University of Groningen
Clinical and molecular phenotyping of asthma and COPD
Boudewijn, Ilse Maria
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Boudewijn, I. M. (2019). Clinical and molecular phenotyping of asthma and COPD. University of Groningen.
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5
Predictors of clinical response to
extrafine and non-extrafine particle
inhaled corticosteroids in smokers
and ex-smokers with asthma
Fajri Gafar,Ilse M. Boudewijn, Claire A. Cox, Judith M. Vonk, Siebrig Schokker, Anne J. Lexmond, Henderik W. Frijlink, Paul Hagedoorn, Dirkje S. Postma, Maarten van den Berge
Respiratory Research 2018;19(1):256
Chapter 5
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Predictors of response to extrafine and non-extrafine ICS in (ex-)smokers with asthma
5
To the Editor,
Asthma patients who smoke experience more severe symptoms as well as airflow limitation, and benefit less from treatment with inhaled corticosteroids (ICS) compared with non-smoking asthmatics(1).Additionally, smoking is associated with small airways dysfunction (SAD)(2). We hypothesized that smokers and ex-smokers with asthma would benefit more from extrafine than non-extrafine particle ICS. However, our OLiVIA-study showed that extrafine and non-extrafine particle ICS were equally effective in improving small airways function in current and ex-smokers with asthma(3). This outcome might be ascribed to the fact that the presence of SAD was not an inclusion criterion in our study. Therefore, we performed a post-hoc analysis to investigate whether current and ex-smoking asthmatics with SAD show a better clinical improvement in response to extrafine compared to non-extrafine particle ICS. Next, we investigated which clinical parameters, apart from the presence of SAD, predict a favorable response to extrafine and non-extrafine particle ICS.
The OLiVIA-study was an open-label, randomized, three-way crossover, two-center study, comparing two-week treatment with extrafine hydrofluoroalkane (HFA)-beclomethasone 200 µg b.i.d. (QVAR) to non-extrafine HFA-(HFA)-beclomethasone 400 µg b.i.d. (Clenil) and non-extrafine HFA-fluticasone 250 µg b.i.d. (Flixotide)(3). The primary outcome was the change in airway hyperresponsiveness (AHR) to small particle adenosine, expressed as the provocative dose of adenosine causing a 20% drop in FEV1 (forced expiratory volume at 1 second) from baseline to post-treatment (ΔPD20). To define SAD, we applied cut-off values by spirometry (forced expiratory flow between 25% and 75% of forced vital capacity [FEF25-75] <lower limit of normal [LLN]); body plethysmography (ratio of residual volume to total lung capacity [RV/TLC] >upper limit of normal [ULN]); impulse oscillometry (difference between resistance at 5Hz and 20Hz [R5-R20] >0.1 kPa sL-1)(4); and multiple breath nitrogen washout (ventilation
heterogeneity of the acinar structures [Sacin] and conductive airways [Scond] >ULN)(5). Statistical analyses are described in the online supplement.
Baseline characteristics of the study population are presented in Table E1. We analyzed 43 asthma patients (22 smokers and 21 ex-smokers), 42% being male, with mean (standard deviation [SD]) age 45 (12.6) years, FEV1 83 (14.5) %predicted, and PD20 2.69 (3.41) mg. SAD was present in 72% of subjects based on FEF25-75, in 14% based on RV/ TLC, in 44% based on R5-R20,in 51% based on Sacin and 31% based on Scond (Table E2). Asthma patients with SAD based on FEF25-75, RV/TLC, R5-R20, and Sacin cut-offs had similar improvements of PD20 in response to extrafine (QVAR) and non-extrafine particle ICS treatments (Clenil and Flixotide) (Figures 1A-D). Asthma patients with SAD based on
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Chapter 5
Scond showed higher improvement of PD20 (p<0.01) in response to Clenil compared to QVAR, mean (SD) ΔPD20 1.7 (1.2) and 0.3 (1.1) doubling doses, respectively (Figure 1E). Additionally, asthma patients with and without SAD had similar improvements of PD20 in response to QVAR, Clenil or Flixotide (Figures 1A-E).
Table E3 presents results of univariate correlation analyses. Multivariate regression analyses showed that higher blood eosinophils were associated with better improvements in PD20 in patients treated with Clenil and Flixotide (both p<0.05). Furthermore, lower blood neutrophils were associated with higher improvements in PD20, independently of the level of blood eosinophils, in patients treated with QVAR, Clenil and Flixotide (all p<0.05). Finally, ex-smoking was associated with higher improvements in PD20 after using Clenil and Flixotide (p<0.05 and p=0.05 respectively), and younger age was associated with higher improvements in PD20 after using Clenil (p<0.05) (Table 1, Figure E1).
Table 1. Multivariate regression analysis of baseline variables with change in airway hyperresponsiveness to adenosine (ΔPD20) as dependent variable in patients treated with QVAR, Clenil and Flixotide.
Baseline predictors B 95% CI p-value R2
ΔPD20 QVAR Age -0.02 -0.07; 0.02 0.274
Sex, male 0.31 -0.69; 1.31 0.531
Current smoking, yes -0.99 -2.14; 0.15 0.086
Neutrophils, % -0.13 -0.20; -0.06 0.001 0.74
Eosinophils, % 0.10 -0.14; 0.34 0.402
FEV1, % predicted 0.03 -0.01; 0.07 0.170
LCI at 2.5% -0.25 -0.58; 0.07 0.117
ΔPD20 Clenil Age, years -0.06 -0.12; -0.001 0.047
Sex, male 0.66 -0.50; 1.82 0.252
Current smoking, yes -1.43 -2.73; -0.13 0.032
0.53
Neutrophils, % -0.09 -0.17; -0.01 0.027
Eosinophils, % 0.27 0.01; 0.52 0.042
FEV1, % predicted 0.02 -0.02; 0.06 0.339
ΔPD20 Flixotide Age, years -0.04 -0.09; 0.01 0.119
Sex, male 0.51 -0.54; 1.57 0.330
Current smoking, yes -1.12 -2.24; -0.003 0.050
Neutrophils, % -0.12 -0.19; -0.05 0.001 0.62
Eosinophils, % 0.26 0.04; 0.48 0.020
FEV1, % predicted -0.01 -0.05; 0.03 0.603
RV/TLC, % predicted -0.03 -0.06; 0.002 0.068
B: regression coefficients; CI: Confidence Intervals; R2: total explained variance; ΔPD
20: the change from baseline to
post-treatment in the provocative dose of adenosine causing a 20% drop in FEV1; FEV1: forced expiratory volume in 1 second; LCI: lung clearance index; and RV/TLC: the ratio of residual volume to total lung capacity. Complete methods are presented in the online supplement.
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Predictors of response to extrafine and non-extrafine ICS in (ex-)smokers with asthma
5
Figure 1A-E: Change in PD20 from baseline to post-treatment with QVAR, Clenil and Flixotide in patients with and without small airways dysfunction (SAD). We show results for 5 definitions of SAD, based on (A)
FEF25-75, (B) RV/TLC, (C) R5-R20, (D) Sacin and (E) Scond. Each line depicts a subject while the bold line depicts the
mean change in PD20 adenosine in response to the treatment. PD20 = provocative dose of adenosine causing
a 20% drop in forced expiratory volume at 1 second (FEV1); FEF25-75 = forced expiratory flow between 25% and 75% of forced vital capacity (FVC); RV/TLC = the ratio of residual volume to total lung capacity; R5-R20 =
the difference between resistance at 5 Hz and 20 Hz; Sacin= ventilation heterogeneity of the acinar structures; Scond= ventilation heterogeneity of the conductive airways.
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Chapter 5
This study shows that the presence of SAD, defined by 4 parameters (i.e. FEF25-75, RV/TLC, R5-R20, and Sacin), does not predict a better treatment response to extrafine particle ICS in smokers and ex-smokers with asthma. In contrast, we found that patients with SAD based on Scond improve more in PD20 after treatment with non-extrafine Clenil than extrafine QVAR. Previous results of the OLiVIA-study already showed that treatment with Clenil resulted in greater FEV1 improvement than QVAR(3). The explanation of this result in our previous publication also applies to the current results. In the past, beclomethasone was administered using a chlorofluorocarbon (CFC) pressured metered-dose inhaler (pMDI). When HFA became available, it was shown that extrafine HFA-beclomethasone was twice as effective as CFC-beclomethasone, while non-extrafine beclomethasone was considered equally effective as CFC-beclomethasone. Based on these findings, we adjusted the doses in our study (i.e. 200 µg b.i.d. for QVAR and 400 µg b.i.d. for Clenil) [3]. However, the higher spray temperature and lower plume velocity of the HFA-pMDI used with Clenil may have led to higher lung deposition than CFC-beclomethasone(6), and therefore we may have administered a higher effective dose of Clenil than QVAR. The latter might suggest that patients with SAD need a higher dose of ICS to get an optimal effect.
In line with previous reports on better clinical effects of ICS in asthmatics with eosinophilia(7-9), we show that higher blood eosinophil numbers are associated with greater AHR improvement in response to non-extrafine particle ICS treatment. A new finding in our study is that higher blood neutrophils associate with a worse improvement in AHR to both extrafine and non-extrafine particle ICS, independently from the level of blood eosinophils. Findings by Telenga et al (9) support that lower blood neutrophils are associated with higher improvement in FEV1 after 2-week ICS-therapy. Taken together, we find that higher blood neutrophils associate with a worse clinical ICS-response in smokers and ex-smokers with asthma.
A strength of the study is that we applied multiple measurement techniques to define SAD including spirometry, body plethysmography, impulse oscillometry and multiple breath nitrogen washout. A limitation is the relatively small sample size of patients with SAD and non-SAD, which limits the power of the study.
In conclusion, we show that smoking and ex-smoking asthmatics with and without SAD have a similar improvement in AHR to adenosine after treatment with either extrafine or non-extrafine particle ICS. Of importance, we find that lower blood neutrophils and higher blood eosinophils are independent predictors for a favorable ICS response. These findings can aid clinicians in guiding ICS therapy in smokers and ex-smokers with asthma.
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Predictors of response to extrafine and non-extrafine ICS in (ex-)smokers with asthma
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ACKNOWLEDGEMENTS
We would like to thank all patients for their participation in the study.
SUPPORT
This study was supported by TEVA pharmaceutical Industries Ltd, which was in no way involved in study design, writing or reviewing of the manuscript.
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Chapter 5
REFERENCES
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Curr Opin Allergy Clin Immunol 2005; 5(1): 57-63.
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(6) Gabrio BJ, Stein SW, Velasquez DJ. A new method to evaluate plume characteristics of hydrofluoroalkane and chlorofluorocarbon metered dose inhalers. Int J Pharm 1999; 186(1): 3-12.
(7) Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002; 109(3): 410-418.
(8) Meijer RJ, Postma DS, Kauffman HF, Arends LR, Koëter GH, Kerstjens HAM. Accuracy of eosinophils and
eosinophil cationic protein to predict steroid improvement in asthma. Clin Exp Allergy 2002;32(7):1096-1103.
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SUPPLEMENTAL MATERIAL
Supplemental material is online available by scanning the following QR-code or using the URL: www.publicatie-online.nl/publicaties/i-boudewijn/chapter-5-supplemental/
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