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

Outcome of AECOPD In ICU pts In hospital pts In ER pts In outpatients Hospital mortality 24% Hospital mortality 6%-12% Relapse (repeat ER visit) 22%-32% Treatment failure rate 13%-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.

Etiology of COPD Exacerbation 20% non-infectious 80% infectious Environmental factors Non-compliance with medications Bacterial pathogens 40 - 50% Viral infection 30 - 40% Atypical Bacteria 5 - 10% Sethi S, et al. Chest 2000;117:380s-385s

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

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

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: 759-64

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

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 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 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 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 # 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: 465-71 – p.468 Table 3 Sethi S et al. N Engl J Med. 2002 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. 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.

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

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;58:680-685

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

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

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

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

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

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 C2-0438.

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 C2-0438.

Correlation of bacterial eradication and clinical outcome in AECB 0% 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; 18:171-176; Aldons JAC 1991; 27 (Suppl A):101-108; Guay J Int Med Res 1992; 231:295-301; 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):136-141; Chodosh Am J Med 1993; 94(Suppl 3A):131-135; Klietmann Antimicrob Agents Chemother 1993; 37(11): 2298-2306; Beghi J Chemother 1995; 7(2):146-152; Perez-Gonzalvo Clin Therapeutics 1996; 18(3): 440-447; Cazzola J Chemother 1995; 7(5): 432-441. Pechere, Inf Med 15:46,1998 9

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: 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 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: 1114-21

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;2:109-115.

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)

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