Broncopneumopatia cronica ostruttiva (BPCO)

1. Broncopneumopatia cronica ostruttiva (BPCO)

2. COPD • Definition, Classification • Burden of COPD • Risk Factors • Pathogenesis, Pathology, Pathophysiology • Practical Considerations

3. COPD chronic bronchitis emphysema unremitting asthma

4. COPD: old definition.…airflow obstruction due to emphysema and chronic bronchitis

5. Definition of COPD • COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. • Its pulmonary component is characterized by airflow limitation that is not fully reversible. • The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.

6. Venn diagram illustrating the overlap between asthma and COPD COPD Chronic bronchitis Asthma ? Chronic bronchiolitis Emphysema reversible irreversible Jeffery, AJRCCM 2001

7. Tosse e catarro cronici possono precedere lo sviluppo di BPCO di molti anni Per converso, alcuni pazienti sviluppano una significativa ostruzione al flusso in assenza di sintomi respiratori cronici. Storia naturale della malattia

8. Airway obstruction Structural changes Muco-ciliary dysfunction Inflammation COPD is a multicomponent disease Airflow limitation Cazzola and Dahl, Chest 2004

9. Classification of COPD Severity by Spirometry Stage I: Mild FEV1/FVC < 0.70 FEV1> 80% predicted Stage II: Moderate FEV1/FVC < 0.70 50% < FEV1 < 80% predicted Stage III: Severe FEV1/FVC < 0.70 30% < FEV1 < 50% predicted Stage IV: Very Severe FEV1/FVC < 0.70 FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure

10. Comparison of ATS 1995 and ATS/ERS 2004 disease staging systems

11. “At Risk” for COPD • COPD includes four stages of severity classified by spirometry. • A fifth category--Stage 0: At Risk--that appeared in the 2001 report is no longer included as a stage of COPD, as there is incomplete evidence that the individuals who meet the definition of “At Risk” (chronic cough and sputum production, normal spirometry) necessarily progress on to Stage I: Mild COPD. • The public health message is that chronic cough and sputum are not normal remains important - their presence should trigger a search for underlying cause(s).

12. Global Strategy for Diagnosis, Management and Prevention of COPD • Definition, Classification • Burden of COPD • Risk Factors • Pathogenesis, Pathology, Pathophysiology • Practical Considerations

13. Burden of COPD: Key Points • COPD is a leading cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing • COPD prevalence, morbidity, and mortality vary across countries and across different groups within countries • The burden of COPD is projected to increase in the coming decades due to continued exposure to COPD risk factors and the changing age structure of the world’s population

14. Burden of COPD: Prevalence • Many sources of variation can affect estimates of COPD prevalence, including e.g., sampling methods, response rates and quality of spirometry. • Data are emerging to provide evidence that prevalence of Stage I: Mild COPD and higher is appreciably higher in: - smokers and ex-smokers - people over 40 years of age - males

15. COPD Prevalence Study in Latin America The prevalence of post-bronchodilator FEV1/FVC < 0.70 increases steeply with age in 5 Latin American Cities Source: Menezes AM et al. Lancet 2005

16. FEV1/FVC% in asymptomatic, elderly never-smokers Hardie J, ERJ 2002

17. Burden of COPD: Mortality • COPD is a leading cause of mortality worldwide and projected to increase in the next several decades. • COPD mortality trends generally track several decades behind smoking trends. • In the US and Canada, COPD mortality for both men and women have been increasing. • In the US in 2000, the number of COPD deaths was greater among women than men.

18. Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998 Proportion of 1965 Rate 3.0 Coronary Heart Disease Stroke Other CVD COPD All Other Causes 2.5 2.0 1.5 1.0 0.5 –59% –64% –35% +163% –7% 0 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 Source: NHLBI/NIH/DHHS

19. Of the six leading causes of death in the United States, only COPD has been increasing steadily since 1970 Source:Jemal A. et al. JAMA 2005

20. COPD Mortality by Gender,U.S., 1980-2000 Number Deaths x 1000 Source: US Centers for Disease Control and Prevention, 2002

21. La morbidità è prevista in notevole aumento nel mondo con uno spostamento dal 12 ° al 6° posto. In termini di ricoveri ospedalieri in Italia i casi di BPCO risultano al 7° posto (fonte ISTAT 2003). Morbidità

22. Ricoveri in Regime Ordinario (FONTE SDO – MINISTERO DELLA SALUTE) % sul totale dei ricoveri 2000 48.685 0.49% 2001 77.264 0.78% 2002 88.083 0.91% 2003 94.829 1.03% Bronchite cronica ostruttiva,con riacutizzazione icd9cm 491.21 * Dati che, pur sottostimati a causa dei limiti di codifica,evidenziano un trend in netto aumento dei ricoveri

23. La BPCO è un problema non trascurabile fin dall’età giovanile. Studi epidemiologici hanno evidenziato che, nei soggetti tra 20 e 44 anni, il 10% presenta tosse ed espettorato senza segni di ostruzione bronchiale ed il 3.6% sintomi di ostruzione bronchiale (Stadi I - III). Prevalenza de Marco at al Thorax 2004; 59:120-125

24. Global Strategy for Diagnosis, Management and Prevention of COPD • Definition, Classification • Burden of COPD • Risk Factors • Pathogenesis, Pathology, Pathophysiology • Practical Considerations

25. Risk Factors for COPD • Genes • Exposure to particles • Tobacco smoke • Occupational dusts, organic and inorganic • Indoor air pollution from heating and cooking with biomass in poorly ventilated dwellings • Outdoor air pollution Lung growth and development Oxidative stress Gender Age Respiratory infections Socioeconomic status Nutrition Comorbidities

26. Never smoked or notsusceptible to smoke Susceptible smoker predicted decline if patient stops smoking COPD: Natural History 100 75 FEV1 (% predicted at age 25 years) 50 Disability 25 Death 0 25 50 75 Age (years) Fletcher C & Peto R. BMJ 1977;1:1645-8

27. Gli italiani secondo l’abitudine del fumo (stima su dati Doxa 2006) Totale Maschi Femmine FUMATORI 12,2 milioni circa  6,9 milioni circa  5,3 milioni circa (24,3%) (28,6%) (20,3%)  EX-FUMATORI 9 milioni circa  5,8 milioni circa 3,3 milioni circa (18,1%) (24%) = (11,2%)  NON FUMATORI 29 milioni circa  11,4 milioni circa 17,5 milioni circa (57,6%) (47,4%)  (67,1%)  OSSFAD, Istituto Superiore di Sanità – Indagine DOXA 2006

28. Circa il 30% dei fumatori (> 10 pack-year) oltre i 40 anni presenta una limitazione al flusso aereo. Circa il 40-50% dei fumatori sviluppa BPCO. Fumo di sigaretta Fletcher C, Peto R. BMJ 1977; 1: 1645 Jyrki-Tapani K, et al.COPD 2005; 2:331 Lokke A, et al. Thorax 2006; 61:935 Shahab L, et al. Thorax 2006; 61:1043 Pelkonen M, et al. Chest 2006; 130:1129 Rennard SI, et al. Lancet 2006; 367:1216

29. Anche l`esposizione al fumo passivo può contribuire all`insorgenza di sintomi respiratori e della malattia, aumentando il carico globale di particelle e gas inalati. Fumo passivo de Marco at al Thorax 2004; 59:120-125

30. alpha1-antitrypsin alpha1-antichymotrypsin MMPs TIMP-2 CFTR TNF /TNFR Vit D binding protein Microsomial epoxide hydrolase Heme-oxygenase-1 GSH S-transferase (M1,T1,P) IL-1b / IL-1RN beta2-adrenoceptor Cytochrome P450 Association in a given ethnic group Incosistent results when repeated in different populations of the same ethnic group or tested in multiple ethnic groups Negative results Association Studies for Assessment of Genetics in COPD (1987-2004)

31. Why case-control association studies for the genetics of COPD have been so far poorly informative ? Silverman & Palmer AJRCMB 2000;22:645

32. Or is it a matter of a poor definition of the phenotype ? COPD

33. Extreme Phenotypes Can Be Determined in the Minority of COPD subjects

34. Emphysema and cigarette smoking

35. Ogni incremento di 10 µg/m3 di particelle fini è associato a circa il 4% di aumento del rischio di mortalità per qualsiasi causa, il 6% per cause cardiopolmonari, l’8% per cancro al polmone Inquinamento outdoor Pope CA 3 rd, Burnett RT, Thum MJ, Calle EE, et all. Lung cancer, cardiopulmonary mortality, and tong –term exposure to fine particulate air pollution. JAMA 2002;287:1132-41

36. Inquinamento indoor • Nei Paesi a basso livello di sviluppo economico, l’utilizzo di combustibili biologici in ambienti con scarsa ventilazioneè un fattore causale di BPCO Warwick H, et al. ITDG Publishing, 2004: 103; http://www.idgpublishing.org.uk; Ezzati M. Lancet 2005; 336: 104; Oroczo-Levi M, et al. Eur Respir J 2006; 27: 542

37. E’ dimostrata una relazione significativa tra basso livello di istruzione ed aumento della mortalità per BPCO, indipendentemente dall’abitudine al fumo Basso livello di stato socioeconomico Prescott E, Godtfredsen N, VestboJ, Osler M. Social position and mortality from respiratory diseases in males and females. Eur Respir j 2003;21:821-6

38. Risk Factors for COPD Nutrition Infections Socio-economic status Aging Populations

39. Probabilità di contrarre la malattia nei 10 anni successivi all’età del soggetto, in funzione dei fattori di rischio (ISS, 2004)

40. Global Strategy for Diagnosis, Management and Prevention of COPD • Definition, Classification • Burden of COPD • Risk Factors • Pathogenesis, Pathology, Pathophysiology • Practical Considerations

42. Global Strategy for Diagnosis, Management and Prevention of COPD • Definition, Classification • Burden of COPD • Risk Factors • Pathogenesis, Pathology, Pathophysiology • Practical Considerations

43. Pathogenesis of COPD Cigarette smoke Biomass particles Particulates Host factors Amplifying mechanisms LUNG INFLAMMATION Anti-oxidants Anti-proteinases Oxidative stress Proteinases Repair mechanisms COPD PATHOLOGY Source: Peter J. Barnes, MD

44. Oxidative Stress in COPD Macrophage Neutrophil Anti-proteases SLPI 1-AT NF-B Proteolysis IL-8 TNF- ↓ HDAC2 ↑Inflammation Steroid resistance O2-, H202 OH., ONOO- Neutrophil recruitment Isoprostanes Bronchoconstriction Plasma leak  Mucus secretion Source: Peter J. Barnes, MD

45. Fixed effect meta-analysis results of selected biochemical variables Franciosi et al, Pulm Pharmacol Ther 2006;19:189-199

46. Changes in Large Airways of COPD Patients Mucus hypersecretion Neutrophils in sputum Squamous metaplasia of epithelium No basement membrane thickening Goblet cell hyperplasia ↑ Macrophages ↑ CD8+ lymphocytes Mucus gland hyperplasia Little increase in airway smooth muscle Source: Peter J. Barnes, MD

47. Ranked sputum neutrophil data demonstrating overlap of the ATS’ FEV1-based disease stages Franciosi et al, Pulm Pharmacol Ther 2006;19:189-199

48. Changes in Small Airways in COPD Patients Inflammatory exudate in lumen Disrupted alveolar attachments Thickened wall with inflammatory cells - macrophages, CD8+ cells, fibroblasts Peribronchial fibrosis Lymphoid follicle Source: Peter J. Barnes, MD

49. Changes in Lung Parenchyma in COPD Alveolar wall destruction Loss of elasticity Destruction of pulmonary capillary bed ↑ Inflammatory cells macrophages, CD8+ lymphocytes Source: Peter J. Barnes, MD

50. Air Trapping in COPD Mild/moderateCOPD Normal Severe COPD Inspiration small airway alveolar attachments loss of elasticity loss of alveolar attachments Expiration closure Dyspnea ↓ Exercise capacity Air trapping Hyperinflation ↓ Health status Source: Peter J. Barnes, MD