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Published ahead of print on April 27, 2006, doi:10.1164/rccm.200510-1589OC
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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 127-133, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200510-1589OC

Original Article

Effects of Smoking Cessation on Lung Function and Airway Inflammation in Smokers with Asthma

Rekha Chaudhuri, Eric Livingston, Alex D. McMahon, Jane Lafferty, Iona Fraser, Mark Spears, Charles P. McSharry and Neil C. Thomson

Departments of Respiratory Medicine and Immunology, University of Glasgow; and Robertson Centre for Biostatistics, Glasgow, United Kingdom

Correspondence and requests for reprints should be addressed to Neil C. Thomson, FRCP, Department of Respiratory Medicine, Division of Immunology, Infection and Inflammation, University of Glasgow and Western Infirmary, Glasgow G11 6NT, UK. E-mail: n.c.thomson{at}clinmed.gla.ac.uk


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Active smoking in asthma is associated with worsening of symptoms, accelerated decline in lung function, and impaired response to corticosteroids.

Objectives: To examine the short-term effects of smoking cessation on lung function, airway inflammation, and corticosteroid responsiveness in smokers with asthma.

Methods and Measurements: Smokers with asthma were given the option to quit or continue smoking. Both groups underwent spirometry and induced sputum at baseline and at 1, 3, and 6 wk. Cutaneous vasoconstrictor response to topical beclometasone, airway response to oral prednisolone, and sensitivity of peripheral blood lymphocytes to corticosteroids were measured before smoking cessation and at 6 wk.

Main Results: Of 32 subjects recruited, 11 opted to continue smoking (smoking control group). Of 21 subjects who opted for smoking cessation, 10 quit smoking for 6 wk (quit group). In the comparison of quitters with smokers at 6 wk, the mean (confidence interval [CI]) difference in FEV1 was 407 ml (21, 793), p = 0.040, and the proportion of sputum neutrophils was reduced by 29 (51, 8), p = 0.039. Total cutaneous vasoconstrictor response score to topical beclometasone improved after smoking cessation with a mean (CI) difference of 3.56 (0.84, 6.28), p = 0.042, between quitters and smokers. There was no change in airway corticosteroid responses after smoking cessation.

Conclusions: By 6 wk after smoking cessation, subjects who quit smoking had achieved considerable improvement in lung function and a fall in sputum neutrophil count compared with subjects who continued to smoke. These findings highlight the importance of smoking cessation in asthma.

Key Words: airway inflammation • asthma • lung function • smoking • smoking cessation

Active cigarette smoking has detrimental effects on asthma morbidity. Compared with nonsmokers with asthma, smokers with asthma have more severe symptoms (1, 2), increased rates of hospitalization (3), accelerated decline in lung function (4, 5), and impaired therapeutic responses to inhaled (6, 7) and oral corticosteroids (8). Furthermore, the prevalence rates for cigarette smoking in individuals with asthma are similar to that of the general population (9), and in many developed countries more than 20% of adults with asthma are active smokers (1, 2, 9–12). Particularly high rates have been noted in adults presenting to hospital emergency departments with acute asthma (3). There is limited information on the effects of cigarette smoking on airway inflammation in asthma (13). Sputum neutrophil counts are reported to be increased in heavy smokers with mild asthma compared with nonsmokers with asthma (14), and sputum concentrations of cytokines such as interleukin 8 (IL-8) are raised (14) and others such as IL-18 are suppressed (15) in smokers with asthma.

Despite its importance, there are limited published data on the effects of smoking cessation on symptoms, lung function, and corticosteroid responsiveness in smokers with asthma. In an uncontrolled study, seven subjects who quit smoking for a week showed improvements in symptoms and lung function (16). In a longer term study, a prospective cohort of smokers with asthma reported improvements in symptoms and bronchial hyperreactivity after 4 mo of smoking cessation (17). In 10 subjects with asthma who were ex-smokers for at least a year, the therapeutic response to oral corticosteroids was midway between that of current smokers and never smokers, suggesting that smoking cessation may partially restore corticosteroid responsiveness (8).

The effect of smoking cessation on airway inflammation in healthy smokers shows a dose-dependent relationship between smoking and airway inflammation (18). In these subjects, 2 mo smoking reduction led to a significant fall in bronchoalveolar lavage neutrophil and macrophage counts (19). In contrast to the improvement in airway inflammation found in healthy smokers after smoking cessation, there was minimal change in airway inflammation in patients with chronic obstructive pulmonary disease (COPD) after quitting smoking (20–22), and the effect of smoking cessation on airway inflammation in smokers with asthma is not known.

Our hypothesis is that smoking cessation improves lung function, reduces airway inflammation, and restores corticosteroid responsiveness in smokers with asthma. The aim of the study was to prospectively study smokers with asthma who successfully quit smoking and compare outcome measures with smokers with asthma who continued to smoke; measurements included lung function, asthma control score, induced sputum cell counts, and mediator levels. A secondary aim was to assess the airway, cutaneous, and lymphocyte sensitivity to corticosteroids after smoking cessation. Some of the results have been reported in abstract form (23).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Smokers with asthma (American Thoracic Society [ATS] criteria [24]), aged 18–60 yr, with baseline FEV1 <= 85% predicted, >= 15% reversibility of FEV1 after nebulized albuterol, a smoking history of >= 10 pack-years, and currently smoking >= 10 cigarettes/d were recruited. The study was approved by the West Glasgow Ethics Committee.

Study Design
This was a prospective, controlled study. Airway corticosteroid sensitivity to oral prednisolone, 40 mg daily for 14 d, was assessed in all subjects by change in prealbuterol FEV1, asthma control score, morning and evening PEF, daily morning and night symptoms, and use of beta-agonist inhalers. Subjects were recalled to discuss smoking cessation 2 to 12 mo after the corticosteroid trial. Spirometry, induced sputum, exhaled nitric oxide (FENO), exhaled carbon monoxide (CO), asthma control score, skin vasoconstrictor response to beclometasone, serum cotinine, and peripheral blood lymphocyte proliferation assay were performed. All subjects were given the option to quit or continue smoking. Both groups were issued diary cards. Visits were arranged 1, 3, and 6 wk later. After the 6-wk visit, both groups received a second course of oral prednisolone of 40 mg daily for 14 d, with similar endpoints used to compare results. Spirometry, exhaled gases, and asthma control score were recorded at all visits; induced sputum at 3 and 6 wk; cutaneous vasoconstrictor test and peripheral blood lymphocyte proliferation assay at 6 wk. Patient adherence to smoking cessation was accepted by patient history.

Measurements
ATS asthma impairment score (25) and a validated asthma control questionnaire (26) were recorded. Patients maintained a validated diary card (27), recording morning and night PEF (Mini-Wright; Clement Clarke, Harlow, UK), daytime symptoms, night awakenings, use of inhaled rescue medication, and study tablet consumption. Spirometry was measured with a dry spirometer (Vitalograph Ltd., Buckingham, UK). Sputum was induced as previously described (14, 28, 29). FENO and CO were measured using a chemiluminescence analyzer (Logan Research Ltd., Rochester, UK) (30) and serum cotinine by enzyme immunoassay (Cozart Bioscience Ltd., Abingdon, UK). Treatment compliance was assessed by tablet count.

Cutaneous vasoconstrictor response to topical beclometasone was measured as described previously (31, 32). Concentrations of 0, 1, 3, 10, 30, 100, 300, and 1,000 µg/ml were applied to the skin in a random double-blind manner and the degree of blanching assessed visually after 18 h by a single trained observer. Blanching at each concentration was graded according to a 4-point scale (0–3) and a total score was calculated (0–24). Sensitivity of peripheral blood T lymphocytes to glucocorticoids was assessed in a functional assay as described previously (33). The percentage of suppression at the final concentration of corticosteroid used was defined as the maximum inhibitory dose (Imax %).

Statistical Analysis
Baseline characteristics were compared by {chi}2, Wilcoxon, and t tests. Response to smoking cessation on lung function, diary data, induced sputum, mediator levels, skin vasoconstrictor response, and oral prednisolone trials for smokers versus never smokers was assessed by analysis of covariance models that adjusted each factor by its baseline measure. Correlations were assessed by Spearman's rank correlations. Only those subjects who completed the study through the 6-wk visit were included in the analysis. Significance at a level of 5% was considered for the primary endpoint, the change in FEV1 at 6 wk. Tests were performed using SAS version 9.0 (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Recruitment
The flow of participants through the study is depicted in Figure 1. A group of 11 of the 32 subjects opted to continue smoking (smoking control subjects). Of the 21 who opted to attempt quitting smoking, 14 completed 1 wk of smoking cessation and 10 of these completed 6 wk.


Figure 1
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  		Figure 1. Flow of subjects through the study.

 
Baseline Characteristics
There were no differences in age, duration of asthma, equivalent dose of inhaled beclometasone, asthma control score, ATS impairment score, IgE levels, spirometry, skin vasoconstrictor test score, inhibitory dose of dexamethasone maximally suppressing lymphocyte proliferation in vitro, induced sputum cell counts, or inflammatory mediators between the smoking control and quit groups. Mean (SD) baseline FEV1 percentage predicted was 68 (11) in the quit group and 64 (94) in the control group (Tables 1 and 2). Baseline reversibility of FEV1 to inhaled albuterol, mean % (SD), was 25 (11) in the quit group and 19 (6) in the control group. Age, sex distribution, atopic status, smoking history, duration of asthma, and serum cotinine levels were similar in the successful quitters and those subjects who opted for the quit group but were unable to achieve a week off smoking (n = 7). Of the 10 subjects who successfully quit smoking and completed the study, five used nicotine patches, one used acupuncture, and four quit without any aid.


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  		TABLE 1. DEMOGRAPHICS AT BASELINE OF SMOKERS WITH ASTHMA WHO CONTINUED SMOKING VERSUS SMOKERS WITH ASTHMA WHO QUIT SMOKING

 

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  		TABLE 2. BASELINE INDUCED SPUTUM CELL COUNTS, MEDIATORS IN SPUTUM EXHALED GASES, AND TESTS OF CORTICOSTEROID RESPONSIVENESS IN TWO GROUPS OF SMOKERS WITH ASTHMA

 
Change in Lung Function, Asthma Control, and Airway Inflammatory Markers with Smoking Cessation
Lung function.
The mean (SD) change in FEV1 in ml in the quit group was 356 (278) at 1 wk, 390 (311) at 3 wk, and 450 (471) at 6 wk of smoking cessation (p values: 0.015, 0.009, and 0.031, respectively). There was no difference in the equivalent FEV1 measures in the smoking control group. In the comparison of quitters with control smokers at 6-wk cessation, there was a mean improvement of 407 ml in FEV1, 15.2% in FEV1% predicted and 93 L/min in PEF (Figure 2, Table 3). There was no correlation with the improvement in FEV1 and age, sex, atopy, duration of smoking, pack-years smoked, dose of inhaled corticosteroids, or sputum cell counts.


Figure 2
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  		Figure 2. Mean (95% confidence interval) difference between quitters and control smokers in change in FEV1 (ml) compared with baseline.

 

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  		TABLE 3. QUIT SMOKING GROUP VERSUS CONTINUED SMOKING GROUP OF SUBJECTS WITH ASTHMA

 
Asthma control.
The mean (confidence interval [CI]) asthma control score showed an improvement at 6 wk after smoking cessation of –1.2 (–2.2, –0.2; p = 0.021; Table 3).

Induced sputum.
Quitters showed a decrease in proportion of sputum neutrophils compared with control at 6 wk (mean % difference [CI], –29 [–51, –8]; p = 0.013), with no change in inflammatory mediator levels (Table 4). The mean (CI) difference for absolute neutrophil count in sputum at 3 wk cessation was –52 (–141, 36; p = 0.224); and at 6 wk it was –121 (–215, –26; p = 0.017). The degree of improvement in FEV1 was not related to the baseline neutrophil level (r = 0.24, p = 0.248) or the change in neutrophil proportion (r = –0.11, p = 0.819). There was no difference in mediator response in those quitters who used nicotine replacement therapy compared with those who did not.


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  		TABLE 4. CHANGE IN INDUCED SPUTUM CELL COUNTS AND MEDIATORS IN SMOKERS WITH ASTHMA AT 3 AND 6 wk AFTER SMOKING CESSATION COMPARED WITH SMOKING CONTROL SUBJECTS

 
Exhaled gases.
Compared with the control smokers, the quit group showed a reduction in exhaled CO at 1, 3, and 6 wk (Table 3). There was no change in exhaled NO levels.

Response to Corticosteroids
Airway response.
There was no difference in the FEV1 response to oral prednisolone while smoking or at 8 wk after smoking cessation in the control smokers compared with the quitters. The mean (CI) change in FEV1, in ml, with the first prednisolone course when subjects were smoking was 105 (–231, 441; p = 0.518) for the quit group versus the smoking control group and after 8 wk of smoking cessation, the difference was 190 (–121, 501; p = 0.214). Compliance with medication was 89% in the control group and 100% in the quit group for the first corticosteroid course and 89% in the control group and 100% in the quit group for the second course.

Cutaneous vasoconstrictor response to topical beclometasone.
The mean (CI) total cutaneous vasoconstrictor response score to topical beclometasone improved, comparing quitters with control smokers, after smoking cessation with a mean difference of 3.56 (0.84, 6.28; p = 0.014).

Lymphocyte proliferation response.
There was no difference in the lymphocyte proliferation response after 6 wk of smoking cessation. The mean difference (CI) Imax % for dexamethasone suppression of lymphocyte proliferation was –9.3 (–28.4, 9.9; p = 0.322), for quitters compared with smokers, and for prednisolone suppression was –4.0 (–17.1, 9.0; p = 0.522).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Active cigarette smoking is known to worsen the severity of asthma (13). This study has demonstrated that lung function of smokers with asthma improves by a considerable degree within a week of stopping smoking. This improvement in FEV1, mean (CI) at 1 wk, was of the order of 396 (129, 664) ml compared with those that continued to smoke, and this improvement increased up to 6 wk after smoking cessation. In addition, there was a fall in the sputum neutrophil counts, evident at 6 wk after smoking cessation.

Subjects in the quit group progressed through the study unless they admitted to smoking. This method of assessment of smoking status is known to overestimate the number of subjects who effectively quit smoking. Due to the short half-life, only daily measurements of carbon monoxide or cotinine could have provided objective evidence for smoking cessation in between clinic visits. Cotinine can be affected by nicotine replacement therapy used for cessation, and daily measurements for 8 wk were not feasible. However the reduction in exhaled carbon monoxide in the quit group compared with the control group at all visits provided objective evidence for effective smoking cessation, at least for the previous 24 to 48 h before each clinic assessment. If some of the subjects in the quit group had not stopped smoking completely, the results obtained may underestimate the extent of the improvement in lung function and neutrophil count possible with smoking cessation.

The improvement in lung function seen after smoking cessation was clinically significant. This demonstrates that there is a reversible component to the harmful effects of smoking on the airways in asthma. The degree of improvement noted by smoking cessation far exceeds that of high-dose antiinflammatory treatment, such as oral prednisolone, 40 mg daily for 2 wk, which had no effect on lung function in smokers in our current study and in our previous work (8). The improvement in lung function could be due to removal of the acute bronchoconstrictor effects of cigarette smoke (34) or a reduction in the proinflammatory effects of cigarette smoke on the airways (14). It is also possible that stopping smoking leads to a reduction in corticosteroid insensitivity, as ex-smokers who had quit smoking for at least 1 yr had a better response to oral prednisolone compared with current smokers (8). Reduced histone deacetylase activity is one of the possible mechanisms of corticosteroid insensitivity in smokers (34), but there are no reports of measurement of histone deacetylase levels after smoking cessation.

In asthma, there have been two previous studies looking at the effect of smoking cessation on lung function. The first was a small uncontrolled study in which seven subjects quit smoking for a week and showed improvements in PEF, symptoms, and specific airway conductance (16). There was a reduction in histamine airway responsiveness after 24 h of smoking cessation (16). A prospective cohort study compared the effects of smoking cessation, smoking reduction, and continuing smoking on asthma control and biomarkers of exposure to cigarette smoke (17). This study showed a significant improvement in symptoms and bronchial hyperreactivity after 4 mo of smoking cessation, but no change in FEV1. The baseline FEV1 % predicted was much higher than in our subjects and hence it is possible that scope for further improvement was limited.

In our study, although the asthma control score improved, we did not obtain improvement in symptoms in the diary card up to 2 mo after cessation. In a study by Hillerdahl and Rylander, two-thirds of subjects with asthma who quit smoking reported no improvement or worsening of symptoms after smoking cessation (35). A cross-sectional study of 3,197 subjects with asthma, including smokers, ex-smokers (stopped smoking for at least 1 yr), and nonsmokers, reported that exsmokers had significantly less cough, wheeze, night symptoms, and sputum production compared with current smokers, but a similar degree of shortness of breath (36). This implies that many, but not all, asthma symptoms can return to the level of never smokers with smoking cessation.

The raised sputum neutrophil count found in high intensity smokers with asthma (14, 37) may be partly responsible for their reduced responsiveness to corticosteroids. Unlike eosinophils, which are exquisitely sensitive to corticosteroids, neutrophils are poorly responsive to corticosteroid therapy (37) and their survival and proliferation is promoted by glucocorticoids (38). We demonstrated a reduction in induced sputum neutrophils with smoking cessation, but no change in mediator levels. We are unaware of any previous published studies that have measured airway inflammation in smokers with asthma after smoking cessation. In healthy heavy smokers bronchoalveolar lavage neutrophil counts were reduced 2 mo after smoking reduction (19). In contrast, the effect of smoking cessation on airway inflammation in chronic obstructive pulmonary disease has shown that most inflammatory cells, including neutrophils, persist in ex-smokers (20, 22, 39) and can even increase (40). The mechanisms by which the neutrophil count is reduced after smoking cessation are unclear at present. It seems unrelated to the continued presence of neutrophil chemoattractants leukotriene B4 and IL-8 in the airways, and may therefore be related to reduced diapedesis after the down-regulatory effects of smoking cessation on adhesion molecules (41), perhaps in addition to more efficient apoptosis of neutrophils by alveolar macrophages after smoking cessation (42, 43).

The short-term improvement in FEV1 was not related to the change in neutrophil count, which might suggest that the removal of bronchoconstrictor effects of cigarette smoke is more important than neutrophils themselves; but the small number of subjects studied may explain our findings. The levels of the inflammatory mediators in induced sputum did not change at 6 wk after smoking cessation. This result is similar to the finding in chronic obstructive pulmonary disease, where IL-8 levels in sputum were similar in smokers and ex-smokers (44), and chronic bronchitis, where bronchoalveolar lavage levels of tumor necrosis factor {alpha} were unaltered by smoking cessation (22). It is possible that clinical improvement may precede changes in inflammation, as in the Third National Health and Nutrition Examination Survey (NHANES III) inflammatory markers (C-reactive protein, white cell count, fibrinogen, and albumin) resolved more slowly than traditional cardiovascular risk factors (45).

Smoking cessation did not improve corticosteroid responsiveness measured by changes in FEV1 and PEF. However, there was a large improvement in baseline lung function with smoking cessation and it is possible that this reduced the scope for further improvement in lung function, after corticosteroids. In a previous study, ex-smokers with asthma who had quit smoking for at least a year showed an improvement in morning PEF, but not FEV1, after high-dose oral prednisolone compared with placebo (8).

The skin vasoconstrictor response to topical beclometasone (32, 46), which is based on the ability of corticosteroids to cause transient vasoconstriction and skin blanching, has been used as a screening test to determine the relative antiinflammatory potency of inhaled corticosteroids (47) and as an index of systemic sensitivity to corticosteroids (31). Objective methods of detecting glucocorticoid-induced skin blanching have been compared with the visual scoring system, but the human eye has been found to be the most sensitive tool to measure dermal blanching (32). The cutaneous vasoconstrictor test for corticosteroid sensitivity showed an improvement after 6 wk of cessation, implying some restoration in peripheral corticosteroid sensitivity within this period. The mechanism for skin vasoconstriction with corticosteroids is not known, but a possible explanation is that glucocorticoids increase the sensitivity of vascular smooth muscle to the vasoconstrictor effects of noradrenaline (48). The blanching is possibly mediated through glucocorticoid receptors, because oral administration of RU 486, a glucocorticoid receptor antagonist, can abolish this response (49). Smoking causes vascular dysfunction but the additive effect of nicotine on corticosteroids has not been studied in skin vasculature. The lymphocyte proliferative response did not alter with smoking cessation in our study. A lack of correlation between different tests of tissue sensitivity to corticosteroids has been reported previously in healthy human volunteers (50).

In conclusion, in smokers with asthma, improvement in lung function occurs as early as 1 wk after smoking cessation with a further improvement up to 6 wk. There is a reduction of sputum neutrophil percentage after 6 wk of smoking cessation but no change in common inflammatory mediator levels. These findings highlight the importance of smoking cessation in asthma.


   Acknowledgments
 
The authors thank Kathy McFall, Medical Illustration Department, North Glasgow NHS University Division, for assistance with the figures.


   FOOTNOTES
 
Supported by Asthma UK, Scottish Council for Postgraduate Medical and Dental Education and Chief Scientist Office, and Chest Heart and Stroke, Scotland.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200510-1589OC on April 27, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the manuscript.

Received in original form October 11, 2005; accepted in final form April 24, 2006


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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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