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Editorials: Point and Counterpoint |

Rebuttal From Dr Barnes FREE TO VIEW

Peter J. Barnes, DM, Master FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURE: The authors have reported to CHEST the following: P. J. B. has served on the scientific advisory boards of AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson & Johnson, Napp, Novartis, Takeda, Pfizer, Prosonix, Respivert, Teva, and Zambon and has received research funding from AstraZeneca, Boehringer-Ingelheim, Chiesi, Novartis, and Takeda.

Airway Disease Section, National Heart and Lung Institute, Imperial College, London, England

CORRESPONDENCE TO: Peter J. Barnes, DM, Master FCCP, Airway Disease Section, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, UK


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(1):21-22. doi:10.1016/j.chest.2016.09.025
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We both agree that poor adherence is the major reason for poor control of asthma and that true severe refractory asthma is rare. Asthma may also be difficult to control because of poor inhaler technique, comorbidities, and exposure to exacerbating factors. Dr O’Byrne suggests that patients with truly refractory asthma compose 5% to 8% of all patients with asthma, but recent accurate estimates suggest a figure of less than 4%. Of these patients, only a proportion (about 30%) have increased eosinophils in induced sputum, whereas others have increased neutrophils, a mixed granulocytic pattern, or no increase in inflammatory cells and therefore are presumably much less likely to respond to a specific anti-eosinophilic therapy. However, to classify the inflammatory phenotype of asthma, it is necessary to study induced sputum. This is technically demanding (especially in patients with severe disease), time consuming, and expensive with respect to staff costs, and not all patients with asthma are able to produce a suitable sputum sample. Another problem is that these inflammatory phenotypes of asthma are not stable; in a recent study, the phenotype in about half of patients with asthma changed on repeated testing. This means that induced sputum analysis is not practical in clinical practice. Determination of fractional exhaled nitric oxide is less invasive, is easy to perform in the clinic, and reflects airway eosinophilic inflammation, but results are affected by several factors, particularly cigarette smoking and the use of inhaled corticosteroids. Indeed, fractional exhaled nitric oxide is often used currently as a measurement of adherence to corticosteroid therapy. However, nitric oxide analyzers are relatively expensive so may not be available in most clinical practices. The simplest approach would be to measure eosinophils in blood, which is a readily available test, but the relationship between eosinophils in blood (total or differential counts) to eosinophils in sputum and the airways is not yet clear. Furthermore, inhaled corticosteroid therapy reduces eosinophils in blood.

I agree with Dr O’Byrne that anti-IL-5 and probably the anti-IL-4α receptor will be very useful for selected patients and have a good possibility of reducing exacerbations and the need for oral corticosteroids, yet they are unlikely to be sufficient therapies alone, and patients will still need to use inhaled corticosteroids and bronchodilators (usually as a combination inhaler). Apart from the problem of patient selection, there is an issue of cost. Anti-eosinophilic biologic agents are expensive, and it is difficult to show cost-effectiveness. For example, omalizumab is only cost-effective in the United States for patients having five or more exacerbations per year (or > 20 in-patient d/y), and such patients are rare. In the United Kingdom, the National Institute for Health and Care Excellence has not approved mepolizumab based on its poor cost-effectiveness, so this is likely to be a limiting factor in many countries. Oral drugs that block prostaglandin D2 (CRTh2) antagonists, such as fevipiprant, reduce eosinophils in sputum in patients with severe asthma and are likely to be more cost-effective, although their clinical impact has not yet been reported.

I am in agreement with Dr O’Byrne that the development of biologic agents that target eosinophilic inflammation has been an important advance in asthma therapy, but this approach is suitable for a very small proportion of patients with asthma, and even in these patients there may be cost issues. It would be unfortunate if the introduction of anti-eosinophil biologic agents turns out to be a very expensive alternative to improving asthma control by better adherence to existing relatively inexpensive therapies and checking and improving inhaler technique.

References

O'Byrne P.M. . Point: Will new anti-eosinophilic drugs be useful in asthma management? Yes. Chest. 2017;151:14-17 [PubMed]journal
 
Hekking P.P. .Wener R.R. .Amelink M. .Zwinderman A.H. .Bouvy M.L. .Bel E.H. . The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135:896-902 [PubMed]journal. [CrossRef] [PubMed]
 
Simpson J.L. .Scott R. .Boyle M.J. .Gibson P.G. . Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006;11:54-61 [PubMed]journal. [CrossRef] [PubMed]
 
Suarez-Cuartin G. .Crespo A. .Mateus E. .et al Variability in asthma inflammatory phenotype in induced sputum. Frequency and causes. Arch Bronconeumol. 2016;52:76-81 [PubMed]journal. [PubMed]
 
Westerhof G.A. .Korevaar D.A. .Amelink M. .et al Biomarkers to identify sputum eosinophilia in different adult asthma phenotypes. Eur Respir J. 2015;46:688-696 [PubMed]journal. [CrossRef] [PubMed]
 
Evans P.M. .O'Connor B.J. .Fuller R.W. .Barnes P.J. .Chung K.F. . Effect of inhaled corticosteroids on peripheral eosinophil counts and density profiles in asthma. J Allergy Clin Immunol. 1993;91:643-649 [PubMed]journal. [CrossRef] [PubMed]
 
Oba Y. .Salzman G.A. . Cost-effectiveness analysis of omalizumab in adults and adolescents with moderate-to-severe allergic asthma. J Allergy Clin.Immunol. 2004;114:265-269 [PubMed]journal. [CrossRef] [PubMed]
 
Gonem S. .Berair R. .Singapuri A. .et al Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med. 2016;4:699-707 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

O'Byrne P.M. . Point: Will new anti-eosinophilic drugs be useful in asthma management? Yes. Chest. 2017;151:14-17 [PubMed]journal
 
Hekking P.P. .Wener R.R. .Amelink M. .Zwinderman A.H. .Bouvy M.L. .Bel E.H. . The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135:896-902 [PubMed]journal. [CrossRef] [PubMed]
 
Simpson J.L. .Scott R. .Boyle M.J. .Gibson P.G. . Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006;11:54-61 [PubMed]journal. [CrossRef] [PubMed]
 
Suarez-Cuartin G. .Crespo A. .Mateus E. .et al Variability in asthma inflammatory phenotype in induced sputum. Frequency and causes. Arch Bronconeumol. 2016;52:76-81 [PubMed]journal. [PubMed]
 
Westerhof G.A. .Korevaar D.A. .Amelink M. .et al Biomarkers to identify sputum eosinophilia in different adult asthma phenotypes. Eur Respir J. 2015;46:688-696 [PubMed]journal. [CrossRef] [PubMed]
 
Evans P.M. .O'Connor B.J. .Fuller R.W. .Barnes P.J. .Chung K.F. . Effect of inhaled corticosteroids on peripheral eosinophil counts and density profiles in asthma. J Allergy Clin Immunol. 1993;91:643-649 [PubMed]journal. [CrossRef] [PubMed]
 
Oba Y. .Salzman G.A. . Cost-effectiveness analysis of omalizumab in adults and adolescents with moderate-to-severe allergic asthma. J Allergy Clin.Immunol. 2004;114:265-269 [PubMed]journal. [CrossRef] [PubMed]
 
Gonem S. .Berair R. .Singapuri A. .et al Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med. 2016;4:699-707 [PubMed]journal. [CrossRef] [PubMed]
 
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