While SARS-CoV-2 has yet to be detected in the CNS, it is important to consider prolonged anosmia as part of COVID-19 symptomatology given the neuroinvasive potentials of previously studied coronavirus strains. In this case report, a 59-year-old male who had SARS-related respiratory symptoms experienced four-limb twitching and status epilepticus. 2020; Spinato et al. SARS-CoV-infected immune cells are hypothesized to promote a pro-inflammatory state that contributes to severe disease, and a similar mechanism is implicated in SARS-CoV-2 (Perlman and Dandekar 2005; Mehta et al. From each dendritic knob of an OSN, 10–30 cilia protrude out into the mucus layer (Glezer and Malnic 2019). Delayed Septal Perforation as a Complication of COVID-19: A Case Report. Therefore, this review will be focused on the olfactory system. 1994). Please enable it to take advantage of the complete set of features! Although the etiology of MS remains disputed, it is postulated that genetic factors (Ebers and Sadovnick 1994) and viral pathogens, such as HCoV, induce CNS demyelination via chronic infection of oligodendrocytes (Perlman 1998; Arbour et al. 2020 Apr 16;5(3):354-359. doi: 10.1002/lio2.384. Olfactory Cleft Measurements and COVID-19-Related Anosmia. 2020; Lechien et al. Contribution of authors A well-known side effect of having one’s nose clogged with mucus after contracting a cold or the flu, anosmia (loss of smell) can be long-lasting or even permanent in a small number of patients. Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, Dequanter D, Blecic S, El Afia F, Distinguin L, et al. HCA Lung Biological Network. Golf activation stimulates adenylyl cyclase, followed by the formation of cyclic adenosine monophosphate. USA.gov. Indeed, in addition to anosmia and hyposmia, olfactory dysfunctions, such as phantosmia (distorted sense of smell) and olfactory hallucination (perceived distortion in the absence of an odorant), can occur in epilepsy, migraine, meningitis, and disorders of the CNS (Hong et al. Akerlund A, Bende M, Murphy C. 1995. Olfactory dysfunction in multiple sclerosis. And while doctors are hopeful many will recover this sense, it could take months to years, because the neurons in your nose have to replace themselves, and then they have grow new axons that extend up and connect … We aim to review the pathophysiology of anosmia related to viral upper respiratory infections and the prognostic implications. COVID-19; anosmia; coronavirus; olfaction; post-viral anosmia. Miwa T, Furukawa M, Tsukatani T, Costanzo RM, DiNardo LJ, Reiter ER. Of note, HCoV-229E uses human aminopeptidase N as the receptor for host entry, which is different from SARS-CoV and SARS-CoV-2 that use ACE2 (Yeager et al. e-mail: Olfactory threshold and nasal mucosal changes in experimentally induced common cold, Olfactory memory representations are stored in the anterior olfactory nucleus, Neuroinvasion by human respiratory coronaviruses, Chronic cortical and subcortical pathology with associated neurological deficits ensuing experimental herpes encephalitis, Olfactory dysfunction in multiple sclerosis, Identification and molecular regulation of neural stem cells in the olfactory epithelium, Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts, Vesicular stomatitis virus infection of the central nervous system activates both innate and acquired immunity, Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia, Evaluation of olfactory dysfunction in the Connecticut Chemosensory Clinical Research Center, Olfactory function and cognition in relapsing-remitting and secondary-progressive multiple sclerosis, The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2, Host immune response to vesicular stomatitis virus infection of the central nervous system in C57BL/6 mice, Topical dexamethasone administration impairs protein synthesis and neuronal regeneration in the olfactory epithelium, Molecular signatures of neural connectivity in the olfactory cortex, An interactive web-based dashboard to track COVID-19 in real time, The spike protein of SARS-CoV–a target for vaccine and therapeutic development, Herpes simplex virus type 1 infection of the central nervous system: insights into proposed interrelationships with neurodegenerative disorders, Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43, The olfactory bulb: an immunosensory effector organ during neurotropic viral infections, The role of genetic factors in multiple sclerosis susceptibility, Loss of sense of smell as marker of COVID-19 infection [press release], SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium, Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia: the first report. Currently, the CDC lists fever, cough and shortness of breath as the most common symptoms of COVID-19. Reports of olfactory dysfunction in otherwise asymptomatic persons have led to interest in this sign as a potential early indicator of SARS-CoV-2 infection (Hopkins et al. At least five cell types exist in this epithelial layer: olfactory sensory neurons (OSNs), sustentacular cells, microvillar cells, duct cells of the olfactory (Bowman’s) glands, and basal cells (van Riel et al. Postviral anosmia has been reported after HCoV-229E infection, and the olfactory dysfunction lasted more than 6 months (Suzuki et al. A viral infection of the nasal OE can result in injury to part or all of the nasal OE, including OSNs. An anecdotal survey of patients in South Korea revealed that about 30% had anosmia as their major presenting symptom of COVID-19 (ENT UK 2020). 2010). In mouse models of HSE, necrotic debris was present in the olfactory bulb within 5 days postinfection, then within the cranial nerve tracts and nuclei with presence of neutrophils, macrophages, and lymphocytes by 7 days (Armien et al. Galván-Tejada CE, Herrera-García CF, Godina-González S, Villagrana-Bañuelos KE, Amaro JDL, Herrera-García K, Rodríguez-Quiñones C, Zanella-Calzada LA, Ramírez-Barranco J, Avila JLR, Reyes-Escobedo F, Celaya-Padilla JM, Galván-Tejada JI, Gamboa-Rosales H, Martínez-Acuña M, Cervantes-Villagrana A, Rivas-Santiago B, Gonzalez-Curiel IE. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. It is therefore perhaps no surprise that the novel COVID-19 virus would also cause anosmia in infected patients. -. Supporting evidence that SARS-CoV-2 causes conductive olfactory dysfunction comes from the time of onset of anosmia in these patients: olfactory dysfunction after (26.7–65.4%) or at the same time (22.8%) as the general or ENT symptoms in COVID-19 patients (Lechien et al. B) Patients with no COVID infection (LOS more than 3 months): An MRI scan of brain is recommended if endoscopy is normal. For permissions, please e-mail: journals.permissions@oup.com. All'inizio della pandemia, medici e ricercatori temevano che l'anosmia legata a COVID-19 potesse indicare che il virus arriva nel cervello attraverso il naso, dove potrebbe causare danni gravi e duraturi. Bertram S, Heurich A, Lavender H, Gierer S, Danisch S, Perin P, Lucas JM, Nelson PS, Pöhlmann S, Soilleux EJ. Isolated loss of smell (LOS) A) Patients with COVID infection (regardless of LOS duration): An MRI scan of brain is not recommended. This paper reviews the olfactory physiology, summarizes the clinical reports of anosmia in current and previous viral outbreaks, and specifically discusses neurological implications of this syndrome. The researchers from France and Belgium can’t explain why anosmia indicates a better prognosis for COVID-19. The pathophysiology of “postviral anosmia” and histological analyses have been described in the literature, mainly following rhinovirus infection. Permanent anosmia has been described in patients who recovered from HSE (Landis et al. Covid-19 testing. 2020. Suzuki M, Saito K, Min WP, Vladau C, Toida K, Itoh H, Murakami S. Temmel AF, Quint C, Schickinger-Fischer B, Klimek L, Stoller E, Hummel T. Twomey JA, Barker CM, Robinson G, Howell DA. The clinical course of neuroinvasion of SARS-CoV-2 is yet unclear; however, an extended follow-up of these patients to assess for neurological sequelae, including encephalitis, cerebrovascular accidents, and long-term neurodegenerative risk may be indicated. 2020 May 14:bjaa031. COVID-19-related anosmia is a new description in the medical literature. The recovery time was not assessed in this particular study, and it is not clear whether this was conductive or sensorineural olfactory dysfunction (Akerlund et al. Anosmia is associated with dysgeusia in more than 80% of cases. 1992; Hoffmann et al. Corona Viruses and the Chemical Senses: Past, Present, and Future. Interestingly, administering cyclosporine to induce immune suppression during HCoV-OC43 inoculation did not prevent the formation of vacuolating lesions and neuronal death in mice, which suggests that some aspects of neurodegeneration are not immunologically mediated (Jacomy and Talbot 2003). With few studies published yet, we can only speculate on the mechanism of anosmia symptoms in SARS-CoV-2 patients. 2016). The N-terminal end of the spike protein (S1) contains the receptor-binding domain that binds to the host’s angiotensin-converting enzyme 2 (ACE2), resulting in a conformational change of the S protein. All rights reserved. 2020). It is possible that the apparently increasing incidence of olfactory dysfunction is due to greater awareness and more careful assessment of the symptom. 2004). Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, Cao Y, Yousif AS, Bals J, Hauser BM, et al. 1995; Lane et al. We aim to review the pathophysiology of anosmia related to viral upper respiratory infections and the prognostic implications. 2020). Viral infection and smell loss: The case of COVID-19. Jafek BW, Hartman D, Eller PM, Johnson EW, Strahan RC, Moran DT. More recent olfactory surveys on COVID-19 patients showed olfactory dysfunction in 20–85% of patients (Giacomelli et al. The rates of permanent anosmia post-COVID-19 infection and impact of viral treatment regimens should be assessed. 2016). The single-cell RNA-seq approach has been used to identify specific cells of the OE that coexpress ACE2 and TMPRSS2. 2020). Strictly speaking, olfactory dysfunction due to central causes would require involvement of the brain areas processing olfactory information. 1 1 COVID-19 Anosmia Reporting Tool: Initial Findings 2 3 Rachel Kaye, MD, Rutgers New Jersey Medical School, Newark, NJ 4 5 C.W. Albert Y Han, Laith Mukdad, Jennifer L Long, Ivan A Lopez, Anosmia in COVID-19: Mechanisms and Significance, Chemical Senses, Volume 45, Issue 6, July 2020, Pages 423–428, https://doi.org/10.1093/chemse/bjaa040. 2015). The outcome seems favourable in less than 28 days. Preliminary data from Fodoulian et al. Isolated sudden onset anosmia in COVID-19 infection. 1990) as do other RNA viruses, such as rhabdoviruses (Christian et al. COVID-19 is an emerging, rapidly evolving situation. BACKGROUND AND PURPOSE: Unique among the acute neurologic manifestations of Severe Acute Respiratory Syndrome coronavirus 2, the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, is chemosensory dysfunction (anosmia or dysgeusia), which can be seen in patients who are otherwise oligosymptomatic or even asymptomatic. Nevertheless, it has become clear that there is a striking incidence of neurological involvement in this disease, the symptoms of which span reversible anosmia, stroke-related disability, and death. Anosmia can be broadly categorized into conductive or sensorineural olfactory loss (Goncalves and Goldstein 2016). • Viral URIs classically manifest as rhinorrhea and nasal obstruction, leading to conductive olfactory loss. Online ahead of print. Atalar AÇ, Erdal Y, Tekin B, Yıldız M, Akdoğan Ö, Emre U. Beites CL, Kawauchi S, Crocker CE, Calof AL. A prospective study of hospitalized patients showed that patients with these endemic HCoV strains showed rhinitis, pharyngitis, and laryngitis, although less commonly than lower respiratory symptoms (Greenberg 2011). Arbour N, Day R, Newcombe J, Talbot PJ. About 72.6% of these patients recovered olfactory function within the first 8 days, which suggests that the majority of anosmia is temporary in nature (Lechien et al. This may be an area for further investigation. 2018). Recent evidence suggests that SARS-CoV-2 causes cardiac injury by targeting pericytes in the heart with high expression of ACE2 (Chen et al. OSNs in the OE undergo continuous turnover throughout a person’s life. Persistence of COVID-19 Symptoms after Recovery in Mexican Population. Post-HSE anosmia often presents with other neurological sequelae, including epilepsy, amnesia, and cognitive deficits. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, et al. Insufficient PCR testing capability further hindered diagnosis and early containment within the United States. Initially, odorants enter the superior aspect of the nasal cavity, which is lined by the olfactory epithelium (OE; see Whitman and Greer 2009). Anosmia post covid-19 Anosmia, non sento odori da oltre un anno Anosmia fluttuante e perdita parziale del gusto con episodi di percezione di odore sgradevole -, Armien AG, Hu S, Little MR, Robinson N, Lokensgard JR, Low WC, Cheeran MC. The axons of the second-order olfactory neurons (mitral and tufted cells) subsequently project to diverse olfactory areas of the central nervous system (CNS). To our knowledge, our study is the main monocentric cohort of confirmed COVID-19 patients with anosmia in France and in the medical literature. The propagation of HCoV-OC43 viral particles is mediated by axonal transport in neuron-to-neuron transmission (Dubé et al. The mechanism of SARS-CoV entry into host cells has been well characterized and resembles that of the human immunodeficiency virus and the influenza virus. 2005). 2021 Jan-Feb;42(1):102796. doi: 10.1016/j.amjoto.2020.102796. 1995). Published by Oxford University Press. Recent preliminary data showed ACE2 expression in perivascular cells of the OE, which supports the hypothesis of hematologic spread of SARS-CoV-2, although further studies are required to delineate the exact mechanism of pathogenesis (Brann et al. HHS 2020). Chronic cortical and subcortical pathology with associated neurological deficits ensuing experimental herpes encephalitis. Cain WS, Gent JF, Goodspeed RB, Leonard G. Carotenuto A, Costabile T, Moccia M, Falco F, Scala MR, Russo CV, Saccà F, De Rosa A, Lanzillo R, Brescia Morra V. Chen L, Li X, Chen M, Feng Y, Xiong C. Christian AY, Barna M, Bi Z, Reiss CS. Acta Otolaryngol. Current evidence suggests that SARS-CoV-2-related anosmia may be a new viral syndrome specific to COVID-19 and can be mediated by intranasal inoculation of SARS-CoV-2 into the olfactory neural circuitry. 2020 Sep 24:10.1111/jnc.15197. This is followed by proteolytic cleavage of the S protein by TMPRSS2 (Chen and Subbarao 2007; Shulla et al. Methods This was a prospective, monocentric, case-controlled study. 2020). Online ahead of print. Online ahead of print. -, Atalar AÇ, Erdal Y, Tekin B, Yıldız M, Akdoğan Ö, Emre U. 2001; Seiden and Duncan 2001; Temmel et al. Anecdotal and preliminary evidence from multiple institutions shows that these patients present with a sudden onset of anosmia … Recent studies have shown that the AON utilizes input from the hippocampus for storage of olfactory memory representations (Aqrabawi and Kim 2020). Indeed, the degree and quality of olfactory deficit in post-HSE patients varies, suggesting that some patients might suffer from a more “central” pattern of olfactory impairment involving limbic areas (Landis et al. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al. 2020 Nov 16:1-5. doi: 10.1017/S0022215120002455. Half of the patients with COVID-19 present with anosmia. 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The cerebrospinal fluid of this patient was found to have a high SARS-CoV viral load (6884 copies/mL). Interestingly, recent studies have indicated that olfactory dysfunction is correlated with progressive cognitive impairment and physical disability in MS patients (Atalar et al. We report 5 cases (3 with anosmia) of adult patients with COVID-19 in whom injury to the olfactory bulbs was interpreted as microbleeding or abnormal enhancement on MR imaging. Several possible mechanisms are suggested for the SARS-CoV-2 anosmia that may cause anosmia alone or in concert. of symptoms of anosmia and dysgeusia for COVID-19. Evaluation of the OE of HSE patients revealed diffuse inflammation and ragged appearance due to vesicles between the cells. The basal cells (both globose and horizontal types) are pluripotent and can give rise to all subtypes of OE cells (Beites et al. Online ahead of print. All rights reserved. Since the olfactory bulb is considered an immunological organ contributing to prevent the invasion of viruses, it could have a role in host defense. SARS-CoV-2, part of the family Coronaviridae, is an enveloped, positive-sense single-stranded ribonucleotide acid (RNA) virus. 2020). 2020; Ziegler et al. 115(1):88–92. Fodoulian L, Tuberosa J, Rossier D, Landis BN, Carleton A, Rodriguez I. Galougahi MK, Ghorbani J, Bakhshayeshkaram M, Naeini AS, Haseli S. Giacomelli A., Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L, Rusconi S, Gervasoni C, Ridolfo AL, Rizzardini D, et al. Certainly, this hypothesis would require longitudinal patient studies to delineate and gather more evidence on the progressive decline of neurological function. 2018). Olfactory function provides critical information about the environment, which is why substantial neural circuitry is dedicated to processing olfaction and multisensory integration. 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