Loss of smell or taste, or both, is common in COVID-19 infected patients, particularly in patients with mild symptoms. Although research has focused on the causes underlying lung infections in COVID-19 patients, the causes of neurological symptoms have remained a mystery.

Researchers have now explained the mechanisms involved in the loss of smell (anosmia) in patients infected with SARS-CoV-2 at different stages of the disease, in an article published in Science Translational Medicine, “COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters.”

SARs-CoV-2 infects olfactory sensory neurons and enters the central nervous system through a process called retrograde invasion. [Source: Pierre-Marie Lledo/Institut Pasteur].
Using noninvasive nasal brush sampling, scientists at the Institut Pasteur, CNRS, Inserm, University of Paris, and Assistance Publique – Hôpitaux de Paris, examined the nasal linings in 11 patients with COVID-19 reporting loss of smell and detected SARS-CoV-2 viral particles and inflammation in several cell types in the lining of the nasal cavity (olfactory neuroepithelium) including sensory neurons. The researchers showed SARS-CoV-2 infects and multiplies in the olfactory epithelium of hamsters and in individuals with COVID-19 for several months after infection.

The team, led by Pierre-Marie Lledo, PhD, showed golden Syrian hamsters infected with SARS-CoV-2 lose their sense of smell. This is associated with the spread of the virus in the nasal mucosa and central nervous system accompanied by tenacious inflammation.

In four patients that developed persistent loss of smell, the authors detected lasting SARS-CoV-2 presence in the nasal mucosa, even when the virus RNA could not be detected in nasopharyngeal swabs through routine diagnostic RT-qPCR. This unexpected finding prompted the authors to suggest that diagnosis of SARS-CoV-2 by nasal brushing can complement nasopharyngeal swabbing for PCR testing in patients with loss of smell.

The study revealed the step-by-step mechanism of COVID-19-related loss of smell in chronological order. Upon viral infection, the cilia on the surface of sensory neurons disappear. These cilia are slender projections of the cell’s bounding membrane that latch onto odorant molecules and constitute the first step in the perception of smell. The authors showed that SARS-CoV-2 can persist in the nasal sensory neurons in humans for several months after the symptoms of the disease have resolved.

SARS-CoV-2 induces loss of cilia in the nasal lining. [Source: Pierre-Marie Lledo/Institut Pasteur].
The nasal epithelium is a highly organized bed of flattened cells that makes smelling possible. The authors showed SARS-CoV-2 infection disrupts the organization of the nasal epithelium by inducing programmed cell death (apoptosis).

“We also found that this inflammatory process that takes place in the nasal cavity spreads to the olfactory bulb,” the authors noted. The olfactory bulb constitutes the first cerebral relay station of the olfactory system. These findings are consistent with other studies on deceased patients with COVID-19, where the olfactory bulb shows inflammatory signatures such as microgliosis.

The authors showed SARs-CoV-2 infection of nasal sensory neurons and subsequent infection of the olfactory bulb act as a portal for its entry into more remote regions of the brain such as the brainstem and the cerebral cortex, through a process called “retrograde invasion.”

“The findings we obtained are clinically relevant in the care to patients with COVID-19, since olfactory function loss could be regarded as a sensitive sign of persistent viral infection, and should be considered in-patient management,” the authors noted.

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