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Alberto Papi Respiratory Medicine & Research Centre on Asthma & COPD University of Ferrara, I Pulmonary and Systemic Inflammation in COPD Exacerbations

Definitions Airway inflammation –Changes vs baseline –Inflamation vs infections Systemic inflammation –Changes vs baseline –Predictive value

A change in the patient’s baseline dyspnea, cough and/or sputum that is beyond normal day-to day variations, is acute in onset, and may warrant a change in regular medications in a patient with underlying COPD.A change in the patient’s baseline dyspnea, cough and/or sputum that is beyond normal day-to day variations, is acute in onset, and may warrant a change in regular medications in a patient with underlying COPD. (GOLD 2010) COPD exacerbation: Definition

Pulmonary and Systemic Inflammation in COPD Exacerbations Definitions Airway inflammation –Changes vs baseline –Inflamation vs infections Systemic inflammation –Changes vs baseline –Predictive value

AIRFLOW AIRWAY INFLAMMATION SYMPTOMS Increased mucus Airway wall thickening and oedema Bronchoconstriction Airflow limitation V/Q mismatch Hyperinflation Dyspnea Cough Sputum PATHOGENESIS OF COPD EXACERBATIONS

Percent decrease FEV 1 at exacerbation Increase in sputum neutrophils at exacerbations (10 6 /g) Results: sputum PMN r = 0.35 P<0.01 Papi, Fabbri & Johnston et al. AJRCCM 2006

Increased TCC4,6,7 Neutrophils3,4,5 Eosinophils4 Lymphocytes4,8 IL-84, 9 – 11 IL-62,8,12 NE4,5 TNF-α9 1) Roland et al. Thorax ) Hurst et al. AJRCCM ) Bhowmik et al. Thorax ) Seemungal et al. ERJ ) Tsoumakidou et al. Resp Med ) Aaron et al. AJRCCM ) Fujimoto et al. ERJ ) Wilkinson et al. Chest ) Papi et al. AJRCCM ) Drost et al. Thorax ) Caramori et al. Thorax ) Perera et al. ERJ 2007 No Change 1,2,3 1,2,6,8 1,2,5,8 1,2,3,5,6 1,2,7,8 1,5,4,7,10 11

Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations ns ns (Bhowmik et al. Thorax 2000) Delta FEV1 (%) Perera WR, ERJ 2007

Contoli, Saetta, Fabbri, & Papi et al. JACI 2010 Fixed airflow obstruction in asthma and COPD: 5 years of follow up Baseline sputum eosinophils (% of total non squamous cells) Exacerbations/years Baseline sputum neutrophils (% of total non squamous cells) Exacerbations/years

Risk of exacerbations and airway inflammation Bhowmik et al. Thorax N=23 N=21 ≤2≥3 0 10,000 20,000 Number of Exacerbations in Previous Year IL-8 (pg/mL) P=0.05 > 2.58 exac/year < 2.58 exac/year

Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD Powrie DJ; Eur Respir J. 2007

Inflammation & COPD exacerbations. Bronchial biopsies E B E B E B *** *** ** EosinophilsEG-2Neutrophils Cells/mm 2 (Saetta et al 1994)

Changes in sputum T-lymphocite subpopulations at the onset of severe exacerbations of COPD ** (Tsoumakidou, Siafakas et al. Resp Med 2005)

Oxidative stress VirusesBacteria Noninfective Epithelial cells Macrophages Neutrophils Eosinophils NF-kB CXCL8 IL-6 TNF-α NF-kB RANTES Caramori et al, Thorax 2003 Rhinovirus Oxidant formation I-kB degradation NF-kB InflammatoryResponse Receptor Papi A, Contoli M J Biol Chem 2008 X Reducing agents

Pulmonary and Systemic Inflammation in COPD Exacerbations Definitions Airway inflammation –Changes vs baseline –Inflamation and infections Systemic inflammation –Changes vs baseline –Predictive value

.A change in the patient’s baseline dyspnea, cough and/or sputum that is beyond normal day-to day variations, is acute in onset, and may warrant a change in regular medications in a patient with underlying COPD. –Medical history An increase in sputum volume and purulence points to a bacterial cause, as does a prior history of chronic sputum production.An increase in sputum volume and purulence points to a bacterial cause, as does a prior history of chronic sputum production. (GOLD 2010) COPD exacerbations: Definition

Etiology The most common causes of an exacerbation are infection of the tracheobronchial tree and air pollution, but the cause of about one-third of severe exacerbations cannot be identified. The role of bacterial infections is controversial, but recent investigations have shown that at least 50% of patients have bacteria in high concentrations in their lower airways during exacerbations. The association of neutrophilic inflammation with bacterial exacerbations, also support the bacterial causation of a proportion of exacerbations. GOLD 2010 The most common causes of an exacerbation are infection of the tracheobronchial tree and air pollution, but the cause of about one-third of severe exacerbations cannot be identified. The role of bacterial infections is controversial, but recent investigations have shown that at least 50% of patients have bacteria in high concentrations in their lower airways during exacerbations. The association of neutrophilic inflammation with bacterial exacerbations, also support the bacterial causation of a proportion of exacerbations.

(Sethi et al. Chest 2000) Pathogens + Pathogens - IL-8 (pg/ml) *** Airway Inflammation and Etiology of Acute Exacerbations of Chronic Bronchitis

Prospective follow up of cohort of COPD patients 64 hospitalised patients with severe AE-COPD Seen again when stable 8 weeks later Sputum induction within 24hrs of AE Age male, 8 female 48 pack years Viral & bacterial aetiology of COPD exacerbations Papi A, Fabbri L, Johnston SL. AJRCCM 2006

Viruses and bacteria in COPD exacerbations Viruses Viruses & Bacteria No pathogen 24% 25% 21% 30% Papi, Fabbri & Johnston et al. AJRCCM 2006

Viruses & bacteria in COPD exacerbations Viral and/or bacterial infection in 79% of exacerbations –viruses in 48.8% (6.2% when stable, P<0.001) –bacteria in 54.7% (37.5% when stable, P=0.08) Infectious exacerbations –longer hospitalizations (P<0.02) –greater impairment of several measures of lung function (all P<0.05) 25% viral/bacterial co-infection - most severe –greater impairment of lung function(P<0.02) –longer hospitalizations (P=0.001). Papi, Fabbri & Johnston et al. AJRCCM 2006

Sputum Neutrophils increased in all AE Papi, Fabbri & Johnston et al. AJRCCM 2006

Eosinophils increased only in virus related AE

Criterion for exacerbation: increase over baseline in LRT symptom score of >2 for 2 days Upper & lower respiratory tract scores Rhinovirus infections in COPD (Mallia, Johnston et al. Respir Res 2006)

SYMPTOMS – URT AND LRT Mallia P, Message S, Contoli M, Papi A, Johnston SL et al AJRCCM 2011 in press

Lung function and airway inflammation Mallia P, Message S, Contoli M, Papi A, Johnston SL et al AJRCCM 2011 in press

VIRUS LOAD – time course NASAL LAVAGE SPUTUMBAL COPDHSCOPDHSCOPDHS 91%100%64%55%60%42% Mallia P, Message S, Contoli M, Papi A, Johnston SL et al AJRCCM 2011

After inoculation with RV16 18% of HS and 63.7% of COPD subjects developed a positive bacterial sputum culture (p=0.081). Courtesy SL Johnston BACTERIAL INFECTION

Time course of virus and bacterial load Courtesy SL Johnston

MMP-9 (mcg/g sputum) Pre ExEx MMP-9:TIMP-1 molar ratio Pre ExEx Proteinase-AntiProteinase balance during COPD exacerbations Mercer PF, Resp Res 2005

Pulmonary and Systemic Inflammation in COPD Exacerbations Definitions Airway inflammation –Changes vs baseline –Inflamation vs infections Systemic inflammation –Changes vs baseline –Predictive value

Diffrences in plasma markers between baseline and exacerbations MarkerUnitsBaseline median (IQR) Exacerbation median(IQR) Median (% change) P value CRPmg/L4.0 ( )15.6 ( )+ 185<0.001 IL-6pg/ml1.55 ( )3.25 ( )+66<0.001 MPIF-1pg/ml734 ( )901 ( )+18<0.001 PARCpg/ml1.1 ( ) x ( ) x ACRP-30pg/ml1.5 ( ) x ( ) x S-ICAM-1pg/ml4.8 ( ) x ( ) x Plasma Biomarkers at exacerbation of COPD Hurst JR, AJRCCM 2006

Blood neutrophils at exacerbation of COPD Papi, Fabbri & Johnston et al. AJRCCM 2006

Correlations between inflammatory markers Sputum Vs Serum Serum IL-6CRP Sputum Leukocyte count r = 0.38r = 0.39 p = 0.013p = IL-8 r = 0.35r = 0.24 p = 0.026p = Hurst JR, AJRCCM 2006 Systemic and lower airway inflammation at Exacerbation of COPD

ROC analysis AUC95% CI CRP > 5mg/L CRP + one major symptom Any major symptom CRP (pg/ml) Plasma Biomarkers at exacerbation of COPD Hurst JR, AJRCCM 2006

Perera WR, ERJ 2007 Recovery time days Changes in sputum IL-6 Between baseline and day 7 (pg/ml) Changes in sputum IL-8 Between baseline and day 7 (pg/ml) CRP log10 mg/ml 14 days Time to next exacerbation days Time from exacerbation days CRP change from exacerbation % Recovered Non Recovered Inflammatory changes, recovery and recurrence at COPD exacerbation

Donaldson GC, Chest 2005 (years) FEV1 % predicted Fibrinogen (g/l) (years) Frq exacerbations Infrq exacerbation Low fibrinogen High fibrinogen Systemic Inflammation and Decline in Lung Function in Patients With COPD

Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 level. (Wedzicha et al. Thromb Haemost 2000) Fibrinogen g/l IL-6 pg/ml

COPD Exacerbations and CV Risk CRP –increases the expression of intercellular adhesion molecules, –induces monocyte chemoattractant production, –activates complement and –mediates low density lipoprotein uptake by macrophages. –deposits directly into the arterial wall during atherogenesis to create foam cells. Increased circulating fibrinogen levels during acute exacerbations result in increased pro-thrombotic state.

IRRs for MI event on days 1 to 5 1 – 5 days Type of exacerbationIRR (95% CI)P value Antibiotics1.14 ( )0.57 Steroids1.55 ( )0.15 Antibiotics + steroids2.27( )0.03 Myocardial infarction (per 100 pateint per year) >= Donaldson GC, Chest 2010 Risk of MI following exacerbation of COPD

Pulmonary and Systemic Inflammation in COPD Exacerbations Annual meeting Linee guida Rinite Asma BPCO, Modena 1-3/3/ Percent decrease FEV 1 at exacerbation Increase in sputum neutrophils at exacerbations (10 6 /g) Results: sputum PMN r = 0.35 P<0.01 N=23 N=21 ≤2≥3 0 10,000 20,000 Number of Exacerbations in Previous Year IL-8 (pg/mL) P=0.05 > 2.58 exac/year < 2.58 exac/year CRP (pg/ml) CRP log10 mg/ml 14 days Time to next exacerbation days (years) FEV1 % predicted