new concepts in microbiology of exacerbations of copd
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New Concepts in Microbiology of Exacerbations of COPD. Sanjay Sethi MD Professor Pulmonary, Critical Care and Sleep Medicine University at Buffalo, SUNY [email protected]. Perception A nuisance problem with no serious consequences. Reality Contributes to: Cost of health care (35-45%) - PowerPoint PPT PresentationTRANSCRIPT
New Concepts in New Concepts in Microbiology of Microbiology of
Exacerbations of COPD Exacerbations of COPD Sanjay Sethi MDSanjay Sethi MD
ProfessorProfessorPulmonary, Critical Care and Sleep MedicinePulmonary, Critical Care and Sleep Medicine
University at Buffalo, SUNYUniversity at Buffalo, [email protected]@buffalo.edu
AECOPD: Perception vs RealityAECOPD: Perception vs Reality
PerceptionPerception A nuisance A nuisance
problem with no problem with no serious serious consequencesconsequences
RealityReality Contributes to:Contributes to:
Cost of health Cost of health care care (35-45%)(35-45%)
Poor quality of lifePoor quality of life Mortality Mortality Progression of Progression of
lung diseaselung diseaseMannino et al. MMWR 2002;51(SS-6):1-16Andersson et al. Resp Med 2002;96:700-8
Etiology of AECOPDEtiology of AECOPD
S. pneumoniae
H. influenzae
M. catarrhalisVirus
Chlamydia
Pseudomonas
Gram -
H para
Non-infectious
Obaji & Sethi. Drugs and Aging; 2001;18:1-11
Etiology of AECOPDEtiology of AECOPD
Bacteria
Bacteria and Virus
Virus
Non-infectious
Papi et al AJRCCM 2006;173:1114-21
AECOPD: Bacterial etiologyAECOPD: Bacterial etiologySputum culture studiesSputum culture studies
Gump et al. ARRD 1976;113:465-473
25 patients
Outpatient clinic every 2 weeks for 4 years
Sputum culture
1886 clinic visits
116 exacerbations
1870 stable
StableExacerbation
00
1010
2020
3030
4040
5050
6060
SP NTHI
%%
33.1
59.957.0
37.2
Bacterial load model of Bacterial load model of pathogenesis of AECBpathogenesis of AECB
S E S E S E S
1,E+08
1,E+07
1,E+06
1,E+05
1,E+04
1,E+03
1,E+02
NTHI titer
Bacterial Load ModelBacterial Load Model
0
1
2
3
4
5
6
7
8
9
10
HI HH MC SP HP
Pathogen
stable
exacerbation
Log Titer
*
*
Sethi et al AJRCCM 2007
Bacterial Bacterial Infection in Infection in
COPDCOPD
Acquisition of new bacterial strain
Level of symptoms
Exacerbation
Strain-specific immune response
+/- antibiotics
Elimination of infecting strain
Colonization
Persistent infection
Tissue invasionAntigenic alteration
Pathogen virulenceHost lung defense
Change in airway inflammation
Acquisition of new bacterial strain
Level of symptoms
Exacerbation
Strain-specific immune response
+/- antibiotics
Elimination of infecting strain
Colonization
Persistent infection
Tissue invasionAntigenic alteration
Pathogen virulenceHost lung defense
Change in airway inflammation
Bacterial Bacterial Infection in Infection in
COPDCOPD
COPD Study ClinicCOPD Study Clinic
AimsAims Dynamics of Dynamics of
bacterial infection in bacterial infection in COPDCOPD
HypothesisHypothesis Acquisition of new Acquisition of new
strains of bacterial strains of bacterial pathogens is pathogens is associated with an associated with an increased risk of increased risk of exacerbationexacerbation
Clinic visits:Clinic visits: MonthlyMonthly Suspected Suspected
exacerbationexacerbation
At each visit:At each visit: Clinical evaluation Clinical evaluation Serum sampleSerum sample Sputum sample for Sputum sample for
quantitative quantitative bacteriologybacteriology
Sethi et al. NEJM 2002, 347:465-471
ex ex ex
Patient 6: Time line
HI HI HI HI HI
108 106 106 108 107
1 month
1 2 3 4 5 6 7 8 9 10 11 12 13
Typing the NontypeableTyping the Nontypeable
Nontypeable Nontypeable H. H. influenzae influenzae sputum sputum isolatesisolates Whole bacterial Whole bacterial
lysates lysates Analyzed on a SDS- Analyzed on a SDS-
PAGE gelPAGE gel
Sethi et al. NEJM 2002, 347:465-471
Patient 6: Time line
1 2 3 4 5 6 7 8 9 10 11 12 13
ex ex ex1 month
HI HI HI HI HI
108 106 106 108 107
A A B C C
33
15.4
26.2
17.1
48.8
16.6
32
18
13.6
18.2
0
10
20
30
40
50
Any NTHI MC SP PA
COPD Study Clinic: New strain isolation COPD Study Clinic: New strain isolation and exacerbationand exacerbation
*
*
*
*
Relative risk (95% CI) of exacerbation:
Any 2.15 (1.83–2.63)
NTHI 1.69 (1.37–2.09)
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
New strain +New strain –
*p<0.05
Exacerbation frequency
Pathogen
AECB: Bacterial etiologyAECB: Bacterial etiologySputum culture studiesSputum culture studies
Gump et al. ARRD 1976;113:465-473
25 patients
Outpatient clinic every 2 weeks for 4 years
Sputum culture
1886 clinic visits
116 exacerbations
1870 stable
StableExacerbation
00
1010
2020
3030
4040
5050
6060
SP NTHI
%%
33.1
59.957.0
37.2
Bacterial Bacterial Infection in Infection in
COPDCOPD
Acquisition of new bacterial strain
Level of symptoms
Exacerbation
Strain-specific immune response
+/- antibiotics
Elimination of infecting strain
Colonization
Persistent infection
Tissue invasionAntigenic alteration
Pathogen virulenceHost lung defense
Change in airway inflammation
NTHI Colonization vs Exacerbation NTHI Colonization vs Exacerbation strainsstrains
•10 exacerbation strains
•7 colonization strains
•In vivo mouse model
•In vitro respiratory epithelial cell line
Chin et al AJRCCM 2005
Bacterial Infection Bacterial Infection in COPDin COPD
Acquisition of new bacterial strain
Level of symptoms
Exacerbation
Strain-specific immune response
+/- antibiotics
Elimination of infecting strain
Colonization
Persistent infection
Tissue invasionAntigenic alteration
Pathogen virulence
Host lung defense
Change in airway inflammation
Moraxella catarrhalisMoraxella catarrhalisFrequency of Immune Response Frequency of Immune Response
0
10
20
30
40
50
60
% p
osi
tive
Sputum IgA Serum IgG
Exacerbation
Colonization
p = 0.009p = 0.009 p = 0.11p = 0.11
Murphy et al, AJRCCM 2005
Lymphocyte Proliferative Response to Lymphocyte Proliferative Response to OMP P6 of NTHIOMP P6 of NTHI
PBMC stimulated with PBMC stimulated with purified OMP P6purified OMP P6
GroupsGroups H: healthy controlsH: healthy controls C: COPD without C: COPD without
NTHI exacerbation NTHI exacerbation in previous 12 in previous 12 monthsmonths
N: COPD with NTHI N: COPD with NTHI exacerbation in exacerbation in previous 12 monthsprevious 12 months
Abe et al AJRCCM, 165:967-71, 2002
Bacterial Infection Bacterial Infection in COPDin COPD
Acquisition of new bacterial strain
Level of symptoms
Exacerbation
Strain-specific immune response
+/- antibiotics
Elimination of infecting strain
Colonization
Persistent infection
Tissue invasionAntigenic alteration
Pathogen virulenceHost lung defense
Change in airway inflammation
Patient 6:Time line
1 2 3 4 5 6 7 8 9 10 11 12 13
ex ex ex1 month
HI HI HI HI HI
108 106 106 108 107
A A B C C
SP0 0 0 0 0 0
Changes in Airway Inflammation with Onset of Exacerbations
-2
-1
0
1
2
3
4
5
No new strain New strain
IL-8
ch
ang
e n
g/m
l
p = 0.40
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
No new strain New strain
TN
Fα
ch
ang
e n
g/m
l
p < 0.001
-100
0
100
200
300
400
500
600
No new strain New strain
NE
ch
ang
e n
M
p = 0.01
• Airway inflammation increases with exacerbations
• Bacterial exacerbations are associated with greater neutrophilic inflammation
Sethi et al ATS, 2005
Changes in Airway Inflammation with Resolution of Exacerbations
-3
-2
-1
0
1
2
3
Non-resolution Resolution
IL-8
ch
ang
e n
g/m
l
p = 0.35 p = 0.05
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
Non-resolution Resolution
TN
Fα
ch
ang
e n
g/m
l
p = 0.79 p = 0.007
-200
-100
0
100
200
300
400
500
Non-resolution Resolution
NE
ch
ang
e n
M
p = 0.18 p = 0.02
Sethi et al ATS, 2005
• Airway inflammation decreases with resolution of exacerbation
• Correlation between clinical resolution and resolution of inflammation
Bacterial Persistence and Bacterial Persistence and Airway Inflammation following Airway Inflammation following
AECOPDAECOPD
White et al. Thorax 2003;58:680-685
LT
B4
(nM
)
100
10
1
0.1
0.01
1 10 1 10
Bacteria eradicated by day 10
Bacteria persisting at day 10
p<0.001p<0.001
Day
MP
O (
un
its/
ml)
10
1
0.1
0.01
1 10 1 10
Bacteria eradicated by day 10
Bacteria persisting at day 10
p<0.05p<0.001
Day
Bacterial Infection Bacterial Infection in COPDin COPD
Acquisition of new bacterial strain
Level of symptoms
Exacerbation
Strain-specific immune response
+/- antibiotics
Elimination of infecting strain
Colonization
Persistent infection
Tissue invasionAntigenic alteration
Pathogen virulenceHost lung defense
Change in airway inflammation
H. influenzaeH. influenzae: : Bactericidal Bactericidal assaysassays
%
Kil
l
-20
0
20
40
60
80
100
120
Pre-exacerbationserum
Post-exacerbationserum
• New bactericidal antibody developed to 18 of 26 (69.2%) new strains following exacerbation
Sethi et al AJRCCM 169;448-453, 2004
Strain-specificity of bactericidal Strain-specificity of bactericidal antibodies to NTHIantibodies to NTHI
Bactericidal antibodies Bactericidal antibodies from 10 patients were from 10 patients were tested against 9 tested against 9 heterologous strains heterologous strains each. each.
79 of 90 (88%) of 79 of 90 (88%) of heterologous strains heterologous strains were were notnot killed. killed.
8 of the 10 sera killed 8 of the 10 sera killed only the homologous only the homologous strain or 1 strain or 1 heterologous strain.heterologous strain.
0
12
34
5
67
89
n
11 13 14 18 32 37 45 55 6 70
patient #
Sethi et al AJRCCM 169;448-453, 2004
Viral AECB:Culture and Viral AECB:Culture and Serology StudiesSerology Studies
Percentage of total viral isolates
n %Viral
Rhino Infl Parainfl
RSV Corona Adeno
Total 1081
Mean 135 36 38 26 15 11 10 3
Range 42-522 20–61 0-78 0-45 0-39 0-40 6-18 0-10
Comments 8studies
7studies
4studies
Carilli 1964, Eadie 1966, McNamara 1969, Lamy 1974,
Gump 1976, Buscho 1978, Smith 1980, McHardy 1980
Viral RTI: Cohort StudyViral RTI: Cohort Study
171722223939RTVI/RI %RTVI/RI %0.520.520.380.380.540.54RTVI/yrRTVI/yr3.03.01.81.81.41.4RI/yrRI/yr323230305555nn
FEVFEV11<50%<50%FEVFEV11 >50% >50%ControlsControls
Greenberg et al AJRCCM, 2000;162:167-173
Viral RTI: Clinical Viral RTI: Clinical Manifestations and Lung Manifestations and Lung
FunctionFunction
0
10
20
30
40
50
60
70
80
90
% o
f R
TVI
Controls FEV1>50% FEV1<50%
URI
URI + LRI
LRI
Greenberg et al AJRCCM, 2000;162:167-173
Greenberg SB, et al. Am J Respir Crit Care Med. 2000;162:167-173.
Viral RTI: PathogensViral RTI: Pathogens
0
5
10
15
20
25
30
35
Picorna-viruses
Para-influenzaviruses
Corona-viruses
Influenzaviruses
RSV Adeno-viruses
Control
FEV1 50%
FEV1 <50%
% o
f T
ota
l Id
enti
fied
RSV Infection in Elderly RSV Infection in Elderly High-Risk AdultsHigh-Risk Adults
Falsey AR, et al. New Engl J Med. 2005;1749-1759.
VariableVariable RSV RSV infectioninfection
Influenza AInfluenza A
Duration of illnessDuration of illness 15 15 ± 13 days± 13 days 17 17 ± 10 days± 10 daysHospitalizationHospitalization 16%16% 20%20%HouseboundHousebound 41%41% 55%55%Confined to bedConfined to bed 25%25% 25%25%Unable to Unable to perform ADLperform ADL
45%45% 60%60%
DeathsDeaths 4%4% 0%0%
Airway Inflammation and Airway Inflammation and EtiologyEtiology
Papi et al AJRCCM 2006;173:1114-21
New DirectionsNew Directions
Bacterial-viral-environmental Bacterial-viral-environmental
interactioninteraction
Molecular detection and Molecular detection and
quantification of infectious quantification of infectious
pathogenspathogens
Host susceptibility to infectionHost susceptibility to infection
Effect of Pathogen Combinations Effect of Pathogen Combinations on % Decrease in FEVon % Decrease in FEV11 at at
ExacerbationExacerbation
Wilkinson, T. M. A. et al. Chest 2006;129:317-324
PCR detection of bacterial PCR detection of bacterial pathogens in COPDpathogens in COPD
S. pneumoniae
0
5
10
15
20
25
30
Num
ber
posi
tive
Visit
CulturePCR
+
-
lytA
psaA
p<0.05
El-Dika et al ATS 2007
ConclusionsConclusions
Exacerbations are importantExacerbations are important Bacteria cause a significant Bacteria cause a significant
proportion of exacerbationsproportion of exacerbations Understanding Host-Pathogen Understanding Host-Pathogen
interaction is keyinteraction is key Therapeutic interventionTherapeutic intervention