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Editorial |

Measuring Eosinophils to Make Treatment Decisions in Asthma FREE TO VIEW

Parameswaran Nair, MD, PhD; Paul M. O’Byrne, MB, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: P. N. is supported by the Frederick E. Hargreave Teva Innovation Chair in Airway Diseases. P. M. O. and P. N. are supported by the AllerGen National Centre of Excellence. Both P. N. and P. M. O. have held grants-in-aid from GSK for the investigation of mepolizumab. P. N. also reports grants from AstraZeneca, Sanofi, Teva, Novartis, Boehringer Ingelheim, and Roche, and honoraria for consultancies and lectures from Sanofi, Roche, Teva, AstraZeneca, Knopp, and Daiichi Sankyo. P. M. O. also reports grants and personal fees from AstraZeneca; personal fees from Chiesi, Boehringer Ingelheim, GSK, MedImmune, Merck, Takeda, and Abbott; and grants from Amgen, Novartis, Genentech, Axican, and Alakos outside of the submitted work.

Division of Respirology, Department of Medicine, McMaster University and St Joseph’s Healthcare, Hamilton, ON, Canada

CORRESPONDENCE TO: Paul M. O’Byrne, MB, FCCP, McMaster University Medical Centre, 1280 Main St W, Hamilton, ON, Canada, L8S 4L8


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


Chest. 2016;150(3):485-487. doi:10.1016/j.chest.2016.07.009
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The recognition of the association between eosinophils and asthma is not new. Following its discovery by Jones in 1846 and Ehrlich’s identification of its proclivity for aniline dyes to stain its granules, the progress in elucidating the biological characteristics of eosinophils has been described in four phases. The first related to the refinement of staining techniques; the second was the description of the association between eosinophils and allergic diseases, including asthma; the third related to the granular chemical and biological features of eosinophils; and the fourth is the current era of the development of strategies to specifically target the molecular pathways that are involved in the development, maturation, and trafficking of eosinophils.

Long before the availability of the first monoclonal antibody to target eosinophils, the association between asthma severity and the intensity of eosinophilia in peripheral blood, as a surrogate of airway eosinophilia, was identified. Over the years, astute clinicians like Brown recognized the clinical benefit of monitoring eosinophils in sputum rather than blood as a predictor of response to treatment with corticosteroids in patients with asthma or COPD. Since this technique was qualitative, a clinical research program led by Drs Hargreave and Dolovich developed and standardized a method to quantify eosinophil count in cytospin cell samples of dispersed saliva-free sputum. This technique has since been modified and adapted by a number of laboratories worldwide. For > 2 decades, practice in our clinics has relied on a quantitative eosinophil count in sputum to guide the use of corticosteroids in a variety of airway diseases, such as severe asthma, COPD, and chronic cough.

Although the presence of eosinophils in sputum is a predictor of response to corticosteroids in asthma and COPD, it was unclear if eosinophils were directly contributing to the pathobiological aspects of disease. The identification, cloning, and characterization of the IL-5 gene and protein led to the development of two monoclonal antibodies (mepolizumab and reslizumab) directed against IL-5, which were very effective in decreasing eosinophil numbers in peripheral blood and in the airway tissue and lumen. However, early clinical trials in patients with asthma were disappointing. This was likely because the patients selected for the study did not have eosinophils as major effector cells contributing to their disease. Subsequently, two clinical trials, in patients with severe asthma, who were identified as having significant eosinophils in their sputum, showed mepolizumab to be very effective in decreasing asthma exacerbations. This has since been demonstrated with reslizumab as well.

Because of the perceived difficulty in implementing quantitative cell counts in sputum in clinical practice, and because measurements of blood eosinophils are readily available, the utility of eosinophil counts in blood has been revisited. Not surprisingly, there is a modest correlation between eosinophil numbers in the airway and those in the blood, but this gets weaker as asthma gets more severe and as patients are exposed to higher doses of corticosteroids. Nevertheless, a number of recent clinical trials have shown that patients with moderate to severe asthma and an elevated peripheral blood eosinophil count derive significant benefit for exacerbation reduction with mepolizumab,, reslizumab, or benralizumab, which is a monoclonal antibody directed against the α-subunit of the IL-5 receptor.

There are still a number of unresolved issues related to the application of blood eosinophil counts in clinical practice. These issues include (1) the association between clinical outcomes, such as asthma exacerbations or FEV1, and baseline blood eosinophilia; (2) the level of baseline eosinophils that predicts a response to treatment with an anti-IL5 monoclonal antibody; (3) the number of times this would have to be demonstrated to be confident of a clinical response; and (4) perhaps most importantly, whether blood eosinophils are helpful in monitoring the course of therapy, as opposed to initiating therapy. This is particularly relevant in patients with more severe disease, who may have persistent sputum eosinophilia and evidence of eosinophilic activity (degranulation and eosinophil peroxidase release) but a normal blood eosinophil count.

Ortega et al tried to address the second of these questions by performing a post hoc analysis of data from two randomized double-blind, placebo-controlled studies of mepolizumab. The doses of mepolizumab differed in these studies. In the Mepolizumab for severe eosinophilic asthma (DREAM) trial, IV mepolizumab 75 mg, 250 mg, or 750 mg was evaluated, whereas in the Mepolizumab as Adjunctive Therapy in Patients With Severe Asthma (MENSA) trial, 75 mg IV or 100 mg subcutaneously was studied. In addition to standard care (high-dose inhaled corticosteroids plus ≥ one additional controller with or without daily oral corticosteroids), these doses were given to patients with a history of at least two severe asthma exacerbations in the previous year and raised peripheral blood eosinophil counts. In the DREAM trial, sputum eosinophils were enumerated in 14% of patients. The study by Ortega et al examined the effect of treatment (all doses combined) on the annualized rate of exacerbations in patients stratified by baseline eosinophil counts (≥ 150 cells/μL, ≥ 300 cells/μL, ≥ 400 cells/μL, and ≥ 500 cells/μL) and baseline blood eosinophil ranges (< 150 cells/μL, ≥ 150 cells/μL to < 300 cells/μL, ≥ 300 cells/μL to < 500 cells/μL, and ≥ 500 cells/μL). The main observation was that the asthma exacerbation rate reduction with mepolizumab increased progressively from 52% in patients with a baseline blood eosinophil count of at least 150 cells/μL to 70% in patients with a baseline count of at least 500 cells/μL. A similar gradation in exacerbation reduction was observed with baseline eosinophil count ranges (26% for < 150 cells/μL to 70% for ≥ 500 cells/μL). Thus, it is clear from this analysis that when exacerbation rates are modeled as a function of blood eosinophils and measured on a continuous scale, the higher the level of blood eosinophil count, the greater the treatment response to anti-IL5 therapy. A similar relationship between blood eosinophil counts and treatment response has been reported with reslizumab and benralizumab. The data that are currently available to us do not allow us to derive any inferences as to whether a particular cutoff value of blood eosinophil count (eg, > 150 cells/μL or, historically, > 300 cells/μL for mepolizumab, > 300 cells/μL for benralizumab or > 400 cells/μL for reslizumab) is specific to the treatment responses of all of these monoclonal antibodies.

A second important aspect of the analysis reported by Ortega et al is that the exacerbation rate reductions were similar for different doses of mepolizumab irrespective of baseline eosinophil counts. It is important to examine these data in relation to the dose of corticosteroids at baseline. Overall, fewer than one-third of patients (31% in the DREAM study and 25% in the MENSA study) were receiving maintenance oral corticosteroids. In patients who are taking daily prednisone and who have high blood and sputum eosinophil counts, low doses of mepolizumab do not suppress sputum eosinophilia in approximately 50% of patients, and they have more modest exacerbation reduction and prednisone sparing, compared with patients whose sputum eosinophilia is suppressed. More information is necessary to compare the utility of sputum and blood eosinophil counts in monitoring response to therapy in patients with prednisone-dependent eosinophilic asthma.

In conclusion, patients who continue to be symptomatic despite being adherent to high doses of corticosteroids and who continue to have a persistently high peripheral blood eosinophil count now have another treatment option with an anti-IL-5 monoclonal antibody. The thresholds for the dose of corticosteroids being used by the patient and the eosinophil count in peripheral blood to support initiation of treatment with these more expensive therapies is unclear; however, it is clear that the higher the peripheral blood eosinophil count, the greater the benefits of therapy. In patients with more severe asthma who are dependent on oral corticosteroids, monitoring of disease by peripheral blood eosinophil counts alone (which may be normal), without considering airway eosinophil numbers and activity, may lead to an incorrect decision about the value of initiating treatment with an anti-IL-5 monoclonal antibody.

References

Gleich GJ. historical overview and perspective on the role of the eosinophil in health and disease. In: Rosenberg H, Lee JJ, eds.Eosinophils in Health and Disease. San Diego, CA: Academic Press; 2012:1-11.
 
Horn R.H. .Robin E.D. .Theodore J. .Van Kessel A. . Total eosinophil counts in the management of bronchial asthma. N Engl J Med. 1975;292:1152-1155 [PubMed]journal. [CrossRef] [PubMed]
 
Brown H.M. . Treatment of chronic asthma with prednisolone; significance of eosinophils in the sputum. Lancet. 1958;2:1245-1247 [PubMed]journal. [PubMed]
 
Lim H.F. .Nair P. . The evolution of sputum cytometry to assess bronchitis. Can Respir J. 2013;20:415-416 [PubMed]journal. [CrossRef] [PubMed]
 
D'silva L. .Hassan N. .Wang H.Y. .et al Heterogeneity of bronchitis in airway diseases in tertiary care clinical practice. Can Respir J. 2011;18:144-148 [PubMed]journal. [CrossRef] [PubMed]
 
Brightling C.E. .Green R.H. .Pavord I.D. . Biomarkers predicting response to corticosteroid therapy in asthma. Treat Respir Med. 2005;4:309-316 [PubMed]journal. [CrossRef] [PubMed]
 
O'Byrne P.M. . The demise of anti IL-5 for asthma, or not. Am J Respir Crit Care Med. 2007;176:1059-1060 [PubMed]journal. [CrossRef] [PubMed]
 
Nair P. .Pizzichini M.M. .Kjarsgaard M. .et al Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985-993 [PubMed]journal. [CrossRef] [PubMed]
 
Haldar P. .Brightling C.E. .Hargadon B. .et al Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973-984 [PubMed]journal. [CrossRef] [PubMed]
 
Castro M. .Mathur S. .Hargreave F. . Res-5-0010 Study Groupet al Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184:1125-1132 [PubMed]journal. [CrossRef] [PubMed]
 
Wagener A.H. .de Nijs S.B. .Lutter R. .et al External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015;70:115-120 [PubMed]journal. [CrossRef] [PubMed]
 
Mukherjee M. .Nair P. . Blood or sputum eosinophils to guide asthma therapy? Lancet Respir Med. 2015;3:824-825 [PubMed]journal. [CrossRef] [PubMed]
 
Pavord I.D. .Korn S. .Howarth P. .et al Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380:651-659 [PubMed]journal. [CrossRef] [PubMed]
 
Ortega H.G. .Liu M.C. .Pavord I.D. . MENSA Investigatorset al Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207 [PubMed]journal. [CrossRef] [PubMed]
 
Castro M. .Zangrilli J. .Wechsler M.E. .et al Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:355-366 [PubMed]journal. [CrossRef] [PubMed]
 
Castro M. .Wenzel S.E. .Bleecker E.R. .et al Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014;2:879-890 [PubMed]journal. [CrossRef] [PubMed]
 
Smith S.G. .Chen R. .Kjarsgaard M. .et al Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016;137:75-86 [PubMed]journal. [CrossRef] [PubMed]
 
Ortega H.G. .Yancey S.W. .Mayer B. .et al Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016;4:549-556 [PubMed]journal. [CrossRef] [PubMed]
 
Sehmi R. .Smith S.G. .Kjarsgaard M. .et al Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma. Clin Exp Allergy. 2016;46:793-802 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Gleich GJ. historical overview and perspective on the role of the eosinophil in health and disease. In: Rosenberg H, Lee JJ, eds.Eosinophils in Health and Disease. San Diego, CA: Academic Press; 2012:1-11.
 
Horn R.H. .Robin E.D. .Theodore J. .Van Kessel A. . Total eosinophil counts in the management of bronchial asthma. N Engl J Med. 1975;292:1152-1155 [PubMed]journal. [CrossRef] [PubMed]
 
Brown H.M. . Treatment of chronic asthma with prednisolone; significance of eosinophils in the sputum. Lancet. 1958;2:1245-1247 [PubMed]journal. [PubMed]
 
Lim H.F. .Nair P. . The evolution of sputum cytometry to assess bronchitis. Can Respir J. 2013;20:415-416 [PubMed]journal. [CrossRef] [PubMed]
 
D'silva L. .Hassan N. .Wang H.Y. .et al Heterogeneity of bronchitis in airway diseases in tertiary care clinical practice. Can Respir J. 2011;18:144-148 [PubMed]journal. [CrossRef] [PubMed]
 
Brightling C.E. .Green R.H. .Pavord I.D. . Biomarkers predicting response to corticosteroid therapy in asthma. Treat Respir Med. 2005;4:309-316 [PubMed]journal. [CrossRef] [PubMed]
 
O'Byrne P.M. . The demise of anti IL-5 for asthma, or not. Am J Respir Crit Care Med. 2007;176:1059-1060 [PubMed]journal. [CrossRef] [PubMed]
 
Nair P. .Pizzichini M.M. .Kjarsgaard M. .et al Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985-993 [PubMed]journal. [CrossRef] [PubMed]
 
Haldar P. .Brightling C.E. .Hargadon B. .et al Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973-984 [PubMed]journal. [CrossRef] [PubMed]
 
Castro M. .Mathur S. .Hargreave F. . Res-5-0010 Study Groupet al Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184:1125-1132 [PubMed]journal. [CrossRef] [PubMed]
 
Wagener A.H. .de Nijs S.B. .Lutter R. .et al External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015;70:115-120 [PubMed]journal. [CrossRef] [PubMed]
 
Mukherjee M. .Nair P. . Blood or sputum eosinophils to guide asthma therapy? Lancet Respir Med. 2015;3:824-825 [PubMed]journal. [CrossRef] [PubMed]
 
Pavord I.D. .Korn S. .Howarth P. .et al Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380:651-659 [PubMed]journal. [CrossRef] [PubMed]
 
Ortega H.G. .Liu M.C. .Pavord I.D. . MENSA Investigatorset al Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207 [PubMed]journal. [CrossRef] [PubMed]
 
Castro M. .Zangrilli J. .Wechsler M.E. .et al Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:355-366 [PubMed]journal. [CrossRef] [PubMed]
 
Castro M. .Wenzel S.E. .Bleecker E.R. .et al Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014;2:879-890 [PubMed]journal. [CrossRef] [PubMed]
 
Smith S.G. .Chen R. .Kjarsgaard M. .et al Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016;137:75-86 [PubMed]journal. [CrossRef] [PubMed]
 
Ortega H.G. .Yancey S.W. .Mayer B. .et al Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016;4:549-556 [PubMed]journal. [CrossRef] [PubMed]
 
Sehmi R. .Smith S.G. .Kjarsgaard M. .et al Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma. Clin Exp Allergy. 2016;46:793-802 [PubMed]journal. [CrossRef] [PubMed]
 
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