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