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

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Presentation on theme: "Smoking and asthma (effect on treatment) George Kontopyrgias MD, FCCP Respiratory department, Metropolitan General Hospital."— Presentation transcript:

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)

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)

8 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

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

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)

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

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 Chalmers G et al Thorax 2002;57: Inh fluticasone Greater increase in PEF in nonsmokers compared with smokers 27 L/min - 5 L/min P = 0.001

17 Inhaled corticosteroids Chalmers G et al Thorax 2002;57: Only in non smokers Increase in PEF Increase in FEV1 Increase in PC 20 Decrease in sputum eosinophils “active smoking impairs the efficacy of short term inhaled corticosteroids”

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

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 12weeks mPEFnon-smokers > smokers 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 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 Chaudhuri R et al AJRCCM 2003;168: Improvement in FEV1 in non smokers but not in smokers 47ml 237ml

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

27 Oral corticosteroids Chaudhuri R et al AJRCCM 2003;168: Oral corticosteroids are not effective Partial response in the group of ex-smokers Corticosteroid insensitivity is partially reversible?

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 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:  post hoc anlysis – no data about smoking intensity  patients could have concurrent therapy with inh or oral CS to achieve asthma control

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)

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

35 Other drugs

36 Theophylline

37 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 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:

40 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:

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

44 Other 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 Smokers Non -Smokers Montelukast Increased morning PEF only in smokers Lazarus S et al AJRCCM 2007;175:

48 Leukotriene receptor antagonists Smokers Non -Smokers Montelukast no effect on PC 20 Lazarus S et al AJRCCM 2007;175:

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

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

51 Other 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)

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 Jang AS et al Allergy Asthma Immunol Res. 2010;2: quitters - asthma 22 smokers – asthma Inh Fluticasone 1mg/day 3 months % change FEV1 % change FEV1/FVC

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 Chaudhuri R et al AJRCCM 2006;174: Improvement in lung function ( ↑ FEV1 407 ml after 6wks) 2.Improvement in Asthma Control Score

58 Smoking cessation Chaudhuri R et al AJRCCM 2006;174: Fall in sputum neutrophil count 4. Better results than 40 mg prednisolone for 2 wks

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


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