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
San Antonio, Texas

2. Outcome of AECOPD In ICU pts In hospital pts In ER pts In outpatients
Hospital mortality %
Hospital mortality %-12%
Relapse (repeat ER visit) 22%-32%
Treatment failure rate %-33%
In hospital pts
In ER pts
Acute exacerbations are associated with significant morbidity and mortality.
They should not be taken lightly.
In outpatients
Seneff et al. JAMA. 1995;274:1852; Murata et al. Ann Emerg Med. 1991;20:125; Adams et al. Chest. 2000;117:1345.

3. Etiology of COPD Exacerbation
20%
non-infectious
80%
infectious
Environmental factors
Non-compliance
with medications
Bacterial pathogens %
Viral infection %
Atypical Bacteria
5 - 10%
Sethi S, et al. Chest 2000;117:380s-385s

4. Viruses and bacteria in COPD exacerbations
No pathogen
Virus 21 24 30
Bacteria 25
Virus &
Bacteria
Papi A, Fabbri L, Johnston SL et al. AJRCCM 2006

5. Pooled studies of bronchoscopy in stable COPD and patient during AECB
Percent of patients
with > 102 DFU/ml
with particular organism
Percent of patients
Rosell et al. Arch Int Med 2005; 165: 891-7

6. Exacerbation frequency and airway bacterial colonization
1.2
1.0
0.8
Proportion of patients with LABC
0.6
0.4
0.2
0.0
-0.2
N = 14 14
< 2.58 per year
> 2.58 per year
Exacerbation frequency
Patel, et al. Thorax 2002; 57:

7. Bresser et al. AJRCCM 2000;162:947-952
TNF AND PATHOGENS
Bresser et al. AJRCCM 2000;162:

8. Patient 6
Time Line ex ex ex
1month 1 2 3 4 5 6 7 8 9 10 11 12 13
HI HI HI HI HI
Sethi et al. N Engl J Med. 2002;347:465

9. 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.

10. Patient 6
Time Line ex ex ex
1month 1 2 3 4 5 6 7 8 9 10 11 12 13
HI HI HI HI HI
A A B C C
Sethi et al. N Engl J Med. 2002;347:465

11. Rate of Exacerbations Dependent on Pathogen and New Strain of Pathogen
# exacerbations/# visits (%)
Isolation of a new strain of a pathogen was associated with a significant increase in the frequency of exacerbation (33% vs 15%).
The relative risk of an exacerbation in association with the isolation of a new strain of H. influenzae was 1.69 (p < 0.001), compared to the lack of risk associated with simple isolation of H. influenzae.
The relative risk of an exacerbation in association with the isolation of a new strain of M. catarrhalis was 2.96 (p < 0.001) and 1.77 for S. pneumoniae (p = 0.01). For these two pathogens, strain analysis magnified the association shown with and without a pathogen.
Acquisition of new strain of bacteria may lead to an exacerbation
Results do not change current clinical practice
Use of empiric antibiotics in AECOPD is supported
Reinforces the knowledge gap in choosing the appropriate antibiotic in the face of emerging resistance
Conclusions were limited by the observation that some patients had new bacterial strains in the absence of an exacerbation. The reasons for this may be:
Strain may be less virulent.
Symptoms may be present but not severe enough to prompt reporting.
Please see indication and usage slide for specific pathogens.
Sethi S, et al. N Engl J Med. 2002;347: – p.468 Table 3
Sethi S et al. N Engl J Med Aug 15;347(7):468
p < 0.001
p < 0.001
p < 0.001
p = 0.01
Any Strain
Haemophilus
influenzae
Moraxella
catarrhalis
Streptococcus
pneumoniae
Sethi S et al. N Engl J Med Aug 15;347(7):465-71

12. NTHI from patients with AECBs elicit greater inflammation and epithelial cell adhesion than colonizing strains
Chin et al. AJRCCM 2005; 172:

13. Pathogen-Positive AECBs Have Higher Levels of Inflammatory Markers
IL-8 (pg/mL)
TNF-a (pg/mL)
NE (mU/mL)
Pathogen+
Pathogen–
Pathogen+
Pathogen–
Pathogen+
Pathogen–
Clinical score correlated
with sputum elastase activity
NE (mU/mL)
Rho = 0.441
P < 0.004
Clinical Score
Sethi et al. Chest. 2000; 118:1557

14. Bacterial Persistence and Airway Inflammation following AECOPD
eradicated
by day 10
Bacteria
persisting
at day 10
Bacteria
eradicated
by day 10
Bacteria
persisting
at day 10
100 10 10 1
LTB4 (nM) 1
MPO (units/ml)
0.1
0.1
p<0.001
p<0.001
0.01
p<0.001
0.01
p<0.05 1 10 1 10 1 10 1 10
Day
Day
White et al. Thorax 2003;58:

15. Etiology of exacerbation - biomarkers
Sethi S. et al AJRCCM 2008; 177:491

16. Serum CRP is higher with new strains.8 .7 .6 .5
Cell Mean .4 .3 .2 .1
Path Negative New Strain Pre-existing strain
Sethi S. et al. AJRCCM 2008; 177:491

17. Biomarkers – identify new strains
ROC-identify new strains using: sputum TNF and NE; and serum CRP
Sethi S. et al AJRCCM 2008; 177:491

19. Pseudomonas sp and COPD exacerbations
Murphy et al AJRCCM 2008; 177:853

20. Relative risk for exacerbations with pseudomonas colonization and presence of new strains
Murphy et al AJRCCM 2008; 177:853

21. Pseudomonas sp and COPD exacerbations
- Two distinct patters of carriage:
Short term colonization follow by clearance
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.
Murphy et al AJRCCM 2008; 177:853

22. Airway bacterial concentration and AE COPD*
New
Strain *
Mean [log]
Mean [log]
Pre-existing
Strain *
Sethi et al, AJRCCM 2007

23. Recent Antibiotic Exposure and S. pneumoniae Resistance in COPD
Erythromycin MIC1
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 C

24. Recent Antibiotic Exposure and S. pneumoniae Resistance in COPD
PCN MIC0.12
PCN MIC2
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 C

25. Correlation of bacterial eradication and clinical outcome in AECB0%
10%
20%
30%
40%
50%
60%
70%
80%
Clinical failure (%)
Bacteriological failure (%)
R=0.78
Graph shows the relationship between clinical failure and bacteriological failure taken from 11 recent published studies
There is a clear correlation between clinical and bacteriological outcome in AECB
Background notes:
Data based on bacteriological and clinical failure following a review of recent AECB papers
Fraschini, J Int Med Res 1990; 18: ; Aldons JAC 1991; 27 (Suppl A): ; Guay J Int Med Res 1992; 231: ; Gotfried Am J Med 1992; 92(Suppl 4A); Legnani J Hosp Infect 1992; 22(Suppl A):69-74; Ulmer Am J med 1993; 94(Suppl 3A): ; Chodosh Am J Med 1993; 94(Suppl 3A): ; Klietmann Antimicrob Agents Chemother 1993; 37(11): ; Beghi J Chemother 1995; 7(2): ; Perez-Gonzalvo Clin Therapeutics 1996; 18(3): ; Cazzola J Chemother 1995; 7(5):
Pechere, Inf Med 15:46,1998 9

26. Rhinovirus in AECB 83/ 137 pts with > 1 AECB 168 reported AECBs
107 (64%) with cold within 18d
85 (51%) with cold at presentation
66 (39%) VRTI +
39 (23%) RV +
Viral AECBs
Greater symptom count
Longer recovery time (13 vs 6 d)
Seemungal et al. Am J Respir Crit Care Med. 2001;164:

27. 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)

28. Neutrophilic and Eosinophilic Inflammation During AE COPD
64 patients hospitalized with AE COPD
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:

29. Bacterial Infection in COPD
Acquisition of new bacterial strain
Pathogen virulence
Host lung defense
Change in airway inflammation
Level of symptoms
Colonization
Exacerbation
Strain-specific
immune response
+/- antibiotics
Tissue invasion
Antigenic alteration
Elimination of infecting strain
Persistent infection
Veeramachaneni SB, Sethi S. COPD. 2006;2:

30. Why does it matter to identify the etiology of COPD Exacerbation ?
Return the patient to baseline (pulmonary function, symptoms, etc.)
Reduce morbidity,
hospitalization and mortality
Decrease the risk of failure or return visit
(extend the “exacerbation-free” interval)

31. It is important not to stop questioning !!!
FUTURE
It is important not to stop questioning !!!
Albert Einstein