Interactive effect of orthostatic hypotension on gray matter atrophy associated with hyposmia and RBD in de novo Parkinson's disease.

BACKGROUND: Orthostatic hypotension (OH) is a potential modifiable risk factor for cognitive impairment in patients with Parkinson's disease (PD). Although other risk factors for dementia, hyposmia and REM sleep behavior disorder (RBD), are closely associated with autonomic dysfunction in PD, little is known about how these risk factors influence cognitive function and cerebral pathology. OBJECTIVE: We investigated how these three factors contribute to gray matter atrophy by considering the interaction of OH with hyposmia and RBD. METHODS: We analyzed cortical thickness, subcortical gray matter volume, and cognitive measures from 78 patients with de novo PD who underwent the head-up tilt test for the diagnosis of OH. RESULTS: Whole-brain analyses with Monte Carlo corrections revealed that hyposmia was associated with decreased cortical thickness in a marginal branch of the cingulate sulcus among patients with OH, and cortical thickness in this area correlated with cognitive functioning only in patients with OH. Subcortical gray matter volume analysis indicated that severe RBD was associated with decreased volume in the left hippocampus and bilateral amygdala among patients with OH. CONCLUSION: Even in early PD, OH exerts effects on gray matter atrophy and cognitive dysfunction by interacting with RBD and hyposmia. OH might exacerbate cerebral pathology induced by hyposmia or RBD.

Decreased frontal and orbital volumes and increased cerebellar volumes in patients with anosmia Of Unknown origin: A subtle connection?

PURPOSE: Neuroimaging studies have shown that anosmia is accompanied by a decreased olfactory bulb volume, yet little is known about alterations in cerebral and cerebellar lobule volumes. The purpose of this study was to investigate structural brain alterations in anosmic patients. METHODS: Sixteen anosmic patients (mean age 42.62 ± 16.57 years; 6 women and 10 men) and 16 healthy controls (mean age 43.37 ± 18.98 years; 9 women and 7 men) were included in this retrospective study. All subjects who underwent magnetic resonance imaging scans were analyzed using VolBrain and voxel-based morphometry after olfactory testing. RESULTS: Despite being statistically insignificant, analysis using VBM revealed greater gray matter (GM) and white matter in the anosmia group compared to the healthy subjects. However, decreased GM (p < 0.001) and increased cerebellar (p = 0.046) volumes were observed in the anosmic patients. CONCLUSIONS: The study revealed structural brain alterations in specific areas beyond the olfactory bulb. Our results indicate that the cerebellum may play an exceptional role in the olfactory process and that this will be worth evaluating with further dynamic neuroimaging studies.

Brain structural analysis in patients with post-traumatic anosmia: Voxel-based and surface-based morphometry.

PURPOSE AND BACKGROUND: Voxel-based morphometry (VBM) and surfaced-based morphometry (SBM) investigate the characteristics of gray matter (GM) in various diseases such as post-traumatic anosmia (PTA). This study uses SBM and VBM to examine neuroanatomical measurements of GM and its functional correlates in patients with PTA. METHODS: MRI images and olfactory test results were collected from 39 PTA patients and 39 healthy controls. Sniffin' Sticks test was used to assess olfactory function. GM structure was analyzed using CAT12 and FreeSurfer, and olfactory bulb (OB) volume and olfactory sulcus (OS) depth were calculated using 3D-Slicer. RESULTS: Anosmic patients showed lower scores in the Sniffin' Sticks olfactory test, as well as reduction of OB volume and OS depth compared to control subjects. In these patients, overlapping changes were found between the VBM and SBM findings in the areas with significant effects, in particular, orbitofrontal cortex, superior and middle frontal gyrus, superior and middle temporal gyrus, anterior cingulate cortex, and insular cortex. Using SBM, decreased cortical thickness clusters were located in inferior and superior parietal gyrus. Further analysis in the region of interest demonstrated correlations between the orbitofrontal cortex and odor threshold score as well as the middle frontal gyrus and smell loss duration. CONCLUSION: These findings show that the morphological alterations in the OB, OS, and the central olfactory pathways might contribute to the pathogenic mechanism of olfactory dysfunction after head injury.

Reconsidering the olfactory and brain structures in Kallmann's syndrome: New findings in the analysis of volumetry.

OBJECTIVE: Kallmann's syndrome (KS) is characterized by hypogonadotropic hypogonadism and olfactory disorders. The complementary exams for evaluating of patients with hypogonadotrophic hypogonadism are important for the diagnosis and management of these patients. PATIENTS: We performed a well-established olfactory Sniffin' Stick test (SST) on 17 adult patients with KS and brain magnetic resonance imaging (MRI) to evaluate olfactory structures and further analysis by Freesurfer, a software for segmentation and volumetric evaluation of brain structures. We compared the Freesurfer results with 34 healthy patients matched for age and sex and performed correlations between the data studied. RESULTS: More than half of the patients with KS reported preserved smell but had olfactory disorders in the SST. In the MRI, 16 patients showed changes in the olfactory groove, the olfactory bulb-tract complex was altered in all of them and 52% had symmetrical structural changes. Interestingly, the pituitary gland was normal in only 29%. Regarding correlations, symmetrical changes in the olfactory structures were related to anosmia in 100%, while asymmetric changes induced anosmia in only 50% (p = .0294). In Freesurfer's assessment, patients with KS, compared to controls, had lower brainstem volume. In those with aplastic anterior olfactory sulcus, the brainstem volume was lower than in hypoplasia (p = .0333). CONCLUSIONS: Olfactory assessment and MRI proved to be important auxiliary tools for the diagnosis and management of patients with KS. New studies are needed to confirm the decrease in brainstem volume found by the Freesurfer software in patients with KS. Further studies are needed to confirm the decrease in brainstem volume found by the Freesurfer software in patients with KS.

Anosmia, mild cognitive impairment, and biomarkers of brain aging in older adults.

Olfactory impairment is a potential marker for prodromal dementia, but the underlying mechanisms are poorly understood. This population-based study included 4214 dementia-free participants (age ≥65 years). Olfaction was assessed using the 16-item Sniffin' Sticks identification test. In the subsamples, we measured plasma amyloid beta (Aß)40, Aß42, total tau, and neurofilament light chain (NfL; n = 1054); and quantified hippocampal, entorhinal cortex, and white matter hyperintensity (WMH) volumes, and Alzheimer's disease (AD)-signature cortical thickness (n = 917). Data were analyzed with logistic and linear regression models. In the total sample, mild cognitive impairment (MCI) was diagnosed in 1102 persons (26.2%; amnestic MCI, n = 931; non-amnestic MCI, n = 171). Olfactory impairment was significantly associated with increased likelihoods of MCI, amnestic MCI, and non-amnestic MCI. In the subsamples, anosmia was significantly associated with higher plasma total tau and NfL concentrations, smaller hippocampal and entorhinal cortex volumes, and greater WMH volume, and marginally with lower AD-signature cortical thickness. These results suggest that cerebral neurodegenerative and microvascular lesions are common neuropathologies linking anosmia with MCI in older adults.

Recovery of anosmia in hamsters infected with SARS-CoV-2 is correlated with repair of the olfactory epithelium.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for a pandemic affecting billions of people worldwide. Apart from the extreme global economic impact, the pandemic will likely have a lasting impact through long-term sequelae not yet fully understood. Fully understanding the mechanisms driving the various symptoms and sequelae of SARS-CoV-2 infection will allow for the eventual development of therapeutics to prevent or treat such life-altering symptoms. In this study, we developed a behavioral test of anosmia in SARS-CoV-2-infected hamsters. We find a moderately strong correlation between the level of anosmia and the score of histological damage within the olfactory epithelium. We also find a moderately strong correlation between the level of anosmia and the thickness of the olfactory epithelium, previously demonstrated to be severely damaged upon infection. Thus, this food-searching behavioral test can act as a simple and effective screening method in a hamster model for various therapeutics for SARS-CoV-2-related anosmia.

High Frequencies of Functional Virus-Specific CD4+ T Cells in SARS-CoV-2 Subjects With Olfactory and Taste Disorders.

Olfactory and taste disorders (OTD) are commonly found as presenting symptoms of SARS-CoV-2 infection in patients with clinically mild COVID-19. Virus-specific T cells are thought to play an important role in the clearance of SARS-CoV-2; therefore the study of T cell specific immune responses in patients with mild symptoms may help to understand their possible role in protection from severe disease. We evaluated SARS-CoV-2-specific T cell responses to four different peptide megapools covering all SARS-CoV-2 proteins during the acute phase of the disease in 33 individuals with mild or no other symptom beside OTD and in 22 age-matched patients with severe infection. A control group of 15 outpatients with OTD and consistently negative nasopharyngeal SARS-CoV-2 RNA swabs and virus-specific IgG serology was included in the study. Increased frequencies of virus-specific CD4+ and CD8+ T cells were found in SARS-CoV-2 positive patients with OTD compared with those with severe COVID-19 and with SARS-CoV-2 negative OTD individuals. Moreover, enhanced CD4+ and CD8+ T-cell activation induced by SARS-CoV-2 peptides was associated with higher interferon (IFN)γ production. Increased frequencies of Spike (S1/S2)-specific CD4+ T cells showing enhanced IFNγ secretion and granzyme B content were associated with serum spike-specific IgG in the OTD group. In conclusion, patients with SARS-CoV-2 induced OTD develop highly functional virus-specific CD4+ and CD8+ T cells during the symptomatic phase of the disease, suggesting that robust and coordinated T-cell responses provide protection against extension of COVID-19 to the lower respiratory tract.

Neurological symptoms and axonal damage in COVID-19 survivors: are there sequelae?

The persistence of neurological symptoms after SARS-CoV-2 infection, as well as the presence of late axonal damage, is still unknown. We performed extensive systemic and neurological follow-up evaluations in 107 out of 193 consecutive patients admitted to the COVID-19 medical unit, University Hospital of Verona, Italy between March and June 2020. We analysed serum neurofilament light chain (NfL) levels in all cases including a subgroup (n = 29) of patients with available onset samples. Comparisons between clinical and biomarker data were then performed. Neurological symptoms were still present in a significant number (n = 49) of patients over the follow-up. The most common reported symptoms were hyposmia (n = 11), fatigue (n = 28), myalgia (n = 14), and impaired memory (n = 11) and were more common in cases with severe acute COVID-19. Follow-up serum NfL values (15.2 pg/mL, range 2.4-62.4) were within normal range in all except 5 patients and did not differentiate patients with vs without persistent neurological symptoms. In patients with available onset and follow-up samples, a significant (p < 0.001) decrease of NfL levels was observed and was more evident in patients with a severe acute disease. Despite the common persistence of neurological symptoms, COVID-19 survivors do not show active axonal damage, which seems a peculiar feature of acute SARS-CoV-2 infection.

Slow Motion Analysis of Repetitive Tapping (SMART) Test: Measuring Bradykinesia in Recently Diagnosed Parkinson's Disease and Idiopathic Anosmia.

BACKGROUND: Bradykinesia is the defining motor feature of Parkinson's disease (PD). There are limitations to its assessment using standard clinical rating scales, especially in the early stages of PD when a floor effect may be observed. OBJECTIVE: To develop a quantitative method to track repetitive tapping movements and to compare people in the early stages of PD, healthy controls, and individuals with idiopathic anosmia. METHODS: This was a cross-sectional study of 99 participants (early-stage PD = 26, controls = 64, idiopathic anosmia = 9). For each participant, repetitive finger tapping was recorded over 20 seconds using a smartphone at 240 frames per second. From each video, amplitude between fingers, frequency (number of taps per second), and velocity (distance travelled per second) was extracted. Clinical assessment was based on the motor section of the MDS-UPDRS. RESULTS: People in the early stage of PD performed the task with slower velocity (p < 0.001) and with greater frequency slope than controls (p = 0.003). The combination of reduced velocity and greater frequency slope obtained the best accuracy to separate early-stage PD from controls based on metric thresholds alone (AUC = 0.88). Individuals with anosmia exhibited slower velocity (p = 0.001) and smaller amplitude (p < 0.001) compared with controls. CONCLUSION: We present a simple, proof-of-concept method to detect early motor dysfunction in PD. Mean tap velocity appeared to be the best parameter to differentiate patients with PD from controls. Patients with anosmia also showed detectable differences in motor performance compared with controls which may suggest that some were in the prodromal phase of PD.

COVID-19 and Parkinson's disease: Defects in neurogenesis as the potential cause of olfactory system impairments and anosmia.

Anosmia, a neuropathogenic condition of loss of smell, has been recognized as a key pathogenic hallmark of the current pandemic SARS-CoV-2 infection responsible for COVID-19. While the anosmia resulting from olfactory bulb (OB) pathology is the prominent clinical characteristic of Parkinson's disease (PD), SARS-CoV-2 infection has been predicted as a potential risk factor for developing Parkinsonism-related symptoms in a significant portion of COVID-19 patients and survivors. SARS-CoV-2 infection appears to alter the dopamine system and induce the loss of dopaminergic neurons that have been known to be the cause of PD. However, the underlying biological basis of anosmia and the potential link between COVID-19 and PD remains obscure. Ample experimental studies in rodents suggest that the occurrence of neural stem cell (NSC) mediated neurogenesis in the olfactory epithelium (OE) and OB is important for olfaction. Though the occurrence of neurogenesis in the human forebrain has been a subject of debate, considerable experimental evidence strongly supports the incidence of neurogenesis in the human OB in adulthood. To note, various viral infections and neuropathogenic conditions including PD with olfactory dysfunctions have been characterized by impaired neurogenesis in OB and OE. Therefore, this article describes and examines the recent reports on SARS-CoV-2 mediated OB dysfunctions and defects in the dopaminergic system responsible for PD. Further, the article emphasizes that COVID-19 and PD associated anosmia could result from the regenerative failure in the replenishment of the dopaminergic neurons in OB and olfactory sensory neurons in OE.

Hyposmia Is Associated with Reduced Cognitive Function in COVID-19: First Preliminary Results.

BACKGROUND: Hyposmia is frequently reported as an initial symptom in coronavirus disease 2019 (COVID-19). OBJECTIVE: As hyposmia accompanies cognitive impairment in several neurological disorders, we aimed to study whether hyposmia represents a clinical biomarker for both neurological involvement and cognitive impairment in mild CO-VID-19. We aimed to study whether olfactory dysfunction (OD) represents a clinical biomarker for both neurological involvement and cognitive impairment in mild COVID-19. METHODS: Formal olfactory testing using the Sniffin'Sticks® Screening test, neuropsychological assessment using the Montreal Cognitive Assessment (MoCA), and detailed neurological examination were performed in 7 COVID-19 patients with mild disease course and no history of olfactory or cognitive impairment, and 7 controls matched for age, sex, and education. Controls were initially admitted to a dedicated COVID-19 screening ward but tested negative by real-time PCR. RESULTS: The number of correctly identified odors was significantly lower in COVID-19 than in controls (6 ± 3, vs. 10 ± 1 p = 0.028, r = 0.58). Total MoCA score was significantly lower in COVID-19 patients than in controls (20 ± 5 vs. 26 ± 3, p = 0.042, r = 0.54). Cognitive performance indicated by MoCA was associated with number of correctly identified odors in COVID-19 patients and controls (COVID-19: p = 0.018, 95% CI = 9-19; controls: p = 0.18, r = 0.63, 95% CI = 13-18.5 r = 0.64). DISCUSSION/CONCLUSION: OD is associated with cognitive impairment in controls and mild COVID-19. OD may represent a potentially useful clinical biomarker for subtle and even subclinical neurological involvement in severe acute respiratory distress syndrome coronavirus-2 infection.

Covid-19 and oral diseases: Crosstalk, synergy or association?

The coronavirus disease 2019 (Covid-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that clinically affects multiple organs of the human body. Cells in the oral cavity express viral entry receptor angiotensin-converting enzyme 2 that allows viral replication and may cause tissue inflammation and destruction. Recent studies have reported that Covid-19 patients present oral manifestations with multiple clinical aspects. In this review, we aim to summarise main signs and symptoms of Covid-19 in the oral cavity, its possible association with oral diseases, and the plausible underlying mechanisms of hyperinflammation reflecting crosstalk between Covid-19 and oral diseases. Ulcers, blisters, necrotising gingivitis, opportunistic coinfections, salivary gland alterations, white and erythematous plaques and gustatory dysfunction were the most reported clinical oral manifestations in patients with Covid-19. In general, the lesions appear concomitant with the loss of smell and taste. Multiple reports show evidences of necrotic/ulcerative gingiva, oral blisters and hypergrowth of opportunistic oral pathogens. SARS-CoV-2 exhibits tropism for endothelial cells and Covid-19-mediated endotheliitis can not only promote inflammation in oral tissues but can also facilitate virus spread. In addition, elevated levels of proinflammatory mediators in patients with Covid-19 and oral infectious disease can impair tissue homeostasis and cause delayed disease resolution. This suggests potential crosstalk of immune-mediated pathways underlying pathogenesis. Interestingly, few reports suggest recurrent herpetic lesions and higher bacterial growth in Covid-19 subjects, indicating SARS-CoV-2 and oral virus/bacteria interaction. Larger cohort studies comparing SARS-CoV-2 negative and positive subjects will reveal oral manifestation of the virus on oral health and its role in exacerbating oral infection.

Spiking dependence of SARS-CoV-2 pathogenicity on TMPRSS2.

Epidemiological data shows a discrepancy in COVID-19 susceptibility and outcomes with some regions being more heavily affected than others. However, the factors that determine host susceptibility and pathogenicity remain elusive. An increasing number of publications highlight the role of Transmembrane Serine Protease 2 (TMPRSS2) in the susceptibility of the host cell to SARS-CoV-2. Cleavage of viral spike protein via the host cell's TMPRSS2 enzyme activity mediates viral entry into the host cell. The enzyme synthesis is regulated by the TMPRSS2 gene, which has also been implicated in the entry mechanisms of previously reported Coronavirus infections. In this review, we have investigated the pathogenicity of SARS-CoV-2 and disease susceptibility dependence on the TMPRSS2 gene as expressed in various population groups. We further discuss how the differential expression of this gene in various ethnic groups can affect the SARS-CoV-2 infection and Coronavirus disease (COVID)-19 outcomes. Moreover, promising new TMPRSS2 protease blockers and inhibitors are discussed for COVID-19 treatment.

Validation of Olfactory Questionnaire in Koreans: an Alternative for Conventional Psychophysical Olfactory Tests.

BACKGROUND: The patients with coronavirus disease 2019 (COVID-19), a worldwide pandemic infection, frequently complain of olfactory disorders. However, psychophysical olfactory tests performed by an examiner are very difficult in these highly infectious patients. This study aimed to develop and validate a questionnaire for olfactory function that can be readily used to evaluate olfactory loss. METHODS: Fourteen smell-related questions were created based on smells familiar to Koreans. Among them, questions with a κ value of 0.6 or higher were finally selected through a test-retest reliability analysis. The correlations between the scores of the olfactory questionnaire and those of olfactory function tests (Butanol Threshold Test [BTT] and Cross Cultural Smell Identification Test [CCSIT]) were analyzed. To evaluate the predictive ability of the questionnaire and elicit cutoff values, receiver operating characteristic (ROC) curves were generated. RESULTS: Out of the 14 questions in the questionnaire, 11 (κ > 0.6) were selected for the olfactory questionnaire. We analyzed 2,273 subjects, and there was a significant correlation between the total score of the olfactory questionnaire and the BTT (r = 0.643, P < 0.001) or CCSIT (r = 0.615, P < 0.001) scores. ROC curves for the olfactory questionnaire, BTT, and CCSIT all demonstrated high predictive power to discriminate anosmia and severe hyposmia from normosmia. Regarding mild to moderate hyposmia, however, ROC curve for the olfactory questionnaire alone showed high predictive power of discrimination from normosmia. Based on the results of ROC curves among the subclasses, we suggest the classification of the total score of the questionnaire as 0-4, 5-17, 18-27, 28-41, and 42-44, for anosmia, severe hyposmia, moderate hyposmia, mild hyposmia, and normosmia, respectively. CONCLUSION: The total scores of the questionnaires correlated with the BTT and CCSIT scores. The symptom questionnaire for olfactory dysfunction may be useful as an alternative tool for olfactory function testing, when unavailable.

A comparative study on the clinical features of COVID-19 with non-SARS-CoV-2 respiratory viral infections.

During this coronavirus disease 2019 (COVID-19) pandemic, physicians have the important task of risk stratifying patients who present with acute respiratory illnesses. Clinical presentation of COVID-19, however, can be difficult to distinguish from other respiratory viral infections. Thus, identifying clinical features that are strongly associated with COVID-19 in comparison to other respiratory viruses can aid risk stratification and testing prioritization especially in situations where resources for virological testing and resources for isolation facilities are limited. In our retrospective cohort study comparing the clinical presentation of COVID-19 and other respiratory viral infections, we found that anosmia and dysgeusia were symptoms independently associated with COVID-19 and can be important differentiating symptoms in patients presenting with acute respiratory illness. On the other hand, laboratory abnormalities and radiological findings were not statistically different between the two groups. In comparing outcomes, patients with COVID-19 were more likely to need high dependency or intensive care unit care and had a longer median length of stay. With our findings, we emphasize that epidemiological risk factors and clinical symptoms are more useful than laboratory and radiological abnormalities in differentiating COVID-19 from other respiratory viral infections.

SARS-CoV-2 respiratory viral loads and association with clinical and biological features.

To determine the distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) respiratory viral loads (VL) during the acute phase of infection and their correlation with clinical presentation and inflammation-related biomarkers. Nasopharyngeal swabs from 453 adult SARS-CoV-2-infected patients from the Department of Infectious Diseases, Besançon, France, were collected at the time of admission or consultation for reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Clinical information and concentrations of biological parameters (C-reactive protein [CRP], fibrinogen, lactate dehydrogenase [LDH], prealbumin) were noticed. Mean respiratory VL homogeneously decreased from 7.2 log10 copies/ml (95% confidence interval [CI]: 6.6-7.8) on the first day of symptoms until 4.6 log10 copies/ml (95% CI: 3.8-5.4) at day 10 (slope = -0.24; R2 = .95). VL were poorly correlated with COVID-19 symptoms and outcome, excepted for dyspnea and anosmia, which were significantly associated with lower VL (p < .05). CRP, fibrinogen, and LDH concentrations significantly increased over the first 10 days (median CRP concentrations from 36.8 mg/L at days 0-1 to 99.5 mg/L at days 8-10; p < .01), whereas prealbumin concentrations tended to decrease. Since SARS-CoV-2 respiratory VL regularly decrease in the acute phase of infection, determining the level of VL may help predicting the onset of virus shedding in a specific patient. However, the role of SARS-CoV-2 VL as a biomarker of severity is limited.

Olfactory Cleft Measurements and COVID-19-Related Anosmia.

OBJECTIVE: This study aimed to investigate the differences in olfactory cleft (OC) morphology in coronavirus disease 2019 (COVID-19) anosmia compared to control subjects and postviral anosmia related to infection other than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). STUDY DESIGN: Prospective. SETTING: This study comprises 91 cases, including 24 cases with anosmia due to SARS-CoV-2, 38 patients with olfactory dysfunction (OD) due to viral infection other than SARS-CoV-2, and a control group of 29 normosmic cases. METHODS: All cases had paranasal sinus computed tomography (CT), and cases with OD had magnetic resonance imaging (MRI) dedicated to the olfactory nerve. The OC width and volumes were measured on CT, and T2-weighted signal intensity (SI), olfactory bulb volumes, and olfactory sulcus depths were assessed on MRI. RESULTS: This study showed 3 major findings: the right and left OC widths were significantly wider in anosmic patients due to SARS-CoV-2 (group 1) or OD due to non-SARS-CoV-2 viral infection (group 2) when compared to healthy controls. OC volumes were significantly higher in group 1 or 2 than in healthy controls, and T2 SI of OC area was higher in groups 1 and 2 than in healthy controls. There was no significant difference in olfactory bulb volumes and olfactory sulcus depths on MRI among groups 1 and 2. CONCLUSION: In this study, patients with COVID-19 anosmia had higher OC widths and volumes compared to control subjects. In addition, there was higher T2 SI of the olfactory bulb in COVID-19 anosmia compared to control subjects, suggesting underlying inflammatory changes. There was a significant negative correlation between these morphological findings and threshold discrimination identification scores. LEVEL OF EVIDENCE: Level 4.

The Cellular basis of loss of smell in 2019-nCoV-infected individuals.

A prominent clinical symptom of 2019-novel coronavirus (nCoV) infection is hyposmia/anosmia (decrease or loss of sense of smell), along with general symptoms such as fatigue, shortness of breath, fever and cough. The identity of the cell lineages that underpin the infection-associated loss of olfaction could be critical for the clinical management of 2019-nCoV-infected individuals. Recent research has confirmed the role of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) as key host-specific cellular moieties responsible for the cellular entry of the virus. Accordingly, the ongoing medical examinations and the autopsy reports of the deceased individuals indicate that organs/tissues with high expression levels of ACE2, TMPRSS2 and other putative viral entry-associated genes are most vulnerable to the infection. We studied if anosmia in 2019-nCoV-infected individuals can be explained by the expression patterns associated with these host-specific moieties across the known olfactory epithelial cell types, identified from a recently published single-cell expression study. Our findings underscore selective expression of these viral entry-associated genes in a subset of sustentacular cells (SUSs), Bowman's gland cells (BGCs) and stem cells of the olfactory epithelium. Co-expression analysis of ACE2 and TMPRSS2 and protein-protein interaction among the host and viral proteins elected regulatory cytoskeleton protein-enriched SUSs as the most vulnerable cell type of the olfactory epithelium. Furthermore, expression, structural and docking analyses of ACE2 revealed the potential risk of olfactory dysfunction in four additional mammalian species, revealing an evolutionarily conserved infection susceptibility. In summary, our findings provide a plausible cellular basis for the loss of smell in 2019-nCoV-infected patients.

Gaining Back What Is Lost: Recovering the Sense of Smell in Mild to Moderate Patients After COVID-19.

The purpose of our cohort study was to quantify olfactory deficits in Coronavirus disease 2019 (COVID-19) patients using Sniffin' Sticks and a pre-post design to evaluate olfactory recovery. Thirty adult patients with laboratory-confirmed mild to moderate forms of COVID-19 underwent a quantitative olfactory test performed with the Sniffin' Sticks test (SST; Burghardt, Wedel, Germany), considering olfactory threshold (T), odor discrimination (D), and odor identification (I). Results were presented as a composite TDI score (range 1-48) that used to define functional anosmia (TDI ≤ 16.5), hyposmia (16.5 < TDI < 30.5), or functionally normal ability to smell (TDI ≥ 30.5). Patients also self-evaluated their olfactory function by rating their ability to smell on a visual analogue scale (Visual Analog Scale rating) and answering a validated Italian questionnaire (Hyposmia Rating Scale). Patients were tested during hospitalization and about 2 months after symptoms onset. During the hospitalization, the overall TDI score indicated that our cohort had impairments in their olfactory ability (10% was diagnosed with anosmia and more than 50% were hyposmic). Almost all patients showed a significant improvement at around 1 month following the first test and for all the parts of the SST except for odor identification. None of the subjects at 1 month was still diagnosed with anosmia. We also quantified the improvement in the TDI score based on initial diagnosis. Anosmic subjects showed a greater improvement than hyposmic and normosmic subjects. In conclusion, within a month time window and 2 months after symptoms' onset, in our cohort of patients we observed a substantial improvement in the olfactory abilities.

Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.

OBJECTIVE: To assess the physiopathology of olfactory function loss (OFL) in patients with coronavirus disease 2019 (COVID-19), we evaluated the olfactory clefts (OC) on MRI during the early stage of the disease and 1 month later. METHODS: This was a prospective, monocentric, case-controlled study. Twenty severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-infected patients with OFL were included and compared to 20 age-matched healthy controls. All infected patients underwent olfactory function assessment and 3T MRI, performed both at the early stage of the disease and at the 1-month follow-up. RESULTS: At the early stage, SARS-CoV2-infected patients had a mean olfactory score of 2.8 ± 2.7 (range 0-8), and MRI displayed a complete obstruction of the OC in 19 of 20 patients. Controls had normal olfactory scores and no obstruction of the OC on MRI. At the 1 month follow-up, the olfactory score had improved to 8.3 ± 1.9 (range 4-10) in patients, and only 7 of 20 patients still had an obstruction of the OC. There was a correlation between olfactory score and obstruction of the OC (p = 0.004). CONCLUSION: OFL in SARS-CoV2-infected patients is associated with a reversible obstruction of the OC.