The effects of benralizumab on airway geometry and dynamics in severe eosinophilic asthma: a single-arm study design exploring a functional respiratory imaging approach.

BACKGROUND: Severe eosinophilic asthma (SEA) is characterised by elevated blood/sputum eosinophil counts and airway inflammation, which can lead to mucus plug-mediated airway obstruction, increased exacerbation frequency, declines in lung function, and death. Benralizumab targets the alpha-subunit of the interleukin-5 receptor found on eosinophils, leading to rapid and near complete eosinophil depletion. This is expected to result in reduced eosinophilic inflammation, reduced mucus plugging and improved airway patency and airflow distribution. METHODS: BURAN is an interventional, single-arm, open-label, uncontrolled, prospective, multicentre study during which participants will receive three 30 mg subcutaneous doses of benralizumab at 4-week intervals. This study will use functional respiratory imaging (FRI), a novel, quantitative method of assessing patients' lung structure and function based on detailed, three-dimensional models of the airways, with direct comparison of images taken at Weeks 0 and 13. Patients aged ≥ 18 years with established SEA who may be receiving oral corticosteroids and/or other asthma controller medications, who are inadequately controlled on inhaled corticosteroid-long-acting ß2-agonist therapies and who have had ≥ 2 asthma exacerbations in the previous 12 months will be included. The objectives of BURAN are to describe changes in airway geometry and dynamics, measured by specific image-based airway volume and other FRI endpoints, following benralizumab therapy. Outcomes will be evaluated using descriptive statistics. Changes in FRI parameters, mucus plugging scores and central/peripheral ratio will be quantified as mean percent change from baseline (Week 0) to Week 13 (± 5 days) and statistical significance will be evaluated using paired t-tests. Relationships between FRI parameters/mucus plugging scores and conventional lung function measurements at baseline will be assessed with linear regression analyses for associations between outcomes, scatterplots to visualise the relationship, and correlation coefficients (Spearman's rank and Pearson's) to quantify the strength of these associations. CONCLUSIONS: The BURAN study will represent one of the first applications of FRI-a novel, non-invasive, highly sensitive method of assessing lung structure, function and health-in the field of biologic respiratory therapies. Findings from this study will increase understanding of cellular-level eosinophil depletion mechanisms and improvements in lung function and asthma control following benralizumab treatment. Trial registration EudraCT: 2022-000152-11 and NCT05552508.

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis.

RATIONALE: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown. OBJECTIVES: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF. METHODS: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects. MEASUREMENTS AND MAIN RESULTS: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes. CONCLUSIONS: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.

[Thoracic imaging in cystic fibrosis : Radiography]. / Thoraxbildgebung bei zystischer Fibrose : Radiographie.

CLINICAL ISSUE: Patients with cystic fibrosis (CF) require regular follow-up examinations, usually from birth onwards, using imaging techniques. METHODS: The conventional chest x­ray examination is the only technique recommended by the guidelines at this age. The examination can be performed at every age and is well standardized. The radiation dose to the patient is small and does not require any sedation. RADIOLOGICAL FINDINGS AND CLASSIFICATION: The typical structural changes of the bronchi and the lung parenchyma can be depicted. Typical findings are air-trapping, bronchiectasis, peribronchial cuffing, bronchial wall thickening, mucus plugging, nodular opacities, atelectasis and/or consolidations and hilar lymphadenopathy. Different scoring systems have been developed to allow for a relatively easy but reproducible assessment of the severity of the disease. The most important ones for daily clinical practice are the Chrispin-Norman score, Brasfield score, and the Wisconsin score. All of them show a good correlation with pulmonary function parameters and the clinical picture of the patients. PRACTICAL RECOMMENDATIONS: It is recommended to take an annual X­ray for patients with CF, and in addition in individual cases with clinical deterioration. Computed tomography (CT) can be performed if relevant information for treatment is expected to gained.

Clinical Associations of Mucus Plugging in Moderate to Severe Asthma.

BACKGROUND: Mucus plugging is recognized as a contributory factor to airway obstruction and symptoms in persistent asthma. OBJECTIVE: We aimed to determine phenotypic associations of mucus plugging in patients with moderate to severe asthma in a real-life clinic setting. METHODS: Mucus plugs (MPs) were identified by a thoracic radiologist upon high-resolution computed tomography imaging. A MP score was subsequently calculated and analyzed along with type 2 biomarkers, spirometry, severe exacerbations, and asthma control for 126 patients with moderate to severe asthma before biologic therapy. RESULTS: Asthma patients with MP had significantly worse FEV1%, forced expiratory flow at 25% to 75% of FVC percent, and FEV1/FVC as well as higher levels of peripheral blood eosinophils, FeNO, total IgE, and Aspergillus fumigatus IgE titers, and had previously experienced more frequent severe exacerbations. FEV1/FVC, more than two exacerbations per year, blood eosinophils, total IgE, and A fumigatus IgE titers were associated with MPs after adjusting for confounders. CONCLUSIONS: Poorly controlled asthma patients with MPs exhibited significantly worse airflow obstruction and greater type 2 inflammation associated with more frequent severe exacerbations. Impaired spirometry, more frequent exacerbations, raised blood eosinophils, total IgE, and A fumigatus IgE increased the likelihood of MPs.

Structural changes in lung morphology detected by MRI after modulating therapy with elexacaftor/tezacaftor/ivacaftor in adolescent and adult patients with cystic fibrosis.

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves CFTR function in cystic fibrosis (CF) patients homozygous or heterozygous for F508del mutation. The aim of the study was to evaluate the response to ELX/TEZ/IVA treatment both clinically and morphologically in terms of bronchiectasis, bronchial wall thickening, mucus plugging, abscess and consolidations. METHODS: We retrospectively collected data from CF patients followed at Parma CF Centre (Italy) treated by ELX/TEZ/IVA between March and November 2021. Post-treatment changes in respiratory function, quality of life, sweat chloride concentration, body mass index, pulmonary exacerbations and lung structure by chest magnetic resonance imaging (MRI) were assessed. T2-and T1-weighted sequences were acquired with a 20 min-long scanning protocol on a 1.5T MRI scanner (Philips Ingenia) without administration of intravenous contrast media. RESULTS: 19 patients (32.5 ± 10.2 years) were included in the study. After 6 months of treatment with ELX/TEZ/IVA, MRI showed significant improvements in the morphological score (p < 0.001), with a reduction in bronchial wall thickening (p < 0.001) and mucus plugging (p 0.01). Respiratory function showed significant improvement in predicted FEV1% (58.5 ± 17.5 vs 71.4 ± 20.1, p < 0.001), FVC% (79.0 ± 11.1 vs 88.3 ± 14.4, p < 0.001), FEV1/FVC (0.61 ± 0.16 vs 0.67 ± 0.15, <0.001) and LCI2.5% (17.8 ± 4.3 vs 15.8 ± 4.1 p < 0.005). Significant improvement was found in body mass index (20.6 ± 2.7 vs 21.9 ± 2.4, p < 0.001), pulmonary exacerbations (2.3 ± 1.3 vs 1.4 ± 1.3 p 0.018) and sweat chloride concentration (96.5 ± 36.6 vs 41.1 ± 16.9, p < 0.001). CONCLUSIONS: Our study confirms the efficacy of ELX/TEZ/IVA in CF patients not only from a clinical point of view but also in terms of morphological changes of the lungs.

Lobar Mucus Plugging Reflecting Central Bronchial Tumoral Obstruction: A Case Report.

Early diagnosis of bronchopulmonary carcinoid tumors is crucial as the surgical excision is the main treatment and determines the prognosis. We present the case of a 66-year-old heavy-smoker man who had started to complain about a cough a few months ago. We diagnosed him with an endobronchial mass on a chest computed tomography scan and lobar bronchoceles resulting from mucus plugging distal to the tumor obstruction. These findings were retrospectively visible on the previous chest radiograph that had initially been interpreted as non-contributary.

Saved by the PEEP: Resolution of Complete Unilateral Lung Collapse Secondary to Mucus Plugging With Ventilator Technique.

Bronchoscopy can be used to resolve respiratory failure caused by tenacious mucus plugs. However, emergent bronchoscopy to resolve mucus plugging is not always available in small rural hospitals around the country. We present a case in which increasing the positive end-expiratory pressure settings on the ventilator resulted in immediate improvement in patient oxygenation and imaging findings during a respiratory emergency caused by mucus plugging.

Investigational approaches for unmet need in severe asthma.

INTRODUCTION: Molecular antibodies (mAb) targeting inflammatory mediators are effective in T2-high asthma. The recent approval of Tezepelumab presents a novel mAb therapeutic option for those with T2-low asthma. AREAS COVERED: We discuss a number of clinical problems pertinent to severe asthma that are less responsive to current therapies, such as persistent airflow obstruction and airway hyperresponsiveness. We discuss selected investigational approaches, including a number of candidate therapies under investigation in two adaptive platform trials currently in progress, with particular reference to this unmet need, as well as their potential in phenotypes such as neutrophilic asthma and obese asthma, which may or may not overlap with a T2-high phenotype. EXPERT OPINION: The application of discrete targeting approaches to T2-low molecular phenotypes, including those phenotypes in which inflammation may not arise within the airway, has yielded variable results to date. Endotypes associated with T2-low asthma are likely to be diverse but await validation. Investigational therapeutic approaches must, likewise, be diverse if the goal of remission is to become attainable for all those living with asthma.

Respiratory Candida in Patients with Bronchitis, Mucus Plugging, and Atelectasis.

BACKGROUND: The significance of Candida in pulmonary secretions is unclear, and usually is regarded as colonization, not contributing to symptoms or disease. Yet, in our experience, Candida seemed associated with chronic sputum, mucus plugging, atelectasis, and poor outcome. OBJECTIVE: The aim of this study is to describe the clinical findings of patients with Candida in pulmonary (sputum or bronchoscopy) secretions and the significance of Candida. METHODS: Retrospective study of inpatients and outpatients referred for pulmonary consultation with Candida in pulmonary secretions. Clinical parameters and estimates of whether Candida was likely clinically significant, were determined. RESULTS: 82 inpatients and 11 outpatients were identified, of which 61 (66%) had atelectasis and 68 (73%) bronchoscopies. Of patients having bronchoscopies, 56 (82%) had mucus, and 43 (63%) mucus plugging. Of the inpatients death (or probable death) occurred in 43 (63%), 42 (98%) of which were from definite or probable respiratory failure, with 13 (31%) likely related to mucus plugging, 16 (38%) possibly from mucus plugging, 6 (14%) unknown, and 7 (17%) not due to mucus plugging. Candida was felt likely clinically significant in 57 patients (61%), uncertain significance in 23 (25%), and not significant in 13 (14%). All outpatients had exacerbations, including 7 (64%) within a year. CONCLUSION: Patients requiring pulmonary consultation with Candida in pulmonary secretions often have chronic sputum production, exacerbations, mucus plugging, atelectasis, and death from respiratory failure. Candida was likely clinically significant in most patients. Recommendations to consider Candida in pulmonary secretions as colonization should be reconsidered.

Heat and moisture exchanger use reduces in-hospital complications following total laryngectomy: a case-control study.

BACKGROUND: Total laryngectomy (TL) is an appropriate oncologic operation for many patients with laryngeal cancer delivering excellent oncologic outcomes, however it remains beset with significant functional consequences. Following TL, the upper and lower airways are permanently disconnected, which causes unfiltered, cold air with reduced humidity to enter the tracheobronchial tree, resulting in mucus overproduction and an increase in the viscosity of the mucus. In response to this, Heat and moisture exchangers were developed to compensate for the lost functions of the upper respiratory tract and their effect on the patients' respiratory performance in addition to their quality of life. METHODS: The case records of 48 patients undergoing total laryngectomy were reviewed and data concerning demographics, surgical details, post-operative care requirements and adverse events was retrieved. Post hoc analysis of the case patients was undertaken to identify any benefit of using a heat and moisture exchanger (HME) system with particular reference to post-operative respiratory outcomes. RESULTS: There was no significant difference between case and control subjects based on demographics, extent of surgery or need for flap repair. 16 patients had used a HME and 32 patients had used external humidification (EH). Of those experiencing mucous plugging, only 3/24 (12.5 %) had used a HME system, in contrast to 21/24 (87.5 %) who used EH (Chi square = 9.375, p = 0.002). The odds ratio of having an adverse event if not using HME was 8.27 (CI = 1.94 - 35.71). Use of HME also significantly reduced the number of days requiring physiotherapy (1.75 days vs. 3.20 days, p = 0.034). CONCLUSION: Use of an HME system can reduce in-hospital complications, in particular episodes of mucus plugging, and post-operative care requirements. Furthermore, there is a cost benefit to using HME systems that warrants more widespread introduction of these devices in head and neck surgery centers.

Plugs of the Air Passages: A Clinicopathologic Review.

Although mucus is a normal product of the tracheobronchial tree, some diseases of the respiratory tract are characterized by unusually thick (inspissated) forms of mucus that accumulate within the airways. These are known as mucus plugs. The pathologic composition of these plugs is surprisingly diverse and, in many cases, correlates with distinctive clinical, radiologic, and bronchoscopic findings. The best-known conditions that involve mucus plugs are allergic bronchopulmonary aspergillosis, plastic bronchitis, and asthma. Other lung diseases occasionally associated with plugs within the airways include Aspergillus tracheobronchitis, hyper-IgE syndrome, exogenous lipoid pneumonia, pulmonary alveolar proteinosis, and chronic eosinophilic pneumonia. In this review, we describe and illustrate the bronchoscopic, pathologic, and imaging findings in respiratory disorders characterized by mucus plugs or plugs composed of other similar materials. Recognition of the characteristic appearance and differential diagnosis of mucus plugs will hopefully facilitate diagnosis and management of these diseases.

Efecto de la rhDNasa sobre la obstrucción bronquial irreversible en adultos con asma grave / Effect of rhDNase on irreversible bronchial obstruction in severe adult asthma

Introducción: En algunos pacientes asmáticos la obstrucción de las vías aéreas no puede ser revertida por tratamiento broncodilatador y/o corticosteroideo. Esta obstrucción irreversible se ha atribuido a la remodelación de las vías aéreas, pero otros mecanismos, como el taponamiento mucoso, no se han explorado. Objetivo: Evaluar si la rhDNasa, enzima ampliamente usada para fluidificar el moco respiratorio en la fibrosis quística, mejora las variables espirométricas y la calidad de vida de pacientes con asma grave. Pacientes y métodos: Diez pacientes adultos (6 mujeres) con asma grave, dependientes de corticosteroides, recibieron nebulizaciones diarias de 2.5 mg de rhDNasa durante 14-28 días. Se realizaron espirometrías por lo menos cada semana, evaluando la capacidad vital forzada (FVC), el volumen espiratorio forzado al primer segundo (FEV1, la relación FEV1/ FVC y el flujo espiratorio máximo (PEF). Los cambios espirométricos se evaluaron mediante análisis de regresión. Se aplicó un cuestionario de calidad de vida antes y al final del tratamiento. Resultados: Las variables espirométricas no cambiaron en la mayoría de los pacientes. Sin embargo, al menos un paciente tuvo mejoría de la función pulmonar, de acuerdo con las pendientes ascendentes estadísticamente significativas en la FVC, el FEV1 y la relación FEV1/FVC. Aunque otros sujetos también tuvieron cambios ascendentes (2 pacientes) o descendentes (2 pacientes) de las pendientes, éstos sólo ocurrieron en una de las variables espirométricas. Como grupo, los pacientes mostraron tendencia a la mejoría en la calidad de vida. Conclusiones: Aunque la rhDNasa no modifica la obstrucción bronquial irreversible en la gran mayoría de los pacientes con asma grave, una pequeña proporción de ellos podría obtener algún efecto benéfico.

Background: In some asthma patients airway obstruction can not be reverted by bronchodilator and/ or corticosteroid treatment. This irreversible obstruction has been attributed to the remodeling process of airways, but other mechanisms such as mucus plugging have not been explored. Objective: To evaluate if rhDNase, an enzyme extensively used to fluidize the mucus in cystic fibrosis, improves spirometric variables and quality of life of asthmatic patients. Patients and methods: Ten adult patients (6 females) with severe corticosteroid-dependent asthma received daily nebulizations of 2.5 mg rhDNase during 14-28 days. Spirometries were performed at least at weekly intervals to evaluate the forced vital capacity (FVC), forced expiratory flow at the first second (FEV1, the FEV1/FVC ratio and peak expiratory flow (PEF). Changes in spirometric variables were assessed by regression analysis. An asthma quality of life questionnaire was applied before and at the end of treatment. Results: Spirometric variables did not change in most patients. However, pulmonary function improved in one patient, according to the statistically significant ascending slopes in FVC, FEV1 and FEV1/FVC. Although other subjects also had ascending (2 patients) or descending (2 patients) slopes, these changes only occurred in one spirometric variable. As a group, there was a trend for improvement in quality of life. Conclusions: Although rhDNase does not modify the irreversible bronchial obstruction in most patients with severe asthma, a small proportion of them might obtain some beneficial effect.