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![Page 1: Infections in acute exacerbation of COPD: are the agents the same ? Antonio Anzueto, M.D. Professor of Medicine University of Texas Health Science Center.](https://reader036.fdocuments.in/reader036/viewer/2022070407/56649e315503460f94b21efe/html5/thumbnails/1.jpg)
Infections in acute exacerbation of COPD:
are the agents the same ?
Antonio Anzueto, M.D.
Professor of Medicine
University of Texas Health Science Center
San Antonio, Texas
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Hospital mortality 24%
Hospital mortality 6%-12%
Relapse (repeat ER visit) 22%-32%
Treatment failure rate 13%-33%
Outcome of AECOPD
Seneff et al. JAMA. 1995;274:1852; Murata et al. Ann Emerg Med. 1991;20:125; Adams et al. Chest. 2000;117:1345.
In hospital pts
In ER pts
In ICU pts
In outpatients
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Etiology of COPD Exacerbation
Sethi S, et al. Chest 2000;117:380s-385s
80% 80% infectiousinfectious
20% 20% non-infectiousnon-infectious
Bacterial pathogens Bacterial pathogens 40 - 50%40 - 50%
Viral infectionViral infection30 - 40% 30 - 40%
Atypical Bacteria Atypical Bacteria 5 - 10%5 - 10%
Environmental Environmental factorsfactors
Non-compliance Non-compliance with medicationswith medications
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Viruses and bacteria in COPD exacerbations
Virus
Virus &Bacteria
Bacteria
No pathogen
24
25
21
30
Papi A, Fabbri L, Johnston SL et al. AJRCCM 2006
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Pooled studies of bronchoscopy in Pooled studies of bronchoscopy in stable COPD and patient during AECBstable COPD and patient during AECB
0
10
20
30
40
50
60
Healthy Stable COPD AECB
Per
cent
of
patie
nts
with
> 1
02 D
FU
/ml
0
5
10
15
20
25
30
Healthy Stable COPD AECB
H. flu
S. pneumo
M. cat
P. aer
Per
cent
of
patie
nts
with
par
ticul
ar o
rgan
ism
Rosell et al. Arch Int Med 2005; 165: 891-7Rosell et al. Arch Int Med 2005; 165: 891-7
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Exacerbation frequency and airway bacterial colonization
Exacerbation frequency
Pro
po
rtio
n o
f p
atie
nts
w
ith
LA
BC
1414N => 2.58 per year< 2.58 per year
1.2
1.0
0.8
0.6
0.4
0.2
0.0
-0.2
Patel, et al. Thorax 2002; 57: 759-64
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Bresser et al. AJRCCM 2000;162:947-952
TNF AND PATHOGENSTNF AND PATHOGENS
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Patient 6Time Line
1month
1 2 3 4 5 6 7 8 9 10 11 12 13
HI HI HI HI HI
ex ex ex
108 106 106 108 107
Sethi et al. N Engl J Med. 2002;347:465
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Typing the Nontypeable
Nontypeable H. influenzae sputum isolates– Whole bacterial
lysates – Analyzed on a SDS-
PAGE gel
Sethi et al. N Engl J Med. 2002;347:465.
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Patient 6Time Line
1month
1 2 3 4 5 6 7 8 9 10 11 12 13
HI HI HI HI HI
ex ex ex
A A B C C
108 106 106 108 107
Sethi et al. N Engl J Med. 2002;347:465
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Rate of Exacerbations Dependent on Pathogen and New Strain of Pathogen
33
26
49
32
15 17 17 18
0
10
20
30
40
50
60
New Strain No New Strain
Any Strain Haemophilusinfluenzae
Moraxellacatarrhalis
Streptococcuspneumoniae
p < 0.001 p < 0.001 p < 0.001 p = 0.01
# ex
acer
batio
ns/#
vis
its (
%)
Sethi S Sethi S et al. N Engl J Medet al. N Engl J Med. 2002 Aug 15;347(7):465-71. 2002 Aug 15;347(7):465-71
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NTHI from patients with AECBs elicit greater inflammation and epithelial cell
adhesion than colonizing strains
Chin et al. AJRCCM 2005; 172: 85-91.Chin et al. AJRCCM 2005; 172: 85-91.
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Pathogen+ Pathogen–Pathogen+ Pathogen–
Sethi et al. Chest. 2000; 118:1557
Pathogen-Positive AECBs Have Higher Levels of Inflammatory Markers
500
1000
1500
2000
2500
3000
3500
IL-8
(p
g/m
L)
1
10
100
1000
TN
F-a
(p
g/m
L)
1
10
100
1000
10000
NE
(m
U/m
L)
P = 0.004
Pathogen+ Pathogen–
P = 0.036 P = 0.004
Clinical score correlatedwith sputum elastase activity
1
10
100
1,000
10,000
100,000
1,000,000
10 12 14 16 18 20 22 24 26 28
Clinical Score
NE
(m
U/m
L)
Rho = 0.441P < 0.004
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Bacterial Persistence and Airway Inflammation following AECOPD
White et al. Thorax 2003;58:680-685
LTB
4 (n
M)
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 (
units
/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
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Etiology of exacerbation - biomarkers
Sethi S. et al AJRCCM 2008; 177:491
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Serum CRP is higher with new strainsSerum CRP is higher with new strains
p = 0.004 p = 0.007
Path Negative New Strain Pre-existing strain
Sethi S. et al. AJRCCM 2008; 177:491
0
.1
.2
.3
.4
.5
.6
.7
.8
Cel
l Mea
n
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Biomarkers – identify new strains
ROC-identify new strains using: sputum TNF and NE; and serum CRP
Sethi S. et al AJRCCM 2008; 177:491
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Pseudomonas sp and COPD exacerbations
Murphy et al AJRCCM 2008; 177:853
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Relative risk for exacerbations with pseudomonas colonization and presence of
new strains
Murphy et al AJRCCM 2008; 177:853
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- Two distinct patters of carriage:
1. Short term colonization follow by clearance
2. Long term persistence
- Mucoid strains showed persistence
- Acquisition of PA is associated with the occurrence of exacerbation.
- Serum antibody response do not mediate PA clearance.
Pseudomonas sp and COPD exacerbations
Murphy et al AJRCCM 2008; 177:853
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Airway bacterial concentration and AE COPD
6
7
8
9
HI MC SP
Stable Exacerbation
Mea
n [
log
]
NewStrain
**
6
7
8
9
HI MC SP
Stable Exacerbation
Mea
n [
log
]
Pre-existingStrain
*
Sethi et al, AJRCCM 2007
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Recent Antibiotic Exposure and S. pneumoniae Resistance in COPD
0
10
20
30
40
50
60
Macrolide in past 3 months
No macrolide in past 3 months
MIC = minimum inhibitory concentration.
Sethi S, et al. Abstract presented at 46th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 27-30, 2006; San Francisco. Presentation Number C2-0438.
P = .009
Erythromycin MIC1
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Recent Antibiotic Exposure and S. pneumoniae Resistance in COPD
0
5
10
15
20
25
30
35
40
45
Beta-lactam in past 3 monthsNo beta-lactam in past 3 months
P = .04 P = .22
PCN = penicillin.
Sethi S, et al. Abstract presented at 46th Interscience Conference on Antimicrobial Agents and Chemotherapy. ICAAC; September 27-30, 2006; San Francisco. Presentation Number C2-0438.
PCN MIC0.12 PCN MIC2
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Correlation of bacterial eradication Correlation of bacterial eradication and clinical outcome in AECBand clinical outcome in AECB
0%
10%
20%
30%
40%
50%
60%
70%
80%
0% 10% 20% 30% 40% 50% 60%
Clinical failure (%)
Bac
teri
olo
gic
al f
ailu
re (
%) R=0.78
Pechere, Inf Med 15:46,1998
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Rhinovirus in AECBRhinovirus in AECB
83/ 137 pts with 83/ 137 pts with >> 1 AECB 1 AECB 168 reported AECBs168 reported AECBs 107 (64%) with cold within 18d107 (64%) with cold within 18d 85 (51%) with cold at presentation85 (51%) with cold at presentation 66 (39%) VRTI + 66 (39%) VRTI + 39 (23%) RV +39 (23%) RV +
Viral AECBsGreater symptom countLonger recovery time (13 vs 6 d)
Seemungal et al. Am J Respir Crit Care Med. 2001;164: 1618-23.
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Bacterial load increased by
rhinovirus infection
2/10 (20%) controls
5/9 (55.6%) COPD group developed a positive bacterial culture (p=0.17)
Johnston S (preliminary data, with permission)
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Neutrophilic and Eosinophilic Inflammation During AE COPD
64 patients hospitalized with AE COPD64 patients hospitalized with AE COPD Viral and/or bacterial infection detected in 78%Viral and/or bacterial infection detected in 78%
– Infectious exacerbation (29.7% bacterial; 23.4% viral; 25% both)
– Exacerbation with co-infection
Papi A, et al. Am J Respir Crit Care Med 2006; 173: 1114-21
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Bacterial Infection in 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
Veeramachaneni SB, Sethi S. COPD. 2006;2:109-115.
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Why does it matter to identify the etiology of COPD Exacerbation ?
Decrease the risk of failure or return visitDecrease the risk of failure or return visit(extend the “exacerbation-free” interval)(extend the “exacerbation-free” interval)
Return the patient Return the patient to baselineto baseline(pulmonary function, symptoms(pulmonary function, symptoms, etc.), etc.)
Reduce morbidity,Reduce morbidity,hospitalization and hospitalization and mortalitymortality
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It is important not to stop questioning !!!
It is important not to stop questioning !!!
Albert Einstein www.brainyquote.com
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