Location of eosinophils in the airway wall is critical for specific features of airway hyperresponsiveness and T2 inflammation in asthma

Eosinophils are implicated as effector cells in asthma but the functional implications of the precise location of eosinophils in the airway wall is poorly understood. We aimed to quantify eosinophils in the different compartments of the airway wall and associate these findings with clinical features of asthma and markers of airway inflammation.In this cross-sectional study, we utilised design-based stereology to accurately partition the numerical density of eosinophils in both the epithelial compartment and the subepithelial space (airway wall area below the basal lamina including the submucosa) in individuals with and without asthma and related these findings to airway hyperresponsiveness (AHR) and features of airway inflammation.Intraepithelial eosinophils were linked to the presence of asthma and endogenous AHR, the type of AHR that is most specific for asthma. In contrast, both intraepithelial and subepithelial eosinophils were associated with type-2 (T2) inflammation, with the strongest association between IL5 expression and intraepithelial eosinophils. Eosinophil infiltration of the airway wall was linked to a specific mast cell phenotype that has been described in asthma. We found that IL-33 and IL-5 additively increased cysteinyl leukotriene (CysLT) production by eosinophils and that the CysLT LTC4 along with IL-33 increased IL13 expression in mast cells and altered their protease profile.We conclude that intraepithelial eosinophils are associated with endogenous AHR and T2 inflammation and may interact with intraepithelial mast cells via CysLTs to regulate airway inflammation.

STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma

Airway remodeling and airway hyperresponsiveness are central drivers of asthma severity. Airway remodeling is a structural change involving the dedifferentiation of airway smooth muscle (ASM) cells from a quiescent to a proliferative and secretory phenotype. Here, we show up-regulation of the endoplasmic reticulum Ca2+ sensor stromal-interacting molecule 1 (STIM1) in ASM of asthmatic mice. STIM1 is required for metabolic and transcriptional reprogramming that supports airway remodeling, including ASM proliferation, migration, secretion of cytokines and extracellular matrix, enhanced mitochondrial mass, and increased oxidative phosphorylation and glycolytic flux. Mechanistically, STIM1-mediated Ca2+ influx is critical for the activation of nuclear factor of activated T cells 4 and subsequent interleukin-6 secretion and transcription of pro-remodeling transcription factors, growth factors, surface receptors, and asthma-associated proteins. STIM1 drives airway hyperresponsiveness in asthmatic mice through enhanced frequency and amplitude of ASM cytosolic Ca2+ oscillations. Our data advocates for ASM STIM1 as a target for asthma therapy.

Advances and Challenges of Antibody Therapeutics for Severe Bronchial Asthma

Asthma is a disease that consists of three main components: airway inflammation, airway hyperresponsiveness, and airway remodeling. Persistent airway inflammation leads to the destruction and degeneration of normal airway tissues, resulting in thickening of the airway wall, decreased reversibility, and increased airway hyperresponsiveness. The progression of irreversible airway narrowing and the associated increase in airway hyperresponsiveness are major factors in severe asthma. This has led to the identification of effective pharmacological targets and the recognition of several biomarkers that enable a more personalized approach to asthma. However, the efficacies of current antibody therapeutics and biomarkers are still unsatisfactory in clinical practice. The establishment of an ideal phenotype classification that will predict the response of antibody treatment is urgently needed. Here, we review recent advancements in antibody therapeutics and novel findings related to the disease process for severe asthma.

Changes in lung inflation in asthma in patients with osmotic airway hyperresponsiveness

The scientific literature does not provide enough information on whether bronchial hyperresponsiveness to hypoosmotic stimulus in patients with asthma can lead to more pronounced disturbances of regional lung ventilation.Aim. to characterize lung inflation in asthma patients with osmotic airway hyperresponsiveness.Methods. The lung inflation was studied by body plethysmography, as well as by three-dimensional volumetry, planimetry, and multispiral CT densitometry in 24 patients (group 1) with persistent mild asthma and osmotic airway hyperresponsiveness, identified by the bronchoprovocation test with inhalation of distilled water (IDW) (the average ДРБУ1 was —21.1 ± 3.2%). The comparison group (group 2) consisted of 49 patients with no response to IDW (the average ДББУ1 was —3.7 ± 0.5%; p = 0.00001).Results. Group 1 had lower lung function (FEVj was 83.6 ± 4.5%; FEF50 was 58.1 ± 5.8%) at baseline in comparison with the group 2 (96.7 ± 2.2%, p = 0.0042 and 75.5 ± 2.2%, p = 0.016, respectively) and higher indices of lung inflation at body plethysmography (RV was 153.2 ± 12.5 and 127.5 ± 4.0%, respectively; p = 0,027; RV/TLC was 128.8 ± 5.5 and 109.9 ± 2.8%, respectively; p = 0.015). According to three-dimensional volumetry, the indicators of expiratory lung inflation (526.0 ± 117.8 vox) and average residual inflation of both lungs (13.1 ± 2.6 vox) in group 1 were significantly higher than in group 2 (301.5 ± 55.8 vox, р < 0.05 and 9.1 ± 1.6 vox,р < 0,05, respectively). The patients with osmotic airway hyperresponsiveness also showed higher values of the expiratory area in the middle zone (235.3 ± 29.4 and 149.2 ± 14.9 pix, respectively; p = 0.00 47) and the lower zone (292.3 ± 37.9 and 178.6 ± 18.6 pix, respectively; p = 0.0034) of the lungs.Conclusion. Asthma patients with osmotic airway hyperresponsiveness have lung hyperinflation with impaired lung ventilation predominantly in the middle and lower zones.

Predictors of Airway Hyperresponsiveness in Symptomatic Children with Normal Spirometry and Suspicious of Possible Asthma

<b><i>Background:</i></b> Asthma diagnosis may be challenging particularly in patients with mild symptoms without an obstructive pattern in spirometry. Detection of airway hyperresponsiveness (AHR) by a positive methacholine challenge (MCC) is still an important diagnostic tool to confirm the presence of asthma with reasonable certainty. However, it is time consuming and could be exhausting for patients. We aimed to identify the predictive factors for AHR in children with respiratory symptoms without obstructive pattern in spirometry. <b><i>Methods:</i></b> Data from children who had undergone MCC were analyzed retrospectively. The demographic features of patients along with laboratory results were collected. <b><i>Results:</i></b> A total of 123 children with a median age of 10.5 years were enrolled. AHR was detected in 81 children (65.8%). The age of the children with AHR was significantly younger. The prevalences of aeroallergen sensitization, nocturnal cough, wheezing, and a baseline forced expiratory flow at 75% of vital capacity (FEF₇₅) &#x3c;65% were significantly more frequent in children with AHR. Multivariate logistic regression analysis revealed age, ever wheezing, nocturnal cough, tree pollen allergy, and FEF₇₅ &#x3c;65% as independent predictors of AHR. A weighted clinical risk score was developed (range, 0–75 points). At a cutoff point of 35, the presence of AHR is predicted with a specificity of 90.5% and a positive predictive value of 91.5%. <b><i>Conclusion:</i></b> In children suspected of having asthma, but without an obstructive pattern in the spirometry, combining independent predictors, which can be easily obtained in clinical practice, might be used to identify children with AHR.

Clinical analysis of the “small plateau” sign on the flow-volume curve followed by deep learning automated recognition

Background Small plateau (SP) on the flow-volume curve was found in parts of patients with suspected asthma or upper airway abnormalities, but it lacks clear scientific proof. Therefore, we aimed to characterize its clinical features. Methods We involved patients by reviewing the bronchoprovocation test (BPT) and bronchodilator test (BDT) completed between October 2017 and October 2020 to assess the characteristics of the sign. Patients who underwent laryngoscopy were assigned to perform spirometry to analyze the relationship of the sign and upper airway abnormalities. SP-Network was developed to recognition of the sign using flow-volume curves. Results Of 13,661 BPTs and 8,168 BDTs completed, we labeled 2,123 (15.5%) and 219 (2.7%) patients with the sign, respectively. Among them, there were 1,782 (83.9%) with the negative-BPT and 194 (88.6%) with the negative-BDT. Patients with SP sign had higher median FVC and FEV1% predicted (both P < .0001). Of 48 patients (16 with and 32 without the sign) who performed laryngoscopy and spirometry, the rate of laryngoscopy-diagnosis upper airway abnormalities in patients with the sign (63%) was higher than those without the sign (31%) (P = 0.038). SP-Network achieved an accuracy of 95.2% in the task of automatic recognition of the sign. Conclusions SP sign is featured on the flow-volume curve and recognized by the SP-Network model. Patients with the sign are less likely to have airway hyperresponsiveness, automatic visualizing of this sign is helpful for primary care centers where BPT cannot available.