Smoking and asthma
(effect on treatment)
George Kontopyrgias MD, FCCP
Respiratory department, Metropolitan General Hospital
Smoking and asthma
(effect on treatment)
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Smoking asthma in numbers
Clinical features
Response to corticosteroids
Other drugs
Smoking cessation
Smoking and asthma
(effect on treatment)
• Smoking asthma in numbers
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Clinical features
Response to corticosteroids
Other drugs
Smoking cessation
Smoking asthma in numbers
Prevalence rates similar to general population
20 – 30% of asthma patients are active smokers
20 – 30% of asthma patients are former smokers
1/2
of asthma patients are active or former smokers
Demoly P et al Eur Respir Rev 2009
Siroux V et al Eur Respir J 2000
Yun S et al Prev Med 2006
Smoking asthma in numbers
Higher prevalence rates
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Adolescents
Tyc V et al Pediatrics 2006
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Developing countries
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35% of asthma patients in emergency departments
(50% smoking makes their asthma worse)
(4% smoking might have been the trigger)
Silverman R et al Chest 2003
Smoking asthma in numbers
USA
17 million Americans have asthma
30% of asthma patients are active smokers
5 million Americans smokers with asthma
60% have persistent asthma
require 1 canister of inh CS / month
$ 2.2 billion per year for inh CS
Lazarus S et al AJRCCM 2007
Smoking and asthma
(effect on treatment)
• Smoking asthma in numbers
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Clinical features
Response to corticosteroids
Other drugs
Smoking cessation
Clinical features
• More severe symptoms
Althuis et al J Asthma 1999
Siroux V et al Eur Respir J 2000
• Poorer control
Boulet L et al Can Respir J 2008
Demoly P et al Eur Respir Rev 2009
• Worse asthma-specific quality of life
Eisner et al Nicotine Tob Res 2007
Clinical features
Current smokers with asthma
Less likely to attend asthma education programs
Abdulwadud et al Resp Med 1997
Gallefoss et al ERJ 2000
Lack of self-management skills
Acute asthma
Chronic asthma
Radeos et al AJEM 2001
Marks et al ERJ 1997
Clinical features
Accelerated loss of lung function
Decline in FEV1 (4000 adults, 18-30 yrs, followed up for 10 yrs)
In 10 yrs
8% FEV1
Apostol G et al AJRCCM 2002
Clinical features
• Increased emergency department visits
Boulet L et al Can Respir J 2008
• Increased rates of hospitalization
Sippel J et al Chest 1999
• Increased mortality
Marquette C Am Rev Respir Dis 1992
Smoking and asthma
(effect on treatment)
• Smoking asthma in numbers
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Clinical features
Response to corticosteroids
Other drugs
Smoking cessation
Inhaled corticosteroids
 ICS are recommended as 1st line treatment in
international guidelines
 The evidence for this recommendation is based on
clinical trials in never smokers or ex-smokers
 Some studies suggest that efficacy of
corticosteroids is reduced in asthma patients that
are active smokers
Inhaled corticosteroids
1st study questioning the efficacy of ICS to asthmatic smokers
Pedersen B et al Am J Respir Crit Care Med 1996;153:1519-1529
Inhaled corticosteroids
Randomized placebo controlled study
38 patients with mild asthma
21 non-smokers and 17 smokers
Inh fluticasone 1 mg/day vs placebo
3 weeks
Chalmers G et al Thorax 2002;57:226-230
Inhaled corticosteroids
P = 0.001
Inh fluticasone
Greater increase in PEF
in nonsmokers compared
with smokers
27 L/min
- 5 L/min
Chalmers G et al Thorax 2002;57:226-230
Inhaled corticosteroids
Only in non smokers
• Increase in PEF
• Increase in FEV1
• Increase in PC20
• Decrease in sputum eosinophils
“active smoking impairs the efficacy of short term
inhaled corticosteroids”
Chalmers G et al Thorax 2002;57:226-230
Inhaled corticosteroids
Randomized controlled study (SMOG Trial)
Mild to moderate asthma
44 non-smokers 39 smokers (7 pys)
Inh HFA-beclomethasone 320 μg/day
tb montelukast 10mg/day
8 weeks
Lazarus S et al AJRCCM 2007;175:783-790
Inhaled corticosteroids
Inh beclomethasone
Increased FEV1
only in non-smokers
Non -Smokers
Smokers
Lazarus S et al AJRCCM 2007;175:783-790
Inhaled corticosteroids
Higher dose? Longer period of treatment?
Randomized double blind, parallel group study
95 patients with mild asthma
Inh beclomethasone 400 μg (19 smokers vs 28 non-smokers)
Inh beclomethasone 2000 μg (21 smokers vs 27 non-smokers)
12 weeks
Tomlinson J et al Thorax 2005;60:282-287
Inhaled corticosteroids
Non
smokers
Smokers
mPEF
12weeks
non-smokers > smokers
Tomlinson J et al Thorax 2005;60:282-287
Inhaled corticosteroids
400μg
Non smokers
Non-smokers
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
better mPEF
less exacerbations
2000μg
(same results smaller differences)
Tomlinson J et al Thorax 2005;60:282-287
Inhaled corticosteroids
Low doses are ineffective even for longer treatment
Fail to reduce exacerbations
Higher doses are more effective
Safety issues !!
Tomlinson J et al Thorax 2005;60:282-287
Oral corticosteroids
Route of administration?
Randomized placebo controlled study
Asthma patients
26 non-smokers 10 ex-smokers 14 smokers
Oral prednisolone 40 mg/day vs placebo
2 weeks
Chaudhuri R et al AJRCCM 2003;168:1308-1311
Oral corticosteroids
Improvement in FEV1
in non smokers
but not in smokers
47ml
237ml
Chaudhuri R et al AJRCCM 2003;168:1308-1311
Oral corticosteroids
Improvement in
Asthma Control Score
in non smokers
but not in smokers
Chaudhuri R et al AJRCCM 2003;168:1308-1311
Oral corticosteroids
Oral corticosteroids are not effective
Partial response in the group of ex-smokers
Corticosteroid insensitivity is partially reversible?
Chaudhuri R et al AJRCCM 2003;168:1308-1311
Inhaled corticosteroids
START study (post hoc analysis)
492 smokers and 2432 nonsmokers
Inhaled budesonide 400 μg or placebo
3 years
O'Byrne et al Chest 2009;136:1514-1520
Inhaled corticosteroids
1. The rate of decline in FEV1 of
smokers was greater than in
non- smokers (placebo arm)
2. Inh budesonide could equally
attenuate the decline in FEV1
in smokers and in nonsmokers
 post hoc anlysis – no data about smoking intensity
 patients could have concurrent therapy with inh or oral CS
to achieve asthma control
O'Byrne et al Chest 2009;136:1514-1520
Corticosteroid insensitivity
A) Altered airway inflammation
Increased neutrophils in sputum of smokers with asthma
Chalmers G et al Chest 2001
Neutrophilia in the airways is associated with a poor
response to inhaled corticosteroids in asthma
Green R et al Thorax 2002
Corticosteroid insensitivity
B) Altered α/β glucocorticosteroid receptor ratio
Glucocorticosteroid receptor β variant has negative activity
Oakley RJ et al J Biol Chem 1999
Smokers have decreased glucocorticoid receptor α/β ratio
Livingston E et al J Allergy Clin Immunol 2004
More GR-β  less glucocorticoid effectiveness
Corticosteroid insensitivity
C) Reduced histone deacetylase 2 (HDAC2) activity
Smoking  oxidative stress  ↓ HDAC2 activity 
↓antiinflammatory activity of GCS
Barnes PJ Proc Am Thorac Soc 2009
Smoking and asthma
(effect on treatment)
• Smoking asthma in numbers
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•
•
•
Clinical features
Response to corticosteroids
Other drugs
Smoking cessation
Other drugs
Restore steroid sensitivity ?
Combination therapy ?
Effective drugs ?
New drugs ?
Other drugs
Restore steroid sensitivity
Combination therapy
Effective drugs
New drugs
Theophylline
Theophylline
Theophylline increases HDAC activity in alveolar
macrophages in smokers
Cosio B J Exp Med 2004;200:689–695
Theophylline
Low dose theophylline increases HDAC activity and
improves the anti-inflammatory effects of steroids
during COPD exacerbations
Cosio B Thorax 2009;64:424-429
Theophylline
Double blind parallel group pilot study
68 asthmatic smokers
1. Inh beclomethasone 200 μg/day
2. tb theophylline 400 mg/day
3. Both treatments combined
4 weeks
Spears et al Eur Respir J 2009;33:1010-1017
Theophylline
Low dose theophylline added to beclometasone
(mean concentration of theophylline = 4.3 mg/L)
1. Improvement in PEF
2. Improvement in ACQ score
3. Borderline improvement in preFEV1
Low dose theophylline alone
(mean concentration of theophylline = 4.9 mg/L)
1. Improvement in ACQ score
2. No improvement in lung function
“These results need to be confirmed in larger trials”
Spears et al Eur Respir J 2009;33:1010-1017
Other drugs
Restore steroid sensitivity
Combination therapy
Effective drugs
New drugs
Combination therapy
ICS + LABA
Post hoc analysis of GOAL trial
ICS + LABA VS ICS
Reduction in exacerbation rates with ICS+LABA in smokers
Boushey et al J Allergy Clin Immunol 2005
Combination therapy
Tiotropium as an add on therapy
Comparable results for smokers and non-smokers
Iwamoto H et al Eur Respir J 2008
Other drugs
Restore steroid sensitivity
Combination therapy
Effective drugs
New drugs
Leukotriene receptor antagonists
Smoking  dose related increase in urinary LTE4
Fauler J et al Eur J Clin Invest 1997
“Healthy” smokers  Increased 15-lipoxygenase
activity in the airways
Zhu J et al Am J Respir Cell Mol Biol 2002
Smoking  increase in urinary LTE4
YES in asthma patients
NO in COPD
NO in “normal” subjects
Gaki E et al Respir Med 2007
Leukotriene receptor antagonists
Randomized placebo controlled study (SMOG Trial)
Mild to moderate asthma
44 non-smokers 39 smokers
Inh HFA-beclomethasone 320 μg/day
oral montelukast 10 mg
8 weeks
Lazarus S et al AJRCCM 2007;175:783-790
Leukotriene receptor antagonists
Non -Smokers
Montelukast
Increased morning
PEF only
in smokers
Smokers
Lazarus S et al AJRCCM 2007;175:783-790
Leukotriene receptor antagonists
Non -Smokers
Montelukast
no effect on PC20
Smokers
Lazarus S et al AJRCCM 2007;175:783-790
Leukotriene receptor antagonists
Non -Smokers
Montelukast
no effect on
sputum eosinophils
Smokers
Lazarus S et al AJRCCM 2007;175:783-790
Leukotriene receptor antagonists
Efficacy and safety of montelukast in smokers with asthma ?
Other drugs
Restore steroid sensitivity
Combination therapy
Effective drugs
New drugs
New drugs
Better Steroids (inhalers, safety profile)
Antioxidants
Target specific cells or mediators
anti IL-8 (neutrophils)
anti IL-1β
anti TNFα
Target NF-κB
Better drugs for smoking cessation
Smoking and asthma
(effect on treatment)
• Smoking asthma in numbers
•
•
•
•
Clinical features
Response to corticosteroids
Other drugs
Smoking cessation
Smoking cessation
Ex-smokers with asthma (stopped for at least 1 year)
Improvement in many symptoms (wheeze, cough)
Suzuki K J Asthma 2003
(27 out of 220 smoker asthmatics quit smoking for 4 months)
Reduce respiratory symptoms
Reduce airway hyperresponsiveness
Reduce need for rescue medication
Tonnesen et al Nicotine Tob Res 2005
Smoking cessation
10 quitters - asthma
22 smokers – asthma
Inh Fluticasone 1mg/day
3 months
% change FEV1
% change FEV1/FVC
Jang AS et al Allergy Asthma Immunol Res. 2010;2:254-259
Smoking cessation
Prospective, controlled study
Asthma patients
10 continue smoking VS 10 quit smoking
6 weeks
Chaudhuri R et al AJRCCM 2006;174:127-133
Smoking cessation
1. Improvement in lung function ( ↑ FEV1 407 ml after 6wks)
2. Improvement in Asthma Control Score
Chaudhuri R et al AJRCCM 2006;174:127-133
Smoking cessation
3. Fall in sputum neutrophil count
4. Better results than 40 mg prednisolone for 2 wks
Chaudhuri R et al AJRCCM 2006;174:127-133
Smoking cessation
Improved lung function (starting the 1st week)
Change in inflammatory pattern
Better asthma control
Chaudhuri R et al AJRCCM 2006;174:127-133
Smoking cessation
Conclusions
• Smoking cessation the best option
• International guidelines
– Step-up in treatment is likely to be required at an
earlier stage of the disease
– Higher doses of ICS
– Leukotriene receptor antagonists
– Theophylline
• We need more data from clinical trials
(older patients, overlap COPD and asthma)
Thank you