Download of exacerbation

New Concepts in Microbiology
of Exacerbations of COPD
Sanjay Sethi MD
Professor
Pulmonary, Critical Care and Sleep Medicine
University at Buffalo, SUNY
[email protected]
AECOPD: Perception vs Reality
Reality
Perception

A nuisance
problem with no
serious
consequences

Contributes to:




Mannino et al. MMWR 2002;51(SS-6):1-16
Andersson et al. Resp Med 2002;96:700-8
Cost of health care
(35-45%)
Poor quality of life
Mortality
Progression of lung
disease
Etiology of AECOPD
Non-infectious
S. pneumoniae
H para
Gram -
H. influenzae
Pseudomonas
Chlamydia
Virus
Obaji & Sethi. Drugs and Aging; 2001;18:1-11
M. catarrhalis
Etiology of AECOPD
Non-infectious
Bacteria
Virus
Bacteria and
Virus
Papi et al AJRCCM 2006;173:1114-21
AECOPD: Bacterial etiology
Sputum culture studies
Stable
Exacerbation
%
60
59.9
57.0
50
25 patients
Outpatient clinic
every 2 weeks
for 4 years
Sputum culture
40
37.2
30
33.1
1886 clinic visits
20
116 exacerbations
10
1870 stable
0
SP
NTHI
Gump et al. ARRD 1976;113:465-473
Bacterial load model of
pathogenesis of AECB
1,E+08
NTHI titer
1,E+07
1,E+06
1,E+05
1,E+04
1,E+03
1,E+02
S
E
S
E
S
E
S
Bacterial Load Model
10
*
9
*
8
7
6
stable
Log Titer
5
4
3
2
exacerbation
1
0
HI
HH
MC
SP
HP
Pathogen
Sethi et al AJRCCM 2007
Bacterial
Infection in
COPD
Acquisition of new
bacterial strain
Pathogen virulence
Host lung defense
Change in airway inflammation
Level of symptoms
Colonization
Strain-specific
immune response
+/- antibiotics
Elimination of
infecting strain
Exacerbation
Tissue invasion
Antigenic alteration
Persistent infection
Bacterial
Infection in
COPD
Acquisition of new
bacterial strain
Pathogen virulence
Host lung defense
Change in airway inflammation
Level of symptoms
Colonization
Strain-specific
immune response
+/- antibiotics
Elimination of
infecting strain
Exacerbation
Tissue invasion
Antigenic alteration
Persistent infection
COPD Study Clinic

Aims


Dynamics of bacterial
infection in COPD
Hypothesis


Acquisition of new
strains of bacterial
pathogens is
associated with an
increased risk of
exacerbation
Sethi et al. NEJM 2002, 347:465-471
Clinic visits:



Monthly
Suspected exacerbation
At each visit:



Clinical evaluation
Serum sample
Sputum sample for
quantitative
bacteriology
Patient 6: Time line
ex
ex
ex
1 month
1
2
3
4
5
6
7 8
9
HI HI
HI HI
HI
108 106
106 108 107
10 11 12 13
Typing the Nontypeable

Nontypeable H.
influenzae sputum
isolates


Sethi et al. NEJM 2002, 347:465-471
Whole bacterial lysates
Analyzed on a SDSPAGE gel
Patient 6: Time line
ex
ex
ex
1 month
1
2
3
4
5
6
7 8
9
HI HI
HI HI
HI
A A
B C
C
108 106
106 108 107
10 11 12 13
COPD Study Clinic: New strain isolation
and exacerbation
New strain +
New strain –
Exacerbation frequency
50
48.8
*
*p<0.05
Relative risk (95% CI)
of exacerbation:
40
*
30
*
33
Any
32
*
NTHI 1.69 (1.37–2.09)
26.2
20
15.4
17.1
16.6
Any
18.2
18
13.6
10
0
NTHI
MC
Pathogen
2.15 (1.83–2.63)
SP
PA
MC
2.96 (2.39–3.67)
SP
1.77 (1.14–2.75)
PA
0.61 (0.21–1.82)
Sethi et al. NEJM 2002;347:465-71
AECB: Bacterial etiology
Sputum culture studies
Stable
Exacerbation
%
60
59.9
57.0
50
25 patients
Outpatient clinic
every 2 weeks
for 4 years
Sputum culture
40
37.2
30
33.1
1886 clinic visits
20
116 exacerbations
10
1870 stable
0
SP
NTHI
Gump et al. ARRD 1976;113:465-473
Bacterial
Infection in
COPD
Acquisition of new
bacterial strain
Pathogen virulence
Host lung defense
Change in airway inflammation
Level of symptoms
Colonization
Strain-specific
immune response
+/- antibiotics
Elimination of
infecting strain
Exacerbation
Tissue invasion
Antigenic alteration
Persistent infection
NTHI Colonization vs Exacerbation
strains
•10 exacerbation strains
•7 colonization strains
•In vivo mouse model
•In vitro respiratory
epithelial cell line
Chin et al AJRCCM 2005
Acquisition of new
bacterial strain
Bacterial Infection
in COPD
Pathogen virulence
Host lung defense
Change in airway inflammation
Level of symptoms
Colonization
Strain-specific
immune response
+/- antibiotics
Elimination of
infecting strain
Exacerbation
Tissue invasion
Antigenic alteration
Persistent infection
Moraxella catarrhalis
Frequency of Immune Response
p = 0.009
p = 0.11
60
50
% positive
40
Exacerbation
Colonization
30
20
10
0
Sputum IgA
Murphy et al, AJRCCM 2005
Serum IgG
Lymphocyte Proliferative Response to
OMP P6 of NTHI


PBMC stimulated with
purified OMP P6
Groups
 H: healthy controls
 C: COPD without
NTHI exacerbation in
previous 12 months
 N: COPD with NTHI
exacerbation in
previous 12 months
Abe et al AJRCCM, 165:967-71, 2002
Acquisition of new
bacterial strain
Bacterial Infection
in COPD
Pathogen virulence
Host lung defense
Change in airway inflammation
Level of symptoms
Colonization
Strain-specific
immune response
+/- antibiotics
Elimination of
infecting strain
Exacerbation
Tissue invasion
Antigenic alteration
Persistent infection
Patient 6:Time line
ex
ex
ex
1 month
1
2
3
0 SP 0
4
5
6
7 8
9
10 11 12 13
HI HI
HI HI
HI 0
A A
B C
C
108 106
106 108 107
0
0
0
Changes in Airway Inflammation with
Onset of Exacerbations
5
IL-8
change
ng/ml
p = 0.40
4
600
3
500
2
NE
change
nM
1
0
p = 0.01
400
300
200
100
-1
0
-2
No new strain
New strain
-100
No new strain
1.2
• Airway inflammation increases
with exacerbations
p < 0.001
1
0.8
TNFα
change
ng/ml
New strain
• Bacterial exacerbations are
associated with greater
neutrophilic inflammation
0.6
0.4
0.2
0
-0.2
No new strain
New strain
Sethi et al ATS, 2005
Changes in Airway Inflammation with
Resolution of Exacerbations
p = 0.35
p = 0.05
500
3
p = 0.18
p = 0.02
Non-resolution
Resolution
400
2
300
IL-8
change
ng/ml
1
NE
change
nM
0
-1
100
0
-2
-100
-3
Non-resolution
p = 0.79
Resolution
p = 0.007
1
0.8
0.6
TNFα
change
ng/ml
200
0.4
0.2
0
-0.2
-0.4
-200
• Airway inflammation decreases
with resolution of exacerbation
• Correlation between clinical
resolution and resolution of
inflammation
-0.6
-0.8
-1
Non-resolution
Resolution
Sethi et al ATS, 2005
Bacterial Persistence and Airway
Inflammation following AECOPD
Bacteria
eradicated
by day 10
Bacteria
persisting
at day 10
Bacteria
eradicated
by day 10
100
MPO (units/ml)
10
10
LTB4 (nM)
Bacteria
persisting
at day 10
1
0.1
1
0.1
p<0.001
p<0.001
p<0.001
0.01
1
10
1
Day
p<0.05
0.01
10
1
10
1
10
Day
White et al. Thorax 2003;58:680-685
Acquisition of new
bacterial strain
Bacterial Infection
in COPD
Pathogen virulence
Host lung defense
Change in airway inflammation
Level of symptoms
Colonization
Strain-specific
immune response
+/- antibiotics
Elimination of
infecting strain
Exacerbation
Tissue invasion
Antigenic alteration
Persistent infection
H. influenzae: Bactericidal assays
120
100
• New bactericidal
antibody
developed to 18 of
26 (69.2%) new
strains following
exacerbation
80
%
Kill
60
40
20
0
-20
Pre-exacerbation
serum
Post-exacerbation
serum
Sethi et al AJRCCM 169;448-453, 2004



Bactericidal antibodies
from 10 patients were
tested against 9
heterologous strains
each.
79 of 90 (88%) of
heterologous strains
were not killed.
8 of the 10 sera killed
only the homologous
strain or 1
heterologous strain.
n
Strain-specificity of bactericidal
antibodies to NTHI
9
8
7
6
5
4
3
2
1
0
11
Sethi et al AJRCCM 169;448-453, 2004
13
14
18
32
37
45
patient #
55
6
70
Viral AECB:Culture and Serology
Studies
Percentage of total viral isolates
n
%
Viral
Rhino
Infl
Para RSV Corona Adeno
infl
38
26
15
Total
1081
Mean
135
36
Range
42-522
20–61 0-78
Comments 8
studies
7
studies
0-45 0-39
11
10
3
0-40
6-18
0-10
4
studies
Carilli 1964, Eadie 1966, McNamara 1969, Lamy 1974,
Gump 1976, Buscho 1978, Smith 1980, McHardy 1980
Viral RTI: Cohort Study
n
RI/yr
RTVI/yr
RTVI/RI %
Controls
FEV1 >50%
FEV1<50%
55
1.4
0.54
39
30
1.8
0.38
22
32
3.0
0.52
17
Greenberg et al AJRCCM, 2000;162:167-173
Viral RTI: Clinical Manifestations
and Lung Function
90
% of RTVI
80
70
60
50
40
30
URI
URI + LRI
LRI
20
10
0
Controls
FEV1>50%
Greenberg et al AJRCCM, 2000;162:167-173
FEV1<50%
Viral RTI: Pathogens
35
Control
% of Total Identified
30
FEV1 50%
25
FEV1 <50%
20
15
10
5
0
Picornaviruses
Parainfluenza
viruses
Coronaviruses
Influenza
viruses
RSV
Greenberg SB, et al. Am J Respir Crit Care Med. 2000;162:167-173.
Adenoviruses
RSV Infection in Elderly HighRisk Adults
Variable
RSV infection Influenza A
Duration of illness
15 ± 13 days
16%
41%
25%
45%
17 ± 10 days
20%
55%
25%
60%
4%
0%
Hospitalization
Housebound
Confined to bed
Unable to perform
ADL
Deaths
Falsey AR, et al. New Engl J Med. 2005;1749-1759.
Airway Inflammation and
Etiology
Papi et al AJRCCM 2006;173:1114-21
New Directions

Bacterial-viral-environmental interaction

Molecular detection and quantification of
infectious pathogens

Host susceptibility to infection
Effect of Pathogen Combinations on %
Decrease in FEV1 at Exacerbation
Wilkinson, T. M. A. et al. Chest 2006;129:317-324
PCR detection of bacterial
pathogens in COPD
S. pneumoniae
p<0.05
30
-
Number positive
+
25
psaA
20
Culture
PCR
15
lytA
10
5
0
Visit
El-Dika et al ATS 2007
Conclusions




Exacerbations are important
Bacteria cause a significant proportion of
exacerbations
Understanding Host-Pathogen interaction
is key
Therapeutic intervention