Post-viral effects of COVID-19 in the olfactory system and their implications

BackgroundThe 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 developmentsThe 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 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. 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. 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. Until 2002, when SARS-CoV crossed the species barrier to infect humans, coronaviruses were considered as minor human pathogens.1Ksiazek TG Erdman D Goldsmith CS et al.A novel coronavirus associated with severe acute respiratory syndrome.N Engl J Med. 2003; 348: 1953-1966Crossref PubMed Scopus (3334) Google Scholar SARS-CoV and SARS-CoV-2 are related coronaviruses and have 72·8% nucleic acid sequence homology.2Zhou P Yang XL Wang XG et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (12018) Google Scholar Furthermore, both viruses use angiotensin converting enzyme 2 (ACE2) as an entry receptor, which engages the trimeric spike glycoprotein located on the surface of the virion. 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In this Rapid Review, we discuss the association between post-viral olfactory dysfunction and infection by SARS-CoV-2, summarise the biological pathways, contextualise histological evidence from autopsy studies, and propose a hypothesis about the usefulness of this dysfunction for predicting subsequent neurological disorders. Considering the intertwined relation between smell and taste,9Cho R To Z Yeung Z et al.COVID-19 viral load in the severity of and recovery from olfactory and gustatory dysfunction.Laryngoscope. 2020; 130: 2680-2685Crossref PubMed Scopus (48) Google Scholar, 11Vaira LA Hopkins C Petrocelli M et al.Smell and taste recovery in coronavirus disease 2019 patients: a 60-day objective and prospective study.J Laryngol Otol. 2020; 134: 703-709Crossref PubMed Scopus (107) Google Scholar, 15Lechien JR Chiesa-Estomba CM De Siati DR et al.Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study.Eur Arch Otorhinolaryngol. 2020; 277: 2251-2261Crossref PubMed Scopus (1550) Google Scholar, 17Andrews P Pendolino A Ottaviano G et al.Olfactory and taste dysfunction among mild-to-moderate symptomatic COVID-19 positive healthcare workers: an international survey.Investigative Laryngol. 2020; 5: 1019-1028Crossref PubMed Scopus (21) Google Scholar and because little is known about the underlying mechanisms that could account for the complete ageusia (ie, loss of taste) and loss of oral chemesthesis seen alongside post-viral olfactory dysfunction in people with COVID-19, we focus on olfactory symptomatology alone. The mechanisms underlying olfactory dysfunction in people who have had COVID-19 are difficult to disentangle because of the heterogeneity of presentations (panel 1). Such heterogeneity implies that SARS-CoV-2 infection can impair olfactory function at multiple anatomical levels and through various pathophysiological mechanisms that are not mutually exclusive. The factors underlying differences in recovery are unknown. In most cases of COVID-19, recovery of olfactory function is rapid, seemingly complete, and typically occurs in parallel with the resolution of physical, sinonasal, and coryzal symptoms. The median time of recovery of function after symptoms of olfactory dysfunction manifest is approximately 10 days, although residual and inapparent hyposmia, along with perceptual distortions, can persist.9Cho R To Z Yeung Z et al.COVID-19 viral load in the severity of and recovery from olfactory and gustatory dysfunction.Laryngoscope. 2020; 130: 2680-2685Crossref PubMed Scopus (48) Google Scholar, 11Vaira LA Hopkins C Petrocelli M et al.Smell and taste recovery in coronavirus disease 2019 patients: a 60-day objective and prospective study.J Laryngol Otol. 2020; 134: 703-709Crossref PubMed Scopus (107) Google Scholar, 14Lechien JR Chiesa-Estomba CM Place S et al.Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019.J Intern Med. 2020; 288: 335-344Crossref PubMed Scopus (484) Google Scholar, 26Dell'Era V Farri F Garzaro G Gatto M Aluffi Valletti P Garzaro M Smell and taste disorders during COVID-19 outbreak: cross-sectional study on 355 patients.Head Neck. 2020; 42: 1591-1596Crossref PubMed Scopus (73) Google Scholar, 27Lechner M Counsell N Liu J Eynon-Lewis N et al.Anosmia and hyposmia in healthcare workers with undiagnosed SARS-CoV-2 infection.Lancet Microbe. 2020; 1: e150Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 28Chiesa-Estomba C Lechien J Radulesco T et al.Patterns of smell recovery in 751 patients affected by the COVID-19 outbreak.Eur J Neurol. 2020; 27: 2318-2321Crossref PubMed Scopus (65) Google Scholar, 29Boscolo-Rizzo P Borsetto D Fabbris C et al.Evolution of altered sense of smell or taste in patients with mildly symptomatic COVID-19.JAMA Otolaryngol Head Neck Surg. 2020; 146: 729-732Crossref PubMed Scopus (109) Google ScholarPanel 1Types of olfactory dysfunction after viral infectionTransitory or short-term dysfunction•Conductive (obstructive) or mechanical losses (eg, congestion) resulting from blockage of inspired air due to local inflammation and oedema of mucosal tissue in the olfactory cleft and upper nasal passages•Sensorineural (olfactory epithelium and cranial nerve 1) dysfunction can be subdivided into two types:•Altered quantity or function of odorant-binding receptor molecules•Neuropraxia or dysfunction of olfactory sensory neurons•Central (olfactory bulbs and brain) dysfunction could be further subdivided *Top-down effects on central olfactory dysfunction (eg, acute head trauma or Parkinson's disease) are poorly understood.24Xydakis M Mulligan L Smith A Olsen C Lyon D Belluscio L Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study.Neurology. 2015; 84: 1559-1567Crossref PubMed Scopus (32) Google Scholar into: *Top-down effects on central olfactory dysfunction (eg, acute head trauma or Parkinson's disease) are poorly understood.24Xydakis M Mulligan L Smith A Olsen C Lyon D Belluscio L Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study.Neurology. 2015; 84: 1559-1567Crossref PubMed Scopus (32) Google Scholar•Pathosis isolated to the olfactory bulbs•Pathosis isolated to higher-order brain regions such as the piriform cortex and orbitofrontal cortex.Chronic or permanent dysfunction•Loss of olfactory epithelium (possibly because of death of neural stem cells)•Disruption of central olfactory processing networks24Xydakis M Mulligan L Smith A Olsen C Lyon D Belluscio L Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study.Neurology. 2015; 84: 1559-1567Crossref PubMed Scopus (32) Google Scholar, 25Holbrook EH Leopold DA Schwob JE Abnormalities of axon growth in human olfactory mucosa.Laryngoscope. 2005; 115: 2144-2154Crossref PubMed Scopus (59) Google Scholar•Uncertain functional recovery Transitory or short-term dysfunction •Conductive (obstructive) or mechanical losses (eg, congestion) resulting from blockage of inspired air due to local inflammation and oedema of mucosal tissue in the olfactory cleft and upper nasal passages•Sensorineural (olfactory epithelium and cranial nerve 1) dysfunction can be subdivided into two types:•Altered quantity or function of odorant-binding receptor molecules•Neuropraxia or dysfunction of olfactory sensory neurons•Central (olfactory bulbs and brain) dysfunction could be further subdivided *Top-down effects on central olfactory dysfunction (eg, acute head trauma or Parkinson's disease) are poorly understood.24Xydakis M Mulligan L Smith A Olsen C Lyon D Belluscio L Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study.Neurology. 2015; 84: 1559-1567Crossref PubMed Scopus (32) Google Scholar into: *Top-down effects on central olfactory dysfunction (eg, acute head trauma or Parkinson's disease) are poorly understood.24Xydakis M Mulligan L Smith A Olsen C Lyon D Belluscio L Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study.Neurology. 2015; 84: 1559-1567Crossref PubMed Scopus (32) Google Scholar•Pathosis isolated to the olfactory bulbs•Pathosis isolated to higher-order brain regions such as the piriform cortex and orbitofrontal cortex. Chronic or permanent dysfunction •Loss of olfactory epithelium (possibly because of death of neural stem cells)•Disruption of central olfactory processing networks24Xydakis M Mulligan L Smith A Olsen C Lyon D Belluscio L Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study.Neurology. 2015; 84: 1559-1567Crossref PubMed Scopus (32) Google Scholar, 25Holbrook EH Leopold DA Schwob JE Abnormalities of axon growth in human olfactory mucosa.Laryngoscope. 2005; 115: 2144-2154Crossref PubMed Scopus (59) Google Scholar•Uncertain functional recovery In people with COVID-19, endoscopic and radiographic evidence shows that the olfactory clefts of the superior nasal vault are not obstructed, suggesting that hyposmia is not accounted for by the conductive model. However, reversible nasal obstruction of airflow through the superior meatus (so-called olfactory cleft syndrome) is also found in a subset of people with olfactory dysfunction after SARS-CoV-2 infection.8Naeini A Karimi-Galougahi M Raad N et al.Paranasal sinuses computed tomography findings in anosmia of COVID-19.Am J Otolaryngol. 2020; 41102636Crossref PubMed Scopus (32) Google Scholar, 15Lechien JR Chiesa-Estomba CM De Siati DR et al.Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study.Eur Arch Otorhinolaryngol. 2020; 277: 2251-2261Crossref PubMed Scopus (1550) Google Scholar, 30Strauss SB Lantos JE Heier LA Shatzkes DR Phillips CD Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.AJNR Am J Neuroradiol. 2020; 41: 1882-1887Crossref PubMed Scopus (25) Google Scholar, 31Lechien J Michel J Radulesco T et al.Clinical and radiological evaluations of COVID-19 patients with anosmia: preliminary report.Laryngoscope. 2020; 130: 2526-2531Crossref PubMed Scopus (33) Google Scholar, 32Chung T Sridhar S Zhang A et al.Olfactory dysfunction in coronavirus disease 2019 patients: observational cohort study and systematic review.Open Forum Infect Dis. 2020; 7ofaa199Crossref PubMed Scopus (58) Google Scholar, 33Gelardi M Notargiacomo M Trecca EMC Cassano M Ciprandi G COVID-19 and nasal cytobrush cytology.Acta Cytol. 2020; 64: 397-398Crossref PubMed Scopus (10) Google Scholar, 34Eliezer M Hamel A Houdart E et al.Loss of smell in COVID-19 patients: MRI data reveals a transient edema of the olfactory clefts.Neurology. 2020; 95: e3145-e3152Crossref PubMed Scopus (58) Google Scholar The recovery rate of olfactory function in people with so-called long COVID (ie, individuals with persistent symptoms for more than 3 months) is still unknown (table). A 12–24 month observation period is required before chronic olfactory impairment can be classified as permanent. Moreover, current studies are generally based on self-reported data rather than a complete rhinological and psychophysical olfactometric examination. Importantly, unlike a cardinal symptom of ongoing infection (eg, fever), continued olfactory impairment does not reflect a contagious state or persistence of SARS-CoV-2 infection.29Boscolo-Rizzo P Borsetto D Fabbris C et al.Evolution of altered sense of smell or taste in patients with mildly symptomatic COVID-19.JAMA Otolaryngol Head Neck Surg. 2020; 146: 729-732Crossref PubMed Scopus (109) Google Scholar In individuals with COVID-19 who have not yet returned to baseline olfactory function, it is unclear whether chronic olfactory impairment is due to irreversible damage of the intranasal primary olfactory neurons embedded in the epithelium of the nasal vault, damage to the olfactory bulb, or dysfunction within other CNS pathways.TablePersistence of olfactory dysfunction beyond 45 days in patients with COVID-19Prevalence of dysfunctionFollow-up from symptom onsetCountryAssessment method*Quantitative olfactometry includes either the use of an odour identification test or the Connecticut Chemosensory Clinical Research Center orthonasal olfaction test.Confirmation of infectionVaira et al11Vaira LA Hopkins C Petrocelli M et al.Smell and taste recovery in coronavirus disease 2019 patients: a 60-day objective and prospective study.J Laryngol Otol. 2020; 134: 703-709Crossref PubMed Scopus (107) Google Scholar29 (21%) of 138 patients60 daysItalySelf-report or quantitative olfactometry†Quantitative olfactometry in inpatients and self-report in outpatients.PCRAndrews et al17Andrews P Pendolino A Ottaviano G et al.Olfactory and taste dysfunction among mild-to-moderate symptomatic COVID-19 positive healthcare workers: an international survey.Investigative Laryngol. 2020; 5: 1019-1028Crossref PubMed Scopus (21) Google Scholar60 (68%) of 88 patients52 days (mean)Italy and UKSelf-reportPCRChiesa-Estomba et al28Chiesa-Estomba C Lechien J Radulesco T et al.Patterns of smell recovery in 751 patients affected by the COVID-19 outbreak.Eur J Neurol. 2020; 27: 2318-2321Crossref PubMed Scopus (65) Google Scholar384 (51%) of 751 patients47 days (mean)Belgium, France, and SpainSelf-reportPCR or IgG and IgMOtte et al35Otte MS Klussmann JP Luers JC Persisting olfactory dysfunction in patients after recovering from COVID-19.J Infect. 2020; 81: e58Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar27 (54%) of 50 patients49 daysGermanyQuantitative olfactometryPCRCarfì et al36Carfì A Bernabei R Landi F Persistent symptoms in patients after acute COVID-19.JAMA. 2020; 324: 603-605Crossref PubMed Scopus (1883) Google Scholar21 (15%) of 143 patients60 days (mean)ItalySelf-reportPCROtte et al37Otte MS Eckel HNC Poluschkin L Klussmann JP Luers JC Olfactory dysfunction in patients after recovering from COVID-19.Acta Otolaryngol. 2020; 140: 1032-1035Crossref PubMed Scopus (44) Google Scholar42 (46%) of 91 patients58 days (mean)GermanyQuantitative olfactometryPCRBoscolo-Rizzo et al38Boscolo-Rizzo P Polesel J Spinato G et al.Predominance of an altered sense of smell or taste among long-lasting symptoms in patients with mildly symptomatic COVID-19.Rhinology. 2020; 58: 524-525Crossref PubMed Scopus (29) Google Scholar34 (19%) of 183 patients56 days (mean)ItalySelf-reportPCRKlein et al39Klein H Asseo K Karni N et al.Onset, duration, and persistence of taste and smell changes and other COVID-19 symptoms: longitudinal study in Israeli patients.medRxiv. 2020; (published online Oct 17.) (preprint).https://doi.org/10.1101/2020.09.25.20201343Google Scholar15 (14%) of 105 patients6 monthsIsraelSelf-reportPCRLogue et al40Logue JK Franko NM McCulloch DJ et al.Sequelae in adults at 6 months after COVID-19 infection.JAMA Netw Open. 2021; 4e210830Crossref PubMed Scopus (345) Google Scholar24 (14%) of 177 patients169 days (median)USASelf-reportPCRBoscolo-Rizzo et al41Boscolo-Rizzo P Menegaldo A Fabbris C et al.Six-month psychophysical evaluation of olfactory dysfunction in patients with COVID-19.Chem Senses. 2021; (published online Feb 12.)https://doi.org/10.1093/chemse/bjab006Crossref PubMed Scopus (66) Google Scholar87 (60%) of 145 patients6 monthsItalyQuantitative olfactometryPCRHuang et al42Huang C Huang L Wang Y et al.6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.Lancet. 2021; 397: 220-232Summary Full Text Full Text PDF PubMed Scopus (1846) Google Scholar176 (11%) of 1655 patients6 monthsChinaSelf-reportPCRPilotto et al43Pilotto A Cristillo V Piccinelli C et al.Long-term neurological manifestations of COVID-19: prevalence and predictive factors.medRxiv. 2021; (published online March 14.) (preprint).https://doi.org/10.1101/2020.12.27.20248903Google Scholar26 (16%) of 165 patients6 monthsItalySelf-reportPCR* Quantitative olfactometry includes either the use of an odour identification test or the Connecticut Chemosensory Clinical Research Center orthonasal olfaction test.† Quantitative olfactometry in inpatients and self-report in outpatients. Open table in a new tab To the best of our knowledge, no historical data exists on how pathosis confined within the olfactory bulbs (eg, infection and neuroinflammation) manifests clinically, and it is not clear whether pathosis would present as anosmia, perceptual distortions (ie, parosmias or phantosmias), or focal or mild encephalitis.44Casez O Willaume G Grand S et al.Teaching NeuroImages: SARS-CoV-2-related encephalitis: MRI pattern of olfactory tract involvement.Neurology. 2021; 96: e645-e646Crossref PubMed Scopus (14) Google Scholar A local disease process that is isolated to, and contained within, the olfactory bulbs might not produce sufficient characteristic signs and symptoms to enable clinicians to suspect CNS pathosis on clinical grounds alone and, thus, be able to judge these symptoms as being associated with SARS-CoV-2. In addition, acute aseptic encephalitis is a very difficult condition to diagnose, even with clinical, laboratory, and neurodiagnostic findings considered pathognomonic.44Casez O Willaume G Grand S et al.Teaching NeuroImages: SARS-CoV-2-related encephalitis: MRI pattern of olfactory tract involvement.Neurology. 2021; 96: e645-e646Crossref PubMed Scopus (14) Google Scholar, 45Moriguchi T Harii N Goto J et al.A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.Int J Infect Dis. 2020; 94: 55-58Summary Full Text Full Text PDF PubMed Scopus (1235) Google Scholar A distinctive portrait of short-term and intermediate-term neurological manifesta