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Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma - 03/03/23

Doi : 10.1016/j.jaci.2022.10.028 
Rory Chan, MBChB, Chris RuiWen Kuo, MBChB, Sunny Jabbal, MD, Brian J. Lipworth, MD
 From the Scottish Centre for Respiratory Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom 

Corresponding author: Brian J. Lipworth, MD, Scottish Centre for Respiratory Research, Ninewells Hospital and Medical School, University of Dundee, DD1 9SY, Scotland, United Kingdom.Scottish Centre for Respiratory ResearchNinewells Hospital and Medical SchoolUniversity of DundeeDD1 9SYScotlandUnited Kingdom

Graphical abstract




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Abstract

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 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.

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Key words : Airway hyperresponsiveness, benralizumab, mannitol, severe asthma, asthma control, quality of life

Abbreviations used : ACQ, AHR, CI, DD, EDN, Feno, ICS, MCID, Mini-AQLQ, PD10, PEF, RDR, SEA


Plan


 This study was externally funded as an unrestricted research grant by AstraZeneca to the University of Dundee.
 Disclosure of potential conflict of interest: R. Chan reports personal fees (talks) and other support (attending European Respiratory Society [ERS]) from AstraZeneca; and personal fees (talks) from Thorasys. C. R. W. Kuo reports personal fees (talks) from AstraZeneca, personal fees (advisory board) from Circassia, personal fees (talks) in relation to the submitted work, and personal fees (talks) and other support from Chiesi (attending British Thoracic Society [BTS]) outside of the submitted work. S. Jabbal reports personal fees from AstraZeneca and Chiesi (talks) and other support (attending BTS and ERS). B. J. Lipworth reports nonfinancial support (equipment) from GSK; 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 in relation to the submitted work; grants, personal fees (consulting, talks, advisory board), and other support (attending ERS) from Teva; personal fees (talks and consulting), grants, and other support (attending ERS and BTS) 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), and other support (attending BTS) from Boehringer Ingelheim; and grants and personal fees (advisory board and talks) from Mylan outside of the submitted work. In addition, the son of B. J. Lipworth is presently an employee of AstraZeneca.


© 2022  The Authors. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 151 - N° 3

P. 700 - mars 2023 Retour au numéro
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