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Innate (Native) Immunity in COPD
Sanjay Sethi MD Professor Pulmonary, Critical Care and Sleep Medicine University at Buffalo, SUNY
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COPD: Etiology
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NOXIOUS AGENT (tobacco smoke, pollutants, occupational agent)
Pathogenesis of COPD NOXIOUS AGENT (tobacco smoke, pollutants, occupational agent) Airflow Obstruction Genetic factors Respiratory infection Airway Hyper-reactivity Nutritional factors
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Infections in COPD Acute or Chronic Pathogens Viruses Typical bacteria
Nontypeable Haemophilus influenzae Streptococcus pneumoniae Moraxella catarrhalis Pseudomonas aeruginosa Atypical bacteria Chlamydia pneumoniae Mycoplasma pneumoniae Viruses Influenza Parainfluenza Rhinovirus Adenovirus RSV Fungi Pneumocystis jirvocei
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Infections in COPD Acute or Chronic Pathogens Viruses Typical bacteria
Nontypeable Haemophilus influenzae Streptococcus pneumoniae Moraxella catarrhalis Pseudomonas aeruginosa Atypical bacteria Chlamydia pneumoniae Mycoplasma pneumoniae Viruses Influenza Parainfluenza Rhinovirus Adenovirus RSV Fungi Pneumocystis jirvocei
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Buffalo VA COPD Study Clinic
Patient 14 Time Line 1 month ex HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI A A A A B B B B B B C D D D D D D D D D D
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SDS- PAGE PCR-P2 gene, sputum pellets Clinic visit 25 30 35 40 45 50
Hi Hi Hi Hi Hi Hi SDS- PAGE PFGE Haemophilus influenzae PCR-P2 gene, sputum pellets Murphy et al AJRCCM 2004
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COPD Pathogenesis: Infection
Smoking/irritants Impaired host defenses: respiratory viruses new strains of bacteria environmental irritants Chronic bacterial colonization Acute cycle Chronic cycle Impaired lung defense Acute on chronic inflammation (pathogen + host- mediated inflammatory factors) Chronic inflammation (bacterial + host- mediated inflammatory factors) Progressive loss of lung function and deteriorating quality of life
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Murphy and Sethi ARRD, 1992;146:1067-83
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Modified from Murphy and Sethi ARRD, 1992;146:1067-83
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Definition of ‘Colonization’
Absence of immune response Absence of damaging effects to the host Not defined by absence of symptoms Mandell et al, Principles and Practice of Infectious Diseases
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Small Airways in COPD Inflammatory mucus exudates
Hogg et al, NEJM, June 2004
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Small Airways in COPD Lymphocytes
Hogg et al, NEJM, June 2004
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Sputum Inflammation and Bacterial Colonization
Banerjee D et al Eur Respir J ;23:
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Bronchial Inflammation and Bacterial colonization
Bronchoscopy with BAL Stable COPD (n = 52) Healthy Smokers (n = 18) Non-smokers (n = 8) PPM colonization 32% Stable COPD 42% Smokers 0% Non-smokers Increased airway inflammation with bacterial colonization * * Soler et al ERJ 1999;14:
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Bacterial Colonization in Ex-smokers with COPD
Group % positive for PPM >/=102/ml Pathogens isolated Titer 1 (ex-smokers with COPD) 34.6 % (9/26) 1) NTHI and HP 2) NTHI and SP 3) HP 4) PA 5) SA 6) NTHI 7) NTHI 8) HP 9) HP 3 x x 102 7 x x 104 1 x 102 6 x 102 1.5 x 104 5 x 105 6.5 x 105 3 x 105 2 (ex-smokers without COPD) 0% (0/20) 3 (healthy non-smokers) 6.7% (1/15) 1) HP 2 x 102 Sethi et al AJRCCM 2006, 173:991-8
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Bacterial Colonization in Ex-smokers with COPD
10 20 30 40 50 60 70 80 90 COPD PPB+ PPB- Ex-smokers Non-smokers % PMN Groups p<0.001 p=0.03 p=0.02 p=0.004 p=0.007 p<0.001 p=0.02 450000 400000 350000 PMN/ml 300000 250000 200000 150000 100000 50000 COPD PPB+ COPD PPB- Ex-smokers Non-smokers Groups Sethi et al AJRCCM 2006, 173:991-8
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Bacterial Colonization in Ex-smokers with COPD
1 10 100 1000 10000 100000 Active MMP-9 units/ml Groups p=0.04 p<0.001 p=0.01 p=0.002 p=0.007 COPD PPB+ PPB- Ex-smokers Non-smokers 1 10 100 1000 IL-8 pg/ml Groups p=0.006 p<0.001 p=0.02 Ex-smokers Non-smokers COPD PPB+ PPB- Sethi et al AJRCCM 2006, 173:991-8
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COPD Pathogenesis: Infection
Smoking/irritants Impaired host defenses: respiratory viruses new strains of bacteria environmental irritants Chronic bacterial colonization Acute cycle Chronic cycle Impaired lung defense Acute on chronic inflammation (pathogen + host- mediated inflammatory factors) Chronic inflammation (bacterial + host- mediated inflammatory factors) Progressive loss of lung function and deteriorating quality of life
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Cause or Effect Discovery of specific pathways of innate immunity
Very small clinically relevant quantities of bacterial molecules are pro-inflammatory Persistence mechanisms of NTHI not dependent on airway inflammation Impaired ability of innate defense to clear NTHI What is the evidence that inflammation induces ‘colonization’ in the lower respiratory tract?
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TLR activation and signaling
Clin. Sci. (2005) 109,
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NTHI Components are Potent Stimulants of Macrophages
Purified components of NTHI OMP P6 OMP P2 LOS Total OMP Biologically relevant concentrations Sputum levels with 107 bacteria/ml P6: 4 µg/ml P2: 95 µg/ml Berenson et al Infect Immun 2005;73:
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H. influenzae in Bronchial Tissue
NTHI in tissue 13 of 15 critically ill patients with acute exacerbation 8 of 24 stable COPD 0 of 7 healthy controls Bandi et al AJRCCM 2001;164:
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Biofilm Formation by NTHI
Jursicek J et al , Infect Immun 2005;73:
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COPD Pathogenesis: Infection
Smoking/irritants Impaired host defenses: respiratory viruses new strains of bacteria environmental irritants Chronic bacterial colonization Acute cycle Chronic cycle Impaired lung defense Acute on chronic inflammation (pathogen + host- mediated inflammatory factors) Chronic inflammation (bacterial + host- mediated inflammatory factors) Progressive loss of lung function and deteriorating quality of life
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Innate Lung Defense Mechanisms
Mucociliary clearance Airway antimicrobial peptides Cationic polypeptides Lysozyme Lactoferrin SLPI Cathelicidin Collectins Surfactant protein A Surfactant protein D Defensins Airway epithelium Adherence Cytokine/Chemokine Lung macrophages Opsonophagocytosis Inflammatory cells Immunoglobulins IgA
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Surfactant proteins in COPD
spD ng/ml spA ng/ml Surfactant proteins in COPD SpA SpD 45000 3000 40000 2500 35000 30000 2000 25000 1500 20000 1000 15000 10000 500 5000 -5000 -500 Non-smokers COPD Ex-smokers Non-smokers COPD Ex-smokers
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Cytokine Response of Macrophages to NTHI antigens
Berenson C et al AJRCCM 2006
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Phagocytosis of NTHI by Lung and Blood Macrophages
Alveolar Macrophages Blood Macrophages .5 1 1.5 2 2.5 COPD n = 10 Non-COPD n = 17 Non-smokers n = 9 NTHI Strain 14P13H5 Phagocytosis Index * ** .5 1 1.5 2 2.5 3 3.5 COPD n = 12 Non-COPD n = 17 Non-smokers n = 9 NTHI Strain 14P13H5 Phagocytosis Index Berenson C et al JID 2006
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Chronic Chlamydia pneumoniae Infection in COPD
Subjects Severe COPD n = 41 Mild – Moderate COPD n = 13 Controls (CAP) n = 23 C. pneumoniae + if at least 2 of 3 Sputum PCR Sputum IgA Serum IgG ≥128 and IgA ≥ 40 % positive Von Hertzen et al Epidemiol Infect 1997;118:155-64
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Latent Adenovirus Infection in COPD
Increased amount of Adenovirus DNA (E1A region) by PCR in lung tissue in COPD Latent infection with adenoviral E1A DNA is pro-inflammatory Cell Lines Smoke exposed Guinea pigs Lung Resection Specimens Vitalis et al ERJ 1998;11:664-9 Retamales et al AJRCCM 2001;164:469-73
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Chronic Pneumocystis Infection in COPD
Morris et al AJRCCM 2004;170:408-13, Morris et al ATS 2005
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Infection in COPD Progression Why consider it?
Susceptibility to Smoking is unexplained Pathology and Disease progression in ex-smokers Clinical consequences of bacterial colonization It is there It should not be there It is associated with neutrophilic inflammation
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Bacterial Load and FEV1 Decline
30 patients (19 ex-smokers) Mean FEV1 of 0.95L 1 Year Follow up Mean FEV1 decline was 57.6 ml/year Correlation between Bacterial ‘load’ in sputum and FEV1 decline (r = 0.56) Wilkinson et al AJRCCM ;
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Results PA positive - COPD Related Hospitalizations
Univariate model Multivariate model Factor P-value % FEV1 0.02 PA positive 0.03 Age 0.15 Smoking 0.29 p = 0.008 El Dika et al ATS 2006
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Results PA Positive - COPD Related Mortality
Univariate model Multivariate model Factor P-value % FEV1 0.001 PA positive 0.03 Age 0.12 Smoking 0.19 El Dika et al ATS 2006 p = 0.02
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Infection in COPD Progression Why consider it?
Susceptibility to Smoking is unexplained Pathology and Disease progression in ex-smokers Clinical consequences of bacterial colonization It is there It should not be there It is associated with neutrophilic inflammation
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H. influenzae in bronchial tissues
NTHI in tissue 13 of 15 critically ill patients with acute exacerbation 8 of 24 stable COPD 0 of 7 healthy controls Bandi et al AJRCCM 2001;164:
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Infection in COPD Progression Why consider it?
Susceptibility to Smoking is unexplained Pathology and Disease progression in ex-smokers It is there It should not be there It is associated with neutrophilic inflammation
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British Hypothesis Mucus Hypersecretion Infective exacerbations
Ciba Guest Symposium 1959, Thorax;14:286-99 Fletcher and Peto BMJ 1977,1:1645-8
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Conclusions Further elucidation of
Mechanisms of colonization and inflammation Impact of colonization on disease progression Treatments to interrupt the vicious cycle Antibiotics (PULSE study) Alternative treatments that interrupt the inflammatory or infectious process The British may have been right all the time!!
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Acknowledgments
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Acknowledgments
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