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Marcelo Basso Gazzana Serviço de Pneumologia Hospital de Clínicas de Porto Alegre

Congresso Brasileiro de Pneumologia e Tisiologia Brasília, 23 de Novembro de 2008. Fibrose Pulmonar Idiopática FPI e Tabagismo ( IPF and Smoking ). Marcelo Basso Gazzana Serviço de Pneumologia Hospital de Clínicas de Porto Alegre E-mail: mbgazzana@hcpa.ufrgs.br.

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Marcelo Basso Gazzana Serviço de Pneumologia Hospital de Clínicas de Porto Alegre

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  1. Congresso Brasileiro de Pneumologia e Tisiologia Brasília, 23 de Novembro de 2008 Fibrose Pulmonar Idiopática FPI e Tabagismo ( IPF and Smoking ) Marcelo Basso Gazzana Serviço de Pneumologia Hospital de Clínicas de Porto Alegre E-mail: mbgazzana@hcpa.ufrgs.br

  2. Potenciais Conflitos de Interesse ( 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

  3. IPF and Smoking Objectives • Smoking as a etiologic factor • Diagnostic context • Concomitant smoking-related disease • Prognostic implications • Smoking cessation as a therapy MBGazzana

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

  5. Cigarette Smoking and Diffuse Pulmonary Fibrosis Survey of 2.825 adults came to Association’s Central X-ray Unit, Philadelphia 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 • Good relationship between DPF and smoking duration ( not daily amount ) • Negligible DPF if smoking duration less than 20 years Weiss W. Am Rev Respir Dis 1969; 99: 67

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

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

  8. IPF Pathology Usual 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

  9. IPF pathgenesis – Fas Pathway Chapman HA. J Clin Invest 1999; 104: 1

  10. IPF Pathogenesis Cigarette 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 )

  11. Diagnostic Cenario : Smoking and Diffuse Lung Disease IPF versus Other smoking-related lung disease IPF plus Other smoking-related lung disease

  12. Smoking and Diffuse Lung Disease Usual Interstitial Pneumonia (UIP) Eosinophilic Granuloma (EG) Descamative Interstitial Pneumonia (DIP) Respiratory Bronchiolitis associeted- Interstitial Lung Disease (RB-ILD) Nonspecific Interstitial Pneumonia (NSIP)

  13. Smoking-related Diffuse Lung Disease 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 ? Katzenstein ALA, Myers JL. Am J Resp Crit Care Med 1997; 157: 1301 Ryu JH et al. Eur Resp J 2001; 17: 122

  14. Smoking-related Diffuse Lung Disease Bjoraker JA et al. Am J Resp Crit Care Med 1998; 157: 199

  15. Idiopathic Pulmonary Fibrosis Clinical Diagnosis (ATS-ERS) Immunocompetent adult : 4 major AND 3 minor • 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 ATS-ERS. Am J Resp Crit Care Med 2000; 161: 646

  16. IPF in Nonsmokers • 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) Lopes AJ et al. J Bras Pneumol 2007; 33: 671

  17. IPF and Lung Cancer

  18. IPF and Lung Cancer Daniels CE et al. Curr Opin Pulm Med 2005; 11: 431

  19. IPF and Lung Cancer • 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 % Aubry MC et al. Mayo Clin Proc 2002; 77: 763

  20. IPF and Lung Cancer Aubry MC et al. Mayo Clin Proc 2002; 77: 763

  21. IPF and Lung Cancer • Populational-based cohort (UK) • CFA n = 890 • Controls n = 5.884 Hubbard R et al. Am J Resp Crit Care Med 2000; 161: 5

  22. IPF and Emphysema n = 21 Thorax 1997; 52: 998-1002

  23. IPF and Emphysema Resp Med 2005; 99: 948-954 n = 61 Eur Resp J 2005; 26: 586-593

  24. 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

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

  26. Smokers have a better survival ? n = 249 n = 63 n = 166 n = 20 • n = 238 • Prospective • Survival score King Jr TE et al. Am J Resp Crit Care Med 2001; 164: 1171

  27. Smoking and IPF Prognostic Implications • Cohort - 81 biopsy-proven IPF patients Collard HR et al. Am J Resp Crit Care Med 2003; 168: 538

  28. Smoking and IPF Prognostic 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 Current versus Ever smoking MBGazzana

  29. Smokers have a better survival ? n = 249 CPI Adjusted-survival Current = Former Never > Former Never > Ever n = 63 n = 166 n = 20 “ Healthy smoker lead-time effect ” Antoniou KM, Wells AU et al. Am J Resp Crit Care Med 2008; 177: 190 CPI = Composite Physiologic Index

  30. Smoking Cessation and Idiopathic Pulmonary Fibrosis • No specific studies • Nothig in IPF guidelines

  31. IPF and Smoking Patients 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

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

  33. IPF and Smoking 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

  34. Obrigado pela atenção ! mbgazzana@hcpa.ufrgs.br Hospital de Clínicas de Porto Alegre ( HCPA ) Universidade Federal do Rio Grande do Sul ( UFRGS ) Campus da Saúde MBGazzana

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