American Journal of Respiratory and Critical Care Medicine

To the Editor:

Cigarette smoking decreases corticosteroid sensitivity in patients with asthma and worsens their symptoms and exacerbation frequency (1, 2). Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment. However, the optimal therapies for smokers with asthma are not well defined because smokers (and ex-smokers with a >10 pack-year history) are usually excluded from clinical trials (3, 4).

Exposure to even low levels of cigarette smoke is known to induce small airway inflammation (5, 6), which is associated with worse asthma control (5, 7). Therefore, ICS deposition in small airways, which increases with small- versus standard-size–particle ICS (8, 9), might be an important determinant of ICS effectiveness in smokers with asthma.

To explore this hypothesis, a historical matched cohort study was designed to compare the effectiveness of representative small-particle and standard-size–particle ICS for current and ex-smokers with asthma and to investigate any differential effect compared with effects in nonsmokers. Some of the results of this study have been previously reported in the form of abstracts (10, 11).

We examined anonymized medical record data for patients with asthma in two large UK electronic data sets, the General Practice Research Database (now in the Clinical Practice Research Datalink) and the Optimum Patient Care Research Database (12, 13). We studied patients aged 30–70 years when they were prescribed a step-up in asthma therapy of 50% or more increase in ICS dose, using hydrofluoroalkane beclomethasone dipropionate (Qvar; Teva Respiratory, LLC, Sellersville, PA; particles of median mass aerodynamic diameter, 1.1 μm) or fluticasone propionate (Flixotide; GlaxoSmithKline Australia Pty Ltd, Melbourne, Australia; median mass aerodynamic diameter, 2.4–3.2 μm) by pressurized metered-dose inhaler (14). Eligible patients had 2 consecutive years of data within the study period (January 1999–2010), including 1 baseline year before and 1 outcome year after the step-up index date, and remained at the stepped-up ICS dose during the outcome year, with at least one additional asthma prescription. Exclusion criteria were any chronic respiratory disease other than asthma, maintenance oral corticosteroid therapy during baseline, multiple ICS prescriptions on the index date, and baseline or index date prescription of fixed-dose combination ICS plus long-acting β-agonist. Moreover, ex-smoking status had to be recorded at age 30 years or older to ensure long-term smoking. Patients stepped-up to small-particle ICS from 2005 onward were matched 1:1 to patients prescribed standard-size–particle ICS from 2000 onward to maximize patient numbers.

The primary effectiveness measure in this study was the rate of severe exacerbations, defined according to expert working group criteria (15) as an asthma-related emergency hospital attendance/admission or an oral corticosteroid pulse. Other effectiveness measures were the rate of acute respiratory events, defined as a severe exacerbation or general practice consultation for lower respiratory tract infection, and risk-domain asthma control, defined as the absence of any acute respiratory event.

Patients in small-particle and standard-size–particle ICS cohorts were matched sequentially in a 1:1 ratio for demographic characteristics and baseline markers of asthma severity, including sex, age (±5 yr within subgroups of ≥30–60 and >60–70 yr), smoking status, and baseline mean daily ICS dose, mean daily short-acting β-agonist dose, number of severe exacerbations, number of asthma consultations without oral corticosteroid prescription (i.e., without exacerbation), asthma control status, and index date year (±5 yr).

Outcome year exacerbation and acute respiratory event rates were compared using conditional Poisson regression models. The adjusted odds of achieving risk-domain asthma control were compared using a conditional binary logistic regression model. Potential confounding variables considered were those that differed between cohorts at baseline (P < 0.10) and those that were predictive (P < 0.05) of each outcome variable in multivariable analyses. All models included treatment, smoking status (current/ex-smoker vs. nonsmoker), and interaction between treatment and smoking status to determine any difference in treatment effect by smoking status. A P value less than 0.10 was considered significant for the exploratory interaction analysis. Analyses were performed using SPSS Statistics version 19 (SPSS Statistics, IBM, Somers, NY), SAS version 9.3 (SAS Institute, Cary, NC), and Microsoft Excel 2007 (Microsoft, Bellevue, WA).

After matching, there were 889 patients in each cohort, including 314 (35%) current or ex-smokers (Table 1). Nonsmokers in the standard-size–particle ICS cohort were more likely to have concomitant rhinitis or receive rhinitis therapy than nonsmokers in the small-particle ICS cohort. Patients in the standard-size–particle ICS cohorts were more likely to have been prescribed a long-acting β-agonist during the baseline year. Other differences between cohorts after matching were not clinically important.

Table 1. Summary of Key Baseline Patient Characteristics by Matched Treatment Cohorts and Smoking Status

CharacteristicSmall-Particle ICS (n = 314)Standard-Size–Particle ICS (n = 314)P Value*Small-Particle ICS (n = 575)Standard-Size–Particle ICS (n = 575)P Value*
Female sex, n (%)187 (59.6)187 (59.6)N/A401 (69.7)401 (69.7)N/A
Age at index date, yr, mean (SD)49.2 (10.9)49.1 (10.9)0.4049.7 (10.7)49.6 (10.8)0.57
30–60 yr of age, n (%)250 (79.6)250 (79.6)N/A457 (79.5)457 (79.5)N/A
61–70 yr of age, n (%)64 (20.4)64 (20.4) 118 (20.5)118 (20.5) 
BMI in kg/m2, mean (SD)28.7 (6.9)28.2 (6.0)0.4428.2 (6.1)29.1 (6.7)0.02
Time since first asthma  prescription, n (%)      
 Within 1 mo before index date2 (0.6)0 (0)1.000 (0)4 (0.7)0.01
 1–12 mo38 (12.1)38 (12.1) 55 (9.6)66 (11.5) 
 1–6 yr110 (35.0)116 (36.9) 187 (32.5)213 (37.0) 
 >6 yr164 (52.2)160 (51.0) 333 (57.9)292 (50.8) 
Recorded comorbidity, n (%)§      
 Rhinitis diagnosis64 (20.4)67 (21.3)0.77152 (26.4)205 (35.7)0.001
 GERD diagnosis42 (13.4)41 (13.1)0.9169 (12.0)82 (14.3)0.26
 Cardiac disease diagnosis18 (5.7)31 (9.9)0.0629 (5.0)41 (7.1)0.14
Risk-domain asthma control, n (%)213 (67.8)213 (67.8)N/A393 (68.3)393 (68.3)N/A
Spacer device used, n (%)49 (15.6)59 (18.8)0.29102 (17.7)98 (17.0)0.74
Recorded % predicted PEF, n (%)212 (67.5)251 (80.0)<0.001426 (74.1)488 (84.9)<0.001
 % Predicted PEF, mean (SD)82.9 (22.1)81.9 (18.8)0.9285.0 (27.4)85.1 (18.7)0.75
Mean daily SABA dose, n (%)      
 0 μg/d11 (3.5)11 (3.5)0.5953 (9.2)53 (9.2)0.31
 1–100 μg/d44 (14.0)48 (15.3) 88 (15.3)99 (17.2) 
 101–200 μg/d87 (27.7)83 (26.4) 191 (33.2)180 (31.3) 
 201–400 μg/d84 (26.8)84 (26.8) 133 (23.1)133 (23.1) 
 >400 μg/d88 (28.0)88 (28.0) 110 (19.1)110 (19.1) 
Mean daily ICS dose, n (%)||      
 1–50 μg/d59 (18.8)59 (18.8)N/A97 (16.9)97 (16.9)N/A
 51–100 μg/d85 (27.1)85 (27.1) 159 (27.7)159 (27.7) 
 101–200 μg/d90 (28.7)90 (28.7) 190 (33.0)190 (33.0) 
 >200 μg/d80 (25.5)80 (25.5) 129 (22.4)129 (22.4) 
LABA prescription (separate or FDC), n (%)49 (15.6)65 (20.7)0.07693 (16.2)130 (22.6)0.004
Severe exacerbations, n (%)      
 0239 (76.1)239 (76.1)N/A430 (74.8)430 (74.8)N/A
 147 (15.0)47 (15.0) 100 (17.4)100 (17.4) 
 ≥228 (8.9)28 (8.9) 45 (7.8)45 (7.8) 
Acute respiratory events,  n (%)      
 0215 (68.5)216 (68.8)0.67402 (69.9)403 (70.1)0.68
 157 (18.2)57 (18.2) 110 (19.1)105 (18.3) 
 ≥242 (13.4)41 (13.1) 63 (11.0)67 (11.7) 
Asthma consultation/no oral  corticosteroids, n (%)      
 0127 (40.4)127 (40.4)N/A206 (35.8)206 (35.8)N/A 
 1102 (32.5)102 (32.5) 216 (37.6)216 (37.6)  
 ≥285 (27.1)85 (27.1) 153 (26.6)153 (26.6)  
GP consultation for LRTI  requiring antibiotic, n (%)      
 0254 (80.9)271 (86.3)0.11508 (88.3)505 (87.8)0.50 
 ≥160 (19.1)43 (13.7) 67 (11.6)70 (12.2)  

Definition of abbreviations: BMI = body mass index; FDC = fixed-dose combination; GERD = gastroesophageal reflux disease; GP = general practice; ICS = inhaled corticosteroid; LABA = long-acting β-agonist; LRTI = lower respiratory tract infection; N/A = not applicable; PEF = peak expiratory flow; SABA = short-acting β-agonist.

In each treatment cohort there were 119 (13.4%) current smokers and 195 (21.9%) ex-smokers (first recorded as ex-smokers at ≥30 yr of age).

*Matched cohorts were compared using conditional logistic regression.

Matching variable (age matching was ±5 yr).

Recorded BMI data were available for 861 (97%) and 853 (96%) patients in the small-particle ICS and standard-size–particle ICS cohorts, respectively.

§Diagnosis defined as database Read code for the condition.

||The baseline doses of ICS were standardized to equivalence with small-particle beclomethasone and fluticasone; thus, doses of large-particle beclomethasone (Clenil Modulite) and budesonide were halved.

On the index date, small-particle ICS was prescribed at significantly lower doses than standard-size–particle ICS (median [interquartile range (IQR)], 400 [200–400] vs. 500 [500–1,000] μg/d; P < 0.001). During the outcome year, ICS dose exposure was also significantly lower in the small-particle ICS cohort (median [IQR], 301 [164–438] μg/d vs. 397 [238–658] μg/d; P < 0.001). The short-acting β-agonist dose was similar in the two cohorts (median [IQR], 219 [110–438] μg/d).

Adjusted rates of severe exacerbations during outcome were significantly lower for current/ex-smokers and nonsmokers in the small-particle than in the standard-size–particle ICS cohort, with no interaction between treatment and smoking status (P = 0.31; Figure 1). In contrast, for current and ex-smokers, adjusted rates of acute respiratory events were significantly lower, and adjusted odds of risk-domain asthma control significantly higher, with small-particle than with standard-size–particle ICS; for nonsmokers, no difference was found. The interaction between treatment and smoking status was significant at the 10% level for both of these outcomes (Figure 1).

When we examined results separately for smokers and ex-smokers, the same trends were observed for each group (as compared with nonsmokers): for risk-domain asthma control, the adjusted odds ratio (95% confidence interval) for small-particle ICS as compared with standard-size–particle ICS was 1.85 (0.96–3.58) for smokers, 1.88 (1.07–3.28) for ex-smokers, and 1.17 (0.86–1.60) for nonsmokers. Others have reported similarities in inflammation and treatment response between smokers and ex-smokers (16).

Another explanation for the similar findings for smokers and ex-smokers in this study could be the so-called “healthy smoker effect,” whereby patients with fewer respiratory symptoms tend to keep smoking and those with more symptoms tend to quit (17). Finally, an interaction between effects of age and smoking can be hypothesized because ex-smokers were older on average (mean [SD] age, 53 [10.2] yr) than smokers (43 [9.0]) and nonsmokers (50 [10.8]), and thus may have had more pack-years’ exposure than the current smokers.

These results confirm previous studies showing that in asthma, small-particle ICSs are at least as effective as standard-size–particle ICS despite being administered at significantly lower doses (18, 19). They also suggest a possible differential treatment effect with regard to smoking status and particle size of ICS, with a clear trend for greater beneficial effects of small-particle ICS for current/ex-smokers in terms of acute respiratory events and asthma control. This finding could be explained by increased small airway disease induced by smoking and improved targeting of small airways by smaller ICS particles. Thus, small-particle ICS may be a preferred treatment choice for patients who are current or ex-smokers.

In any observational study, confounding (although limited by the matching process) and partial characterization of patients, most of whom lacked recorded lung function, must be considered. Another study limitation is the lack of detailed information on smoking history, which prevented us from examining the influence of smoke-free duration for ex-smokers and of pack-years for smokers and ex-smokers. As a result, the findings of this study should be considered exploratory. Nonetheless, we believe further investigation of a possible differential effect is warranted.

1. Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J 2013;41:716726.
2. Tomlinson JE, McMahon AD, Chaudhuri R, Thompson JM, Wood SF, Thomson NC. Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax 2005;60:282287.
3. Thomson NC, Spears M. Asthma guidelines and smokers: it’s time to be inclusive. Chest 2012;141:286288.
4. Price D, Bjermer L, Popov TA, Chisholm A. Integrating evidence for managing asthma in patients who smoke. Allergy Asthma Immunol Res 2014;6:114120.
5. Contoli M, Kraft M, Hamid Q, Bousquet J, Rabe KF, Fabbri LM, Papi A. Do small airway abnormalities characterize asthma phenotypes? In search of proof. Clin Exp Allergy 2012;42:11501160.
6. Strulovici-Barel Y, Omberg L, O’Mahony M, Gordon C, Hollmann C, Tilley AE, Salit J, Mezey J, Harvey BG, Crystal RG. Threshold of biologic responses of the small airway epithelium to low levels of tobacco smoke. Am J Respir Crit Care Med 2010;182:15241532.
7. van der Wiel E, ten Hacken NH, Postma DS, van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: a systematic review. J Allergy Clin Immunol 2013;131:646657.
8. Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone: a cross-over study in healthy volunteers. Chest 2002;122:510516.
9. Cohen J, Postma DS, Douma WR, Vonk JM, De Boer AH, ten Hacken NH. Particle size matters: diagnostics and treatment of small airways involvement in asthma. Eur Respir J 2011;37:532540.
10. Price D, Martin RJ, Milton-Edwards M, Israel E, Roche N, Burden A, von Ziegenweidt J, Gould SE, Hillyer E, Colice GL. Comparative effectiveness of extrafine hydrofluoroalkane beclomethasone (EF HFA-BDP) and fluticasone propionate (FP) in smoking asthmatic patients—a retrospective, real-life observational study in a UK primary care asthma population [abstract]. J Allergy Clin Immunol 2013;131:AB3.
11. Price D, Martin RJ, Milton-Edwards M, Israel E, Roche N, Burden A, von Ziegenweidt J, Gould SE, Hillyer E, Colice GL. Comparative effectiveness of extrafine hydrofluoroalkane beclometasone (EF HFA-BDP) and fluticasone propionate (FP) in smoking asthmatic patients—a retrospective, real-life observational study in a UK primary care asthma population [abstract]. Prim Care Respir J 2013;22:A8.
12. Clinical Practice Research Datalink. Welcome to The Clinical Practice Research Datalink [accessed 2014 Nov 24]. Available from:
13. Optimum Patient Care (OPC). OPC Home [accessed 2014 Nov 24]. Available from:
14. Cripps A, Riebe M, Schulze M, Woodhouse R. Pharmaceutical transition to non-CFC pressurized metered dose inhalers. Respir Med 2000;94(Suppl B):S3S9.
15. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, Chanez P, Enright PL, Gibson PG, et al.; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180:5999.
16. Telenga ED, Kerstjens HA, Ten Hacken NH, Postma DS, van den Berge M. Inflammation and corticosteroid responsiveness in ex-, current- and never-smoking asthmatics. BMC Pulm Med 2013;13:58.
17. Becklake MR, Lalloo U. The ‘healthy smoker’: a phenomenon of health selection? Respiration 1990;57:137144.
18. Price D, Martin RJ, Barnes N, Dorinsky P, Israel E, Roche N, Chisholm A, Hillyer EV, Kemp L, Lee AJ, et al. Prescribing practices and asthma control with hydrofluoroalkane-beclomethasone and fluticasone: a real-world observational study. J Allergy Clin Immunol 2010;126:511518.
19. Colice G, Martin RJ, Israel E, Roche N, Barnes N, Burden A, Polos P, Dorinsky P, Hillyer EV, Lee AJ, et al. Asthma outcomes and costs of therapy with extrafine beclomethasone and fluticasone. J Allergy Clin Immunol 2013;132:4554.

Supported by an unrestricted grant from Teva Pharmaceuticals Limited of Petach Tikva, Israel (for data acquisition and analysis). Access to data from the Optimum Patient Care Research Database was cofunded by Research in Real-Life Ltd.

Author disclosures are available with the text of this letter at


No related items
Comments Post a Comment

New User Registration

Not Yet Registered?
Benefits of Registration Include:
 •  A Unique User Profile that will allow you to manage your current subscriptions (including online access)
 •  The ability to create favorites lists down to the article level
 •  The ability to customize email alerts to receive specific notifications about the topics you care most about and special offers
American Journal of Respiratory and Critical Care Medicine

Click to see any corrections or updates and to confirm this is the authentic version of record