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INTRODUCTION: Asthma is associated with upper airway diseases and allergic diseases; however, the causal effects need to be investigated further. Thus, we performed this two-sample Mendelian randomization (MR) analysis to explore and measure the causal effects of asthma on allergic rhinitis (AR), vasomotor rhinitis (VMR), allergic conjunctivitis (AC), atopic dermatitis (AD), and allergic urticaria (AU). METHODS: The data for asthma, AR, VMR, AC, AD, and AU were obtained from large-scale genome-wide association studies summarized recently. We defined single-nucleotide polymorphisms satisfying the MR assumptions as instrumental variables. Inverse-variance weighted (IVW) approach under random-effects was applied as the dominant method for causal estimation. The weighted median approach, MR-Egger regression analysis, MR pleiotropy residual sum and outlier test, and leave-one-out sensitivity analysis were performed as sensitivity analysis. Horizontal pleiotropy was measured using MR-Egger regression analysis. Significant causal effects were attempted for replication and meta-analysis. RESULTS: We revealed that asthma had causal effects on AR (IVW, odds ratio [OR] = 1.93; 95% confidence interval [CI], 1.74-2.14; p < 0.001), VMR (IVW, OR = 1.40; 95% CI, 1.15-1.71; p < 0.001), AC (IVW, OR = 1.65; 95% CI, 1.49-1.82; p < 0.001), and AD (IVW, OR = 2.13; 95% CI, 1.82-2.49; p < 0.001). No causal effect of asthma on AU was observed. Sensitivity analysis further assured the robustness of these results. The evaluation of the replication stage and meta-analysis further confirmed the causal effect of asthma on AR (IVW OR = 1.81, 95% CI 1.62-2.02, p < 0.001), AC (IVW OR = 1.44, 95% CI 1.11-1.87, p < 0.001), and AD (IVW OR = 1.85, 95% CI 1.42-2.41, p < 0.001). CONCLUSIONS: We revealed and quantified the causal effects of asthma on AR, VMR, AC, and AD. These findings can provide powerful causal evidence of asthma on upper airway diseases and allergic diseases, suggesting that the treatment of asthma should be a preventive and therapeutic strategy for AR, VMR, AC, and AD.

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This study investigated using a 160-slice multidetector computed tomography (CT) scanner for conscious image acquisition in dogs with upper airway disease, and describes findings in dogs that had previously undergone soft palate surgery. Seventeen client-owned dogs with upper airway disease were retrospectively reviewed, and classified into three groups: group I, "untreated brachycephalic obstructive airway syndrome (BOAS) patients"; group II, "previously treated BOAS patients"; and group III, "patients with respiratory disease other than BOAS". Data included signalment, clinical history, direct laryngoscopy and endoscopy findings, previous surgeries and CT findings. CT scans in group I revealed overlong and thickened soft palates in all dogs, and signs of laryngeal collapse in four dogs. Patients in group II exhibited normal soft palate lengths, while patients in group III displayed various findings such as nasopharyngeal narrowing and tracheal collapse. Upper airway examinations under general anaesthesia confirmed most CT findings. This study demonstrates the feasibility and value of conscious CT scanning for assessing upper airway diseases in dogs, providing valuable diagnostic information while eliminating the need for chemical immobilisation, thus reducing patient stress and cost. These findings offer new insight into upper airway anatomy in awake patients, especially in brachycephalic breeds, and lay a foundation for future research.

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Introduction: Pediatric subglottic stenosis (SGS) results from prolonged intubation where scar tissue leads to airway narrowing that requires invasive surgery. We have recently discovered that modulating the laryngotracheal microbiome can prevent SGS. Herein, we show how our patent-pending antimicrobial peptide-eluting endotracheal tube (AMP-ET) effectively modulates the local airway microbiota resulting in reduced inflammation and stenosis resolution. Materials and Methods: We fabricated mouse-sized ETs coated with a polymeric AMP-eluting layer, quantified AMP release over 10 days, and validated bactericidal activity for both planktonic and biofilm-resident bacteria against Staphylococcus aureus and Pseudomonas aeruginosa. Ex vivo testing: we inserted AMP-ETs and ET controls into excised laryngotracheal complexes (LTCs) of C57BL/6 mice and assessed biofilm formation after 24 h. In vivo testing: AMP-ETs and ET controls were inserted in sham or SGS-induced LTCs, which were then implanted subcutaneously in receptor mice, and assessed for immune response and SGS severity after 7 days. Results: We achieved reproducible, linear AMP release at 1.16 µg/day resulting in strong bacterial inhibition in vitro and ex vivo. In vivo, SGS-induced LTCs exhibited a thickened scar tissue typical of stenosis, while the use of AMP-ETs abrogated stenosis. Notably, SGS airways exhibited high infiltration of T cells and macrophages, which was reversed with AMP-ET treatment. This suggests that by modulating the microbiome, AMP-ETs reduce macrophage activation and antigen specific T cell responses resolving stenosis progression. Conclusion: We developed an AMP-ET platform that reduces T cell and macrophage responses and reduces SGS in vivo via airway microbiome modulation. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-023-00769-9.

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Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a heterogeneous upper airway disease that is prevalent globally. Recent research into the molecular basis of the disease has led to the development of biologics as a new therapeutic option for severe and recalcitrant forms of CRSwNP. Mepolizumab is a monoclonal antibody targeting IL-5, one of the signature cytokines of the type 2 immune response and which plays an important role in the pathogenesis of CRSwNP. Here we present the latest evidence behind mepolizumab, examining disease pathophysiology and pharmacology, as well as data from clinical trials, real-life studies and meta-analyses. As we welcome this promising step forward into precision medicine, we discuss practical issues and future perspectives on mepolizumab and biologics for CRSwNP.

Mepolizumab is a new injectable drug developed to control difficult-to-treat cases of chronic rhinosinusitis with nasal polyposis (CRSwNP), an inflammatory disease of the nose that affects many people worldwide. It works by blocking the action of IL-5, an important protein in the body that regulates inflammation. One of the main effects of this protein is promoting the activity of eosinophils, a type of white blood cell. Eosinophils contribute to tissue damage when activated inappropriately. A recent large-scale study (SYNAPSE) on patients using this drug has been completed, reporting favorable results. In this article, we discuss the science behind the disease, the drug and data from patient studies. We conclude by discussing several future challenges and opportunities in the management of CRSwNP.

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BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) often coexists with lower airway disease. With the overlap between upper and lower airway disease, optimal management of the upper airways is undertaken in conjunction with that of the lower airways. Biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of both upper and lower airway diseases. Knowledge gaps nevertheless exist in how best to approach patient care as a whole. There have been sixteen randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL- 5R, IL-33, and immunoglobulin (Ig)E. This white paper considers the perspectives of experts in various disciplines such as rhinology, allergy, and respirology across Canada, all of whom have unique and valuable insights to contribute on how to best approach patients with upper airway disease from a multidisciplinary perspective. METHODS: A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. A national multidisciplinary expert panel of 34 certified specialists was created, composed of 16 rhinologists, 7 allergists, and 11 respirologists who evaluated the 20 original statements on a scale of 1-9 and provided comments. All ratings were quantitively reviewed by mean, median, mode, range, standard deviation and inter-rater reliability. Consensus was defined by relative interrater reliability measures-kappa coefficient ([Formula: see text]) value > 0.61. RESULTS: After three rounds, a total of 22 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with upper airway disease. CONCLUSION: This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of upper airway disease from a multidisciplinary perspective, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years.

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Asthma is a heterogeneous disease sharing airway instability but with different biology, risk factors, and response-to-therapy patterns. Biologics have revolutionized the one-size-fits-to-all approach to personalized medicine in severe asthma (SA), which relies on the identification of biomarkers that define distinct endotypes. Thus, blood eosinophils and, to some extent, exhaled nitric oxide (FeNO) can predict the response to approved anti-type 2 (T2) biologics (anti-IgE, anti-IL-5, and anti-IL-4R alpha), whereas age at onset and comorbidities such as anxiety/depression, obesity, reflux, and upper airway disease (UAD) also influence therapeutic responses in SA. In this article, focusing on the predictive value of biomarkers for the therapeutic response to biologics in SA, we first summarize the level of prediction achieved by T2 biomarkers (blood eosinophils, FeNO) and then review whether data support the predictive value of upper airway diagnosis on such outcomes. Post hoc analysis of most studies with T2 biologics suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) and, to a lower extent, allergic rhinitis may help in predicting clinical response. Considering that T2 biologics are now also approved for the treatment of severe CRSwNP, diagnosis of upper airway disease is a key step in determining eligibility for such therapy.

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OBJECTIVES: Chronic rhinosinusitis (CRS) is prevalent in people with cystic fibrosis (PwCF) and is often refractory to treatments. Uncontrolled CRS might negatively impact the lower airways and the quality of life. The aim of this study is to evaluate the burden of cystic fibrosis (CF)-related CRS in the era of CF transmembrane conductance regulator (CFTR) modulators. METHODS: Adult PwCF were asked to fill in a questionnaire on sinonasal complaints, they underwent a nasal endoscopy, bacteriological sampling, and a CT scan. Afterwards, these outcome measures were compared between patients treated with and without modulators. RESULTS: In the 122 included patients, CRS was present in 83%. CFTR modulators were prescribed in 48% of the patients, with a median of 10 months since the start of the treatment. Subjectively, the median SNOT-22 score was 16/110. Objectively, a median Lund-Kennedy score of 6/12 and modified Lund-Mackay score of 10/24 were observed. No correlation could be found between SNOT-22 score and other outcome measures including endoscopy and radiology. Altogether, 21% of the patients had controlled disease. When comparing patients treated with and without modulators, significantly lower CT scores (p = 0.0018) and less bacterial colonization (p = 0.0082) were observed in patients receiving modulators. CONCLUSION: CF-CRS is highly prevalent in our cohort and only the minority of PwCF has a well-controlled disease. A multidisciplinary ENT-pneumology clinic would be beneficial, as there is a high discrepancy between patient-reported symptoms and the extent of the disease. CFTR modulators are promising, as lower CT scores and less bacterial colonization were observed in the modulator group. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 133:2898-2909, 2023.

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Immunoglobulin E (IgE) is a well-known key factor in allergic airway disease; however, its central role in non-allergic airway inflammation is often underestimated. In some airway diseases, IgE is produced as a result of allergic sensitization. However, in others, IgE production occurs despite the lack of a specific allergen. Although multiple pathways contribute to the production of IgE in airway disease, it is its activity in mediating the inflammatory response that is associated with disease. Therefore, an understanding of IgE as the unifying component of upper and lower airway diseases has important implications for both diagnosis and treatment. Understanding the role of IgE in each upper and lower airway disease highlights its potential utility as a diagnostic marker and therapeutic target. Further classification of these diseases by whether they are IgE mediated or non-IgE mediated, rather than by the existence of an underlying allergic component, accounts for both systemic and localized IgE activity. Improvements in diagnostic methodologies and standardization of clinical practices with this classification in mind can help identify patients with IgE-mediated diseases. In doing so, this group of patients can receive optimal care through targeted anti-IgE therapeutics, which have already demonstrated efficacy across numerous IgE-mediated upper and lower airway diseases.

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BACKGROUND: There are few studies regarding severe chronic upper-airway disease (SCUAD) that represents an important socioeconomic problem for the treatment of rhinitis and associated comorbidities, particularly asthma. OBJECTIVES: The aim of our study is to evaluate the prevalence of this pathology in patients with allergic rhinitis (AR) in real life, to phenotype allergic patients with SCUAD, and to identify which factors are related to the severity of the disease. METHODS: We studied 113 patients with uncontrolled AR despite optimal adherence to therapy according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in a multicenter Italian study, analyzing comorbidity, use of additional drugs, not scheduled visits, and the number of emergency room admissions. RESULTS: Our data suggest that polysensitization is the only statistically significant factor correlating with SCUAD. Asthma does not seem to represent a correlating factor. An important finding is the poor use (20%) of allergy immunotherapy (AIT), although patients were suffering from AR and the ARIA guidelines recommend the use of AIT in moderate/severe AR. CONCLUSIONS: The SCUAD population seems not to have a specific phenotype; there is a greater presence of SCUAD in polysensibilized patients, perhaps a sign of greater inflammation.

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The exhaled air of healthy people contains nitric oxide.Under the physiological condition, nasal nitric oxide(NNO) comes primarily from the sinuses, a little is produced in the nasal mucosa.Fractional exhaled nitric oxide is mainly from the trachea and bronchus.When airway diseases occur, it can influence the concentration of exhaled nitric oxide.Therefore, with the continuous improvement of technology in recent years, the measurement of NNO has been widely used in upper airway diseases of children.It is characteristics of quantitative, non-invasive, simple and safe.This article reviews the measurement methods of NNO and its clinical application in children upper airway diseases such as rhinitis, sinusitis, nasal polyps and adenoid hypertrophy.

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Physical exercise requires proper function of the upper and lower airways in order to meet exertional ventilatory requirements. Athletes performing frequent intensive exercise experience more sino-nasal symptoms and demonstrate objective decreases in sino-nasal function when compared with the general population. Sino-nasal dysfunction is known to interfere with sport performance. Nasal epithelial injury, neutrophilic influx, and decreased mucociliary clearance have been associated with intensive training. In this review, the authors provide a comprehensive overview of the prevalence of sino-nasal disease in athletes, the possible underlying pathophysiologic mechanisms, and a summary of diagnostic and treatment options.

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OBJECTIVE/HYPOTHESIS: Patients with laryngeal disorders often exhibit changes to cough function contributing to aspiration episodes. Two primary cough variables (peak cough flow: PCF and compression phase duration: CPD) were examined within a biomechanical model to determine their impact on characteristics that impact airway compromise. STUDY DESIGN: Computational study. METHODS: A Computational Fluid Dynamics (CFD) technique was used to simulate fluid flow within an upper airway model reconstructed from patient CT images. The model utilized a finite-volume numerical scheme to simulate cough-induced airflow, allowing for turbulent particle interaction, collision, and break-up. Liquid penetrants at 8 anatomical release locations were tracked during the simulated cough. Cough flow velocity was computed for a base case and four simulated cases. Airway clearance was evaluated through assessment of the fate of particles in the airway following simulated cough. RESULTS: Peak-expiratory phase resulted in very high airway velocities for all simulated cases modelled. The highest velocity predicted was 49.96 m/s, 88 m/s, and 117 m/s for Cases 1 and 3, Base case, and Cases 2 and 4 respectively. In the base case, 25% of the penetrants cleared the laryngeal airway. The highest percentage (50%) of penetrants clearing the laryngeal airway are observed in Case 2 (with -40% CPD, +40% PCF), while only 12.5% cleared in Case 3 (with +40% CPD, -40% PCF). The proportion that cleared in Cases 1 and 4 was 37.5%. CONCLUSION: Airway modelling may be beneficial to the study of aspiration in patients with impaired cough function including those with upper airway and neurological diseases. It can be used to enhance understanding of cough flow dynamics within the airway and to inform strategies for treatment with "cough-assist devices" or devices to improve cough strength. LEVEL OF EVIDENCE: N/A.

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BACKGROUND: Severe asthma is often associated with sinonasal diseases. Shin'iseihaito is a Japanese traditional herbal medicine, which is used to treat rhinosinusitis. However, its effectiveness in the treatment of asthma has not been elucidated. OBJECTIVE: The aims of this study were to examine the effectiveness of Shin'iseihaito in asthmatic patients with upper airway disease and to identify the characteristics of responders. METHODS: The medical records were retrospectively analyzed of asthmatic patients concomitant with upper airway disease in the outpatient department who had been administered Shin'iseihaito at least once from September 2011 to February 2015. They were classified into responders and non-responders, and the differences in characteristics were compared between the two groups. RESULTS: Shin'iseihaito was effective in 21/40 (52.5%) patients. There was no significant difference between responders and non-responders with regard to age, sex, or age of asthma onset. However, the frequency of aspirin intolerance, the treatment step of asthma, and serum immunoglobulin E levels were significantly higher in responders than they were in non-responders (p = 0.022, p = 0.017, and p = 0.017, respectively). The frequency of occurrence of concomitant eosinophilic chronic rhinosinusitis was not significantly different in both groups. CONCLUSION: Shin'iseihaito could be a potential alternative for the treatment of asthma in patients with upper airway diseases.

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Once released into the air, humidifier disinfectants became tiny nano-size particles, and resulted in chemical bronchoalveolitis. Families had lost their most beloved members, and even some of them became broken. Based on an estimate of two million potential victims who had experienced adverse effects from the use of humidifier disinfectants, we can say that what we have observed was only the tip of the iceberg. Problems of entire airways, as well as other systemic effects, should be examined, as we know these nano-size particles can irritate cell membranes and migrate into systemic circulation. The story of humidifier disinfectant is not finished yet.

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Once released into the air, humidifier disinfectants became tiny nano-size particles, and resulted in chemical bronchoalveolitis. Families had lost their most beloved members, and even some of them became broken. Based on an estimate of two million potential victims who had experienced adverse effects from the use of humidifier disinfectants, we can say that what we have observed was only the tip of the iceberg. Problems of entire airways, as well as other systemic effects, should be examined, as we know these nano-size particles can irritate cell membranes and migrate into systemic circulation. The story of humidifier disinfectant is not finished yet.

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The term SCUAD (severe chronic upper airway disease) has been previously introduced to describe cases with upper airway disorders and symptoms not adequately controlled despite correct diagnosis and management. It has been so far applied mainly in adults and no specific focus has been given on the pediatric population. When the term SCUAD is considered for children specifically, a series of issues may arise. These issues involve accurate definition, epidemiology, clinical characteristics, pathophysiology, and socioeconomic implications. These issues seem to clearly differentiate adult from pediatric SCUAD. We attempt to shed light on these issues in an effort to provide directions for future guideline development and research. In this context, P-SCUAD (pediatric severe chronic upper airway disease) is hereby introduced.

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This article reviews the approach to a patient with respiratory distress, with a focus on clues obtained from the physical examination. Respiratory distress is a common reason for presentation of a companion animal to a veterinarian on an emergency basis, and thus the clinician should have a comfort level with the approach to these patients. Our discussion includes a basic review of respiratory pathophysiology and the differential diagnoses for hypoxemia. In the majority of cases, physical examination should allow localization of the cause of the respiratory problem to the upper airways, lower airways, pleural space, or pulmonary parenchyma. Such localization, coupled with signalment and historical clues, guides additional diagnostics and therapeutics based on the most likely differential diagnoses. Although managing a patient with respiratory distress can be challenging, a systematic approach such as the one presented here should ensure appropriate intervention in a timely fashion and maximize the chance of a good outcome.

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