Background
The mechanisms by which any upper respiratory virus, including SARS-CoV-2, alters chemosensory function are unknown. COVID-19 is frequently associated with olfactory dysfunction following viral infection, providing a research opportunity to evaluate the natural course of this neurological finding.
Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples.
Although data from neuropathological specimens are now available, neurological imaging of the olfactory system during the acute phase of infection remains uncommon due to concerns about infection control and critical illness, and represents a substantial gap in knowledge. .
Recent developments
Active replication of SARS-CoV-2 within the brain parenchyma (i.e., in neurons and glia) has not been proven. However, post-viral olfactory dysfunction can be seen as a focal neurological deficit in patients with COVID-19.
There is also little evidence of a direct causal relationship between SARS-CoV-2 infection and abnormal brain findings at autopsy, and of trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb.
Taken together, the clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in the olfactory epithelium, the olfactory bulb, or both.
This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19.
Neuroimaging has revealed localized inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen.
As follows?
The prevalence of CNS and olfactory bulb pathology in patients with COVID-19 is unknown. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be predictive of a higher likelihood of long-term neurological sequelae or neurodegenerative disorders.
An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions could accelerate pathological processes and symptomatic progression of neurodegenerative disease.
Persistent olfactory impairment with or without perceptual distortions (i.e., parosmias or phantosmias) following SARS-CoV-2 infection could therefore serve as a marker to identify individuals at increased long-term risk. of neurological disease.
Until 2002, when SARS-CoV crossed the species barrier to infect humans, coronaviruses were considered minor human pathogens. SARS-CoV and SARS-CoV-2 are related coronaviruses and have 72.8% nucleic acid sequence homology. Furthermore, both viruses use angiotensin-converting enzyme 2 (ACE2) as an entry receptor, which couples to the trimeric spike glycoprotein located on the surface of the virion. Despite these similarities, each viral infection has a different clinical course. Unlike SARS-CoV-2 infection, SARS-CoV infection does not cause olfactory impairment and mainly affects the lower respiratory tract.
| Standing principle in virology : Although viral entry receptors and cofactors on the surface of host cells determine infectivity, pathogenesis cannot be inferred from the expression pattern of the viral entry receptor alone. |
The neurotropic, neuroinvasive, and neurovirulent characteristics of SARS-CoV-2 are not fully understood. Although sudden-onset anosmia or hyposmia (i.e., complete or partial loss of smell) are specific indicators of early infection, the precise manner in which the olfactory system deteriorates has not been fully elucidated.
Pooled prevalence estimates reveal olfactory dysfunction in approximately half to three-quarters of people diagnosed with COVID-19, and estimates tend to increase when using semi-objective quantitative diagnostic tools, which grade levels of impairment to detect subclinical loss of smell.
SARS-CoV-2 is highly pathogenic and possibly infects several types of cells and tissues. As a result, SARS-CoV-2 infection causes a variety of systemic symptoms. However, it is unclear whether the symptoms are the result of direct tissue invasion of the virus or of systemic, dysregulated inflammation or generalized microangiopathy (often with resulting microcirculatory thrombi).
Viruses with the intrinsic ability to access neural tissue are quite rare. Neuroinvasion can be facultative and opportunistic (i.e., the virus spreads infrequently to off-target cells and tissues) or obligate (i.e., the virus replicates within neurons). It is unclear whether SARS-CoV-2 strains are explicitly tropic, cytopathic, or both for neural tissue (neurons and glia) or neurovasculature (endothelium).
The viral nucleic acid, detected by RT-PCR in neural tissue, may not reflect a direct infection at that site, but rather hematogenous spread from distant infected tissues. These knowledge gaps regarding SARS-CoV-2 tropism and pathogenicity are considerable barriers to understanding the clinical effects of SARS-CoV-2 infection on the olfactory nervous system and CNS.
In this Rapid Review, we discuss the association between post-viral olfactory dysfunction and SARS-CoV-2 infection, summarize the biological pathways, contextualize the histological evidence from autopsy studies, and propose a hypothesis about the usefulness of this dysfunction for predict subsequent neurological dysfunction. disorders.
Given the intertwined relationship between smell and taste, and because little is known about the underlying mechanisms that could explain complete ageusia (i.e., loss of taste) and the loss of oral chemosthesis observed in conjunction with smell post-viral dysfunction in people with COVID-19, we focused only on olfactory symptomatology.
Olfactory dysfunction after SARS-CoV-2 infection
The mechanisms underlying olfactory dysfunction in people who have had COVID-19 are difficult to disentangle due to the heterogeneity of presentations. Such heterogeneity implies that SARS-CoV-2 infection can alter olfactory function at multiple anatomical levels and through several pathophysiological mechanisms that are not mutually exclusive.
The factors underlying the differences in recovery are unknown. In most cases of COVID-19, recovery of olfactory function is rapid, apparently complete , and usually occurs in parallel with the resolution of physical, sinonasal, and choryzal symptoms.
The median time to recovery of function after symptoms of olfactory dysfunction manifest is approximately 10 days , although residual, inapparent hyposmia, along with perceptual distortions, may persist.
Panel 1
Loss of olfactory epithelium (possibly due to death of neural stem cells).
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In people with COVID-19, endoscopic and radiographic evidence shows that the olfactory clefts of the upper nasal vault are unobstructed , suggesting that hyposmia is not explained by the driver model. However, reversible nasal obstruction of airflow through the superior meatus (so-called olfactory cleft syndrome ) is also found in a subset of people with olfactory dysfunction after SARS-CoV-2 infection.
The rate of recovery of olfactory function in people with so-called long COVID (i.e. people with persistent symptoms for more than 3 months) is still unknown. An observation period of 12 to 24 months is required before chronic olfactory disturbance can be classified as permanent .
Furthermore, current studies are generally based on self-reported data rather than a comprehensive rhinological and psychophysical olfactometric examination. Importantly, unlike a cardinal symptom of an ongoing infection (e.g., fever), ongoing olfactory impairment does not reflect a contagious state or persistence of SARS-CoV-2 infection.
In people with COVID-19 who have not yet returned to baseline olfactory function, it is unclear whether chronic olfactory impairment is due to irreversible damage to intranasal primary olfactory neurons embedded in the epithelium of the nasal vault, damage to the olfactory bulb, or dysfunction within other CNS pathways.
Manifestations of central olfactory dysfunction
To our knowledge, there are no historical data on how pathosis confined within the olfactory bulbs (e.g., infection and neuroinflammation) manifests clinically, and it is unclear whether pathosis would present as anosmia, perceptual distortions (i.e. that is, parosmias or phantosmias), or focal or mild encephalitis.
A local disease process that is isolated and contained within the olfactory bulbs may not produce sufficient characteristic signs and symptoms to allow clinicians to suspect CNS pathoses on clinical grounds alone and therefore be able to judge these symptoms as associated with SARS-CoV-2. Furthermore, acute aseptic encephalitis is a very difficult entity to diagnose, even with clinical, laboratory, and neurodiagnostic findings considered pathognomonic.
A distinctive portrait of short- and medium-term neurological manifestations in COVID-19 survivors has not yet emerged. A diverse range of non-specific neurological symptoms (i.e. headache, dizziness, fatigue and dysautonomia) and a COVID-19 diagnosis suggest a causal link, which is often used to suggest neuropathogenicity. However, these vague and ubiquitous symptoms often occur in respiratory virus infections and are more likely to be transient alterations in acute neurological function than signs of a neuropathic disease process.
The CNS is protected from infection by intrinsic and innate defense mechanisms. The release of non-cytolytic antiviral cytokines by activated or infiltrating glial inflammatory cells is the usual mechanism to block viral replication and dissemination in the CNS. Much research is underway into the extent to which the neurological symptoms of COVID-19 are due to the direct effect on neurons versus maladaptive cytokine dysregulation. Currently, evidence showing SARS-CoV-2 infection in the brain or spinal cord is scarce.
The parainfectious cytokine storm hypothesis states that postviral neurological disease is due to a sterile, exuberant, and uncontrolled immunopathology, with active viral replication playing an initiating but secondary role.
Impaired smell has not been routinely identified as a neurological sequelae of the acute or recovery phases in patients with noninfectious critical illness-related encephalopathy, a condition that would also be expected to generate innate proinflammatory responses in the brain.
Persistent olfactory dysfunction is a feature that is unique to COVID-19 patients and suggests intrinsic pathosis within olfactory-eloquent intracranial structures, possibly with persistent alterations of primary olfactory neurons.
The mechanisms underlying the loss or perturbation of chemosensory function are unclear, but research is ongoing at the cellular level. Evidence supporting direct viral invasion of olfactory sensory neurons is elusive targeting by SARS-CoV-2 to non-neuronal receptor-sustainacular supporting cells, which express the ACE2 receptor and TMPRSS2 (transmembrane protease serine 2).
Once infected and damaged, these cells can alter the electrophysiological and biochemical homeostasis of the olfactory sensory neurons present. , and the resulting resource-restricted environment could silence the olfactory receptor in a manner consistent with transient neuropraxia.
Other pathophysiological models propose that the local inflammatory response could result in a reduction in the expression or function of cognate odorant binding receptor molecules expressed on the apical surface of bipolar neurons, leading to impairment of odotransduction.
Pathosis within the olfactory bulbs
Dissemination of virions or subviral ribonucleoprotein complexes may occur through the cribriform plate to the olfactory bulbs of the CNS via a transcellular or paracellular route (figure), although the evidence is scarce and circumstantial. Standard hematoxylin and eosin staining has revealed pronounced and preferential inflammation in the olfactory bulbs of some people who have died from COVID-19
Using standard RT-PCR, the amount of viral RNA was quantified at autopsy and was found to be at higher concentrations in the olfactory bulbs than in other brain regions.
By immunohistochemistry, a spike glycoprotein has been detected within the parenchyma of the olfactory bulbs in a person who died of COVID-19.
Furthermore, sterile inflammation of the olfactory bulbs, due to a fulminant and persistent infection of the underlying intranasal olfactory receptor, could also be sufficient to cause or contribute to the activation of microglia and astroglia.
Conclusions and future directions
After infection with SARS-CoV-2, the olfactory system could be said to serve as a so-called viral sensor , alerting healthcare professionals to the presence of the pathogen. One benefit of early detection may be interruption of direct transmission.
Currently available radiographic, histological, and molecular data cannot definitively rule out transcriptional, transcellular, or paracellular trafficking of subviral virions or macromolecules from the infected olfactory epithelium to the olfactory bulbs in patients with acute postviral olfactory dysfunction.
Neuropathy and brain damage to the olfactory system are consistent with residual olfactory dysfunction with or without perceptual distortions (eg, parosmias and phantosmias). However, these statements could change as more post-mortem studies are completed, more histopathological and ultrastructural data are completed, and quantitative olfactometric examinations are published.
Future efforts involving structural and functional MRI of the olfactory system in people with anosmia, performed during the acute phase of SARS-CoV-2 infection, would help close this knowledge gap. Future clinical trials could also be useful to evaluate whether immunomodulatory agents reduce persistent olfactory deficits.
Long-term neurodegenerative sequelae may take years to manifest and may be clinically silent at this early point in the COVID-19 pandemic. Although a definitive link between chronic or permanent olfactory impairment and future neurological vulnerability cannot yet be established, some studies suggest an association.
Growing evidence implicates neuroinflammatory signaling within the brain as a key driver of neurodegenerative diseases. Brain regions involved in processing olfactory input are early sites of pathological hallmarks of neurodegenerative disease and connect with adjacent brain regions involved in memory and attention.
Permanent olfactory deficit could be a predictor of a higher probability of neurological sequelae or long-term neurodegenerative disorders.
Inflammatory pathways induced by SARS-CoV-2 in the nasal epithelium substantially overlap with inflammatory signaling described in subsets of dementia patients. An inflammatory stimulus from the nasal epithelium to the olfactory bulbs and connected brain regions could therefore be accelerated.
Pathological processes and progression of neurodegenerative diseases. Although the prevalence of inflammatory signaling in the olfactory bulbs of COVID-19 patients is unknown, intense inflammation in the nasal olfactory epithelium (as seen in SARS-CoV-2 infections) may spread sterile inflammation to the bulbs. olfactory in animal models.
COVID-19 survivors, with or without persistent olfactory impairment, may be at risk for accelerated onset or progression of neurodegenerative disease and should be studied longitudinally with imaging and molecular biomarkers, and cognitive profiles, to test this postulated risk. Furthermore, as vaccination efforts reduce mortality, they will also have a lasting impact on morbidity by reducing the neurological sequelae of SARS-CoV-2.
