1. Smoking and asthma (effect on treatment)
George Kontopyrgias MD, FCCP
Respiratory department, Metropolitan General Hospital

2. Smoking and asthma (effect on treatment)
Smoking asthma in numbers
Clinical features
Response to corticosteroids
Other drugs
Smoking cessation

3. Smoking and asthma (effect on treatment)
Smoking asthma in numbers
Clinical features
Response to corticosteroids
Other drugs
Smoking cessation

4. 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

5. Smoking asthma in numbers
Higher prevalence rates
Adolescents
Tyc 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

6. 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

7. Smoking and asthma (effect on treatment)
Smoking asthma in numbers
Clinical features
Response to corticosteroids
Other drugs
Smoking cessation

8. Clinical features More severe symptoms Poorer control
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

9. Current smokers with asthma
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 Radeos et al AJEM 2001
Chronic asthma Marks et al ERJ 1997

10. Clinical features Accelerated loss of lung function
Decline in FEV1 (4000 adults, yrs, followed up for 10 yrs)
In 10 yrs 8% FEV1
Apostol G et al AJRCCM 2002

11. 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

12. Smoking and asthma (effect on treatment)
Smoking asthma in numbers
Clinical features
Response to corticosteroids
Other drugs
Smoking cessation

13. 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

14. Inhaled corticosteroids
1st study questioning the efficacy of ICS to asthmatic smokers
Pedersen B et al Am J Respir Crit Care Med 1996;153:

15. 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:

16. 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:

17. 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:

18. 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:

19. Inhaled corticosteroids
Inh beclomethasone
Increased FEV1 only in non-smokers
Non -Smokers
Smokers
Lazarus S et al AJRCCM 2007;175:

20. 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:

21. Inhaled corticosteroids
Non
smokers
Smokers
12weeks
mPEF non-smokers > smokers
Tomlinson J et al Thorax 2005;60:

22. Inhaled corticosteroids
400μg
Non smokers  better mPEF
Non-smokers  less exacerbations
2000μg
(same results smaller differences)
Tomlinson J et al Thorax 2005;60:

23. 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:

24. Route of administration?
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:

25. Oral corticosteroids Improvement in FEV1 in non smokers
but not in smokers
237ml
47ml
Chaudhuri R et al AJRCCM 2003;168:

26. Oral corticosteroids Improvement in Asthma Control Score
in non smokers
but not in smokers
Chaudhuri R et al AJRCCM 2003;168:

27. 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:

28. 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:

29. Inhaled corticosteroids
The rate of decline in FEV1 of smokers was greater than in non- smokers (placebo arm)
Inh budesonide could equally attenuate the decline in FEV1 in smokers and in non-smokers
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:

30. 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

31. 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

32. 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

33. Smoking and asthma (effect on treatment)
Smoking asthma in numbers
Clinical features
Response to corticosteroids
Other drugs
Smoking cessation

34. Restore steroid sensitivity ?
Other drugs
Restore steroid sensitivity ?
Combination therapy ?
Effective drugs ?
New drugs ?

35. Restore steroid sensitivity
Other drugs
Restore steroid sensitivity
Combination therapy
Effective drugs
New drugs

36. Theophylline

37. Theophylline
Theophylline increases HDAC activity in alveolar macrophages in smokers
Cosio B J Exp Med 2004;200:689–695

38. Theophylline
Low dose theophylline increases HDAC activity and improves the anti-inflammatory effects of steroids during COPD exacerbations
Cosio B Thorax 2009;64:

39. Theophylline Double blind parallel group pilot study
68 asthmatic smokers
Inh beclomethasone 200 μg/day
tb theophylline 400 mg/day
Both treatments combined
4 weeks
Spears et al Eur Respir J 2009;33:

40. Theophylline Low dose theophylline added to beclometasone
(mean concentration of theophylline = 4.3 mg/L)
Improvement in PEF
Improvement in ACQ score
Borderline improvement in preFEV1
Low dose theophylline alone
(mean concentration of theophylline = 4.9 mg/L)
No improvement in lung function
“These results need to be confirmed in larger trials”
Spears et al Eur Respir J 2009;33:

41. Restore steroid sensitivity
Other drugs
Restore steroid sensitivity
Combination therapy
Effective drugs
New drugs

42. 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

43. Combination therapy Tiotropium as an add on therapy
Comparable results for smokers and non-smokers
Iwamoto H et al Eur Respir J 2008

44. Restore steroid sensitivity
Other drugs
Restore steroid sensitivity
Combination therapy
Effective drugs
New drugs

45. 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

46. 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:

47. Leukotriene receptor antagonists
Non -Smokers
Montelukast
Increased morning PEF only
in smokers
Smokers
Lazarus S et al AJRCCM 2007;175:

48. Leukotriene receptor antagonists
Non -Smokers
Montelukast
no effect on PC20
Smokers
Lazarus S et al AJRCCM 2007;175:

49. Leukotriene receptor antagonists
Non -Smokers
Montelukast
no effect on
sputum eosinophils
Smokers
Lazarus S et al AJRCCM 2007;175:

50. Leukotriene receptor antagonists
Efficacy and safety of montelukast in smokers with asthma ?

51. Restore steroid sensitivity
Other drugs
Restore steroid sensitivity
Combination therapy
Effective drugs
New drugs

52. 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

53. Smoking and asthma (effect on treatment)
Smoking asthma in numbers
Clinical features
Response to corticosteroids
Other drugs
Smoking cessation

54. 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

55. 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:

56. Smoking cessation Prospective, controlled study Asthma patients
10 continue smoking VS 10 quit smoking
6 weeks
Chaudhuri R et al AJRCCM 2006;174:

57. Smoking cessation
Improvement in lung function ( ↑ FEV1 407 ml after 6wks)
Improvement in Asthma Control Score
Chaudhuri R et al AJRCCM 2006;174:

58. 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:

59. Smoking cessation Improved lung function (starting the 1st week)
Change in inflammatory pattern
Better asthma control
Chaudhuri R et al AJRCCM 2006;174:

60. Smoking cessation

61. 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)

62. Thank you