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Alberto Papi

Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale. Pulmonary and Systemic Inflammation in COPD Exacerbations. Alberto Papi.

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Alberto Papi

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  1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra.Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

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

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

  4. 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. COPD exacerbation: Definition (GOLD 2010)

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

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

  7. Results: sputum PMN 200 r = 0.35 P<0.01 150 100 Increase in sputum neutrophils at exacerbations (106/g) 50 0 -5 0 5 10 15 20 25 30 35 Percent decrease FEV1 at exacerbation Papi, Fabbri & Johnston et al. AJRCCM 2006

  8. 1)Roland et al. Thorax 2001 7) Hurst et al. AJRCCM 2006 2) Bhowmik et al. Thorax 2000 8) Seemungal et al. ERJ 2000 3) Tsoumakidou et al. Resp Med. 2005 9) Aaron et al. AJRCCM 2001 4) Fujimoto et al. ERJ 2005 10) Wilkinson et al. Chest 2006 5) Papi et al. AJRCCM 2006 11) Drost et al. Thorax 2005 6) Caramori et al. Thorax 2003 12) Perera et al. ERJ 2007

  9. Relation ofsputuminflammatorymarkerstosymptoms and lungfunctionchanges in COPD exacerbations ns ns Delta FEV1 (%) (Bhowmiket al. Thorax 2000) Perera WR, ERJ 2007

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

  11. Risk of exacerbations and airway inflammation 20,000 N=23 IL-8 (pg/mL) 10,000 N=21 0 ≤2 ≥3 Number of Exacerbations in Previous Year < 2.58 exac/year > 2.58 exac/year P=0.05 Bhowmik et al. Thorax. 2000

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

  13. Inflammation & COPD exacerbations. Bronchial biopsies Eosinophils EG-2 Neutrophils 400 ** *** *** 300 200 Cells/mm2 100 0 B B B E E E (Saetta et al 1994)

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

  15. I-kB degradation NF-kB Oxidant formation NF-kB Inflammatory Response Noninfective Bacteria Viruses Rhinovirus Receptor Epithelial cells NF-kB NF-kB RANTES Macrophages IL-6 Eosinophils CXCL8 TNF-α Reducingagents X Neutrophils Oxidative stress Caramori et al, Thorax 2003 Papi A, Contoli M J Biol Chem 2008

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

  17. 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 purulencepointsto a bacterial cause, asdoes a priorhistoryofchronicsputum production. COPD exacerbations: Definition (GOLD 2010)

  18. Etiology • The most common causesofanexacerbation are infectionof the tracheobronchialtree and air pollution, but the cause ofaboutone-thirdof severe exacerbationscannotbeidentified. • 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. • 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

  19. Airway Inflammation and Etiology of Acute Exacerbations of Chronic Bronchitis 3500 *** 2500 IL-8 (pg/ml) 1500 500 0 Pathogens + Pathogens - (Sethi et al. Chest 2000)

  20. Viral & bacterial aetiology of COPD exacerbations • 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 70 • 56 male, 8 female • 48 pack years Papi A, Fabbri L, Johnston SL. AJRCCM 2006

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

  22. 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

  23. ** ** ** ** 1000 100 10 10 6 Sputum neutrophils 1 /g plug 0,1 0,01 E S E S E S E S Virus Virus + Bacteria No pathogens bacteria Sputum Neutrophils increased in all AE Papi, Fabbri & Johnston et al. AJRCCM 2006

  24. * * * * 10 ** ** 8 6 4 10 6 2 SputumEosinophils /mg plug 0 E S E S E S E S Virus Virus & Bacteria No pathogen Bacteria Eosinophils increased only in virus related AE

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

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

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

  28. VIRUS LOAD – time course Mallia P, Message S, Contoli M, Papi A, Johnston SL et al AJRCCM 2011

  29. BACTERIAL INFECTION 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

  30. Time course of virus and bacterial load Courtesy SL Johnston

  31. Proteinase-AntiProteinase balance during COPD exacerbations 120 110 80 100 70 90 60 80 70 MMP-9 (mcg/g sputum) 50 60 MMP-9:TIMP-1 molar ratio 40 50 30 40 30 20 20 10 10 0 0 Pre Ex Ex Pre Ex Ex Mercer PF, Resp Res 2005

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

  33. Plasma Biomarkers at exacerbation of COPD Hurst JR, AJRCCM 2006

  34. 8000 6000 4000 2000 Increase in peripheral blood neutrophils at exacerbation (cells/dL) 0 -2000 -4000 -5 0 5 10 15 20 25 30 Percent decrease in FEV at exacerbation 1 Blood neutrophils at exacerbation of COPD Papi, Fabbri & Johnston et al. AJRCCM 2006

  35. Systemic and lower airway inflammation at Exacerbation of COPD 150 100 Serum CRP 50 0 Sputum PPM Neg Sputum PPM Pos Hurst JR, AJRCCM 2006

  36. Plasma Biomarkers at exacerbation of COPD CRP (pg/ml) Hurst JR, AJRCCM 2006

  37. Inflammatory changes, recovery and recurrence at COPD exacerbation Recovered Non Recovered CRP change from exacerbation % CRP log10 mg/ml 14 days Time from exacerbation days Time to next exacerbation days Recovery time days Recovery time days Changes in sputum IL-6 Betweenbaseline and day7 (pg/ml) Changes in sputum IL-8 Betweenbaseline and day7 (pg/ml) Perera WR, ERJ 2007

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

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

  40. 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.

  41. Risk of MI following exacerbation of COPD 5 4 Myocardial infarction (per 100 pateint per year) 3 2 1 0 >= 0 1 2 3 4 5 Donaldson GC, Chest 2010

  42. ** ** ** ** 1000 100 20,000 N=23 10 10 6 Sputum neutrophils 1 /g plug IL-8 (pg/mL) 10,000 N=21 0,1 0,01 0 ≤2 ≥3 E S E S E S E S Number of Exacerbations in Previous Year Virus Virus + Bacteria No pathogens bacteria Pulmonary and Systemic Inflammation in COPD ExacerbationsAnnual meeting Linee guida Rinite Asma BPCO, Modena 1-3/3/2011 Results: sputum PMN 200 < 2.58 exac/year > 2.58 exac/year CRP log10 mg/ml 14 days CRP (pg/ml) r = 0.35 P<0.01 150 P=0.05 100 Increase in sputum neutrophils at exacerbations (106/g) Time to next exacerbation days FEV1 % predicted 50 0 (years) -5 0 5 10 15 20 25 30 35 Percent decrease FEV1 at exacerbation

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