COVID-19 and loss of smell

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A die symptoms of COVID-19 is an olfactory dysfunction, which is the reduced or distorted ability to smell while sniffing or consuming.

A recent review published in the journal Virus examines the high sensitivity of the olfactory epithelium, which is the protective layer in the nasal cavity that is responsible for smell, to infection with SARS-CoV-2, and the plausible causes of persistent olfactory dysfunction in some COVID-19 convalescents.

To study: Anosmia: high prevalence, plural neuropathogenic mechanisms and rare neurotropism of SARS-CoV-2? Image Credit: Design_Cells / Shutterstock.com

Olfactory dysfunctions

Olfactory dysfunctions are common disorders of the nose caused by nasal congestion, inflammation of the olfactory epithelium, infection, structural and functional damage or abnormalities of the olfactory nerve, olfactory bulb or other structures of the central nervous system (SNC).

Olfactory dysfunctions in COVID-19 are different from the conventional meaning of these disorders, as they sometimes appear before other symptoms and may even be the only symptoms of infection.

The incidence of smell and / or taste disturbances in patients with COVID-19 varies. Studies show a prevalence of 5 to 98%, depending on the region, the population, the variants of SARS-CoV-2 and the diagnostic methods. However, most studies report a rate of olfactory dysfunction between 20% and 80%. The majority of olfactory dysfunctions linked to COVID-19 resolve themselves within a few weeks; however, in some patients, these effects may persist long after other symptoms of COVID-19 resolve.

Olfactory epithelium and susceptibility to SARS-CoV-2

The sense of smell or smell begins when airborne odor molecules bind to their receptors on the surface of the olfactory epithelium in the nasal cavity. Scents trigger electrical signals that are transmitted by the olfactory nerves to the olfactory bulb in the brain.

The olfactory epithelium lines the nasal cavity near the entrance to the upper respiratory tract. This fabric helps in the early detection of important or potentially harmful odorous substances in the air. It is important to note that the positioning of the olfactory epithelium also makes it vulnerable to pathogens or other types of damage.

The olfactory epithelium is like the respiratory epithelium which also lines the nasal cavity. However, close examination reveals minute structural differences between these two tissues.

Electron micrographs showing the perpendicular (A) and tangential / oblique section (B) from the apical part of the OE rat. The dotted line in panel A indicates the apical surface of sustentacular cells (S) of the apical part of rat EO. The dotted line in panel A indicates the apical surface of sustentacular cells (S) from which the long, thin microvilli of sustentacular cells protrude into the nasal cavity for approximately 2-3 m. whose long, thin, sustentacular cell microvilli protrude into the nasal cavity for about 2 to 3 m. The ORN dendritic buttons (DN) and cilia (C) at the apical ends of the ORN dendrites (D) are mainly found. The ORN dendritic buttons (DN) and cilia (C) at the apical ends of the ORN dendrites (D) are mainly found among the sustentaculars. microvilli (most small unlabeled profile structures in (B) and in the sustentacular microvilli area (most small unlabeled profile structures in (B)B) and in the area above the dotted line in (A). The human EO is organized in the same way [52–54]. Scale bars = 0.5 m. the dotted line in (A). The human EO is organized in the same way [52–54]. Scale bars = 0.5 m.

For example, there is a difference in expression of the angiotensin converting enzyme receptor 2 (ACE2), which is used by SARS-CoV-2 to enter the host cell, between the olfactory epithelium and the respiratory epithelium. Indeed, the expression of ACE2 is hundreds of times greater in the olfactory epithelium than in the respiratory epithelium. In addition, the olfactory epithelium has cellular microvilli which have an increased cell surface area for binding or absorption.

Neuropathology of SARS-CoV-2

Viruses can preferentially bind to and enter nerves, indicating their neurotropic nature. The majority of neurotropic viruses bind to receptors on neurons. ACE2 is present on specific cell types within the olfactory epithelium and respiratory epithelium; however, there is little or no ACE2 on mature nerves of the olfactory system.

Several studies report the infection and / or pathology of SARS-CoV-2 in various cells, tissues and organs in human autopsy or biopsy samples and in animal models. In addition, some studies have also reported the presence of SARS-CoV-2 spike protein in the olfactory epithelium and the respiratory epithelium.

In one study, a biopsy from a patient with loss of smell three months after recovering from COVID-19 showed disruption and massive damage to the olfactory epithelium. SARS-CoV-2 has rarely been detected in the cerebrospinal fluid (CSF) of COVID-19 patients; however, inflammation or immune reactions have been observed frequently.

There is no direct evidence that SARS-CoV-2 infects the brain. COVID-19 autopsies show extensive inflammation of areas of the brain and lesions of the olfactory bulb.

Mechanisms of COVID-19 neuropathogenesis

SARS-CoV-2 primarily infects the olfactory sustentacular cells of the olfactory epithelium which express high levels of ACE2. Infection and damage to sustentacular cells can lead to inflammation, immune reactions, as well as the release of cytokines and signaling that can cause olfactory dysfunction and damage to the nerves of the olfactory system.

In the case of persistent olfactory dysfunctions post-COVID-19, the pathogenic mechanisms may include damage to certain cells, continued inflammation or chronic infection with SARS-CoV-2 in the olfactory epithelium. The transport of pathogenic molecules from the olfactory epithelium to the olfactory bulb via the nerves can lead to dysfunction and degeneration of the nerves of the olfactory bulb. Infection with SARS-CoV-2 of cells in the capillary blood vessels of the brain can compromise the blood-brain barrier and cause neuropathology and dysfunction in various regions of the brain.

In patients with COVID-19 who have obvious nasal congestion, obstructed airflow through the nasal cavity would also negatively affect olfaction and intensify olfactory dysfunctions.

Schematic diagrams showing the possible mechanisms of olfactory neuropathogenesis in COVID-19. (A) A schematic outline to illustrate the relationships between the nasal cavity, the olfactory epithelium (OE), the olfactory nerve (ON), the olfactory bulb (OB) and the brain (B) At EO, SARS-CoV-2 primarily infects olfactory sustentacular cells (OSCs) which express high levels of SARS-CoV-2 ACE2 receptor on the luminal surface. Infection and damage to sustentacular cells can lead to inflammation, the SARS-CoV-2 ACE2 receptor on the luminal surface. Infection and damage to sustentacular cells can lead to inflammation, immune responses, release of cytokines and signaling by pathogen-associated molecular models (PAMPs), damaged immune responses, release of cytokines and signaling by Pathogen Associated Molecular Models (PAMPs), Damage Associated Molecular Models (DAMPs) and Pattern Recognition Receptors (PRRs) which in turn may cause malfunctions, damage and / or anterograde degeneration of olfactory receptor neuronal cells (ORN). In the case of persistent olfactory dysfunctions post-COVID-19, pathogenic mechanisms may include basal degenerative damage to neural structures in OB. (D) SARS-CoV-2 infection of endothelial cells or pericytes, and microthrombi transport of pathogenic molecules from EO to OB along ORN axons can lead to dysfunction and transsynaptic in the cells. capillary blood vessels, can compromise the blood-brain barrier, and lead to hematogenous neuropathology and degeneration of neural structures in OB. (D) SARS-CoV-2 infection of endothelial cells or pericytes, and microthrombi dysfunction in various regions of the brain, including OB. in capillary blood vessels, can compromise the blood-brain barrier and cause hematogenous neuropathology and dysfunction in various regions of the brain, including OB.

Long-lasting olfactory dysfunctions after COVID-19

The olfactory epithelium undergoes regular aging and self-replacement throughout life. In addition, this tissue is easily repaired or regenerated after damage.

The absent or slow recovery from olfactory dysfunctions of COVID-19 in some individuals involves severe or lasting damage to the olfactory epithelium by the virus. Another possible explanation is the persistent presence of SARS-CoV-2, chronic inflammation and immune reactions, or increased cell death in the olfactory epithelium. Interestingly, chronic inflammation could shift the function of some cells in the olfactory epithelium from regeneration to inflammatory signaling and immune cell proliferation.

Conclusion

There is no evidence that SARS-CoV-2 infects the nerves. Infection with SARS-CoV-2 causes odor dysfunction and damage, most likely through indirect means such as deprivation of support and inflammatory or immune reactions. These processes add to the pathogenic mechanisms of many neurological symptoms and complications of COVID-19.

Overall, it is essential to study the causes and treatments of chronic SARS-CoV-2 infection of the olfactory epithelium and persistent olfactory dysfunctions post-COVID-19 in several COVID-19 convalescents.