Leonardo M. FabbriLeonardo M. Fabbri

fabbri.leonardo@unimo.itfabbri.leonardo@unimo.it

Türk Toraks Derneği11. Yillik Kongresi

Maritim Pine Beach Hotel

Belek-Antalya23-27 Nisan 2008

COPD and systemic

inflammation

http//pneumologia.unimo.ithttp//pneumologia.unimo.it

COPD and systemic inflammation

Complex chronic co-morbidities

Effects of treatment of COPD on its co-morbidities

Effects of treatment of COPD co-morbidities on COPD

Guidelines for complex chronic co-morbidities

ERS Research SeminarERS Research Seminar“Complexity of patients with “Complexity of patients with multiple chronic diseases”multiple chronic diseases”

Rome, Italy Rome, Italy February 10-11, 2007February 10-11, 2007

www.ersnet.org www.ersnet.org/learning_resources_player/paper/RS/RS-Rome.htm

Chronic diseases represent a huge proportion of human illness

58 million deaths in 2005:

Cardiovascular disease 30%

Cancer 13%

chronic respiratory diseases 7%

Diabetes 2%

WHO, Lancet, 4 December 2007

Pathogenesis of COPD

Courtesy of PJ Barnes, 2005

Cigarette smokeor air pollutant

Alveolar macrophage

Neutrophil

Proteases

? CD8+ T-cell

Alveolar wall destruction

EMPHYSEMA

Mucus hypersecretion

CHRONIC BRONCHITIS

Inflammatory cytokines(IL-8, LTB4)

CXCL-10CXCL-10

CXCR3CXCR3

Leading Causes of Death in U.S.

1. Myocardial Infarction2. Cancer3. Cerebrovascular Diseases4. COPD

Cigarette Related DiseasesLeading Causes of

Death Worldwide 2010

Inhaled particles:pulmonary and heart co-morbidity

Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily

Inhaled Anticholinergic Bronchodilator

Niewoehner,et al, Ann Intern Med. 2005;143:317-326

COEXISTING ILLNESSES

Vascular (including hypertension) 64%Cardiac 38%

Gastrointestinal 48%Musculoskeletal or connective tissue 46%

Metabolic or nutritional 47%Reproductive or urinary 27%

Neurologic 22%

RECOGNISING HEART FAILURE IN ELDERLY PATIENTS WITH STABLE CHRONIC OBSTRUCTIVE PULMONARY

DISEASE IN PRIMARY CARE

F H Rutten et al, BMJ 2005, Dec;331(4):1379-81

A limited number of items easilyavailable from history and physical examination,withaddition of NT-proBNP and electrocardiography, can

help general practitioners to identify concomitantheart failure in individual patients with stable COPD

Emphysema severity is associated with arterial Emphysema severity is associated with arterial stiffness in patients with COPDstiffness in patients with COPD

Similar pathophysiological processes may be involved Similar pathophysiological processes may be involved in both lung and arterial tissuein both lung and arterial tissue

Further studies are now required to identify the Further studies are now required to identify the mechanism underlying this newly described mechanism underlying this newly described

associationassociation

MacNee W et al, AJRCCM 2007; MacNee W et al, AJRCCM 2007; 176:1208-1214176:1208-1214

ARTERIAL STIFFNESS IS INDEPENDENTLY ARTERIAL STIFFNESS IS INDEPENDENTLY ASSOCIATED WITH EMPHYSEMA SEVERITY IN ASSOCIATED WITH EMPHYSEMA SEVERITY IN

PATIENTS WITH CHRONIC OBSTRUCTIVE PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASEPULMONARY DISEASE

INCREASED RISK OF BOTH ULCERATIVE INCREASED RISK OF BOTH ULCERATIVE COLITIS AND CROHN'S DISEASE IN A COLITIS AND CROHN'S DISEASE IN A

POPULATION SUFFERING FROM COPDPOPULATION SUFFERING FROM COPD

Ekbom A et al, Lung 2008 Mar 11 [Epub ahead of print]Ekbom A et al, Lung 2008 Mar 11 [Epub ahead of print]

The results of this study suggest that COPD The results of this study suggest that COPD and inflammatory bowel diseases may have and inflammatory bowel diseases may have

inflammatory pathways in common, inflammatory pathways in common, including genetic variants of genes including genetic variants of genes

predisposing for diseasepredisposing for disease

INSULIN RESISTANCE AND INFLAMMATION - A INSULIN RESISTANCE AND INFLAMMATION - A FURTHER SYSTEMIC COMPLICATION OF COPDFURTHER SYSTEMIC COMPLICATION OF COPD

Bolton CE et al, COPD. 2007 Jun ;4(2):121-6Bolton CE et al, COPD. 2007 Jun ;4(2):121-6

This study demonstrates greater insulin This study demonstrates greater insulin resistance in non-hypoxaemic patients with resistance in non-hypoxaemic patients with

COPD compared with healthy subjects, COPD compared with healthy subjects, which was related to systemic which was related to systemic

inflammation. This relationship may inflammation. This relationship may indicate a contributory factor in the excess indicate a contributory factor in the excess risk of cardiovascular disease and type II risk of cardiovascular disease and type II

diabetes in COPD diabetes in COPD

©happymiller-graphics

The „Metabolic Syndrome“

ObesityCircumference M>102; F>88cm(BMI>30mg/kg2

WHR M>0.9; F>0.85)

Secondary Complications

Insulin- Resistance (PCO, "HAIR-AN"-Sy)

DyslipidemiaTriglyzeride >1.7mMHDL-C M <1.0mM F <1.3mM

HypertensionBD>130/85mmHg (>160/90)

Diabetes mellitus Type 2P-Glc >6.1mmol/l (IFG), 2x; >7.0mmol/l (Dm)R-Glc / 2h 75g oGTT: >7.8 (IGT); >11 (Dm)

Genes

Alb/Krea i.U. >2.7mg/mmolATP III: Diabet Med 03; 20: 175-81

OBSTRUCTIVESLEEP APNOEA

HYPOXEMIASEDENTARY

SMOKINGRESTRICTION

TLC & VC

Courtesy of B Muller

vanGaal LF et al, Nature 2006; 444: 875

Natural history of atherothrombosis

Atherogenic stimuli (dyslipemia, hypertension, smoking)

Endothelialdysfunction

Destabilizing stimuli

Inflammation

Inflammation, atherosclerosis and coronary artery disease Inflammation, atherosclerosis and coronary artery disease Hansson GK, N Engl J Med. 2005;352(16):1685-95Hansson GK, N Engl J Med. 2005;352(16):1685-95

Activation of a type 1 immune response in atheroma formationActivation of a type 1 immune response in atheroma formation

Inflammation in the wall of intra-myocardial arteries

in DOCA-salt hypertension

Uni-Nx DOCA-salt

Larivière & Schiffrin, J Mol Cell Cardiol 1995;27:2123-2131

Courtesy of E Schiffrin

Mechanism of inflammatory bone lossMechanism of inflammatory bone loss

Takayanagi , J Mol Medicine Takayanagi , J Mol Medicine 2005; 2005; 83:170-983:170-9

MuscleWeakness / Wasting

Metabolic Syndrome Type 2 diabetes

Osteoporosis

CRP

CardiovascularEvents Liver

+ve

?LocalInflammation

TNF IL-6

Fabbri LM et al, Eur Respir J 2008; JanuaryFabbri LM et al, Eur Respir J 2008; January

Cardiovascular mortality in Cardiovascular mortality in COPDCOPD

For every 10% decrease in FEVFor every 10% decrease in FEV11, ,

cardiovascular mortality increases by cardiovascular mortality increases by approximately 28% and non-fatal coronary approximately 28% and non-fatal coronary event increases by approximately 20% in event increases by approximately 20% in

mild to moderate COPDmild to moderate COPD

Anthonisen et al, Am J Respir Crit Care Med 2002Anthonisen et al, Am J Respir Crit Care Med 2002

Add inhaled glucocorticosteroids if repeated exacerbations

IV: Very Severe III: Severe II: Moderate I: Mild

Therapy at Each Stage of COPDTherapy at Each Stage of COPD

FEV1/FVC < 70%

FEV1 > 80% predicted

FEV1/FVC < 70%

50% < FEV1 < 80% predicted

FEV1/FVC < 70%

30% < FEV1 < 50% predicted

FEV1/FVC < 70%

FEV1 < 30% predictedor FEV1 < 50%

predicted plus chronic respiratory failure

Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation

Active reduction of risk factor(s); influenza vaccinationAdd short-acting bronchodilator (when needed)

Add long term oxygen if chronic respiratory failure. Consider surgical treatments

Courtesy of K.F.Rabe, 2007

Prevalence of heart failure in Prevalence of heart failure in stablestable ‘COPD’ ‘COPD’ (aged 65 years or over)(aged 65 years or over) Rutten FH et al, Eur Heart J 2005;26:1887-94Rutten FH et al, Eur Heart J 2005;26:1887-94

405 ‘COPD‘

65years

244 (60.2%)

COPD (GOLD)

191 (39.8%)

‘rest’

33 (20.5%)

Heart failure

50 (20.5%)

heart failure

8%

12%

48%

32%

H F o n ly

H F +C O P D

C O P D o n ly

H F - / C O P D -

Rutten FH et al, Eur Heart J 2005;26:1887-94

PNEUMOUPDATE 2005 Funktion - Magnussen

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 FEV1 % des Solls

10

20

30

40

50

60

70

80

90

100

110F

EV

1 /

FV

C %

n = 500

not classified at risk

III IIIb IIa

FE

V1

/ IV

C %

Köhler D , Fischer J, et al. Thorax 58:825 (2003)

Is COPD a systemic disease ?

Is COPD just one component of a systemic chronic disease?

Should we examine and treat COPD or the patient with COPD?

Complex chronic co-morbidities

Effects of treatment of COPD on its co-morbidities

Effects of treatment of COPD co-morbidities on COPD

Guidelines for complex chronic co-morbidities

COPD and systemic inflammation

Add inhaled glucocorticosteroids if repeated exacerbations

IV: Very Severe III: Severe II: Moderate I: Mild

Therapy at Each Stage of COPDTherapy at Each Stage of COPD

FEV1/FVC < 70%

FEV1 > 80% predicted

FEV1/FVC < 70%

50% < FEV1 < 80% predicted

FEV1/FVC < 70%

30% < FEV1 < 50% predicted

FEV1/FVC < 70%

FEV1 < 30% predictedor FEV1 < 50%

predicted plus chronic respiratory failure

Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation

Active reduction of risk factor(s); influenza vaccinationAdd short-acting bronchodilator (when needed)

Add long term oxygen if chronic respiratory failure. Consider surgical treatments

Courtesy of K.F.Rabe, 2007

Primary analysis: all-cause mortality at 3 years

Vertical bars are standard errors

15241533

14641487

13991426

1293 Plc1339 SFC

Numberalive

0

2

4

6

8

10

12

14

16

18

0 12 24 36 48 60 72 84 96 108 120 132 144 156Time to death (weeks)

Probability of death (%)

FSC 12.6%Placebo 15.2%

HR 0.825, p=0.05217.5% risk reduction

2.6% absolute reduction

Calverley et al, NEJM, 2007

Cause of death on treatment

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

Cardio-vascular

Pulmonary Cancer Other Unknown

Deaths (%)

Placebo SFC

Calverley et al. NEJM 2007

TORCH

Calverley et al NEJM 2007

Medication allocated

Yes No RR (95% CI)

Salmeterol 13.0 % 15.6 % 0.83 (0.74-0.95)

Fluticasone 14.3 % 14.3 % 1.00 (0.89-1.13)

2x2 factorial: Independent effects of fluticasone &

salmeterol

Understanding the Potential

Long-term Impacts on Function

with Tiotropium

POSSIBLE PROTECTION BY INHALED POSSIBLE PROTECTION BY INHALED BUDESONIDE AGAINST ISCHAEMIC CARDIAC BUDESONIDE AGAINST ISCHAEMIC CARDIAC

EVENTS IN MILD COPDEVENTS IN MILD COPD

Löfdahl CG et al, Eur Respir J. 2007 Jun;29(6):1115-9Löfdahl CG et al, Eur Respir J. 2007 Jun;29(6):1115-9

The results of the present study The results of the present study support the hypothesis that treatment support the hypothesis that treatment

with inhaled budesonide reduces with inhaled budesonide reduces ischaemic cardiac events in patients ischaemic cardiac events in patients

with mild chronic obstructive with mild chronic obstructive pulmonary diseasepulmonary disease

Smoking cessation reduces symptoms and improves the Smoking cessation reduces symptoms and improves the accelerated decline in FEV1accelerated decline in FEV1

which strongly indicates that important inflammatory which strongly indicates that important inflammatory and/or remodelling processes should be positively affectedand/or remodelling processes should be positively affected

Data from well-designed studies are lacking regarding the effects Data from well-designed studies are lacking regarding the effects

on inflammation and remodellingon inflammation and remodelling

In COPD, a few histopathological studies suggest In COPD, a few histopathological studies suggest

that airway inflammation persists in exsmokers that airway inflammation persists in exsmokers

Willemse et al, ERJ 2004; 23:464-76Willemse et al, ERJ 2004; 23:464-76

THE IMPACT OF SMOKING CESSATION ONTHE IMPACT OF SMOKING CESSATION ONRESPIRATORY SYMPTOMS, LUNG FUNCTION,RESPIRATORY SYMPTOMS, LUNG FUNCTION,

AIRWAY HYPERRESPONSIVENESS AND INFLAMMATIONAIRWAY HYPERRESPONSIVENESS AND INFLAMMATION

Pulmonary rehabilitation in chronic Pulmonary rehabilitation in chronic obstructive pulmonary diseaseobstructive pulmonary disease

Troosters et al Am J Respir Crit Care Med. 2005 Jul 1;172(1):19-38.Troosters et al Am J Respir Crit Care Med. 2005 Jul 1;172(1):19-38.

Today the question is no longer "should patients with Today the question is no longer "should patients with chronic obstructive lung disease receive pulmonary chronic obstructive lung disease receive pulmonary rehabilitation?" but rather "how should pulmonary rehabilitation?" but rather "how should pulmonary rehabilitation be delivered to patients with COPD?" rehabilitation be delivered to patients with COPD?"

"which components form the basis of the success of "which components form the basis of the success of pulmonary rehabilitation programs?" pulmonary rehabilitation programs?"

The review focuses the physiological rationale for exercise The review focuses the physiological rationale for exercise training, the potential of the multidisciplinary approach training, the potential of the multidisciplinary approach

during rehabilitation programsduring rehabilitation programs

COPD and systemic inflammation

Complex chronic co-morbidities

Effects of treatment of COPD on its co-morbidities

Effects of treatment of COPD co-morbidities on COPD

Guidelines for complex chronic co-morbidities

REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND

ANGIOTENSIN RECEPTOR BLOCKERS IN COPDANGIOTENSIN RECEPTOR BLOCKERS IN COPD

The combination of statins and either ACE inhibitors or ARBs is associated with a reduction in COPD

hospitalization and total mortality not only in the high CV risk cohort but also in the low CV risk cohort

The combination also reduced myocardial infarction in the high CV risk cohort (RR 0.39, 95% CI 0.31 to 0.49)

Benefits were similar when steroid users were included

Mancini JB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60Mancini JB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60

In smokers and former smokers, statins are In smokers and former smokers, statins are associated with a slower decline in pulmonary associated with a slower decline in pulmonary function, independent of the underlying lung function, independent of the underlying lung

disease.disease.

Prospective, randomized trials are needed to Prospective, randomized trials are needed to study the effect of statins on lung functionstudy the effect of statins on lung function

Keddissi JI et al, Chest 2007;132(6):1764-71Keddissi JI et al, Chest 2007;132(6):1764-71

THE USE OF STATINS AND LUNG FUNCTION IN THE USE OF STATINS AND LUNG FUNCTION IN CURRENT AND FORMER SMOKERSCURRENT AND FORMER SMOKERS

STATINS REDUCE THE RISK OF LUNG CANCER STATINS REDUCE THE RISK OF LUNG CANCER IN HUMANS: A LARGE CASE-CONTROL STUDY IN HUMANS: A LARGE CASE-CONTROL STUDY

OF US VETERANSOF US VETERANS

KhuranaKhurana V et al, V et al, Chest, May 2007; 131: 1282 - 1288Chest, May 2007; 131: 1282 - 1288

Statins appear to be protective against Statins appear to be protective against the development of lung cancer, and the development of lung cancer, and

further studies need to be done to define further studies need to be done to define the clinical utility of statins as chemo the clinical utility of statins as chemo

protective agentsprotective agents

EFFECT OF VERY HIGH-INTENSITY STATIN THERAPYEFFECT OF VERY HIGH-INTENSITY STATIN THERAPYON REGRESSION OF CORONARY ATHEROSCLEROSISON REGRESSION OF CORONARY ATHEROSCLEROSIS

THE ASTEROID TRIALTHE ASTEROID TRIAL

Two year treatment with rosuvastatin 40 mg/d Two year treatment with rosuvastatin 40 mg/d reduced LDL-C to 60.8 mg/dL and increased HDL-C reduced LDL-C to 60.8 mg/dL and increased HDL-C by 14.7%, and resulted in significant regression of by 14.7%, and resulted in significant regression of

atherosclerosis.atherosclerosis.

Further studies are needed to determine the effect Further studies are needed to determine the effect of the observed changes on clinical outcomeof the observed changes on clinical outcome

Nissens ES et al, JAMA, April 5, 2006—Vol 295, No. 13Nissens ES et al, JAMA, April 5, 2006—Vol 295, No. 13

THE JUPITER TRIAL, A TRIAL OF STATIN AMONG THE JUPITER TRIAL, A TRIAL OF STATIN AMONG INDIVIDUALS WITH LOW LDL CHOLESTEROL AND INDIVIDUALS WITH LOW LDL CHOLESTEROL AND

ELEVATED hsCRPELEVATED hsCRP

Men 50 years or older, women 60 years or oldernormal LDL cholesterol (< 130mg/dL)

increased C-Reactive Protein (CRP)(> 2.0mg/L)

Investigate whether long-term treatment with rosuvastatin compared decreases cardiovascular events

Stopped early because of reduction in cardiovascular morbidity and mortality

Ridker PM et al Am J Cardiol 2007;100:1659 –1664Ridker PM et al Am J Cardiol 2007;100:1659 –1664

Unstable anginaor non–Q-wave

MI

Temporary resolution of instability

Future high-risk lesion

Acute MI

Pathophysiology of ACS: Disrupted Pathophysiology of ACS: Disrupted PlaquePlaque

Adapted from Yeghiazarians et al. Adapted from Yeghiazarians et al. N Engl J MedN Engl J Med. 2000;342:101-114.. 2000;342:101-114.

PlaquePlaquerupturerupture

Thin capThin cap

High High macrophagemacrophage

contentcontent

Large lipid coreLarge lipid core

Incomplete Incomplete coronarycoronaryocclusionocclusion

CompleteCompletecoronarycoronaryocclusionocclusion

Spontaneous lysis,Spontaneous lysis,repair, and wall remodelingrepair, and wall remodeling

Germinal center

Dark zone

1)Cytopatches = Collections of lymphocytes

2)Mature lymphoid follicles with germinal centers and dark zone .

3) No capsule

4)No Afferent lymphatics

M Cells

Courtesy of Prof. Jim Hogg

The Mucosal Immune System in the Airways

Percentage of airways containing positive ce lls in the ir lumen content

84 4 7

37

53

17

9 8

60

40

11

1823

61

43

12

2

23

66

0

20

40

60

80

100

120

CD4 cells CD8 cells B cells PMNs Macrophages

Inflam m atory cells

Air

wa

ys

wit

h M

ea

su

rab

le C

ell

s (

%)

GOLD stage 0 GOLD stage 1 GOLD stages 2 and 3 GOLD stage 4

Percent airways with cells in lumen content

Percentage of airways containing positive cells in their airway wall

63

85

7

67

54

8780

8

55

66

77

88

45

84

73

9498

37

10092

0

20

40

60

80

100

120

CD4 cells CD8 cells B cells PMNs Macrophages

Inflammatory Ce lls

Air

wa

ys

wit

h M

ea

su

rab

le C

ell

s

(%)

GOLD stage 0 GOLD stage 1 GOLD stages 2 and 3 GOLD stage 4

Percent airways with cells in their walls

Courtesy of Prof. Jim Hogg

Saetta et al. ERJ 1994

Centrilobularemphysema

Panlobularemphysema

Use of beta blockers and the risk of death in Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of hospitalised patients with acute exacerbations of

COPDCOPD

In-hospital mortality was 5.2%In-hospital mortality was 5.2%

Those receiving beta blockers (n = 142) were older and more Those receiving beta blockers (n = 142) were older and more frequently had cardiovascular disease than those who did notfrequently had cardiovascular disease than those who did not

Beta blocker use was associated with reduced mortality (OR = Beta blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99) 0.39; 95% CI 0.14 to 0.99)

The use of beta blockers by inpatients with exacerbations of The use of beta blockers by inpatients with exacerbations of COPD is well tolerated and may be associated with reduced COPD is well tolerated and may be associated with reduced

mortalitymortality

Dransfield MT, Thorax. 2008 Apr;63(4):301-5.Thorax. 2008 Apr;63(4):301-5.

THE IMPACT OF CARDIOSELECTIVE BETA-BLOCKERS THE IMPACT OF CARDIOSELECTIVE BETA-BLOCKERS ON MORTALITY IN PATIENTS WITH COPD AND ON MORTALITY IN PATIENTS WITH COPD AND

ATHEROSCLEROSISATHEROSCLEROSIS

Beta1-blockers may reduced mortality in COPD Beta1-blockers may reduced mortality in COPD patients undergoing vascular surgerypatients undergoing vascular surgery

In some patients with COPD selective beta1-In some patients with COPD selective beta1-blockers are safe and may reduce mortalityblockers are safe and may reduce mortality

COPD and systemic inflammation

Complex chronic co-morbidities

Effects of treatment of COPD on its co-morbidities

Effects of treatment of COPD co-morbidities on COPD

Guidelines for complex chronic co-morbidities

Clinical practice guidelines (CPGs) and quality of care for Clinical practice guidelines (CPGs) and quality of care for older patients with multiple comorbid diseases: older patients with multiple comorbid diseases:

implications for pay for performanceimplications for pay for performance

Boyd C et al, JAMA. 2005 Aug 10;294(6):716-24Boyd C et al, JAMA. 2005 Aug 10;294(6):716-24

This review suggests that adhering to current CPGs in caring This review suggests that adhering to current CPGs in caring for an older person with several comorbidities may have for an older person with several comorbidities may have

undesirable effectsundesirable effects

Basing standards on existing CPGs could lead to inappropriate Basing standards on existing CPGs could lead to inappropriate judgment of the care provided to older individuals with complex judgment of the care provided to older individuals with complex

comorbiditiescomorbidities

Developing measures of the quality of the care needed by older Developing measures of the quality of the care needed by older patients with complex comorbidities is critical to improving their patients with complex comorbidities is critical to improving their

carecare

Chronic Systemic Inflammatory Syndrome

(CSIS)

Age > 50 years

Smoking > 10 pack/years

Abnormal lung function

Ventricular dysfunction and/or ↑ BNP

Metabolic syndrome

↑ CRP

Fabbri and Rabe, The Lancet 1 September 2007

CSISCSISChronic Systemic Inflammatory Syndrome (CSIS)Chronic Systemic Inflammatory Syndrome (CSIS)

……OR…OR…

Center for Strategic and International Studies (CSIS)Center for Strategic and International Studies (CSIS)California School Information Services (CSIS)California School Information Services (CSIS)

Civil Service Insurance Society (CSIS)Civil Service Insurance Society (CSIS)Computer Science and Information Systems (CSIS) Computer Science and Information Systems (CSIS)

Canadian Society for Italian Studies Canadian Society for Italian Studies Canadian Society for Industrial Security Inc. (Csis, Inc.)Canadian Society for Industrial Security Inc. (Csis, Inc.)

Canadian Security Intelligence Service (CSIS) Canadian Security Intelligence Service (CSIS) CSIS - Center for Spatial Information Science (Tokyo)CSIS - Center for Spatial Information Science (Tokyo)

Commercial Sex Information Service (CSIS) Commercial Sex Information Service (CSIS) Citizens' Summit on the Information Society (CSIS)Citizens' Summit on the Information Society (CSIS)

COPD Guidelines: COPD Guidelines:

The important thing is not to stop questioningThe important thing is not to stop questioning

Once we accept our limits, we go beyond them. The important thing is not to stop questioning

The whole of science is nothing more than a refinement of everyday thinking

To raise new questions, new possibilities, to regard old problems from a new angle, requires creative imagination and marks real advance in science

Albert Einstein. Albert Einstein. Autobiographical notes. 1879-1955Autobiographical notes. 1879-1955

COPD and systemic inflammation

Complex chronic co-morbidities

Effects of treatment of COPD on its co-morbidities

Effects of treatment of COPD co-morbidities on COPD

Guidelines for complex chronic co-morbidities

Leonardo M. FabbriLeonardo M. Fabbri

fabbri.leonardo@unimo.itfabbri.leonardo@unimo.it

Türk Toraks Derneği11. Yillik Kongresi

Maritim Pine Beach Hotel

Belek-Antalya23-27 Nisan 2008

COPD and systemic

inflammation

http//pneumologia.unimo.ithttp//pneumologia.unimo.it