Insight into the mechanisms of olfactory dysfunction by COVID-19.

One of the unique symptoms of COVID-19 is chemosensory dysfunction. Almost three years since the beginning of the pandemic of COVID-19, there have been many studies on the symptoms, progress, and possible causes, and also studies on methods that may facilitate recovery of the senses. Studies have shown that some people recover their senses even within a couple of weeks whereas there are other patients that fail to recover chemosensory functions fully for several months and some never fully recover. Here we summarize the symptoms and the progress, and then review the papers on the causation as well as the treatments that may help facilitate the recovery of the symptoms. Depending on the differences in the levels of severity and the locations where the main pathological venues are, what is most effective in facilitating recovery can vary largely across patients and thus may require individualized strategies for each patient. The goal of this paper is to provide some thoughts on these choices depending on the differences in the causes and severity.

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.

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.

Possible Use of Phytochemicals for Recovery from COVID-19-Induced Anosmia and Ageusia.

The year 2020 became the year of the outbreak of coronavirus, SARS-CoV-2, which escalated into a worldwide pandemic and continued into 2021. One of the unique symptoms of the SARS-CoV-2 disease, COVID-19, is the loss of chemical senses, i.e., smell and taste. Smell training is one of the methods used in facilitating recovery of the olfactory sense, and it uses essential oils of lemon, rose, clove, and eucalyptus. These essential oils were not selected based on their chemical constituents. Although scientific studies have shown that they improve recovery, there may be better combinations for facilitating recovery. Many phytochemicals have bioactive properties with anti-inflammatory and anti-viral effects. In this review, we describe the chemical compounds with anti- inflammatory and anti-viral effects, and we list the plants that contain these chemical compounds. We expand the review from terpenes to the less volatile flavonoids in order to propose a combination of essential oils and diets that can be used to develop a new taste training method, as there has been no taste training so far. Finally, we discuss the possible use of these in clinical settings.

Loss of Smell and Taste in Patients With Suspected COVID-19: Analyses of Patients' Reports on Social Media.

BACKGROUND: The year 2020 was the year of the global COVID-19 pandemic. The severity of the situation has become so substantial that many or even most of the patients with mild to moderate symptoms had to self-isolate without specific medical treatments or even without being tested for COVID-19. Many patients joined internet membership groups to exchange information and support each other. OBJECTIVE: Our goal is to determine the benefits and limits of using social media to understand the symptoms of patients with suspected COVID-19 with mild to moderate symptoms and, in particular, their symptoms of anosmia (loss of the sense of smell) and ageusia (loss of the sense of taste). The voluntary reports on an internet website of a membership group will be the platform of the analyses. METHODS: Posts and comments of members of an internet group known as COVID-19 Smell and Taste Loss, founded on March 24, 2020, to support patients with suspected COVID-19 were collected and analyzed daily. Demographic data were collected using the software mechanism called Group Insights on the membership group website. RESULTS: Membership groups on social media have become rare sources of support for patients with suspected COVID-19 with mild to moderate symptoms. These groups provided mental support to their members and became resources for information on COVID-19 tests and medicines or supplements. However, the membership was voluntary, and often the members leave without notification. It is hard to be precise from the free voluntary reports. The number of women in the group (6995/9227, 75.38% as of October 12, 2020) was about three times more than men (2272/9227, 24.62% as of October 12, 2020), and the peak age of members was between 20-40 years in both men and women. Patients who were asymptomatic other than the senses comprised 14.93% (53/355) of the total patients. Recovery of the senses was higher in the patients who were asymptomatic besides having anosmia and ageusia. Most (112/123, 91.06%) patients experienced other symptoms first and then lost their senses, on average, 4.2 days later. Patients without other symptoms tended to recover earlier (P=.02). Patients with anosmia and ageusia occasionally reported distorted smell and taste (parosmia and dysgeusia) as well as experiencing or perceiving the smell and taste without the sources of the smell or taste (phantosmia and phantogeusia). CONCLUSIONS: Our analysis of the social media database of suspected COVID-19 patients' voices demonstrated that, although accurate diagnosis of patients is not always obtained with social media-based analyses, it may be a useful tool to collect a large amount of data on symptoms and the clinical course of worldwide rapidly growing infectious diseases.

Expression of ACE2, TMPRSS2, and Furin in Mouse Ear Tissue, and the Implications for SARS-CoV-2 Infection.

OBJECTIVES/HYPOTHESIS: Intracellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) depends on the interaction between its spike protein with the cellular receptor angiotensin-converting enzyme 2 (ACE2) and depends on Furin-mediated spike protein cleavage and spike protein priming by host cell proteases, including transmembrane protease serine 2 (TMPRSS2). As the expression of ACE2, TMPRSS2, and Furin in the middle and inner ear remain unclear, we analyzed the expression of these proteins in mouse ear tissues. STUDY DESIGN: Animal Research. METHODS: We performed immunohistochemical analysis to examine the distribution of ACE2, TMPRSS2, and Furin in the Eustachian tube, middle ear spaces, and cochlea of mice. RESULTS: ACE2 was present in the nucleus of the epithelium of the middle ear and Eustachian tube, as well as in some nuclei of the hair cells in the organ of Corti, in the stria vascularis, and the spiral ganglion cells. ACE2 was also expressed in the cytoplasm of the stria vascularis. TMPRSS2 was expressed in both the nucleus and cytoplasm in the middle spaces, with the expression being stronger in the nucleus in the mucosal epithelium of the middle ear spaces and Eustachian tube. TMPRSS2 was present in the cytoplasm in the organ of Corti and stria vascularis and in the nucleus and cytoplasm in the spiral ganglion. Furin was expressed in the cytoplasm in the middle ear spaces, Eustachian tube, and cochlea. CONCLUSIONS: ACE2, TMPRSS2, and Furin are diffusely present in the Eustachian tube, middle ear spaces, and cochlea, suggesting that these tissues are susceptible to SARS-CoV-2 infection. LEVEL OF EVIDENCE: NA Laryngoscope, 131:E2013-E2017, 2021.

Expression of ACE2 and TMPRSS2 Proteins in the Upper and Lower Aerodigestive Tracts of Rats: Implications on COVID 19 Infections.

OBJECTIVE: Patients with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibit not only respiratory symptoms but also symptoms of chemo-sensitive disorders. Cellular entry of SARS-CoV-2 depends on the binding of its spike protein to a cellular receptor named angiotensin-converting enzyme 2 (ACE2), and the subsequent spike protein-priming by host cell proteases, including transmembrane protease serine 2 (TMPRSS2). Thus, high expression of ACE2 and TMPRSS2 is considered to enhance the invading capacity of SARS-CoV-2. METHODS: To elucidate the underlying histological mechanisms of the aerodigestive disorders caused by SARS-CoV-2, we investigated the expression of ACE2 and TMPRSS2 proteins using immunohistochemistry, in the aerodigestive tracts of the tongue, hard palate with partial nasal tissue, larynx with hypopharynx, trachea, esophagus, and lung of rats. RESULTS: Co-expression of ACE2 and TMPRSS2 proteins was observed in the taste buds of the tongue, nasal epithelium, trachea, bronchioles, and alveoli with varying degrees of expression. Remarkably, TMPRSS2 expression was more distinct in the peripheral alveoli than in the central alveoli. These results coincide with the reported clinical symptoms of COVID-19, such as the loss of taste, loss of olfaction, and respiratory dysfunction. CONCLUSIONS: A wide range of organs have been speculated to be affected by SARS-CoV-2 depending on the expression levels of ACE2 and TMPRSS2. Differential distribution of TMPRSS2 in the lung indicated the COVID-19 symptoms to possibly be exacerbated by TMPRSS2 expression. This study might provide potential clues for further investigation of the pathogenesis of COVID-19. LEVEL OF EVIDENCE: NA Laryngoscope, 131:E932-E939, 2021.

Society of swallowing and dysphagia of Japan: Position statement on dysphagia management during the COVID-19 outbreak.

On April 14, the Society of Swallowing and Dysphagia of Japan (SSDJ) proposed its position statement on dysphagia treatment considering the ongoing spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main routes of transmission of SARS-CoV-2 are physical contact with infected persons and exposure to respiratory droplets. In cases of infection, the nasal cavity and nasopharynx have the highest viral load in the body. Swallowing occurs in the oral cavity and pharynx, which correspond to the sites of viral proliferation. In addition, the possibility of infection by aerosol transmission is also concerning. Dysphagia treatment includes a broad range of clinical assessments and examinations, dysphagia rehabilitation, oral care, nursing care, and surgical treatments. Any of these can lead to the production of droplets and aerosols, as well as contact with viral particles. In terms of proper infection control measures, all healthcare professionals involved in dysphagia treatment must be fully briefed and must appropriately implement all measures. In addition, most patients with dysphagia should be considered to be at a higher risk for severe illness from COVID-19 because they are elderly and have complications including heart diseases, diabetes, respiratory diseases, and cerebrovascular diseases. This statement establishes three regional categories according to the status of SARS-CoV-2 infection. Accordingly, the SSDJ proposes specific infection countermeasures that should be implemented considering 1) the current status of SARS-CoV-2 infection in the region, 2) the patient status of SARS-CoV-2 infection, and 3) whether the examinations or procedures conducted correspond to aerosol-generating procedures, depending on the status of dysphagia treatment. This statement is arranged into separate sections providing information and advice in consideration of the COVID-19 outbreak, including "terminology", "clinical swallowing assessment and examination", "swallowing therapy", "oral care", "surgical procedure for dysphagia", "tracheotomy care", and "nursing care". In areas where SARS-CoV-2 infection is widespread, sufficient personal protective equipment should be used when performing aerosol generation procedures. The current set of statements on dysphagia management in the COVID-19 outbreak is not an evidence-based clinical practice guideline, but a guide for all healthcare workers involved in the treatment of dysphagia during the COVID-19 epidemic to prevent SARS-CoV-2 infection.