Bronchial colonisation in COPDPotentially pathogenic microorganisms in the lower airwayCultures of bronchial secretions are positive• without a clinical response BUT• inflammatory response:• in bronchial secretions and bronchial mucosa.
Bronchial colonisation in COPD• Bronchial infection: microorganisms proliferate and cause symptoms. In patients with COPD bronchial infection can be recognized as either exacerbation or pneumonia Arch Bronconeumol 2004;40(12):543-6
Microbiology of colonization• Quantitative cultures of bronchial secretions by PSB) has been reported to be positive for PPMs in one quarter of the patients with stable COPD Cabello H et al Eur Respir J. 1997; 10:1137-1144. Monsó E et al Am J Respir Crit Care Med. 1995;152:1316-1320 Zalacaín R et al Eur Respir J. 1999;13:343- 348.
Pooled studies of bronchoscopy in stable and exacerbated COPD MMN H influenzae S pneumoniae M.catarrhalis P.aeruginosa 30 with a particular organism Rosell. Arch 25 Int Med 2005; 165: 891 20 15 % patients 10 5 0 Healthy Stable COPD Exacerbated COPDBacteria were present in clinically significant concentrations in the airways of 4% ofhealthy adults, 29% of adults with stable COPD, and 54% of adults withexacerbated COPD.
How bacteria is linked to exacerbation?1. Bacterial load2. Acquisition of new strain
A Study of Stable and Exacerbated Outpatients Using the Protected Specimen Brush AM J RESPIR CRIT CARE MED 1995;152:1316-20.
Bacterial load hypothesis Antibiotics 108Bacterial load 107 (cfu/mL) 106 105 (Sethi S et al. Clin Microbiol Rev 2001)
The "fall and rise" hypothesis Miravitlles. Eur Respir J 2002: 20: 9s-19s
Acquisition of New Bacterial Strains• Aims • Clinic visits: – Dynamics of bacterial • Monthly infection in COPD • Suspected exacerbation• Hypothesis • At each visit: • Clinical evaluation – Acquisition of new • Serum sample strains of bacterial • Sputum sample for pathogens is associated quantitative bacteriology with an increased risk of exacerbation Sethi et al. NEJM 2002, 347:465-471
Acquisition of New Bacterial Strains pulsed-field gel electrophoresis
Typing the Non-typeable • Nontypeable H. influenzae sputum isolates – Whole bacterial lysates – Analyzed on a SDS- PAGE gelSethi et al. N Engl J Med. 2002;347:465.
Why should the acquisition of anew NTHI strain be associated with exacerbations?• One explanation is that the absence of preexisting immunity to the strain allows proliferation of the bacteria in the lower airways, the associated inflammatory response results in increased symptoms, manifesting clinically as an acute exacerbation. Curr Opin Pulm Med 12:118–124.
Why bactericidal antibodies not protective against subsequent infection?• Bactericidal antibodies to the infecting NTHI strains were demonstrated in 69% of the post- exacerbation serum samples
New bactericidal antibodies developed afterexacerbations were highly strain specific, showingbactericidal activity for only 11 of 90 (12.2%)heterologous strains.The strain specificity of the immune response likelyrepresents a mechanism of recurrent exacerbations.
IMPACT OF LABC• Increase inflammation• Rapid lung function decline• Increase frequency of exacerbation, a major determinant of health related QOL.• Any relation to bronchiectasis in COPD needs to be evaluated
EXACERBATION FREQUENCY AND BACTERIAL COLONIZATION 1.2 Proportion of patients with LABC 1.0 0.8 0.6 0.4 0.2 0.0 -0.2 <2.58 per year >2.58 per year (n=14) (n=14) Exacerbation frequencyPatel et al. Thorax 2002
Impact of bacterial colonization rho = 0.459 p = 0.02
Am J Respir Crit Care Med Vol172. pp 85–91, 2005
These results support the possibility that acquisition of a new, more virulent or more proinflammatory bacterial species or strain may be one pathway for induction of COPD exacerbations.Chin et al. AJRCCM 2005; 172: 85-91.
Not all new strains produce AE-COPD• Difference in the proinflammatory properties among NTHI strains• Another possible explanation is that these new strains did cause symptoms, but they were not severe enough to prompt the patient to seek medical help.• Host factors
It’s not the bug, what about the body? Low and High Responder phenotype ‘healthy volunteers’ = low responders = high responders J Immunol 2005;175;2570-2578
COPD patients infections “Low Responder” “High Responder” “Normal Responder” Effective immune response Inappropriate immune response Inappropriate immune response (Impaired clearance of the pathogen) (Excessive inflammation) Low Risk High Risk High Risk Antibiotic prophylaxis Anti-inflammatory drugsTanja GeelenDept. Medical ExacerbationMicrobiologyMaastricht UniversityMedical Centrethe Netherlands
Airway Bacterial Load and FEV1 Decline Rate of FEV1 decline (ml/yr) Bacterial count (log cfu/ml) Am J Respir Crit Care Med Vol 167. pp 1090– 1095, 2003
Colonisation and inflammation Asterisks indicate Hill. Am J Med significant 2000;109:288-295 differences when compared with samples containing normal flora alone (*P ,0.05, **P ,0.001).
FEV1 DECLINE AND CHANGE IN BACTERIAL ISOLATE 40 Percentage Decline in FEV1 %/yr 30 20 10 0 -10-0.2 -0.1 0 0.2 0.4 -20 -30 -40 p=0.01 0 0 1 1 Change in Bacterial IsolateDecline expressed as percentage of baselineFEV1 (negative values indicate improving lung Wilkinson et al AJRCCM 2003function).
Relation of Lung Function and Bacterial Infection in Patients With COPD Flare Chest 1998;113:1542-1548
Pattern of LABC• In moderate COPD – Bronchial colonisation is common. – Recurrent colonisation in near half of the cases. – Persistent colonisation in one tenth of patients. Marin. Eur Respir J 2010;35:295
Serum CRP is higher with new strains .8 p = 0.004 p = 0.007 .7 .6 .5Cell Mean .4 .3 .2 .1 0 Path Negative New Strain Pre-existing strainSethi S. et al. AJRCCM 2008; 177:491
H.influenzae is not an exclusively extracellular pathogen. It is capable of invading airways’ tissues. This tissue invasion could explain how these bacteria can persist in patients with COPD for long periods of time and evade bactericidal antibodies and antibacterial agents. patients intubated for exacerbations NTHI were found in the bronchial tissues ofAm J Respir Crit Care Med 87% of patients with exacerbations compared with 33% of stable COPD patients and 0% ofVol 164. pp 2114-2119, 2001 healthy controls.
Role of nontypeable H. influenzae in progression of COPD
Inflammatory profile of new bacterial strain in acute exacerbations of COPD How often do we find new strains ?n = 150 acute exacerbationsBacteriological n %classificationNew strain 39 26Preexisting strain 15 10Non-PPM 30 20Negative 66 44 Sethi S et al., Am J Respir Crit Care Med 2008
Pseudomonas aeruginosa in COPDAuthor, year Risk factorsEller, 1998 FEV1 < 35% Pretreatment with antibioticsMiravitlles, 1999 FEV1 < 50%Monsó, 2003 Low FEV1 Oral corticosteroid use Antibiotics in the previous 3 months Protective effect of anitinfluenza vaccineAllegra, 2005 FEV1 < 35%Lode, 2007 FEV1 < 35% Systemic steroid use Antibiotics in the previous 3 months
Antibody responses donot mediate clearance ofP. aeruginosa in view ofthe observation that only9.7% of episodes ofclearance from therespiratory tract wereassociated with anantibody response
Pseudomonas aeruginosa in COPDNew strain acquisition is associated with acute exacerbation Murphy TF et al., Am J Respir Crit Care Med 2008
• In comparison with isolates from blood culture, the COPD isolates generally showed• an increased mutation rate• increased antibiotic resistance• reduced production of proteases• less cytotoxicity Clin Infect Dis 2008; 47: 1526–33• less motility• greater biofilm production in in vitro assays.
Exacerbations caused by P. aeruginosa are morelikely to be seen in patients withmore-advanced COPDThose who have received recent antibiotictherapyThose who require mechanical ventilation for anexacerbation Clin Infect Dis 2008; 47: 1526–33
• Most patients with CF eventually acquire P. aeruginosa, and chronic infection accounts for much of the early mortality associated with CF• P. aeruginosa colonization occurs in only a minority of patients with COPD, and many of these episodes are transient colonizations• Mucoid strains play a prominent role in the course of CF, whereas only a small number in COPD
Host Defense: colonization or exacerbation• Adequate cellular response to H. influenzae antigens suppresses newly acquired strains of this pathogen and therefore prevents exacerbations
Am J Respir Crit Care Med Vol 165. pp967–971, 2002• Decreased proliferation of T cells to P6 is associated with exacerbations of COPD and suggest that the ability of T cells to recognize P6 is associated with relative protection from exacerbations due to NTHI.
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
The PULSE StudySethi et al. Respiratory Research 2010, 11:10
Hypothesis: chronic intermittent pulsed suppressive antibiotic therapy will – reduce pulmonary damage resulting from the chronic interplay between bacterial colonisation and the host inflammatory response – result in both fewer and less severe exacerbations of COPD – decrease the deterioration of pulmonary function over time – result in an improved quality of life for COPD patients
PULSE study design• Double-blind, parallel group, multi-centre, international study• 1,157 patients with stable COPD, randomised to receive as maintenance either: ─ moxifloxacin 400 mg PO q.d. 5 days ─ matching placebo PO q.d. 5 days• Treatment repeated every 8 weeks for 6 courses• At least 50% of patients with FEV1 <50% predicted• Active treatment duration 48 weeks, with 24 week follow-up period Sethi et al 2010
The endpoint• Primary efficacy variable –Number of exacerbations (primary definition) recorded after 48 weeks of intermittent pulse therapy• Secondary efficacy variables: • Hospitalization and mortality • Changes in disease-related health status assessed with the SGRQ • Changes in lung function measured as percent predicted forced expiration volume in 1 second (%PFEV1)
At 48 weeks OR for suffering an exacerbationfavored moxifloxacin:per-protocol (PP) population (N = 738, OR0.75, 95% CI 0.565-0.994, p = 0.046)Intent-to-treat (ITT) population (N = 1149, OR0.81, 95% CI 0.645-1.008, p = 0.059)Post-hoc analysis of PP patients withpurulent/mucopurulent sputum production atbaseline (N = 323, OR 0.55, 95% CI 0.36-0.84, p =0.006).
SECONDARY EFFICACY ENDPOINTS:• No significant between treatment differences were seen in: • frequency of hospitalizations • mortality rates • lung function (% predicted FEV1,or adjusted mean change in FEV1)Sethi et al 2010 66