Diagnosi precoce di BPCO

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1 Diagnosi precoce di BPCO Matteo Sofia Cattedra di Malattie Respiratorie Università Federico II Napoli UOC Clinica Pneumologica Federico II AORN Monaldi Napoli

2 Epidemiologia della BPCO Ricoveri in regime ordinario Regione Campania Provincia totale Napoli Salerno Caserta Avellino Benevento totale interrogazione per dati SDO - Ministero della Salute, 2005

3 Mortality (%) COPD Exacerbations : Mortality % 1016 pts with severe COPD exacerbation (PaCO 2 > 50 mm Hg) 43% 33% 20% 49% 0 Hospital stay 60 days 180 days 1 year 2 years Connors AF Jr et al. Am J Respir Crit Care Med. 1996;154:959-67

4 Declino clinico-funzionale nella BPCO Sutherland, E. R. et al. N Engl J Med 2004;350:

5 No lung pathology in smokers with GOLD stages 1 or 2 Hogg, NEJM 2004

6 GOLD stage 1 smokers are not rapid fallers Lung Health Study continuing smokers No change GOLD 2 moderate COPD GOLD 1 mild COPD -1.2%/yr No difference -1.7%/yr 60% 70% 75% 82% 87% Baseline FEV1 % predicted Scanlon AJRCCM 2000

7 Rapporto tra picco di VO2 e stadio GOLD Picco VO2 % Th Casanova CHEST 2006 Stadio BPCO

8 Marker biologici su aria espirata non invasivi semplici ripetibili self made

9 FeNO FeNO Monitoraggio di Ossido Nitrico Espirato nella BPCO con analizzatore portatile Confronto NOA - MINO ppb Months ppb Months > eno variation > exacerbation < < eno variation < exacerbation de Laurentiis et al Pulmonary Pharmacology 2008

10 Analisi del condensato di aria espirata ( EBC )

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12 Metabonomic analysis of EBC by NMR Design of the study EBC/saliva sample (2-4 ml) Magnet Computer Statistic (Quantitative) analysis (PCA, PLS-DA) Spectra (Qualitative) analysis

13 analisi qualitativa degli spettri di saliva e condensato di espirato (EBC) Saliva HS EBC Laryngectomized Saliva spectra were strictly different from corresponding EBC samples. COPD de Laurentiis G. et al. ERJ 2008

14 Analisi Quantitativa di EBC senza contaminazione healthy laryngectomized COPD De Laurentiis et al ERJ 2008

15 HS Metabonomic analysis of EBC by NMR Caratterizzazione delle differenze qualiquantitative di spettro tra soggetti COPD Laryngectomized Laryngectomized HS acetate crea COPD methanol Loading plot spectra of HS and COPD showing an increased intensity of signals of metabolites maybe involved in increased cellular oxidative stress.

16 Metabolomics and System Biology Assessment. A new tool to explore COPD universe To study the entire (measureable) metabolic content / output of a biological system This system may be a cell, tissue, organ or organism Anderson ERS 2008

17 Salute del Respiro,Biologia di Sistema e Vita dell Uomo

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19 NO su espirato nasale durante humming nell ostruzione dei seni paranasali Lundberg, Maniscalco,Sofia et al. JAMA 2003

20 Classificazione spirometrica(*) di gravità STADIO I LIEVE II MODERATA III GRAVE CARATTERISTICHE VEMS/CVF < 0.7; VEMS 80% del teorico VEMS/CVF< 0.7; 50% VEMS < 80% VEMS/CVF < 0.7; 30% VEMS < 50% IV MOLTO GRAVE VEMS/CVF < 0.7; VEMS < 30% del teorico o VEMS < 50% del teorico in presenza di insufficienza respiratoria (PaO 2 < 60 mmhg) (*) Basata sulla spirometria post-broncodilatatore

21 Impatto della spirometria sul medico di Famiglia 570 Italian GPs were given a free MIR spirometer Spirometry tests done per month Lusuardi, CHEST 2006

22 GOLD stage 2 smokers have a rapid fall Lung Health Study continuing smokers No change GOLD 2 moderate COPD GOLD 1 mild COPD -1.2%/yr -1.7%/yr 60% 70% 75% 82% 87% Baseline FEV1 % predicted Scanlon AJRCCM 2000

23 spirometria e screening di BPCO adulti candidabili a terapia 90 BPCO candidabili a terapia 6 % Riduzione del rischio di riacutizzazione 7 BPCO protetti da > 1 riacutizzazione Soggetti da valutare per prevenire 1 episodio n= 4013

24 Monitoring asthma and COPD Disease markers symptoms variable airways obstruction individual biomarkers in sputum or exhaled air Traditional measurements based on clinical / pathophysiological reasoning requiring a variety of assays Alternative high-throughput methods: omics technology empirical, hypothesis-free approach based on probabilistic evidence only proteomics, transcriptomics, metabolomics, breatheomics?

25 Carraro et al. Am J Respir Crit Care Med 2007;175: Metabolomics with NMR spectroscopy of exhaled breath condensage Asthmatics Controls

26 Gas chromatography and mass spectometry (GC/MS) Instrumental repeatability van Berkel, van Schooten et al. J Chromatography 2008

27 Volatile organic compounds in exhaled air isobutane methanol ethanol benzene formaldehyde xylene acetone pentane dimethylsulfide carbon disulfide hydrogen sulfide acetaldehyde isoprene propanal isopropanol toluene phenol etc, etc Moser et al. Respir Physiol Neurobiol 2005;145:

28 GC/MS GC/MS of of exhaled exhaled breath breath Subject 1 Subject 1 Subject 2 Subject 3 van Berkel et al. J Chromatography 2008

29 Alveolar gradient GC/MS of exhaled breath in lung cancer methylation site carbon chain length Phillips M et al. Chest 2003;123:

30 Principal component analysis of VOCs in exhaled air Healthy Lung cancer Chronic bronchitis Chen et al. Cancer 2007;110:

31 Electronic nose Cyranose organic polymer sensor array Reversible binding of multiple VOCs depending on: molecular size molecular shape dipole moment hydrogen binding capacity Lewis NS. Acc Chem Res 2004;37:

32 Sensors VOCs induce swelling of polymers with carbon particles This changes electrical resistance

33 Relative electrical resistance enose sensor responses Time (sec)

34 The array of sensors provides a signature (smellprint) of the air

35 Mammalian nose Electronic nose Axel & Buck, Nobel prize 2004 Lewis, Acc Chem Res 2004;37:

36 Asthma versus controls principal component analysis cross-validation: 100% cross-validation: 90% Dragoniere et al. J Allergy Clin Immunol 2007;120:

37 Mobile phone enose? Applied Nanodetectors Ltd 2009

38 Progressione del danno funzionale respiratorio in 137 pazienti COPD seguiti per 5 anni VO2peak VEpeak Fenotipo dispneizzante a bassa capacita funzionale Vtpeak VEMS1%pred Decline in peak VO 2 (32ml/min/year)was more rapid than the decline in FEV 1 (25.4 ml/year). Oga et al, Chest 2005

39 Lung Function Bpco e pattern vems1 Never smoked Exacerbation Exacerbation Smoker Exacerbation Time (Years) Fletcher C. BMJ 1977;1:

40 Rapporti tra VO2 peak e Stadio COPD ( Casanova CHEST 2007)

41 Standard toluene Standard toluene Condizioni basali Esposizione al toluene 10 post-esposizione 1 ora post-esposizione 5 ore post-esposizione

42 Condensato Analisi metabolomica del condensato Saliva Spettroscopia di Risonanza Magnetica Nucleare 1H: metabolite fingerprint. Differenziazione tra componenti molecolari saliva ed espirato condensato EBC Saliva De Laurentiis et al, submitted

43 Mortality in COPD Peak VO 2 5-Year survival according to the peak exercise VO 2 Oga T, et al. Am J Respir Crit Care Med 2003; 167:

44 New anni maschi: blu, femmine : rosa, verde: totale (ISS su dati DOXA 2006)

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47 INFLAMMATORY MECHANISMS IN COPD Cigarette smoke and other irritants Epithelial cells TNF-a, IL-1b IL-8, GM-CSF TGF-b Macrophage TNF-a, LTB 4 IL-8, CXC chemokines Growth factors Fibroblast CD8+ lymphocyte Proteases Neutrophil Neutrophil elastase Cathepsins MMPs Bronchiolar Fibrosis Alveolar-wall destruction (Emphysema) Mucus hypersecretion (Chronic bronchitis)

48 Fattori di rischio della BPCO Rischio assoluto di BPCO (popolazione maschile)

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50 Ossido Nitrico (NO) su espirato orale e nasale Misurazione NO vie aeree inferiori Misurazione NO nasale

51 Misura di Ossido Nitrico su espirato dalle vie aeree inferiori Sistema portatile

52 Raccolta ed analisi del condensato Il condensato di aria espirata (Exhaled breath condensate, EBC), è un nuovo metodo semplice e non invasivo di raccolta del liquido di rivestimento delle vie aeree inferiori. L EBC consente la raccolta e l analisi sia di molecole volatili che non volatili.

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54 Surgery LVRS Transplantation

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57 Treatment for Patients With Moderate COPD

58 Mean FEV 1 decline in the placebo group from recent large, long-term studies Study FEV 1 mean (SD) Mean loss (ml/year) Smokers (%) Drop-out rate (%) EUROSCOP 2.54 (0.64) Copenhagen CLS 2.39 (0.86) ISOLDE 1.40 (0.48) LHS II 2.22 (0.65) NR BRONCUS 1.65 (0.39) FEV 1, forced expiratory volume in one second; NR, not recorded Decramer et al. Thorax 2005;60: ; Sutherland et al. Thorax 2003;58: ; Decramer et al. Lancet 2005;365:

59 Walking time (min) Activity Healthy GOLD I&II GOLD III GOLD IV FEV 1 65% FEV 1 38% FEV 1 25% COPD patients are very inactive This inactivity may be present in all GOLD-stages Pitta et al. Am J Respir Crit Care Med 2005; 171:

60 Mildly low lung function in smokers often does not progress to COPD! (n=1054) * * * One-third of LHS smokers *never developed impaired lung function after 11 years, despite airway obstruction at baseline. FEV1 % predicted at year 11 Anthonisen, AJRCCM 2002

61 Inhalers don t help smokers with mild-moderate COPD. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Peter Barnes and Robert Stockley, ERJ 2005

62 Smokers with spirometry are not more likely to quit smoking. 100,000 smokers in Poland had spirometry. Of 3077 with 12 month follow-up visits, those with obstruction were more likely to have quit smoking (16% vs 12%). But an RCT of spirometry (or not) for 1206 smokers in Belgium showed no difference in quit rates after 12 months (22% vs 20%). Bednarek, Thorax 2007, Buffels, Respir Med 2006