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Pulmonary and Systemic Inflammation in COPD
Exacerbations
Alberto Papi
Respiratory Medicine &
Research Centre on Asthma & COPD
University of Ferrara, I
Pulmonary and Systemic Inflammation in
COPD Exacerbations
• Definitions
• Airway inflammation
– Changes vs baseline
– Inflamation vs infections
• Systemic inflammation
– Changes vs baseline
– Predictive value
COPD exacerbation: Definition
• 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.
(GOLD 2010)
Pulmonary and Systemic Inflammation in
COPD Exacerbations
• Definitions
• Airway inflammation
– Changes vs baseline
– Inflamation vs infections
• Systemic inflammation
– Changes vs baseline
– Predictive value
PATHOGENESIS OF COPD EXACERBATIONS
AIRWAY
INFLAMMATION
SYMPTOMS
AIRFLOW
Airflow limitation
V/Q mismatch
Hyperinflation
Increased mucus
Airway wall thickening and oedema
Bronchoconstriction
Dyspnea
Cough
Sputum
Results: sputum PMN
Increase in sputum neutrophils
at exacerbations (106/g)
200
r = 0.35
P<0.01
150
100
50
0
-5
0
5
10
15
20
25
30
35
Percent decrease FEV1 at exacerbation
Papi, Fabbri & Johnston et al. AJRCCM 2006
Increased
No Change
TCC
4,6,7
1,2,3
Neutrophils
3,4,5
1,2,6,8
Eosinophils
4
1,2,5,8
4,8
1,2,3,5,6
IL-8
4, 9 – 11
1,2,7,8
IL-6
2,8,12
1,5,4,7,10
NE
4,5
Lymphocytes
TNF-α
9
1) Roland et al. Thorax 2001
2) Bhowmik et al. Thorax 2000
3) Tsoumakidou et al. Resp Med. 2005
4) Fujimoto et al. ERJ 2005
5) Papi et al. AJRCCM 2006
6) Caramori et al. Thorax 2003
11
7) Hurst et al. AJRCCM 2006
8) Seemungal et al. ERJ 2000
9) Aaron et al. AJRCCM 2001
10) Wilkinson et al. Chest 2006
11) Drost et al. Thorax 2005
12) Perera et al. ERJ 2007
ns
4
3
100
ns
75
2
50
1
25
0
0
Exac
Stable
Exac
(Bhowmik et al. Thorax 2000)
Delta FEV1 (%)
Stable
Neutrophils in sputum (%)
Cells in sputum (x105/g)
Relation of sputum inflammatory markers to symptoms and lung
function changes in COPD exacerbations
Perera WR, ERJ 2007
4
4
3
3
Exacerbations/years
Exacerbations/years
Fixed airflow obstruction in asthma and COPD:
5 years of follow up
2
1
0
60
70
80
Baseline sputum neutrophils
(% of total non squamous cells)
90
2
1
0
0
10
20
Baseline sputum eosinophils
(% of total non squamous cells)
Contoli, Saetta, Fabbri, & Papi et al. JACI 2010
30
Risk of exacerbations and airway
inflammation
< 2.58 exac/year
> 2.58 exac/year
20,000
N=23
IL-8 (pg/mL)
P=0.05
10,000
N=21
0
≤2
≥3
Number of Exacerbations in Previous Year
Bhowmik et al. Thorax. 2000
Effect of tiotropium on sputum and serum
inflammatory markers and
exacerbations in COPD
MPO log10 week*pg/ml
13
12
3.20
3.15
3.10
Ti
ot
ro
pi
um
Pl
ac
um
op
i
Ti
ot
r
eb
o
3.05
11
eb
o
Ti
ot
ro
pi
um
eb
o
3.5
14
ac
3.6
3.25
15
Pl
IL-8 log10 week*pg/ml 104
3.7
Pl
ac
IL-6 log10 week*pg/ml
3.8
Powrie DJ; Eur Respir J. 2007
Inflammation & COPD exacerbations.
Bronchial biopsies
Eosinophils
EG-2
Neutrophils
400
**
***
Cells/mm2
300
***
200
100
0
E
B
E
B
E
B
(Saetta et al 1994)
Changes in sputum T-lymphocite subpopulations at the
onset of severe exacerbations of COPD
*
CD4/CD8 ratio
1.75
1.50
1.25
1.00
0.75
Stable
*
70
CD8-IFN- g/CD8-IL4 ratio
2.00
Exacerbation
60
50
40
30
20
10
Stable
Exacerbation
(Tsoumakidou, Siafakas et al. Resp Med 2005)
Bacteria
Viruses
Noninfective
Inflammatory
Response
Rhinovirus
Receptor
NF-kB
Epithelial cells
NF-kB
RANTES
Macrophages
I-kB
degradationIL-6
CXCL8
Eosinophils
TNF-α
Reducing agents
NF-kB
Oxidant formation
X
Neutrophils
Oxidative stress
NF-kB
Caramori et al, Thorax 2003
Papi A, Contoli M J Biol Chem 2008
Pulmonary and Systemic Inflammation in
COPD Exacerbations
• Definitions
• Airway inflammation
– Changes vs baseline
– Inflamation and infections
• Systemic inflammation
– Changes vs baseline
– Predictive value
COPD exacerbations: Definition
• 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 history
• An increase in sputum volume and purulence points
to a bacterial cause, as does a prior history of chronic
sputum production.
(GOLD 2010)
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
Airway Inflammation and Etiology of Acute
Exacerbations of Chronic Bronchitis
IL-8 (pg/ml)
3500
***
2500
1500
500
0
Pathogens +
Pathogens (Sethi et al. Chest 2000)
Viral & bacterial aetiology of COPD
exacerbations
• 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
Papi A, Fabbri L, Johnston SL. AJRCCM 2006
Viruses and bacteria in COPD
exacerbations
No pathogen
Viruses
21%
Bacteria
30%
Papi, Fabbri & Johnston et al. AJRCCM 2006
24%
25%
Viruses &
Bacteria
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
Sputum Neutrophils increased in all AE
1000
**
**
**
**
Sputum neutrophils
10 6 /g plug
100
10
1
0,1
0,01
E
S
Virus
E
S
Virus +
bacteria
E
S
Bacteria
E
S
No pathogens
Papi, Fabbri & Johnston et al. AJRCCM 2006
Eosinophils increased only in virus related
AE
*
*
*
10
*
**
**
Sputum Eosinophils
10 6 /mg plug
8
6
4
2
0
E
Virus
S
E
S
Virus &
Bacteria
E
S
Bacteria
E
S
No pathogen
Rhinovirus infections in COPD
Criterion for exacerbation: increase over baseline in LRT symptom score of
>2 for 2 days
Upper & lower respiratory tract scores
(Mallia, Johnston et al. Respir Res 2006)
SYMPTOMS – URT AND LRT
10
*p<0.05
8
HS
COPD
6
4
*
*
* *
2
**
Daily LRT symptom scores
Daily URT symptom scores
12
6
5
*
* p<0.05
HS
COPD
4
3
2
*
*
1
0
-6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Study days
0
-6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Study days
Mallia P, Message S, Contoli M, Papi A, Johnston SL et al AJRCCM 2011 in press
Post-BD PEF (% baseline)
Lung function and airway inflammation
115
HS
COPD
110
105
100
95
90
85
BASE D5
D9
D12
D15 3/52 4/52 5/52 6/52
Time
Mallia P, Message S, Contoli M, Papi A, Johnston SL et al AJRCCM 2011 in press
Sputum virus load (log 10 RNA copies/ml)
VIRUS LOAD – time course
8
7
HS
COPD
6
5
4
3
2
1
0
D0
D5
D9
D12
D15
3/52
4/52
Study days
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
5/52
6/52
BACTERIAL INFECTION
Bacterial load (log10 CFU)
5
4
HS
COPD
3
2
1
0
0
D0
D5
D9
D12
D15
3/52
4/52
5/52
6/52
Study days
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
6
6
5
5
VIRUS
BACTERIA
4
4
3
3
2
2
1
1
0
0
D0
D5
D9
D12
D15
Bacterial load (log10 CFU)
Sputum virus load (log10 RNA copies/ml)
Time course of virus and bacterial load
3/52 4/52 5/52 6/52
Courtesy SL Johnston
Proteinase-AntiProteinase balance during
COPD exacerbations
120
80
100
MMP-9:TIMP-1 molar ratio
MMP-9 (mcg/g sputum)
110
90
80
70
60
50
40
30
20
10
70
60
50
40
30
20
10
0
0
Pre Ex
Ex
Pre Ex
Ex
Mercer PF, Resp Res 2005
Pulmonary and Systemic Inflammation in
COPD Exacerbations
• Definitions
• Airway inflammation
– Changes vs baseline
– Inflamation vs infections
• Systemic inflammation
– Changes vs baseline
– Predictive value
Plasma Biomarkers at exacerbation of COPD
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
Hurst JR, AJRCCM 2006
Blood neutrophils at exacerbation
of COPD
Increase in peripheral blood neutrophils
at exacerbation (cells/dL)
8000
6000
4000
2000
0
-2000
-4000
-5
0
5
10
15
20
Percent decrease in FEV 1 at exacerbation
Papi, Fabbri & Johnston et al. AJRCCM 2006
25
30
Correlations between inflammatory markers
Sputum Vs Serum
Serum
IL-6
CRP
r = 0.38
r = 0.39
p = 0.013
p = 0.016
r = 0.35
r = 0.24
p = 0.026
p = 0.134
Systemic and lower airway
inflammation at Exacerbation
of COPD
Sputum
IL-8
Hurst JR, AJRCCM 2006
150
Serum CRP
Leukocyte count
100
50
0
Sputum PPM Neg
Sputum PPM Pos
Plasma Biomarkers at exacerbation of COPD
CRP (pg/ml)
60000
40000
20000
0
Baseline
Exacerbation
Hurst JR, AJRCCM 2006
ROC analysis
AUC
95% CI
CRP > 5mg/L
CRP + one major symptom
0.73
0.88
0.66-0.80
0.82-0.93
Any major symptom
0.83
0.77-0.89
200
Recovered
Non Recovered
150
100
2.5
2.0
0
0
10
CRP log10 mg/ml
14 days
50
1.5
201.0
30
40
0.5
Time from exacerbation days
0.0
-0.5
30
0
100
200
Recovery time days
30
Recovery time days
CRP change from exacerbation %
Inflammatory changes, recovery and
recurrence at COPD exacerbation
400
Time to next exacerbation days
20
10
0
-500
300
0
Changes in sputum IL-6
Between baseline and day 7 (pg/ml)
500
20
10
0
-4000
-2000
0
2000
4000
Changes in sputum IL-8
Between baseline and day 7 (pg/ml)
Perera WR, ERJ 2007
Systemic Inflammation and Decline in Lung
Function in Patients With COPD
FEV1 % predicted
6
Fibrinogen (g/l)
50
Frq exacerbations
Infrq exacerbation
5
4
3
0
1
2
3
4
(years)
5
6
7
Low fibrinogen
High fibrinogen
40
30
20
0
1
2
3
(years)
Donaldson GC, Chest 2005
4
5
6
7
Acute exacerbations of chronic obstructive
pulmonary disease are accompanied by elevations
of plasma fibrinogen and serum IL-6 level.
4.6
Fibrinogen g/l
IL-6 pg/ml
4.4
4.2
4
3.8
3.6
3.4
3.2
3
Stable
(Wedzicha et al. Thromb Haemost 2000)
Exacerbation
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.
Risk of MI following exacerbation of COPD
IRRs for MI event on days 1 to 5
1 – 5 days
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)
0.03
Myocardial infarction
(per 100 pateint per year)
Type of exacerbation
5
4
3
2
1
0
0
1
2
3
4
>=5
Donaldson GC, Chest 2010
Pulmonary and Systemic Inflammation in COPD
Exacerbations
Annual meeting Linee guida Rinite Asma BPCO, Modena 1-3/3/2011
Results: sputum PMN
r = 0.35
P<0.01
N=23
IL-8 (pg/mL)
Increase in sputum neutrophils
at exacerbations (106/g)
20,000
200
**
**
100
N=21
10
1
50
0
0
≤2
≥3
Number of Exacerbations in Previous Year
0,1
0,01
-5
0
5 10 15 20 25 30 35
Percent decrease FEV1 at exacerbation
E S
Virus
2.5
E S
Bacteria
E S
No pathogens
50
20000
1.5
1.0
0.5
0.0
-0.5
Baseline
Exacerbation
FEV1 % predicted
CRP log10 mg/ml
14 days
40000
0
E
S
Virus +
bacteria
2.0
60000
CRP (pg/ml)
**
P=0.05
10,000
100
Sputum neutrophils
106 /g plug
< 2.58 exac/year
> 2.58 exac/year
150
**
1000
0
100
200
300
Time to next exacerbation days
400
40
30
20
0
1
2
3
(years)
4
5
6
7