The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides a research opportunity to evaluate the natural course of this neurological finding. Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples. Although data from neuropathological specimens are now available, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge.

Recent developments

The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen.

Where next?

The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.


The mechanisms of smell loss after SARS-CoV-2 infection


COVID-19 has brought the importance of smell to the public’s attention. In addition to the roles of olfaction in hygiene, pleasure, and nutrition, this underappreciated sense serves as an early warning system for environmental hazards such as spoiled food, fire, leaking natural gas, and air pollution. The olfactory system’s receptor cells are uniquely exposed to the outside environment, making them, along with other epithelial cells crucial for their function, susceptible to damage from airborne viruses, bacteria, and nanoparticles. As first order neurons, olfactory receptor cells can transport xenobiotics from the environment directly to the brain. Smell loss has been associated with early mortality and can signal the first stages of Alzheimer’s disease and Parkinson’s disease.,
In a Rapid Review in The Lancet Neurology, Michael Xydakis and colleaguesdiscuss the possible causes and the longevity of olfactory dysfunction associated with viruses, in particular SARS-CoV-2. They postulate that individuals who have smell loss due to COVID-19 might have increased susceptibility to future neurological disorders. There is precedent for this thinking.
In a 2-year longitudinal study of 1604 adults (aged >65 years) without dementia,cognitive decline was greater for those who had anosmia and carried at least one APOE ε4 allele than for normosmics who had no APOE ε4 allele (odds ratio 4·9, 95% CI 1·6–14·9), emphasising the importance of genotype with respect to loss of olfactory function and future cognitive decline. Cognitive decline was greatest in women with olfactory dysfunction and at least one APOE ε4 allele (odds ratio 9·7, 1·3–70·4). Before the discovery of genetic mutations and toxins (eg, 1-methyl-4-phenylpyridinium) that can damage dopaminergic neurons, viruses were considered the primary cause of Parkinson’s disease.More than 90% of patients with Parkinson’s disease have some degree of smell loss that precedes the motor symptoms by 4–8 years and, in some people, by up to 10 years.During the 1918 influenza pandemic, approximately 80% of individuals who recovered from encephalitis lethargica subsequently developed symptoms similar to those of Parkinson’s disease.
Several airborne viruses adversely affect the ability to smell. Indeed, the most frequent causes of permanent smell loss are virus-induced acute upper respiratory infections, including those caused by respiratory syncytial viruses, rhinoviruses, coronaviruses, and influenza viruses.Aside from the initial inflammation-related nasal blockage that accompanies most upper respiratory infections, incomplete damage to the olfactory neuroepithelium is common. Such damage is cumulative and can lead to greater pathogenic epithelial vulnerability later in life.Environmental factors, including viruses, seem to be more important than genetic ones in relation to age-related olfactory decrements.Rats reared in pathogen-free environments have less age-related decline in mature olfactory neurons than rats reared in standard laboratory conditions. Although the olfactory epithelium can regenerate, the process of regeneration is rarely complete after severe viral infections, resulting in a patchy and thin epithelium containing islands of interspersed metaplastic squamous epithelia and fewer cilia, olfactory receptor cells, and supporting cells.The proportion of the roughly 6 000 000 receptor cells in the human olfactory epithelium that needs to be damaged to produce noticeable olfactory deficits is unknown.
It is in this context of degeneration and regeneration that the effect of COVID-19 on olfaction can be seen. In a quantitative study addressing the reversal of smell loss due to COVID-19, which was not included in Xydakis and colleagues’ Rapid Review, Moein and colleaguesfound that 96 (96%) of 100 patients who were admitted to hospital for COVID-19 had measurable olfactory dysfunction near the end of the acute phase of their disease. Retesting 82 of these patients up to 8 weeks after the onset of COVID-19 symptoms found that 50 participants no longer had measurable olfactory dysfunction (61%; normosmia), 18 had mild dysfunction (22%; mild microsmia), 11 had moderate dysfunction (13%; moderate microsmia), and 3 had severe dysfunction (4%; severe microsmia). None of the patients had total smell loss (anosmia) when retested at 7–8 weeks after the onset of COVID-19 symptoms (figure).
In their Rapid Review, Xydakis and colleaguesdiscuss a multitude of possible causes for the smell loss associated with COVID-19 and highlight that supporting data are largely absent for most of them. Perhaps the smell loss associated with COVID-19 is simply the same, in both the degree and pathogenesis, as that of most upper respiratory infections. Men with COVID-19 appear to be more susceptible to smell loss than are women with this disease,a sex association similar to that seen with the common cold. The trajectory of return of function appears to be similar for COVID-19 and the common cold, although more detailed studies are needed.
The widespread awareness of smell loss from COVID-19 suggests it has a greater effect on the smell system than either the common cold or influenza. However, this suggestion could be misleading. For example, in the case of the common cold, nearly every affected individual has smell loss that is attributed to nasal congestion (as the loss largely dissipates once congestion subsides). Smell loss could also reflect underlying subtle inflammation or damage to the olfactory epithelium during infection. Moreover, when objectively measured, some degree of smell dysfunction can remain for days after the resolution of common cold-related congestion.
Since, unlike the common cold, COVID-19 is rarely accompanied by noticeable nasal congestion, the absence of an obvious explanation for the associated smell loss would magnify the apparent uniqueness of the loss. Could the smell loss associated with COVID-19 be the same as that of the common cold? Do ACE2 gene variants affect olfactory sequelae? Future research should be done to answer these questions.
RLD is a consultant to Eisai, Merck Pharmaceuticals, the Michael J Fox Foundation for Parkinson’s Research, Septodont, and Johnson & Johnson; receives royalties from Cambridge University Press, Johns Hopkins University Press, and John Wiley & Sons; and is president of, and a major shareholder in, Sensonics International, a manufacturer and distributor of smell and taste tests.

Reprinted for educational purposes and social benefit, not for profit.