Systemiska effekter vid KOL

Transkript

1 Systemiska effekter vid KOL Svensk Lungmedicinsk Förenings Vårmöte Linköping Kjell Larsson IMM Karolinska Institutet

2 KOL och andra sjukdomstillstånd Parallella fenomen? Kausalsamband? Muskeldysfunktion Kognitiv dysfunktion KOL Kranskärlssjukdom Hjärtsvikt Osteoporos Malnutrition Diabetes Åldrande Exponering (rökning)

3 Rökning Lung/luftvägsinflammation Systemisk inflammation Systemisk oxidativ stress Förändrad kärlfunktion (vasomotor, endotel) Påverkan på koagulationssystemet Samvariation med KOL Kranskärlssjukdom Hjärtsvikt Lunginfektioner Cancer Diabetes Hypertoni Osteoporos Kakexi Sarcopeni

4 Martinisi et al Exp Mol Pathol 2006;80:219

5 Martinisi et al Exp Mol Pathol 2006;80:219

6 Orsaker till systemiska effekter vid KOL Systemisk inflammation Oxidativ stress Vävnadshypoxi Fysisk inaktivitet Metabola rubbningar

7 Vad menas med systemisk inflammation? A state in which individuals display abnormally elevated levels of circulating molecules that are a part of the inflammatory cascade Sin & Man Can J Physiol Pharmacol 2007;85:141

8 Arterioskleros Hjärtsjukdom Diabetes? Systemisk inflammation vid KOL Mortalitet Kakexi Anorexi Osteoporos Muskel- Depression dysfunktion

9 Exposure Exposure v (tobacco smoke, occupational exposure etc) Target cells Airway and v lung cells Mediators Cytokines Chemokines Growth factors Enzymes v Arachidonic acid metabolites Reactive oxygen/nitrogen species Other agents (acetylcholine NO etc) Tissue effects Goblet cell metaplasia Submucous gland enlargement Alveolar destruction Fibrosis Loss of alveolar v attachments Proteolysis Smooth muscle contraction Muscle dysfunction Osteoporosis Coronary heart disease Heart failure Weight loss Etc Outcome Mucus secretion Tissue remodeling Emphysema Bronchoconstriction v From Larsson K JIM 2007;262:311

10 Exponering för proinflammatoriska agens Bronchitis Bronchiolitis IL-8 Alveol Kapillär Emphysema Cytokiner IL-6, IL1-β GM-CSF, IL-6 IL-6, TNF

11 CRP Leucocytes Fibrinogen TNF Gan et al. Thorax 2004;59:574

12 Risk for increased CRP Interaction between smoking and reduced lung function Q 1 : FEV % pred Q 4 : FEV 1 > 107.1% pred Cot: Serumcotinine (ng/ml) Gan et al Chest 2005;125:558

13 Increased CRP in severe COPD Metabolic and functional impairment CRP elevated in 48/102 patients High CRP was related to Increase in IL-6 (p<0.001) Higher resting energy expenditure (p=0.002) Lower maximal and submaximal exercise capacity Shorter walking distance (6-min walking test) Higher symptom score Worse quality of life (SGRQ) Lower FEV 1 CRP predicted BMI and fat mass index Broekhuizen et al Thorax 2006;61:17

14 n=2442 Relation between FEV 1 and CRP in adults n=1301 Fogarty et al Thorax 2008;62:515

15 Relation of biomarkers of inflammation to FEV 1 Framingham Heart Study Biomarkers are presented as predicted difference in FEV 1 (95% C I) associated with 1 standard deviation higher concentration of respective marker Walter et al Chest 2008;133:19

16 Annual FEV 1 - decline and inflammatory markers Low levels of plasma fibrinogen and sputum IL-6 at study entry High levels of plasma fibrinogen and sputum IL-6 at study entry Donaldson et al Chest 2005;128:1995

17 Hospitalisation and inflammation sensitive plasma proteins Fibrinogen Ceruloplasmin Haptoglobin α 1 -Antitrypsin Orosomucoid Engström et al Thorax 2009;64:211

18 Association between Cardiac Infarction Injury Score (CIIS), CRP and obstruction in COPD (Data from NHANES III) CIIS (detection of mycardial infarction): Sensitivity: 85% Specificity 95% (Rautaharju Circulation 1981;64:249) Sin et al Circulation 2003;107:1514

19 All cause mortality Mortality and risk of cardiovascular disease related to serum CRP Lung Health Study Risk of cardiovascular disease From Sin & Man Can J Physiol Pharmacol 2007;85:141

20 Time to first severe exacerbation related to serum levels of fibrinogen Groenewegen et al Chest 2008;133:350

21 Prognosis related to serum CRP in COPD 8 years follow up n = 1302 Dahl et al AJRCCM 2007;175:250

22 Relationship between inflammatory markers of different compartments at COPD exacerbation Hurst et al AJRCCM 2006;173:71

23 Systemic engagement in relation to potentially pathogenic microorganisms in sputum at COPD exacerbation PPM: Potentially Pathogenic Microorganisms Hurst et al AJRCCM 2006;173:71

24 Faktorer som ger ospeoporos vid KOL Rökning Lågt BMI Faktorer som påverkar muskelfunktion vid KOL Exacerbationer Hypoxi Fysisk inaktivitet Steroidbehandling Systemisk inflammation

25 Circulating inflammatory markers related to body composition in COPD Normal BMI and CHI Normal BMI, low CHI Low BMI and CHI CHI = creatinine height index <80% of normal indicates sceletal muscle depletion Eid et al AJRCCM 2001;164:1414

26 Vikt och systemisk inflammation vid KOL Matchade grupper FEV 1 <60 % av förväntat värde Ej ödem Inga tecken på infektion Underviktiga: TNF 70,2 pg/ml i serum Normalviktiga: TNF 6,7 pg/ml i serum Di Francia et al AJRCCM 1994;150:1453

27 Body mass wasting TNF in blood in COPD is related to fall in body mass TNF is correlated with resting metabolic rate Acute phase proteins are correlated with resting metabolic rate Effects on leptin mediated energy balance Higher in patients with emphysema, related to systemic inflammation - related to weight loss Higher during exacerbations Wouters et al Thorax 2002;57:1067 Wouters et al PATS 2005:2:26

28 Inflammatory parameters related to sceletal muscle depletion CHI:Creatinine height index Eid et al AJRCCM 2001;164;1414

29 Effects of infliximab in COPD Rennard et al AJRCCM 2007;175:926

30 Placebo FP 0.5 mgx2 Pred 30 mgx1 Sin et al AJRCCM 2004;170:760

31 Fluticasone vs placebo in COPD FEV 1 (l) 1,5 1,45 1,4 1,35 1,3 1,25 Fluticasone propionate 1 mg *** *** *** *** N = 751 FEV1: 50% pred Placebo *** 1, Time on treatment (months) Burge et al BMJ 2000;320:1297

32 Fluticasone vs placebo in COPD SGRQ (total score) Placebo Fluticasone Threshold of cliniccal significance P= Time from start of inhaled treatment (months) Burge et al BMJ 2000;320:1297

33 Hospitalization free survival in COPD Influence of prescribed inhaled steroids n = n = Sin & Tu AJRCCM 2001;164:580

34 Primary analysis (TORCH) All-cause mortality at 3 years Placebo (n = 1,524) SFC (n = 1,533) Probability of death by 3 years (%)* HR 95% CI p Unadjusted (0.677, 0.993) Adjusted (0.681, 1.002) Estimated 17.5% reduction in risk of dying at any time in 3 years; 2.6% absolute risk reduction *Kaplan-Meier estimate, stratified by smoking status Adjusted to a significance level of 0.05, and taking the interim analyses into account Calverley et al ERS 2006

35 Cardio-ischemic events in COPD patients treated with inhaled corticosteroids o EUROSCOP n = years follow up o No cardiac disease at randomisation o 60 new events in 49 patients: Placebo: 31/582 Budesonide: 18/592 p<0.05 Post-hoc study showing a preventive effect on cardio-ishaemic events with inhlaed budesonide in COPD Löfdahl CG et al Abstract ERS Copenhagen 2005

36 KOL en systemsjukdom Det finns ett systemengagemang som ökar med svårighetsgrad vid KOL Morbiditet, förlopp och prognos vid KOL relaterar till extrapulmonella faktorer Ökad medvetenhet om systemiskt engagemang förbättrar KOL-vården Framtida behandling skall inriktas mot att behandla den systemiska inflammationen