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Blood or sputum eosinophils to guide asthma therapy?
Comment
Blood or sputum eosinophils to guide asthma therapy? Published Online October 20, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00419-1 See Articles page 849
Infiltration of airways by eosinophils and their degranulation in patients with asthma have been recognised since the late 19th century when Paul Ehrlich described methods for eosinophil staining. Not long after this, Gollasch recorded the association between eosinophils in sputum and asthma severity. Improvements in methods to disperse sputum and to obtain cytospins helped to quantitate eosinophils and to use counts to improve clinical care of patients with asthma. This work has improved our understanding of the pathogenesis, pathophysiology, and treatment of airway diseases. Additionally, it has helped to assess new monoclonal antibodies directed against interleukin 5 in patients with asthma, in whom eosinophils have a dominant pathobiological role.1 Despite this evidence, quantitative sputum counts are not widely used in clinical practice because of the perceived difficulties in setting up laboratories that can reliably process sputum. As an alternative, perhaps fuelled by the imminent availability of anti-interleukin-5 monoclonal antibodies for clinical use, blood eosinophil count has been described in recent literature as a useful biomarker to assess patients with asthma. Raised absolute eosinophil counts have been reported as a predictor of response to treatment with corticosteroids,2 anti-interleukin-5 monoclonal antibodies,3 and poor asthma control and exacerbations in large community-based epidemiological surveys.4 However, the use of blood eosinophil counts is not a new concept. Their association with asthma severity5 and their use in managing patients with mild-to-moderate asthma2 were described almost 40 years ago. Indeed, in
2006 we recommended prudence in decreasing doses of corticosteroids in well controlled patients with asthma who had raised blood eosinophil counts.6 In this issue of The Lancet Respiratory Medicine, David Price and colleagues7 address the question of the best cut-off values for blood eosinophil count to assess asthma control and severity. The authors report blood eosinophil counts and prospective annual disease burden in a retrospective analysis of over 130 000 patients from a general practice database in the UK. The authors found that 16% of the population had an eosinophil count greater than 400 cells per μL and that these patients were at a greater risk of severe asthma exacerbations and acute asthma-related respiratory events during the subsequent year compared with patients with lower counts. This observation emphasises the need to pay more attention to the humble eosinophil count, even in this ‘omics’ era. Using blood eosinophil count to identify patients at risk of exacerbations might be different from using it to adjust doses of anti-inflammatory therapies. In a large randomised controlled clinical trial, blood eosinophil count (examined in all 616 patients) was a better predictor than sputum eosinophil count (examined in only 86 patients) of response to treatment with mepolizumab.3 For a number of reasons, one has to be cautious when using blood eosinophil counts for the management of patients with more severe asthma; particularly those who need regular systemic corticosteroids. First, sputum eosinophil counts are a more sensitive marker of loss of asthma control than blood eosinophil counts.8 Second, although
A
B 6
r=–0·079 p=0·5661
Bias 0·4792, SD 1·232
4
40
2·894 30
Difference
Sputum eosinophils (%)
100
20
2 0·479
0 1
10
2
–2
3 –1·936
–4
0 0
0·3
0·6
0·9
1·0
1·5
2·0
Average
Blood eosinophils (× 109/L)
Figure: Association between sputum and blood eosinophils (A) Spearman correlation plotted between matched blood eosinophil counts and sputum eosinophil percentage from 54 well-characterised patients with severe uncontrolled eosinophilic asthma despite being on daily prednisone (median dose 10 mg daily [range 2·5–40]). (B) Altman-Bland plot comparing 54 matched blood and sputum eosinophil counts with the representation of the limits of agreement (dotted line), within 1·96 SD.
824
www.thelancet.com/respiratory Vol 3 November 2015
Comment
modest correlations have been reported between blood and sputum eosinophils, and raised blood eosinophil counts predict sputum eosinophilia,9 the correlation becomes weaker as asthma becomes more severe (appendix). In our own cohort of 54 patients who need daily prednisone for asthma control, there is no correlation and poor concurrence between sputum and blood eosinophil counts (figure). Indeed, patients with normal blood eosinophil counts but raised sputum eosinophils are reported to have lower forced expiratory volume in 1 s, greater airway responsiveness, and poorer asthma control than those with raised blood eosinophil count and normal sputum eosinophil count.10 Third, one of the reasons for the discordance between blood and sputum eosinophil levels in patients with severe asthma might be the persistence of sputum eosinophils in patients with normal blood eosinophil counts, facilitated by the proliferation of the newly described type 2 innate lymphoid cells that can elaborate eosinophilopoietic cytokines such as interleukin 5 and interleukin 13 locally within the airway.11 In patients whose asthma is being treated with anti-interleukin-5 monoclonal antibody given in low doses subcutaneously and monitored by observing blood eosinophil count, this situation might potentially be an indicator of inadequate tissue concentrations of the monoclonal antibody. This hypothesis needs to be investigated. Fourth, the intriguing observation of an increase in blood eosinophil count with the administration of monoclonal antibodies directed against interleukin 1312 despite clinical improvement brings into question the contribution of circulating eosinophils to asthma pathobiology in patients with moderate-to-severe asthma. Finally, eosinophil degranulation and activation might be more clinically relevant than absolute numbers. Eosinophil activation occurs as the cell moves from one compartment to another and is most evident (as shown by eosinophil peroxidase level) in the lumen than in blood.13 In conclusion, it is reasonable to acknowledge that blood eosinophils present practitioners with an easy biomarker to identify patients with asthma who are potentially at risk for an exacerbation. An absolute circulating eosinophil count of greater than 400 cells per μL in symptomatic patients who are compliant to high doses of inhaled or systemic corticosteroids could be a predictor of response to antiinterleukin-5 therapies. Sputum eosinophil counts of greater than 3% would be a more sensitive and reliable biomarker to guide corticosteroid and anti-interleukin-5 therapies www.thelancet.com/respiratory Vol 3 November 2015
in patients who are on daily systemic corticosteroids, particularly in those who remain symptomatic despite normal circulating eosinophil counts. Further research is needed to investigate if eosinophil activity would be a better biomarker than absolute count to guide therapy. Although anecdotal reports suggest the usefulness of using blood eosinophil count,14 a head-to-head comparison of treatment algorithms guided by blood versus sputum eosinophil count or activity might be necessary to provide recommendations on the best strategies to initiate and monitor novel antiinflammatory therapies, such as biologicals, in patients with severe eosinophilic asthma.
See Online for appendix
Manali Mukherjee, *Parameswaran Nair Department of Medicine, McMaster University & St Joseph’s Healthcare, Hamilton, Ontario, Canada [email protected] MM declares no competing interests. PN has received grants from GlaxoSmithKline, Novartis, AstraZeneca, and Teva, and has provided consultancy to AstraZeneca–MedImmune, Sanofi, Teva, Boehringer Ingelheim, Mitsubishi, Cipla, and Cellometrics; PN is listed on a patent for a sputum filtration device. PN is supported by a Canada Research Chair in Airway Inflammometry. 1
2 3
4
5 6
7
8 9
10
11
12 13
14
Nair P, Pizzichini M, Kjarsgaard M, et al. Mepolizumab for prednisonedependent asthma with sputum eosinophilia. N Engl J Med 2009; 360: 985–93. Horn BR, Robin ED, Theodore J, Van Kessel A. Total eosinophil counts in the management of bronchial asthma. N Engl J Med 1975; 292: 1152–55. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma: a multi-centre, double-blind, placebo-controlled trial. Lancet 2012; 380: 651–59. Tran TN, Khatry DB, Ke X, et al. High blood eosinophil count is associated with more frequent asthma attacks in asthma patients. Ann Allergy Asthma Immunol 2014; 113: 19–24. Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990; 323: 1033–39. Belda J, Nair P, Lemiere C, Kamada D, O’Byrne PM, Hargreave FE. Predictors of loss of asthma control induced by corticosteroid withdrawal. Can Respir J 2006; 13: 129–33. Price DB, Rigazio A, Campbell JD, et al. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med 2015; published online Oct 20. http://dx.doi. org/10.1016/S2213-2600(15)00367-7. Pizzichini M, Pizzichini E, Clelland L, et al. Prednisone-dependent asthma: inflammatory indices in induced sputum. Eur Respir J 1999; 13: 15–21. Fowler SJ, Tavernier G, Niven R, et al. High blood eosinophil counts predict sputum eosinophilia in patients with severe asthma. J Allergy Clin Immunol 2015; 135: 822–24.e2. Schleich FN, Chevremont A, Paulus V, et al. Importance of concomitant local and systemic eosinophilia in uncontrolled asthma. Eur Respir J 2014; 44: 97–108. Smith SG, 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 2015; published online July 17. DOI: 10.1016/j.jaci.2015.05.037. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365: 1088–98. Nair P, Ochkur SI, Protheroe C, et al. Eosinophil peroxidase in sputum represents a unique biomarker of airway eosinophilia. Allergy 2013; 68: 1177–84. Wark PAB, McDonald VM, Gibson PG. Adjusting prednisone using blood eosinophils reduces exacerbations and improves asthma control in difficult patients with asthma. Respirology 2015; published online Aug 12. DOI:10.1111/resp.12602.
825
Blood or sputum eosinophils to guide asthma therapy? Published Online October 20, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00419-1 See Articles page 849
Infiltration of airways by eosinophils and their degranulation in patients with asthma have been recognised since the late 19th century when Paul Ehrlich described methods for eosinophil staining. Not long after this, Gollasch recorded the association between eosinophils in sputum and asthma severity. Improvements in methods to disperse sputum and to obtain cytospins helped to quantitate eosinophils and to use counts to improve clinical care of patients with asthma. This work has improved our understanding of the pathogenesis, pathophysiology, and treatment of airway diseases. Additionally, it has helped to assess new monoclonal antibodies directed against interleukin 5 in patients with asthma, in whom eosinophils have a dominant pathobiological role.1 Despite this evidence, quantitative sputum counts are not widely used in clinical practice because of the perceived difficulties in setting up laboratories that can reliably process sputum. As an alternative, perhaps fuelled by the imminent availability of anti-interleukin-5 monoclonal antibodies for clinical use, blood eosinophil count has been described in recent literature as a useful biomarker to assess patients with asthma. Raised absolute eosinophil counts have been reported as a predictor of response to treatment with corticosteroids,2 anti-interleukin-5 monoclonal antibodies,3 and poor asthma control and exacerbations in large community-based epidemiological surveys.4 However, the use of blood eosinophil counts is not a new concept. Their association with asthma severity5 and their use in managing patients with mild-to-moderate asthma2 were described almost 40 years ago. Indeed, in
2006 we recommended prudence in decreasing doses of corticosteroids in well controlled patients with asthma who had raised blood eosinophil counts.6 In this issue of The Lancet Respiratory Medicine, David Price and colleagues7 address the question of the best cut-off values for blood eosinophil count to assess asthma control and severity. The authors report blood eosinophil counts and prospective annual disease burden in a retrospective analysis of over 130 000 patients from a general practice database in the UK. The authors found that 16% of the population had an eosinophil count greater than 400 cells per μL and that these patients were at a greater risk of severe asthma exacerbations and acute asthma-related respiratory events during the subsequent year compared with patients with lower counts. This observation emphasises the need to pay more attention to the humble eosinophil count, even in this ‘omics’ era. Using blood eosinophil count to identify patients at risk of exacerbations might be different from using it to adjust doses of anti-inflammatory therapies. In a large randomised controlled clinical trial, blood eosinophil count (examined in all 616 patients) was a better predictor than sputum eosinophil count (examined in only 86 patients) of response to treatment with mepolizumab.3 For a number of reasons, one has to be cautious when using blood eosinophil counts for the management of patients with more severe asthma; particularly those who need regular systemic corticosteroids. First, sputum eosinophil counts are a more sensitive marker of loss of asthma control than blood eosinophil counts.8 Second, although
A
B 6
r=–0·079 p=0·5661
Bias 0·4792, SD 1·232
4
40
2·894 30
Difference
Sputum eosinophils (%)
100
20
2 0·479
0 1
10
2
–2
3 –1·936
–4
0 0
0·3
0·6
0·9
1·0
1·5
2·0
Average
Blood eosinophils (× 109/L)
Figure: Association between sputum and blood eosinophils (A) Spearman correlation plotted between matched blood eosinophil counts and sputum eosinophil percentage from 54 well-characterised patients with severe uncontrolled eosinophilic asthma despite being on daily prednisone (median dose 10 mg daily [range 2·5–40]). (B) Altman-Bland plot comparing 54 matched blood and sputum eosinophil counts with the representation of the limits of agreement (dotted line), within 1·96 SD.
824
www.thelancet.com/respiratory Vol 3 November 2015
Comment
modest correlations have been reported between blood and sputum eosinophils, and raised blood eosinophil counts predict sputum eosinophilia,9 the correlation becomes weaker as asthma becomes more severe (appendix). In our own cohort of 54 patients who need daily prednisone for asthma control, there is no correlation and poor concurrence between sputum and blood eosinophil counts (figure). Indeed, patients with normal blood eosinophil counts but raised sputum eosinophils are reported to have lower forced expiratory volume in 1 s, greater airway responsiveness, and poorer asthma control than those with raised blood eosinophil count and normal sputum eosinophil count.10 Third, one of the reasons for the discordance between blood and sputum eosinophil levels in patients with severe asthma might be the persistence of sputum eosinophils in patients with normal blood eosinophil counts, facilitated by the proliferation of the newly described type 2 innate lymphoid cells that can elaborate eosinophilopoietic cytokines such as interleukin 5 and interleukin 13 locally within the airway.11 In patients whose asthma is being treated with anti-interleukin-5 monoclonal antibody given in low doses subcutaneously and monitored by observing blood eosinophil count, this situation might potentially be an indicator of inadequate tissue concentrations of the monoclonal antibody. This hypothesis needs to be investigated. Fourth, the intriguing observation of an increase in blood eosinophil count with the administration of monoclonal antibodies directed against interleukin 1312 despite clinical improvement brings into question the contribution of circulating eosinophils to asthma pathobiology in patients with moderate-to-severe asthma. Finally, eosinophil degranulation and activation might be more clinically relevant than absolute numbers. Eosinophil activation occurs as the cell moves from one compartment to another and is most evident (as shown by eosinophil peroxidase level) in the lumen than in blood.13 In conclusion, it is reasonable to acknowledge that blood eosinophils present practitioners with an easy biomarker to identify patients with asthma who are potentially at risk for an exacerbation. An absolute circulating eosinophil count of greater than 400 cells per μL in symptomatic patients who are compliant to high doses of inhaled or systemic corticosteroids could be a predictor of response to antiinterleukin-5 therapies. Sputum eosinophil counts of greater than 3% would be a more sensitive and reliable biomarker to guide corticosteroid and anti-interleukin-5 therapies www.thelancet.com/respiratory Vol 3 November 2015
in patients who are on daily systemic corticosteroids, particularly in those who remain symptomatic despite normal circulating eosinophil counts. Further research is needed to investigate if eosinophil activity would be a better biomarker than absolute count to guide therapy. Although anecdotal reports suggest the usefulness of using blood eosinophil count,14 a head-to-head comparison of treatment algorithms guided by blood versus sputum eosinophil count or activity might be necessary to provide recommendations on the best strategies to initiate and monitor novel antiinflammatory therapies, such as biologicals, in patients with severe eosinophilic asthma.
See Online for appendix
Manali Mukherjee, *Parameswaran Nair Department of Medicine, McMaster University & St Joseph’s Healthcare, Hamilton, Ontario, Canada [email protected] MM declares no competing interests. PN has received grants from GlaxoSmithKline, Novartis, AstraZeneca, and Teva, and has provided consultancy to AstraZeneca–MedImmune, Sanofi, Teva, Boehringer Ingelheim, Mitsubishi, Cipla, and Cellometrics; PN is listed on a patent for a sputum filtration device. PN is supported by a Canada Research Chair in Airway Inflammometry. 1
2 3
4
5 6
7
8 9
10
11
12 13
14
Nair P, Pizzichini M, Kjarsgaard M, et al. Mepolizumab for prednisonedependent asthma with sputum eosinophilia. N Engl J Med 2009; 360: 985–93. Horn BR, Robin ED, Theodore J, Van Kessel A. Total eosinophil counts in the management of bronchial asthma. N Engl J Med 1975; 292: 1152–55. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma: a multi-centre, double-blind, placebo-controlled trial. Lancet 2012; 380: 651–59. Tran TN, Khatry DB, Ke X, et al. High blood eosinophil count is associated with more frequent asthma attacks in asthma patients. Ann Allergy Asthma Immunol 2014; 113: 19–24. Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990; 323: 1033–39. Belda J, Nair P, Lemiere C, Kamada D, O’Byrne PM, Hargreave FE. Predictors of loss of asthma control induced by corticosteroid withdrawal. Can Respir J 2006; 13: 129–33. Price DB, Rigazio A, Campbell JD, et al. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med 2015; published online Oct 20. http://dx.doi. org/10.1016/S2213-2600(15)00367-7. Pizzichini M, Pizzichini E, Clelland L, et al. Prednisone-dependent asthma: inflammatory indices in induced sputum. Eur Respir J 1999; 13: 15–21. Fowler SJ, Tavernier G, Niven R, et al. High blood eosinophil counts predict sputum eosinophilia in patients with severe asthma. J Allergy Clin Immunol 2015; 135: 822–24.e2. Schleich FN, Chevremont A, Paulus V, et al. Importance of concomitant local and systemic eosinophilia in uncontrolled asthma. Eur Respir J 2014; 44: 97–108. Smith SG, 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 2015; published online July 17. DOI: 10.1016/j.jaci.2015.05.037. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365: 1088–98. Nair P, Ochkur SI, Protheroe C, et al. Eosinophil peroxidase in sputum represents a unique biomarker of airway eosinophilia. Allergy 2013; 68: 1177–84. Wark PAB, McDonald VM, Gibson PG. Adjusting prednisone using blood eosinophils reduces exacerbations and improves asthma control in difficult patients with asthma. Respirology 2015; published online Aug 12. DOI:10.1111/resp.12602.
825