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Transcript of Smoking and asthma (effect on treatment) George Kontopyrgias MD, FCCP Respiratory department,...
Smoking and asthma (effect on treatment)
George Kontopyrgias MD, FCCPRespiratory department, Metropolitan General Hospital
Smoking and asthma(effect on treatment)
• Smoking asthma in numbers
• Clinical features
• Response to corticosteroids
• Other drugs
• Smoking cessation
Smoking and asthma(effect on treatment)
• Smoking asthma in numbers
• Clinical featuresClinical features
• Response to corticosteroidsResponse to corticosteroids
• Other drugsOther drugs
• Smoking cessationSmoking 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 2009Siroux V et al Eur Respir J 2000
Yun S et al Prev Med 2006
Smoking asthma in numbers
Higher prevalence rates
– AdolescentsTyc V et al Pediatrics 2006
– Developing countries
– 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
USA17 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 numbersSmoking asthma in numbers
• Clinical features
• Response to corticosteroidsResponse to corticosteroids
• Other drugsOther drugs
• Smoking cessationSmoking cessation
Clinical features
• More severe symptomsAlthuis et al J Asthma 1999
Siroux V et al Eur Respir J 2000
• Poorer controlBoulet 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 skillsAcute asthma Radeos et al AJEM 2001
Chronic asthma Marks et al ERJ 1997
Clinical features
Apostol G et al AJRCCM 2002
Decline in FEV1 (4000 adults, 18-30 yrs, followed up for 10 yrs)
Accelerated loss of lung function
In 10 yrs 8% FEV1
Clinical features
• Increased emergency department visitsBoulet L et al Can Respir J 2008
• Increased rates of hospitalizationSippel J et al Chest 1999
• Increased mortalityMarquette C Am Rev Respir Dis 1992
Smoking and asthma(effect on treatment)
• Smoking asthma in numbersSmoking asthma in numbers
• Clinical featuresClinical features
• Response to corticosteroids
• Other drugsOther drugs
• Smoking cessationSmoking 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
Pedersen B et al Am J Respir Crit Care Med 1996;153:1519-1529
1st study questioning the efficacy of ICS to asthmatic smokers
Inhaled corticosteroids
Randomized placebo controlled study
38 patients with mild asthma21 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
Chalmers G et al Thorax 2002;57:226-230
Inh fluticasone
Greater increase in PEF in nonsmokers compared
with smokers
27 L/min
- 5 L/min
P = 0.001
Inhaled corticosteroids
Chalmers G et al Thorax 2002;57:226-230
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”
Inhaled corticosteroids
Randomized controlled study (SMOG Trial)
Mild to moderate asthma44 non-smokers 39 smokers (7 pys)
Inh HFA-beclomethasone 320 μg/daytb montelukast 10mg/day
8 weeksLazarus S et al AJRCCM 2007;175:783-790
Inhaled corticosteroids
Lazarus S et al AJRCCM 2007;175:783-790
Smokers
Non -SmokersInh beclomethasone
Increased FEV1 only in non-smokers
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
12weeks
mPEF non-smokers > smokers
Non
smokers
Smokers
Tomlinson J et al Thorax 2005;60:282-287
Inhaled corticosteroids
400400μμggNon smokers better mPEF
Non-smokers less exacerbations
20002000μμgg(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 corticosteroidsRoute 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
Chaudhuri R et al AJRCCM 2003;168:1308-1311
Improvement in FEV1
in non smokers
but not in smokers
47ml 237ml
Oral corticosteroids
Chaudhuri R et al AJRCCM 2003;168:1308-1311
Improvement in
Asthma Control Score
in non smokers
but not in smokers
Oral corticosteroids
Chaudhuri R et al AJRCCM 2003;168:1308-1311
Oral corticosteroids are not effective
Partial response in the group of ex-smokers
Corticosteroid insensitivity is partially reversible?
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 non-smokers
O'Byrne et al Chest 2009;136:1514-1520
post hoc anlysis – no data about smoking intensity
patients could have concurrent therapy with inh or oral CS to achieve asthma control
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 activityOakley RJ et al J Biol Chem 1999
Smokers have decreased glucocorticoid receptor α/β ratioLivingston 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 numbersSmoking asthma in numbers
• Clinical featuresClinical features
• Response to corticosteroidsResponse to corticosteroids
• Other drugs
• Smoking cessationSmoking cessation
Other drugs
Restore steroid sensitivity ?
Combination therapy ?
Effective drugs ?
New drugs ?
Other drugs
Restore steroid sensitivity
Combination therapy Combination therapy
Effective drugs Effective drugs
New drugsNew 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
TheophyllineLow dose theophylline added to beclometasone
(mean concentration of theophylline = 4.3 mg/L)
1. Improvement in PEF2. Improvement in ACQ score3. Borderline improvement in preFEV1
Low dose theophylline alone(mean concentration of theophylline = 4.9 mg/L)
1. Improvement in ACQ score2. 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 sensitivityRestore steroid sensitivity
Combination therapy
Effective drugs Effective drugs
New 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
Iwamoto H et al Eur Respir J 2008
Comparable results for smokers and non-smokers
Tiotropium as an add on therapy
Other drugs
Restore steroid sensitivityRestore steroid sensitivity
Combination therapyCombination therapy
Effective drugs
New drugs New drugs
Leukotriene receptor antagonists
Smoking dose related increase in urinary LTE4Fauler 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 LTE4YES in asthma patientsNO 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
Smokers
Non -Smokers
MontelukastIncreased morning
PEF onlyin smokers
Lazarus S et al AJRCCM 2007;175:783-790
Leukotriene receptor antagonists
Smokers
Non -Smokers
Montelukastno effect on PC20
Lazarus S et al AJRCCM 2007;175:783-790
Leukotriene receptor antagonists
Smokers
Non -Smokers
Montelukastno effect on
sputum eosinophils
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 sensitivityRestore steroid sensitivity
Combination therapyCombination therapy
Effective drugs Effective drugs
New drugs
New drugs
Better Steroids (inhalers, safety profile)
Antioxidants
Target specific cells or mediatorsanti 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 numbersSmoking asthma in numbers
• Clinical featuresClinical features
• Response to corticosteroidsResponse to corticosteroids
• Other drugsOther 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 symptomsReduce airway hyperresponsivenessReduce need for rescue medication
Tonnesen et al Nicotine Tob Res 2005
Smoking cessation
Jang AS et al Allergy Asthma Immunol Res. 2010;2:254-259
10 quitters - asthma
22 smokers – asthma
Inh Fluticasone 1mg/day
3 months
% change FEV1
% change FEV1/FVC
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
Chaudhuri R et al AJRCCM 2006;174:127-133
1. Improvement in lung function ( ↑ FEV1 407 ml after 6wks)2. Improvement in Asthma Control Score
Smoking cessation
Chaudhuri R et al AJRCCM 2006;174:127-133
3. Fall in sputum neutrophil count4. Better results than 40 mg prednisolone for 2 wks
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