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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.

Chronic obstructive pulmonary disease (COPD) is considered the fourth-leading causes of death worldwide; COPD is caused by inhalation of noxious indoor and outdoor particles, especially cigarette smoke that represents the first risk factor for this respiratory disorder. To mimic the effects of particulate matter on COPD, we isolated peripheral blood mononuclear cells (PBMCs) and treated them with combustion-generated ultrafine particles (UFPs) obtained from two different fuel mixtures, namely, pure ethylene and a mixture of ethylene and dimethylfuran (the latter mimicking the combustion of biofuels). UFPs were separated in two fractions: (1) sub-10 nm particles, named nano organic carbon (NOC) particles and (2) primarily soot particles of 20-40 nm and their agglomerates (200 nm). We found that both NOC and soot UFPs induced the release of IL-18 and IL-33 from unstable/exacerbated COPD-derived PBMCs. This effect was associated with higher levels of mitochondrial dysfunction and derived reactive oxygen species, which were higher in PBMCs from unstable COPD patients after combustion-generated UFP exposure. Moreover, lower mRNA expression of the repairing enzyme OGG1 was associated with the higher levels of 8-OH-dG compared with non-smoker and smokers. It was interesting that IL-18 and IL-33 release from PBMCs of unstable COPD patients was not NOD-like receptor 3/caspase-1 or caspase-8-dependent, but rather correlated to caspase-4 release. This effect was not evident in stable COPD-derived PBMCs. Our data suggest that combustion-generated UFPs induce the release of caspase-4-dependent inflammasome from PBMCs of COPD patients compared with healthy subjects, shedding new light into the biology of this key complex in COPD.

BackgroundChronic 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.MethodsA 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 (\\(\\)) value > 0.61.ResultsAfter 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.ConclusionThis 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.

The prevalence of in situ tracheal stents has increased in the past two decades for the management of malignant and benign central airway diseases for either palliation or definitive therapy. Recent placement of a tracheal stent has been associated with edema of the upper airway; therefore, these patients are at a great risk for airway collapse, especially within the days most recent to the procedure. The authors present the case of a morbidly obese patient with a tracheal stent admitted to the Intensive Care Unit who developed acute respiratory failure and was found to be \"unable to ventilate, unable to intubate.\" Surgical airway approach through a cricothyroidotomy failed to provide a patent airway and the patient subsequently developed cardiac arrest and expired. The presence of tracheal stent poses a high challenge during emergent airway interventions; thus, carefully planned airway manipulation in such patients is paramount in order to avoid catastrophic outcomes.

Objective: Allergic airway diseases (AADs) are a group of heterogeneous disease mediated by T-helper type 2 (Th2) immune response and characterized with airway inflammation and remodeling, including allergic asthma, allergic rhinitis, and chronic rhinosinusitis with allergic background. This review aimed to discuss the abnormal epithelial-mesenchymal crosstalk in the pathogenesis of AADs. Data Sources: Articles referred in this review were collected from the database of PubMed published in English up to January 2018. Study Selection: We had done a literature search using the following terms \"allergic airway disease OR asthma OR allergic rhinitis OR chronic sinusitis AND IL-25 OR IL-33 OR thymic stromal lymphopoietin OR fibrocyte\". Related original or review articles were included and carefully analyzed. Results: It is now believed that abnormal epithelial-mesenchymal crosstalk underlies the pathogenesis of AADs. However, the key regulatory factors and molecular events involved in this process still remain unclear. Epithelium-derived triple cytokines, including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), are shown to act on various target cells and promote the Th2 immune response. Circulating fibrocyte is an important mesenchymal cell that can mediate tissue remodeling. We previously found that IL-25-circulating fibrocyte axis was significantly upregulated in patients with asthma, which may greatly contribute to asthmatic airway inflammation and remodeling. Conclusions: In view of the redundancy of cytokines and \"united airway\" theory, we propose a new concept that IL-25/IL-33/TSLP-fibrocyte axis may play a vital role in the abnormal epithelial-mesenchymal crosstalk in some endotypes of AADs. This novel idea will guide potential new intervention schema for the common treatment of AADs sharing common pathogenesis in the future.

Small airways disease (SAD) is a cardinal feature of chronic obstructive pulmonary disease (COPD) first recognized in the nineteenth century. The diverse histopathological features associated with SAD underpin the heterogeneous nature of COPD. Our understanding of the key molecular mechanisms which drive the pathological changes are not complete. In this article we will provide a historical overview of key histopathological studies which have helped shape our understanding of SAD and discuss the hallmark features of airway remodelling, mucous plugging and inflammation. We focus on the relationship between SAD and emphysema, SAD in the early stages of COPD, and the mechanisms which cause SAD progression, including bacterial colonization and exacerbations. We discuss the need to specifically target SAD to attenuate the progression of COPD.

Background The most common abnormal spirometric pattern reported in WTC worker and volunteer cohorts has consistently been that of a nonobstructive reduced forced vital capacity (low FVC). Low FVC is associated with obesity, which is highly prevalent in these cohorts. We used quantitative CT (QCT) to investigate proximal and distal airway inflammation and emphysema in participants with stable low FVC pattern. Methods We selected study participants with at least two available longitudinal surveillance spirometries, and a chest CT with QCT measurements of proximal airway inflammation (wall area percent, WAP), end-expiratory air trapping, suggestive of distal airway obstruction (expiratory to inspiratory mean lung attenuation ratio, MLA EI ), and emphysema (percentage of lung volume with attenuation below − 950 HU, LAV%). The comparison groups in multinomial logistic regression models were participants with consistently normal spirometries, and participants with stable fixed obstruction (COPD). Results Compared to normal spirometry participants, and after adjusting for age, sex, race/ethnicity, BMI, smoking, and early arrival at the WTC disaster site, low FVC participants had higher WAP (OR adj 1.24, 95% CI 1.06, 1.45, per 5% unit), suggestive of proximal airway inflammation, but did not differ in MLA EI , or LAV%. COPD participants did not differ in WAP with the low FVC ones and were more likely to have higher MLA EI or LAV% than the other two subgroups. Discussion WTC workers with spirometric low FVC have higher QCT-measured WAP compared to those with normal spirometries, but did not differ in distal airway and emphysema measurements, independently of obesity, smoking, and other covariates.

Evidence suggests damage to small airways is a key pathologic lesion in chronic obstructive pulmonary disease (COPD). Computed tomography densitometry has been demonstrated to identify emphysema, but no such studies have been performed linking an imaging metric to small airway abnormality. To correlate parametric response mapping (PRM) analysis to lung tissue measurements of patients with severe COPD treated by lung transplantation and control subjects. Resected lungs were inflated, frozen, and systematically sampled, generating 33 COPD (  = 11 subjects) and 22 control tissue samples (  = 3 subjects) for micro-computed tomography analysis of terminal bronchioles (TBs; last generation of conducting airways) and emphysema. PRM analysis was conducted to differentiate functional small airways disease (PRM ) from emphysema (PRM ). In COPD lungs, TB numbers were reduced (  = 0.01); surviving TBs had increased wall area percentage (  < 0.001), decreased circularity (  < 0.001), reduced cross-sectional luminal area (  < 0.001), and greater airway obstruction (  = 0.008). COPD lungs had increased airspace size (  < 0.001) and decreased alveolar surface area (  < 0.001). Regression analyses demonstrated unique correlations between PRM and TBs, with decreased circularity (  < 0.001), decreased luminal area (  < 0.001), and complete obstruction (  = 0.008). PRM correlated with increased airspace size (  < 0.001), decreased alveolar surface area (  = 0.003), and fewer alveolar attachments per TB (  = 0.01). PRM identifies areas of lung tissue with TB loss, luminal narrowing, and obstruction. This is the first confirmation that an imaging biomarker can identify terminal bronchial pathology in established COPD and provides a noninvasive imaging methodology to identify small airway damage in COPD.

Fungal sensitization is a major risk factor for severe asthma and related airway diseases, spanning presentations from simple sensitization to allergic bronchopulmonary aspergillosis (ABPA). To capture this spectrum, the concept of allergic fungal airway disease (AFAD) has been proposed. Animal models have been central to uncovering how fungi drive airway inflammation. Extract-based models are simple and reproducible and highlight epithelial alarm signaling and type 2 immunity, although they do not reflect chronic infection. Spore-based models using Aspergillus fumigatus or Alternaria alternata more closely mimic human disease, producing mixed eosinophilic and neutrophilic inflammation, airway hyperreactivity, and mucus plugging. Advances using clinical isolates, gene-edited fungal strains, and combined exposure systems (for example, cigarette smoke plus spores) have further improved relevance by linking fungal virulence and host factors to disease severity. This review summarizes available models, their strengths and limitations, and their utility in elucidating AFAD pathogenesis and informing therapy.

Air pollutants include toxic particles and gases emitted in large quantities from many different combustible materials. They also include particulate matter (PM) and ozone, and biological contaminants, such as viruses and bacteria, which can penetrate the human airway and reach the bloodstream, triggering airway inflammation, dysfunction, and fibrosis. Pollutants that accumulate in the lungs exacerbate symptoms of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Asthma, a heterogeneous disease with complex pathological mechanisms, is characterized by particular symptoms such as shortness of breath, a tight chest, coughing, and wheezing. Patients with COPD often experience exacerbations and worsening of symptoms, which may result in hospitalization and disease progression. PM varies in terms of composition, and can include solid and liquid particles of various sizes. PM concentrations are higher in urban areas. Ozone is one of the most toxic photochemical air pollutants. In general, air pollution decreases quality of life and life expectancy. It exacerbates acute and chronic respiratory symptoms in patients with chronic airway diseases, and increases the morbidity and risk of hospitalization associated with respiratory diseases. However, the mechanisms underlying these effects remain unclear. Therefore, we reviewed the impact of air pollutants on airway diseases such as asthma and COPD, focusing on their underlying mechanisms.