Marcelo Basso Gazzana

Serviço de Pneumologia Hospital de Clínicas de Porto Alegre

E-mail: mbgazzana@hcpa.ufrgs.br

Congresso Brasileiro de Pneumologia e TisiologiaBrasília, 23 de Novembro de 2008

Fibrose Pulmonar Idiopática

FPI e Tabagismo( IPF and Smoking )

Potenciais Conflitos de Interesse( CFM nº 1.595 de 18 / 5 / 2000 e ANVISA nº 120 de 30 / 11 / 2000 )( CFM nº 1.595 de 18 / 5 / 2000 e ANVISA nº 120 de 30 / 11 / 2000 )

• Médico do Serviço de Pneumologia do Hospital de Clinicas de Porto Alegre

• Médico Intensivista do Hospital Moinhos de Vento

• Participação em pesquisas da indústria farmacêutica no tema: Não

• Remuneração para conferências no tema: Não

• Patrocínio para congressos no tema: Não

MBGazzana

Objectives

• Smoking as a etiologic factorSmoking as a etiologic factor

• Diagnostic contextDiagnostic context

• Concomitant smoking-related diseaseConcomitant smoking-related disease

• Prognostic implicationsPrognostic implications

• Smoking cessation as a therapySmoking cessation as a therapy

MBGazzana

IPF and Smoking

Auerbach O et al. New Engl J Med 1963; 269: 1045

Smoking Habits and Age in Relation to Pulmonary Changes.

Rupture of Alveolar Septums, Fibrosis and Thickning of Walls of Small Arteries and Arterioles

• Lungs obtained at autopsy

• Changes attributable to cigarette smoking:

― Rupture of the alveolar septa

― Fibrosis of alveolar septa

― Thickening of the walls of the vessels

• Changes were associated with aging, but more common in smokers

• Nonsmokers more than 70 years had less changes than cigarette

smokers less than 45 years of age

Weiss W. Am Rev Respir Dis 1969; 99: 67

Cigarette Smoking and Diffuse Pulmonary Fibrosis

Smoking Habits No Pulmonary fibrosis

No % age-ajusted

Nonsomokers 839 5 0,6

Cigarrete Smokers 1.860 35 2,1

Current 1.513 27 2,2

Ex-smokers ( > 12 m) 347 8 1,7

Survey of 2.825 adults came to Association’s Central X-ray Unit, Philadelphia

• Good relationship between DPF and smoking duration ( not daily amount )

• Negligible DPF if smoking duration less than 20 years

Baumgartner KB et al. Am J Resp Crit Care Med 1997; 155: 242

Cigarette Smoking :A Risk Factor for Idiopathic Pulmonary Fibrosis

• Multicenter case-control study

• 248 cases and 491 control subjects

• Odds ratio (OR) for ever smoking: 1.6 ( 95% CI: 1.1 to 2.4 )

• OR for smokers wtih 21 to 40 pack-year : 2.3 ( 1.3 to 3.8 )

• OR for smokers plus any occupationl exposure : 4.1 ( 1.3 to 13.3 )

Conclusion: “ IPF may be another lung disease caused or

exacerbated by cigarette smoking ”

IPF Pathogenesis

Maher TM, Wells AU et al. Eur Resp J 2007; 30: 835

IPF PathologyUsual Interstitial Pneumonia ( UIP pattern )

• Patchy fibrosis with normal areas

• Minimal inflamation

• Fibroblastic foci

• Honeycombing

Low power view High power view

Dempsey OJ et al. Q J Med 2006; 99: 643

Chapman HA. J Clin Invest 1999; 104: 1

IPF pathgenesis – Fas Pathway

IPF PathogenesisCigarette Smoking and CD8+Fas ligand

• N = 21 patients with non-treated IPF – 7 smokers

• BAL cytology and immunotyping

• Smokers versus nonsmokers

• More lymphocytes CD8 cells (p <0.05)

• More lymphocytes CD8 cells carrying Fas ligand (p<0.05)

• More apoptosis rate in macrophages and lymphocites

• Negative correlation between CD8-Fas ligand and vital capacity

Kopinski P et al. Przegl Lek 2007: 64:689 ( Abstr )

Diagnostic Cenario :Smoking and Diffuse Lung Disease

IPF versus

Other smoking-related lung disease

IPFplus

Other smoking-related lung disease

Smoking and Diffuse Lung Disease

Usual Interstitial Pneumonia (UIP)

Descamative Interstitial Pneumonia (DIP) Respiratory Bronchiolitis associeted-Interstitial Lung Disease (RB-ILD)

Nonspecific Interstitial Pneumonia (NSIP)

Eosinophilic Granuloma (EG)

Smoking-related Diffuse Lung Disease

Katzenstein ALA, Myers JL. Am J Resp Crit Care Med 1997; 157: 1301Ryu JH et al. Eur Resp J 2001; 17: 122

Features UIP DIP RBILD NSIP Eos gr

Mean age, yr 57 42 36 49 34

Smoking, % 71 97 80 31 (?) 94

Mortality rate, % 68 27 0 11 0

Mean survival, y 5-6 12 0 1.5 0

Response to steroids No Yes Yes Yes Yes ?

Smoking-related Diffuse Lung Disease

Bjoraker JA et al. Am J Resp Crit Care Med 1998; 157: 199

ATS-ERS. Am J Resp Crit Care Med 2000; 161: 646

Idiopathic Pulmonary Fibrosis

Clinical Diagnosis (ATS-ERS)

Major criteria

• Exclusion of others ILD

• Abnormal lung function tests

• Tipical findings on HRCT

• TLB or BAL no other diagnosis

Minor criteria

• Age > 50 yr

• Insidious dyspnea on exertion

• Duration of illness >= 3 mo

• Bibasilar velcro crackles

Smoking is not a criteria

Immunocompetent adult : 4 major AND 3 minor

IPF in Nonsmokers

Lopes AJ et al. J Bras Pneumol 2007; 33: 671

• N = 30

• Prospective

• 70.9 y – 18 were female – 15 SurgLBx

• Lung function tests versus HRCT findings

• Correlation between CT-score and LFT

(volume, diffusion, dynamic compliance)

IPF and Lung Cancer

IPF and Lung Cancer

Daniels CE et al. Curr Opin Pulm Med 2005; 11: 431

IPF and Lung Cancer

Aubry MC et al. Mayo Clin Proc 2002; 77: 763

• N = 24 patients with biopsy proven IPF and lung cancer

• Control groups: 63 with IPF only and 532 with lung cancer only

• Caractheristics:

• Male : 88 %

• Age ( median, y ) : 72.8

• Smokers ( ever ) : 92 %

• Pack-years ( median ) : 51

• Incidental cancer : 42 %

• 4 months interval : 67 %

• TLC , FEV1 , SpO2 ex

• NSCLC : 95 %

• Mortality : 67 %

IPF and Lung Cancer

Aubry MC et al. Mayo Clin Proc 2002; 77: 763

IPF and Lung Cancer

Hubbard R et al. Am J Resp Crit Care Med 2000; 161: 5

• Populational-based cohort (UK)• CFA n = 890 • Controls n = 5.884

IPF and Emphysema

Thorax 1997; 52: 998-1002 n = 21

IPF and Emphysema

n = 61

Eur Resp J 2005; 26: 586-593

Resp Med 2005; 99: 948-954

• N = 11 ( 8 male – 3 female ), 70.2 years-old

• ATS-ERS criteria – exclusion of other ILD

• Normal lung volumes in 7, restriction in 3, hyperinflation in 1

• DLco moderate to severe reduction in all

• 6MWT - dessaturation in 9

• PH by echo in 4

Silva DR et al. J Bras Pneumol 2008; 34: 779

Silva DR et al. J Bras Pneumol 2008; 34: 779

Smokers have a better survival ?

King Jr TE et al. Am J Resp Crit Care Med 2001; 164: 1171

n = 63n = 166 n = 20

n = 249

• n = 238

• Prospective

• Survival score

Smoking and IPFPrognostic Implications

Collard HR et al. Am J Resp Crit Care Med 2003; 168: 538

• Cohort - 81 biopsy-proven IPF patients

Smoking and IPFPrognostic Implications

Study Design N Change survival

Rudd RM et al, 2007 Prospective 588 No

Alakhras PA et al, 2007 Retrospective 197 No

Pereira CAC et al, 2006 Retrospective 86 No

Flaherty KR et al, 2006 Prospective 197 No

Collard HR et al, 2003 Prospective 81 No

King Jr TE et al, 2001 Prospective 238 Better ?

Rubin AS et al, 2000 Retrospective 117 No

MBGazzana Current versus Ever smoking

Smokers have a better survival ?

Antoniou KM, Wells AU et al. Am J Resp Crit Care Med 2008; 177: 190

CPI Adjusted-survival

Current = Former

Never > Former

Never > Ever

n = 63n = 166 n = 20

n = 249

“ Healthy smoker

lead-time effect ”

CPI = Composite Physiologic Index

Smoking Cessation and

Idiopathic Pulmonary Fibrosis

• No specific studies

• Nothig in IPF guidelines

IPF and SmokingPatients Experiences

• N = 1.448

• Survey – questionnaires ( 52 questions )

• Focus on patient education and resources use

• Smoking status

― Current : 3.2 %

― Former : 65.7 %

― Never : 30.7 %

• In clinical practice, patients stop smoking

Collard HR et al. Resp Med 2007; 101: 1350

Baumgartner KB et al. Am J Resp Crit Care Med 1997: 155: 242

Smoking Cessation and IPF

• Multicenter case-control study

• 248 cases and 491 control subjects

• Smoking cessation prior to diagnosis:

• Less than 2.5 yr : OR 3.5 ( 95% CI: 1.1 to 11.9 )

• 2.5 to 10 yr : OR 2.3 ( 95% CI: 1.3 to 4.2 )

• 10 to 25 yr : OR 1.9 ( 95% CI: 1.1 to 3.2 )

• 25 or more yr : OR 1.3 ( 95% CI: 0.7 to 2.3 )

Take Home Messages

• Smoking is a risk factor for IPF, but not essential for diagnosis

• IPF (UIP) is different from others smoking-related lung diseases

• Pay attention in concomitant lung cancer and emphysema

• Prognostic implications of smoking in IPF is on debate

• Smoking cessation has not been proved benefit yet,

but it has been recommended in real world !

• Relationship between IPF and smoking is complex

MBGazzana

IPF and Smoking

Obrigado pela atenção !

MBGazzana

Hospital de Clínicas de Porto Alegre ( HCPA )Universidade Federal do Rio Grande do Sul ( UFRGS )

Campus da Saúde

mbgazzana@hcpa.ufrgs.br