Download - Leonardo M. Fabbri [email protected]
Leonardo M. FabbriLeonardo M. Fabbri
[email protected]@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
[email protected]@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