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Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert Greig reports a relationship with AstraZeneca UK Limited that includes: speaking and lecture fees. Chris RuiWen Kuo reports a relationship with AstraZeneca UK Limited that includes: speaking and lecture fees. Chris RuiWen Kuo reports a relationship with Chiesi Ltd that includes: consulting or advisory. Chris RuiWen Kuo reports a relationship with GSK that includes: non-financial support. Rory Chan reports a relationship with AstraZeneca UK Limited that includes: speaking and lecture fees and travel reimbursement. Rory Chan reports a relationship with Vitalograph UK Ltd that includes: consulting or advisory. Rory Chan reports a relationship with Thorasys that includes: speaking and lecture fees. Brian Lipworth reports a relationship with GSK that includes: non-financial support. Brian Lipworth reports a relationship with AstraZeneca UK Limited that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Brian Lipworth reports a relationship with Sanofi UK that includes: speaking and lecture fees. Brian Lipworth reports a relationship with Circassia Pharmaceuticals Plc that includes: consulting or advisory and speaking and lecture fees. Brian Lipworth reports a relationship with Teva UK Ltd that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Brian Lipworth reports a relationship with Chiesi Ltd that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Brian Lipworth reports a relationship with Lupin Healthcare UK Ltd that includes: consulting or advisory. Brian Lipworth reports a relationship with Glenmark Pharmaceuticals Ltd that includes: consulting or advisory. Brian Lipworth reports a relationship with Dr Reddy's Laboratories UK Ltd that includes: consulting or advisory. Brian Lipworth reports a relationship with Sandoz UK Ltd that includes: consulting or advisory. Brian Lipworth reports a relationship with Boehringer Ingelheim Ltd that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Brian Lipworth reports a relationship with Mylan Laboratories Ltd that includes: consulting or advisory and speaking and lecture fees. The son of Dr Brian Lipworth is presently an employee of AstraZeneca. BJL. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Airway hyperresponsiveness (AHR) is a hallmark of persistent asthma. However, effects of IL-4/13 blockade with dupilumab (Dupi) on AHR are unknown., Objectives: This study sought to investigate the effect of 12 weeks of Dupi on AHR, asthma control, and quality of life., Methods: After a 4-week run-in on beclomethasone/formoterol maintenance and reliever therapy (baseline), participants with uncontrolled type-2 high severe asthma received open-label Dupi 300 mg twice weekly, for 12 weeks. Mannitol challenges were done at baseline, 2, 4, and 12 weeks and following a 12-week washout. Study power was 90% to detect 1 doubling difference (dd) in mannitol PD 10 FEV 1 threshold at week 12., Results: Of 24 enrolled patients, 23 completed per protocol mannitol AHR at 12 weeks. Mean baseline values were age 52 years, FEV 1 82%, Asthma Control Questionnaire 2.53, mini-Asthma Quality of Life Questionnaire 3.84, inhaled corticosteroids dose 1300 μg; fractional exhaled nitric oxide 50 parts per billion; Eosinophils 552 cells/μL. Mannitol sensitivity as PD 10 was significantly attenuated by week 4, and reactivity as response dose ratio by week 2. After 12 weeks of Dupi, mean dd for PD 10 was 1.78 (95% CI: 1.23-2.33; P < .001) and for response dose ratio was 3.40 (95% CI: 2.25-4.55; P < .001). At week 12, Asthma Control Questionnaire improved by 1.73 (95% CI: 1.11-2.36; P < .001); mini-Asthma Quality of Life Questionnaire by 2.31 (95% CI: 1.57-3.05; P < .001); FEV 1 by 0.39 L (95% CI: 0.11-0.67; P < .01); and PEF by 61 L/min (95% CI: 24-98; P < .001). Beclomethasone/formoterol maintenance and reliever therapy requirement was reduced at 12 weeks versus baseline by 1.7 puffs/d (95% CI: 0.7-2.7; P < .01). After washout at week 24, the dd change was 0.96 (95% CI: 0.02-1.91; P < .05)., Conclusions: Dupilumab attenuated mannitol AHR to a clinically relevant degree despite concomitant inhaled corticosteroid reduction, combined with improvements in lung function, asthma control, and quality of life., Competing Interests: Disclosure statement Funded by an investigator-led grant from Sanofi. Sanofi had no input into design, execution, data analysis or manuscript writing. Disclosure of potential conflicts of interest: C. RW. Kuo reports personal fees from AstraZeneca, personal fees from Chiesi, and nonfinancial support from GSK outside the submitted work. R. Chan reports personal fees (talks) and support attending ERS from AstraZeneca, personal fees (consulting) from Vitalograph, and personal fees (talks) from Thorasys. B. J. Lipworth reports nonfinancial support (equipment) from GSK; grants, personal fees (consulting, talks, advisory board), other support (attending American Thoracic Society and ERS) from AstraZeneca; personal fees (talks, consulting) from Sanofi and Regeneron, personal fees (consulting, talks, advisory board) from Circassia; grants, personal fees (consulting, talks, advisory board), other support (attending ERS) from Teva; personal fees (talks, consulting), grants, and other support (attending ERS and British Thoracic Society) from Chiesi; personal fees (consulting) from Lupin, personal fees (consulting) from Glenmark; personal fees (consulting) from Dr Reddy; personal fees (consulting) from Sandoz; grants, personal fees (consulting, talks, advisory board), other support (attending British Thoracic Society) from Boehringer Ingelheim; and grants and personal fees (advisory board, talks) from Mylan outside of the submitted work. B. J. Lipworth’s son is presently an employee of AstraZeneca. K. E. Stewart declares that she has no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosures Dr Kuo reports personal fees from AstraZeneca, personal fees from Chiesi, and nonfinancial support from GlaxoSmithKline outside the submitted work. Dr Chan reports personal fees (talks) and support attending the European Respiratory Society (ERS) from AstraZeneca, personal fees (consulting) from Vitalograph, and personal fees (talks) from Thorasys. Dr Lipworth reports nonfinancial support (equipment) from GlaxoSmithKline; grants, personal fees (consulting, talks, and advisory board), and other support (attending American Thoracic Society and ERS) from AstraZeneca; personal fees (talks and consulting) from Sanofi; personal fees (consulting, talks and advisory board) from Circassia; grants, personal fees (consulting, talks, and advisory board), and other support (attending ERS) from Teva; personal fees (talks and consulting), grants, and other support (attending ERS and British Thoracic Society) from Chiesi; personal fees (consulting) from Lupin; personal fees (consulting) from Glenmark; personal fees (consulting) from Dr Reddy; personal fees (consulting) from Sandoz; grants, personal fees (consulting, talks, and advisory board), and other support (attending British Thoracic Society) from Boehringer Ingelheim; and grants and personal fees (advisory board and talks) from Mylan outside of the submitted work. Moreover, Dr Lipworth's son is currently an employee of AstraZeneca. Dr Stewart has no conflicts of interest to report.

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.)

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.)

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 β-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 FEV 1 by 10% (PD 10 ) 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 FEV 1 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 PD 10 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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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.)

Background: Smoking worsens underlying asthma inflammation and also induces resistance to inhaled corticosteroids (ICS). Small airways dysfunction measured by impulse oscillometry (IOS) is associated with worse control., Objectives: We investigated the effects on small airways of adding long-acting beta-agonist (LABA) alone or with long-acting muscarinic antagonist (LAMA) to ICS in asthmatic smokers., Methods: Sixteen current smokers were enrolled: mean age 44 year, FEV1 84%, FEF25-75 47%, R5 158%, ACQ 1.69, 20 pack year . Patients were converted to a reference ICS as HFA-BDP during initial run-in at median dose of 800 µg/day. Open label olodaterol 5 µg od (OLO) or olodaterol 5 µg/tiotropium 5 µg od (OLO/TIO) was added to HFA-BDP for median duration of 3 weeks in a randomized cross over design, including run-in and washout periods on HFA-BDP. IOS and spirometry were measured after each treatment (BDP/OLO/TIO or BDP/OLO) and at baseline after run-in and washout (BDP)., Results: After chronic dosing, IOS outcomes at trough except for R20 were all significantly improved with OLO/TIO compared to OLO. For the primary end-point of total airway resistance (as R5), the mean difference (95%CI) at trough was 0.06 (0.015-0.10) kPa/l/s, peripheral airways resistance (as R5-R20) 0.03 (0.003-0.06) kPa/l/s, peripheral lung reactance area (as AX) 0.38 (0.08-0.68) kPa/l and resonant frequency (as RF) 2.28 (0.45-4.12) Hz. FEF25-75 at trough was also better with OLO/TIO vs TIO: 0.93 (0.86 - 0.95) l/s while FEV1 was not different., Conclusions: ICS/LABA/LAMA was superior to ICS/LABA on trough small airway outcomes in asthma patients who smoke., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Broadly speaking, pharmacological treatments for COVID-19 can be divided into those acting on upstream pathways early on in the disease process via suppression of viral replication or by inhibiting cell entry, and those acting on downstream pathways later on via selective attenuation of the adaptive immune cytokine-mediated inflammatory response. The antiviral drug remdesivir has been shown to shorten duration of disease while interferon beta-1b may speed up viral clearance. The results with hydroxychloroquine have thus far been rather disappointing. Trials with selective cytokine blockers including anti-interleukin-1 (anti-IL-1) and anti-interleukin-6 (anti-IL-6), have shown some promise in more severe cases, with further confirmation being required from large-scale phase-3 randomised controlled trials. The likelihood is that combination therapy addressing both upstream and downstream pathways may be required to prevent progression of severe COVID-19 infection in susceptible older patients with comorbidities and we believe further studies are now warranted to specifically target such at-risk groups who are more prone to worse outcomes., Competing Interests: Dr Kuo reports personal fees from AstraZeneca, personal fees from Chiesi, personal fees from Circassia, outside the submitted work. Dr Lipworth reports no competing interests with respect to the submitted work, and reports personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Chiesi and Sanofi, personal fees from Cipla, Novartis, Lupin and Dr Reddys, from Glenmark, grants and personal fees from Teva and Mylan, personal fees from Vectura, outside the submitted work; Dr Lipworth’s son is an employee of AstraZeneca.