COVID and loss of smell: answers are beginning to emerge

After a COVID-19 infection, some people have regained their ability to perceive odors through olfactory training.Credit: Fabio Bucciarelli/The New York Times/eyevine

Researchers are finally making progress in understanding how the SARS-CoV-2 coronavirus causes loss of smell. And a slew of potential treatments to fight the disease are in clinical trials, including steroids and blood plasma.

Once a telltale sign of COVID-19, odor disturbance is becoming less common as the virus evolves. “Our inboxes aren’t as flooded as they used to be,” says Valentina Parma, a psychologist at the Monell Chemical Senses Center in Philadelphia, Pennsylvania, who helped answer desperate patient requests throughout the first two years of the pandemic.

A study published last month1 surveyed 616,318 people in the United States who have had COVID-19. It found that, compared to those who had been infected with the original virus, people who had contracted the Alpha variant – the first concerning variant to arise – were 50% more likely to have chemosensory disturbance. This probability dropped to 44% for the latest Delta variant and 17% for the latest variant, Omicron.

But the news is not all good: a significant portion of those infected at the start of the pandemic are still experiencing chemosensory effects. A 2021 study2 followed 100 people who had had mild cases of COVID-19 and 100 people who repeatedly tested negative. More than a year after their infections, 46% of those who had COVID-19 still had problems with their sense of smell; in contrast, only 10% of the control group had developed some loss of smell, but for other reasons. Additionally, 7% of those who had been infected still had complete loss of smell, or “anosmia,” at the end of the year. Given that more than 500 million cases of COVID-19 have been confirmed worldwide, tens of millions of people likely have lingering smell problems.

For these people, help cannot come soon enough. Simple activities like tasting food or smelling flowers are now “really emotionally taxing,” says Parma.

scrambled cores

A clearer picture of how SARS-CoV-2 causes this disruption should help create better therapies for the disease. At the start of the pandemic, a study showed3 that the virus attacks cells in the nose, called sustentacular cells, which provide nutrients and support to odor-sensitive neurons.

Since then, clues have emerged about what happens to olfactory neurons after infection. Researchers including biochemist Stavros Lomvardas of Columbia University in New York have examined people who died of COVID-19 and found that, although their neurons were intact, they had fewer membrane-embedded receptors to detect odor molecules than usual.4.

It was because the nuclei of the neurons had been scrambled. Normally, the chromosomes in these nuclei are organized into two compartments – a structure that allows neurons to express specific odor receptors at high levels. But when the team looked at the autopsied neurons, “the nuclear architecture was unrecognizable,” says Lomvardas.

Other studies suggest why only some people experience long-term smell loss. In January, a research team reported5 finding a genetic mutation in people that was associated with a greater propensity for loss of smell or taste. The mutation – a change to a single “letter”, or base, of DNA – was found in two overlapping genes, called UGT2A1 and UGT2A2. Both code for proteins that remove odor molecules from the nostrils after they are detected. But it is not yet known how SARS-CoV-2 interacts with these genes.

There is also evidence of lasting changes in the brains of people with loss of smell. In a study published in March6, 785 people in the UK had their brains scanned twice. About 400 people were infected with COVID-19 between scans, so scientists were able to observe structural changes. COVID-19 survivors showed multiple changes, including markers of tissue damage in areas related to the olfactory center of the brain. It’s unclear why this was the case, but one possibility is the lack of input. “When we cut off the supply from the nose, the brain atrophies,” says Danielle Reed, a geneticist also at Monell. “It’s one of the clearest things we know about taste and smell.”

Test treatments

In the meantime, many treatments are being explored, often in small clinical trials. But that’s still just the beginning, so the only thing most researchers recommend for now is smell training.seven. Patients are given samples of strong-smelling substances to sniff and try to identify, in an effort to help restore olfactory signaling. However, the method seems to only work with people who have partial loss of smell, Reed says. That means it helps about a third of people who experienced chemosensory disruption after COVID-19, Parma adds.

To find treatments for everyone else, many researchers are exploring steroids, which reduce inflammation. COVID-19 is known to trigger significant inflammation, which could play a role in odor disruption. So in theory steroids could help – but in practice the results have been disappointing. For example, a 2021 study8 gave smell training to 100 people with post-COVID anosmia. Fifty of them also received a nasal spray with the steroid mometasone furoate, while the other 50 did not. There was no significant difference in the results between the two groups.

Another therapeutic possibility is platelet-rich plasma; this is made from patients’ blood and is rich in biochemicals that can induce healing. A pilot study published in 20209 followed seven patients who were injected with platelet-rich plasma in the nose: five showed improvement after three months. Similarly, a preprint published in February this yearten followed 56 people and found that platelet-rich plasma made them more sensitive to odors. But these are “very small numbers”, says Carl Philpott, a nose and sinus specialist at the University of East Anglia, Norwich, UK. A US-based team is currently launching a larger study.

Unlike COVID-19 vaccines, which have been tested at unprecedented speed thanks to huge government support, treatments for post-COVID chemosensory dysfunction are advancing. Philpott is in the early stages of a small study on vitamin A, which previous experiments have shown may help with other forms of odor loss. “The reality is that the study will take the rest of this year to unfold, and that will likely take us into the middle of next year before we analyze the data and report it,” Philpott says. “If we find a positive benefit, our next job will be to apply for more funding to do a full trial.”


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Edward L. Robinett