university of dundee blood eosinophils jabbal, sunny

University of Dundee

Blood eosinophils

Jabbal, Sunny; Lipworth, Brian J.

Published in:Clinical and Experimental Allergy

DOI:10.1111/cea.13057

Publication date:2017

Document VersionPeer reviewed version

Link to publication in Discovery Research Portal

Citation for published version (APA):Jabbal, S., & Lipworth, B. J. (2017). Blood eosinophils: The forgotten man of inhaled steroid dose titration .Clinical and Experimental Allergy, 48, 93-95. https://doi.org/10.1111/cea.13057

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Download date: 19. Mar. 2022

https://doi.org/10.1111/cea.13057

https://discovery.dundee.ac.uk/en/publications/e6aded1c-6c77-42d3-872d-ce87499df2ba

https://doi.org/10.1111/cea.13057

For Peer Review

Blood eosinophils: The forgotten man of inhaled steroid

dose titration

Journal: Clinical and Experimental Allergy

Manuscript ID CEA-2017-0282.R1

Manuscript Type: Research Letter

Date Submitted by the Author: 18-Oct-2017

Complete List of Authors: Jabbal, Sunny; University of Dundee School of Medicine, Scottish Centre for Respiratory Research Lipworth, Brian; University of Dundee, Asthma & Allergy Research Group

Keywords: asthma, eosinophils, pneumology

Additional Keywords: nitric oxide

Clinical & Experimental Allergy

For Peer Review

Blood eosinophils: The forgotten man of inhaled steroid dose titration 1

1Sunny Jabbal MB ChB,

1Brian J Lipworth MD 2

1Scottish Centre for Respiratory Research, Ninewells Hospital & Medical School, Dundee, 3

Scotland, DD1 9SY 4

Correspondence to: Dr BJ Lipworth, Scottish Centre for Respiratory Research, Ninewells 5

Hospital & Medical School, University of Dundee, Dundee, DD1 9SY. Tel: +44 1382 383188 6

[email protected] 7

Declaration of funding: Existing departmental funds 8

Trial registration: Not applicable 9

Conflicts of Interest: BJL has received payment for giving talks from Teva ,Meda and Chiesi 10

and Boerhinger Ingelheim , for consulting activity from Chiesi ,Cipla ,Dr Reggys ,Lupin and 11

Sandoz ,for attending meetings from Teva and Boerhinger Ingelheim , for unrestricted research 12

grants from Teva and Chiesi and Meda and multicentre grants from Chiesi , Astrazeneca ,Sanofi 13

, Janssen and Teva. SJ has received reimbursement for attending symposia from Astra Zeneca, 14

Chiesi Limited, NAPP, and Teva Pharmaceuticals. SJ has received fees for speaking from Chiesi 15

Limited, NAPP, Boehringer Ingelheim, Pfizer and Astra Zeneca. 16

Word Count: 1012 17

Figures: 1 18

Tables: 1 19

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Abbreviations: 21

BPD beclometasone equivalent dose 22

ECP eosinophilic cationic protein 23

FeNO Fractional exhaled nitric oxide 24

FEV1 Forced expiratory volume in 1 second 25

IL-5 Interleukin-5 26

ICS Inhaled corticosteroid 27

LTRA Leukotriene receptor antagonist 28

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Blood eosinophil counts which were once regarded as normal, have become of increasing 39

interest in the era of Interluekin-5 (IL-5) asthma treatment. Blood eosinophils as low as 150 40

cells/µL have been suggested as treatment cut-offs for eosinophil depleting therapies such as 41

mepolizumab [1], whilst a value of 300 cells/µL has been deemed a more pragmatic cut off by 42

the National Institute for Health and Care Excellence (United Kingdom). In this era of eosinophil 43

post-truths, inhaled corticosteroids (ICS), the eosinophil’s oldest adversary, are very much the 44

forgotten man. 45

Corticosteroids reduce the numbers of eosinophils in blood and sputum by inhibiting the 46

expression of pro eosinophilic cytokines such as IL-5, and increase the rate of apoptosis and 47

associated phagocytosis. It is known that titrating ICS against sputum eosinophils results in 48

improved asthma control[2]. Whilst it is also known that sputum eosinophils correlate well with 49

blood eosinophils [3], the effects of increasing ICS dose on blood eosinophils are less well 50

documented [4]. 51

We therefore wanted to know if ICS dose titration suppresses blood eosinophil counts in patients 52

with persistent asthma. In addition, we investigated whether leukotriene receptor antagonists 53

(LTRA) has a similar effect when used as add on therapy. Another surrogate marker of TH2 54

mediated inflammation is exhaled breath nitric oxide (FeNO), where it has already been 55

demonstrated that there is a dose-response effect of ICS[5]. 56

We, therefore, performed a pooled analysis of our own studies performed by the Scottish Centre 57

for Respiratory Research, where we measured blood eosinophils and FeNO from a baseline of 58

none or low dose ICS to medium dose ICS with or without LTRA. Fourteen studies were 59

included in this analysis, and are listed in table 1. All were approved by the East of Scotland 60

Regional Ethics Committee and registered at clinicaltrials.gov. 61


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217 non-smoking patients with mild-moderate persistent asthma patients were included in the 62

ICS dose titration analysis, of these 144 also received additive LTRA. Patients had a mean age of 63

38 years, and a mean FEV1 of 85% predicted. In all studies analysed patients must have been 64

free from an asthma exacerbation requiring systemic corticosteroids in the three months prior to 65

trial enrolment. In the nine out of fourteen studies included, patients had at least one positive skin 66

prick test to a common aeroallergen, with a mean number of positive tests of two. 67

Baseline median low dose inhaled corticosteroid (ICS) dose was 200µg/day as beclometasone 68

diproprionate (BDP) equivalent dose .Baseline mean eosinophils were 356 cells/µL, mean 69

eosinophilic cationic protein (ECP) was 24.9 µg/L, and mean exhaled nitric oxide (FeNO) was 70

41.4 ppb. Participants were stepped up to medium dose ICS as median 800 µg/day BDP 71

equivalent, with a median treatment duration of two weeks. Median treatment duration of 72

additive LTRA was also two weeks. 73

Changes in blood eosinophils and FeNO are presented in figure 1. We observed a significant 74

mean fall in eosinophils of 71 cells/µL (95% CI 38 to 105) p=0.001 comparing low versus 75

medium dose ICS, and a further non-significant fall with LTRA amounting to 20 cells/µL. FeNO 76

also significantly fell by 14.5ppb (95% CI 7.9 to 21.1), p=0.001 comparing low and medium 77

dose ICS, but did not decrease further with addition of LTRA. Mean ECP levels for low and 78

medium dose ICS were 24.9 µg/L and 18.8 µg/L respectively, representing a significant 79

(p=0.005) decrease of 6.1 µg/L (95% CI 2.4 to 9.6), although, there were insufficient data to 80

assess effects of LTRA. FEV1% predicted did not significantly change between low and medium 81

dose ICS: 1.6% (95% CI -0.5 to 3.2). 82

We demonstrated that ICS even at a medium dose of 800ug BDP results in a significant fall in 83

blood eosinophils over a period of two weeks. Our data showed a non-significant further fall in 84


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blood eosinophils amounting to 20 cells/µL when adding LTRA, while Laviolette et al found a 85

significant additive effect of LTRA amounting to a mean change of 40 cells [6]. In contrast 86

Greene et al found no significant additive fall with LTRA on top of ICS , albeit measuring 87

sputum rather than blood eosinophils[7]. Their study also found no significant additive effect on 88

FeNO in keeping with our data. In terms of ICS dose response, Kips et al reported significantly 89

lower sputum eosinophils comparing medium and low dose ICS, but no commensurate fall in 90

sputum ECP [8] , in contrast to our observation of a significant fall in both blood eosinophils and 91

ECP. 92

In a retrospective observational cohort study, Price et al. demonstrated that those with 93

eosinophils ≥400 cells/µL experience more severe exacerbations and have worse asthma control 94

[9]. The fundamental question therefore is whether ICS dose should be titrated against blood 95

eosinophils as a surrogate inflammatory marker, especially given that pulmonary function shows 96

a plateau in response above 400ug/day BDP equivalent dose [10]. In this regard Green et al 97

showed that titrating ICS against sputum eosinophils resulted in significantly reduced 98

exacerbations [2]; whether the same outcome would be achieved by titrating against blood 99

remains to be answered. We appreciate the limitations of our data which were only short term 100

and we did not report any outcomes of asthma control. Furthermore, the observed effect might be 101

due to possible systemic absorption from the lung, assessment of which would have required a 102

surrogate marker of systemic cortisol suppression. Finally, our study lacks a placebo arm or a 103

control arm with a fixed ICS dose, meaning we are unable to account for natural variation in 104

blood eosinophils over time. In a more sever cohort of asthma patients, it has been demonstrated 105

for subjects who have an initial blood eosinophil count above 150 cells/µl, 85% of them remain 106


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above this value, even up to 56 weeks (based on four weekly blood eosinophil measurements) 107

[11]. 108

As we consider ever more complex anti-inflammatory therapies as the future of asthma care, we 109

must not overlook inhaled corticosteroids and their effects on blood eosinophils as the forgotten 110

man of asthma therapy. Perhaps a randomized control trial comparing ICS dose titration against 111

conventional markers (pulmonary function, reliever use, and symptoms) versus titration against 112

blood eosinophils over one year might be worth pursuing. 113

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References 128

1. Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, Brightling CE, Pavord ID, 129

Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil 130

thresholds: a secondary analysis of the DREAM and MENSA studies. The Lancet Respiratory 131

medicine 2016;4: 549-56. 132

2. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, Wardlaw AJ, Pavord ID, 133

Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 134

(London, England) 2002;360: 1715-21. 135

3. Wagener AH, de Nijs SB, Lutter R, Sousa AR, Weersink EJ, Bel EH, Sterk PJ, External validation of 136

blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. 137

Thorax 2015;70: 115-20. 138

4. Evans PM, O'Connor BJ, Fuller RW, Barnes PJ, Chung KF, Effect of inhaled corticosteroids on 139

peripheral blood eosinophil counts and density profiles in asthma. The Journal of allergy and 140

clinical immunology 1993;91: 643-50. 141

5. Anderson WJ, Short PM, Williamson PA, Lipworth BJ, Inhaled corticosteroid dose response 142

using domiciliary exhaled nitric oxide in persistent asthma: the FENOtype trial. Chest 143

2012;142: 1553-61. 144

6. Laviolette M, Malmstrom K, Lu S, Chervinsky P, Pujet JC, Peszek I, Zhang J, Reiss TF, Montelukast 145

added to inhaled beclomethasone in treatment of asthma. Montelukast/Beclomethasone 146

Additivity Group. American journal of respiratory and critical care medicine 1999;160: 1862-8. 147


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7. Green RH, Brightling CE, McKenna S, Hargadon B, Neale N, Parker D, Ruse C, Hall IP, Pavord ID, 148

Comparison of asthma treatment given in addition to inhaled corticosteroids on airway 149

inflammation and responsiveness. The European respiratory journal 2006;27: 1144-51. 150

8. Kips JC, O'Connor BJ, Inman MD, Svensson K, Pauwels RA, O'Byrne PM, A long-term study of the 151

antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in 152

asthma. American journal of respiratory and critical care medicine 2000;161: 996-1001. 153

9. Price DB, Rigazio A, Campbell JD, Bleecker ER, Corrigan CJ, Thomas M, Wenzel SE, Wilson AM, 154

Small MB, Gopalan G, Ashton VL, Burden A, Hillyer EV, Kerkhof M, Pavord ID, Blood eosinophil 155

count and prospective annual asthma disease burden: a UK cohort study. The Lancet Respiratory 156

medicine 2015;3: 849-58. 157

10. Masoli M, Weatherall M, Holt S, Beasley R, Clinical dose-response relationship of fluticasone 158

propionate in adults with asthma. Thorax 2004;59: 16-20. 159

11. Katz LE, Gleich GJ, Hartley BF, Yancey SW, Ortega HG, Blood eosinophil count is a useful 160

biomarker to identify patients with severe eosinophilic asthma. Annals of the American Thoracic 161

Society 2014;11: 531-6. 162

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Figure legend 172

Comparison of low (200ug BDP equivalent) and medium dose (800ug BDP equivalent) inhaled 173

corticosteroid (ICS) on blood eosinophils (top) and exhaled breath nitric oxide (bottom) in n=217 174

asthma patients, depicted as means and SEM. Effects of add on therapy with leukotriene receptor 175

antagonists (LTRA) are also shown in 144 patients. 176

177


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Table 1. Source data

Reference ICS dose

(BDP µg

equivalent)

Total

Exposure

(days)

1. Lipworth BJ et al. Am J Med 2000; 109:114-21. 600µg +/- LTRA 14

2. Aziz I et al. Chest 2000; 118:1049-58. 400-800ug 28

3. Wilson AM et al Chest 2001; 119:1021-6. 800µg +/-LTRA 14

4. Dempsey OJ et al. J Allergy Clin Immunol 2002;

109:68-74. 0-400µg 28

5. Currie GP et al. Am J Respir Crit Care Med 2003;

167:1232-8. 500µg-1000µg 21

6. Currie GP et al. Allergy 2003; 58:602-7. 0-400µg 14

7. Sims EJ et al. Br J Clin Pharmacol 2003; 56:104-11. 500µg +/-LTRA 14

8. Anderson WJ et al. Clin Sci (Lond) 2014; 127:635-43. 200 -800µg 42

9. Anderson WJ et al. Chest 2012; 142:1553-61. 200-1000µg 28

10. Lipworth BJ et al. Chest 2012; 141:607-15. 400-1200µg 365

11. Menzies D et al. Allergy 2007; 62:661-7. 200-800µg+/-

LTRA 35

12. Barnes ML et al. Allergy 2007; 62:73-80. 0-400µg 70

13. Dempsey OJ et al. Chest 2002; 122:151-9. 100-400µg +/-

LTRA 42

14. Wilson AM et al. Br J Clin Pharmacol 1999; 48:579-85. 1000-2000µg 8


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178


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Figure legend Comparison of low (200ug BDP equivalent) and medium dose (800ug BDP equivalent) inhaled corticosteroid

(ICS) on blood eosinophils (top) and exhaled breath nitric oxide (bottom) in n=217 asthma patients,

depicted as means and SEM. Effects of add on therapy with leukotriene receptor antagonists (LTRA) are also shown in 144 patients.

266x502mm (300 x 300 DPI)


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