Anatomophysiological relationships and clinical considerations of taste and smell loss in patients with COVID-19

Table 1 Seventeen studies that meet the eligibility criteria

Database	Title	Ref.	Sample/study type	Conclusion	Anatomophysiological relationship
PubMed/MEDLINE and Web of Science	A structural equation model to examine the clinical features of mild to moderate coronavirus disease 2019 (COVID-19): An Italian multicenter study	Barillari et al[15], 2021	294 patients/multicenter study	It has been reported that anosmia should be considered as a specific symptom for COVID-19, especially when the patient is "suspected" or untested	Inflammation in the olfactory epithelium or damage to olfactory receptor neurons, since the cells that make up this tissue have high expression of ACE2 and TMPRSS2, which have a strong capacity to bind the virus, being particularly susceptible to infection
PubMed/MEDLINE and Web of Science	Acute loss of smell and taste among patients with symptoms compatible with COVID-19	Bodnia and Katzeinstein[20], 2020	95 patients/cross-sectional study	There was persistence of mild olfactory and/or taste changes even after the other symptoms of COVID-19 had disappeared. In addition, loss of smell and taste was reported in 50% of patients with COVID-19, especially in adults	Human angiotensin-converting enzyme 2 is the main receptor of the SARS-CoV-2 host cell, present in nasal and olfactory respiratory epithelial cells. In addition, ACE2 is expressed in the oral cavity
PubMed/MEDLINE	Anosmia in COVID-19 associated with olfactory bulb lesion evidenced on MRI	Aragão et al[19], 2020	5 patients/retrospective study	This study documented for the first time, through neuroimaging, a type of lesion of the olfactory bulb in patients with COVID-19, demonstrating that the possible mechanism of action that causes olfactory dysfunction, either through the olfactory bulbs or intracranially, by a microvascular phenomenon	Intracranial olfactory bulb lesion, studied and documented by magnetic resonance imaging
PubMed/MEDLINE	COVID-19 viral load in the severity and recovery of olfactory and gustatory dysfunction	Cho et al[21], 2020	143 patients/Prospective cross-sectional cohort study	Symptom severity is not correlated with SARS-CoV-2 viral load, and there is a high prevalence of olfactory and gustatory dysfunction in COVID-19	The virus has affinity for ACE2 receptors that are found in the nasal and olfactory epithelium, causing peripheral neuropathy, which affects the functions of smell and taste. The virus is also able to invade the central nervous system through the olfactory bulb
PubMed/MEDLINE and Scopus	Evolution of olfactory disorders in patients with COVID-19	Gorzkowski et al[14], 2020	229 patients/Cross-sectional study	Olfactory and taste disturbances can be an isolated symptom of COVID-19, being reported in two-thirds of COVID-19 patients. Knowledge of these symptoms and their evolution can be useful in creating therapeutic strategies for cases of persistence even after the resolution of other symptoms of COVID-19	Mechanisms of olfactory disorders related to SARS-CoV-2 infection are still unknown, but it is likely to be associated with the outcomes of various patterns, such as nasal mucosa edema, olfactory epithelial damage (including neural and non-neural epithelium), and even involvement of olfactory pathways
PubMed/MEDLINE and Web of Science	Frequency and outcome of olfactory impairment and sinonasal involvement in hospitalized patients with COVID-19	Jalessi et al[22], 2020	100 patients/prospective descriptive study	In patients with COVID-19, there is a high prevalence of sudden temporary olfactory loss and upper airway infection symptoms. However, among all these symptoms, there was a predominance of olfactory loss, showing that this symptom is not associated with the generalized mucosal edema that occurs during an upper respiratory infection with common coronaviruses	Binding between ACE2 receptors and SARS-CoV-2 spike protein on target cells. In addition, infected cells secrete pro-inflammatory cytokines and chemokines, which can generate localized edema
PubMed/MEDLINE	Importance of anosmia in SARS-CoV-2: from phenomenology for neurobiology	Pallanti[13], 2020	2 patients/descriptive study	Anosmia and hypogeusia among respiratory symptoms can be considered a symptom of COVID-19 infection, if confirmed; these symptoms could represent early markers or signs of SARS-CoV-2 infection to trigger quarantine. These symptoms go beyond sensory aspects, involving extensive neural circuits	The neuroinvasive potential of SARS-CoV-2 was highlighted: When penetrated transnasally, it may access the brain, possibly via the olfactory torsion nerves, and from there rapidly spread to some specific brain areas, including the thalamus and brainstem
PubMed/MEDLINE and Web of Science	Loss of smell in COVID-19 patients: MRI data reveal transient swelling of the olfactory clefts	Eliezer et al[16], 2020	20 patients/prospective, mono-centric, case-controlled study	Olfactory clefts were evaluated, as well as olfactory function in a cohort study of patients with SARS-CoV-2 infection with loss of olfactory function, which was present in the initial phase of the disease, with improvement at 1-mo follow-up, supporting the hypothesis that this loss, in patients infected with SARS-CoV-2, is caused, at least in part, by reversible inflammatory changes in the olfactory epithelium	SARS-CoV-2 infects cells through interactions between its S protein and ACE2 protein on target cells. Furthermore, it is suggested that SARS-CoV-2 could invade the brain through the cribriform plate near the medulla and olfactory epithelium, causing some structural changes in the olfactory bulb
PubMed/MEDLINE and Web of Science	Olfactory dysfunction and sinonasal symptomatology in COVID-19: prevalence, severity, time and associated characteristics	Speth et al[17], 2020	103 patients/prospective, cross-sectional	Olfactory dysfunction is very prevalent during COVID-19, often in conjunction with loss of taste. This dysfunction is negatively associated with advanced age and positively associated with female sex	SARS-CoV-2 has great affinity with the host cell surface receptor, ACE2, located in the nasal mucosa, in particular in the ciliated epithelium and goblet cells. In addition, the virus appears to have neurotropism in which olfactory neurons are susceptible to infection
PubMed/MEDLINE	Histopathological findings of the olfactory epithelium reported anosmia due to long-term coronavirus disease 2019	Vaira et al[18], 2020	1 patient/case report	3 mo after the onset of COVID-19 anosmia, a biopsy was performed, which showed massive rupture of the olfactory epithelium, changing the focus of invasion of the olfactory bulb, encouraging further studies of treatments aimed at the superficial epithelium	The epithelium showed thinning with loss of the characteristic three-layer structure, and reduction in the number of olfactory receptor cells, while those that were present had no cilia. There was also an irregular regeneration of the olfactory epithelium interspersed with the respiratory epithelium and, in some cases, the olfactory epithelium was replaced by metaplastic squamous epithelium
PubMed/MEDLINE, Web of Science and Scopus	Psychophysical assessment of chemosensory functions after 5 weeks of olfactory loss due to COVID-19: a prospective cohort study in 72 patients	Le Bon et al[23], 2021	72 patients/prospective cohort study	Possibly, SARS-CoV-2 mainly affected odor thresholds, suggesting that the main cause of the loss of smell is at the level of the olfactory neuroepithelium rather than the central nervous system	The loss of taste may be related to a direct injury to the taste organ, and ACE2 receptors have been identified in the mouth and, in particular, on the tongue. ACE-2 receptors are also found in olfactory tissue, inducing olfactory loss at the peripheral rather than the more central nervous level. There is thickening of the olfactory cleft mucosa during COVID-19, reporting olfactory neuritis during COVID-19. There may also be viral spread to the central nervous system that started in the olfactory neuroepithelium
PubMed/MEDLINE	Head and neck symptomatology in coronavirus disease (COVID-19): A possible neuroinvasive action of SARS-CoV-2	Freni et al[24], 2020	50 patients/ prospective descriptive study	The authors tried to confirm the theories about the neuroinvasiveness of the virus, from a clinical point of view, so the coronaviruses are neurotropic since the neural cells express the ACE2 entry protein, being able to enter the CNS by several routes, mainly by intranasal inoculation and by peripheral nerve pathway using trans-synaptic pathways. In addition, anosmia, dysgeusia, and xerostomia are the first symptoms of COVID-19, which can be exploited for early quarantine and a limitation of viral contagion	SARS-CoV-2 has neuroinvasive and neurotropic properties. First, there is infection of the neuronal olfactory receptor in the olfactory mucosa, then the virus is transported antegrade to the olfactory bulb, and then there is diffusion through channels formed by cells of the olfactory envelope, which form an open connection with the central nervous system
PubMed/MEDLINE	Trends in olfactory and gustatory dysfunction in quarantined COVID-19 patients	Seo et al[25], 2020	62 patients/prospective surveillance study	The prevalence of olfactory and gustatory dysfunction was 24.2% in patients with mild COVID-19, which may be characteristic indicators in these cases. All patients had hyposmia due to sensorineural olfactory dysfunction, confirmed by validated methods of olfactory and gustatory assessment and endoscopic examinations	It may involve olfactory neurons related to the central nervous system or non-neuronal olfactory epithelial cells. When viral infection occurs in olfactory neurons, permanent olfactory dysfunction may occur, and even if there is recovery, it may take a long time. Therefore, the location of olfactory neurons with sensorineural olfactory dysfunction can be inferred from the clinical course
Web of Science	Taste and smell disorders in COVID-19 patients: role of interleukin-6	Cazzolla et al[26], 2020	125 patients/observational study	This study based on clinical evidence and laboratory data highlighted the importance of IL-6 in the pathogenesis of chemosensitive disorders	Action of local inflammatory phenomena on the receptors of olfactory and gustatory cells, rather than permanent cell damage linked to the action of the virus. The dysfunctions may be linked to the peripheral action of IL-6 at the level of cell receptors infected by the virus and to the central action of IL-6 at the level of intermediate taste stations and olfactory pathways, especially in the thalamus
Scopus	Brain metabolic correlates with persistent olfactory dysfunction after SARS-Cov-2 infection	Donegani et al[27], 2021	22 patients/cross-sectional study	The study provided a group analysis on brain metabolism of patients with persistent olfactory dysfunction after infection with SARS-CoV-2 for the first time proven by olfactory test. It highlighted the confusion of the subtle sequelae of SARS-COV-2 infection and its reflection on PET and other biomarkers	The virus can enter the central nervous system through the first neurons of the olfactory pathway located in the olfactory mucosa. Post-infectious olfactory dysfunction is thought to be caused by damage to the olfactory epithelium or central olfactory processing pathways, with current evidence that hypometabolism in two symmetrical and similar regions within the limbic cortex may support the occurrence of distal olfactory pathway involvement
Scopus	Olfactory function and chest CT findings in COVID-19: is there any correlation?	Mangia et al[28], 2021	57 patients/cohort-nested cross-sectional study	Olfactory dysfunction does not correlate with radiological lung involvement in hospitalized patients with COVID-19	The nasal mucosa is an important entry site for SARS-COV-2, as it has a predilection for this neuroepithelium, in addition to having neurotrophic properties. The smell disorder in COVID-19 would not arise from local edema and nasal secretion, preventing odor molecules from reaching the olfactory neuroepithelium
Scopus	Structural and metabolic brain abnormalities in patients with sudden loss of smell with COVID-19	Niesen et al[29], 2021	12 patients/ prospective descriptive study	This PET-MR study suggests that the sudden loss of smell in COVID-19 is not related to central involvement due to SARS-CoV-2 neuroinvasiveness. Loss of smell is associated with subtle brain metabolic changes in high-order central and cortical olfactory areas, likely related to combined processes of deaeration and active functional reorganization secondary to lack of olfactory stimulation	Considering that the metabolic abnormalities were not associated with any MRI signal abnormalities, they likely do not represent neuroimaging evidence supporting the neuroinvasive potential of SARS-CoV-2, but rather functional brain markers of olfactory deficit

ACE2: Angiotensin-converting enzyme 2; COVID-19: Coronavirus 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; MRI: Magnetic resonance imaging; PET: Positron emission tomography; CT: Computed tomography.