Otitis media in severe asthma associated with chronic rhinosinusitis with nasal polyps: a new therapeutic target for biologics.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNPs) is associated with otitis media with effusion (OME) in about 25% of cases. The objective of this study was to assess the clinical efficacy of the 4 biologic agents currently available in France for severe asthma (omalizumab, mepolizumab, benralizumab and dupilumab) in 17 patients followed for both asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) and presenting otitis media with effusion (OME) on otoscopy. Methods: It was a multicenter retrospective study performed in 4 academic ENT and respiratory departments in Paris, France, with assessment of the clinical evolution of 17 patients with severe eosinophilic asthma and with chronic refractory OME and CRSwNPs treated by biologic agents. Global evaluation of treatment effectiveness (GETE) on asthma, CRSwNP and OME was classified on a 5-point scale as 1, excellent; 2, good; 3, moderate; 4, poor; or 5, symptoms worsening. Response was defined as an excellent/good score (1 or 2). Results: 17 patients were prescribed a total of 30 biologics. The evolution of OME did not follow that of asthma and CRSwNPs in 15 (88%) and 12 (70%) cases, respectively. Concerning OME, 19/30 (63%) patients were non-responders. Among the 10 patients who successively received ≥ 2 biologic agents, the OME response differed, depending on the considered agent Dupilumab had the highest response rate. Conclusions: Resistant OME, associated with asthma and chronic rhinosinusitis with nasal polyps, can present a disconnected evolution under biologics. CRSwNP-associated OME requires a specific evaluation to define the best treatment.

Oncostatin M Contributes to Airway Epithelial Cell Dysfunction in Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a typical type-2 inflammation involving several cytokines and is associated with epithelial cell dysfunction. Oncostatin M (OSM) (belonging to the interleukin(IL)-6 family) could be a key driver of epithelial barrier dysfunction. Therefore, we investigated the presence of OSM and IL-6 and the expression pattern of tight junctions (TJs) in the nasal tissue of CRSwNP patients and controls using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Then, their potential role in the epithelial barrier was evaluated in vitro in 27 different primary cultures of human nasal epithelial cells (HNECs) by measuring TJ expression and transepithelial electric resistance (TEER) with or without OSM or IL-6 (1, 10, and 100 ng/mL). The effect on ciliary beating efficiency was evaluated by high-speed videomicroscopy and on repair mechanisms with a wound healing model with or without OSM. OSM and IL-6 were both overexpressed, and TJ (ZO-1 and occludin) expression was decreased in the nasal polyps compared to the control mucosa. OSM (100 ng/mL) but not IL-6 induced a significant decrease in TJ expression, TEER, and ciliary beating efficiency in HNECs. After 24 h, the wound repair rate was significantly higher in OSM-stimulated HNECs at 100 ng/mL. These results suggest that OSM could become a new target for monoclonal antibodies.

Apalutamide Prevents SARS-CoV-2 Infection in Lung Epithelial Cells and in Human Nasal Epithelial Cells.

In early 2020, the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, and rapidly propagated worldwide causing a global health emergency. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) protein for cell entry, followed by proteolytic cleavage of the Spike (S) protein by the transmembrane serine protease 2 (TMPRSS2), allowing fusion of the viral and cellular membranes. Interestingly, TMPRSS2 is a key regulator in prostate cancer (PCa) progression which is regulated by androgen receptor (AR) signaling. Our hypothesis is that the AR signaling may regulate the expression of TMPRSS2 in human respiratory cells and thus influence the membrane fusion entry pathway of SARS-CoV-2. We show here that TMPRSS2 and AR are expressed in Calu-3 lung cells. In this cell line, TMPRSS2 expression is regulated by androgens. Finally, pre-treatment with anti-androgen drugs such as apalutamide significantly reduced SARS-CoV-2 entry and infection in Calu-3 lung cells but also in primary human nasal epithelial cells. Altogether, these data provide strong evidence to support the use of apalutamide as a treatment option for the PCa population vulnerable to severe COVID-19.

Zwitterionic Polymers toward the Development of Orientation-Sensitive Bioprobes.

Dynamics with an orientational degree of freedom are fundamental in biological events. Probes with polarized luminescence enable a determination of the orientation. Lanthanide-doped nanocrystals can provide more precise analysis than quantum dots due to the nonphotoblinking/bleaching nature and the multiple line-shaped emission. However, the intrinsic polarization property of the original nanocrystals often deteriorates in complex physiological environments because the colloidal stability easily breaks and the probes aggregate in the media with abundant salts and macromolecules. Engineering the surface chemistry of the probes is thus essential to be compatible with biosystems, which has remained a challenging task that should be exclusively addressed for each specific probe. Here, we demonstrate a facile and efficient surface functionalization of lanthanide-doped nanorods by zwitterionic block copolymers. Due to the steric interaction and the intrinsic zwitterionic nature of the polymers, high colloidal stability of the zwitterionic nanorod suspension is achieved over wide ranges of pH and concentration of salts, even giving rise to the lyotropic liquid crystalline behavior of the nanorods in physiological media. The shear-aligned ability is shown to be unaltered by the coated polymers, and thus, the strongly polarized emission of Eu3+ is preserved. Besides, biological experiments reveal good biocompatibility of the zwitterionic nanorods with negligible nonspecific binding. This study is a stepping stone for the use of the nanorods as orientation probes in biofluids and validates the strategy of coupling zwitterions to lanthanide-doped nanocrystals for various bioapplications.

Otoskills training during covid-19 pandemic: a before-after study.

BACKGROUND: The ongoing COVID-19 pandemic has disrupted the surgical training of residents. There is a real concern that trainees will not be able to meet their training requirements. Low-fidelity surgical simulation appears to be an alternative for surgical training. The educational benefits of repeating ossiculoplasty simulations under a microscope have never been evaluated. With this study we aimed to evaluate the differences in performance scores and on a global rating scale before and after training on an ossiculoplasty simulator. METHODS: In this quasi-experimental, prospective, single-centre, before-after study with blinded rater evaluation, residents performed five microscopic ossiculoplasty tasks with a difficulty gradient (sliding beads onto rods, the insertion of a partial prosthesis, the insertion of a total prosthesis, and the insertion of a stapedotomy piston under microscopic or endoscopic surgery) before and after training on the same simulator. Performance scores were defined for each task, and total performance scores (score/min) were calculated. All data were collected prospectively. RESULTS: Six out of seven intermediate residents and 8/9 novices strongly agreed that the simulator was an effective training device and should be included in the ENT residency program. The mean effect of training was a significant increase in the total performance score (+ 0.52 points/min, [95 % CI, 0.40-0.64], p < 0.001), without a significant difference between novice and intermediate residents. CONCLUSIONS: This preliminary study shows that techniques for middle-ear surgery can be acquired using a simulator, avoiding any risk for patients, even under lockdown measures.

FcRn as a Transporter for Nasal Delivery of Biologics: A Systematic Review.

FcRn plays a major role in regulating immune homeostasis, but it is also able to transport biologics across cellular barriers. The question of whether FcRn could be an efficient transporter of biologics across the nasal epithelial barrier is of particular interest, as it would allow a less invasive strategy for the administration of biologics in comparison to subcutaneous, intramuscular or intravenous administrations, which are often used in clinical practice. A focused systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It was registered on the international prospective register of systematic reviews PROSPERO, which helped in identifying articles that met the inclusion criteria. Clinical and preclinical studies involving FcRn and the nasal delivery of biologics were screened, and the risk of bias was assessed across studies using the Oral Health Assessment Tool (OHAT). Among the 12 studies finally included in this systematic review (out of the 758 studies screened), 11 demonstrated efficient transcytosis of biologics through the nasal epithelium. Only three studies evaluated the potential toxicity of biologics' intranasal delivery, and they all showed that it was safe. This systematic review confirmed that FcRn is expressed in the nasal airway and the olfactory epithelium, and that FcRn may play a role in IgG and/or IgG-derived molecule-transcytosis across the airway epithelium. However, additional research is needed to better characterize the pharmacokinetic and pharmacodynamic properties of biologics after their intranasal delivery.

Is image interpretation in drug-induced sleep endoscopy that reliable?

PURPOSE: Previous studies have assessed drug-induced sleep endoscopy (DISE) as an interobserver reliable exam, with a learning curve effect. The objective was to check its assumed interobserver agreement and variability of between two groups of experienced and inexperienced French ENT physicians. METHODS: Prospective study. Seventy-six French ENT physicians (69 inexperienced in DISE and seven experienced) observed seven DISE videos. They were asked to determine the level(s), the configuration, and the degree of collapse, according to the VOTE classification. Specific and global agreements using the Fleiss' Kappa coefficient (k) were calculated. RESULTS: The interobserver agreement varied from poor to good in determining the level; the best agreement being found for the oropharynx (global agreement = 0.82 and k = 0.6 in the experienced group, global agreement = 0.87 and k = 0.7 in the inexperienced group), followed by the soft palate and the larynx; the worst agreement being found for the tongue base (k = 0.29 in the experienced group and k = 0.38 in the inexperienced group). The agreement for the configuration and the degree of collapse was moderate except for the tongue base where the concordance was poor. In both groups, agreement was at best good without any statistically significant difference between the two levels of experience groups. CONCLUSION: Even in a French ENT Sleep Experts group, DISE appears to be a technique with a limited interobserver agreement in the detection of obstructive sites, without any learning curve effect. In its current state, DISE interpretation may not be totally reliable.

Dupilumab prevents nasal epithelial function alteration by IL-4 in vitro: Evidence for its efficacy.

BACKGROUND: Chronic rhinosinusitis with nasal polyp (CRSwNP) is a typical type 2 inflammation involving interleukin (IL)-4 and IL-13. Dupilumab is a fully human monoclonal antibody targeting IL-4 receptor α subunit, thereby blocking signaling by both cytokines. Our hypothesis was that IL-4 and IL-13, by inducing a severe epithelial dysregulation, are involved in CRSwNP pathogenesis. This study aimed to evaluate the in vitro direct effect of IL-4, IL-13, and dupilumab on nasal epithelial functions. METHODS: Nasal polyps and control mucosa from 28 patients, as well as human nasal epithelial cells (HNEC) from 35 patients with CRSwNP were used. Three major epithelial functions were investigated: the epithelial barrier function (characterized by transepithelial electrical resistance measurements and tight junction protein expression), the ciliary motion (characterized by the ciliary beating efficiency index), and wound healing (characterized by the wound repair rate) under various stimulations (IL-4, IL-13, and dupilumab). The main outcome was a significant change in epithelial functions following exposure to IL-4, IL-13, and dupilumab for 48 h in the basal media. RESULTS: IL-4 (1, 10, and 100 ng/mL) but not IL-13 induced a significant decrease in occludin and zonula-occludens protein expression, ciliary beating efficiency, and wound repair rate in HNEC. Dupilumab (0.04 mg/mL) had no effect on HNEC and specifically restored all epithelial functions altered when cells were exposed to a 48-h IL-4 stimulation. CONCLUSION: Dupilumab, in vitro, restored epithelial integrity by counteracting the effect of IL-4 on the epithelial barrier (increased epithelial permeability, decreased ciliary beating efficiency, and decreased wound repair rate).

The Prognostic Value of Olfactory Dysfunction in Patients with COVID-19: The COVIDORA Study.

BACKGROUND: Among all studies describing COVID-19 clinical features during the first wave of the pandemic, only a few retrospective studies have assessed the correlation between olfac-tory dysfunction (OD) and the evolution of disease severity. The main aim was to assess whether OD is a predictive factor of COVID-19 severity based on the patient's medical management (outpa-tient care, standard hospital admission, and ICU admission). METHODS: A national, prospective, mul-ticenter cohort study was conducted in 20 public hospitals and a public center for COVID-19 screen-ing. During the first wave of the pandemic, from 6 April to 11 May 2020, all patients tested positive for COVID-19 confirmed by RT-PCR underwent two follow-up ENT consultations within 10 days of symptom onset. The main outcome measures were the evolution of medical management (out-patient care, standard hospital admission, and ICU admission) at diagnosis and along the clinical course of COVID-19 disease. RESULTS: Among 481 patients included, the prevalence of OD was 60.7%, and it affected mostly female patients (74.3%) under 65 years old (92.5%), with fewer comor-bidities than patients with normal olfactory function. Here, 99.3% (290/292) of patients with OD presented with non-severe COVID-19 disease. Patients reporting OD were significantly less hospi-talized than the ones managed as outpatients, in either a standard medical unit or an ICU. Conclu-sions: As regards the clinical course of COVID-19 disease, OD could predict a decreased risk of hospitalization during the first wave of the pandemic.

Definition of severity and treatment response in chronic rhinosinusitis with nasal polyps: a Delphi study among French experts.

INTRODUCTION: The introduction of biotherapies has significantly changed the management of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). These drugs are generally reserved for severe or recurrent CRSwNP. Thus, the concepts of severity of the disease and treatment response must be mastered by otorhinolaryngologists. However, a clear definition of these concepts in CRSwNP is missing. METHODS: This article focuses on definitions of severity and treatment response in CRSwNP by providing an expert consensus among French rhinologists, using a Delphi study. RESULTS: The severity assessment should seek the presence of uncontrolled asthma, olfactory disorders, nasal blockage, impaired quality of life (QOL) and cumulative annual dose of systemic corticosteroids.The treatment response should assess the presence of olfactory disorders, nasal blockage, QOL impairment, response to background therapy, resistance and/or dependence to oral corticosteroids, cumulative annual dose of systemic corticosteroids, response to surgery and to biologics.A failure after polypectomy should not be considered as a failure of surgical management of CRSwNP and must discuss the realization of an extended sinus surgery procedure before the prescription of biologics. CONCLUSION: Definitions of severity, control of CRSwNP, as well as therapeutic strategies to improve patients' QOL achieved high level of consensus.

Amylo-AFFECT-QOL, a self-reported questionnaire to assess health-related quality of life and to determine the prognosis in cardiac amyloidosis.

Background and aims: Self-reported questionnaires are useful for estimating the health-related quality of life (HR-QoL), impact of interventions, and prognosis. To our knowledge, no HR-QoL questionnaire has been developed for cardiac amyloidosis (CA). This study aimed to validate Amylo-AFFECT-QOL questionnaire to assess HR-QoL and its prognostic value in CA. Methods: A self-reported questionnaire, "Amylo-AFFECT" had been designed and validated for CA symptoms evaluation and screening by physicians. It was adapted here to assess HR-QoL (Amylo-AFFECT-QOL) and its prognostic value in CA. To validate the theoretical model, internal consistency and convergent validity were assessed, particularly correlations between Amylo-AFFECT-QOL and the HR-QoL Minnesota Living Heart Failure (MLHF) questionnaire. Results: Amylo-AFFECT-QOL was completed by 515 patients, 425 of whom (82.5%) had CA. Wild-type and hereditary transthyretin amyloidosis (ATTRwt and ATTRv) and immunoglobulin light-chain amyloidosis (AL) were diagnosed in 47.8, 14.7, and 18.8% of cases, respectively. The best HR-QoL evaluation was obtained with five dimensions: "Heart failure," "Vascular dysautonomia," "Neuropathy," "Ear, gastrointestinal, and urinary dysautonomia," and "Skin or mucosal involvement." The global Amylo-AFFECT-QOL and MLHF scores showed significant positive correlations (rs = 0.72, p < 0.05). Patients with a final diagnosis of CA had a global Amylo-AFFECT-QOL score significantly higher than the control group composed by patients with other diagnoses (22.2 ± 13.6 vs. 16.2 ± 13.8, respectively, p-value < 0.01). According to the Amylo-AFFECT-QOL global results, ATTRv patients' QoL was more affected than AL patients' QoL or ATTRwt patients' QoL. Patients with a higher HR-QoL score had a greater risk of death or heart transplant after 1 year of follow-up (log-rank < 0.01). Conclusion: Amylo-AFFECT-QOL demonstrates good psychometric properties and is useful for quantifying HR-QoL and estimating CA prognosis. Its use may help to improve overall management of patients with CA.

Changes in amyloidosis phenotype over 11 years in a cardiac amyloidosis referral centre cohort in France.

BACKGROUND: Early cardiac amyloidosis (CA) diagnosis enables patients to access effective treatments for better long-term outcomes, yet it remains under-recognised, misdiagnosed and inadequately managed. AIM: To reduce diagnostic delays, we aimed to describe the epidemiological and clinical characteristics and changes over an 11-year period. METHODS: This was a retrospective, observational cohort study of all patients referred to the Henri-Mondor Hospital for suspected CA. RESULTS: Overall, 3194 patients were identified and 3022 were included and analysed. Our patients came from varied ethnic backgrounds, and more than half (55.2%) had confirmed CA. Over 11 years, referrals increased 4.4-fold, mostly from cardiologists. Notably, wild-type transthyretin amyloidosis (ATTRwt) became the predominant diagnosis, with referrals increasing 15-fold from 20 in 2010-2012 to 308 in 2019-2020. The number of amyloid light chain (AL) diagnoses increased, whilst variant transthyretin amyloidosis (ATTRv) numbers remained relatively stable. Concerning disease severity, AL patients presented more frequently with severe cardiac involvement whereas an increasing number of ATTRwt patients presented with National Amyloid Centre stage I (22.0% in 2013-2014 to 45.9% in 2019-2020). Lastly, among patients diagnosed with ATTRv in 2019-2020, 83.9% had ATTR Val122Ile cardiac phenotype. CONCLUSIONS: This study shows that increasing cardiologist awareness and referrals have increased CA diagnoses. With improved awareness and non-invasive diagnostic techniques, more patients with ATTRwt with milder disease and more ATTRv Val122Ile mutations are being referred and diagnosed. Although more AL cases are being recognised, patients are diagnosed with severe cardiac involvement.

Sublabial bioactive glass implantation for the management of primary atrophic rhinitis and empty nose syndrome: Operative technique.

OBJECTIVES: Atrophic rhinitis (AR) and empty nose syndrome (ENS) are chronic diseases characterized by a paradoxical nasal obstruction. These rare syndromes tend to occur after nasal surgery of the inferior turbinates in ENS and can be idiopathic in AR. Medical treatments alone are often insufficient. Surgical options are challenging and numerous resorbable and nonresorbable implants have been described in small series, with as many surgical techniques described. Whereas current surgical procedures are for risk of extrusions, graft rejections or poor lasting results, the use of GlassBONE™ (Sodimed®, Avignon, France), a bioactive glass, for a vestibular approach in AR and ENS has never been reported for this indication. METHODS: We described an original technique of nasal submucoperiosteal bilateral ceramic glass implantation in two patients with AR and ENS. RESULTS: The two cases presented a postoperative satisfying endoscopic and sinus CT-scan results with filling of the nasal cavities, with less crusts and a complete wound healing. They had no short-term complications. CONCLUSION: This innovative approach is easily feasible and could be an option considered for the surgical management of AR and ENS. Level of evidence: 4.

Objective diagnosis of internal nasal valve collapse by four-phase rhinomanometry.

Background: Internal valve collapse is a frequent cause of nasal obstruction but remains poorly understood and is sometimes treated inappropriately as a result. No functional or imaging test for the condition has been validated and the reference diagnostic technique is physical examination. The objective of this study was to evaluate the potential of four-phase rhinomanometry as a diagnostic test for internal valve collapse. Methods: In a case-control diagnostic accuracy study, the nostrils of adult patients consulting for chronic nasal obstruction were classified as "collapsed" or "non-collapsed" based on clinical findings. Four-phase rhinomanometry was performed in all patients. The area defined by the path of the flow/pressure curve in the two phases of inspiration (the "inspiratory loop area" or "hysteresis loop area") was calculated for both nasal cavities and the threshold value with the highest Youden index was identified. Results: Sixty-six patients (132 nostrils) were included with 72 nostrils classified as collapsed and 60 as non-collapsed. Before nasal decongestion, the inspiratory loop area with the highest Youden index was 17.3 Pa L s-1 and the corresponding sensitivity and specificity were 88.3% (95% confidence interval, 80.0-95.0%) and 89.9% (82.6-95.7%), respectively. Conclusions: In these patients, a cutoff inspiratory loop area in four-phase rhinomanometry data reproduced clinical diagnoses of internal valve collapse with high sensitivity and specificity. This method may offer a firmer basis for treatment indications than subjective physical examinations. Level of evidence: Level 4.

Covid-19 outbreak: does the use of a surgical mask impact the sense of smell?

BACKGROUND: The current context of Covid-19 pandemic has broadened mask use. OBJECTIVES: Evaluate the impact of wearing a surgical mask on sense of smell by comparing the results of sniffin' sticks test (SST) with and without a surgical mask and evaluate the feasibility of practicing SST with a mask. MATERIAL AND METHODS: A crossover prospective comparative study between two groups of volunteers. The results of SST with a mask were compared to the results without a mask: group 1 first performed SST with a surgical mask and then one week later performed SST without a mask, while group 2 started without a mask. RESULTS: Twenty volunteers were included. In group 1 and 2, all the subjects, except one, had a significantly better total score (TDI) without a mask. The average TDI difference score with and without a mask, was inferior to 5. 8/20 (40%) subjects had a TDI difference superior to 5 with and without mask, while 4/20 (20%) were normosmic without a mask, while being recategorized as hyposmic with a mask. CONCLUSIONS AND SIGNIFICANCE: Wearing a surgical mask may reduce the sense of smell, in a cohort of normosmic patients. Further larger studies must be conducted in hyposmic subjects.

Estimated Costs Associated With Management of Otosclerosis With Hearing Aids vs Surgery in Europe.

Importance: Surgery and hearing aids have similar outcomes in terms of hearing acuity but differ in terms of cost, aesthetics, and patient quality of life. The cost-effectiveness and budget impact of otosclerosis treatments have never been studied in Europe. Objectives: To compare the estimated mean costs per patient over 10 years of surgery vs hearing aids for the treatment of otosclerosis and to estimate the budget impact of an increase in the proportion of patients receiving surgical treatment. Design, Setting, and Participants: This economic evaluation analyzed French and European epidemiological data on the surgical management of symptomatic otosclerosis and compared them with data from the literature to build economic models. The analysis was conducted in January 2021. Exposures: Two care pathways were considered in the treatment of otosclerosis, either hearing aid or surgery. Main Outcomes and Measures: Costs were studied over 10 years using Markov models of the 2 care pathways (hearing aid vs surgery). The budget impact analysis was performed over 5 and 10 years, assuming a 1-percentage point yearly increase in the proportion of patients receiving surgical treatment. Results: Over 10 years, the estimated mean cost per patient was significantly lower in the surgery group compared with the hearing aid group (€3446.9 vs €6088.4; mean difference, -€2641.5; 95% CI -€4064.8 to -€1379.4 [US $3913.4 vs US $6912.4; mean difference, -US $2999.0; 95% CI, -US $4614.9 to -US $1566.1]). Increasing surgical treatment by 1 percentage point per year for 10 years would lead to overall savings of €1 762 304 (US $2 000 798) in France, with an increase of €1 322 920 (US $1 501 952) at 10 years for the public health insurance system and a decrease of €3 085 224 (US $3 502 750) at 10 years for patients and private health insurers. Sensitivity analyses showed that these results were robust. Conclusions and Relevance: These results suggest that in France, treating otosclerosis surgically is slightly less expensive over 10 years than using hearing aids, when considering all payers. The proposed models developed in this study could be adjusted to perform the same analysis in other countries.

Desloratadine, an FDA-approved cationic amphiphilic drug, inhibits SARS-CoV-2 infection in cell culture and primary human nasal epithelial cells by blocking viral entry.

The 2019 global coronavirus (COVID-19) pandemic has brought the world to a grinding halt, highlighting the urgent need for therapeutic and preventive solutions to slow the spread of emerging viruses. The objective of this study was to assess the anti-SARS-CoV-2 effectiveness of 8 FDA-approved cationic amphiphilic drugs (CADs). SARS-CoV-2-infected Vero cells, Calu-3 cells and primary Human Nasal Epithelial Cells (HNEC) were used to investigate the effects of CADs and revealed their antiviral mode of action. Among the CADs tested, desloratadine, a commonly used antiallergic, well-tolerated with no major side effects, potently reduced the production of SARS-CoV-2 RNA in Vero-E6 cells. Interestingly, desloratadine was also effective against HCoV-229E and HCoV-OC43 showing that it possessed broad-spectrum anti-coronavirus activity. Investigation of its mode of action revealed that it targeted an early step of virus lifecycle and blocked SARS-CoV-2 entry through the endosomal pathway. Finally, the ex vivo kinetic of the antiviral effect of desloratadine was evaluated on primary Human Nasal Epithelial Cells (HNEC), showing a significant delay of viral RNA production with a maximal reduction reached after 72 h of treatment. Thus, this treatment could provide a substantial contribution to prophylaxis and systemic therapy of COVID-19 or other coronaviruses infections and requires further studies.

Proviral role of human respiratory epithelial cell-derived small extracellular vesicles in SARS-CoV-2 infection.

Small Extracellular Vesicles (sEVs) are 50-200 nm in diameter vesicles delimited by a lipid bilayer, formed within the endosomal network or derived from the plasma membrane. They are secreted in various biological fluids, including airway nasal mucus. The goal of this work was to understand the role of sEVs present in the mucus (mu-sEVs) produced by human nasal epithelial cells (HNECs) in SARS-CoV-2 infection. We show that uninfected HNECs produce mu-sEVs containing SARS-CoV-2 receptor ACE2 and activated protease TMPRSS2. mu-sEVs cleave prefusion viral Spike proteins at the S1/S2 boundary, resulting in higher proportions of prefusion S proteins exposing their receptor binding domain in an 'open' conformation, thereby facilitating receptor binding at the cell surface. We show that the role of nasal mu-sEVs is to complete prefusion Spike priming performed by intracellular furin during viral egress from infected cells. This effect is mediated by vesicular TMPRSS2 activity, rendering SARS-CoV-2 virions prone to entry into target cells using the 'early', TMPRSS2-dependent pathway instead of the 'late', cathepsin-dependent route. These results indicate that prefusion Spike priming by mu-sEVs in the nasal cavity plays a role in viral tropism. They also show that nasal mucus does not protect from SARS-CoV-2 infection, but instead facilitates it.

Self-reported loss of smell without nasal obstruction to identify COVID-19. The multicenter Coranosmia cohort study.

OBJECTIVES: To determine the frequency of SARS-CoV-2 positive samples in a subset of patients consulting for primarily isolated acute (<7 days) loss of smell and to assess the diagnostic accuracy of olfactory/gustatory dysfunction for COVID-19 diagnosis in the overall population tested for COVID-19 in the same period. METHODS: Prospective multicentric cohort study in four olfactory ENT units and a screening center for COVID-19. RESULTS: i) Among a subset of 55 patients consulting for primarily recent loss of smell, we found that 51 (92.7%) had a COVID-19 positive test (median viral load of 28.8 cycle threshold). Loss of smell was mostly total (anosmia), rarely associated with nasal obstruction but associated with a taste disorder in 80%. Olfactory dysfunction occurred suddenly, either as first complaint or preceded by mild symptoms occurring a median of 3 days. The majority of patients (72.9%) partially recovered the sense of smell within 15 days. ii) In a population of 1824 patients tested for COVID-19, the positive predictive value and the specificity of loss of smell and/or taste were 78.5% and 90.3% respectively (sensitivity (40.8%), negative predictive value (63.6%)). CONCLUSIONS: Self-reported loss of smell had a high predictive positive value to identify COVID-19. Making this sign well known publicly could help to adopt isolation measures and inform potential contacts.

Association between hearing loss and hereditary ATTR amyloidosis.

Background: Hereditary transthyretin (TTR) related amyloidosis (ATTRv) is a life-threatening condition, which can potentially affect all organs. The objective was to identify the hearing status of patients with cardiac ATTRv and describe their audiological pattern. Methods: Nineteen patients with confirmed diagnosis of ATTRv cardiac amyloidosis (CA) underwent otoscopy and audiological tests, including pure tone and speech audiometry. Results: 74% were male, with a mean age of 72 ± 1.8 years. The main mutations were Val122Ile (n = 7) and Val30Met (n = 6). Objective hearing loss was detected in 17 patients (89%), whereas only 37% complained of hearing loss. ATTRv patients presented a different audiometric profile compared to patients of the same age with presbycusis: a higher prevalence and worse hearing thresholds compared to age-related expectations (ISO). Hearing loss affected all frequencies with, unexpectedly, mixed or conductive hearing loss (35%). According to the type of mutation, there was an increased rate of sensorineural or mixed/conductive hearing loss. Conclusions: the present study indicates that hearing loss is more prevalent and worse in patients with ATTRv amyloidosis than in the general population, while mostly clinically under-estimated. It suggests that ATTRv deposits could infiltrate the various anatomical structures of the inner and mild ear.