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Background: Postviral olfactory dysfunction (PVOD) is a clinical challenge due to limited therapeutic options and poor prognosis. Both steroids and olfactory training have been proved to be effective for olfactory dysfunction with varied etiologies. We sought to perform a systematic review to summarize the evidence of steroids or olfactory training for patients with PVOD. Methods: A systematic literature review using PubMed, Embase, Cochrane Library, and Web of Science was conducted to identify studies assessing olfactory change in patients with PVOD receiving steroid or olfactory training. Results: Of the initial 273 abstracts reviewed, 20 articles with data from 2,415 patients with PVOD were included. Treatments including topical steroids, systemic steroids, classical olfactory training (COT), modified olfactory training (MOT), and olfactory training with steroid were analyzed. Both psychophysical olfactory testing and subjective symptom scores were utilized to assess the olfactory function. The routine use of nasal steroid spray alone during the management of PVOD seems to have no positive effect on olfactory dysfunction. Direct injection of steroid or nasal steroid spray into the olfactory cleft significantly improved the olfactory function in patients with PVOD. Olfactory improvement is greater than that of the natural course of the disease with short-term COT. Patients with PVOD would benefit more from long-term COT (>12 weeks). Treatment duration, various odorants, olfactory training devices, changing the types of odors periodically, different molecular odorants, and different concentrations of odorants tended to increase the efficiency of MOT. Clinically significant improvement after olfactory training was defined as an increase of threshold, discrimination, and identification (TDI) score ≥6. From week 24 to week 36, both COT and MOT groups reached the maximum therapeutic effect regarding the number of participants achieving clinically significant improvement. A combination of local or oral steroids with olfactory training is more efficient than COT only. Conclusion: Olfactory function in patients with PVOD was effectively improved through direct steroid administration in the olfactory cleft, COT, or modification of COT. The addition of topical steroids to COT therapy showed a tendency for greater olfactory improvement in patients with PVOD.

Purpose Although the prevalence of olfactory dysfunction in children is thought to be lower compared to adults, little is known about the actual frequency of etiologies of smell dysfunction in children. Aim of the study was (i) to describe the epidemiology of olfactory dysfunction in a pediatric population and (ii) to compare the distribution of etiologies to adults. Material and methods Data of patients consulting a smell and taste clinic between 2000 and 2017 were retrospectively analyzed. Frequency of major causes of olfactory dysfunction was examined with a focus on the pediatric population. Results A total of 7153 patients (164 children) were included in the analysis. Most children presented with congenital olfactory dysfunction (67%), or head-trauma (12%). In contrast, the cumulative frequency of olfactory loss associated with sinonasal disorders or acute infections of the upper airways was 6%. The frequency of etiologies of olfactory dysfunction changed with age: While the frequency of patients with congenital anosmia decreased, the frequency of causes related to infections of the upper respiratory tract and idiopathic causes increased. Conclusion About 2/3 of olfactory dysfunction in children are congenital while 1/3 is acquired. The frequency of etiologies causing olfactory dysfunction change significantly from children to an adult population.

Objectives: Post-viral olfactory dysfunction (PVOD) is a neurogenic disorder caused by a common cold virus. Based on the homology of deduced amino acid sequences, olfactory sensory neurons (OSNs) in both mice and humans express either class I or class II odorant receptor genes encoding class I and class II OSNs. The purpose of this study was to determine whether OSN damage in PVOD occurs uniformly in both neuron types. Materials and methods: The characteristics of PVOD patients were compared with those of patients with chronic rhinosinusitis (CRS) or post-traumatic olfactory dysfunction (PTOD). Briefly, subjects underwent orthonasal olfaction tests using five different odors (T&T odors) and a retronasal olfaction test using a single odor (IVO odor). The regions in the mouse olfactory bulb (OB) activated by the T&T and the IVO odors were also examined. Results: Multivariate analysis of 307 cases of olfactory dysfunction (PVOD, 118 cases; CRS, 161 cases; and PTOD, 28 cases) revealed that a combination of responses to the IVO odor, but not to the T&T odors, is characteristic of PVOD, with high specificity (p < 0.001). Imaging analysis of GCaMP3 mice showed that the IVO odor selectively activated the OB region in which the axons of class I OSNs converged, whereas the T&T odors broadly activated the OB region in which axons of class I and class II OSNs converged. Conclusions: A response to T&T odors, but not IVO odor, in PVOD suggests that class I OSNs are injured preferentially, and that OSN damage in PVOD may occur heterogeneously in a neuron-type-dependent manner.

Anosmia; COVID-19 vaccination; Dysgeusia; Gustatory dysfunction; Olfactory dysfunction INTRODUCTION Starting with a cluster of unknown pneumonia cases in Wuhan, China, in December 2019 was the outbreak of 2019 novel strain of coronavirus which was declared a global emergency by the World Health Organization (WHO) on March 11,2020, officially announcing the disease as \"coronavirus disease 2019 (COVID-19)\" and the virus as \"severe acute respiratory syndrome-coronavirus 2 (SARS-COV-2). [5]The Centers for Disease Control and Prevention and WHO endorsed new-onset smell or taste loss as symptoms of SARS-CoV-2 infection after a meta-analysis reported 47% prevalence of loss of smell or taste among COVID-19 patients.PA7] Equitable access to safe and effective vaccines is critical to ending the COVID-19 pandemic. [8] Chemosensory disorders such as anosmia and altered taste sensation have a significant impact on health and quality of life of individuals. Information on the duration and reversibility of post-COVID-19 vaccination chemosensory impairment is also lacking. [...]it is important to determine the prevalence and duration of altered smell and taste post-COVID-19 vaccination.

Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Parkinson’s disease and other synucleinopathies, Alzheimer’s disease (AD), and mild cognitive impairment heralding its progression to dementia. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb/tract, primary olfactory cortices, and their secondary targets. Olfactory dysfunction is related to deposition of pathological proteins, α-synuclein, hyperphosphorylated tau protein, and neurofilament protein in these areas, featured by neurofibrillary tangles, Lewy bodies and neurites inducing a complex cascade of molecular processes including oxidative damage, neuroinflammation, and cytosolic disruption of cellular processes leading to cell death. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with severe anosmia. Recent studies of olfactory dysfunction have focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Here, we summarize the current knowledge on neuropathological and pathophysiological changes of the olfactory system in the most frequent neurodegenerative diseases, in particular AD and synucleinopathies. We also present neuropathological findings in the olfactory bulb and tract in a large autopsy cohort ( n  = 536, 57.8 % female, mean age 81.3 years). The severity of olfactory bulb HPτ, Aβ, and αSyn pathology correlated and increased significantly ( P  < 0.001) with increasing neuritic Braak stages, Thal Aβ phases, and cerebral Lewy body pathology, respectively. Hence, further studies are warranted to investigate the potential role of olfactory biopsies (possibly restricted to the olfactory epithelium) in the diagnostic process of neurodegenerative diseases in particular in clinical drug trials to identify subjects showing early, preclinical stages of neurodegeneration and to stratify clinically impaired cohorts according to the underlying cerebral neuropathology.

The biological substrate of persistent post-COVID-19 hyposmia is still unclear. However, as many neurodegenerative diseases present with smell impairment at onset, it may theoretically reflect degeneration within the central olfactory circuits. However, no data still exist regarding the post-COVID-19 patients. As the olfactory neurons (ONs) mirror pathological changes in the brain, allowing for tracking the underlying molecular events, here, we performed a broad analysis of ONs from patients with persistent post-COVID-19 OD to identify traces of potential neurodegeneration. ONs were collected through the non-invasive brushing of the olfactory mucosa from ten patients with persistent post-COVID-19 hyposmia (lasting > 6 months after infection) and ten age/sex-matched controls. Immunofluorescence staining for protein quantification and RT-PCR for gene expression levels were combined to measure ONs markers of α-synuclein, amyloid-β, and tau pathology, axonal injury, and mitochondrial network. Patients and controls had similar ONs levels of oligomeric α-synuclein, amyloid-β peptide, tau protein, neurofilament light chain (NfL), cytochrome C oxidase subunit 3 (COX3), and the heat shock protein 60 (HSP60). Our findings thus did not provide evidence for synucleinopathy and amyloid-β mismetabolism or gross traces of neuronal injury and mitochondrial dysfunction within the olfactory system in the early phase of persistent post-COVID-19 hyposmia.

Olfactory dysfunction is a clinical marker of prodromal Parkinson’s disease (PD), yet the underlying mechanisms remain unclear. To explore this relationship, we developed a zebrafish model that recapitulates the olfactory impairment observed in prodromal PD without affecting motor function. We used zebrafish due to their olfactory system’s similarity to mammals and their unique nervous system regenerative capacity. By injecting 6-hydroxydopamine (6-OHDA) into the dorsal telencephalic ventricle, we observed a significant loss of dopaminergic (DA) periglomerular neurons in the olfactory bulb (OB) and retrograde degeneration of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE). These alterations impaired olfactory responses to cadaverine, an aversive odorant, while responses to alanine remained intact. 6-OHDA also triggered robust neuroinflammatory responses. By 7 days post-injection, dopaminergic synapses in the OB were remodeled, OSNs in the OE appeared recovered, and neuroinflammation subsided, leading to full recovery of olfactory responses to cadaverine. These findings highlight the remarkable neuroplasticity of zebrafish and suggest that this model of olfactory dysfunction associated with dopaminergic loss could provide valuable insights into some features of early PD pathology. Understanding the interplay between dopaminergic loss and olfactory dysfunction in a highly regenerative vertebrate may inform therapeutic strategies for individuals suffering from olfactory loss.

Background: Persistent olfactory dysfunction (OD) is a significant complication of SARS-CoV-2 infection. Olfactory training (OT) using aromatic oils are recommended to improve olfactory recovery, but quantitative data are missing. Objective: We aimed to quantify the benefit of OT associated with visual stimulation assisted by a dedicated web-application on patients with 1-month or more OD. Methods: We performed an observational real-life data-based study on a cohort of patients with at least 1-month persistent OD included between 1/30/21 and 3/26/2021. Analysis was performed after a 4-weeks mean time of OT and at least 500 patients assessable for primary outcome. Participants exposed themselves twice daily to odors from four high concentration oils and visual stimulation assisted by a dedicated web-application. Improvement was defined as a 2/10 points increase on self-assessed olfactory visual analogue scale. Results: 548 were assessable for primary outcome assessment. The mean baseline self-assessed olfactory score was 1.9/10 (SD 1.7) and increase to 4.6 (SD 2.8) beyond a mean time of olfactory training of 27.7 days (SD 17.2). Olfactory training was associated with at least 2-points increase in 64.2% (n=352). The rate of patients with improvement was higher in patients having trained for more than 28 days versus patients having trained for less than 28 days (72.2% vs 59.0% respectively, p=.002). The kinetic of improvement was 8 days faster in hyposmic than in anosmic patients (p<.001). The benefit was observed regardless of the duration of the OD. OT associated with visual stimulation assisted by a dedicated web-application was associated with significant improvement in olfaction, especially if OT duration was superior to 28 days.

Smell dysfunction is a common and underdiagnosed medical condition that can have serious consequences. It is also an early biomarker of neurodegenerative diseases, including Alzheimer’s disease, where olfactory deficits precede detectable memory loss. Clinical tests that evaluate the sense of smell face two major challenges. First, human sensitivity to individual odorants varies significantly, so test results may be unreliable in people with low sensitivity to a test odorant but an otherwise normal sense of smell. Second, prior familiarity with odor stimuli can bias smell test performance. We have developed nonsemantic tests for olfactory sensitivity (SMELL-S) and olfactory resolution (SMELL-R) that use mixtures of odorants that have unfamiliar smells. The tests can be self-administered by healthy individuals with minimal training and show high test–retest reliability. Because SMELL-S uses odor mixtures rather than a single molecule, odor-specific insensitivity is averaged out, and the test accurately distinguished people with normal and dysfunctional smell. SMELL-R is a discrimination test in which the difference between two stimulus mixtures can be altered stepwise. This is an advance over current discrimination tests, which ask subjects to discriminate monomolecular odorants whose difference in odor cannot be quantified. SMELL-R showed significantly less bias in scores between North American and Taiwanese subjects than conventional semantically based smell tests that need to be adapted to different languages and cultures. Based on these proof-of-principle results in healthy individuals, we predict that SMELL-S and SMELL-R will be broadly effective in diagnosing smell dysfunction.

Background and objective Despite olfactory disorders being among the most common neurological complications of coronavirus disease 2019 (COVID-19), their pathogenesis has not been fully elucidated yet. Brain MR imaging is a consolidated method for evaluating olfactory system’s morphological modification, but a few quantitative studies have been published so far. The aim of the study was to provide MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms, including olfactory dysfunction. Methods 196 COVID-19 patients (median age: 53 years, 56% females) and 39 controls (median age 55 years, 49% females) were included in this cross-sectional observational study; 78 of the patients reported olfactory loss as the only neurological symptom. MRI processing was performed by ad-hoc semi-automatic processing procedures. Olfactory bulb (OB) volume was measured on T2-weighted MRI based on manual tracing and normalized to the brain volume. Olfactory tract (OT) median signal intensity was quantified on fluid attenuated inversion recovery (FLAIR) sequences, after preliminary intensity normalization. Results COVID-19 patients showed significantly lower left, right and total OB volumes than controls ( p  < 0.05). Age-related OB atrophy was found in the control but not in the patient population. No significant difference was found between patients with olfactory disorders and other neurological symptoms. Several outliers with abnormally high OT FLAIR signal intensity were found in the patient group. Conclusions Brain MRI findings demonstrated OB damage in COVID-19 patients with neurological complications. Future longitudinal studies are needed to clarify the transient or permanent nature of OB atrophy in COVID-19 pathology. Graphical abstract