Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma.

BACKGROUND: Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma. OBJECTIVE: We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design. METHODS: After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting ß-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV1 by 10% (PD10) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire. RESULTS: Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV1 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) µg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P < .01) change in PD10 at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/µL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab. CONCLUSION: Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients.

Nodules, nodes and non-functioning macrophages: A risk with ibrutinib therapy.

We describe the case of a 70-year-old never smoker with chronic lymphocytic leukaemia, treated with single agent ibrutinib therapy. Chest imaging noted nodular change and mediastinal lymphadenopathy, which showed avid uptake on positron emission tomography and guided subsequent biopsies (bronchoscopy using endobronchial ultrasound, mediastinoscopy). Despite negative aspergillus blood immunology tests, he was found to have invasive aspergillosis, which is a known risk with ibrutinib therapy. He has since been successfully treated with antifungal therapy.

Pragmatic Clinical Perspective on Biologics for Severe Refractory Type 2 Asthma.

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.