The Pulmonologist’s Guide The Pulmonologist’s Guide to the Pulmonary Consequences to the Pulmonary Consequences

of Smoking and the Benefits of of Smoking and the Benefits of CessationCessation

OverviewOverview

Chronic obstructive pulmonary disease (COPD)Chronic obstructive pulmonary disease (COPD)– EmphysemaEmphysema– Chronic bronchitisChronic bronchitis

AsthmaAsthma

Lung cancerLung cancer

GOLD Initiative 2006. http://www.goldcopd.com. Accessed July 24, 2007;Celli et al. Eur Respir J. 2004;23:932-946.

Smoking and COPDSmoking and COPD

Cumulative Incidence of COPDCumulative Incidence of COPD For continuous smokers it is 35.5% and for never smokers it is 7.8%For continuous smokers it is 35.5% and for never smokers it is 7.8%aa

aCalculated incidence rates for COPD, men and women combined. bStaging was done according to the criteria of the American Thoracic Society and the European Respiratory Society. cStudy participants were evaluated 4 times over a 30-year period. “Early intermediate and late quitters” refer to those who stopped smoking between the first and second, second and third, third and fourth evaluations, respectively. Mild=Stage 1, Moderate=Stage 2, and Severe= Stages 3 and 4. Løkke et al. Thorax. 2006;61(11):935-939; GOLD Initiative 2006. http://www.goldcopd.com. Accessed July 19, 2007.

Severe COPDb

Moderate COPD

Mild COPD

NeverSmokers

40

0

Cu

mu

lati

ve I

nci

den

ce 35

30

25

20

15

10

5

Ex-smokers Early Interm Late ContinuousSmokers

Abstainersc

COPD MortalityCOPD Mortality

Worldwide, 80 million people have Worldwide, 80 million people have moderate-to-severe COPDmoderate-to-severe COPD

Half of all COPD patients die within a Half of all COPD patients die within a decade of diagnosisdecade of diagnosis

COPD predicted to become the fourth COPD predicted to become the fourth leading cause of death worldwide by 2030leading cause of death worldwide by 2030

In 2005, 3 million people died of COPDIn 2005, 3 million people died of COPD

Anto. Eur Respir J. 2001;17:982-994; http://www.who.int/respiratory/copd/en/. Accessed April 27, 2007; World Health Organization. http://www.who.int/en. Accessed July 19, 2007; http://www.istockphoto.com/file_closeup/who/people_specific_attributes/body_parts/848586_puff_2_smoke_version.php?id=848586. Accessed October 22, 2007.

Radiographic Features of HyperinflationRadiographic Features of Hyperinflation

http://www.mevis.de/~hhj/Lunge/imaCOPD/EmTh1136.JPG. Accessed April 27, 2007; GOLD Initiative 2006. http://www.jend.de. Accessed October 31, 2007.

COPD: PathophysiologyCOPD: PathophysiologyAirflow LimitationAirflow Limitation

Irreversible airflow limitation measured during forced Irreversible airflow limitation measured during forced expiration is caused by eitherexpiration is caused by either– An increase in the resistance of the small conducting airwaysAn increase in the resistance of the small conducting airways– An increase in lung compliance due to emphysematous lung An increase in lung compliance due to emphysematous lung

destruction destruction – Both Both

Airflow limitation is usually progressive and associated withAirflow limitation is usually progressive and associated with– Lesions that obstruct the small conducting airwaysLesions that obstruct the small conducting airways– Emphysematous destruction of the lung’s Emphysematous destruction of the lung’s

elastic recoil forceelastic recoil force– Abnormal inflammatory response to noxious particles or Abnormal inflammatory response to noxious particles or

gases, primarily caused by cigarette smokinggases, primarily caused by cigarette smoking

Hogg. Lancet. 2004;364(9435):709-721; Anderson. Neurology. 2005;64:1488-1489; Celli et al. Eur Respir J. 2004;23:932-946.

Increased Rate of Decline in FEVIncreased Rate of Decline in FEV11aa in in

SmokersSmokers Susceptible smokers develop significant lung function declineSusceptible smokers develop significant lung function decline

aFEV1 =volume of air that can be expired in 1 second. bGOLD (Global Initiative for Chronic Obstructive Lung Disease) classification of severity of COPD. Adapted from Fletcher et al. BMJ. 1977;1:1645-1648; The GOLD Workshop Panel. Bethesda, MD: National Heart, Lung, and Blood Institute; 2001. NIH publication 2701.

FE

V1

(Per

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f V

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Ag

e 25

)

Age (years)

100

0

75

50

25

10025 50 75

Never smoked or not susceptible to smoke

Stopped at 50 years

Stopped at 65 years

GOLD 0+1b

GOLD 2

GOLD 3

GOLD 4 Disability

Death

Smoked regularly and susceptible to effects of smoking

Air Trapping Links Pathophysiology and Air Trapping Links Pathophysiology and Patient-Centered Outcomes in COPDPatient-Centered Outcomes in COPD

Cooper. Am J Med. 2006;119(10A):S21-S31.

Poor Health-Related Quality of LifePoor Health-Related Quality of Life

Activity LimitationActivity

LimitationDyspneaDyspnea

Air TrappingAir Trapping

HyperinflationHyperinflation

Airflow ObstructionAirflow Obstruction

Patient-CenteredOutcomes

AnxietyAnxiety

TachypneaTachypnea Ventilatory Requirement Ventilatory Requirement

DeconditioningDeconditioning

COPDCOPD

HypoxemiaHypoxemia ExacerbationsExacerbations

Inflammatory Mechanisms in COPDInflammatory Mechanisms in COPDCigarette Smoke

and Other Irritants

Cigarette Smoke and Other Irritants

Epithelial Cells Alveolar Macrophage

ProteasesNeutrophil ElastaseCathepsinsMatrix Metalloproteinases

ProteasesNeutrophil ElastaseCathepsinsMatrix Metalloproteinases

Protease InhibitorsProtease Inhibitors

Neutrophil

CD8+ T Lymphocytes

MCP-1

Alveolar-Wall Destruction

(Emphysema)Mucus Hypersecretion

(Chronic Bronchitis)MCP-1=monocyte chemotactic protein-1.Adapted from Barnes. Curr Opin Pharmacol. 2004;4(3):265; Celli et al. Eur Respir J. 2004;23:932-946.

Neutrophil Chemotactic FactorsInterleukin-8, Leukotriene B4

Neutrophil Chemotactic FactorsInterleukin-8, Leukotriene B4

040

58

3.4

270

20

0

50

100

150

200

250

300

350

400

450

500

2.6

1400

750

7.8300

4000

0

500

1000

1500

2000

2500

3000

3500

4000

4500

COPD: Pulmonary Inflammatory ResponseCOPD: Pulmonary Inflammatory Response Cigarette smoke induces a significant inflammatory response in the Cigarette smoke induces a significant inflammatory response in the

lungs of patients with emphysemalungs of patients with emphysema

CD4=T lymphocyte; CD8=T lymphocyte; CD20=B lymphocyte; Eos=eosinophils; Macro=macrophages; PMN=polymorphonuclear. aP<.01 from control and mild. bLung tissue from respective patients was obtained following lung resection.Retamales et al. Am J Respir Crit Care Med. 2001;164(3):469-473.

PMN, ×10

12

Macro,

×1012

Eos, ×10

8

CD4, ×10

12

CD8, ×10

12

CD20, ×

1012

PMN, ×10

12

Macro,

×1012

Eos, ×10

8

CD4, ×10

12

CD8, ×10

12

CD20, ×

1012

Infla

mm

ator

y C

ells

a

a

a

a

a

Normal lung functionb Severe emphysemab

Infla

mm

ator

y C

ells

Oxidative Stress in COPDOxidative Stress in COPD

Decrease in Antiproteases1-Antitrypsin and Secretory

Leukoprotease Inhibitor

Decrease in Antiproteases1-Antitrypsin and Secretory

Leukoprotease Inhibitor

Increased MucusSecretion

Plasma Leak lsoprostanes

Bronchoconstriction

NeutrophilRecruitment

Interleukin-8

Activation ofNuclear Factor-B

TumorNecrosisFactor-

O2, H2O2

OH, ONOO

Cigarette SmokeInflammatory Cells

(Neutrophils, Macrophages)

Cigarette SmokeInflammatory Cells

(Neutrophils, Macrophages)

Barnes. Curr Opin Pharmacol. 2004;4:265; GOLD Initiative 2006. http://www.goldcopd.com. Accessed July 23, 2007.

Pathology of COPD: Obstruction of Small Pathology of COPD: Obstruction of Small Conducting AirwaysConducting Airways

Normal small airway Mucus plug

Inflamed airway, lumen partly filled with mucus and cells

Airway surrounded by connective tissue,might restrict normal enlargement of lumen

Hogg. Lancet. 2004;364(9434):709-721; GOLD Initiative 2006. htt://www.goldcopd.com. Accessed July 24, 2007.

Pathology of COPD: Pathology of COPD: Emphysematous Lung DestructionEmphysematous Lung Destruction

The centrilobular pattern of The centrilobular pattern of emphysematous destruction emphysematous destruction is most closely associated is most closely associated with cigarette smokingwith cigarette smoking

Centrilobular emphysema Centrilobular emphysema results from dilatation and results from dilatation and destruction of the respiratory destruction of the respiratory bronchiolesbronchioles Centrilobular

emphysematous lesion

Hogg. Lancet. 2004;364(9435):709-721.

COPD: Pathology of EmphysemaCOPD: Pathology of Emphysema

http://db2.photoresearchers.com/cgi-bin/big_preview.txt?image_iid=10991009. Accessed October 19, 2007; http://pathhsw5m54.ucsf.edu/case25/images25/cle.jpg. Accessed April 27, 2007; Hogg. Lancet. 2004;364(9435):709-721.

Histopathology ofemphysema

Section of lung with both panacinar panlobular and centrilobular emphysema

Pathophysiology: Inhibition of Pulmonary Pathophysiology: Inhibition of Pulmonary Artery Endothelial Cell AngiogenesisArtery Endothelial Cell Angiogenesis

aEndothelial monolayer wound repair distance is expressed as the difference between width of the wound before CSE exposure and after CSE exposure (mm). P.05 vs 0 (control).Su et al. Am J Physiol Lung Cell Mol Physiol. 2004;287(4):L794-800.

Cigarette smoke extract (CSE) inhibits angiogenesis of pulmonary Cigarette smoke extract (CSE) inhibits angiogenesis of pulmonary artery endothelial cellsartery endothelial cells

Impaired angiogenesis may impede the pulmonary repair process Impaired angiogenesis may impede the pulmonary repair process and contribute to altered structural remodelingand contribute to altered structural remodeling

Rep

air

Dis

tan

ce (

mm

)a

0 2.5 5.0 7.5 10Cigarette Smoke Extract (%)

.35

0

.20

.10

.05

.15

.25

.30

Smoking Cessation: Improvement in Smoking Cessation: Improvement in Postbronchodilator FEVPostbronchodilator FEV11 Decline Decline

Anthonisen et al. JAMA. 1994;272(19):1497-1505; Kanner et al. Am J Med. 1999;106(4):410-416.

Follow up (y)

Po

stb

ron

cho

dil

ato

r F

EV

1 L

2.4

2.5

2.6

2.7

2.8

2.9

Screen 2 1 2 3 4 5

Sustained Quitters

Continuous Smokers

Susceptible smokers develop significant lung function declineSusceptible smokers develop significant lung function decline

Smoking Cessation: Improvement in FEVSmoking Cessation: Improvement in FEV11

Scanlon et al. Am J Respir Crit Care Med. 2000;161:381-390.

Annual Visits (AV)

72

74

76

78

80

82

Baseline AV 1 AV 2 AV 3 AV 4 AV 5

Pred

icte

d FE

V 1 (%

)

Sustained Quitters

Continuous Smokers

134

3723152

54208

146

2335

2059

1818

1652

2682

840

507541

599673

124

0

50

100

150

200

Smoking Cessation: Effects on Airway Smoking Cessation: Effects on Airway HyperresponsivenessHyperresponsiveness Smoking cessation improves bronchial hyperresponsivenessSmoking cessation improves bronchial hyperresponsiveness

PC

20

AM

P m

g/m

L-1

cP

C2

0 M

ch m

g/m

L-1

b

a P.05 before quitting vs 12 months after quitting. bPC20 Mch=provocative concentration of methacholine (Mch) that inducesa 20% fall in FEV1. c PC20 AMP=provocative concentration of adenosine-5 ‘ monophosphate (AMP) that induces a 20% fall in FEV1.

Willemse et al. Eur Respir J. 2004;24(3):391-396.

0

2

4

6

8

10

176a

44

Baseline 12 Months After Quitting

Baseline 12 Months After Quitting

8.1a

2.57

Smoking Cessation: Airway Inflammation Smoking Cessation: Airway Inflammation and COPDand COPD Cross-sectional studies suggest ongoing inflammation Cross-sectional studies suggest ongoing inflammation

in ex-smokers in ex-smokers

Willemse et al evaluated the effect of smoking cessation on airway Willemse et al evaluated the effect of smoking cessation on airway inflammation ininflammation in– Smokers with COPDSmokers with COPD– Smokers with normal lung functionSmokers with normal lung function

Upon smoking cessationUpon smoking cessation– COPD candidates had persistent airway inflammation and increased COPD candidates had persistent airway inflammation and increased

sputum inflammatory cells sputum inflammatory cells – Asymptomatic smokers had either significant reduction in sputum Asymptomatic smokers had either significant reduction in sputum

inflammatory cells or demonstrated no changeinflammatory cells or demonstrated no change

Observed persistent inflammation in patients with COPD may be related Observed persistent inflammation in patients with COPD may be related to repair of tissue damage in the airwaysto repair of tissue damage in the airways

Willemse et al. Eur Resp J. 2005;26(5):835-845.

Notes Continuationof Previous Slide

Smoking Cessation: Effects on Smoking Cessation: Effects on Respiratory SymptomsRespiratory Symptoms

aAdjusted for sex, age, clinic, body mass index, baseline cigarettes/day, nonwhite race, dust/fume exposure, years of education, lung problems before 16 years of age, FEV1 % predicted, bronchodilator response %, Mch reactivity, and baseline symptoms. Mean prevalence at first through the fifth annual visits. bFor all variables evaluated.Kanner et al. Am J Med. 1999;106(4):410-416.

43.6 42.2

55.451.6

58.764.960.664.7

0

10

20

30

40

50

60

70

Baseline Symptom

Cough≥3 month/year

Phlegm≥3 month/year

Wheezing Dyspnea

Intervention Usual care

Rep

ort

ed S

ymp

tom

s at

Bas

elin

e (%

)a

P.00001b

Chronic BronchitisChronic Bronchitis

Chronic inflammatory process associated with Chronic inflammatory process associated with – Increased production of mucusIncreased production of mucus– Defective mucociliary clearanceDefective mucociliary clearance– Disruption of the epithelial barrierDisruption of the epithelial barrier

Smoking increases neutrophil recruitment to the lungSmoking increases neutrophil recruitment to the lung

Productive cough for a minimum of 3 months a yearProductive cough for a minimum of 3 months a year

Approximately 2 out of 5 continuous smokers ultimately Approximately 2 out of 5 continuous smokers ultimately develop chronic bronchitis develop chronic bronchitis

Approximately half of smokers who have chronic Approximately half of smokers who have chronic bronchitis develop COPDbronchitis develop COPD

Pelkonen et al. Chest. 2006;130(4):1129-1137; Hill et al. Eur Respir J. 2000;15(5):886-890; Hogg. Lancet. 2004;364(9435):709-721; Celli et al. Eur Respir J. 2004;23:932-946.

Incidence of Chronic BronchitisIncidence of Chronic Bronchitis The cumulative incidence of chronic bronchitis was 42% in continuous The cumulative incidence of chronic bronchitis was 42% in continuous

smokers compared with 26% and 22% in ex-smokers and never- smokers compared with 26% and 22% in ex-smokers and never- smokers, respectivelysmokers, respectivelybb

CIa

of

Ch

ron

ic B

ron

chit

is (

%) Continuous Smokers

Ex-smokers

Never Smokers

40 45 50 55 60 65 70 7505

101520253035404550

Age in Years

aCumulative incidence. b1711 middle-aged men belonging to 2 groups were followed up for up to 40 years.Pelkonen et al. Chest. 2006;130(4):1129-1137.

Chronic Bronchitis: Effects of Smoking Chronic Bronchitis: Effects of Smoking CessationCessation

Smoking cessation in chronic bronchitis results inSmoking cessation in chronic bronchitis results in

– Reduction in IL-8 concentration in airways Reduction in IL-8 concentration in airways

– Decreased neutrophil recruitment Decreased neutrophil recruitment

– Slowed progression of lung diseaseSlowed progression of lung disease

Hill et al. Eur Respir J. 2000;15(5):886-890.

Chronic Bronchitis: Effect of Smoking Chronic Bronchitis: Effect of Smoking Reduction on SurvivalReduction on Survival

Decrease in daily smokinga

No changeb

Cu

mu

lati

ve S

urv

ival

P

rob

abil

ity

(%)

5 10 15 20 25 300

102030405060708090

100

Years of Follow-up After the First Report of Chronic Bronchitis

Based on the Cox model (P<.001), adjusted for age, pulmonary function, and the study year of examination at which chronic bronchitis was diagnosed for the first time. Decrease in daily smoking was calculated as a change in the mean number of cigarettes per day.aOn average, smokers had reduced their smoking by 13 cigarettes (SD, 5); their previous consumption had been 22 cigarettes (SD, 5). bSubjects smoked on average 19 cigarettes per day (SD, 6).Pelkonen et al. Chest. 2006;130(4):1129-1137.

Summary: Smoking and COPDSummary: Smoking and COPD

COPDCOPD– Increased incidence in smokersIncreased incidence in smokers– PathophysiologyPathophysiology

• Inflammation and oxidative stress result in Inflammation and oxidative stress result in – Obstructive lesions of the small conducting airwaysObstructive lesions of the small conducting airways– Dilatation and destruction of respiratory bronchiolesDilatation and destruction of respiratory bronchioles

• Smoking induces significant lung function declineSmoking induces significant lung function decline

– Smoking cessationSmoking cessation• Associated with improved lung functionAssociated with improved lung function• Reduces airway hyperresponsivenessReduces airway hyperresponsiveness

– Chronic bronchitisChronic bronchitis• Increased incidence in smokersIncreased incidence in smokers• Smoking cessationSmoking cessation

– Slows progression of lung diseaseSlows progression of lung disease– Reduces mortalityReduces mortality

Smoking and AsthmaSmoking and Asthma

Asthma and Environmental Tobacco Asthma and Environmental Tobacco Smoke (ETS)Smoke (ETS)

ETS aggravates asthma in ETS aggravates asthma in childhoodchildhood

Asthmatic children whose mothers Asthmatic children whose mothers smoke have more severe cases of smoke have more severe cases of asthma compared with those whose asthma compared with those whose mothers don’t smokemothers don’t smoke

Prenatal smoking is causally Prenatal smoking is causally associated with increased associated with increased prevalence of asthma in childrenprevalence of asthma in children

Chan-Yeung et al. Respirology. 2003;8:131-139; Courtesy of Getty Images. http://delivery.gettyimages.com/xc/BB6074-001.jpg?v=1&c=CFW&k=2&d=2EA4B0C59585DB42C1FF2DD0E5B2E618EC7C5022FB410D56. Accessed October 11, 2007.

Prenatal Smoking and Asthma in Prenatal Smoking and Asthma in ChildrenChildren

Analysis of 60 studies revealed Analysis of 60 studies revealed that the risk of asthma in school- that the risk of asthma in school- aged children is increased if aged children is increased if either parent smokes; Odds either parent smokes; Odds Ratio (OR)Ratio (OR)aa=1.21 (95% CI, 1.10-=1.21 (95% CI, 1.10-1.34)1.34)

Maternal smoking did have a Maternal smoking did have a greater effect than paternal greater effect than paternal smoking, yet the effect of the smoking, yet the effect of the father only was clearly significant father only was clearly significant

Results suggest postnatal effect Results suggest postnatal effect is also importantis also important

aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons. Cook et al. Thorax. 1997;52(12):1081-1094; http://www.worldofstock.com/closeups/PHE1195.php. Accessed October 11, 2007.

Asthma: Effects of Environmental Tobacco Asthma: Effects of Environmental Tobacco Smoke in Utero or Early ChildhoodSmoke in Utero or Early Childhood

Exposure to pre- and postnatal smoking carries a substantial risk for Exposure to pre- and postnatal smoking carries a substantial risk for developing adult asthmadeveloping adult asthma

aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons. Adjusted for sex, age, educational level, active smoking in terms of both smoking habits and pack/years, occupational exposure, and hay fever. In addition, when estimating the ORs for the 3 maternal smoking variables, adjustment was made for exposure to smoking from other household members.Skorge et al. Am J Resp Crit Care Med. 2005;172:61-66.

1 1 1

3.5

1.9

2.9

0

1

2

3

4

5

6

7

Od

ds

Rat

io (

95%

CI)

a

Prenatal Postnatal Pre- and Postnatal

No exposure to maternal smoking

Exposure to maternal smoking

Smoking: Asthma SeveritySmoking: Asthma Severity

Compared with Never Compared with Never Smokers and Ex-Smokers and Ex-smokers, Current smokers, Current Smokers reportedSmokers reported– Significantly more Significantly more

attacks of attacks of breathlessnessbreathlessness

– Significantly higher Significantly higher severity scoresseverity scores

60.6 60.3

89.2

0

20

40

60

80

100

aAt rest in the last 12 months. bRelationship between attacks of breathlessness and smoking.cSeverity score for asthma was established using an a priori decisional tree.dStrength of the relationship betweenseverity score and smoking.The 3 classes were coded 1, 2, and 3 for quantitative analysis. Severity score was adjusted for age, sex, and educational level.Siroux et al. Eur Respir J. 2000;15(3):470-477.

Never Smokers

Ex-smokers

CurrentSmokers

Att

acks

of

Bre

ath

less

nes

s (%

)aS

ever

ity

Sco

rec

2.21 2.232.66

0

1

2

3

P=.004b

P=.01d

Asthmatic Smokers: Smoking DurationAsthmatic Smokers: Smoking Duration

Siroux et al. Eur Respir J. 2000;15(3):470-477.

Duration of Smoking/ Years

0

Cu

rren

tly

Sm

oki

ng

(Wo

men

)C

urr

entl

y S

mo

kin

g(M

en)

10

20

30 40 500

0.2

0.4

0.6

0.8

1.0

0

0.2

0.4

0.6

0.8

1.0 Childhood onset

Adult onset

Nonasthmatic

10

20

30 40 500

Smoking and Asthma: Diminished Smoking and Asthma: Diminished Response to Inhaled CorticosteroidsResponse to Inhaled Corticosteroids

a All P values reflect difference in pulmonary function within groups before and after beclomethasone therapy. b AM PEF= AM peak expiratory flow; cPC20 Mch=PC20 methacholine Lazarus et al. Am J Respir Crit Care Med. 2007;175(8):783-790.

0.20

0.15

0.10

0.05

0.00Ch

ang

e in

FE

V1(

L)

Beclomethasone

15

10

5

0

Ch

ang

e in

A

M P

EF

b (

L/M

)

Beclomethasone

0.8

0.4

0.0

Ch

ang

e in

PC

20

Mch

c

Beclomethasone

P=.0003a

P=NSa

P=.0006a

P=.03a

P=.03a

NSa

Nonsmokers Current smokers

0.17

0.06

0.530.69

11.74

8.30

Smoking Cessation: Improved Lung Smoking Cessation: Improved Lung Function in AsthmaticsFunction in Asthmatics

Chaudhuri et al. Am J Respir Crit Care Med. 2006;174(2):127-133.

0

10

20

30

40

1-wkCessation

3-wkCessation

6-wkCessation

8-wkCessation

AfterSteroids

Ch

ang

e in

FE

V1 (%

Pre

dic

ted

)

P≤.05P≤.05

P≤.05

P≤.01

Summary: Smoking and AsthmaSummary: Smoking and Asthma

Environmental tobacco smoke aggravates asthma in Environmental tobacco smoke aggravates asthma in childhoodchildhood

Asthmatic children whose parents smoke have more Asthmatic children whose parents smoke have more severe asthma than those whose parents don’t smokesevere asthma than those whose parents don’t smoke

Exposure to pre- and postnatal smoking carries a Exposure to pre- and postnatal smoking carries a substantial risk of developing adult asthmasubstantial risk of developing adult asthma

Smoking asthmatics have a diminished response to Smoking asthmatics have a diminished response to inhaled corticosteroidsinhaled corticosteroids

Smoking and TuberculosisSmoking and Tuberculosis

Smoking: Risk of Smoking: Risk of Mycobacterium Mycobacterium TuberculosisTuberculosis Infection Infection Smoking may increase the risk of Smoking may increase the risk of M tuberculosisM tuberculosis infection infection

aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons. Adjusted for pack/years, age, sex, and taking into account possible clustering at address level.den Boon et al. Thorax. 2005;60(7):555-557.

1.00

1.901.771.77

0.0

1.0

2.0

3.0

Pack/Years5 5-15 15

Od

ds

Rat

io (

95%

CI)

a

Never Smokers

Current Smokers

Smoking and Pulmonary TBSmoking and Pulmonary TB

aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons. Crude OR was adjusted for age.  To minimize the effect of other confounders the study population was restricted to men aged 20 to 50 years only.TB=tuberculosis.Kolappan et al. Thorax. 2002;57(11):964-966; www.medscape.com/viewarticle/452428_2. Accessed May 13, 2007.

1.00

2.24

0.0

1.0

2.0

3.0

4.0

Od

ds

Rat

io (9

5% C

I)a

NonsmokersNonsmokers

Smoking is a risk factor for the development of pulmonary TBSmoking is a risk factor for the development of pulmonary TB

Current SmokersCurrent Smokers

Potential Pathogenetic Mechanisms of Potential Pathogenetic Mechanisms of Smoking-Induced TB ReactivationSmoking-Induced TB Reactivation

Nicotine binding to the Nicotine binding to the -7 subunit of the nicotinic acetylcholine -7 subunit of the nicotinic acetylcholine receptors may trigger a cascade of events that result in TB reactivationreceptors may trigger a cascade of events that result in TB reactivation

iNOS=inducible nitric oxide synthase; NO=nitric oxide; MTb=Mycobacterium tuberculosisDavies et al. Trans R Soc Trop Med Hyg. 2006;100:291-298.

TNF-TNF-

(–)(–)

(–)(–)

-7-7

()()

ArginineArginine

iNOSiNOS

NONOLatentLatent

MTbMTb

Neutralizing antibodyto TNF-

Neutralizing antibodyto TNF-

NicotineNicotine

PhagosomePhagosome

PhagosomePhagosome

Environmental Tobacco Smoke: Risk of Environmental Tobacco Smoke: Risk of Active TB Immediately Following Active TB Immediately Following InfectionInfection Environmental tobacco smoke (ETS) exposure is a risk factor for the Environmental tobacco smoke (ETS) exposure is a risk factor for the

development of active pulmonary TB immediately following infectiondevelopment of active pulmonary TB immediately following infection

aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons.Altet et al. Tuber Lung Dis. 1996;77(6):537-544.

1.00

5.29

0

2

4

6

8

10

12

14

Exposed to Smoking

Od

ds

Rat

io (9

5% C

I)a P.00005

Not Exposed to Smoking

Odds Ratioa (95% CI)

Environmental Tobacco Smoke: Risk of Environmental Tobacco Smoke: Risk of Active TB Immediately Following Active TB Immediately Following Infection (cont’d)Infection (cont’d) The risk of developing active pulmonary TB following infection The risk of developing active pulmonary TB following infection

increases with the number of cigarettes smoked daily by household increases with the number of cigarettes smoked daily by household adultsadults

aThe ratio of the odds of development of disease in exposed persons to the odds of development of disease in nonexposed persons. Odds ratio adjusted for sex, age, and father's social class IV-V using multiple logistic regression analysis. Altet et al. Tuber Lung Dis. 1996;77(6):537-544.

1.00

7.76

3.95

1.61

0 3 6 9 12 15 18

None

21-40

40

1-20

P.01

P.001

Cig

aret

tes/

Day

Smoking: Adherence to Latent TB Smoking: Adherence to Latent TB Infection (LTBI) TherapyInfection (LTBI) Therapy

Nonsmokers are more likely Nonsmokers are more likely to be adherent with LTBI to be adherent with LTBI therapytherapy

As a result of their reduced As a result of their reduced LTBI compliance, smokers LTBI compliance, smokers increased their risk of increased their risk of developing active TBdeveloping active TB

Lavigne et al. BMC Public Health. 2006;6:66.

Current Current SmokerSmoker

1.8

1.0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

OR

fo

r C

om

pli

ance

(95

% C

I)

NonsmokersNonsmokers

Smoking: TB-Related MortalitySmoking: TB-Related Mortality

In India, approximately 32% of TB deaths may be In India, approximately 32% of TB deaths may be attributed to bidiattributed to bidiaa smoking smoking

aBidi is a cheap smoking stick made by rolling a dried, rectangular piece of temburni leaf with about 0.2 g of sun-dried, flaked tobacco. bThe probability of an event (developing a disease) occurring in exposed people compared with the probability of the event in nonexposed people. Adjusted for age, education, and smokeless tobacco use. Pednekar et al. Prev Med. 2007;44(6):496-498.

1.00

2.60

2.12

0.0

1.0

2.0

3.0

4.0

Never Smokers Cigarette Smokers Bidi Smokers

Rel

ativ

e R

isk (9

5% C

I)b

Smoking and Lung CancerSmoking and Lung Cancer

Risk of Lung CancerRisk of Lung Cancer

aThe relative likelihood of experiencing a particular event or the effect of an explanatory variable on the hazard or risk of an event.Mannino et al. Arch Intern Med. 2003;163:1475-1480.

Current smokers have a higher risk of developing lung cancer than ex-Current smokers have a higher risk of developing lung cancer than ex-smokers or nonsmokerssmokers or nonsmokers

8.4

3.6

1.0

0

2

4

6

8

10

12

14

16

18

Never Smokers Ex-smokers Current Smokers

Haz

ard

Rat

io (

95%

CI)

a

Risk of Lung CancerRisk of Lung Cancer

The risk of developing lung cancer is directly related to the amount The risk of developing lung cancer is directly related to the amount smokedsmoked

1.02.9

9.0

19.9

0

5

10

15

20

25

30

35

40

Never Smokers 30 30 to 60 60

Pack/YearsCurrent Smokers

Haz

ard

Rat

io (

95%

CI)

a

Pack/year was calculated by multiplying the average number of cigarettes smoked daily by the number of years smoked and dividing the product by 20.aThe relative likelihood of experiencing a particular event or the effect of an explanatory variable on the hazard or risk of an event.Mannino et al. Arch Intern Med. 2003;163:1475-1480.

COPD: Risk Factor for Lung CancerCOPD: Risk Factor for Lung Cancer

When evaluated long-term, diagnosis of COPD is a predictor of lung When evaluated long-term, diagnosis of COPD is a predictor of lung cancer developmentcancer development

Moderate/Severe COPD

Mild COPD

Normal Lung Function

Kaplan-Meier curves for incident lung cancer.Adjusted for age, race, sex, education, smoking status, pack-years, and years since regular smoking.Mannino et al. Arch Intern Med. 2003;163(12):1475-1480.

Pro

po

rtio

n W

ith

Lu

ng

Can

cer

Time Until Lung Cancer Diagnosis (Years)

0.14

0.12

0.10

0.06

0.02

0.00 5 10 15 20 25

Restrictive Lung Disease

0.08

0.04

2.8

1.41

0

1

2

3

4

5

Impairment of Lung Function:Impairment of Lung Function:Risk Factor for Lung CancerRisk Factor for Lung Canceraa

Degree of impairment correlates with risk of lung cancerDegree of impairment correlates with risk of lung cancer

aFrom the National Health and Nutrition Examination Survey (NHANES) I, 1971-1975, and follow-up through 1992. bThe relative likelihood of experiencing a particular event or the effect of an explanatory variable on the hazard or risk of an event. cDefined as FEV1/FVC of <70% and FVC of 80%. dDefined as FEV1/FVC of <70% and FVC of <80% predicted. FVC=forced vital capacity. Mannino et al. Arch Intern Med. 2003;163(12):1475-1480.

Haz

ard

Rat

io (

95%

CI)

b

NormalLung Function

Mild COPDc

Moderate/Severe COPDd

Environmental Tobacco Smoke and Lung Environmental Tobacco Smoke and Lung Cancer: Dose ResponseCancer: Dose Response There is a dose–response relationship between a nonsmoker’s risk of lung There is a dose–response relationship between a nonsmoker’s risk of lung

cancer and the number of cigarettes and years of exposure to the smokercancer and the number of cigarettes and years of exposure to the smoker

aThe probability of an event (developing a disease) occurring in exposed people compared with the probability of the event in nonexposed people.Hackshaw et al. BMJ. 1997;315(7114):980-988; Geng et al. In: Smoking and Health. Amsterdam, The Netherlands: Elsevier Science; 1988:483-486.

Rel

ativ

e R

iska

(Lo

g S

cale

)

0 1-19 10-19 20Cigarettes Smoked

Daily by Spouse

Rel

ativ

e R

iska

(Lo

g S

cale

)0 1-19 20-39 40

Years Living WithSpouse Who Smokes

1

2

3

4

5

1

2

3

4

5

Lung Cancer Risk by Smoking StatusLung Cancer Risk by Smoking Status

Reducing tobacco consumption markedly decreases lung cancer Reducing tobacco consumption markedly decreases lung cancer risk risk

a The relative likelihood of experiencing a particular event, or the effect of an explanatory variable on the hazard or risk of an event.Adjusted for sex, cohort of origin, inhalation habits (yes/no), tobacco type (cigarettes, cigars/pipe/cheroots, mixed), and years as smokers (continuous). bCompared with heavy smokers, (15 cigarettes/day), reducers (reduced from ≥15 cigarettes/day by minimum of 50% without quitting), light smokers (1-14 cigarettes/day).Godtfredsen et al. JAMA. 2005;294(12);1505-1510.

HeavySmokers

Reducersb LightSmokersb

Ex-smokersb

Never SmokersbQuitters

0

0.2

0.4

0.6

0.8

1

Haz

ard

Rat

io (

95%

CI)a

0.09

0.17

0.44

0.5

0.73

0

0.2

0.4

0.6

0.8

1

Smoking Cessation: Smoking Cessation: Lung Cancer Risk ReductionLung Cancer Risk Reduction Lung cancer risk declines with increasing duration of abstinenceLung cancer risk declines with increasing duration of abstinence

aThe probability of an event (developing a disease) occurring in exposed people compared with the probability of the event in nonexposed people. Compared with current smokers.Data for relative risk given as median (range). Ebbert et al. J Clin Oncol. 2003;21(5);921-926.

Years of Smoking Abstinence

Rel

ativ

e R

isk

(95%

CI)

a Iowa Women’s Health Study

0-5 6-10 11-20 21-30 30

1.0 1.0 1.0

10.9

16.6

0

4

8

12

16

20

24

Smoking Cessation: Lung Cancer Risk Smoking Cessation: Lung Cancer Risk ReductionReduction

Lung cancer risk declines with increased duration of abstinence and Lung cancer risk declines with increased duration of abstinence and approaches that of nonsmokersapproaches that of nonsmokers

Adjusted for age, physical activity, education, body mass index, waist circumference, alcohol use, and fruit consumption. aThe probability of an event (developing a disease) occurring in exposed people compared with the probability of the event in nonexposed people. bRecent ex-smoker (quit 5 years at baseline). cDistant ex-smoker (quit >5 years at baseline).Ebbert et al. J Clin Oncol. 2003;21(5);921-926.

Rel

ativ

e R

isk

(95%

CI)

a

Current Smokers

Recent Ex- smokersb

DistantEx- smokersc

3.4

Nonsmokers Nonsmokers Nonsmokers

Smoking Cessation: Effects on MortalitySmoking Cessation: Effects on Mortality

CHD=coronary heart disease; CVD=cardiovascular disease.Athonisen et al. Ann Intern Med. 2005;142(4):233-239.

4

2

1

0

Rat

e o

f D

eath

per

100

0 P

erso

n-Y

ears

OtherCHD CVD Lung Cancer

Other Cancer

Respiratory Disease

Unknown

Causes of Death

Sustained Quitters Intermittent Quitters Continuing Smokers

3

Impact of Smoking Cessation on Impact of Smoking Cessation on Mortality: MenMortality: Men Risk of death from lung cancer progressively decreases with increased Risk of death from lung cancer progressively decreases with increased

duration of abstinenceduration of abstinence

aThe combined risks from aggregate exposures to multiple agents or stressors.US Environmental Protection Agency National Center for Environmental Assessment. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=54944. Accessed May 7, 2007; Peto et al. BMJ. 2000;321(7257);323-329.

16

750

45Age (years)

12

8

4

Continuing Cigarette Smokers

Stopped at age 60

Stopped at age 50

Stopped at age 40

Stopped at age 30

Lifelong Nonsmokers

14

10

6

2

6555

Cu

mu

lati

ve R

isk

% (

Men

)a

0

0.1

0.2

0.3

0.4

0.5

0.6

Impact of Smoking Cessation on Impact of Smoking Cessation on Mortality: WomenMortality: Women Risk of death from lung cancer among women who quit before age Risk of death from lung cancer among women who quit before age

50 is substantially lower than the risk among current smokers 50 is substantially lower than the risk among current smokers

aThe relative likelihood of experiencing a particular event, or the effect of an explanatory variable on the hazard or risk of an event. Adjusted for age at enrollment (years), university education (yes/no), BMI (kg/m2) moderate physical activity (hours/week in quartiles, plus missing), alcohol consumption (g/day), HRT use (ever/never), total fat (g/day), cereal fiber (g/day), beta carotene (µg/day), vitamin A (IU/day), vitamin C (µg/day), and vitamin E (µg/day); bP.01; cP.001.Zhang et al. Ann Epidemiol. 2005;15(4):302-309.

Haz

ard

Rat

io (9

5% C

I)a

0.06b0.1c

30 Years 30-39 Years 40-49 Years

0.26c

Age at Quitting

Summary: Smoking and Lung CancerSummary: Smoking and Lung Cancer

Risk of lung cancer increases with Risk of lung cancer increases with – Quantity and duration of smokingQuantity and duration of smoking– Diagnosis and severity of COPDDiagnosis and severity of COPD– Severity of lung functionSeverity of lung function– Quantity and duration of environmental tobacco smoke Quantity and duration of environmental tobacco smoke

exposureexposure

Risk of lung cancer decreases withRisk of lung cancer decreases with– Duration of abstinenceDuration of abstinence– Age at cessationAge at cessation

Risk of death from lung cancer progressively decreases Risk of death from lung cancer progressively decreases with increased duration of abstinence with increased duration of abstinence