Benralizumab in severe eosinophilic asthma in real life: confirmed effectiveness and contrasted effect on sputum eosinophilia versus exhaled nitric oxide fraction - PROMISE.

Background: Randomised controlled trials have shown that benralizumab, an anti-interleukin-5 receptor monoclonal antibody, reduces exacerbations and oral corticosteroid dose and improves asthma control and lung function in severe eosinophilic asthma. The aim of this study was to confirm results of randomised controlled trials in real life in a population of 73 patients with severe eosinophilic asthma treated with benralizumab for at least 12 months. Methods: Patients underwent careful monitoring of asthma exacerbations, exhaled nitric oxide fraction, lung function, asthma control and quality of life questionnaire responses and sputum induction, and gave a blood sample at baseline, after 6 months and then every year. Results: We found significant reductions in exacerbations (by 92%, p<0.0001) and oral corticosteroid dose (by 83%, p<0.001) after 6 months that were maintained over time, with 78% of patients able to stop oral corticosteroid therapy. Patients improved their Asthma Control Test (ACT) score (from 11.7±5.1 to 16.9±5.35, p<0.0001), Asthma Control Questionnaire (ACQ) score (from 2.88±1.26 to 1.77±1.32, p<0.0001) and Asthma Quality of Life Questionnaire score (+1.04, p<0.0001) at 6 months and this was maintained during follow-up. Only 35% and 43% of patients reached asthma control according to an ACT score ≥20 and ACQ score <1.5, respectively. We observed stable post-bronchodilation lung function over time and a significant reduction in sputum eosinophil count, with 85% of patients exhibiting sputum eosinophil counts <3% after 6 months (p<0.01) with no effect on exhaled nitric oxide fraction. Conclusion: In our real-life study, we confirm the results published in randomised controlled trials showing a sharp reduction in exacerbations and oral corticosteroid therapy, an improvement in asthma control and quality of life, and a dramatic reduction in sputum eosinophil count.

Temporal Stability of Ciliary Beating Post Nasal Brushing, Modulated by Storage Temperature.

Primary ciliary dyskinesia is a heterogeneous, inherited motile ciliopathy in which respiratory cilia beat abnormally, and some ultrastructural ciliary defects and specific genetic mutations have been associated with particular ciliary beating alterations. Ciliary beating can be evaluated using digital high-speed videomicroscopy (DHSV). However, normal reference values, essential to assess ciliary beating in patients referred for a PCD diagnostic, vary between centres, as minor variations in protocols might influence ciliary beating. Consequently, establishment of normal values is essential for each PCD diagnostic centre. We aimed to evaluate whether delay after sampling, and temperature for conservation of respiratory ciliated samples, might modify assessments of ciliary beating. In total, 37 healthy nasal brushing samples of respiratory ciliated epithelia were collected. Video sequences were recorded at 37 °C immediately using DHSV. Then, the samples were divided and conserved at 4 °C or at room temperature (RT). Ciliated beating edges were then recorded at 37 °C, at 3 h and at 9 h post sampling. In six samples, recordings were continued up to 72 h after sampling. Ciliary beating was assessed manually by ciliary beat frequency (CBFM) and ciliary beat pattern (CBP). A semi-automatic software was used for quantitative analysis. Both CBF and CBP evaluated manually and by a semi-automated method were stable 9 h after sampling. CBFM was higher when evaluated using samples stored at RT than at 4 °C. CBP and the semi-automated evaluation of ciliary beating were not affected by storage temperature. When establishing normal references values, ciliary beating can be evaluated at 37 °C up to 9 h after nasal brushing, but the storage temperature modifies ciliary beating and needs to be controlled.

From nose to brain: The effect of lemon inhalation observed by whole brain voxel to voxel functional connectivity.

Lemon fragrance is known for its stimulating properties, but its mechanisms of action are not well known yet. This study aimed to examine the effect of lemon essential oil inhalation on healthy participants' alertness level and their neural correlates using magnetic resonance imaging (MRI). Twenty-one healthy men underwent functional MRI scans in different conditions: a resting state condition, a condition where they were exposed to passive lemon smelling (alternating exposure to lemon and breathing fresh air), and a control condition without lemon fragrance diffusion -the order of the last two conditions being randomized. Alertness levels were assessed immediately after each condition using the Karolinska Sleepiness Scale. Voxel-wise whole-brain global functional connectivity and graph theory analyses were computed to investigate brain functional connectivity and network topology alterations. After lemon fragrance inhalation, we observed a higher level of alertness as compared to resting state -but not compared to control condition. During lemon fragrance inhalation, we found increased global functional connectivity in the thalamus, paralleled by decreased global connectivity in several cortical regions such as precuneus, postcentral and precentral gyrus, lateral occipital cortex and paracingulate gyrus. Graph theory analysis revealed increased network integration in cortical regions typically involved in olfaction and emotion processing such as olfactory bulb, hypothalamus and thalamus, while decreased network segregation in several regions of the posterior part of the brain during olfaction as compared to resting state. The present findings suggest that lemon essential oil inhalation could increase the level of alertness.

Characteristics of Otologic Disease Among Patients With Primary Ciliary Dyskinesia.

Importance: Otologic disease is common among people with primary ciliary dyskinesia (PCD), yet little is known about its spectrum and severity. Objective: To characterize otologic disease among participants with PCD using data from the Ear-Nose-Throat Prospective International Cohort. Design, Setting, and Participants: This cross-sectional analysis of baseline cohort data from February 2020 through July 2022 included participants from 12 specialized centers in 10 countries. Children and adults with PCD diagnoses; routine ear, nose, and throat examinations; and completed symptom questionnaires at the same visit or within 2 weeks were prospectively included. Exposures: Potential risk factors associated with increased risk of ear disease. Main Outcomes and Measures: The prevalence and characteristics of patient-reported otologic symptoms and findings from otologic examinations, including potential factors associated with increased risk of ear inflammation and hearing impairment. Results: A total of 397 individuals were eligible to participate in this study (median [range] age, 15.2 [0.2-72.4] years; 186 (47%) female). Of the included participants, 204 (51%) reported ear pain, 110 (28%) reported ear discharge, and 183 (46%) reported hearing problems. Adults reported ear pain and hearing problems more frequently when compared with children. Otitis media with effusion-usually bilateral-was the most common otoscopic finding among 121 of 384 (32%) participants. Retracted tympanic membrane and tympanic sclerosis were more commonly seen among adults. Tympanometry was performed for 216 participants and showed pathologic type B results for 114 (53%). Audiometry was performed for 273 participants and showed hearing impairment in at least 1 ear, most commonly mild. Season of visit was the strongest risk factor for problems associated with ear inflammation (autumn vs spring: odds ratio, 2.40; 95% CI, 1.51-3.81) and age 30 years and older for hearing impairment (41-50 years vs ≤10 years: odds ratio, 3.33; 95% CI, 1.12-9.91). Conclusion and Relevance: In this cross-sectional study, many people with PCD experienced ear problems, yet frequency varied, highlighting disease expression differences and possible clinical phenotypes. Understanding differences in otologic disease expression and progression during lifetime may inform clinical decisions about follow-up and medical care. Multidisciplinary PCD management should be recommended, including regular otologic assessments for all ages, even without specific complaints.

Sinonasal disease among patients with primary ciliary dyskinesia: an international study.

Background: Sinonasal symptoms are a common feature of primary ciliary dyskinesia (PCD); however, literature about their severity and frequency, particularly during the life course, is scarce. Using baseline data from the Ear, nose and throat (ENT) Prospective International Cohort of PCD patients, we describe sinonasal disease in PCD. Methods: We included participants who had a routine sinonasal examination during which they completed a symptoms questionnaire. We compared frequency of reported symptoms and examination findings among children and adults, and identified characteristics potentially associated with higher risk of sinonasal disease using ordinal regression. Results: 12 centres contributed 384 participants; median age was 16 years (IQR 9-22), and 54% were male. Chronic nasal problems were the most common feature, reported by 341 (89%). More adults (33; 24%) than children (10; 4%) described hyposmia. Quality of life was moderately affected by rhinosinusitis among 136 participants with completed SNOT-22 questionnaires (median score 31; IQR 23-45). Examinations revealed nasal polyps among 51 of 345 participants (15%) and hypertrophic inferior nasal turbinates among 127 of 341 participants (37%). Facial pain was detected in 50 of 342 participants (15%). Nasal polyps, hypertrophic turbinates, deviated septum and facial pain were found more commonly in adults than children. The only characteristic associated with higher risk of sinonasal disease was age 10 years and older. Conclusions: Based on our findings, regular sinonasal examinations are relevant for patients with PCD of all ages. There is a need for improved management of sinonasal disease supported by evidence-based guidelines.

Validation of mandibular movements' analysis to measure sleep in adults with sleep complaints by comparison with actigraphy and polysomnography.

Objective: In adults with sleep complaints, we assessed the software of automatic analysis of mandibular movements to identify sleep and wake states by confrontation with the polysomnography (PSG) and the actigraphy (ACTG). Material and Methods: Simultaneous and synchronized in-lab PSG, ACTG, and JAWAC were carried out in 100 patients with a sleep complaint. Epoch by epoch analysis was realized to assess the ability to sleep-wake distinction. Sleep parameters as measured by the three devices were compared. These included three regularly reported parameters: total sleep time (TST), sleep onset latency (SOL), and wake after sleep onset (WASO). Also, two supplementary parameters, wake during sleep period (WDSP) and latency to arising (LTA) were added to measure separately the quiet wakefulness states. Results: The epoch by epoch analysis showed that the JAWAC, as compared to ACTG, classified sleep and wake states with greater specificity, while the overall accuracy and sensitivity of the two devices were comparable. The sleep parameters analysis showed that for the JAWAC estimates, the differences in TST, SOL, and LTA values were not statistically significant. However, WDSP and subsequently WASO were slightly underestimated. In contrast, the dissimilarities between ACTG estimates and PSG measurements of all the above sleep parameters were statistically significant; TST was overestimated whilst SOL, LTA, WDSP, and WASO were underestimated. Conclusion: This study indicated that, besides its ability to reliably estimate TST, the JAWAC based on mandibular movements' analysis was able, in adults with sleep complaints, to overcome the important problem of the recognition of the state of quiet wakefulness.

Use of Vandenberg and Kuse Mental Rotation Test to Predict Practical Performance of Sinus Endoscopy.

OBJECTIVES: The aim of this study was to assess the predictive value of the Vandenberg and Kuse Mental Rotation Test (MRT) on performance of novice medical students for manipulation of a nasal endoscope on a cadaveric model. MATERIAL AND METHOD: We randomly selected 39 medical students who had never handled a nasal endoscope and subjected them to the MRT. General information including experience in manual, technical, or surgical activities and testing of anatomical knowledge were collected to exclude possible confounding factors. They were then asked to perform series of cadaveric model exercises using a nasal endoscope. Their cadaver performance was evaluated by 2 blinded observers, using a standardized scale. RESULTS: We found that medical students with higher mental rotation skills had significantly increased endoscopic sinus performance (P = .0002 using multivariate regression adjusted for specialty choice, previous surgical exposure, and anatomy knowledge). Higher anatomy knowledge was also associated with better endoscopic sinus performance (P = .0141). Other parameters had no impact on endoscopic sinus performance measured by the endoscopic scale (P > .05). CONCLUSION: The score obtained on the MRT was correlated with the practical performance of manipulating the nasal endoscope in cadaver. It could therefore be a useful spatial ability tool for directing targeted training in rhinology.

Nasal Brushing Sampling and Processing using Digital High Speed Ciliary Videomicroscopy - Adaptation for the COVID-19 Pandemic.

Primary Ciliary Dyskinesia (PCD) is a genetic motile ciliopathy, leading to significant otosinopulmonary disease. PCD diagnosis is often missed or delayed due to challenges with different diagnostic modalities. Ciliary videomicroscopy, using Digital High-Speed Videomicroscopy (DHSV), one of the diagnostic tools for PCD, is considered the optimal method to perform ciliary functional analysis (CFA), comprising of ciliary beat frequency (CBF) and beat pattern (CBP) analysis. However, DHSV lacks standardized, published operating procedure for processing and analyzing samples. It also uses living respiratory epithelium, a significant infection control issue during the COVID-19 pandemic. To continue providing a diagnostic service during this health crisis, the ciliary videomicroscopy protocol has been adapted to include adequate infection control measures. Here, we describe a revised protocol for sampling and laboratory processing of ciliated respiratory samples, highlighting adaptations made to comply with COVID-19 infection control measures. Representative results of CFA from nasal brushing samples obtained from 16 healthy subjects, processed and analyzed according to this protocol, are described. We also illustrate the importance of obtaining and processing optimal quality epithelial ciliated strips, as samples not meeting quality selection criteria do now allow for CFA, potentially decreasing the diagnostic reliability and the efficiency of this technique.

Impact of a shift in treatment funding on a multidisciplinary sleep clinic: a cohort study.

Multidisciplinary Sleep Clinics for sleep apnea have long existed, bringing together neurologists, sleep specialists, dentists, orthodontists and surgeons. In Belgium, a shift in funding for obstructive sleep apnea treatment was implemented from January 1st, 2017. Funding was allowed for moderate to severe obstructive sleep apnea and the rules shifted for treatments delivery and monitoring by authorised medical opinion. We aimed to assess whether a shift in treatment funding was associated with a change in the multidisciplinary sleep practice. Sample consisted of all patients discussed in the sleep multidisciplinary team meetings of the University Hospital of Liege from January 2016 to December 2018. Interrupted times series, Mann-Whitney U tests and descriptive statistics were produced. There were no differences in patients age, male sex preponderance, body mass index, clinical presentation and level of obstruction. Baseline obstructive sleep apnea severity was significantly lower (mean apnea-hypopnea index and mean oxygen desaturation index lowered with p = 0.0189 and p = 0.0466, respectively) after the funding rules changed. Oral appliance and ENT surgery were more often offered after the shift in funding. The key changes of the new funding rules for obstructive sleep apnea were reflected in the patient selection and management by sleep multidisciplinary team meeting. Funding terms could influence the care we give, not only in treatment options, but also in patients selection.

A pilot study to determine the effects of nasal co-phenylcaine on drug-induced sleep endoscopy.

PURPOSE: The use of nasal decongestant and nasal anaesthesia is currently not recommended during drug-induced sleep endoscopy (DISE) according to the European position paper. The evaluation of the effects of nasal decongestant/anaesthesia on DISE has not been performed before and our aim is to perform a pilot study to determine whether nasal decongestants/anaesthesia affects DISE outcomes. METHODS: 27 patients undergoing DISE for OSA or for simple snoring were included. On each patient, DISE was performed twice, before and approximately 10 min after the administration of two puffs of co-phenylcaine nasal spray (lidocaine hydrochloride 5%, phenylephrine 0.5%, and benzalkonium chloride 0.01%) into each nostril. A nasal peak inspiratory flow was used for the objective assessment of nasal airway obstruction. During the first and the second DISE the loudness of the snoring was also recorded. RESULTS: Change in DISE total grading after nasal spray administration was not statistically significant. For the same grading, changes in percentage of contribution to collapse were not statistically significant. Sex, AHI, BMI, tonsils grade, presence of rhinitis, turbinate hypertrophy, nasal septal deviation, or nasal peak inspiratory flow limitation had no influence on the effect of nasal spray. Co-phenylcaine did not significantly influence the loudness of snoring. CONCLUSIONS: Our pilot study supports the use of co-phenylcaine nasal spray during DISE and the positive effects of the nasal spray do not influence the grading outcome. Importantly, the decongestant enhances the nasal assessment during DISE and potentially aids in the diagnosis of nasal obstruction while the nasal anaesthetic component may be beneficial by reducing nasal discomfort during DISE and thereby helping to reduce the total dose of intravenous anaesthetic administered. However, further studies on a larger population are needed to confirm our results.

Responsiveness of acoustic rhinometry to septorhinoplasty by comparison with rhinomanometry and subjective instruments.

OBJECTIVES: Nose patency measures and instruments assessing subjective health are increasingly being used in rhinology. However, there is very little evidence of comparing existing methods' responsiveness to change. We evaluated the responsiveness of acoustic rhinometry to nasal valve surgery by comparison with rhinomanometry and patient-reported outcome instruments. DESIGN: Prospective case-control study. SETTING: Tertiary referral University Hospital. PARTICIPANTS: Sixty consecutive patients with internal nasal valve dysfunction and 20 healthy volunteers as control group were enrolled. Prospectively collected data included acoustic rhinometry, rhinomanometry, NOSE scale, SNOT-23 questionnaire, visual analogue scale and demographics. MAIN OUTCOME MEASURES: Primary endpoint was the responsiveness of acoustic rhinometry to functional septorhinoplasty surgery at 3 months. Secondary endpoints were ability of acoustic rhinometry to reflect "known group" differences and correlation to subjective symptoms. RESULTS: Acoustic rhinometry was highly responsive to septorhinoplasty (P < 0.0001) while anterior rhinomanometry was not (P = 0.08). Based on the quartiles of the postoperative change in NOSE score, patients were classified as, respectively, non-responders, mild, moderate and good responders to surgery. Logistic regression model showed that acoustic rhinometry was able to discriminate non-responders to responders to surgery (P = 0.019), while anterior rhinomanometry failed (P = 0.611). Sensitivity and specificity of acoustic rhinometry were significantly higher (ROC area = 0.76) than rhinomanometry (ROC area = 0.48). Acoustic rhinometry was also superior than rhinomanometry to discriminate patients from control subjects and agreed better with patients-based subjective questionnaires. CONCLUSIONS: Our study confirms and quantifies the responsiveness of acoustic rhinometry to nasal valve surgery, with a higher sensitivity and specificity than rhinomanometry.

Postoperative care in endoscopic sinus surgery: a critical review.

PURPOSE OF REVIEW: Chronic rhinosinusitis with and without nasal polyps is a common disease affecting people all over the world. Functional endoscopic sinus surgery (FESS) has become the gold standard treatment for medically refractive disease. Postoperative care is recommended by international leaders as an important part of the patient's management. This article is a critical review and discussion focusing on postoperative care, which is based on expert opinion, clinical studies, randomized controlled trials and meta-analysis studies. RECENT FINDINGS: Postoperative care including nasal rinsing, topical corticosteroids, antibiotics and avoidance of nasal packing are unanimously considered to be the cornerstone of best practice following FESS. However, the effectiveness of in-office nasal debridement is still under debate. SUMMARY: There is a lack of consensus regarding the necessity of performing in-office nasal debridement and the majority of clinicians carry out their postoperative care according to experience and their own preference. This is often determined by the extent of surgery performed, the severity of the postoperative inflammation, as well as being dependent on the patient's discomfort, the time constraints associated with postoperative care and the costs associated with additional appointments. Ideally, nasal debridement should be performed by the operating surgeon under endoscopic control both gently and atraumatically.

Validation of midsagittal jaw movements to measure sleep in healthy adults by comparison with actigraphy and polysomnography.

OBJECTIVE: In a device based on midsagittal jaw movements analysis, we assessed a sleep-wake automatic detector as an objective method to measure sleep in healthy adults by comparison with wrist actigraphy against polysomnography (PSG). METHODS: Simultaneous and synchronized in-lab PSG, wrist actigraphy and jaw movements were carried out in 38 healthy participants. Epoch by epoch analysis was realized to assess the ability to sleep-wake distinction. Sleep parameters as measured by the three devices were compared. This included three regularly reported parameters: total sleep time, sleep onset latency, and wake after sleep onset. Also, two supplementary parameters, wake during sleep period and latency time, were added to measure quiet wakefulness state. RESULTS: The jaw movements showed sensitivity level equal to actigraphy 96% and higher specificity level (64% and 48% respectively). The level of agreement between the two devices was high (87%). The analysis of their disagreement by discrepant resolution analysis used PSG as resolver revealed that jaw movements was right (58.9%) more often than actigraphy (41%). In sleep parameters comparison, the coefficient correlation of jaw movements was higher than actigraphy in all parameters. Moreover, its ability to distinct sleep-wake state allowed for a more effective estimation of the parameters that measured the quiet wakefulness state. CONCLUSIONS: Midsagittal jaw movements analysis is a reliable method to measure sleep. In healthy adults, this device proved to be superior to actigraphy in terms of estimation of all sleep parameters and distinction of sleep-wake status.

Three-dimensional analysis of craniofacial bones and soft tissues in obstructive sleep apnea using cone beam computed tomography.

A total of 154 adult patients with sleep complaints underwent a polysomnography and a craniofacial cone beam computed tomography (CBCT). OSA was defined as an apnea and hypopnea index (AHI) or an oxygen desaturation index (ODI) ≥ 10. Soft tissues and craniofacial bones volumes were prospectively measured by CBCT and collected blindly from sleep polysomnography. Among the study patients, 127 (83%) suffered from OSA and 27 (17%) did not. OSA patients demonstrated a narrower maxillo-palatine core volume (11.7±3.2 vs 14.6±4.9cm3) even when adjusting for age, gender, height, neck circumference and body mass index. These upper airway measures provide a comprehensive analysis of bony structures and soft tissues, which can be involved in OSA.

Safety of human olfactory mucosal biopsy for the purpose of olfactory ensheathing cell harvest and nerve repair: a prospective controlled study in patients undergoing endoscopic sinus surgery.

BACKGROUND: Nasal olfactory mucosa is an accessible source of olfactory ensheathing cells for spinal cord regeneration. However, safety of the biopsy technique and the effects on sense of smell and nasal function have not been robustly assessed in the form of a prospective controlled study. METHODOLOGY: National Health Service ethical approval was granted for this study of 131 patients. The primary outcome measure was olfactory function and the secondary outcomes included postoperative complication rates as well as the SNOT 22, NOSE scale scores and surgeon reported (Lund-Kennedy score) nasal function outcomes. RESULTS: 65 patients underwent functional endoscopic sinus surgery (FESS) and superior turbinate biopsy, and 66 patients underwent FESS only as the control group. There was no significant difference in complication rates between the two groups. All Olfactory function outcomes were unaffected following olfactory biopsy. We demonstrated that the patients quality of life and nasal patency as well as surgeon reported outcome measurements remain unaffected following olfactory harvesting. CONCLUSIONS: We have uniquely provided level 2a evidence for the safety of endoscopic biopsy of olfactory mucosa, which does not affect nasal function or the sense of smell compared to standard FESS without biopsy.

Upper airway imaging in sleep-disordered breathing.

Our understanding of sleep-disordered breathing has evolved considerably over the past three decades, and clinical techniques of evaluation have progressed tremendously. Myriad imaging techniques are now available for the physician to approach the dynamic features resulting in turbulent airflow, upper airway narrowing or collapse at different levels. Controversy exists in the choice of investigations, probably because the best evaluation should be a combination of different techniques. Physical, radiographic, endoscopic and acoustic evaluations could be integrated to understand the degree and the levels of airway reduction and/or obstruction in a given patient. This review focuses on cost-effective and easily implemented techniques in daily practice, allowing quality assessment of the dynamic anatomy of sleep-disordered breathing: cephalometry, (sleep-)endoscopy and acoustic reflectometry of the upper airway.

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells.

Hearing requires an optimal afferent innervation of sensory hair cells by spiral ganglion neurons in the cochlea. Here we report that complementary expression of ephrin-A5 in hair cells and EphA4 receptor among spiral ganglion neuron populations controls the targeting of type I and type II afferent fibres to inner and outer hair cells, respectively. In the absence of ephrin-A5 or EphA4 forward signalling, a subset of type I projections aberrantly overshoot the inner hair cell layer and invade the outer hair cell area. Lack of type I afferent synapses impairs neurotransmission from inner hair cells to the auditory nerve. By contrast, radial shift of type I projections coincides with a gain of presynaptic ribbons that could enhance the afferent signalling from outer hair cells. Ephexin-1, cofilin and myosin light chain kinase act downstream of EphA4 to induce type I spiral ganglion neuron growth cone collapse. Our findings constitute the first identification of an Eph/ephrin-mediated mutual repulsion mechanism responsible for specific sorting of auditory projections in the cochlea.