How long after loss of smell do other symptoms appear

Since the start of the pandemic, Brad Goldstein, an associate professor at Duke University, has noticed something odd. Unlike the flu or the common cold, which causes some patients to lose their sense of smell or taste from post-viral mucus build-up in the nose and throat, COVID-19 patients often experience losses of smell and taste before any other symptoms.

“With COVID-19, the loss of smell and taste is very abrupt and often occurs even in the absence of other symptoms,” said Goldstein, from the Departments of Head and Neck Surgery and Communication and Sciences and Neurobiology. “And in a lot of patients, it may last a few weeks or a month and then resolve, but it’s become clear that, in some people, it doesn’t seem to go away very quickly. We’re starting to see people three or five months out who have pretty much recovered, except that their sense of smell is still not working well.”

To understand this mysterious effect of COVID-19, Goldstein has partnered with a team of scientists at Duke to get to the bottom of it.

Targeting the support cells

Goldstein teamed up with Hiro Matsunami, a professor in the Departments of Molecular Genetics and Microbiology and Neurobiology. Having studied the cells that live in the nose for decades, Goldstein and Matsunami were easily able to apply that knowledge to study COVID-19. For example, early in the pandemic, scientists found that the coronavirus enters human cells through a protein receptor called ACE-2, which sits on the surface of many types of cells. The coronavirus uses the spiky protein on its own surface to fit into the ACE-2 protein—like a key into a lock—and is then able to invade and infect the cell.

When this news broke, Matsunami and Goldstein teamed up with a multi-institutional group of scientists to hunt for the ACE-2 receptor on cells in the nose. By analyzing mouse, non-human primate and human nose tissue samples, they found that the ACE-2 receptor is located on the support cells for olfactory sensory neurons. These support cells, called sustentacular cells, are the ‘nurses’ of the olfactory system, providing structural and metabolic support to the neurons.

To test whether these support cells are indeed an entry point for SARS-CoV-2, the team will need to infect mice with the virus and observe the pathways that the virus uses to invade. If the virus is found to infect this way, that will be one key difference in SARS-CoV-2 and flu transmission. Earlier this year, Heaton and Moseman, who have long studied flu transmission, found that influenza B targets the olfactory sensory neurons. The cells become infected, then eliminate the virus and survive in the host after the infection has been resolved.

Why the viruses may use different nasal cells to invade is a mystery but could be related to the different effects of the infections. Losses of smell associated with SARS-CoV-2 usually appear rapidly, within two days to a week, while with flu, people seem to notice losses of smell after a few weeks, according to the scientists.

“Loss of smell has been reported with flu, but it’s definitely more frequent with SARS-CoV-2. What’s more, it happens a lot earlier in infection with SARS-CoV-2,” said Heaton, who has developed tracking tools to study respiratory virus transmission. “From a public health standpoint, this is a blessing in disguise, because it helps people to realize that they should stay home and keeps them from transmitting the virus to others.”

Moseman studies the immune cells of the nose that form a barrier against pathogens. He suspects that the long-lasting smell loss observed in some COVID-19 patients is related to the immune system’s ability (or inability) to restore the damaged barrier.

“Overall, we want to understand the ramifications of SARS-CoV-2 infection on sense of smell on the ability of the olfactory system to regenerate itself and protect against future infections,” said Moseman. “Understanding how the immune system responds to SARS-CoV-2 could also assist in developing therapies down the road.”

Now, the team’s goal is to dissect the immune response within the olfactory tissues from human COVID-19 patients and in mouse models to gain an understanding of what changes are occurring and how these might explain short- and long-term sensory disruption. To do so, they have applied for funding at the National Institutes of Health to analyse olfactory samples taken from people infected with COVID-19.

For Goldstein, the biggest motivator is to develop new therapies to help patients who suffer from smell and taste loss regain these senses. In a society where so much immediate sensory enjoyment is based on sight and sound, smell and taste don’t get as much of the limelight, he said. But once they’re gone, their importance is immediately recognised. In addition to facilitating the enjoyment of a meal, they also keep us safe, helping us to sniff out smoke from the stove or a gas leak. And thanks to the way the sensory system is wired, they help us remember key moments in our lives.

“Everyone knows that feeling of smelling something you haven’t smelled for a long time, how it immediately triggers an old memory and the feelings associated with it like ‘Oh, that reminds me of going to visit grandma when I was little and she would make these cookies.’ Ultimately, we want to help people recover this important sensory function that is connected to so many wonderful memories.”

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