Alberto Papi
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Grazie per aver scelto di utilizzare a scopo didattico questo materiale
delle Guidelines 2011 libra.Le ricordiamo che questo materiale è
di proprietà dell’autore e fornito come supporto didattico per uso
personale.
Alberto Papi
Respiratory Medicine &Respiratory Medicine &Research Centre on Asthma & COPDResearch Centre on Asthma & COPD
University of Ferrara, IUniversity of Ferrara, I
Pulmonary and Systemic Inflammation in COPD Pulmonary and Systemic Inflammation in COPD ExacerbationsExacerbations
Pulmonary and Systemic Inflammation in Pulmonary and Systemic Inflammation in COPD ExacerbationsCOPD Exacerbations
• Definitions• Airway inflammation
– Changes vs baseline
– Inflamation vs infections
• Systemic inflammation– Changes vs baseline
– Predictive value
• A change in the patient’s baseline dyspnea, A change in the patient’s baseline dyspnea,
cough and/or sputum that is beyond normal cough and/or sputum that is beyond normal
day-to day variations, is acute in onset, and day-to day variations, is acute in onset, and
may warrant a change in regular medications may warrant a change in regular medications
in a patient with underlying COPDin a patient with underlying COPD. .
(GOLD 2010)(GOLD 2010)
COPD exacerbation: DefinitionCOPD exacerbation: Definition
Pulmonary and Systemic Inflammation in Pulmonary and Systemic Inflammation in COPD ExacerbationsCOPD Exacerbations
• Definitions• Airway inflammation
– Changes vs baseline
– Inflamation vs infections
• Systemic inflammation– Changes vs baseline
– Predictive value
AIRFLOW
AIRWAY INFLAMMATION
SYMPTOMS
Increased mucusAirway wall thickening and oedemaBronchoconstriction
Airflow limitationV/Q mismatchHyperinflation
DyspneaCoughSputum
PATHOGENESIS OF COPD EXACERBATIONS
-5 0 5 10 15 20 25 30 35
0
50
100
150
200
Percent decrease FEVPercent decrease FEV11 at exacerbation at exacerbation
Incr
ease
in s
pu
tum
neu
tro
ph
ilsIn
crea
se in
sp
utu
m n
eutr
op
hils
at e
xace
rbat
ion
s (1
0at
exa
cerb
atio
ns
(1066 /
g)
/g)
Results: sputum PMNResults: sputum PMN
r = 0.35P<0.01
Papi, Fabbri & Johnston et al. AJRCCM 2006
Increased
TCC 4,6,7
Neutrophils 3,4,5
Eosinophils 4
Lymphocytes 4,8
IL-8 4, 9 – 11
IL-6 2,8,12
NE 4,5
TNF-α 9
1) Roland et al. Thorax 2001 7) Hurst et al. AJRCCM 2006
2) Bhowmik et al. Thorax 2000 8) Seemungal et al. ERJ 2000
3) Tsoumakidou et al. Resp Med. 2005 9) Aaron et al. AJRCCM 2001
4) Fujimoto et al. ERJ 2005 10) Wilkinson et al. Chest 2006
5) Papi et al. AJRCCM 2006 11) Drost et al. Thorax 2005
6) Caramori et al. Thorax 2003 12) Perera et al. ERJ 2007
No Change
1,2,3
1,2,6,8
1,2,5,8
1,2,3,5,6
1,2,7,8
1,5,4,7,10
11
Relation of sputum inflammatory markers to symptoms and lung Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbationsfunction changes in COPD exacerbations
Stable Exac Stable Exac0
1
2
3
4
0
25
50
75
100
Cel
ls i
n s
pu
tum
(x1
05/g
)
Neu
trop
hils in
spu
tum
(%)
nsns
nsns
(Bhowmik et al. Thorax 2000)(Bhowmik et al. Thorax 2000)
Stable state Excaerbation0.65
0.75
0.85
0.95
1.05
1.15
1.25
1.35
-20
-15
-10
-5
0
5
10
Del
ta F
EV
1 (%
)
Perera WR, ERJ 2007
Contoli, Saetta, Fabbri, & Papi et al. JACI 2010Contoli, Saetta, Fabbri, & Papi et al. JACI 2010
Fixed airflow obstruction in asthma and COPD: Fixed airflow obstruction in asthma and COPD: 5 years of follow up5 years of follow up
0 10 20 300
1
2
3
4
Baseline sputum eosinophils(% of total non squamous cells)
Exac
erba
tions
/yea
rs
60 70 80 900
1
2
3
4
Baseline sputum neutrophils(% of total non squamous cells)
Exac
erba
tions
/yea
rs
Risk of exacerbations and airway inflammation
Bhowmik et al. Thorax. 2000
N=23
N=21
≤2 ≥30
10,000
20,000
Number of Exacerbations in Previous Year
IL-8
(pg
/mL)
P=0.05
> 2.58 exac/year < 2.58 exac/year
Effect of tiotropium on sputum and serum inflammatory markers and
exacerbations in COPD
Powrie DJ; Eur Respir J. 2007
Place
bo
Tiotro
pium
3.5
3.6
3.7
3.8
IL-6
lo
g10
wee
k*p
g/m
l
Place
bo
Tiotro
pium
11
12
13
14
15
IL-8
lo
g10
wee
k*p
g/m
l 10
4
Place
bo
Tiotro
pium
3.05
3.10
3.15
3.20
3.25
MP
O l
og
10 w
eek*
pg
/ml
Inflammation & COPD exacerbations. Bronchial biopsies
EE BB EE BB EE BB
************ ****
00
100100
200200
300300
400400EosinophilsEosinophils EG-2EG-2 NeutrophilsNeutrophils
Cel
ls/m
mC
ells
/mm
22
(Saetta et al 1994)(Saetta et al 1994)
Changes in sputum T-lymphocite subpopulations at the Changes in sputum T-lymphocite subpopulations at the onset of severe exacerbations of COPDonset of severe exacerbations of COPD
Stable Exacerbation0.75
1.00
1.25
1.50
1.75
2.00
CD
4/C
D8
rati
o
**
Stable Exacerbation10
20
30
40
50
60
70
CD
8-IF
N-g
/CD
8-IL
4 ra
tio
**
(Tsoumakidou, Siafakas et al. Resp Med 2005)(Tsoumakidou, Siafakas et al. Resp Med 2005)
Oxidative stressOxidative stress
VirusesBacteria Noninfective
Epithelial cells
Macrophages
Neutrophils
Eosinophils
NF-kBNF-kB
CXCL8 IL-6
TNF-α
NF-kBNF-kB
RANTES
Caramori et al, Thorax 2003
RhinovirusRhinovirus
Oxidant formationOxidant formation
I-kB degradationI-kB degradation
NF-kB
NF-kB
InflammatoryInflammatoryResponseResponse
ReceptorReceptor
Papi A, Contoli M J Biol Chem 2008
XX
Reducing agentsReducing agents
Pulmonary and Systemic Inflammation in Pulmonary and Systemic Inflammation in COPD ExacerbationsCOPD Exacerbations
• Definitions• Airway inflammation
– Changes vs baseline
– Inflamation and infections
• Systemic inflammation– Changes vs baseline
– Predictive value
• A change in the patient’s baseline dyspnea, cough and/or sputum
that is beyond normal day-to day variations, is acute in onset, and
may warrant a change in regular medications in a patient with
underlying COPD. .
– Medical historyMedical history
• An increase in sputum volume and purulence points to An increase in sputum volume and purulence points to
a bacterial cause, as does a prior history of chronic a bacterial cause, as does a prior history of chronic
sputum productionsputum production..
(GOLD 2010)(GOLD 2010)
COPD exacerbations: DefinitionCOPD exacerbations: Definition
Etiology
• The most common causes of an exacerbation are infection of the tracheobronchial tree and air pollution, but the cause of about one-third of severe exacerbations cannot be identified.
• The role of bacterial infections is controversial, but recent investigations have shown that at least 50% of patients have bacteria in high concentrations in their lower airways during exacerbations.
• The association of neutrophilic inflammation with bacterial exacerbations, also support the bacterial causation of a proportion of exacerbations.
•GOLD 2010
• The most common causes of an exacerbation are infection of the tracheobronchial tree and air pollution, but the cause of about one-third of severe exacerbations cannot be identified.
• The role of bacterial infections is controversial, but recent investigations have shown that at least 50% of patients have bacteria in high concentrations in their lower airways during exacerbations.
• The association of neutrophilic inflammation with bacterial exacerbations, also support the bacterial causation of a proportion of exacerbations.
(Sethi et al. Chest 2000)(Sethi et al. Chest 2000)
Pathogens +Pathogens + Pathogens -Pathogens -
IL-8
(pg
/ml)
IL-8
(pg
/ml)
35003500
25002500
15001500
500500
00
******
Airway Inflammation and Etiology of Acute Airway Inflammation and Etiology of Acute Exacerbations of Chronic BronchitisExacerbations of Chronic Bronchitis
• Prospective follow up of cohort of COPD patients
• 64 hospitalised patients with severe AE-COPD• Seen again when stable 8 weeks later• Sputum induction within 24hrs of AE• Age 70• 56 male, 8 female• 48 pack years
Viral & bacterial aetiology of COPD exacerbations
Papi A, Fabbri L, Johnston SL. AJRCCM 2006
Viruses and bacteria in COPD exacerbations
Viruses
Viruses &Bacteria
Bacteria
No pathogen
24%
25%
21%
30%
Papi, Fabbri & Johnston et al. AJRCCM 2006
Viruses & bacteria in COPD exacerbations
• Viral and/or bacterial infection in 79% of exacerbations– viruses in 48.8% (6.2% when stable, P<0.001)– bacteria in 54.7% (37.5% when stable, P=0.08)
• Infectious exacerbations– longer hospitalizations (P<0.02)– greater impairment of several measures of lung
function (all P<0.05)• 25% viral/bacterial co-infection - most severe
– greater impairment of lung function(P<0.02)– longer hospitalizations (P=0.001).
Papi, Fabbri & Johnston et al. AJRCCM 2006
Sp
utu
m n
eutr
op
hil
s S
pu
tum
neu
tro
ph
ils
1010
66/g
plu
g/g
plu
g
0,010,01
0,10,1
11
1010
100100
10001000
EE EE EE EESS SS SS SS
VirusVirus Virus +Virus +bacteriabacteria
BacteriaBacteria No pathogensNo pathogens
**** **** **** ****
Sputum Neutrophils increased in all AESputum Neutrophils increased in all AE
Papi, Fabbri & Johnston et al. AJRCCM 2006
Eosinophils increased only in virus related AE
Virus Virus & Bacteria No pathogen Bacteria
Sp
utu
m E
osi
no
ph
ilsS
pu
tum
Eo
sin
op
hils
1010
66/m
g p
lug
/mg
plu
g
00
2
4
6
8
10
EE EE EE EESS SS SS SS
**** ******
****
**
Criterion for exacerbation: increase over baseline in LRT symptom score of >2 for 2 days
Upper & lower respiratory tract scores
Rhinovirus infections in COPD
(Mallia, Johnston et al. Respir Res 2006)(Mallia, Johnston et al. Respir Res 2006)
0
1
2
3
4
5
6
-6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 420
1
2
3
4
5
6
COPD
HS
**
* *p<0.05
Study daysD
ail
y L
RT
sym
pto
m s
co
res
-6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 420
2
4
6
8
10
12
**
*p<0.05
*
* * *
HSCOPD
Study days
Dai
ly U
RT
sym
pto
m s
core
s
SYMPTOMS – URT AND LRT
Mallia P, Message S, Contoli M, Papi A, Johnston SL et al AJRCCM 2011 in press
Lung function and airway inflammation
BASE D5 D9 D12 D15 3/52 4/52 5/52 6/5285
90
95
100
105
110
115HSCOPD
Time
Pos
t-BD
PE
F (%
bas
elin
e)
Mallia P, Message S, Contoli M, Papi A, Johnston SL et al AJRCCM 2011 in press
D0 D5 D9 D12 D15 3/52 4/52 5/52 6/520
1
2
3
4
5
6
7
8
HSCOPD
Study days
Sp
utu
m v
iru
s l
oa
d (
log
10
RN
A c
op
ies
/ml)
VIRUS LOAD – time course
NASAL LAVAGE
SPUTUM BAL
COPD HS COPD HS COPD HS
91% 100% 64% 55% 60% 42%
Mallia P, Message S, Contoli M, Papi A, Johnston SL et al AJRCCM 2011
0 D0 D5 D9 D12 D15 3/52 4/52 5/52 6/520
1
2
3
4
5
HSCOPD
Study days
Bac
teri
al l
oad
(lo
g1
0 C
FU
)
After inoculation with RV16 18% of HS and 63.7% of COPD subjects
developed a positive bacterial sputum culture (p=0.081).
Courtesy SL Johnston
BACTERIAL INFECTION
D0 D5 D9 D12 D15 3/52 4/52 5/52 6/520
1
2
3
4
5
6
VIRUSBACTERIA
0
1
2
3
4
5
6
Sp
utu
m v
iru
s lo
ad (
log
10
RN
A c
op
ies/
ml)
Bacterial lo
ad (lo
g1
0 CF
U)
Time course of virus and bacterial load
Courtesy SL Johnston
MM
P-9
(m
cg/g
spu
tum
)
Pre Ex Ex0
10
20
30
40
50
60
70
80
90
100
110
120
MM
P-9
:TIM
P-1
mol
ar r
atio
Pre Ex Ex0
10
20
30
40
50
60
70
80
Proteinase-AntiProteinase balance during COPD exacerbations
Mercer PF, Resp Res 2005
Pulmonary and Systemic Inflammation in Pulmonary and Systemic Inflammation in COPD ExacerbationsCOPD Exacerbations
• Definitions• Airway inflammation
– Changes vs baseline
– Inflamation vs infections
• Systemic inflammation– Changes vs baseline
– Predictive value
Diffrences in plasma markers between baseline and exacerbations
Marker Units Baseline median (IQR)
Exacerbation median(IQR)
Median (% change)
P value
CRP mg/L 4.0 (2.0-12.0) 15.6 (4.5-74.0) + 185 <0.001
IL-6 pg/ml 1.55 (0.94-3.07) 3.25 (1.48-6.12) +66 <0.001
MPIF-1 pg/ml 734 (574-944) 901 (72-1237) +18 <0.001
PARC pg/ml 1.1 (0.8-1.5) x 105 1.3 (0.9-1.7) x 105 +10 0.002
ACRP-30 pg/ml 1.5 (0.9-2.3) x 107 1.6 (1.1 -2.6) x 107 +11 0.001
S-ICAM-1 pg/ml 4.8 (3.7-5.9) x 105 5.0 (4.1-6.4) x 105 +6 0.003
Plasma Biomarkers at exacerbation of COPD
Hurst JR, AJRCCM 2006
Blood neutrophils at exacerbation of COPD
Percent decrease in FEVPercent decrease in FEV11 at exacerbationat exacerbation
-5-5 00 55 1010 1515 2020 2525 3030
Inc
rea
se
in
pe
rip
he
ral
blo
od
ne
utr
op
hil
sIn
cre
as
e i
n p
eri
ph
era
l b
loo
d n
eu
tro
ph
ils
at
ex
ac
erb
ati
on
(c
ell
s/d
L)
at
ex
ac
erb
ati
on
(c
ell
s/d
L)
-4000-4000
-2000-2000
00
20002000
40004000
60006000
80008000
Papi, Fabbri & Johnston et al. AJRCCM 2006
Correlations between inflammatory markersSputum Vs Serum
Serum
IL-6 CRP
Sputum
Leukocyte count r = 0.38 r = 0.39
p = 0.013 p = 0.016
IL-8 r = 0.35 r = 0.24
p = 0.026 p = 0.134
Ser
um
CR
P
Sputum PPM Neg Sputum PPM Pos0
50
100
150
Hurst JR, AJRCCM 2006
Systemic and lower airway inflammation at Exacerbation
of COPD
ROC analysis
AUC 95% CI
CRP > 5mg/L 0.73 0.66-0.80
CRP + one major symptom 0.88 0.82-0.93
Any major symptom 0.83 0.77-0.89
Baseline Exacerbation0
20000
40000
60000
CR
P (
pg
/ml)
Plasma Biomarkers at exacerbation of COPD
Hurst JR, AJRCCM 2006
Perera WR, ERJ 2007
-4000 -2000 0 2000 40000
10
20
30
-500 0 5000
10
20
30
Rec
over
y tim
e da
ys
Rec
over
y tim
e da
ys
Changes in sputum IL-6Between baseline and day 7 (pg/ml)
Changes in sputum IL-8Between baseline and day 7 (pg/ml)
0 100 200 300 400-0.5
0.0
0.5
1.0
1.5
2.0
2.5
CR
P lo
g10
mg/
ml
14 d
ays
Time to next exacerbation days
Time from exacerbation days
CR
P c
ha
ng
e f
rom
exa
cerb
atio
n %
0 10 20 30 400
50
100
150
200RecoveredNon Recovered
Inflammatory changes, recovery and recurrence at COPD exacerbation
Donaldson GC, Chest 2005
0 1 2 3 4 5 6 720
30
40
50
(years)
FE
V1
% p
red
icte
d
Fib
rino
ge
n (
g/l)
0 1 2 3 4 5 6 73
4
5
6
(years)
Frq exacerbationsInfrq exacerbation
Low fibrinogenHigh fibrinogen
Systemic Inflammation and Decline in Lung Function in Patients With COPD
Acute exacerbations of chronic obstructive Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations pulmonary disease are accompanied by elevations
of plasma fibrinogen and serum IL-6 level.of plasma fibrinogen and serum IL-6 level.
(Wedzicha et al. Thromb Haemost 2000)(Wedzicha et al. Thromb Haemost 2000)
Fib
rinog
en g
/lF
ibrin
ogen
g/l
IL-6
pg/
ml
IL-6
pg/
ml
COPD Exacerbations and CV Risk
• CRP – increases the expression of intercellular adhesion molecules,
– induces monocyte chemoattractant production,
– activates complement and
– mediates low density lipoprotein uptake by macrophages.
– deposits directly into the arterial wall during atherogenesis to create foam cells.
• Increased circulating fibrinogen levels during acute exacerbations result in increased pro-thrombotic state.
IRRs for MI event on days 1 to 5
1 – 5 days
Type of exacerbation IRR (95% CI) P value
Antibiotics 1.14 (0.7-1.8) 0.57
Steroids 1.55 (0.9-2.8) 0.15
Antibiotics + steroids 2.27(1.1-4.7) 0.03M
yoca
rdia
l in
farc
tion
(pe
r 1
00
pa
tein
t p
er
yea
r)
>=0 1 2 3 4 50
1
2
3
4
5
Donaldson GC, Chest 2010
Risk of MI following exacerbation of COPD
Pulmonary and Systemic Inflammation in COPD Exacerbations
Annual meeting Linee guida Rinite Asma BPCO, Modena 1-3/3/2011
-5 0 5 10 15 20 25 30 35
0
50
100
150
200
Percent decrease FEVPercent decrease FEV11 at exacerbation at exacerbation
Incr
ease
in
sp
utu
m n
eutr
op
hil
sIn
crea
se i
n s
pu
tum
neu
tro
ph
ils
at e
xace
rbat
ion
s (1
0at
exa
cerb
atio
ns
(1066 /
g)
/g)
Results: sputum PMNResults: sputum PMN
r = 0.35P<0.01
N=23
N=21
≤2 ≥30
10,000
20,000
Number of Exacerbations in Previous Year
IL-8
(pg
/mL) P=0.05
> 2.58 exac/year < 2.58 exac/year
Sp
utu
m n
eutr
op
hil
s S
pu
tum
neu
tro
ph
ils
101066
/g p
lug
/g p
lug
0,010,01
0,10,1
11
1010
100100
10001000
EE EE EE EESS SS SS SSVirusVirus Virus +Virus +
bacteriabacteriaBacteriaBacteria No pathogensNo pathogens
**** **** **** ****
Baseline Exacerbation0
20000
40000
60000
CR
P (
pg/m
l)
0 100 200 300 400-0.5
0.0
0.5
1.0
1.5
2.0
2.5
CR
P lo
g10
mg/
ml
14 d
ays
Time to next exacerbation days 0 1 2 3 4 5 6 720
30
40
50
(years)
FE
V1
% p
redi
cted
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