In COVID-19, the sense of smell can diminish, vanish, or oddly skew, for weeks or months. The loss usually starts suddenly and is more than the temporarily dulled chemical senses of a stuffy nose from the common cold. As researchers followed up mounting reports of loss of olfaction, a surprising source of perhaps the longest-lasting cases emerged: stem cells in the olfactory epithelium.
A Common Symptom
Facebook groups may be ahead of the medical literature in providing vivid descriptions of the loss of olfaction as people swap advice and compare how long they’ve been unable to smell. The experiences can be bizarre, but at the same time, shared.
A favorite robust wine suddenly has no taste.
A parent must peek into or feel a child’s diaper to see if action is needed.
Shower gel reeks, while clean dryer sheets, vinegar, detergent, and bleach have no odor.
Carbonated beverages release an odd, unnamable aroma.
Celebrations suffer as people can’t smell birthday cake, pizza, even the stinky hallmark of Passover, gefilte fish.
Many people smell cigarette smoke, although none is around, or dirt, or the stench of rotten coffee grounds or moldy garlic.
Chefs can’t smell their food. Runners can’t smell their sweat. People fear they won’t detect their house on fire.
Some people list the things they can smell, because these are far fewer than the odors that they can’t detect.
Medicine has names for the disorders of olfaction. Anosmia is absence of the sense of smell, cacosmia the odor of rot, and phantosmia an “olfactory hallucination.”
Ear, Nose, and Throat Clinics Notice Uptick
While people were discovering that their beloved spicy foods had mysteriously gone dull, doctors at ear, nose and throat clinics in Iran were noting an increase in the number of patients complaining of sudden loss of smell.
It was March, just as COVID-19 was on the rise. Coincidence?
Seyed Hamid Reza Baheri and colleagues from the Iran University of Medical Sciences decided to investigate. They started with 10,069 people who’d reported loss of smell within the past month, presenting at clinics between March 12 and 17. And they tracked the increase in COVID cases. Although the study had limitations – self-reporting, not testing for the virus in the anosmic individuals – the investigators concluded that they’d identified “a significant linear correlation between prevalence of COVID-19 and olfactory impairment.”
The group published their findings in the preprint journal medRxiv on March 27 and claimed to be the first to note the correlation between loss of smell and COVID-19. But other groups in several countries were noting the same new symptom, and in the curious new world of time-looped scientific publication where preprints and realprints overlap, loss of the sense of smell soon became common knowledge.
Joining the List of COVID Symptoms
Facebook posts ramped up.
Social media coverage paralleled the scientific literature, as more people took online assessments of their disappearing olfaction, such as from the Global Consortium for Chemosensory Research and through the American Academy of Otolaryngology – Head and Neck Surgery’s COVID-19 Anosmia Reporting Tool.
The Iran team noted that people who lost their sense of smell tended to have milder courses of COVID. On April 24, researchers from the University of California San Diego confirmed the finding in an article in Allergy and Rhinology.
“Loss of smell may be a predictor that a SARS-CoV-2 infection will not be as severe, and less likely to require hospitalization. If an infected person loses that sense, it seems more likely they will experience milder symptoms, barring other underlying risk factors,” such as older age and having an underlying medical condition, said Carol Yan, MD, a rhinologist and head and neck surgeon at UC San Diego Health.
The papers tracking COVID-related anosmia provide an elegant example of the trajectory of scientific inquiry: association to correlation to cause.
Once the correlation became solid as reports skyrocketed, a “round up the usual suspects” approach to discovering a cause pointed initially to the olfactory sensory neurons – a logical anatomical site for blocked signals. But the enigmatic coronavirus held yet another surprise. The source of COVID-related anosmia and perhaps the other anomalies of smell are so-called “supportive” cells – including stem cells.
Single Cell RNA Sequencing Reveals Nasal Sites of Viral Entry
An international team led by neuroscientists from Harvard Medical School zeroed in on the susceptible cells using single cell RNA sequencing to assess gene expression – a powerful way to drill down to the components of a tissue where the action is. The researchers identified cells in the nasal epithelium that have ACE2 and TMPRSS2 receptors, which are the main entryways for the virus, as well as other receptors. The surprising findings are published in Science Advances.
Cells festooned with the relevant receptors are the non-neuronal ones in the olfactory epithelium and olfactory bulb, including support (sustentacular), stem, and perivascular cells. The cilia of the olfactory sensory neurons are devoid of the receptors – the virus can’t get in.
But apparently infecting the surrounding cells is enough to temporarily demolish the sense of smell, or somehow skew it. The role wasn’t recognized earlier in the pandemic because studies initially sought SARS-CoV-2 receptors in the respiratory and not in the olfactory epithelium. Both comprise the nasal epithelium.
A Role for Stem Cells in Injury and Recovery of Olfaction
Also in the Harvard study, experiments in mice with injured olfactory epithelium highlighted a role for the stem cells in regeneration. Immunostaining revealed anti-ACE2 antibodies in activated stem cells. “These results demonstrate that activated stem cells recruited during injury express ACE2 and do so at higher levels than those in resting stem cells,” the researches write.
Sums up senior study author Sandeep Robert Datta, associate professor of neurobiology in the Blavatnik Institute at Harvard Medical School, “Our findings indicate that the novel coronavirus changes the sense of smell in patients not by directly infecting neurons but by affecting the function of supporting cells. I think it’s good news, because once the infection clears, olfactory neurons don’t appear to need to be replaced or rebuilt from scratch. But we need more data and a better understanding of the underlying mechanisms to confirm this conclusion.”
Fortunately, fewer than 2% of stem cells in the nasal epithelium express the ACE2 receptors, leaving plenty in reserve to restore the sense of smell. But the impairment may account for the outliers, people in whom olfaction hasn’t yet returned. Some posts on Facebook are from people who haven’t been able to smell normally since contracting COVID-19 months ago, reporting that their physicians say it could take a year or more for the sense to come back.
It’s likely that viral infection of stem cells isn’t the only way that SARS-CoV-2 can impair olfaction. The researchers point out that inflammation, altered water and ion balance from damage to supportive cells that affects signaling to the brain, alterations to gland cells that could kill neurons, and vascular injury may still play a role. But direct damage to stem cells may explain the unfortunate folks dealing with COVID-19 for whom loss or distortion of the sense of smell lasts weeks or months.