Totul despre relatia Fumat-BPOC Antigona Trofor Clinica Pneumologica Iasi

Sumar Aspecte generale Caracteristici particulare ale BPOC la fumători Beneficiul renunţării la fumat în BPOC Intervenţii terapeutice recomandate De ce pacienţii cu BPOC renunţă mai greu la fumat? Concluzii

Cifrele vorbesc * Fumatul este principala cauză evitabilă de moarte BPOC – a 5-a cauză de mortalitate pe glob Fumatul – principala cauză de BPOC (RR-13) Până la 50% din fumătorii cronici dezvoltă BPOC 80-90% din mortalitatea prin BPOC se datorează fumatului Şi fumatul pasiv este o cauză a BPOC ( în Germania -900 de nefumători mor anual, din 27% expuşi în populaţia generală) * Andreas S., Hering T., Muhlig S., Nowak D., Raupach T., Worth H., Smoking Cessation in COPD- a Clinical Practice Guideline, Dtzch. Arzetbl. Int. 2009, 106 (16), 276-82

Intervenţia este obligatorie Fumul de tutun – aerosol toxic cu implicaţii multiple respiratorii BPOC este o boală sistemică Marea majoritate (80%) a fumătorilor ar vrea să renunţe în principiu, însă doar 30% au cel puţin o tentativă în utimele 12 luni Tentativa de renunţare neasistată are succes în doar 5%

“Worldwide, the most commonly encountered risk factor for COPD is cigarette smoking. At every possible opportunity individuals who smoke should be encouraged to quit. “ GOLD 2008

Un singur pacient – două boli Dependenţa nicotinică BPOC Boala cronică recidivantă- F17.2 Dependenţa fizico-psiho-comportamentală Simptome de sevraj Efecte sistemice ale fumatului: inflamaţie, stress oxidativ la nivelul funcţiei endoteliale şi vasomotorii Boala sistemică cu manifestări respiratorii şi extrarespiratorii: cardiace, musculare, psihice, nutriţionale, sociale, etc. În formele severe: dependenţa de oxigen/de îngrijirile medicale

Endotelial activation Smoking Epithelial cell & PM10 Local Inflammatory response IL-8 MØ PMN cytokines IL-6, IL-1β GM-CSF, IL-6 LIVER IL-1β TNF- BONE MARROW Systemic Inflammatory response Leukocytes and platelets Active phase proteins Endotelial activation Vascular disease Van Eeden SF et al. Proc Am Thorac Soc 2005;2:61

 Ventilatory Requirement Poor Health-Related Quality of Life Air Trapping Links Pathophysiology and Patient-Centered Outcomes in COPD COPD Air Trapping Hyperinflation Airflow Obstruction Hypoxemia Exacerbations Anxiety Tachypnea  Ventilatory Requirement Deconditioning Slide 8 Key Point Air trapping links pathophysiology and patient-centered outcomes in COPD. Air trapping and hyperinflation associated with airflow obstruction result in increased dyspnea and activity limitation. In turn, dyspnea may lead to anxiety and tachypnea, which worsens hyperinflation by allowing less time for exhalation. Inactivity leads to deconditioning, which in turn increases ventilatory requirements, bringing about further air trapping and propagating the negative patient-centered outcomes. Poor Health-Related Quality of Life Activity Limitation Dyspnea Patient-Centered Outcomes Cooper. Am J Med. 2006;119(10A):S21-S31. Reference Cooper CB. The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function. Am J Med. 2006;119(10A):S21-S31.

Inflammatory Mechanisms in COPD Cigarette Smoke and Other Irritants MCP-1 Alveolar Macrophage Epithelial Cells Neutrophil Chemotactic Factors Interleukin-8, Leukotriene B4 Slide 9 CD8+ T Lymphocytes Many inflammatory cells are activated in COPD. Even in patients who have stopped smoking there may be ongoing inflammation. COPD is characterized by inflammation with macrophages, neutrophils, and T lymphocytes, specifically CD8+. Many chemokines and cytokines are involved in COPD. Inflammation leads to excess mucus production, fibrosis, and proteolysis, which may lead to mucus bronchitis, obstructive bronchiolitis, and emphysema. Neutrophil Protease Inhibitors Proteases Neutrophil Elastase Cathepsins Matrix Metalloproteinases 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. Reference Barnes PJ. COPD: is there light at the end of the tunnel? Curr Opin Pharmacol. 2004;4(3):263-272.

COPD: Pulmonary Inflammatory Response Normal lung functionb Severe emphysemab Inflammatory Cells Inflammatory Cells a Slide 10 Key Point Cigarette smoke induces a significant inflammatory response in the lungs of patients with emphysema. Retamales et al examined the hypothesis that in severe emphysema the lung inflammatory process is augmented. Tissue was obtained at the time of lung volume reduction surgery from 7 patients with severe emphysema. Tissue was also obtained from lung lobes resected for tumors from patients with normal lung function, 7 of whom had no emphysema and 7 of whom had mild emphysema. Patients in all 3 groups were heavy smokers. Controls had a 528 pack/year smoking history, patients with mild emphysema from whom tissue was taken had a 286 pack/year history, and patients with severe emphysema had a 6713 pack/year history. The patients with mild emphysema had smoked less than either of the other 2 groups. In terms of age, controls were 612 years of age, patients with mild emphysema from whom tissue was taken were 663 years of age, and patients with severe emphysema were 682 years of age. Patients in all 3 groups had a similar sex distribution. The number of polymorphonuclear cells (PMN), macrophages, CD4, CD8 (T lymphocytes), and eosinophils were increased in the lungs of patients with severe emphysema compared with people who smoked similar amounts but who still had normal lung function. a a a PMN, ×1012 CD8, ×1012 CD20, ×1012 Macro, ×1012 PMN, ×1012 Macro, ×1012 Eos, ×108 CD4, ×1012 Eos, ×108 CD4, ×1012 CD20, ×1012 CD8, ×1012 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. Reference Retamales I, Elliott MW, Meshi B, et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med. 2001;164(3):469-473.

Oxidative Stress in COPD Cigarette Smoke Inflammatory Cells (Neutrophils, Macrophages) Activation of Nuclear Factor-B Decrease in Antiproteases 1-Antitrypsin and Secretory Leukoprotease Inhibitor Tumor Necrosis Factor- Interleukin-8 Slide 11 O2, H2O2 OH, ONOO Neutrophil Recruitment Increased Mucus Secretion Key Point Oxidative stress is increased in patients with COPD. Oxidative stress occurs because of an imbalance between oxidants and antioxidants, either an excess of oxidants and/or reduction of antioxidants. Oxidants are derived from cigarette smoke and released from activated inflammatory cells, such as macrophages and neutrophils. Oxidative stress has several negative effects in the lungs, including inactivation of antiproteases, increasing secretion of mucus, and increasing plasma exudation. Bronchoconstriction Plasma Leak lsoprostanes Barnes. Curr Opin Pharmacol. 2004;4:265; GOLD Initiative 2006. http://www.goldcopd.com. Accessed July 23, 2007. Reference Barnes PJ. COPD: is there light at the end of the tunnel? Curr Opin Pharmacol. 2004;4:263-272. GOLD Initiative 2006. http://www.goldcopd.com. Accessed July 23, 2007.

Ce este diferit la fumătorii cu BPOC vs cei non BPOC? Fumează mai mult Au o dependenţă nicotinică mai severă Sunt mai deprimaţi Sunt mai puţin dispuşi să încerce să renunţe la fumat Au nivele mai ridicate ale monoxidului de carbon în aerul expirat

Differential characteristics of smokers with COPD vs those without Spain a general population study 1023 active smokers, 15% of cases with COPD by spirometry. Differential characteristics of smokers with COPD vs those without Poland 4494 smokers (age 40+, smoking >10 pck/y) . 1177 (26,2%) had airways obstruction Jimenez-Ruiz CA, Masa F, Miravitlles M, et al. Smoking characteristics:differences in attitudes and dependence between healthy smokers and smokers with COPD. Chest 2001;119:1365-70 Bednarek M, Gorecka D, Wielgomas J, et al. Smokers witth airway obstruction are more likely to quit smoking. Thorax 2006;61:869-73.

De ce este benefică renunţarea la fumat în relaţia cu BPOC? Previne dezvoltarea BPOC Previne progresia BPOC: ameliorarea simptomelor, îmbunătăţirea funcţiei pulmonare, reducerea exacerbărilor. Creşte eficacitatea medicaţiei bronhodilatatoare şi a oxigenoterapiei Scade mortalitatea

Smoking Cessation: Improvement in Postbronchodilator FEV1 Decline Susceptible smokers develop significant lung function decline Follow up (y) Postbronchodilator FEV1 L 2.4 2.5 2.6 2.7 2.8 2.9 Screen 2 1 2 3 4 5 Sustained Quitters Continuous Smokers Slide 15 Key Point Smoking cessation is beneficial to lung function. The Lung Health Study (LHS) was a randomized, multicenter clinical trial designed to determine whether a smoking cessation intervention with or without the regular use of a bronchodilator can slow the rate of decline in FEV1 in smokers thought to be in the early stages of COPD. Smokers (N=5887) aged 35 to 60 years with FEV1 of 55% to 90% of predicted and evidence of mild airway obstruction (airway obstruction was defined as FEV1/forced vital capacity [FVC] of 70% or less) were recruited and followed up for 5 years. Subjects were otherwise healthy. Participants were randomly assigned to 1 of 3 groups: Usual care who received no intervention Smoking intervention and the inhaled bronchodilator ipratropium bromide Smoking intervention and an inhaled placebo (SIP). Smoking intervention consisted of a 12-session smoking cessation program combining behavior modification and use of nicotine gum. Those who quit entered a maintenance program aimed at preventing relapse. Participants in all groups underwent annual spirometry and completed annual questionnaires inquiring about respiratory symptoms and history. At the end of the study, participants were classified as sustained quitters if they were determined to be nonsmokers at all annual visits and continuous smokers if they were still smoking at all annual visits. This slide shows the mean postbronchodilator FEV1 over the course of the study for sustained quitters and continuous smokers in the SIP group only. Postbronchodilator FEV1 was examined as the main outcome variable because it was felt to be more strongly related to prognosis in COPD than prebronchodilator FEV1. Study participants in the SIP group who stopped smoking in year 1 had a mean increase in FEV1 of 57 mL at the year 1 visit. While lung function improved during year 1 among quitters, it declined among continuing smokers. Between year 1 and year 5, the continuous smokers in the SIP group had a rate of decline in FEV1 of 63 mL/year. In contrast, in sustained quitters in the SIP group between year 1 and year 5, the FEV1 decreased by 34 mL/year. The overall 5-year decline in FEV1 in sustained quitters in the SIP group was 72 mL, while the FEV1 in continuous smokers declined by 301 mL. Anthonisen et al. JAMA. 1994;272(19):1497-1505; Kanner et al. Am J Med. 1999;106(4):410-416. References Anthonisen NR, Connett JE, Kiley JP; the Lung Health Study Research Group. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study. JAMA. 1994;272(19):1497-1505. Kanner RE, Connett JE, Williams DE, Buist AS; the Lung Health Study Research Group. Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease: the Lung Health Study. Am J Med. 1999;106(4):410-416. Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS, for the Lung Health Study Research Group. Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease: the Lung Health Study. Am J Respir Crit Care Med. 2000;161:381-390.

Renunţarea la fumat: inflamaţia aeriană şi BPOC Date* despre evaluarea efectului renunţării la fumat la fumătorii cu BPOC vs. fumători cu funcţie pulmonară normală pledează pentru menţinerea inflamaţiei aeriene la ex-fumători Chiar şi după ce opresc fumatul, “candidaţii” la BPOC înregistrează o inflamaţie aeriană persistentă şi creşterea celulelor inflamatorii din spută Inflamaţia persistentă observată la pacienţii cu BPOC se datorează refacerii tisulare de la nivelul căilor aeriene Fumătorii asimptomatici au fie un nivel constant, fie o reducere semnificativă a celulelor inflamatorii din spută Slide 16 Key Point Smoking cessation has different effects on the smoke-induced airway inflammation in smokers with COPD vs asymptomatic smokers with normal lung function. Willemse et al sought to determine the effect of smoking cessation on airway inflammation in patients with COPD. Sixty-three participants consisting of patients with COPD, smokers with chronic bronchitis, and asymptomatic smokers, aged 45 to 75 years were selected from the pulmonary outpatient clinic of the Groningen University Hospital of Groningen in The Netherlands and from individuals responding to advertisements in the local newspaper. Subjects had not used inhaled or oral corticosteroids in the previous 6 months. All participants had a >10 pack/years smoking history and smoked 10 cigarettes/day. Subjects were included in the COPD group if they had FEV1/FVC postbronchodilator <0.7 and had chronic respiratory symptoms (chronic cough and sputum production for at least 3 months for 2 consecutive years). The subjects with chronic bronchitis had chronic respiratory symptoms but did not have airflow limitation. The asymptomatic smokers did not have chronic respiratory symptoms or airway obstruction and they had an FEV1 85% predicted. Subjects were included in a 1-year smoking cessation program. Willemse et al. Eur Resp J. 2005;26(5):835-845. Reference Willemse BWM, ten Hacken NHT, Rutgers B, Lesman-Leegte IGAT, Postma DS, Timens W. Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smoking. Eur Resp J. 2005;26(5):835-845. (cont’d)

Terapii de renunţare la fumat în BPOC Consiliere Terapie farmacologică: TSN, bupropion, vareniclină Suport psihologic Terapie comportamentală Materiale informative ajutătoare

Abstinence rates, relative risk and risk differences for the combination of a behavioural intervention and pharmacotherapy (NRT) compared with no intervention Study Treatment Control Rd (fixed) RD (fixed) n/N n/N 95% Cl 95% Cl -0.25 0 0.25 Point prevalence abstinence at 12 months Anthonisen SI-P vs. UC 674/1962 177/1964 0.25 [0.23, 0.28] Anthonisen SH vs. UC 680/1961 177/1964 0.26 [0.23, 0.28] Prolonged abstinence after 5 years Anthonisen SI-P vs. UC 427/1961 102/1964 0.17 [0.15, 0.19] Anthonisen SI-P vs. UC 408/1961 102/1964 0.16 [0.14, 0.18] FAVOURS CONTROL FAVOURS TREATMENT Wagena EJ, van der Meer, Ostelo RJWG, et al. The efficacy of smoking cessation strategies in people with chronic obstructive pulmonary disease: results from a systematic review. Respir Med. 2004;98:805-15

Effects of behavioural smoking cessation intervention (+Tx) in COPD LHS 3923 smokers allocated to group therapy + nicotine gum vs 1964 no intervention Christenhusz study 225 COPD pts allocated to minimal intervention vs group therapy + bupropion 12 mo abstinence rate + NRT + B SR Tashkin DP, Murray RP. Smoking cessation in chronic obstructive pulmonary 2009;103, 963-974

TSN * O rată de succes la 12 luni mai mică: ( 8.7% plasturi 15 mg, 5.1% inhaler, 3.5% inhaler+ plasturi 15 mg) comparativ cu fumătorii sănătoşi Rata similară cu a fumătorilor sănătoşi: 23 % tableta sublinguală vs 10% placebo Lung Health Study: rata abstinenţei pe termen lung a crescut simţitor: 39 % în grupul de intervenţie vs 22%. * Tonnesen et. al. ERJ 2007, vol 29, nr.2, p.390-417

Abstinence rates, relative risk and risk differences for bupropion compared with placebo in COPD Study Treatment Control Rd (fixed) RD (fixed) n/N n/N 95% Cl 95% Cl -0.25 0 0.25 Tashkin 2001 32/204 18/200 0.07 [0.00, 013] Prolonged abstinence after 6 months PAVOURS CONTROL PAVOURS TREATMENT Prolonged abstinence after 12 months Tashkin 2001 21/204 17/200 0.02 [-0.04, 007] Wagena EJ, van der Meer, Ostelo RJWG, et al. The efficacy of smoking cessation strategies in people with chronic obstructive pulmonary disease: results from a systematic review. Respir Med. 2004;98:805-15

Bupropion * Metaanaliza a 19 studii: odds ratio de 2,06 în favoarea bupropion SR vs. placebo 7–12 săptămâni + consiliere Tashkin şi col: până la 14% rata de sevraj Bine tolerat, în privinţa riscului de HTA Repetarea curei creşte rata de succes * Tonnesen et. al. ERJ 2007, vol 29, nr.2, p.390-417

Vareniclina în BPOC * Eficacitatea superioară în săpt. 9-12 (43.3% vs 8.8% la grupul placebo) Eficacitate mai mare în follow-up (săpt.9-52: 18.6% vs 5.6% la grupul placebo) Efecte adverse: 2.8% grup vareniclina vs 4.4% grup placebo *Tashkin D. et. al, Efficacy and safety of varenicline for smoking cessation in mild to moderate COPD, 2009.

Tabel 1 Caracteristici demografice Vareniclina în BPOC

Date de cost – eficienta* Renunţarea la fumat este cost-eficienţa în tratamentul BPOC Costul sevrajului: 1117 € vs. 99 000 € cost economisit/an de viaţa de calitate la un pacient cu BPOC! ( revizuirea a 12 studii 1994-2007) * Smoking cessation compared to treatment of COPD and other smoking-related diseases using cost-effectiveness evidence Jens Dollerup1, Peter Bo Poulsen1, Hans-Jacob Randskov HJ1, Kjeld Møller Pedersen2 1. Pfizer Denmark, Ballerup, Denmark 2. University of Southern Denmark, Inst. of Public Health, Odense, Denmark E-communication 4647

…aproape totul…. Femeile fumătoare-mai susceptibile * BPOC Fumatul: dicontinuitatea MB şi tranziţia mezenchimal-epitelială (EMT): dezagregare, modificări de formă, motilitate ( Sohal et.al.) Femeile fumătoare-mai susceptibile * Fumători vs. nefumători Iniţiat de fumat pasiv în copilărie. E BM LP EMT Fibroblast-like phenotype Loss of tight junction (claudins)

Concluzii Renunţarea la fumat este una dintre cele mai eficiente metode de a preveni morbi-mortalitatea prin BPOC Fumătorii cu BPOC au caracteristici diferite comparativ cu nefumătorii fără BPOC: tentează mai rar oprirea fumatului şi au şanse mai mici de reuşită Intervenţiile nefarmacologice sunt eficace la pacienţi evaluaţi în vederea depistării BPOC Terapia farmacologică însoţită de consiliere sunt obligatorii la fumătorii cu BPOC