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Infections in acute exacerbation of COPD: are the agents the same ?

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. Hospital mortality 24% Hospital mortality 6%-12%

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Infections in acute exacerbation of COPD: are the agents the same ?

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  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 Hospital mortality 24% Hospital mortality 6%-12% Relapse(repeat ERvisit) 22%-32% Treatment failure rate 13%-33% In ICU pts In hospital pts In ER pts 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 40 - 50% Viral infection 30 - 40% 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. Percent of patients with > 102 DFU/ml Percent of patients with particular organism Pooled studies of bronchoscopy in stable COPD and patient during AECB Rosell et al. Arch Int Med 2005; 165: 891-7

  6. Exacerbation frequency and airway bacterial colonization 1.2 1.0 0.8 0.6 Proportion of patients with LABC 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

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

  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 108 106 106 108107 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 108 106 106 108107 Sethi et al. N Engl J Med. 2002;347:465

  11. Rate of Exacerbations Dependent on Pathogen and New Strain of Pathogen # exacerbations/# visits (%) 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

  12. NTHI from patients with AECBs elicit greater inflammation and epithelial cell adhesion than colonizing strains Chin et al. AJRCCM 2005; 172: 85-91.

  13. Pathogen+ Pathogen+ Pathogen+ Pathogen– Pathogen– Pathogen– Pathogen-Positive AECBs Have Higher Levels of Inflammatory Markers P = 0.004 P = 0.036 P = 0.004 NE (mU/mL) TNF-a (pg/mL) IL-8 (pg/mL) 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 Bacteria eradicated by day 10 Bacteria persisting at day 10 Bacteria eradicated by day 10 Bacteria persisting at day 10 100 10 10 1 MPO (units/ml) LTB4 (nM) 1 0.1 0.1 p<0.001 p<0.001 p<0.001 p<0.05 0.01 0.01 1 10 1 10 1 10 1 10 Day Day White et al. Thorax 2003;58:680-685

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

  16. Serum CRP is higher with new strains p = 0.004 p = 0.007 .8 .7 .6 .5 Cell Mean .4 .3 .2 .1 0 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

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

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

  20. 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

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

  22. Recent Antibiotic Exposure and S. pneumoniae Resistance in COPD P = .009 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.

  23. Recent Antibiotic Exposure and S. pneumoniae Resistance in COPD P = .04 P = .22 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.

  24. 80% 70% R=0.78 60% 50% 40% Bacteriological failure (%) 30% 20% 10% 0% 0% 10% 20% 30% 40% 50% 60% Clinical failure (%) Correlation of bacterial eradication and clinical outcome in AECB Pechere, Inf Med 15:46,1998

  25. 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.

  26. 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)

  27. 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

  28. 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.

  29. 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)

  30. Itisimportantnotto stop questioning !!! FUTURE Albert Einstein www.brainyquote.com

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