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The ongoing coronavirus disease 2019 (COVID-19) pandemic is associated with substantial morbidity and mortality. Although much has been learned in the first few months of the pandemic, many features of COVID-19 pathogenesis remain to be determined. For example, anosmia is a common presentation, and many patients with anosmia show no or only minor respiratory symptoms 1 . Studies in animals infected experimentally with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID-19, provide opportunities to study aspects of the disease that are not easily investigated in human patients. Although the severity of COVID-19 ranges from asymptomatic to lethal 2 , most experimental infections provide insights into mild disease 3 . Here, using K18-hACE2 transgenic mice that were originally developed for SARS studies 4 , we show that infection with SARS-CoV-2 causes severe disease in the lung and, in some mice, the brain. Evidence of thrombosis and vasculitis was detected in mice with severe pneumonia. Furthermore, we show that infusion of convalescent plasma from a recovered patient with COVID-19 protected against lethal disease. Mice developed anosmia at early time points after infection. Notably, although pre-treatment with convalescent plasma prevented most signs of clinical disease, it did not prevent anosmia. Thus, K18-hACE2 mice provide a useful model for studying the pathological basis of both mild and lethal COVID-19 and for assessing therapeutic interventions. Transgenic K18-hACE2 mice are a useful model of COVID-19 including anosmia; infection of these mice resulted in severe pneumonia and, in some cases, infection in the brain, which was prevented by convalescent plasma.

Olfactory dysfunction represents one of the most frequent symptoms of coronavirus disease 2019, affecting about 70 per cent of patients. However, the pathogenesis of the olfactory dysfunction in coronavirus disease 2019 has not yet been elucidated. This report presents the radiological and histopathological findings of a patient who presented with anosmia persisting for more than three months after infection with severe acute respiratory syndrome coronavirus-2. The biopsy demonstrated significant disruption of the olfactory epithelium. This shifts the focus away from invasion of the olfactory bulb and encourages further studies of treatments targeted at the surface epithelium.

This study aims to investigate the efficacy of intranasally transplanted neural stem cells (NSCs) in anosmia-induced mice. Twenty-four male mice were included in the study. A food-finding test (FFT) was performed beforehand to confirm that all mice had normal olfactory functions. The mice were then randomly divided into two groups (Groups 1 and 2) and anosmia was induced by 3-methylindole (3-MI). In the first week following the 3-MI injection (week 1), mice in Group 1 received intranasal saline, while mice in Group 2 received intranasal NSCs. The NSCs were prepared from green fluorescent protein (GFP)-transgenic mice. Olfactory function was evaluated through weekly FFTs. One week after NSC or saline administration (week 2), half of the mice in each group were randomly selected and sacrificed for histological examination. The remaining mice were sacrificed for histological examination in week 4. At week 4, the olfactory epithelium of all mice was also examined by polymerase chain reaction (PCR) to detect GFP + cells. The NSC group showed significantly shorter FFT times compared to the saline group. Epithelial damage scores, indicating greater injury, were higher in the saline group, whereas the NSC group exhibited greater epithelial thickness. Immunohistochemical analysis revealed a significantly higher number of olfactory marker protein-expressing cells in the NSC group. GFP + cells were observed in olfactory bulb (OB) and olfactory epithelium (OE) in the NSC group. PCR confirmed the presence of the GFP gene in the OE of NSC-transplanted mice. Intranasal NSCs promoted functional recovery and GFP + cell integration, supporting further research into their therapeutic potential for olfactory dysfunction.

Isolated Congenital Anosmia (ICA) is a rare condition characterized by the absence of the sense of smell due to the underdevelopment of the olfactory bulbs and a corresponding lifelong lack of olfactory input to the brain. Previous studies have reported that ICA patients exhibit structural and volumetric alterations in both gray and white matter regions as well as slightly elevated fractional anisotropy (FA) in the orbitofrontal cortex. This study expanded on these findings by utilizing whole-brain diffusion tensor imaging (DTI) with a 3T MR scanner to investigate microstructural changes in the white matter of 8 ICA patients and 14 age- and gender-matched healthy controls (HCs). Tract-based spatial statistics revealed significantly lower FA values in the right superior corona radiata (SCR) of ICA patients compared to HCs ( p  = 0.001), indicating compromised white matter integrity in this region. Elevated mean diffusivity and radial diffusivity values in the right SCR ( p  = 0.009 and p  = 0.002, respectively) suggest underlying demyelination. In the HC group, FA values in the SCR cluster were positively correlated with odor identification scores (rho = 0.59, p  = 0.026), highlighting the functional relevance of SCR in processing olfactory information and semantic formation of odor perception. These findings underscore the critical role of early sensory input in shaping the architecture of white matter, and illustrate the impact of congenital olfactory deprivation on the structural integrity and functional organization of neural pathways.

Purpose Although COVID-19 anosmia is often transient, patients with persistent olfactory dysfunction (pOD) can experience refractory parosmia and diminished smell. This study evaluated four putative therapies for parosmia in patients with chronic COVID-19 olfactory impairment. Methods After screening nasal endoscopy, 85 patients (49 female, 58%) with pOD and treatment-refractory parosmia were randomized to: (1) ultramicronized palmitoylethanolamide and luteolin + olfactory training (OT) ( umPEALUT group , n = 17), (2) alpha-lipoic acid + OT ( ALA group , n = 21), (3) umPEALUT + ALA + OT ( combination group , n = 28), or 4) olfactory training (OT) alone ( control group , n = 23). Olfactory function was assessed at baseline (T 0 ) and 6 months (T 1 ) using a parosmia questionnaire and Sniffin’ Sticks test of odor threshold, detection, and identification (TDI). Analyses included one-way ANOVA for numeric data and Chi-Square analyses for nominal data on parosmia. Results The umPEALUT group had the largest improvement in TDI scores (21.8 ± 9.4 to 29.7 ± 7.5) followed by the combination group (19.6 ± 6.29 to 27.5 ± 2.7), both p < 0.01. The control and ALA groups had no significant change. Patients in the combination and umPEALUT groups had significantly improved TDI scores compared to ALA and control groups (p < 0.001). Rates of parosmia resolution after 6 months were reported at 96% for combination, 65% for control, 53% for umPEALUT and 29% for ALA (p < 0.001). All treatment regimens were well-tolerated. Conclusions umPEALUT and OT, with or without ALA, was associated with improvement in TDI scores and parosmia, whereas OT alone or OT with ALA were associated with little benefit.

Olfactory perception has implications for human chemosensory communication and in a broader context, it affects well-being. However, most of the studies investigating the consequences of olfactory loss have recruited patients who have already been categorized as having a dysfunctional sense of smell and sought help in an ENT clinic. We revisit these findings by distinguishing subjects with olfactory impairment from a group of subjects who all declared a normal sense of smell when enrolling for this study. In the initial sample of 203 individuals, we found 59 to have impaired olfaction and four with marginal olfactory performance, not useful in daily life. Interestingly, we found a significant between-group difference in cognitive functioning, further supporting the notion of the relationship between cognition and olfactory performance. However, their chemosensory communication and well-being appeared not to be different from subjects with normosmia. Impaired olfactory function certainly has a severe impact on daily life but more so in individuals who are bothered with it and decide to seek treatment. The limited-to-no olfactory perception in the fraction of subjects who neither complain about it nor seek help in ENT clinics does not seem to have a major effect on their social, cognitive, emotional and health functioning. This article is part of the Theo Murphy meeting issue ‘Olfactory communication in humans’.

Rapid detection, isolation, and contact tracing of community COVID-19 cases are essential measures to limit the community spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to identify a parsimonious set of symptoms that jointly predict COVID-19 and investigated whether predictive symptoms differ between the B.1.1.7 (Alpha) lineage (predominating as of April 2021 in the US, UK, and elsewhere) and wild type. We obtained throat and nose swabs with valid SARS-CoV-2 PCR test results from 1,147,370 volunteers aged 5 years and above (6,450 positive cases) in the REal-time Assessment of Community Transmission-1 (REACT-1) study. This study involved repeated community-based random surveys of prevalence in England (study rounds 2 to 8, June 2020 to January 2021, response rates 22%-27%). Participants were asked about symptoms occurring in the week prior to testing. Viral genome sequencing was carried out for PCR-positive samples with N-gene cycle threshold value < 34 (N = 1,079) in round 8 (January 2021). In univariate analysis, all 26 surveyed symptoms were associated with PCR positivity compared with non-symptomatic people. Stability selection (1,000 penalized logistic regression models with 50% subsampling) among people reporting at least 1 symptom identified 7 symptoms as jointly and positively predictive of PCR positivity in rounds 2-7 (June to December 2020): loss or change of sense of smell, loss or change of sense of taste, fever, new persistent cough, chills, appetite loss, and muscle aches. The resulting model (rounds 2-7) predicted PCR positivity in round 8 with area under the curve (AUC) of 0.77. The same 7 symptoms were selected as jointly predictive of B.1.1.7 infection in round 8, although when comparing B.1.1.7 with wild type, new persistent cough and sore throat were more predictive of B.1.1.7 infection while loss or change of sense of smell was more predictive of the wild type. The main limitations of our study are (i) potential participation bias despite random sampling of named individuals from the National Health Service register and weighting designed to achieve a representative sample of the population of England and (ii) the necessary reliance on self-reported symptoms, which may be prone to recall bias and may therefore lead to biased estimates of symptom prevalence in England. Where testing capacity is limited, it is important to use tests in the most efficient way possible. We identified a set of 7 symptoms that, when considered together, maximize detection of COVID-19 in the community, including infection with the B.1.1.7 lineage.

To address the impact of COVID‐19 olfactory loss on the brain, we analyzed the neural connectivity of the central olfactory system in recently SARS‐CoV‐2 infected subjects with persisting olfactory impairment (hyposmia). Twenty‐seven previously SARS‐CoV‐2 infected subjects (10 males, mean age ± SD 40.0 ± 7.6 years) with clinically confirmed COVID‐19 related hyposmia, and eighteen healthy, never SARS‐CoV‐2 infected, normosmic subjects (6 males, mean age ± SD 36.0 ± 7.1 years), were recruited in a 3 Tesla MRI study including high angular resolution diffusion and resting‐state functional MRI acquisitions. Specialized metrics of structural and functional connectivity were derived from a standard parcellation of olfactory brain areas and a previously validated graph‐theoretic model of the human olfactory functional network. These metrics were compared between groups and correlated to a clinical index of olfactory impairment. On the scanning day, all subjects were virus‐free and cognitively unimpaired. Compared to control, both structural and functional connectivity metrics were found significantly increased in previously SARS‐CoV‐2 infected subjects. Greater residual olfactory impairment was associated with more segregated processing within regions more functionally connected to the anterior piriform cortex. An increased neural connectivity within the olfactory cortex was associated with a recent SARS‐CoV‐2 infection when the olfactory loss was a residual COVID‐19 symptom. The functional connectivity of the anterior piriform cortex, the largest cortical recipient of afferent fibers from the olfactory bulb, accounted for the inter‐individual variability in the sensory impairment. Albeit preliminary, these findings could feature a characteristic brain connectivity response in the presence of COVID‐19 related residual hyposmia. A structural and functional neural connectivity analysis of the central olfactory system was performed in previously SARS‐CoV‐2 infected subjects with persisting olfactory impairment. An increased neural connectivity within the olfactory cortex was associated with a recent SARS‐CoV‐2 infection. The functional connectivity of the anterior piriform cortex accounted for the inter‐individual variability in the sensory impairment, suggesting a characteristic brain connectivity response in the presence of COVID‐19 related residual hyposmia.

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. 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. 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). 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.