Χρόνια Αποφρακτική Πνευμονοπάθεια Πολυσυστηματική νόσος Σύγχρονη προσέγγιση

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1 Χρόνια Αποφρακτική Πνευμονοπάθεια Πολυσυστηματική νόσος Σύγχρονη προσέγγιση Σταύρος Τρύφων Πνευμονολόγος MD, PhD, FCCP, ERS National Delegate Διευθυντής ΕΣΥ Γ. Νοσοκ. Γ. Παπανικολάου Θεσ/νίκη

2 Συμβουλευτικές υπηρεσίες-honorarium Astra Zeneca Boehringer Ingelheim Chiesi GSK Elpen Novartis Vianex/MSD UCB

3 The next 90 minutes...

4 World Health Organization - Global Alliance Against Chronic Respiratory Diseases - GARD

5 VERTICAL vs HORIZONTAL PROGRAMS OF CARE H I V A I D S M A L A R I A T B C O P D INTEGRATED PRIMARY CARE

6 The next 10 minutes... Διαπιστώσεις!!

7 Πολυ-συννοσηρότητα στη ΧΑΠ LEGW Vanfleteren et al., Am J Respir Crit Care Med published online epub ahaed of print February 7, 2013

8 Κύρια συνοδά νοσήματα της ΧΑΠ 50% 38% 32% 16% Καρδιαγγειακά νοσήματα Κατάθλιψη Οστεοπόρωση Σακχαρώδη Διαβήτη Wissam M. Chatila, Proc Am Thorac Soc Vol 5. pp , 2008

9 Systemic Disease

10 Systemic Inflammation

11 Systemic Inflammation in COPD COPD is an inflammatory condition Pro-inflammatory mediators may be the driving force behind the disease process Inflammation and actions of pro-inflammatory mediators may extend beyond the lungs and play a part in COPD comorbidities As effective anti-inflammatory therapy becomes available for COPD, it will be important to monitor the effects on lungs and associated comorbidities Sevenoaks MJ, Stockley RA. Respir Res. 2006;7:70.

12 Systemic Inflammation in COPD: C-reactive Protein Is Elevated Dentener Eid Mannino Mendall Yasuda Pooled summary Standardised mean difference of CRP Greater in controls Greater in COPD Gan WQ, et al. Thorax. 2004;59: Copyright 2004 BMJ Publishing Group Limited. All rights reserved.

13 CRP (mg/l) CRP είναι αυξημένη στη ΧΑΠ σε σχέση με καπνιστές και μη καπνιστές 6 5 * 5.03 *P<0.05 versus other groups COPD (N=88) Smokers without COPD (N=33) Nonsmokers without COPD (N=38) Pinto-Plata VM, et al. Thorax. 2006;61:23-8.

14 Systemic Inflammation in COPD: TNF-a Is Elevated de Godoy Di Francia Takabatake Yasuda Pooled summary Standardised mean difference of TNF-alpha Greater in controls Greater in COPD Gan WQ, et al. Thorax. 2004;59: Copyright 2004 BMJ Publishing Group Limited. All rights reserved.

15 Systemic Inflammation Rises With COPD Severity CRP TNF-a Severe COPD Severe COPD Moderate COPD Moderate COPD Mild COPD Mild COPD Healthy Healthy Serum C-Reactive Protein (mg/l) Serum TNF-Alpha (pg/ml) Reprinted from Pulm Pharmacol Ther, Vol 19, Franciosi LG, et al, Markers of disease severity in chronic obstructive pulmonary disease, pp , Copyright 2006, with permission from Elsevier.

16 Systemic Inflammation in COPD: Elevated Leucocytes Dentener Mannino James (smokers) Pooled summary Standardised mean difference of leukocytes Greater in controls Greater in COPD Gan WQ, et al. Thorax. 2004;59: Copyright 2004 BMJ Publishing Group Limited. All rights reserved.

17 Serum VEGF (pg/ml) Systemic Inflammation in COPD: Elevated VEGF P< COPD Patients Normal Controls Kierszniewska-Stepien D, et al. Eur Cytokine Netw. 2006;17:75-79.

18 Comorbidities in COPD

19 Συχνότητα Νοσηλείας διαφόρων ασθενών με η χωρίς ΧΑΠ Musculoskeletal System Genitourinary System Digestive System Controls (N=4,566) COPD (N=1,522) Nervous System Endocrine Disorders Neoplasms Cardiovascular System Respiratory System 0 2 Hospital 4 Discharges 6 8per Patients Mapel DW, et al. Arch Internal Med. 2000;160:

20 Skeletal Muscle Dysfunction

et al. Am J Resp Crit Care Med. 2002;166:485-489.

21 Skeletal Muscle Apoptosis in COPD Healthy Subject COPD Patient Nucleus of apoptotic muscle fiber Agusti AG, et al. Am J Resp Crit Care Med. 2002;166: Copyright 2002 American Thoracic Society. Material Adapted.

22 Fat-free Mass (kg) Fat-free Mass Is Reduced in COPD *P< * COPD (N=40) No COPD (N=46) Sergi G, et al. Respir Med. 2006;100:

23 TNF-a, IL-8 Hypoxemia LEPTIN Cachexia

24 Cardiovascular Disease

Reactive oxygen species Infectious agents

25 Inflammation in Cardiovascular Disease Modified lipoproteins Haemodynamic insults Reactive oxygen species Infectious agents T lymphocyte More cytokines Growth factors Ox-LDL Scavenger receptors MCP-1 M-CSF IL-8 Macrophage CRP moiety Endothelial injury ICAM-1 Available at:

26 COPD Inflammation Can Contribute to Cardiovascular Disease Lung Inflammation Chronic Acute TNF-α C-reactive Protein Autonomic Instability IL-6 Fibrinogen GM-CSF Neutrophils Progressive Atherosclerosis Arrhythmias Coagulation Inflammation GM-CSF = granulocyte-macrophage colony stimulating factor IL = interleukin TNF = tumor necrosis factor Rennard SI. Proc Am Thorac Soc. 2005;2: Permission requested.

27 Percent of Subjects Κίνδυνος καρδιαγγειακής νόσου σε ασθενείς με ΧΑΠ COPD (N=11,493) Controls (N=22,986) * *P<0.05 for between-group difference * 21.1 MI = myocardial infarction CHF = congestive heart failure CVD = cardiovascular disease 11.7 * * * Arrhythmia Angina Acute MI CHF Stroke Other CVD CVD Hospitalisation * * Curkendall SM, et al. Am J Epidemiol. 2006;16:63-70.

28 Relative Hazard Ratio Κίνδυνος εμφάνισης ισχαιμικής νόσου σε σχέση με την FEV P<0.01 for trend in men and P<0.05 for trend in women 95% CI Men Women Reference First Second Third Fourth Fifth Increasing FEV 1 FEV 1 Quintile Hole DJ, et al. BMJ.1996;313:

30 VALIANT Trial: Prevalence of COPD patients included in the trial 1258 clinical diagnosis of COPD (8.6%)

32 Conclusions: Patients with COPD prescribed a β- blocker were significantly less likely to have a COPD exacerbation and had fewer mild COPD exacerbations.

33 Beta-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease Frans H. Rutten, Nicolaas P. A. Zuithoff, EelkoHak, Diederick E. Grobbee, Arno W. Hoes Arch Intern Med. 2010;170(10):

34 Survival in COPD patients according to β-blocker use No significant mortality effect until >20 months after initiation Change in survival rate at ~60 months parallel to no β-blocker

35 Survival in COPD patients referred to pulmonologist Change in slope at ~60 months in pts with severe COPD

36 Osteoporosis

37 Παράγοντες κινδύνου για οστεοπόρωση στη ΧΑΠ Κάπνισμα Αυξημένη πρόσληψη αλκοόλης Χαμηλά επίπεδα βιτγαμίνης D Γενετικοί παράγοντες Θεραπεία με κορτικοειδή Ελάττωση μάζας και ισχύος σκελετικών μυών Χαμηλό BMI και αλλαγές στη σύνθεση του σώματος Ελάττωση των επιπέδων insulin-like growth factors Χρόνια συστηματική φλεγμονή Ionescu AA, et al. Eur Respir J. 2003;22 (Suppl 46):64s-75s.

38 Urinary NTx (nm BCE/u) Log 10 hscrp (mg1) Bone Turnover and Osteoporosis are Correlated With Inflammation Premenopausal Postmenopausal *γ=0-288, P< Log 10 hscrp (mg1) 0-20 P for trend = NTx=N-terminal telopeptide of type I collagen, BCE=bone collagen equivalent Normal (N = 30) Osteoporia (N = 109) Osteoporosis (N = 50) Relationship between serum hscrp concentration and biochemical bone turnover markers in healthy pre- and postmenopausal women, Kim BJ, Yu YM, Kim EN, et al. Copyright 2007 Clinical Endocrinology. Reproduced with permission of Blackwell Publishing Ltd.

39 Percent of Subjects with Osteoporosis Airflow Obstruction and Osteoporosis in COPD Men Women None Mild Moderate Severe Severity of Airflow Obstruction Sin DD, et al. Am J Med. 2003;114:10-14.

40 COPD, ICS, and Osteoporotic Fracture Severe COPD Use of ICS Adjusted Odds Ratio for Osteoporotic Fracture No No 1.06 No Yes 1.08 Yes No 1.47* Yes Yes 1.48* *P<0.05 De Vries F, et al. Eur Respir J. 2005;25:

41 Adjusted Odds Ratio for Vertebral Fracture Inhaled Versus Oral Corticosteroid Use and Fracture Risk in COPD *P<0.05 versus no corticosteroid 95% CI * * ICS Intermittent Continuous Any Use Systemic McEvoy CE, et al. Am J Resp Crit Care Med. 1998;157:

42 Anaemia of Chronic Disease

Inflammatory Processes and Anaemia Activated immune

Dyserythropoiesis TNF Proinflammatory cytokines

IFN- IL-1 TNF IFN-a,β IL-1 TNF HIF-1 Shortened

Reduced EPO-production Reprinted by permission from

43 Inflammatory Processes and Anaemia Activated immune system Erythrocytes Macrophages Erythrophagocytosis Dyserythropoiesis TNF Proinflammatory cytokines ReactiveO 2 composition IFN- IL-1 TNF a1-antitrypsin IFN- IL-1 TNF IFN-a,β IL-1 TNF HIF-1 Shortened survival Impaired iron usage Suppressed BFU-E/CFU-E Reduced EPO-production Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Clinical Oncology, (Bohlius J, et al. Nat Clin Pract Oncol. 2006;3: ), copyright 2006.

44 Anaemia and Mortality in COPD Deaths per 1,000 Patient-years P< COPD with Anaemia COPD without Anaemia Halpern MT, et al. Cost Effect Res Allocation. 2006;4:17-24.

45 Metabolic Abnormalities in COPD

46 HOMA-R 9 8 Tumor Necrosis Factor-a and Diabetes TNF-a Levels Are Correlated With Insulin Resistance r=0.632 P< Type 2 diabetes with IR Type 2 diabetes without IR Normal IR = insulin resistance TNF-a (pg/ml) Reprinted from Res Clin Pract, Vol 52, Mishima Y, et al, Relationship between serum tumor necrosis factor-α and insulin resistance in obese men with Type 2 diabetes mellitus, pp , Copyright 2001, with permission from Elsevier.

47 Percent of Subjects Prevalence of Diabetes Higher in Patients With COPD * COPD (N=2,505) *P<0.05 vs no COPD No COPD (N=726,840) Rana JS, et al. Diabetes Care. 2004;27:

48 Percent with Metabolic Syndrome* Prevalence of Metabolic Syndrome Higher in COPD COPD (N=38) No COPD (N=34) * Metabolic syndrome 3 of the following: abdominal obesity, elevated triglycerides, reduced HDL-C, hypertension, hyperglycaemia Marquis K, et al. J Cardiopulm Rehabil. 2005;25:

49 H Watz et al Chest : Μείωση της ικανότητας για άσκηση σε ασθενείς με ΧΑΠ και Μεταβολικό Σύνδρομο Physical activity level 1,8 1,6 1,4 1,2 1 CB I II III IV GOLD stage No metabolic Syndrom Metabolic Syndrom

51 H Διαβητική μικροαγγειοπάθεια στοχεύει στον πνεύμονα όπως κάνει σε άλλα όργανα. Ακόμα κι αν αναπνευστική δυσλειτουργία στους περισσότερους ασθενείς με διαβήτη είναι υποκλινική Οι δοκιμασίες πνευμονικής λειτουργίας ποσοτικοποιούν αναίμακτα τα αποθέματα που δεν έχουν καταστραφεί από το διαβήτη. Η υποκλινική απώλεια της πνευμονικής λειτουργίας εμφανίζεται υπό συνθήκες στρες, H χρόνια υποξία οφείλεται σε πνευμονική νόσο ή υψηλή έκθεση υψόμετρο, ή υπερφόρτωση όγκου σε καρδιακή και νεφρική ανεπάρκεια. Σε αντίθεση με καρδιακούς ή σκελετικούς μύες, οι πνευμονικοί δείκτες είναι σε μεγάλο βαθμό ανεξάρτητη της φυσικής κατάστασης.

54 ΧΑΠ παράγοντας κινδύνου για Σ/Δ τύπου 2: inflammation oxidative stress, insulin resistance, weight gain alterations in metabolism of adipokines. Ο Σ/Δ τύπου 2 ανεξάρτητος παράγοντας κινδύνου : negatively affecting pulmonary structure pulmonary function. Increased pulmonary infections, exacerbations worsened COPD outcomes.

55 For each 1 mmol/l increase in blood glucose the absolute risk of adverse outcomes increased by 15% (95% CI 4 to 27), p=0.006.

56 Depression

57 Relative Risk for Depression Risk of Depression in Patients With COPD ( ) ( ) 1.1 ( ) 1 Reference All Patients (N=162) FEV <50% Predicted (N=60) FEV 50-80% (N=102) Controls van Manen JG, et al. Thorax. 2002;57:

58 Παράγοντες που σχετίζονται με την εμφάνιση άγχους και κατάθλιψης στη ΧΑΠ Physical disability Long-term oxygen therapy Low body mass index Severe dyspnoea FEV 1 <50% predicted Poor quality of life Presence of cormorbidity Living alone Female gender Current smoking Low social class status Maurer J, et al. Chest. 2008;134 (4 Suppl):43S-56S.

60 Συν-νοσηρότητες : Cote index Divo M et al Blue 2012

61 Συστηματική φλεγμονή και συνοσηρότητες COPD BODY COMPOSITION CARDIOVASCULAR DISEASE INFLAMMATION DIABETES OSTEOPOROSIS GASTROINTESTINAL DISORDER Agusti AG, et al. Eur Respir J. 2003;21: Agusti A. Proc Am Thorac Soc. 2007;4:

62 Fabbri, Lancet 2007

63 Assessing Comorbidities in COPD Look for COPD Comorbidities Look for If Smoker Agusti A and Jardim J, personal communication.

65 Συν-νοσηρότητες : Cote index Divo M et al Blue 2012

66 Effects of COPD Treatment on Systemic Comorbidities

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