Post-viral effects of COVID-19 in the olfactory system and their implications.

BACKGROUND: The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides 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, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge. RECENT DEVELOPMENTS: The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either 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 localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. WHERE NEXT?: The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.

Airborne aerosol olfactory deposition contributes to anosmia in COVID-19.

INTRODUCTION: Olfactory dysfunction (OD) affects a majority of COVID-19 patients, is atypical in duration and recovery, and is associated with focal opacification and inflammation of the olfactory epithelium. Given recent increased emphasis on airborne transmission of SARS-CoV-2, the purpose of the present study was to experimentally characterize aerosol dispersion within olfactory epithelium (OE) and respiratory epithelium (RE) in human subjects, to determine if small (sub 5µm) airborne aerosols selectively deposit in the OE. METHODS: Healthy adult volunteers inhaled fluorescein-labeled nebulized 0.5-5µm airborne aerosol or atomized larger aerosolized droplets (30-100µm). Particulate deposition in the OE and RE was assessed by blue-light filter modified rigid endoscopic evaluation with subsequent image randomization, processing and quantification by a blinded reviewer. RESULTS: 0.5-5µm airborne aerosol deposition, as assessed by fluorescence gray value, was significantly higher in the OE than the RE bilaterally, with minimal to no deposition observed in the RE (maximum fluorescence: OE 19.5(IQR 22.5), RE 1(IQR 3.2), p<0.001; average fluorescence: OE 2.3(IQR 4.5), RE 0.1(IQR 0.2), p<0.01). Conversely, larger 30-100µm aerosolized droplet deposition was significantly greater in the RE than the OE (maximum fluorescence: OE 13(IQR 14.3), RE 38(IQR 45.5), p<0.01; average fluorescence: OE 1.9(IQR 2.1), RE 5.9(IQR 5.9), p<0.01). CONCLUSIONS: Our data experimentally confirm that despite bypassing the majority of the upper airway, small-sized (0.5-5µm) airborne aerosols differentially deposit in significant concentrations within the olfactory epithelium. This provides a compelling aerodynamic mechanism to explain atypical OD in COVID-19.

More that ACE2? NRP1 may play a central role in the underlying pathophysiological mechanism of olfactory dysfunction in COVID-19 and its association with enhanced survival.

Three mechanisms have been proposed to account for COVID-19 associated olfactory dysfunction; obstruction of the olfactory cleft; epithelial injury and infection of the sustentacular supporting cells, which are known to express ACE2, or injury to the olfactory bulb due to axonal transport through olfactory sensory neurones. The absence of ACE2 expression by olfactory sensory neurones has led to the neurotropic potential of COVID-19 to be discounted. While an accumulating body of evidence supports olfactory epithelial injury as an important mechanism, this does not account for all the features of olfactory dysfunction seen in COVID-19; for example the duration of loss in some patients, evidence of changes within the olfactory bulb on MRI imaging, identification of viral particles within the olfactory bulb in post-mortem specimens and the inverse association between severity of COVID-19 and the prevalence of olfactory loss. The recent identification of a second route of viral entry mediated by NRP1 addresses many of these inconsistencies. Expression by the olfactory sensory neurones and their progenitor cells may facilitate direct injury and axonal transport to the olfactory bulb as well as a mechanism for delayed or absent recovery. Expression by regulatory T cells may play a central role in the cytokine storm. Variability in expression by age, race or gender may explain differing morbidity of infection and inverse association between anosmia and severity; in the case of higher expression there may be a higher risk of olfactory function but greater activation of regulatory T cells that may suppress the cytokine storm.

Anosmia: a missing link in the neuroimmunology of coronavirus disease 2019 (COVID-19).

Just before 2020 began, a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), brought for humans a potentially fatal disease known as coronavirus disease 2019 (COVID-19). The world has thoroughly been affected by COVID-19, while there has been little progress towards understanding the pathogenesis of COVID-19. Patients with a severe phenotype of disease and those who died from the disease have shown hyperinflammation and were more likely to develop neurological manifestations, linking the clinical disease with neuroimmunological features. Anosmia frequently occurs early in the course of COVID-19. The prevalence of anosmia would be influenced by self-diagnosis as well as self-misdiagnosis in patients with COVID-19. Despite this, the association between anosmia and COVID-19 has been a hope for research, aiming to understand the pathogenesis of COVID-19. Studies have suggested differently probable mechanisms for the development of anosmia in COVID-19, including olfactory cleft syndrome, postviral anosmia syndrome, cytokine storm, direct damage of olfactory sensory neurons, and impairment of the olfactory perception center in the brain. Thus, the observation of anosmia would direct us to find the pathogenesis of COVID-19 in the central nervous system, and this is consistent with numerous neurological manifestations related to COVID-19. Like other neurotropic viruses, SARS-CoV-2 might be able to enter the central nervous system via the olfactory epithelium and induce innate immune responses at the site of entry. Viral replication in the nonneural olfactory cells indirectly causes damage to the olfactory receptor nerves, and as a consequence, anosmia occurs. Further studies are required to investigate the neuroimmunology of COVID-19 in relation to anosmia.

COVID-19 and the Chemical Senses: Supporting Players Take Center Stage.

The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly.

Smell and taste dysfunction in patients with SARS-CoV-2 infection: A review of epidemiology, pathogenesis, prognosis, and treatment options.

During the initial pandemic wave of COVID-19, apart from common presenting symptoms (cough, fever, and fatigue), many countries have reported a sudden increase in the number of smell and taste dysfunction patients. Smell dysfunction has been reported in other viral infections (parainfluenza, rhinovirus, SARS, and others), but the incidence is much lower than SARS-CoV-2 infection. The pathophysiology of post-infectious olfactory loss was hypothesized that viruses may produce an inflammatory reaction of the nasal mucosa or damage the olfactory neuroepithelium directly. However, loss of smell could be presented in COVID-19 patients without other rhinologic symptoms or significant nasal inflammation. This review aims to provide a brief overview of recent evidence for epidemiology, pathological mechanisms for the smell, and taste dysfunction in SARS-CoV-2 infected patients. Furthermore, prognosis and treatments are reviewed with scanty evidence. We also discuss the possibility of using "smell and taste loss" as a screening tool for COVID-19 and treatment options in the post-SARS-CoV-2 infectious olfactory loss.

Neurological Insights of COVID-19 Pandemic.

The novel coronavirus SARS-CoV-2, which was identified after a recent outbreak in Wuhan, China, in December 2019, has kept the whole world in tenterhooks due to its severe life-threatening nature of the infection. The virus is unlike its previous counterparts, SARS-CoV and MERS-CoV, or anything the world has encountered before both in terms of virulence and severity of the infection. If scientific reports relevant to the SARS-CoV-2 virus are noted, it can be seen that the virus owes much of its killer properties to its unique structure that has a stronger binding affinity with the human angiotensin-converting enzyme 2 (hACE2) protein, which the viruses utilize as an entry point to gain accesses to its hosts. Recent reports suggest that it is not just the lung that the virus may be targeting; the human brain may soon emerge as the new abode of the virus. Already instances of patients with COVID-19 have been reported with mild (anosmia and ageusia) to severe (encephalopathy) neurological manifestations, and if that is so, then it gives us more reasons to be frightened of this killer virus. Keeping in mind that the situation does not worsen from here, immediate awareness and more thorough research regarding the neuroinvasive nature of the virus is the immediate need of the hour. Scientists globally also need to up their game to design more specific therapeutic strategies with the available information to counteract the pandemic. In this Viewpoint, we provide a brief outline of the currently known neurological manifestations of COVID-19 and discuss some probable ways to design therapeutic strategies to overcome the present global crisis.