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New Concepts in Microbiology of Exacerbations of COPD

New Concepts in Microbiology of Exacerbations of COPD. Sanjay Sethi MD Professor Pulmonary, Critical Care and Sleep Medicine University at Buffalo, SUNY ssethi@buffalo.edu. Perception A nuisance problem with no serious consequences. Reality Contributes to: Cost of health care (35-45%)

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New Concepts in Microbiology of Exacerbations of COPD

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  1. New Concepts in Microbiology of Exacerbations of COPD Sanjay Sethi MD Professor Pulmonary, Critical Care and Sleep Medicine University at Buffalo, SUNY ssethi@buffalo.edu

  2. Perception A nuisance problem with no serious consequences Reality Contributes to: Cost of health care (35-45%) Poor quality of life Mortality Progression of lung disease AECOPD: Perception vs Reality Mannino et al. MMWR 2002;51(SS-6):1-16 Andersson et al. Resp Med 2002;96:700-8

  3. Etiology of AECOPD Obaji & Sethi. Drugs and Aging; 2001;18:1-11

  4. Etiology of AECOPD Papi et al AJRCCM 2006;173:1114-21

  5. AECOPD: Bacterial etiologySputum culture studies Stable Exacerbation 25 patients Outpatient clinic every 2 weeks for 4 years Sputum culture 1886 clinic visits 116 exacerbations 1870 stable % 60 59.9 57.0 50 40 37.2 33.1 30 20 10 0 SP NTHI Gump et al. ARRD 1976;113:465-473

  6. Bacterial load model of pathogenesis of AECB 1,E+08 NTHI titer 1,E+07 1,E+06 1,E+05 1,E+04 1,E+03 1,E+02 S E S E S E S

  7. 10 * 9 * 8 7 6 stable 5 4 Log Titer 3 2 exacerbation 1 0 HI HH MC SP HP Pathogen Bacterial Load Model Sethi et al AJRCCM 2007

  8. Acquisition of new bacterial strain Bacterial Infection in COPD 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

  9. Acquisition of new bacterial strain Bacterial Infection in COPD 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

  10. Aims Dynamics of bacterial infection in COPD Hypothesis Acquisition of new strains of bacterial pathogens is associated with an increased risk of exacerbation Clinic visits: Monthly Suspected exacerbation At each visit: Clinical evaluation Serum sample Sputum sample for quantitative bacteriology COPD Study Clinic Sethi et al. NEJM 2002, 347:465-471

  11. 1 month Patient 6: Time line ex ex ex 1 2 3 4 5 6 7 8 9 10 11 12 13 HI HI HI HI HI 108 106 106 108 107

  12. Typing the Nontypeable • Nontypeable H. influenzae sputum isolates • Whole bacterial lysates • Analyzed on a SDS- PAGE gel Sethi et al. NEJM 2002, 347:465-471

  13. 1 month Patient 6: Time line ex ex ex 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

  14. COPD Study Clinic: New strain isolation and exacerbation New strain + New strain – Exacerbation frequency * *p<0.05 50 Relative risk (95% CI) of exacerbation: Any 2.15 (1.83–2.63) NTHI 1.69 (1.37–2.09) MC 2.96 (2.39–3.67) SP 1.77 (1.14–2.75) PA 0.61 (0.21–1.82) 48.8 40 * * * 33 32 30 26.2 20 18.2 18 17.1 16.6 15.4 13.6 10 Sethi et al. NEJM 2002;347:465-71 0 Any NTHI MC SP PA Pathogen

  15. AECB: Bacterial etiologySputum culture studies Stable Exacerbation 25 patients Outpatient clinic every 2 weeks for 4 years Sputum culture 1886 clinic visits 116 exacerbations 1870 stable % 60 59.9 57.0 50 40 37.2 33.1 30 20 10 0 SP NTHI Gump et al. ARRD 1976;113:465-473

  16. Acquisition of new bacterial strain Bacterial Infection in COPD 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

  17. NTHI Colonization vs Exacerbation strains • 10 exacerbation strains • 7 colonization strains • In vivo mouse model • In vitro respiratory epithelial cell line Chin et al AJRCCM 2005

  18. Acquisition of new bacterial strain Bacterial Infection in COPD 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

  19. Moraxella catarrhalisFrequency of Immune Response p = 0.11 p = 0.009 Murphy et al, AJRCCM 2005

  20. Lymphocyte Proliferative Response to OMP P6 of NTHI • PBMC stimulated with purified OMP P6 • Groups • H: healthy controls • C: COPD without NTHI exacerbation in previous 12 months • N: COPD with NTHI exacerbation in previous 12 months Abe et al AJRCCM, 165:967-71, 2002

  21. Acquisition of new bacterial strain Bacterial Infection in COPD 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

  22. 1 month Patient 6:Time line ex ex ex 1 2 3 4 5 6 7 8 9 10 11 12 13 0 SP 0 HI HI HI HI HI 0 0 0 0 A A B C C 108 106 106 108 107

  23. 5 p = 0.40 4 3 IL-8 change ng/ml 2 1 0 -1 -2 No new strain New strain p < 0.001 1.2 1 0.8 TNFα change ng/ml 0.6 0.4 0.2 0 -0.2 No new strain New strain 600 p = 0.01 500 400 NE change nM 300 200 100 0 -100 No new strain New strain Changes in Airway Inflammation with Onset of Exacerbations • Airway inflammation increases with exacerbations • Bacterial exacerbations are associated with greater neutrophilic inflammation Sethi et al ATS, 2005

  24. p = 0.35 p = 0.05 3 2 1 IL-8 change ng/ml 0 -1 -2 -3 Non-resolution Resolution p = 0.79 p = 0.007 1 0.8 0.6 TNFα change ng/ml 0.4 0.2 0 -0.2 -0.4 -0.6 -0.8 -1 Non-resolution Resolution p = 0.18 p = 0.02 500 400 300 NE change nM 200 100 0 -100 -200 Non-resolution Resolution Changes in Airway Inflammation with Resolution of Exacerbations • Airway inflammation decreases with resolution of exacerbation • Correlation between clinical resolution and resolution of inflammation Sethi et al ATS, 2005

  25. 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

  26. Acquisition of new bacterial strain Bacterial Infection in COPD 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

  27. H. influenzae: Bactericidal assays • New bactericidal antibody developed to 18 of 26 (69.2%) new strains following exacerbation % Kill Sethi et al AJRCCM 169;448-453, 2004

  28. Strain-specificity of bactericidal antibodies to NTHI • Bactericidal antibodies from 10 patients were tested against 9 heterologous strains each. • 79 of 90 (88%) of heterologous strains were not killed. • 8 of the 10 sera killed only the homologous strain or 1 heterologous strain. Sethi et al AJRCCM 169;448-453, 2004

  29. Viral AECB:Culture and Serology Studies Carilli 1964, Eadie 1966, McNamara 1969, Lamy 1974, Gump 1976, Buscho 1978, Smith 1980, McHardy 1980

  30. Controls FEV1 >50% FEV1<50% n 55 30 32 RI/yr 1.4 1.8 3.0 RTVI/yr 0.54 0.38 0.52 RTVI/RI % 39 22 17 Viral RTI: Cohort Study Greenberg et al AJRCCM, 2000;162:167-173

  31. Viral RTI: Clinical Manifestations and Lung Function Greenberg et al AJRCCM, 2000;162:167-173

  32. Viral RTI: Pathogens 35 Control 30 FEV1 50% 25 FEV1 <50% 20 % of Total Identified 15 10 5 0 Picorna-viruses Para-influenzaviruses Corona- viruses Influenza viruses RSV Adeno-viruses Greenberg SB, et al. Am J Respir Crit Care Med. 2000;162:167-173.

  33. RSV Infection in Elderly High-Risk Adults Falsey AR, et al. New Engl J Med. 2005;1749-1759.

  34. Airway Inflammation and Etiology Papi et al AJRCCM 2006;173:1114-21

  35. New Directions • Bacterial-viral-environmental interaction • Molecular detection and quantification of infectious pathogens • Host susceptibility to infection

  36. Effect of Pathogen Combinations on % Decrease in FEV1 at Exacerbation Wilkinson, T. M. A. et al. Chest 2006;129:317-324

  37. + - psaA lytA PCR detection of bacterial pathogens in COPD p<0.05 S. pneumoniae El-Dika et al ATS 2007

  38. Conclusions • Exacerbations are important • Bacteria cause a significant proportion of exacerbations • Understanding Host-Pathogen interaction is key • Therapeutic intervention

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