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A WEEK or so after Jackie Dishner lost both her sense of taste and smell, her diagnosis was confirmed 鈥� she had covid-19.

Dishner, an artist living in Phoenix, Arizona, knew that anosmia was a possible symptom of the disease, but she never imagined that after six months, most smells would still elude her, except perhaps the whiff of a particularly strong cup of coffee. She would also occasionally detect phantom odours.

Studies reveal that with covid-19 experience the loss of their olfactory senses, making it one of the most consistent indicators of infection.

Perhaps more importantly, anosmia often shows up days before more concerning, and sometimes life-threatening, respiratory issues. We are now building a picture of why the virus causes smell loss, how this symptom could be used for better diagnosis, and how likely people are to get their sense of smell back.

鈥淯nfortunately, if you can鈥檛 smell at the year mark, you probably won鈥檛 get your sense of smell back鈥�

Certainly, other viruses, including those behind flu and the common cold, can diminish our sense of smell. But this tends to be because the airways are blocked by mucus, preventing air from reaching the olfactory receptors in the nose. The sense of taste is also affected because much of what we perceive as flavour comes from odour molecules in food. The issue then clears up, along with the other symptoms. The smell loss due to SARS-CoV-2, the virus that causes covid-19, is very different.

鈥淵ou don鈥檛 really see the same kind of nasal congestion with covid-19. Which raises questions: what molecular mechanisms might be leading to this smell loss, what does it mean and what does it tell us about this virus?鈥� says Michael Xydakis, an ear, nose and throat surgeon with the US Air Force who studies anosmia.

Olfaction is a complex process. Each time we breathe in air, odour molecules from the environment travel up the nose to the olfactory epithelium. This small patch of tissue contains millions of specialised nerve cells that process smells. Each of these neurons is equipped with tiny hairs, called cilia, that reach through surface mucus to catch the odour molecules as they go floating by. The molecules can then be picked up by receptors on the olfactory neurons. When a particular odour molecule binds to a receptor on one of these cells, it triggers a neural signal that then travels on towards the brain.

Unique pattern

Each receptor is activated only by a specific odour molecule, so the resulting neural firing pattern is unique to that odour, allowing humans to differentiate between thousands of different smells.

In the past few months, we have started to build a picture of how SARS-CoV-2 infection leads to anosmia.

The nose provides an entry for any respiratory pathogen, including SARS-CoV-2. Some viruses, like polio, invade through the nasal passages and directly infect the olfactory neurons, damaging these cells and leading to a temporary or even prolonged loss of taste and smell.

SARS-CoV-2, however, works a little differently. We know that the virus enters cells in the lungs and other parts of the body via proteins called ACE2 receptors. , Maryland, and his colleagues has shown that the virus also attaches to this protein on sustentacular cells in the nose, a type of cell that provides structural and metabolic support to the olfactory epithelium.

鈥淚t鈥檚 a protein we see expressed in many places in the body, like the lungs and kidneys, which helps to regulate blood pressure,鈥� says Lane. 鈥淚t also happens to be highly expressed in sustentacular cells and, for whatever reason, this virus uses that protein to gain access to those cells.鈥�

Once the virus enters these support cells, the immune system kicks in, triggering inflammation in the olfactory epithelium.

According to one recent study that looked both at covid-19 patients and at animals infected with SARS-CoV-2, the . Without those little hairs waving odour molecules in, it is hard for these molecules to be picked up by the receptors on olfactory neurons. , and new cilia can grow.

This mechanism helps explain why, unlike with a cold, the smell loss with covid-19 is often sudden and severe. These properties might also make it a useful diagnostic tool.

鈥淧eople tend to experience a very sudden loss of smell with this virus,鈥� says Valentina Parma, a chemosensory researcher at Temple University in Philadelphia, Pennsylvania. 鈥淚t doesn鈥檛 fluctuate over the course of the day, there鈥檚 not a stuffy nose 鈥� your sense of smell is just gone. And this happens quite early in the course of the disease. This means it could be a diagnostic symptom.鈥�

Sniffing-out spread

Parma points out that many businesses as well as schools rely on temperature checks to help pick up positive cases. 鈥淏ut we see more smell-and-taste dysfunction in covid-19 cases than we do high temperatures, especially in the first few days after infection.鈥�

Parma and her team are working on a standardised smell test to help diagnose people with covid-19, or to at least identify those who should go on for further testing. They have found that using an objective test picks up than using self reports of anosmia.

However, even self-reported smell loss could help to flag the spread of SARS-CoV-2 throughout a population. In one study, Parma and her colleagues showed that reports of loss of smell and taste in a population predicted pressure on the healthcare systems in different communities, and might be a cheaper and easier way to track the spread of covid-19 than widespread testing.

There is little evidence that the loss of these senses can predict how bad a case of covid-19 will be, says Justin Turner at Vanderbilt University in Tennessee. 鈥淧atients with smell dysfunction tend to have less severe disease. They are less likely to be hospitalised or, if they are, to be intubated. But there are a lot of confounding variables,鈥� he says. 鈥淭here鈥檚 still a lot of work that we need to do to understand what relationship is there, if there even is one.鈥�

Typically, anosmia is short-lived. 鈥淭he good news is that, for most people, once that inflammation clears up, within 10 days or so, smell comes back and everything is fine,鈥� says Beverly Cowart at the Monell Chemical Senses Center in Philadelphia. But some people, like Dishner, have sustained smell loss for months.

This area of research is pressing because the loss of smell and taste, particularly over the longer term, can be debilitating.

As well as affecting our enjoyment of food, the olfactory senses are protective, says Turner. Without them 鈥測ou don鈥檛 notice noxious or dangerous smells like smoke, gas or spoiled food. It鈥檚 important to realise that anosmia can really affect people negatively, both in terms of the way they feel and in basic daily functioning.鈥�

鈥淲ithout these senses, you don鈥檛 notice dangerous odours like smoke, gas or spoiled food鈥�

It is possible that in some cases, the inflammation is severe enough to damage olfactory neurons, leading to long-term smell loss, says Cowart, but we don鈥檛 yet know for certain.

鈥淯nfortunately, if you still can鈥檛 smell at the year mark, you probably aren鈥檛 going to get your smell back,鈥� says Xydakis. 鈥淏ut we don鈥檛 know what鈥檚 happening there. These are questions that we are trying to answer.鈥�

Phantom smells, like those experienced by Dishner, are a good sign. It suggests that her olfactory system is recovering, with damaged neurons regenerating or rewiring themselves, says Mark Albers at Harvard Medical School. We are still some way off understanding the extent of damage to the olfactory system in both the short and long term, however. 鈥淭here鈥檚 a lot of interesting mechanistic biology that this virus is going to teach us,鈥� he says. 鈥淏ut it鈥檚 going to take some time.鈥�

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