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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: [email protected]

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

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Marcelo basso gazzana servi o de pneumologia hospital de cl nicas 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: [email protected]


Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

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


Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

IPF and Smoking

Objectives

  • Smoking as a etiologic factor

  • Diagnostic context

  • Concomitant smoking-related disease

  • Prognostic implications

  • Smoking cessation as a therapy

MBGazzana


Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    Cigarette Smoking and

    Diffuse Pulmonary Fibrosis

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

    Smoking HabitsNo 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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    IPF Pathogenesis

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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    IPF pathgenesis – Fas Pathway

    Chapman HA. J Clin Invest 1999; 104: 1


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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 )


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    Diagnostic Cenario :

    Smoking and Diffuse Lung Disease

    IPF

    versus

    Other smoking-related lung disease

    IPF

    plus

    Other smoking-related lung disease


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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)


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    Smoking-related Diffuse Lung Disease

    FeaturesUIP 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 1.50

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    Smoking-related Diffuse Lung Disease

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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    IPF and Lung Cancer


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    IPF and Lung Cancer

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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    IPF and Lung Cancer

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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    IPF and Emphysema

    n = 21

    Thorax 1997; 52: 998-1002


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    IPF and Emphysema

    Resp Med 2005; 99: 948-954

    n = 61

    Eur Resp J 2005; 26: 586-593


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    • 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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    Smoking and IPF

    Prognostic Implications

    • Cohort - 81 biopsy-proven IPF patients

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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    Smoking and IPF

    Prognostic Implications

    Study DesignN Change survival

    Rudd RM et al, 2007Prospective588 No

    Alakhras PA et al, 2007Retrospective197 No

    Pereira CAC et al, 2006Retrospective 86 No

    Flaherty KR et al, 2006Prospective197 No

    Collard HR et al, 2003Prospective 81 No

    King Jr TE et al, 2001Prospective238Better ?

    Rubin AS et al, 2000Retrospective117 No

    Current versus Ever smoking

    MBGazzana


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    Smoking Cessation

    and

    Idiopathic Pulmonary Fibrosis

    • No specific studies

    • Nothig in IPF guidelines


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    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


    Marcelo basso gazzana servi o de pneumologia hospital de cl nicas de porto alegre

    Obrigado

    pela atenção !

    [email protected]

    Hospital de Clínicas de Porto Alegre ( HCPA )

    Universidade Federal do Rio Grande do Sul ( UFRGS )

    Campus da Saúde

    MBGazzana


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