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Diagnosi precoce di BPCO

Matteo Sofia

Cattedra di Malattie Respiratorie Università Federico II

Napoli

UOC Clinica Pneumologica Federico II AORN Monaldi

Napoli

matsouni@libero.it

Provincia totale

Napoli 6.411 3.374 9.785

Salerno 3.455 1.624 5.079

Caserta 1.680 851 2.531

Avellino 1.246 606 1.852

Benevento 610 309 919

totale 13.402 6.764 20.166

Epidemiologia della BPCO

Ricoveri in regime ordinarioRegione Campania

interrogazione per dati SDO - Ministero della Salute,

2005

Hospital

stay60 days 180 days 1 year 2 years

Mo

rta

lity (

%)

60

50

40

30

20

10

0

COPD Exacerbations : Mortality

11%

20%

33%

43%

49%

Connors AF Jr et al. Am J Respir Crit Care Med. 1996;154:959-67

1016 pts with severe COPD exacerbation

(PaCO2 > 50 mm Hg)

Sutherland, E. R. et al. N Engl J Med 2004;350:2689-2697

Declino clinico-funzionale nella BPCO

No lung pathology in smokers with GOLD stages 1 or 2

Hogg, NEJM 2004

GOLD stage 1 smokers are not rapid fallers.

2200 Lung Health Study continuing smokers

Baseline FEV1 % predictedScanlon

AJRCCM 2000

GOLD 1

“mild COPD”

GOLD 2

“moderate COPD”No change

-1.7%/yr

60% 75% 87%70% 82%

-1.2%/yr

No difference

Rapporto tra picco di VO2 e stadio GOLD

Casanova CHEST 2006

Picco VO2 % Th

Stadio BPCO

Marker biologici su aria espirata

• non

invasivi

• semplici

• ripetibili

• self made

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12

Months

FeN

O

ppb

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12

Months

FeN

O

ppb

de Laurentiis et al Pulmonary Pharmacology 2008

Monitoraggio di

Ossido Nitrico Espirato

nella BPCO con analizzatore

portatile

Confronto NOA - MINO

> eNO variation > exacerbation < < eNO variation < exacerbation

Analisi del condensato di aria

espirata ( EBC )

Metabonomic analysis of EBC by NMR

Design of the study

EBC/salivasample (2-4 ml)

Statistic (Quantitative) analysis (PCA, PLS-DA)

Spectra (Qualitative) analysis

Magnet

Computer

analisi qualitativa degli spettri di saliva e

condensato di espirato (EBC)

COPD

HSSaliva

de Laurentiis G. et al. ERJ 2008

Saliva spectra were strictlydifferent from correspondingEBC samples.

EBC

Laryngectomized

Analisi Quantitativa di EBC senza contaminazione

healthy

COPD

laryngectomized

De Laurentiis et al ERJ 2008

COPD

HS

Laryngectomized

Metabonomic analysis of EBC by NMR

Caratterizzazione delle differenze quali-

quantitative di spettro tra soggetti

COPD

HS

Laryngectomized

Loading plot spectra of HS and COPD showing anincreased intensity of signals of metabolites maybeinvolved in increased cellular oxidative stress.

acetate

methanol

crea

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

Salute del Respiro,Biologia di Sistema e

Vita dell‟ Uomo

NO su espirato nasale durante humming

nell’ostruzione dei seni paranasali

Lundberg, Maniscalco,Sofia et al. JAMA 2003

STADIO CARATTERISTICHE

I LIEVE VEMS/CVF < 0.7; VEMS ≥ 80% del teorico

II MODERATA

III GRAVE

VEMS/CVF< 0.7; 50% ≤ VEMS < 80%

VEMS/CVF < 0.7; 30% ≤ VEMS < 50%

IV MOLTOGRAVE

VEMS/CVF < 0.7; VEMS < 30% del teorico oVEMS < 50% del teorico in presenza diinsufficienza respiratoria (PaO2 < 60 mmHg)

Classificazione spirometrica(*) di gravità

(*) Basata sulla spirometria post-broncodilatatore

Lusuardi, CHEST 2006

Impatto della spirometria sul medico di Famiglia

570 Italian GPs were given a free MIR spirometer

Spirometry tests done per month

GOLD stage 2 smokers have a rapid fall...

2200 Lung Health Study continuing smokers

Baseline FEV1 % predictedScanlon

AJRCCM 2000

GOLD 1

“mild COPD”

GOLD 2

“moderate COPD”No change

-1.7%/yr

60% 75% 87%70% 82%

-1.2%/yr

spirometria e screening di BPCO

candidabili a terapia

• 10000 adulti

• 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

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?

Carraro et al. Am J Respir Crit Care Med 2007;175:986-900

Metabolomics with NMR spectroscopy

of exhaled breath condensage

Controls

Asthmatics

Gas chromatography and mass spectometry (GC/MS)

Instrumental repeatability

van Berkel, van Schooten et al. J Chromatography 2008

Volatile organic compounds

in exhaled air

• isobutane

• methanol

• ethanol

• benzene

• formaldehyde

• xylene

• acetone

• pentane

• dimethylsulfide

• carbon disulfide

• hydrogen sulfide

• acetaldehyde

Moser et al. Respir Physiol Neurobiol 2005;145:295-300

• isoprene

• propanal

• isopropanol

• toluene

• phenol

• etc, etc

GC/MS of exhaled breathGC/MS of exhaled breath

Subject 1

Subject 1

Subject 2

Subject 3

van Berkel et al. J Chromatography 2008

Phillips M et al. Chest 2003;123:2115-2123

GC/MS of exhaled breath in lung cancer

methylation

site

carbon

chain

length

Alv

eo

lar

gra

die

nt

Principal component analysis

of VOCs in exhaled air

Chen et al. Cancer 2007;110:835-844

Lung

cancer

Healthy

Chronic

bronchitis

Electronic nose

• Cyranose 320 ®

• 32 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;37:663-672

Sensors

VOCs induce swelling

of polymers with carbon particles

This changes

electrical resistance

eNose sensor responses

Time (sec)

Rela

tive e

lectr

ical re

sis

tan

ce

The array of sensors provides

a signature (smellprint) of the air

Electronic nose

Lewis, Acc Chem Res 2004;37:663-672Axel & Buck, Nobel prize 2004

Mammalian nose

Dragoniere et al. J Allergy Clin Immunol 2007;120:856-862

Asthma versus controls

principal component analysis

cross-validation: 100% cross-validation: 90%

Mobile phone eNose?

Applied Nanodetectors Ltd 2009

Progressione del danno funzionale respiratorio in 137

pazienti COPD seguiti per 5 anni

Decline in peak VO2(32ml/min/year)was more rapid than the decline in FEV1(25.4 ml/year).

Oga et al, Chest 2005

VO2peak VEpeak

Vtpeak VEMS1%pred

Fenotipo dispneizzante a

bassa capacita‟

funzionale

Bpco e pattern vems1L

un

g F

un

cti

on

Time (Years)

Exacerbation

Exacerbation

Exacerbation

Never smoked

Smoker

Fletcher C. BMJ 1977;1:1645-1648.

Rapporti tra VO2 peak e Stadio

COPD ( Casanova CHEST 2007)

10’ post-esposizione 1 ora post-esposizione 5 ore post-esposizione

Condizioni

basali

Standard

toluene

Esposizione al

toluene

Standard

toluene

Analisi metabolomica del condensato

Spettroscopia di Risonanza

Magnetica Nucleare 1H:

“metabolite

fingerprint”.

EBC

Saliva

Condensato

Saliva

Differenziazione tra componenti

molecolari saliva

ed espirato condensato

De Laurentiis et al, submitted

5-Year survival according to the peak exercise VO2

Oga T, et al. Am J Respir Crit Care Med 2003; 167:544-549

Mortality in COPD – Peak VO2

anni

maschi: blu, femmine : rosa, verde: totale

(ISS su dati DOXA 2006)

New

Cigarette smoke

and other irritants

Macrophage

Neutrophil

Alveolar-wall destruction

(Emphysema)

Mucus hypersecretion

(Chronic bronchitis)

Proteases

Epithelial cells

CD8+lymphocyte

TNF-a, LTB4

IL-8, CXC chemokines

Growth factors

Bronchiolar

Fibrosis

INFLAMMATORY MECHANISMS IN COPD

FibroblastNeutrophil elastase

Cathepsins

MMPs

TNF-a, IL-1b

IL-8, GM-CSF

TGF-b

Fattori di rischio della BPCO

Rischio assoluto di BPCO

(popolazione maschile)

Misurazione NO vie aeree inferiori

Misurazione NO nasale

Ossido Nitrico (NO) su espiratoorale e nasale

Misura di Ossido Nitrico su espirato dalle vie aeree inferioriSistema portatile

Raccolta ed analisi del condensato

• Il condensato di aria espirata (Exhaledbreath condensate, EBC), è un nuovometodo semplice e non invasivo diraccolta del liquido di rivestimentodelle vie aeree inferiori.

• L’EBC consente la raccolta e l’analisi siadi molecole volatili che non volatili.

• Surgery

– LVRS

– Transplantation

Treatment for Patients With

Moderate COPD

Mean FEV1 decline in the placebo group from recent large, long-term studies

Study FEV1

mean (SD)

Mean loss

(ml/year)

Smokers

(%)

Drop-out

rate (%)

EUROSCOP 2.54 (0.64) 69 100 30

Copenhagen

CLS

2.39 (0.86) 41.8 77.2 35

ISOLDE 1.40 (0.48) 59 39.2 53

LHS II 2.22 (0.65) 47 89.8 NR

BRONCUS 1.65 (0.39) 47 41 37

FEV1, forced expiratory volume in one second; NR, not recorded

Decramer et al. Thorax 2005;60:335-342; Sutherland et al. Thorax 2003;58:937-941; Decramer et al. Lancet

2005;365:1552-1560

Activity

• COPD patients are

very inactive

• This inactivity may

be present in all

GOLD-stages

FEV1 65%

FEV1 38%

FEV1 25%

0

10

20

30

40

50

60

70

80

90

100

Healthy

GOLD I&II

GOLD III

GOLD IV

Walk

ing

tim

e (

min

)

Pitta et al. Am J Respir Crit Care Med 2005; 171: 972-977.

Mildly low lung function in smokers often does not progress to COPD !

Anthonisen, AJRCCM 2002

One-third of LHS

smokers *never

developed impaired

lung function after 11

years, despite “airway

obstruction” at

baseline.

FEV1 % predicted at year 11

(n=1054) *

*

*

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

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