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Airway hyper-responsiveness (AHR) is a tenet of the persistent asthma phenotype along with reversible airway obstruction and type 2 (T2) inflammation. Indirect acting challenges such as mannitol are more closely related to the underlying T2 inflammatory process as compared with direct challenges. In this review article, we summarise the current literature and explore the future role of mannitol AHR in clinical remission with biologics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Overuse of reliever as short-acting beta-agonist and associated underuse of controller as inhaled corticosteroid (ICS) administered via separate inhalers results in worse asthma outcomes. Such discordance can be obviated by combining both controller and reliever in the same inhaler. So-called anti-inflammatory reliever (AIR) therapy comprises the use of a single inhaler containing an ICS such as budesonide (BUD) in conjunction with a reliever as either albuterol (ALB) or formoterol (FORM), to be used on demand, with variable dosing driven by asthma symptoms in a flexible patient-centered regimen. Global guidelines now support the use of BUD-ALB as AIR therapy to reduce exacerbations, either on its own in mild asthma or in conjunction with fixed-dose maintenance ICS-long-acting beta-agonist in moderate to severe asthma. Using BUD-FORM on its own allows patients to seamlessly move in an intuitive flexible fashion between AIR and maintenance and reliever therapy, by stepping up and down the dosing escalator across a spectrum of asthma severities. Head-to-head clinical studies are indicated to compare BUD-FORM versus BUD-ALB as AIR in mild asthma, and also BUD-FORM as maintenance and reliever therapy versus BUD-ALB as AIR plus maintenance ICS-long-acting beta-agonist in moderate to severe asthma. Patients should be encouraged to make an informed decision in conjunction with their health care professional regarding the best therapeutic option tailored to their individual needs, which in turn is likely to result in long-term compliance and associated optimal asthma control., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A recent study demonstrated a significant correlation between bronchial biopsy airway remodeling and quantitative computed tomography looking at bronchial wall thickness., Objective: To identify clinical associations with bronchial wall thickness in moderate to severe asthma., Methods: Ninety-two respiratory physician-diagnosed Global Initiative for Asthma-defined patients with moderate to severe asthma were included in this retrospective cohort study. Blinded to all clinical data, 2 senior thoracic radiologists independently measured airway lumen and total airway area at 4 different bronchopulmonary segments using high-resolution computed tomography imaging. We calculated adjusted odds ratios with regard to the association of bronchial wall thickness with spirometry, oscillometry, exacerbations, and nasal polyps., Results: The pooled analysis for all 4 bronchopulmonary segments showed that an area under reactance curve greater than or equal to 1.0 kPa/L, an R5-R20 ratio (resistance heterogeneity between 5 and 20 Hz divided by total resistance [R5]) of 25% or more, having 2 or more exacerbations per year, and presence of nasal polyposis exhibited adjusted odds ratios of 3.54 (95% CI, 1.22-10.32), 2.89 (95% CI, 1.03-8.05), 4.17 (95% CI, 1.25-13.90), and 9.85 (95% CI, 2.33-41.74), respectively, in their association with a wall area thickness of 50% or more. These translated into a respective 72%, 65%, 76%, and 90% increased likelihood for a wall area thickness of 50% or more., Conclusions: Bronchial wall thickness is associated with peripheral airways resistance and reactance, severe exacerbations, and nasal polyposis in persistent asthma., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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 FEV 1 %, forced expiratory flow at 25% to 75% of FVC percent, and FEV 1 /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. FEV 1 /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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Biologics, including omalizumab, mepolizumab, benralizumab, and dupilumab, targeting downstream IgE, cytokines IL-5, and IL-4/13, respectively, have shown promising effects in terms of reduction in annualized asthma exacerbation rates (AER), oral corticosteroid-sparing effects, improvements in forced expiratory volume in 1 second, and improved Asthma Control Questionnaire scores. However, despite these welcome advances, approximately 30% of patients with severe asthma receiving biologics tailored to their specific downstream type 2 biomarkers, including total IgE, peripheral blood eosinophils, and fractional exhaled nitric oxide, do not experience meaningful improvements in their AER. Instead of blocking downstream cytokines, targeting upstream epithelial alarmins, including IL-33, thymic stromal lymphopoietin, and IL-25, has been proposed to tackle the immunologic heterogeneity of asthma. This review article aims to pragmatically summarize the latest key clinical data on antialarmin therapies in severe asthma and put these findings into context with regard to currently available downstream cytokine blockers., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with severe chronic rhinosinusitis with nasal polyps represent an unmet clinical need in terms of recurrent disease despite current medical and surgical therapy. Targeting type 2 inflammatory cytokines (IL4/5/13) appears to be a promising therapeutic approach for such patients akin to what has already been seen in severe asthma. An indirect comparison from phase 3 placebo-controlled trials has shown relative improvements in the coprimary end point of nasal polyp score (NPS) ranging from a 15% reduction (-0.8 units) with mepolizumab, 18% with omalizumab (-1.14 units), and 35% (-2.06 units) with dupilumab. This trend was mirrored by relative improvements in health status with the 22-item Sinonasal Outcome Test score showing a 21% reduction (-13.7 units) with mepolizumab, 27% (-16.1 units) with omalizumab, and 43% (-21.1 units) with dupilumab, all exceeding the minimal clinically important difference of 8.9 units. All biologics improved the coprimary end point of nasal airway blockage and also reduced the need for rescue medical and/or surgical polypectomy. We advocate performing real-life studies looking at the response to biologics in patients who are at increased risk for disease recurrence, including initial optimal medical and surgical polyp clearance before commencing biologics., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Patients with severe refractory asthma present a challenging clinical conundrum for practicing clinicians. Biologics that target key mediators in the type 2 inflammation cascade, including IL-4, IL-5, IL-13, and IgE, can be effective strategies for these patients. However, with various biologics available, choosing the optimal one for a particular patient becomes a nuanced decision. We propose a pragmatic algorithm that identifies the optimal biologic class for patients who have specific type 2 disease endotypes. Patients with eosinophilic endotypes fare well with anti-IL-5(rα) medications, comprising mepolizumab, benralizumab, and reslizumab because they have been shown to reduce exacerbations in severe eosinophilic asthma by approximately 50%. In patients with fractional exhaled nitric oxide-high endotypes, anti-IL-4rα such as dupilumab is deemed to be most effective and has demonstrated a 47% reduction in asthma exacerbations. For patients with severe uncontrolled allergic asthma, anti-IgE (omalizumab) is effective and has been shown to confer a 25% reduction in asthma exacerbations. Type 2 comorbidities including chronic rhinosinusitis with nasal polyps, atopic dermatitis, chronic idiopathic urticaria, and eosinophilic esophagitis are important to bear in mind before the prescription of biologics. Further head-to-head studies are indicated to compare biologics in patients with mixed endotypes according to peripheral blood eosinophils, fractional exhaled nitric oxide, and allergic status. The evidence strongly supports endotype-driven prescribing of biologics to achieve clinically relevant outcomes in severe refractory asthma and related comorbidities., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)