BPCO: una sindrome infiammatoria sistemica cronica? · BPCO: una sindrome infiammatoria sistemica...

BPCO: una sindrome infiammatoria sistemica cronica?

Pierpaolo isidori

U.O. Medicina Interna e Pneumologia

Ospedale Fossombrone/Fano

Chronic obstructive pulmonary disease (COPD) is

characterised by poorly reversible airflow limitation that is

usually progressive and associated with an abnormal

inflammatory response of the lungs to noxious particles or

gases, particularly cigarette smoke

The chronic airflow obstruction is due to the presence of

specific abnormalities of both the airways (bronchitis and

bronchiolitis) and the pulmonary parenchyma (emphysema)

that were associated with an inflammatory reaction of the

airways, alveoli, and pulmonary vessels

Chronic obstructive pulmonary disease: molecular and cellular mechanisms

Barnes PJ, Shapiro SD, Pauwels RA. Eur Respir J 2003;22:672–688.

Fisiopatologia

INFIAMMAZIONE

RIDUZIONE DEL

FLUSSO AEREO

Patologia piccole vie aeree

Infiammazione bronchiale

Rimodellamento bronchiale

Distruzione parenchimale

Perdita attacchi alveolari

Riduzione tono elastico

Patologia: vie aeree centrali

• ipertrofia ghiandole bronchiali

e metaplasia globet cell con

eccessiva produzione di muco

• metaplasia squamosa dell’epitelio delle vie aeree, perdita

di cilia e disfunzione ciliare, aumentato spessore del

muscolo liscio e del tessuto connettivo

• nella parete delle vie aeree centrali sono presenti linfociti

(CD8+) ma col progredire della malattia predominano i

neutrofili; negli spazi aerei linfociti, neutrofili e macrofagi

• una bronchiolite è

presente in uno

stadio iniziale

• vi è estensione di globet cell

e metaplasia squamosa

• le cellule presenti nelle pareti e negli spazi aerei sono simili

a quelle delle vie aeree maggiori

• negli stadi avanzati vi è fibrosi e aumentata deposizione di

fibre collagene

Patologia:vie aeree periferiche

Patologia: parenchima polmonare

perdita di pareti alveolari, allargamento degli spazi alveolari

e ridotti attacchi alveolari che contribuiscono al collasso delle vie aeree

• centrolobulare: dilatazione e distruzione dei bronchioli

• panlobuilare: distruzione dell’intero acino

Patologia: vasi polmonari

• ispessimento della parete dei

vasi e alterazione dell’endotelio

• aumento di spessore del

muscolo liscio e infiltrato

Infiammatorio (macrofagi e

linfociti T CD8+)

• deposizione di collagene e

distruzione enfisematosa

del letto capillare

Inflammatory reaction in COPD

This abnormal inflammatory reaction can also be

detected in the systemic circulation.

It is likely that this systemic inflammation contributes

significantly to the pathobiology of numerous

extrapulmonary effects of the disease - the socalled

systemic effects of COPD

Given that COPD is associated with an abnormal

inflammatory response of the lung parenchyma to inhaled

pollutant and gases (mostly through cigarette smoking), the

most obvious explanation for the presence of systemic

inflammation in these patients was that, somehow, this

pulmonary inflammation was “spilling over” into the

systemic circulationAgustì A. Proc Am Thorax Soc 2007;4:552

BPCO patologia respiratoria

con implicazioni sistemiche

The most common comorbidities described in

association with COPD are skeletal muscle

abnormalities,hypertension, diabetes, coronary-

artery disease, heart failure, pulmonary infections,

cancer, and pulmonary vascular disease

Chronic comorbid diseases affect health outcomes

in COPD; in fact, patients with COPD mainly die of

non-respiratory disorders such as cardiovascular

diseases ( ca. 25%) or cancer (mainly lung cancer, 20–33%)

Agustì A. Proc Am Thorax Soc 2007;4:552

Increasing evidence suggests that clinical features of

COPD and airflow limitation are poorly correlated.

Patients with COPD have systemic manifestations that are not

reflected by the FEV1.

The BODE index, a simple multidimensional grading system,

including the body-mass index, FEV1 as a percentage of the

predicted value, score on the MMRC dyspnea scale, and the

distance walked in six minutes,is better than the FEV1 at

predicting the risk of death from any cause and from respiratory

causes among patients with COPD

The Body-Mass Index, Airflow Obstruction,Dyspnea, and Exercise Capacity Indexin COPD

BR Celli. NEJM 2004; 350:1005-12

BR Celli. NEJM 2004; 350:1005-12

COPD is associated with low-grade systemic inflammation

A recent meta-analysis confirmed that patients with

stable COPD present increased numbers of leukocytes

(some of them with an activated phenotype) and

Increased levels of acute phase response proteins (C-

reactive protein [CRP] and fibrinogen) and cytokines

(IL-6) and tumor necrosis factor (TNF)

The intensity of this systemic inflammation increases

during exacerbations of COPD

Gan WQ et al., Thorax 2004;59:574–580

Systemic Effects of COPD


COPD can no longer be judged a disease only of the lungs, as it is

often associated with a wide variety of systemic consequences

other chronic conditions, such as chronic heart failure, obesity,or diabetes, and even the normal process of aging, also appear to be associated with a similar low-grade systemic inflammatory process

add the term “chronic systemic inflammatory syndrome” to the diagnosis of COPD

stimulate discussion around the frequent complex chronic comorbidities in people with COPD and to provoke a new view of the disease in general

From COPD to chronic systemic inflammatory syndrome?

LM Fabbri, KF Rabe Lancet 2007; 370: 797–99

chronic refers to the slow and progressive

development of the abnormalities

systemic refers to the fact that risk factors act directly or indirectly on all target organs simultaneously

inflammatory refers to the association of all components with inflammation

syndrome refers to the association of several clinically

recognisable features, signs, symptoms, or characteristics

that generally arise together, so that the presence of one

feature alerts the doctor to the presence of the others

Chronic systemic inflammatory syndrome


Cigarette smoking is the major risk factor for COPD and is

one of the most important risk factors for all chronic

diseases and some cancers. It causes lung and systemic

inflammation, systemic oxidative stress, marked changes

of vasomotor and endothelial function

Systemic effects of smoking could contribute substantially

to the development not only of the airways and lung

abnormalities characteristic of COPD but also of chronic

diseases - eg, cardiovascular diseases, metabolic

disorders, and some cancers that are induced by smoking

in combination with or without other risk factors such as

obesity, hyperlipidaemia, and increased blood pressure

Comorbidities in COPD

Sevenoaks M, Stockley R. Respir Res 2006; 7: 70

The central role of inflammation in comorbidity is associated with COPD

LM Fabbri et al Eur Respir J 2008; 31: 204–212

Diagnostic components of chronic systemic inflammatory syndrome

Age older than 40 years

Smoking for more than 10 pack-years

Symptoms and abnormal lung function compatible

with COPD

Chronic heart failure

Metabolic syndrome

Increased C-reactive protein

At least three components are needed for

diagnosis


Diagnostic components of chronic systemic inflammatory syndrome

COPD, chronic heart failure, and metabolic syndrome are

diagnosed according to current international guidelines

after comprehensive assessment of lung, cardiac, and

metabolic functions

Other chronic disorders, such as coronary and peripheral

artery diseases, anaemia, osteoporosis, and rheumatoid

arthritis, could be included either as additional

comorbidities, as complications (eg, steroid-induced

osteoporosis), or as independent modifiers of severity of

the chronic syndrome (eg,depression)


SYSTEMIC INFLAMMATION INCHRONIC OBSTRUCTIVE PULMONARY DISEASE:FACTS AND UNKNOWNS

Facts Low-grade systemic inflammation occurs in patients with

clinically stable COPD (and in many other chronic diseases,

including the physiologic process of aging)

In COPD, systemic inflammation persists after quitting smoking and increases during exacerbations of the disease

Steroid therapy (both inhaled and oral) decreases systemic

inflammatory markers in patients with stable COPD

The origin of systemic inflammation in COPD is likely to be

multifactorial. The identification of the different factors

potentially contributing to it and their relative importance

needs to be established.


Unknowns

Why systemic (and pulmonary) inflammation persists after quitting smoking is a key question that is so far unanswered.

It is likely (but currently unproven) that systemic inflammation contributes to the pathophysiology of many systemic effects of COPD, including skeletal muscle dysfunction, cardiovascular disease, and osteoporosis.

The impact on relevant clinical outcomes, such as mortality or health status, of a pharmacologically induced reduction of systemic inflammation in COPD is unproven.


SYSTEMIC INFLAMMATION INCHRONIC OBSTRUCTIVE PULMONARY DISEASE:FACTS AND UNKNOWNS

Pharmacological treatment

Cardiovascular drugs have already been reported to have

beneficial effects in COPD. Statins, which are used

mainly as lipid-lowering agents for treatment of metabolic

syndrome, have potent anti-inflammatory properties that

positively affect COPD, chronic heart failure, and vascular

diseases (1)

Similarly, drugs developed and used to treat

respiratory diseases (eg, inhaled bronchodilators and

steroids) could have substantial beneficial effects for

cardiovascular diseases (2)

1) Calverley PM et al. N Engl J Med 2007; 356: 775–89

2) Sin DD, Man SF. Curr Opin Pulm Med 2007;13: 90–97

Effect of simvastatin

on cigarette smoke-induced

emphysema in rats

Control Smoke

Smoke+statin Statin

Lee JH et al: AJRCCM 2005

↓ Inflammatory cells

↓ MMP-9

↓ eNOS

↓ Pulmonary vascular

remodelling

STATIN IN COPD

Journal of the American College of Cardiology

2006;47:2554-60.

Sin and coworkers showed that, first, the withdrawal of inhaled corticosteroids in patients with COPD increased the plasma levels of CRP, a well-established marker of systemic inflammation,by about 30%. Second, they showed that 2 weeks of treatment with inhaled fluticasone (or oral prednisolone) reduced them by about 50%

A retrospective study has suggested that the risk of acute myocardial infarction in patients with COPD was reduced by 32% in those receiving low doses of inhaled steroids


Sin DD et al, Am J Respir Crit Care Med 2004;170:760–765

Huiart L et al, Eur Respir J 2005;25:634–639

CONCLUSIONI

COPD is a multicomponent disease characterized by pulmonary

and systemic inflammation.

The origin of the latter is unclear and probably multifactorial.

It is likely to be a major contributor to the pathobiology of many

(if not all) of the extrapulmonary effects of COPD, including

skeletal muscle atrophy and dysfunction and cardiovascular

disease.

Available evidence suggests that systemic inflammation in COPD

can be reduced by steroid therapy (both oral and inhaled). The

potential effects of this observation on clinically relevant

outcomes in these patients (e.g., mortality, health status) remain

to be demonstrated, but open a new avenue to improve the

therapy and care of patients with this devastating disease.

Cigarette smoke

(and other irritants)

PROTEASESNeutrophil elastase

Cathepsins

Matrix metalloproteinases

Alveolar wall destruction(Emphysema)

Mucus hypersecretion(Chronic bronchitis)

Fibrosis

(Sm airways)

Fibroblast

TGF-β

CTG

Neutrophil

Chemotactic factors

CD8+

lymphocyte

Monocyte

Alveolar macrophageEpithelial

cells

INFLAMMATORY MECHANISMS IN COPD

Domande ancora senza una

risposta………

• Potrebbe il trattamento anti-infiammatorio polmonare ridurre il

rischio di eventi cardiaci acuti?


rischio di progressione dell’aterosclerosi?


rischio di eventi trombotici?

• Il trattamento della malattia cardiaca può influenzare la

progressione della malattia polmonare?

Lo pneumologo nell’ambito di questo scenario ha senza dubbio

competenze, sensibilità e cultura per contribuire in modo concreto e

pratico alla ricerca in questo campo

Systemic effects of Chronic obstructive

pulmonary disease Weight loss, nutritional abnormalities, and

skeletal muscle dysfunction are well-recognized systemic effects of COPD. Otherless well known but potentially important systemic effects include an increased risk of cardiovascular disease and several neurologic and skeletal defects.

The mechanisms underlying these systemic effects are unclear, but they are probably interrelated and multifactorial, including inactivity, systemic inflammation, tissue hypoxia and oxidative stress among others.


Chronic medical conditions COPD is associated with chronic heart failure in more than

20% of

patients and with osteoporosis in up to 70% of patients, in

part,

independently from treatment with steroids, decreased

physical activity, or both. (Rutten FH et al. Eur J Heart Fail 2006; 8: 706–

11.)

In a small study, almost 50% of patients with COPD had

one or more components of the metabolic syndrome (Marquis

K et al. J Cardiopulm Rehabil 2005; 25: 226–32).

Conversely, chronic heart failure is associated, in more

than 50% of patients, with arterial hypertension and

coronary or peripheral artery diseases, with diabetes

in 20–30%, and with anaemia in 20–30%. (Dahlstrom U.. Eur J

Heart Fail 2005; 7: 309–16.)

Type 2 diabetes is linked to hypertension in more than

70% of individuals and to cardiovascular diseases and

obesity in more than 80% (Walker CG et al. Clin Sci (Lond) 2007; 112: 93–111.)

Diabetes is independently associated with reduced lung

function, which together with obesity could further worsen

the severity of COPD (Poulain M et al. CMAJ 2006; 174: 1293–99).

Chronic medical conditions

COPD and cardiovascular disease


The major risk factor for the development of COPD is cigarette smoking. Smoking is also a major risk factor for a large number of other illnesses, including cardiovascular disease. As a result of sharing common risk factors, patients with COPD are at further increased risk to suffer these comorbidities.

Among patients with COPD, comorbidities are extremely common for a number of reasons.

COPD is a disease that increases in importance with age. Because most chronic disorders of adults also increase with age, statistically, comorbidities will be relatively common among patients with severe COPD.

Almost half of all people aged 65 years or

older have at

least three chronic medical conditions, and a

fifth have

five or more

Boyd CM et al.JAMA 2005; 294: 716–24

Chronic medical conditions

Pharmacological treatment Since pharmacological treatment of chronic

diseases—particularly COPD—is mainly symptomatic, a more comprehensive approach to management of COPD and its comorbidities might provide an opportunity to modify the natural history ofCOPD, allowing for identification of novel targets for treatment.

This idea is especially relevant for disorders that seem to be more preventable and treatable than COPD, such as cardiovascular and metabolic disorders.

van der Harst P et al. Cardiovasc Res 2006; 3: e333.

Mancini GB, et al. J Am Coll Cardiol 2006; 47: 2554–60.

Sfortunatamente esiste una mancanza di specifiche

raccomandazioni per il management dei pazienti con

BPCO e concomitante malattia cardiaca.

Le più recenti linee guida (Global Initiative for Chronic

Obstructive Lung Disease(GOLD) ed dell’ American

Thoracic Society/European Respiratory Society)

sebbene riconoscano che la malattia cardiaca è

spesso presente come comorbilità della BPCO, non

forniscono specifiche e dettagliate raccomandazioni di

come nella pratica clinica questi pazienti devono

essere valutati e trattati.


La BPCO non è descritta nelle linee guida dell’OBESITA’ e dell’IPERTENSIONE e non è inclusa nella lista dei fattori di rischio cardiaco delle linee guida delle malattie cardiovascolari.

In assoluto esiste una mancanza di raccomandazioni che guidano il clinico nella cura specifica dei pazienti con BPCO che sono affetti da obesità, ipercolesterolemia, ipertensione arteriosa, o altri fattori di rischio.


Main COPD comorbidities recently reported

G. Viegi et al, Eur Respir J 2007; 30: 993–1013

LiverIL-6, TNF-α, IL-1βIL-6

CRP

Cardiovascular disease Muscle wasting

Skeletal muscle

Other

Inflammatory

diseases

Circulation

SYSTEMIC EFFECTS OF COPD

Systemic effects

of smoking

Side effects ++

Potentially, the common mechanism by which major risk factors such as smoking, hyperlipidaemia, obesity, and hypertension lead to chronic disease is systemic inflammation.

C-reactive protein is almost invariably

increased in all components of the chronic systemic inflammatory syndrome, suggesting that this acute-phase protein could represent the sentinel biomarker to all chronic diseases.


MacNee W.. Proc Am Thorac Soc 2005;2: 50–60.

Comorbidities are common among patients with COPD for several reasons. One is purely statistical: middle-aged and elderly patients are most often afflicted with COPD, and comorbidities become more common as age increases. Also, although smoking is linked to COPD, it is also a major risk factor for numerous other illnesses, including cardiovascular disease. However, epidemiologists evaluating the risk of heart disease have consistently shown an increased risk among patients with COPD, even when the data are ―corrected‖ for smoking. Additionally, oxidative stress and systemic inflammation are mechanically linked to the extrapulmonary manifestations in COPD


(Man, 2005)

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