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.2Graves AB Bowen JD Rajaram L et al.Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status.Neurology. 1999; 53: 1480-1487Crossref PubMed Google Scholar, 3Doty RL Olfactory dysfunction in neurodegenerative diseases: is there a common pathological substrate?.Lancet Neurol. 2017; 16: 478-488Summary Full Text Full Text PDF PubMed Scopus (176) Google Scholar In a Rapid Review in The Lancet Neurology, Michael Xydakis and colleagues1Xydakis MS Albers MW Holbrook EH et al.Post-viral effects of COVID-19 in the olfactory system and their implications.Lancet Neurol. 2021; (published online July 30.)https://doi.org/10.1016/S1474-4422(21)00182-4Summary Full Text Full Text PDF PubMed Scopus (55) Google Scholar discuss 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,2Graves AB Bowen JD Rajaram L et al.Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status.Neurology. 1999; 53: 1480-1487Crossref PubMed Google Scholar 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.3Doty RL Olfactory dysfunction in neurodegenerative diseases: is there a common pathological substrate?.Lancet Neurol. 2017; 16: 478-488Summary Full Text Full Text PDF PubMed Scopus (176) Google Scholar 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.3Doty RL Olfactory dysfunction in neurodegenerative diseases: is there a common pathological substrate?.Lancet Neurol. 2017; 16: 478-488Summary Full Text Full Text PDF PubMed Scopus (176) Google Scholar During the 1918 influenza pandemic, approximately 80% of individuals who recovered from encephalitis lethargica subsequently developed symptoms similar to those of Parkinson's disease.4Henry J Smeyne RJ Jang H Miller B Okun MS Parkinsonism and neurological manifestations of influenza throughout the 20th and 21st centuries.Parkinsonism Relat Disord. 2010; 16: 566-571Summary Full Text Full Text PDF PubMed Scopus (69) Google Scholar 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.5Potter MR Chen JH Lobban NS Doty RL Olfactory dysfunction from acute upper respiratory infections: relationship to season of onset.Int Forum Allergy Rhinol. 2020; 10: 706-712Crossref PubMed Scopus (22) Google Scholar 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.6Doty RL Petersen I Mensah N Christensen K Genetic and environmental influences on odor identification ability in the very old.Psychol Aging. 2011; 26: 864-871Crossref PubMed Scopus (56) Google Scholar Environmental factors, including viruses, seem to be more important than genetic ones in relation to age-related olfactory decrements.6Doty RL Petersen I Mensah N Christensen K Genetic and environmental influences on odor identification ability in the very old.Psychol Aging. 2011; 26: 864-871Crossref PubMed Scopus (56) Google Scholar Rats reared in pathogen-free environments have less age-related decline in mature olfactory neurons than rats reared in standard laboratory conditions.7Loo AT Youngentob SL Kent PF Schwob JE The aging olfactory epithelium: neurogenesis, response to damage, and odorant-induced activity.Int J Dev Neurosci. 1996; 14: 881-900Crossref PubMed Scopus (128) Google Scholar 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.8Yamagishi M Hasegawa S Nakano Y Examination and classification of human olfactory mucosa in patients with clinical olfactory disturbances.Arch Otorhinolaryngol. 1988; 245: 316-320Crossref PubMed Scopus (44) Google Scholar 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 colleagues9Moein ST Hashemian SM Tabarsi P Doty RL Prevalence and reversibility of smell dysfunction measured psychophysically in a cohort of COVID-19 patients.Int Forum Allergy Rhinol. 2020; 10: 1127-1135Crossref PubMed Scopus (50) Google Scholar found 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 colleagues1Xydakis MS Albers MW Holbrook EH et al.Post-viral effects of COVID-19 in the olfactory system and their implications.Lancet Neurol. 2021; (published online July 30.)https://doi.org/10.1016/S1474-4422(21)00182-4Summary Full Text Full Text PDF PubMed Scopus (55) Google Scholar discuss 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,9Moein ST Hashemian SM Tabarsi P Doty RL Prevalence and reversibility of smell dysfunction measured psychophysically in a cohort of COVID-19 patients.Int Forum Allergy Rhinol. 2020; 10: 1127-1135Crossref PubMed Scopus (50) Google Scholar 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.10Huart C Philpott C Konstantinidis I et al.Comparison of COVID-19 and common cold chemosensory dysfunction.Rhinology. 2020; 58: 623-625Crossref PubMed Scopus (72) Google Scholar 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.10Huart C Philpott C Konstantinidis I et al.Comparison of COVID-19 and common cold chemosensory dysfunction.Rhinology. 2020; 58: 623-625Crossref PubMed Scopus (72) Google Scholar 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. Post-viral effects of COVID-19 in the olfactory system and their implicationsThe 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. Full-Text PDF