alberto papi

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

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




– Inflamation and infections



• 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%


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).


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


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

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


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


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


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

alberto papi

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