Mechanisms of olfactory impairment in COVID-19: a systematic review

One of the symptoms of a new coronavirus infection (COVID-19) is a complete or partial violation of the sense of smell. The aim of the work is to analyze the published results of scientific research on the mechanisms of olfactory impairment in COVID-19. Material and methods. Research was conducted for publications in Pubmed on the problem of olfactory impairment in COVID-19 using terms indexed by MeSH. The systematic review was compiled in accordance with the checklist Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA). Results. Publication's analysis has shown that the existing ideas about conductive anosmia are insufficient to explain the causes of olfactory impairment caused by SARS-CoV-2. It has been established that ACE2 and TMPRSS2 receptors located on the surface of target cells are necessary for the penetration of a new coronavirus. It is known that these receptors are mainly located on the cells of the olfactory epithelium. The main hypothesis of olfactory impairment in COVID-19 is that anosmia/hyposmia is caused by damage not to neuronal cells (as previously assumed), but to the olfactory epithelium. There is no confirmation of the point of view about the damage of SARS-CoV-2 olfactory bulbs and olfactory neurons, since they do not express receptor proteins for the virus on their surface.Copyright © 2022 by the authors.

Neuropathogenesis and Neurological Manifestations of SARS-CoV-2

Neurological complications of COVID-19 contribute significantly to mortality in the intensive care unit (ICU). Preventive therapy, though discussed in literature, is limited for COVID-19 neurological manifestations and treatment algorithms continue to rely on evidence from previous pandemics. Thus, in this chapter we evaluate current in vitro, in vitro, histopathological studies to ascertain the most likely mechanisms of SARS-CoV-2 central nervous system entry. From this understanding, we determine probable mechanisms for neurological compilations observed in COVID-19 as relevant to the clinician. SARS-CoV-2 infection of nasal epithelium and the respiratory tract may allow for a systemic inflammatory response that results in neuroinflammation. While most neurological complications are inflammatory in etiology, rarely, SARS-CoV-2 may enter into the central nervous system and mediate neuronal damage. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Possible consequences of Covid-19 on the nervous system

OBJECTIVES: The aim of the survey was to find out what the possible consequences are of the COVID-19 disease on the nervous system and to propose a method of using artificial intelligence. MATERIAL AND METHODS: Recent research has shown that the risks to patients due to severe acute coronavirus 2 respiratory syndrome (SARS-COV-2) differ most significantly depending on age and the presence of underlying comorbidities such as: cardiovascular disease, hypertension, diabetes and others. The consequences of COVID-19 on the nervous system are especially important. We performed a detailed selection of articles describing the effects of COVID-19 on the nervous system. RESULT(S): We made a clear summary of the main consequences of COVID-19 on the nervous system and suggested a way to use artificial intelligence. CONCLUSION(S): We confirmed research that artificial intelligence methods have the potential to accelerate prediction, especially for the possible consequences of COVID-19 on the nervous system.Copyright © 2020 Neuroendocrinology Letters

Genomic regulatory network of human olfactory neuroepithelial cells infected with novel coronavirus (SARS-COV-2).

Objective To explore the genomic changes of human olfactory neuroepithelial cells after the novel coronavirus (SARS-COV-2) infecting the human body, and establish a protein-protein interaction (PPI) network of differentially expressed genes (DEGs), in order to understand the impact of SARS-COV-2 infection on human olfactory neuroepithelial cells, and provide reference for the prevention and treatment of new coronavirus pneumonia. Methods The public dataset GSE151973 was analyzed by NetworkAnalyst. DEGs were selected by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis. PPI network, DEGs-microRNA regulatory network, transcription factor-DEGs regulatory network, environmental chemicals-DEGs regulatory network, and drug-DEGs regulatory network were created and visualized by using Cytoscape 3.7.2. Results After SAR-COV-2 invading human olfactory neuroepithelial cells, part of the gene expression profile was significantly up-regulated or down-regulated. A total of 568 DEGs were found, including 550 up-regulated genes (96.8%) and 18 down-regulated genes (3.2%). DEGs were mainly involved in biological processes such as endothelial development and angiogenesis of the olfactory epithelium, and the expression of molecular functions such as the binding of the N-terminal myristylation domain. PPI network suggested that RTP1 and RTP2 were core proteins. MAZ was the most influential transcription factor. Hsa-mir-26b-5p had the most obvious interaction with DEGs regulation. Environmental chemical valproic acid and drug ethanol had the most influence on the regulation of DEG. Conclusion The gene expression of olfactory neuroepithelial cells is significantly up-regulated or down-regulated after infection with SAR-COV-2. SARS-CoV-2 may inhibit the proliferation and differentiation of muscle satellite cells by inhibiting the function of PAX7. RTP1 and RTP2 may resist SARS-CoV-2 by promoting the ability of olfactory receptors to coat the membrane and enhancing the ability of olfactory receptors to respond to odorant ligands. MAZ may regulate DEGs by affecting cell growth and proliferation. Micro RNA, environmental chemicals and drugs also play an important role in the anti-SAR-COV-2 infection process of human olfactory neuroepithelial cells.Copyright © 2022 Editorial Department of Journal of Shanghai Second Medical University. All rights reserved.

[The alleged mechanisms of olfactory disorders in the new coronavirus infection]. / Vozmozhnye mekhanizmy narushenii obonyaniya pri novoi koronavirusnoi infektsii.

In March 2020, the World Health Organization (WHO) announced the beginning of the COVID-19 pandemic, which continues to the present. A change in the sense of smell, up to the complete disappearance of odors, is regarded as one of the early symptoms of the disease. Sometimes anosmia was the only sign of infection of the patient. As is known, a disturbance of the sense of smell indicates a serious pathology of the brain, such as the consequences of traumatic brain injuries, strokes, Alzheimer's disease, Parkinson's disease, autoimmune diseases, a side-effect of drug therapy. The review is dedicated to the pathogenesis of anosmia in COVID-19. For a better understanding of the pathogenesis, the article presents a brief anatomy and physiology of the olfactory organ as well as the probable mechanisms of anosmia: encephalitis, inflammatory edema of the olfactory cleft, olfactory epithelium damage, apoptosis of bipolar neurons, damage of olfactory cell cilia and damage of olfactory bulbs. Because of the rapid accumulation of information on this topic, there is a need to structure, periodic systematization and presentation to a wide range of specialists.

Mucosal plasma cells are required to protect the upper airway and brain from infection.

While blood antibodies mediate protective immunity in most organs, whether they protect nasal surfaces in the upper airway is unclear. Using multiple viral infection models in mice, we found that blood-borne antibodies could not defend the olfactory epithelium. Despite high serum antibody titers, pathogens infected nasal turbinates, and neurotropic microbes invaded the brain. Using passive antibody transfers and parabiosis, we identified a restrictive blood-endothelial barrier that excluded circulating antibodies from the olfactory mucosa. Plasma cell depletions demonstrated that plasma cells must reside within olfactory tissue to achieve sterilizing immunity. Antibody blockade and genetically deficient models revealed that this local immunity required CD4+ T cells and CXCR3. Many vaccine adjuvants failed to generate olfactory plasma cells, but mucosal immunizations established humoral protection of the olfactory surface. Our identification of a blood-olfactory barrier and the requirement for tissue-derived antibody has implications for vaccinology, respiratory and CNS pathogen transmission, and B cell fate decisions.

Genomic regulatory network of human olfactory neuroepithelial cells infected with novel coronavirus (SARS-COV-2)

Objective To explore the genomic changes of human olfactory neuroepithelial cells after the novel coronavirus (SARS-COV-2) infecting the human body, and establish a protein-protein interaction (PPI) network of differentially expressed genes (DEGs), in order to understand the impact of SARS-COV-2 infection on human olfactory neuroepithelial cells, and provide reference for the prevention and treatment of new coronavirus pneumonia. Methods The public dataset GSE151973 was analyzed by NetworkAnalyst. DEGs were selected by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis. PPI network, DEGs-microRNA regulatory network, transcription factor-DEGs regulatory network, environmental chemicals-DEGs regulatory network, and drug-DEGs regulatory network were created and visualized by using Cytoscape 3.7.2. Results After SAR-COV-2 invading human olfactory neuroepithelial cells, part of the gene expression profile was significantly up-regulated or down-regulated. A total of 568 DEGs were found, including 550 up-regulated genes (96.8%) and 18 down-regulated genes (3.2%). DEGs were mainly involved in biological processes such as endothelial development and angiogenesis of the olfactory epithelium, and the expression of molecular functions such as the binding of the N-terminal myristylation domain. PPI network suggested that RTP1 and RTP2 were core proteins. MAZ was the most influential transcription factor. Hsa-mir-26b-5p had the most obvious interaction with DEGs regulation. Environmental chemical valproic acid and drug ethanol had the most influence on the regulation of DEG. Conclusion The gene expression of olfactory neuroepithelial cells is significantly up-regulated or down-regulated after infection with SAR-COV-2. SARS-CoV-2 may inhibit the proliferation and differentiation of muscle satellite cells by inhibiting the function of PAX7. RTP1 and RTP2 may resist SARS-CoV-2 by promoting the ability of olfactory receptors to coat the membrane and enhancing the ability of olfactory receptors to respond to odorant ligands. MAZ may regulate DEGs by affecting cell growth and proliferation. Micro RNA, environmental chemicals and drugs also play an important role in the anti-SAR-COV-2 infection process of human olfactory neuroepithelial cells.

Olfactory dysfunction in COVID-19: new insights into the underlying mechanisms.

The mechanisms of olfactory dysfunction in COVID-19 are still unclear. In this review, we examine potential mechanisms that may explain why the sense of smell is lost or altered. Among the current hypotheses, the most plausible is that death of infected support cells in the olfactory epithelium causes, besides altered composition of the mucus, retraction of the cilia on olfactory receptor neurons, possibly because of the lack of support cell-derived glucose in the mucus, which powers olfactory signal transduction within the cilia. This mechanism is consistent with the rapid loss of smell with COVID-19, and its rapid recovery after the regeneration of support cells. Host immune responses that cause downregulation of genes involved in olfactory signal transduction occur too late to trigger anosmia, but may contribute to the duration of the olfactory dysfunction.

Scent of stem cells: How can neurogenesis make us smell better?

Throughout the animal kingdom, olfaction underlies the ability to perceive chemicals in the environment as a fundamental adaptation with a plethora of functions. Unique among senses, olfaction is characterized by the integration of adult born neurons at the level of both the peripheral and central nervous systems. In fact, over the course of life, Neural Stem Cells (NSCs) reside within the peripheral Olfactory Epithelium (OE) and the brain's subventricular zone that generate Olfactory Sensory Neurons (OSNs) and interneurons of the Olfactory Bulb (OB), respectively. Despite this unique hallmark, the role(s) of adult neurogenesis in olfactory function remains elusive. Notably, while the molecular signature and lineage of both peripheral and central NSC are being described with increasing detail and resolution, conflicting evidence about the role of adult born neurons in olfactory sensitivity, discrimination and memory remains. With a currently increasing prevalence in olfactory dysfunctions due to aging populations and infections such as COVID-19, these limited and partly controversial reports highlight the need of a better understanding and more systematic study of this fascinating sensory system. Specifically, here we will address three fundamental questions: What is the role of peripheral adult neurogenesis in sustaining olfactory sensitivity? How can newborn neurons in the brain promote olfactory discrimination and/or memory? And what can we learn from fundamental studies on the biology of olfaction that can be used in the clinical treatment of olfactory dysfunctions?

Evidence for the spread of SARS-CoV-2 and olfactory cell lineage impairment in close-contact infection Syrian hamster models.

Objectives: Close contact with patients with COVID-19 is speculated to be the most common cause of viral transmission, but the pathogenesis of COVID-19 by close contact remains to be elucidated. In addition, despite olfactory impairment being a unique complication of COVID-19, the impact of SARS-CoV-2 on the olfactory cell lineage has not been fully validated. This study aimed to elucidate close-contact viral transmission to the nose and lungs and to investigate the temporal damage in the olfactory receptor neuron (ORN) lineage caused by SARS-CoV-2. Methods: Syrian hamsters were orally administered SARS-CoV-2 nonvariant nCoV-19/JPN/TY/WK521/2020 as direct-infection models. On day 3 after inoculation, infected and uninfected hamsters were housed in the same cage for 30 minutes. These uninfected hamsters were subsequently assigned to a close-contact group. First, viral presence in the nose and lungs was verified in the infection and close-contact groups at several time points. Next, the impacts on the olfactory epithelium, including olfactory progenitors, immature ORNs, and mature ORNs were examined histologically. Then, the viral transmission status and chronological changes in tissue damage were compared between the direct-infection and close-contact groups. Results: In the close-contact group, viral presence could not be detected in both the nose and lungs on day 3, and the virus was identified in both tissues on day 7. In the direct-infection group, the viral load was highest in the nose and lungs on day 3, decreased on day 7, and was no longer detectable on day 14. Histologically, in the direct-infection group, mature ORNs were most depleted on day 3 (p <0.001) and showed a recovery trend on day 14, with similar trends for olfactory progenitors and immature ORNs. In the close-contact group, there was no obvious tissue damage on day 3, but on day 7, the number of all ORN lineage cells significantly decreased (p <0.001). Conclusion: SARS-CoV-2 was transmitted even after brief contact and subsequent olfactory epithelium and lung damage occurred more than 3 days after the trigger of infection. The present study also indicated that SARS-CoV-2 damages all ORN lineage cells, but this damage can begin to recover approximately 14 days post infection.

Probable pathways of SARS-CoV-2 to central nervous system

Various reported cases related to the COVID-19 pandemic since 2019 has shown that SARS-CoV-2 directly or indirectly affects the nervous system besides the upper respiratory tract (Whittaker et al. 2020). SARS-CoV-2 is a zoonotic strain of coronavirus with various structural proteins. It is reported that spike protein, which is one of its structural proteins, can bind to or interact with Neuropilin-1, CD147 (Basigin), KREMEN1, ASGR1 (Asialoglycoprotein Receptor), Furin, LRP1 (Lipoprotein Receptor-Related Protein 1) and Ephrin receptors as well as ACE-2 (Angiotensin Converting Enzyme-2) and TMPRSS2 (Transmembrane Serine Protease 2) receptors. The related studies suggest that these possible receptors in the target of SARS-CoV- 2 cooperate with ACE-2, hence make the central nervous system an open target for the virus (Zalpoor et al. 2022). The first possible route of SARS-CoV-2 is seen as the route from the olfactory epithelium to its bulb via the trigeminal nerve (CN V) and olfactory nerve (CN I) pathway. Additionally, the virus entering the bloodstream can reach the Blood Brain Barier, cross the barrier and spread to neurons through the oligodendrocyte in a process called “Trojen horse”. Lastly, another route considered focuses on the vagal nerves of the enteric system associated with the central nervous system (Guadarrama-Ortiz et al. 2020). This literature review focuses on possible entry routes of SARS-CoV-2 into the nervous system. In this context, a route has been established based on the receptors in the nervous system cells, which are reported to be the target of SARS-CoV-2, based on the studies.

Oral SARS-CoV-2 Inoculation Causes Nasal Viral Infection Leading to Olfactory Bulb Infection: An Experimental Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can cause long-lasting anosmia, but the impact of SARS-CoV-2 infection, which can spread to the nasal cavity via the oral route, on the olfactory receptor neuron (ORN) lineage and olfactory bulb (OB) remains undetermined. Using Syrian hamsters, we explored whether oral SARS-CoV-2 inoculation can lead to nasal viral infection, examined how SARS-CoV-2 affects the ORN lineage by site, and investigated whether SARS-CoV-2 infection can spread to the OB and induce inflammation. On post-inoculation day 7, SARS-CoV-2 presence was confirmed in the lateral area (OCAM-positive) but not the nasal septum of NQO1-positive and OCAM-positive areas. The virus was observed partially infiltrating the olfactory epithelium, and ORN progenitor cells, immature ORNs, and mature ORNs were fewer than in controls. The virus was found in the olfactory nerve bundles to the OB, suggesting the nasal cavity as a route for SARS-CoV-2 brain infection. We demonstrated that transoral SARS-CoV-2 infection can spread from the nasal cavity to the central nervous system and the possibility of central olfactory dysfunction due to SARS-CoV-2 infection. The virus was localized at the infection site and could damage all ORN-lineage cells.

Localization of BDNF and Calretinin in Olfactory Epithelium and Taste Buds of Zebrafish (Danio rerio).

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and it is involved in several fundamental functions in the central and peripheral nervous systems, and in sensory organs. BDNF regulates the chemosensory systems of mammals and is consistently expressed in those organs. In zebrafish, the key role of BDNF in the biology of the hair cells of the inner ear and lateral line system has recently been demonstrated. However, only some information is available about its occurrence in the olfactory epithelium, taste buds, and cutaneous isolated chemosensory cells. Therefore, this study was undertaken to analyze the involvement of BDNF in the chemosensory organs of zebrafish during the larval and adult stages. To identify cells displaying BDNF, we compared the cellular pattern of BDNF-displaying cells with those immunoreactive for calretinin and S100 protein. Our results demonstrate the localization of BDNF in the sensory part of the olfactory epithelium, mainly in the ciliated olfactory sensory neurons in larvae and adult zebrafish. Intense immunoreaction for BDNF was also observed in the chemosensory cells of oral and cutaneous taste buds. Moreover, a subpopulation of olfactory sensory neurons and chemosensory cells of olfactory rosette and taste bud, respectively, showed marked immunopositivity for calcium-binding protein S100 and calretinin. These results demonstrate the possible role of BDNF in the development and maintenance of olfactory sensory neurons and sensory cells in the olfactory epithelium and taste organs of zebrafish during all stages of development.

Molecular underpinnings of olfactory dysfunction following SARS-CoV-2 infection

Olfaction is a closely coordinated partnership between odorant flow and neuronal signaling. Disruption in our ability to detect odors, or anosmia, has emerged as a hallmark symptom of infection with SARS-CoV-2, and yet, decoding the mechanism behind this abrupt sensory deficit remains elusive. Patients with COVID-19 lack symptoms of nasal congestion and rhinorrhea present in many upper respiratory tract infections that result in a conductive reduction in an ability to perceive smells. To investigate the molecular underpinnings of SARS-CoV-2 related smell loss, we performed molecular analysis, including scRNAseq, RNA-FISH, and Hi-C on both human and syrian golden hamster olfactory epithelium. Here, we report that smell loss may be attributable to non-cell autonomous mechanisms that induce genomic compartment dysregulation and subsequent downregulation of critical signaling pathways responsible for production of olfactory receptors.

Comparative pathology of the nasal epithelium in K18-hACE2 Tg mice, hACE2 Tg mice, and hamsters infected with SARS-CoV-2.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes severe viral pneumonia and is associated with a high fatality rate. A substantial proportion of patients infected by SARS-CoV-2 suffer from mild hyposmia to complete loss of olfactory function, resulting in anosmia. However, the pathogenesis of the olfactory dysfunction and comparative pathology of upper respiratory infections with SARS-CoV-2 are unknown. We describe the histopathological, immunohistochemical, and in situ hybridization findings from rodent models of SARS-CoV-2 infection. The main histopathological findings in the olfactory epithelia of K8-hACE2 Tg mice, hACE2 Tg mice, and hamsters were varying degrees of inflammatory lesions, including disordered arrangement, necrosis, exfoliation, and macrophage infiltration of the olfactory epithelia, and inflammatory exudation. On the basis of these observations, the nasal epithelia of these rodent models appeared to develop moderate, mild, and severe rhinitis, respectively. Correspondingly, SARS-CoV-2 viral RNA and antigen were mainly identified in the olfactory epithelia and lamina propria. Moreover, viral RNA was abundant in the cerebrum of K18-hACE2 Tg mice, including the olfactory bulb. The K8-hACE2 Tg mouse, hACE2 Tg mouse, and hamster models could be used to investigate the pathology of SARS-CoV-2 infection in the upper respiratory tract and central nervous system. These models could help to provide a better understanding of the pathogenic process of this virus and to develop effective medications and prophylactic treatments.

Impact of COVID-19 on Taste and Smell Sensation among Population in Western Region of Saudi Arabia

Background: COVID-19 is pandemic disease caused by (SARS-CoV-2) first discovered in China in December 2019. It affects smell and taste sensation among large proportion of patients with COVID-19. The aims of this study is to asses impact of COVID-19 on smell and taste sensation among COVID-19 patients in western region of Saudi Arabia. Methods: The study design was descriptive cross sectional and our sample was be is 500 patients with COVID-19. The data was collected by using structured questionnaire which was distributed electronically and contain (sociodemographic data, diagnosed with COVID-19, status of smell and taste sensation.). The data was analyzed using SPSS program version 22. Results: We were able to collect 404 responses to our questionnaire with response rate of 80.8 %. The mean age of total sample was 32.1 years with standard deviation of 14.34 years and 56.1 % of participants were females. Prevalence of weak or loss of smell or taste after infection with the emerging corona virus was 74.4%. Moreover, we found that patients who had weak or loss of smell or taste because of COVID-19 were older than those whose sense did not be affected. Moreover, non- Saudi Arabian were more affected by losing of smell and taste with significant difference (P=0.026). Considering medical conditions of patients, we found that patients with any medical conditions were associated with significantly higher incidence of losing smell and taste. Conclusion: The prevalence of losing smell and taste among patients with COVID-19 in our sample were high and was higher in older patients, male, Saudi arabian and those with other medical conditions. More investigations should be conducted to assess the same variables using retrospective study design.

Morphological features of changes in peripheral olfactory structures in SARS-COV-2 coronavirus infection

Coronavirus infection caused by the SARS-CoV-2 virus is an extremely important and urgent problem of modern medicine. It spreads quickly, has a high probability of a severe course and a large number of critical complications in patients from the risk group. The presence of pathognomonic symptoms, one of which is the development of hypo- or anosmia, makes it possible to quickly differentiate coronavirus infection from other acute respiratory viral infections, that is, to isolate the patient on time and begin correct treatment, taking all possible risks into account. The aim is to identify the morphological features of olfactory structural elements in patients with coronavirus disease (COVID-19) for a better understanding of the mechanisms of olfactory disorders development in coronavirus infection. Materials and methods. The basis of the work is a retrospective analysis of autopsy material, namely the mucous membrane of the upper parts of the nasal cavity (olfactory epithelium) and olfactory bulbs of nine deceased (4 women and 5 men) aged from 53 to 79 years with a laboratory-confirmed diagnosis of COVID-19 and anosmia in anamnesis. We used standard hematoxylin and eosin staining and immunohistochemical reactions in accordance with the TermoScientific protocols (USA) with antibodies to neurospecific beta-III tubulin (clone TuJ-1) and RnDsystems protocols with antibodies to olfactory marker protein (OMP) and angiotensin converting enzyme (ACE-2). To compare the results, a control group of 9 deaths (3 women and 6 men) aged from 59 to 68 years with a laboratory-refuted diagnosis of COVID-19 was formed. The causes of death of these patients were complications of diabetes, coronary heart disease and cerebrovascular disorders of the ischemic type. Results. The average age of the deceased with a laboratory-confirmed diagnosis of COVID-19 and a history of anosmia and the control group was 64.67 +/- 7.73 and 62.33 +/- 6.48 years, respectively. The expression of olfactory marker protein (OMP) and neurospecific beta-III tubulin (clone TuJ-1) was partially positive (40.89 (25.00-52.00) and 42.44 (29.00-55.00) cells in the field of view at a magnification of 200x, respectively) in seven out of nine sections of the olfactory mucous membrane of deaths with a laboratory-confirmed diagnosis of COVID-19 and anosmia in anamnesis. The reaction with antibodies to angiotensin converting enzyme (ACE-2) was focally or subtotally absent (34.33 (14.00-49.00) cells in the field of view at 200x magnification). There was expression of these three markers in control sections of the olfactory mucosa of a deceased with a laboratory excluded diagnosis of COVID-19 and no symptoms of anosmia (Mann-Whitney test, P < 0.05). In sections of olfactory bulbs of patients with COVID-19 weak (Mann-Whitney test, P < 0.05) expression of receptors for angiotensinconverting enzyme (ACE-2) (26.78 (15.00-39.00) cells in field of view at a magnification of 200x) was revealed in contrast to control sections (100.56 (94.00-107.00) cells in the field of view at a magnification of 200x). Conclusions. The development of anosmia in SARS-CoV-2 coronavirus infection has specific features. This may be due to the primary destruction of cells expressing receptors for the angiotensin-converting enzyme (ACE-2-positive: sustentacular cells of the olfactory mucosa, neurons of the olfactory bulbs). Subsequent dysfunction of olfactory cells (OMP-and TuJ-1positive) is also possible.

Olfactory Characterization and Training in Older Adults: Protocol Study.

The aim of this article is to present the research protocol for a prospective cohort study that will assess the olfactory function and the effect of an intervention based on olfactory training in healthy very old adults (≥75 years old). A convenience sample of 180 older people (50% female) will be recruited in three different environments: hospitalized control group (CH) with stable acute illness (n = 60); ambulatory control group (CA) of community-based living (n = 60); and an experimental odor training group (EOT) from nursing homes (n = 60). The odor training (OT) intervention will last 12 weeks. All the volunteers will be assessed at baseline; CA and EOT groups will also be assessed after 12 weeks. The primary end point will be change in olfactory capacity from baseline to 12 weeks period of intervention or control. The intervention effects will be assessed with the overall score achieved in Sniffin Sticks Test (SST) - Threshold, Discrimination, and Identification (TDI) extended version. Secondary end points will be changes in cognitive tasks, quality of life, mood, immune status, and functional capacity. All these measurements will be complemented with an immune fitness characterization and a deep proteome profiling of the olfactory epithelium (OE) cultured ex vivo. The current study will provide additional evidence to support the implementation of olfactory precision medicine and the development of immunomodulatory nasal therapies based on non-invasive procedures. The proposed intervention will also intend to increase the knowledge about the olfactory function in very elderly people, improve function and quality of life, and promote the recovery of the health.

COVID-19 and anosmia: The story so far.

OBJECTIVES: The pandemic has affected over 182 million coronavirus disease 2019 (COVID-19) cases worldwide. Accumulated evidence indicates that anosmia is one of the significant characteristics of COVID-19 with a high prevalence. However, many aspects of COVID-19-induced anosmia are still far from being fully understood. The purpose of this review is to summarize recent developments in COVID-19-induced anosmia to increase awareness of the condition. METHODS: A literature search was carried out using the PubMed, Embase, Web of Science, and Scopus. We reviewed the latest literature on COVID-19-induced anosmia, including mechanisms of pathogenesis, olfactory testing, anosmia as predictive tool, pathological examinations, imaging findings, affected factors, co-existing diseases, treatments, prognosis, hypothesis theories, and future directions. RESULTS: The possible pathogenesis of COVID-19-induced anosmia may involve inflammation of the olfactory clefts and damage to the olfactory epithelium or olfactory central nervous system by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The D614G spike variant may also play a role in the increased number of anosmia patients. Anosmia may also be an essential indicator of COVID-19 spread and an early indicator of the effectiveness of political decisions. The occurrence and development of COVID-19-induced anosmia may be influenced by smoking behaviors and underlying diseases such as type 2 diabetes, gastroesophageal disorders, and rhinitis. Most patients with COVID-19-induced anosmia can fully or partially recover their olfactory function for varying durations. COVID-19-induced anosmia can be treated with various approaches such as glucocorticoids and olfactory training. CONCLUSION: Anosmia is one of the main features of COVID-19 and the underlying disease of the patient may also influence its occurrence and development. The possible pathogenesis of COVID-19-induced anosmia is very complicated, which may involve inflammation of the olfactory clefts and damage to the olfactory epithelium or olfactory central nervous system.