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

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

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

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

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

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

Bresser et al. AJRCCM 2000;162:947-952

TNF AND PATHOGENSTNF AND PATHOGENS

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

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.

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

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

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.

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

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

Etiology of exacerbation - biomarkers

Sethi S. et al AJRCCM 2008; 177:491

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

Biomarkers – identify new strains

ROC-identify new strains using: sputum TNF and NE; and serum CRP

Sethi S. et al AJRCCM 2008; 177:491

Pseudomonas sp and COPD exacerbations

Murphy et al AJRCCM 2008; 177:853

Relative risk for exacerbations with pseudomonas colonization and presence of

new strains

Murphy et al AJRCCM 2008; 177:853

- 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

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

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

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

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

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.

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)

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

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.

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

It is important not to stop questioning !!!

It is important not to stop questioning !!!

Albert Einstein www.brainyquote.com

FUTUREFUTURE