Olfactory Axon Injuries, Microvascular Pathology Seen in COVID-19

More severe axon pathology, axon losses, and microvasculopathy were found in the olfactory tissue of people who died with SARS-CoV-2 infection than in people who died without such an infection, a postmortem study showed.

Olfactory pathology was especially severe in people who had reported smell alterations, reported Cheng-Ying Ho, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, and colleagues in JAMA Neurology. However, it was not associated with the severity or the timing of COVID infection, or with the presence of SARS-CoV-2 in olfactory tissue.

"This is the first study to demonstrate COVID-19-related injuries at ultrastructure level in the olfactory bulb," Ho told MedPage Today. "It shows nerve damage in the olfactory bulb. The nerve damage may be the main reason why smell is lost."

"Our findings suggest that SARS-CoV-2 infection of the olfactory epithelium leads to inflammation which in turn damages neurons, reduces the numbers of axons available to send signals to the brain, and results in the olfactory bulb becoming dysfunctional," she said.

The results support previous research showing microvascular pathology in the olfactory bulb and brain of people who died with COVID-19.

"The observation of the lack of presence of the virus in the bulb despite the profound pathology is consistent with our findings and those of others," said Avindra Nath, MD, clinical director of the National Institute of Neurological Disorders and Stroke (NINDS), who wasn't involved with the study.

"There are still many unanswered questions," Nath told MedPage Today. "What is causing the vascular pathology and axonal injury? Are they related or independent phenomena? What does repair look like? Some people do regain their sense of smell or develop abnormal smells; what does the pathology look like in these individuals?"

Olfactory dysfunction has been reported by more than half of people with COVID-19. Acute olfactory dysfunction is more prevalent in mild forms of COVID-19 than moderate-to-critical disease. Most people recover their sense of smell within 6 months, but about 5% do not.

In their analysis, Ho and colleagues collected olfactory bulb tissue from 23 people who died with COVID-19 and 14 controls who died with no detectable SARS-CoV-2. Autopsies were performed from April 2020 to September 2021.

Age at death ranged from 28 to 93 (median 62) in the COVID group and from 20 to 77 (median 53.5) among controls. Based on clinical history and postmortem testing, 16 people in the COVID group had active SARS-CoV-2 infection at the time of death.

The researchers evaluated tissue for detectable SARS-CoV-2 particles, severity of degeneration, loss of olfactory axons, and severity of microvasculopathy. Clinical records supplied information about smell and taste changes for three patients and family interviews provided the rest.

Three people in the COVID group had lost their sense of smell, four people had a diminished ability to smell, and two people had lost both smell and taste. No one in the control group had lost either taste or smell.

Results showed:

• The mean axon pathology score (range 1-3) was 1.921 in the COVID group and 1.198 in controls (P<0.001). Axon density was 2.973 × 10⁴/mm² in the COVID group and 3.867 × 10⁴/mm² in controls (P=0.002).
• Endothelial injury of the microvasculature was seen in olfactory tissue. The mean microvasculopathy score (range 1-3) was 1.907 in the COVID group and 1.405 in controls (P<0.001).
• Both axon and microvascular pathology scores were worse in people with COVID-19 who had smell alterations than in people with intact smell (axon pathology scores 2.260 vs 1.63, P=0.002; microvascular pathology scores 2.154 vs 1.694, P=0.02).

Results were similar after controlling for age. Most people in the study had mild to moderate findings, but the severity of pathology in some cases indicated that olfactory dysfunction may be severe and permanent, Ho and co-authors noted.

A limitation of the study is that the researchers were not able to assess how pathologic changes in nasal mucosa may have contributed to smell alterations.

Ho and colleagues plan to conduct a follow-up study of people who died with SARS-CoV-2 Delta and Omicron variants to assess any axon damage and bulb dysfunction in those tissues.

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