchers leading these studies told Neurology Today that if a link between COVID-19 and loss of smell is established, simple smell tests could be administered to health care workers and others to screen for COVID-19, perhaps early in the disease before more obvious symptoms occur.

The clinical and basic science research already underway is impressive, they said.

Cellular Studies

Sandeep Robert Datta, MD, PhD, an associate professor of neurobiology at Harvard Medical School, is part of the Global Consortium for Chemosensory Research, which has mobilized around the question of loss of smell in the COVID-19 pandemic.

Dr. Datta and colleagues published preliminary findings of that research March 28 on bioRxiv, the preprint server for biology, that suggests possible mechanisms through which COVID-19 infection may lead to anosmia or other forms of olfactory dysfunction. [The article has not been peer-reviewed.]

He and his colleagues said that it does not appear to be sensory neurons that are susceptible to the virus, but rather the support cells and stem cells that are also found in the nasal epithelium.     

The researchers analyzed previously published animal and human genetic datasets to study which cells in the olfactory epithelium express receptors that bind to the spike (S) protein that is a hallmark characteristic of SARS-CoV-2, the virus that causes COVID-19.

COV-2 infects cells through interactions between its S protein and the ACE2 protein on target cells, they explained.

"While defects in olfaction may arise from changes in odor conduction associated with CoV-2-induced inflammation, it is also possible that CoV-2 infects and damages cells in the nasal epithelium required for normal olfactory function," Dr. Datta and colleagues wrote in the online article.

In cellular studies of both mouse and human data sets, they found that olfactory sensory neurons do not express two key genes involved in CoV-2 entry, ACE2 and TMPRSS2.

They noted, however, that olfactory epithelial support cells and stem cells express both genes, as do cells in the nasal respiratory epithelium.

"Taken together, these findings suggest possible mechanisms through which CoV-2 infection could lead to anosmia or other forms of olfactory dysfunction," the researchers wrote.

"The fact that CoV-2 does not appear to directly damage mature neurons—and instead seems to more directly affect olfactory function perhaps via damage to or inflammation of support cells—raises the possibility that after COVID-19-associated inflammation has subsided and the tissue has repaired itself, the function of these neurons in the nose may be recovered," Dr. Data told Neurology Today.

"That tentative conclusion requires a better understanding of what actually happens in the nose when CoV-2 attacks the olfactory epithelium."

Dr. Datta said much more needs to be learned about the precise mechanism of action at a cellular level. But in the meantime, he said it is important for researchers to confirm at a population level whether "loss of smell is an early warning sign" of COVID-19.

Quantifying Smell Dysfunction

Richard L. Doty, PhD, of the University of Pennsylvania's Smell and Taste Center, has submitted for publication along with colleagues in Iran the results of a small Iranian study in which COVID-19 patients were tested using a validated quantitative measure of smell function.

The study involved administering the University of Pennsylvania Smell Identification Test to a group of COVID-19 patients.       

"Preliminary evidence suggests that nearly everyone who has this virus has some degree of smell loss," said Dr. Doty, who declined to disclose details of the study until it is published. He said that many people who have COVID-19 may have not realized their smell has been affected.

Meanwhile, Mark Albers, MD, PhD, an assistant professor neurology at Harvard Medical School who specializes in memory and olfactory disorders at Massachusetts General Hospital (MGH), hopes to soon launch a clinical trial—for which he is seeking institutional review board approval—that utilizes "peel and sniff cards" that emit different odors to measure the frequency and degree of smell loss among newly diagnosed COVID-19 patients as well as people at risk for COVID-19 infection.

The disposable "scent cards" would be given to  group of patients who are being screened for COVID-19 or have documented COVID-19 infection at his hospital and two other sites. The screening tool could also be potentially useful for health care and other essential workers who are repeatedly exposed to higher risk situations, Dr. Albers said.

Dr. Albers said it is important to use quantifiable measures to study smell loss because people are not necessarily good at self-reporting their loss of smell. "People can lose part of their smell function and may not realize it," he said.

The odors, supplied by International Flavors & Fragrances, will be printed on different labels that study participants will peel and sniff. They then will use a designated mobile app to log their responses.

The smell test will be self-administered by patients at home so that an increased risk of viral transmission and an added burden are not placed on health care workers who are already working on overdrive, Dr. Albers said. Once the baseline data are collected, the study will follow up with the patients to determine if smell deficits resolve or persist over the coming year.

"Understanding the trajectory of recovery will provide insight into the mechanism" by which COVID-19 can damage the olfactory system, said Dr. Albers.

He said several mechanisms could account for smelling loss induced by the viral infection, including a direct assault on olfactory sensory neurons or stem cells in the lining of the nose; local inflammation mediated by infection of other cells types in the nasal lining, which in turn alters the function of olfactory sensory neurons; or possibly even viral penetration into the brain. One or more of these mechanisms might be present in each patient. 

"Viruses are well known to move up the olfactory tract into the brain," Dr. Albers said, though he favors the inflammation theory for smell loss related to COVID-19.

Thomas Hummel, MD, professor and head of the Interdisciplinary Center for Smell and Taste in the department of otolaryngology at Technische Universität of Dresden in Germany, said his team has begun administering questionnaires on smell and psychophysical olfactory tests—using a test called Sniffin'Sticks to assess odor identification, odor discrimination, and odor thresholds—to patients with suspected or confirmed COVID-19.

Some data coming from South Korea of patients with mild cases of coronavirus indicate that about 30 percent had a loss of smell. But for now, firm data on loss of smell related to the pandemic are lacking and there is no consensus that people with smell loss should be automatically tested for COVID-19.

"I have had many reports from patients who transiently lost their sense of smell, partly or completely, but in most of them it seems to come back after one or two weeks," said Dr. Hummel in an email interview with Neurology Today.

Dr. Hummel said his clinic over the past 20 years has seen approximately 3,000 patients who had some degree of smell loss following an upper respiratory infection, an experience that makes him think that a similar phenomenon is occurring with COVID-19.

Loss of Smell Common in Viruses

The researchers and clinicians who spoke with Neurology Today said it is not surprising that the olfactory system might come under attack by the virus that causes COVID-19, given that  loss of smell is a rather common complaint of  people who get influenza.

"There is a long history of people who have viral infections that involve the nose complaining of acute or long-lasting disturbance in smell," said Dr. Datta, who said loss of smell, if it becomes chronic, can lead to depression and other negative consequences.

The Centers for Disease Control and Prevention (CDC) does not list loss of smell as one of the symptoms of COVID-19, which include fever, dry cough, and shortness of breath. The World Health Organization has said it is looking into reports of loss of smell, and in some cases, taste, associated with COVID-19.

The American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) on March 22 issued a statement that called for anosmia to be added to the list of screening symptoms for the virus. The AAO-HNS  also created a web-based reporting tool for clinicians to file reports of patients experiencing smell loss in relation to COVID-19 so that a better sense of the scope of the problem can be ascertained. A similar professional society in the United Kingdom, ENT UK, also is advocating for a formal recognition of smell loss as a COVID-19 symptom.

Dr. Datta said much more needs to be learned about the precise mechanism of action behind smell loss at a cellular level. But in the meantime, he said it is important for researchers to confirm at a population level whether "loss of smell is an early warning sign of the virus.

"That could be critical to public health," he added.

Dr. Doty of Penn said that while the loss of smell may not seem particularly devastating compared with the life-threatening complications of COVID-19, it can be much more than an inconvenience.

"Nearly everyone has some degree of smell loss as they age," said Dr. Doty, but profound chronic loss of smell can be life-altering. From a safety standpoint, people who lose their sense of smell can't detect smoke, leaking gas, or food that has spoiled.  Eating can become a chore because the flavor of foods is also dimmed or lost, causing weight loss and malnutrition. People can become socially isolated because they find no joy in eating out with friends.

Dr. Doty said some research suggests that old people who lose their sense of smell are three times more likely to die over the course of a five-year period than their peers who don't have smell loss even when dementia is taken out of the equation.

"People often take the sense of smell for granted until they lose it," he said.

Link Up for More Information

Brann DH, Tsukahara T, Weinreb C, et al. Non-neural expression of SARS-CoV-2 entry genes in the olfactory epithelium suggests mechanisms underlying anosmia in COVID-19 patients. bioRxiv 2020; Epub 2020 Mar 28.