{'fraction_non_alphanumeric': 0.035939379360115466, 'fraction_numerical': 0.019292759201347126, 'mean_word_length': 5.095601173020528, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Anatomophysiological relationships and clinical considerations of taste and smell loss in patients with COVID-19

BACKGROUND There are numerous conflicting discussions about the outbreak of the new coronavirus 2019 (COVID-19). AIM To present some anatomical and physiological considerations about two of the symptoms reported by patients: The loss or reduction of smell and taste. METHODS The loss or reduction of smell and taste is presented in a peculiar way, with some cases of persistence even after COVID-19. For this, it was searched in three databases, PubMed/MEDLINE, Web of Science, and Scopus, using the following keywords: "Smell", "Taste", "Smell AND COVID-19", "Taste AND COVID-19", with no publication time restriction, only in English with full text available, excluding also brief communications, letters to the editor, editorials, reviews, comments, and conference abstracts. RESULTS The search found 776 articles in the PubMed/MEDLINE database, 1018 in the Web of Science database, and 552 in the Scopus database, from which duplicates were removed (104 articles). Finally, 17 studies were selected for detailed analysis within the eligibility criteria, with titles and abstracts related to central nervous system lesions responsible for smell and taste. This review suggests that viral mechanisms of action may be related to lesions both at the local level and at the level of the central nervous system, lasting up to 3 to 4 wk. It is considered persistent if it exceeds this period, as reported in one case in this review. There are still few studies about the treatment, and among those addressed in this review, only two studies reported possible treatments and emphasized the scarcity of data, with the best option being treatments that do not cause harm, such as gustatory and olfactory physiotherapy CONCLUSION Given the scarcity of data, this review emphasizes the importance of prevention, through the correct use of personal protective equipment by health professionals and respect for local behavioral indications. It is also emphasized, through five studies, that there is a predominance of such symptoms in patients with COVID-19, which can be a tool to control dissemination, through the early isolation of patients until the results are ready.


INTRODUCTION
In December 2019 in Wuhan (China), the emergence of an acute respiratory syndrome caused by severe acute respiratory syndrome coronavirus 2 CoV (SARS-CoV-2), with a peculiar and highly contagious behavior, was reported [1]. Thus, the World Health Organization decreed on March 11, 2020 a state of pandemic, considering the condition of community transmission of human infection by the virus [2]. In the current world scenario, there are already approximately 493 million infected and 6.1 million dead people. In Brazil, there are approximately 30.1 million infected and 661 thousand dead ones [2]. Such global and national data are alarming and may be related to the high speed of dissemination, high mortality rate in people with comorbidity, and the coping strategies of each country, as well as socioeconomic and health conditions [3,4].
The clinical manifestations of the new coronavirus  are very varied, with the most common symptoms being fever (74%), cough (79%), fatigue (75%), headache (78%), gastrointestinal disorders (57%), and loss of smell (63%) and taste (65%). These symptoms, when present, lead to the diagnostic suspicion of COVID-19, until confirmed by examinations [5,6]. The sensory pathway of smell is initially given by the nerve endings of the olfactory nerve, the primary olfactory neuron, located in the upper third of the nasal cavity and nasal septum, stimulated by chemical substances from the air that are transformed into action potential [7][8][9]. This stimulus travels through the primary neuron crossing the cribriform plate of the ethmoid bone through its foramina [8]. Upon accessing the anterior cavity of the skull, they synapse with the secondary neuron. The olfactory nerve impulses terminate in the primary cortical projection area and travel to the thalamus, which proceeds to the orbitofrontal and rectus olfactory gyrus ( Figure 1). There is also an association of some odors with the limbic system, causing reactions of pleasure or aversion [8][9][10][11] (Figures 2 and 3).
Taste is provided by the specialized sensitivity of the tongue, via the glossopharyngeal nerve (IX cranial nerve) in the posterior third, vagus nerve (X cranial nerve) with few branches at the base of the  tongue and epiglottis, and chorda tympani nerve (branch of the VII cranial nerve, the facialintermediate nerve) in the anterior two thirds of the tongue [7,8]. They receive the stimulus through taste buds that are made up of epithelial cells that have different receptors for each type of flavor, distributed throughout the tongue [12]. From there, the stimuli travel through the primary afferent fibers of the respective gustatory sensory nerves to the solitary tract in the medulla, then to the thalamus, passing to the cortex [8] (Figures 4 and 5).
Given this context, research has sought strategies in order to clarify the sensory alterations of loss of smell and taste, the possible mechanism of action of the virus in these nerves, and its treatment. Thus, the present study aimed to review the anatomy and physiology of the olfactory and gustatory pathways, and their relationship with symptomatology in patients with COVID-19. September

MATERIALS AND METHODS
For this study, PubMed/MEDLINE, Web of Science, and Scopus databases were searched, using the following terms as keywords: "Smell", "Taste", "Smell AND COVID-19", "Taste AND COVID -19", without publication time restriction and only in the English language. Works that present titles and abstracts related to the topic of the initial research were verified, using the variables taste and/or smell and COVID-19. Subsequently, the text was evaluated of the articles previously selected by the abstract. The methodology, results, and relevance were considered to list the choice of articles. For inclusion in the research, the articles must necessarily be accessed in their full content ( Figure 1). The inclusion criteria were: Description of changes in smell and taste due to COVID-19; Human studies; Publications in English only; Publications that allow full access to the text. The exclusion criteria were: Articles that have been duplicated; Animal studies; The title was not related to the objective; There was no loss of taste; There was no loss of smell; Other languages (except English); Access to the full text has not been obtained; Brief communications, letters to the editor, editorials, reviews, comments, and conference abstracts.

RESULTS
The search found 776 articles in the PubMed/MEDLINE database, 1018 in the Web of Science database, and 552 in the Scopus database, from which duplicates were removed (104 articles), then editorials, review articles, brief communications, letters to the editor, comments, conference abstracts, and articles without full text available or not produced in English were excluded, as they are outside the eligibility criteria. Seventeen studies that met the eligibility criteria were selected (Table 1).  during infection and in persistent post-infection cases. In addition, by giving due relevance to this symptomatology, which has a high incidence in patients with COVID-19, isolation is possible of patients with this symptomatology, even before the test results, thus decreasing the transmissibility of SARS-CoV-2 [13,14]. Among all the articles selected, through the methodology used, the presence of a very variable number of patient samples was found, in addition, there was a variability in the anatomical structure placed as the focus of the discussion, which were studied and evaluated by different parameters. Six articles [15,18,20,22,23,28] focused on the olfactory and gustatory epithelium as the main responsible for the loss of smell and taste, due to the fact that they have angiotensin-converting enzyme 2 (ACE2) receptors, which at the time of the entry of SARS-CoV-2 alter and damage this mucosa, making it unable to act as local chemoreceptors. Eleven articles [13,14,16,17,19,21,[24][25][26][27]29] in addition to highlighting ACE2 receptors as a gateway, indicate the olfactory pathways as the access pathways to the central nervous system by SARS-CoV-2, due to its neurotropic properties, which intracranially, are capable of injuring regions responsible for these senses.
Some studies concluded that there is a high prevalence of loss of smell and taste in patients with COVID-19, there was a variation in the ages studied and the degree of severity of the patient's disease [13][14][15][16][17], but due to the strong correlation of the symptomatology with the COVID-19 is considered a specific symptom of the disease [13,14]. These symptoms usually resolve in approximately 1 mo[17]; however, there are cases of persistent loss of smell and taste [18], which was observed by Vaira et al [18]. After biopsy of the nasal mucosa, there was alteration of the olfactory epithelium, which in some places, instead of forming normal tissues, formed metaplastic tissue, which is a possible explanation for the persistence in some cases.
Most articles [13,14,16,17,19,21,[24][25][26][27]29] highlighted the neurotropic activity of SARS-CoV-2, allowing access and changes in the central nervous system. In the study carried out by Aragão et al [19], a microvascular lesion in the olfactory bulb in a patient with COVID-19 and loss of smell and taste were documented through magnetic resonance imaging (MRI), demonstrating a possible mechanism of action of the virus in addition to its action on the olfactory epithelium.
The study by Izquierdo-Dominguez et al [30], not included in this study because it is a systematic review, confirms the change in smell and taste due to the presence of ACE2 receptors in the respective mucosa and the fact that SARS-CoV-2 has affinity for these receptors. In addition to these sites, ACE2 can be found in various types of tissues, such as those of the central nervous system, which may also represent one of the causes of loss of smell and taste, if damaged. Studies that performed the autopsy of patients with COVID-19 and found hyperemic, swollen brain tissue and some sites with degenerated neurons were also discussed in this article, and also detected the presence of SARS-CoV-2 nucleic acid in the cerebrospinal fluid[30].
Among the main questions on the subject, in addition to the cause of the loss of smell and taste, as well as its anatomophysiological relationships, there are also discussions on whether there are possible preventions and what therapeutic measures can be carried out in the treatment in cases of persistent losses. Among the selected articles, there are no reports of possible preventive measures for loss of smell and taste, but Xu et al [31] raised the hypothesis that the use of vitamin D, as it has several independent neuroprotective mechanisms, can generate protection of central and peripheral nervous tissues, through neurotrophins. The authors hypothesized that the neuroprotective potential could prevent the neurological complications of COVID-19 [31].
Regarding therapeutic measures, we selected the study by Vaira et al [18] who cited the existence of evidence of the use of steroid rinses and a pilot study with submucosal injection of platelet-rich plasma into the epithelium, obtaining relevant improvement, but they need more studies to reach significant conclusions and be indicated as clinical treatments for lesions [18]. The study by Kanjanaumpor et al [32], not addressed in our study because it is a systematic review, argued that there is still no significant evidence to recommend any type of pharmacological treatment; however, olfactory training, without contraindications but with low cost and evidence of improvement, is an interesting therapy in patients with persistent loss of smell and taste with COVID- 19[32].
About prognosis, Kanjanaumpor et al [32] revealed that in about 32-66% of patients, there is spontaneous recovery and that a US study reported improvement in the loss of smell and taste in 74% of infected patients correlating with the overall resolution of clinical symptoms. Jalessi et al [22] mentioned recovery of smell in 44.0% of patients in the short term (2 wk) and Vaira et al [18] reported that about 66% of patients achieved complete recovery in an average of 19.3 d from the onset of symptoms.
Regarding preventive measures against COVID-19 and its symptoms, such as loss of smell and taste, the importance of using personal protective equipment (PPE) is found in the literature, as in the study by Kim et al [34]. Limited access to this equipment (mask, lab coat, new gloves, and face shield) was significantly associated with a higher risk of developing symptoms of COVID-19, in addition to being associated with more severe disease, with moderate or severe symptoms [34].
Adequate access to PPE by health professionals, especially those on the front line, is associated with a lower chance of contracting the disease, and even if PPE fails, there is an association with less severe and shorter forms [34].
There are numerous studies in progress, including a study by da Fonseca Orcina et al [36], who proposed the therapeutic use of a phthalocyanine-derived mouthwash, which is able to reduce the severity of the disease locally, the viral load in the oral cavity, and consequently the clinical symptoms, such as sore throat, cough, and mouth ulcers. It can thus also reduce the severity of the general disease by reducing the viral load and dissemination, since the oral cavity and oropharynx are an important means of dissemination of SARS-CoV-2 [35,36]. The authors emphasized the need for more randomized clinical trials for further conclusions [36].
Regarding therapeutic measures in the loss of smell and taste, there are ongoing research testing several drugs; among them, the therapy with sprays and topical rinses based on corticosteroids has obtained good results, in addition to presenting a high safety profile, being appropriate for postinfection patients with persistent loss of these senses [37]. However, smell and taste training is the only specific therapy with proven efficacy. Although the exact mechanism of action is not known, it is believed that through repeated stimulation, there is an increase in the neuroplastic and regenerative capacity of the brain. Thus, it is an important therapy indicated at first in patients with a persistent condition [37][38][39].
There are difficulties in quantifying the prevalence and incidence of gustatory and olfactory dysfunction in the general population, due to causes such as analysis and evaluation methods, sample size and area, and the correct definitions of dysfunctions [40]. Multicentric research from Europe, in the year 2020, showed interesting data: 85.6% of patients with COVID-19 reported olfactory loss. It was also one of the pioneering studies in the identification of taste loss, which at the time was 88.0% in patients with COVID-19. In addition, that study described that infected patients could experience this loss in the absence of other significant symptoms [40].
With the emergence of coronavirus variants, infections caused by Omicron can currently be highlighted, which resulted in mild disease, mainly due to the discovery and use of vaccines. Compared to other strains such as Delta, Omicron infections were more often associated with symptomatology and upper respiratory tract infections, and have lower viral loads, less dysregulated immune cell profiles, and lower levels of pro-inflammatory cytokines [41].
A study, through questionnaires, evaluated the clinical profile of patients who developed COVID-19 after full vaccination, in symptomatic patients. The most frequent symptoms were asthenia (82.4%), chemosensory dysfunction (63.4%), headache (59.5%), coryza (58.2%), muscle pain (54.9%), loss of appetite (54.3%), and nasal obstruction (51.6%). However, 62.3% and 53.6% of survey participants reported olfactory and gustatory dysfunction, respectively. Symptom severity was mild or moderate in almost all cases. Chemosensory dysfunction is still a frequent symptom, even in people who contracted the infection after full vaccination. In this way, the sudden loss of smell and taste may continue to represent a useful and specific diagnostic aid in suspected COVID-19, even in vaccinated individuals [42]. September 25, 2022 Volume 11 Issue 5 As limitations of this study, one can consider the rapid change in the literature on COVID-19, as well as the emergence of new variants, with different symptoms from the initial versions.

CONCLUSION
Most of the articles studied reported that possible anatomophysiological mechanisms related to the loss of smell and taste, are local lesions in the olfactory and gustatory tissue due to having ACE-2 receptors, with the SARS-CoV-2 gateway being the oral and nasal cavity. In addition to local lesions, there are central changes in the tissues of the nervous system related to taste and smell, which are also damaged by the neurotropic capacity of SARS-CoV-2. The duration, in most cases, can extend from 3 to 4 wk, and it is considered persistent after 1 mo.
Therapeutic conducts in persistent cases with better initial results, which could be indicated by the doctor, are the use of steroid-based sprays and rinses and, mainly, the training of the senses of smell and taste. Likewise, the best measure to be taken is prevention, with the correct use of PPE by health professionals, and respect for local health recommendations determined in order to reduce viral spread.

Research background
There are numerous conflicting discussions about the outbreak of the new coronavirus (COVID-19).

Research motivation
Describe the anatomy and physiology relationships of taste and smell losses due to COVID-19

Research objectives
To present some anatomical and physiological considerations about two of the symptoms reported by patients: the loss or reduction of smell and taste.

Research methods
Since, these symptoms are presented in a peculiar way, with some cases of persistence even after COVID-19. For this, it was searched in three databases, PubMed/MEDLINE, Web of Science and Scopus, using the following keywords: "Smell", "Taste", "Smell AND COVID-19", "Taste AND COVID-19", no publication time restriction, only in English with full text available, excluding also brief communications, letters to the editor, editorials, reviews, comments and conference abstracts.

Research results
The search found 776 articles in the database PubMed/MEDLINE, 1018 in the Web of Science database, and 552 in the Scopus database, from which duplicates were removed (104 articles). Finally, 17 studies were selected for detailed analysis within the eligibility criteria, with titles and abstracts related to central nervous system lesions responsible for smell and taste. This review suggests that viral mechanisms of action may be related to lesions both at the local level and at the level of the central nervous system, lasting up to 3 to 4 wk. It is considered persistent if it exceeds this period, as reported in one case in this review. There are still few studies about the treatment, and among those addressed in this review, only two studies reported possible treatments and emphasized the scarcity of data, with the best option being treatments that do not cause harm, such as gustatory and olfactory physiotherapy

Research conclusions
Most of the articles studied reported that possible anatomophysiological mechanisms related to the loss of smell and taste, are local lesions in the olfactory and gustatory tissue due to having ACE-2 receptors, with the SARS-CoV-2 gateway being the oral and nasal cavity. In addition to local lesions, there are central changes in the tissues of the nervous system related to taste and smell, which are also damaged by the neurotropic capacity of SARS-CoV-2. The duration, in most cases, can extend from 3 to 4 wk, and it is considered persistent after 1 mo. Therapeutic conducts in persistent cases with better initial results, which could be indicated by the doctor, are the use of steroid-based sprays and rinses and, mainly, the training of the senses of smell and taste. Likewise, the best measure to be taken is prevention, with the correct use of PPE by health professionals, and respect for local health recommendations determined in order to reduce viral spread.

Research perspectives
Future studies should further describe the relationships between the anatomy and physiology of taste and smell losses due to COVID-19.