Why Loss of Smell Can Persist After COVID-19

Research suggests that long-term smell loss is linked to an ongoing immune response in the nose

New research has provided important insight into why some people fail to fully regain their sense of smell even months after recovering from COVID-19.

The study, published Dec. 21 in Science Translational Medicine and conducted by researchers at Duke Health, Harvard Medical School, and the University of California San Diego, reveals that long-term loss of smell may be linked to an ongoing immune assault on olfactory nerve cells and an associated decline in the number of those cells.

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“This paper allows us to look, for the first time, at COVID-19-associated smell loss in otherwise healthy people — a clinical condition that has affected millions in the United States alone,” said Sandeep Robert Datta, professor of neurobiology in the Blavatnik Institute at HMS and an author on the paper.

An immune assault

Loss of smell is one of the first symptoms that has typically been associated with COVID-19, said senior author Bradley Goldstein, associate professor in Duke’s Department of Head and Neck Surgery and Communication Sciences and the Department of Neurobiology.

oldstein added that many people who experience an altered sense of smell during the acute phase of SARS-CoV-2 infection recover within one to two weeks, but some do not.

 “We need to better understand why this subset of people will go on to have persistent smell loss for months to years after being infected with SARS-CoV-2,” Goldstein said.

Previously, Datta and his team identified the olfactory cell types that are most vulnerable to infection with SARS-CoV-2. In their 2020 paper in Science Advances, they concluded that the virus primarily infects cells that provide metabolic and structural support to olfactory sensory neurons.

“Based on these results, we hypothesized that short-term loss of support causes transient loss of smell, while more persistent infection causes a more profound disruption in olfactory function that can take longer to recover from,” Datta said.

In the new study, the researchers wanted to further investigate the olfactory epithelium — the tissue in the nose where olfactory nerve cells are located — in people with long-term smell loss. The team collected olfactory epithelial samples from a small group of otherwise healthy people who were still experiencing smell loss at least four months after SARS-CoV-2 infection. They then performed single-cell sequencing on the samples to determine the different cell types present. 

The team discovered widespread infiltration of T cells engaged in an inflammatory response in the olfactory epithelium. Moreover, this inflammatory process continued despite the absence of detectable SARS-CoV-2. Additionally, the number of olfactory sensory neurons was diminished, possibly due to damage of the delicate tissue from the ongoing inflammation.

“Essentially, the immune system camps out in the nose — there is an enrichment for subsets of T cells that don’t normally live there,” Datta said. “This is consistent with the idea that a persistent immune reaction is part of what is causing long-term loss of smell.”

“The findings are striking. It’s almost resembling a sort of autoimmune-like process in the nose,” Goldstein said.

Learning what sites are damaged and what cell types are involved is a key step for beginning to design treatments, Goldstein added. He notes that the researchers were encouraged to see that neurons appeared to maintain some ability to repair themselves even after the long-term immune onslaught.

“We are hopeful that modulating the abnormal immune response or repair processes within the nose of these patients could help to at least partially restore a sense of smell,” Goldstein said, noting that this work is currently underway in his lab.

He thinks the findings from this study could inform additional research into other long COVID symptoms such as generalized fatigue, shortness of breath, and brain fog that might be caused by similar inflammatory processes.

Datta is also excited about the new avenue for research on smell that the study opens up.

“These experiments define a kind of template that we can use to better understand how smell works in humans and how diseases like COVID-19 can cause changes in the sense of smell,” he said.

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