From the beginning of the COVID-19 pandemic, profound changes in the sense of smell— including total smell loss—have been a notable (and perplexing) symptom of the infection. Although the changes in smell are often transient, many patients with COVID-19 have long-term olfactory dysfunction. Up until now, it has been unclear how SARS-CoV-2 infection causes persistent smell loss in a subset of patients.

Now, a new study reveals that the reason some people fail to recover their sense of smell after COVID-19 is linked to an ongoing immune assault on olfactory nerve cells and an associated decline in the number of those cells. The study involved analysis of olfactory epithelial samples collected from 24 biopsies, including from nine patients with objectively quantified long-term smell loss after COVID-19.

The study provides important insight into a vexing problem that has plagued millions who have not fully recovered their sense of smell after COVID-19. Although focused on the smell loss, the finding also sheds light on the possible underlying causes of other long COVID-19 symptoms—including generalized fatigue, shortness of breath, and brain fog—that might be triggered by similar biological mechanisms.

This work is published in Science Translational Medicine, in the paper, “Persistent post–COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium.

“One of the first symptoms that has typically been associated with COVID-19 infection is loss of smell,” said Bradley Goldstein, MD, PhD, associate professor in the department of head and neck surgery & communication sciences, Duke University School of Medicine.

“Fortunately, many people who have an altered sense of smell during the acute phase of viral infection will recover smell within the next one to two weeks, but some do not,” Goldstein said. “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-CoV2.”

In the study, Goldstein and colleagues analyzed olfactory epithelial samples collected from 24 biopsies, including nine patients suffering from long-term smell loss following COVID-19.

Single-cell analyses on the biopsies, such as single-cell RNA-seq and immunohistochemistry, revealed widespread infiltration of T cells engaged in an inflammatory response in the olfactory epithelium, the tissue in the nose where smell nerve cells are located. This unique inflammation process persisted despite the absence of detectable SARS-CoV-2 levels.

More specifically, they found a “diffuse infiltrate of T cells expressing interferon-γ and a shift in myeloid cell population composition, including enrichment of CD207+ dendritic cells and depletion of anti-inflammatory M2 macrophages.”

The authors added that, despite the absence of detectable SARS-CoV-2 RNA or protein, gene expression in the sustentacular cells of the olfactory epithelium reflected ongoing inflammatory signaling. Additionally, the number of olfactory sensory neurons were diminished, possibly due to damage of the delicate tissue from the ongoing inflammation.

“The findings are striking,” Goldstein said. “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 toward beginning to design treatments. He added that the researchers were encouraged that neurons appeared to maintain some ability to repair 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 this work is currently underway in his lab.

Findings from this study could also inform additional research into other long COVID-19 symptoms that might be undergoing similar inflammatory processes.