Broncopneumopatia cronica ostruttiva (BPCO). COPD n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology

Broncopneumopatia cronica ostruttiva (BPCO)

COPDCOPD

Definition, Classification

Burden of COPD Risk Factors Pathogenesis,

Pathology, Pathophysiology

Practical Considerations





COPD

unremitting asthma

chronic bronchitis

emphysema

COPD: old definition

.…airflow obstruction due to emphysema and chronic

bronchitis

Definition of COPD

COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients.

Its pulmonary component is characterized by airflow limitation that is not fully reversible.

The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.

Venn diagram illustrating the overlap between asthma and COPD

Asthma?Chronic

bronchitis

Emphysema

Chronicbronchiolitis

reversible

irreversible

COPD

Jeffery, AJRCCM 2001

• Tosse e catarro cronici possono precedere lo sviluppo di BPCO di molti anni

• Per converso, alcuni pazienti sviluppano una significativa ostruzione al flusso in assenza di sintomi respiratori cronici.

Storia naturale della malattia

COPD is a multicomponent disease

InflammationAirway

obstructionStructuralchanges

Airflow limitation

Muco-ciliarydysfunction

Cazzola and Dahl, Chest 2004

Classification of COPD Severity

by SpirometryStage I: Mild FEV1/FVC < 0.70

FEV1 > 80% predicted

Stage II: Moderate FEV1/FVC < 0.70 50% < FEV1 < 80% predicted

Stage III: Severe FEV1/FVC < 0.70 30% < FEV1 < 50% predicted

Stage IV: Very Severe FEV1/FVC < 0.70 FEV1 < 30% predicted or

FEV1 < 50% predicted plus chronic respiratory

failure

Comparison of ATS 1995 and ATS/ERS 2004 disease staging

systems

“At Risk” for COPD

COPD includes four stages of severity classified by spirometry.

A fifth category--Stage 0: At Risk--that appeared in the 2001 report is no longer included as a stage of COPD, as there is incomplete evidence that the individuals who meet the definition of “At Risk” (chronic cough and sputum production, normal spirometry) necessarily progress on to Stage I: Mild COPD.

The public health message is that chronic cough and sputum are not normal remains important - their presence should trigger a search for underlying cause(s).

Global Strategy for Diagnosis, Management and Prevention of COPD









Burden of COPD: Key Points• COPD is a leading cause of morbidity and mortality

worldwide and results in an economic and social burden that is both substantial and increasing

• COPD prevalence, morbidity, and mortality vary across countries and across different groups within countries

• The burden of COPD is projected to increase in the coming decades due to continued exposure to COPD risk factors and the changing age structure of the world’s population

Burden of COPD: Prevalence

• Many sources of variation can affect estimates of COPD prevalence, including e.g., sampling methods, response rates and quality of spirometry.

• Data are emerging to provide evidence that prevalence of Stage I: Mild COPD and higher is appreciably higher in:

- smokers and ex-smokers - people over 40 years of age- males

COPD Prevalence Study in Latin America

The prevalence of post-bronchodilator FEV1/FVC < 0.70 increases steeply with age in 5 Latin American Cities

Source: Menezes AM et al. Lancet 2005

45

50

55

60

65

70

75

80

85

90

95

70 75 80 85 90 95 100

Age

FE

V1/F

VC

%

male

female

Regression both sexes

5th and 95th Percentile

FEV1/FVC% in asymptomatic, elderly never-smokers

Hardie J, ERJ 2002

Burden of COPD: Mortality

COPD is a leading cause of mortality worldwide and projected to increase in the next several decades.

COPD mortality trends generally track several decades behind smoking trends.

In the US and Canada, COPD mortality for both men and women have been increasing.

In the US in 2000, the number of COPD deaths was greater among women than men.

Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998

Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

Proportion of 1965 Rate Proportion of 1965 Rate

1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998

–59%–59% –64%–64% –35%–35% +163%+163% –7%–7%

CoronaryHeart

Disease

CoronaryHeart

Disease

StrokeStroke Other CVDOther CVD COPDCOPD All OtherCauses

All OtherCauses

Source: NHLBI/NIH/DHHSSource: NHLBI/NIH/DHHS

Of the six leading causes of death in the United States, only COPD has been increasing steadily since 1970

Source: Jemal A. et al. JAMA 2005

COPD Mortality by Gender,U.S., 1980-2000

0

10

20

30

40

50

60

70

1980 1985 1990 1995 2000

Men

Women

Num

ber

Death

s x

100

0N

um

ber

Death

s x

100

0

Source: US Centers for Disease Control and Prevention, 2002

Morbidità

• La morbidità è prevista in notevole aumento nel mondo con uno spostamento dal 12 ° al 6° posto.

• In termini di ricoveri ospedalieri in Italia i casi di BPCO risultano al 7° posto (fonte ISTAT 2003).

Bronchite cronica ostruttiva,con riacutizzazione icd9cm 491.21

Ricoveri in Regime Ordinario(FONTE SDO – MINISTERO DELLA SALUTE)

% sul totale dei ricoveri

2000 48.685 0.49%

2001 77.264 0.78%

2002 88.083 0.91%

2003 94.829 1.03%

* Dati che, pur sottostimati a causa dei limiti di codifica,evidenziano un trend in netto aumento dei ricoveri

Prevalenza

• La BPCO è un problema non trascurabile fin dall’età giovanile.

• Studi epidemiologici hanno evidenziato che, nei soggetti tra 20 e 44 anni, il 10% presenta

tosse ed espettorato senza segni di ostruzione bronchiale ed il 3.6% sintomi di ostruzione

bronchiale (Stadi I - III).

de Marco at al Thorax 2004; 59:120-125











Risk Factors for COPD

Lung growth and development

Oxidative stress

Gender

Age

Respiratory infections

Socioeconomic status

Nutrition

Comorbidities

Genes

Exposure to particles

●Tobacco smoke

●Occupational dusts, organic and inorganic

●Indoor air pollution from heating and cooking with biomass in poorly ventilated dwellings

●Outdoor air pollution

Fletcher C & Peto R. BMJ 1977;1:1645-8

FE

V1

(% p

red

icte

d a

t ag

e 2

5 y

ea

rs)

Age (years)25 50 75

0

25

50

75

100 Never smoked or notsusceptible to smoke

Susceptiblesmoker

Disability

Death

predicted declineif patient stops smoking

COPD: Natural COPD: Natural HistoryHistory


Totale Maschi Femmine

FUMATORI 12,2 milioni circa 6,9 milioni circa 5,3 milioni circa (24,3%) (28,6%) (20,3%)

EX-FUMATORI 9 milioni circa 5,8 milioni circa 3,3 milioni circa (18,1%) (24%) = (11,2%)

NON FUMATORI 29 milioni circa 11,4 milioni circa 17,5 milioni circa (57,6%) (47,4%) (67,1%)

OSSFAD, Istituto Superiore di Sanità – Indagine DOXA 2006

Gli italiani secondo l’abitudine del fumo (stima su dati Doxa 2006)

• Circa il 30% dei fumatori (> 10 pack-year) oltre i 40 anni presenta una limitazione al flusso aereo.

• Circa il 40-50% dei fumatori sviluppa BPCO.

Fletcher C, Peto R. BMJ 1977; 1: 1645Jyrki-Tapani K, et al.COPD 2005; 2:331Lokke A, et al. Thorax 2006; 61:935Shahab L, et al. Thorax 2006; 61:1043Pelkonen M, et al. Chest 2006; 130:1129Rennard SI, et al. Lancet 2006; 367:1216

Fumo di sigaretta

Fumo passivo

• Anche l`esposizione al fumo passivo

può contribuire all`insorgenza di sintomi

respiratori e della malattia, aumentandoil carico globale di particelle e gas inalati.

de Marco at al Thorax 2004; 59:120-125

Association Studies for Assessment Association Studies for Assessment of Genetics in COPD (1987-2004)of Genetics in COPD (1987-2004)

• alphaalpha11-antitrypsin-antitrypsin• alpha1-antichymotrypsinalpha1-antichymotrypsin• MMPsMMPs• TIMP-2TIMP-2• CFTRCFTR• TNF /TNFRTNF /TNFR• Vit D binding proteinVit D binding protein• Microsomial epoxide hydrolaseMicrosomial epoxide hydrolase• Heme-oxygenase-1Heme-oxygenase-1• GSH S-transferase (M1,T1,P)GSH S-transferase (M1,T1,P)• IL-1IL-1 / IL-1RN / IL-1RN• beta2-adrenoceptorbeta2-adrenoceptor• Cytochrome P450Cytochrome P450

• Association in a given ethnic Association in a given ethnic groupgroup

• Incosistent results when repeated Incosistent results when repeated in different populations of the in different populations of the same ethnic group or tested in same ethnic group or tested in multiple ethnic groupsmultiple ethnic groups

• Negative resultsNegative results

Why case-control association studies for the genetics of COPD have been so far poorly

informative ? Silverman & Palmer AJRCMB 2000;22:645

Issue Key questions Possible solutions

Selection of gene Biologically ? Demonstration

Positionally ? Linkage – Animal

Group stratification Matched ? Ethnicity

Family-based ass.

Unlinked markers

Hardy-Weinberg e. Control in H-W e.? Calculation

Multi.comparisons How many alleles? Bonferroni

How many loci ? Empirical p value

Or is it a matter of a poor definition of the phenotype ?

COPDCOPD

Extreme Phenotypes Can Be Determined in the Minority of COPD

subjects

Emphysema and cigarette smoking

Inquinamento outdoor

• Ogni incremento di 10 µg/m3 di particelle fini è associato a circa il 4% di aumento del rischio di mortalità per qualsiasi causa, il 6% per cause cardiopolmonari, l’8% per cancro al polmone

Pope CA 3 rd, Burnett RT, Thum MJ, Calle EE, et all. Lung cancer, cardiopulmonary mortality, and tong –term exposure to fine particulate air pollution. JAMA 2002;287:1132-41

Inquinamento indoor

Nei Paesi a basso livello di sviluppo economico, l’utilizzo di combustibili biologici

in ambienti con scarsa ventilazione

è un fattore causale di BPCO

Warwick H, et al. ITDG Publishing, 2004: 103; http://www.idgpublishing.org.uk; Ezzati M. Lancet 2005; 336: 104; Oroczo-Levi M, et al. Eur Respir J 2006; 27: 542

http://www.idgpublishing.org.uk/

Basso livello di stato socioeconomico

• E’ dimostrata una relazione significativa tra basso livello di istruzione ed aumento della mortalità per BPCO, indipendentemente dall’abitudine al fumo

Prescott E, Godtfredsen N, VestboJ, Osler M. Social position and mortality from respiratory diseases in males and females. Eur Respir j 2003;21:821-6

Risk Factors for COPD

NutritionNutrition

InfectionsInfections

Socio-economic Socio-economic statusstatus

Aging PopulationsAging Populations

Probabilità di contrarre la malattia nei 10 anni successivi all’età del soggetto, in funzione dei fattori di rischio (ISS, 2004)





















LUNG INFLAMMATIONLUNG INFLAMMATION

COPD PATHOLOGYCOPD PATHOLOGY

OxidativeOxidativestressstress ProteinasesProteinases

Repair Repair mechanismsmechanisms

Anti-proteinasesAnti-proteinasesAnti-oxidantsAnti-oxidants

Host factorsAmplifying mechanisms

Cigarette smokeCigarette smokeBiomass particlesBiomass particles

ParticulatesParticulates

Source: Peter J. Barnes, MD

Pathogenesis of COPD

Anti-proteases

SLPI 1-AT

Proteolysis

OO22--, H, H220022

OHOH.., ONOO, ONOO--

Mucus secretion

Plasma leak Bronchoconstriction

NF-NF-BB

IL-8IL-8

NeutrophilNeutrophilrecruitmentrecruitment

TNF-TNF-

IsoprostanesIsoprostanes

↓ ↓ HDAC2HDAC2

↑↑InflammationInflammationSteroidSteroid

resistanceresistance

Macrophage NeutrophilOxidative Stress in COPD


Fixed effect meta-analysis results of selected biochemical variables

Franciosi et al, Pulm Pharmacol Ther 2006;19:189-199

Mucus gland hyperplasia

Goblet cellhyperplasia

Mucus hypersecretion Neutrophils in sputum

Squamous metaplasia of epithelium

↑ Macrophages

No basement membrane thickening

Little increase in airway smooth muscle

↑ CD8+ lymphocytes

Changes in Large Airways of COPD Patients

Changes in Large Airways of COPD Patients


Ranked sputum neutrophil data demonstrating overlap of the ATS’ FEV1-based

disease stages

Franciosi et al, Pulm Pharmacol Ther 2006;19:189-199

Disrupted alveolar attachments

Inflammatory exudate in lumen

Peribronchial fibrosisLymphoid follicle

Thickened wall with inflammatory cells- macrophages, CD8+ cells, fibroblasts

Changes in Small Airways in COPD Patients


Alveolar wall destruction

Loss of elasticity

Destruction of pulmonarycapillary bed

↑ Inflammatory cells macrophages, CD8+ lymphocytes


Changes in Lung Parenchyma in COPD

NormalNormalInspiration

Expiration

alveolar attachments

Mild/moderateMild/moderateCOPD COPD

loss of elasticity

Severe Severe COPD COPD

loss of alveolar attachments

closure

small small airwayairway

Dyspnea↓ Exercise capacity

Air trappingAir trappingHyperinflationHyperinflation

↓ ↓ HealthHealthstatusstatus

Air Trapping in COPD


COPD: Small AirwayAbnormalities

Normal COPD

COPD: Pulmonary COPD: Pulmonary EmphysemaEmphysema

Comparison of centrilobular and Comparison of centrilobular and panacinar emphysemapanacinar emphysema

Endothelial dysfunction

Intimal hyperplasia

Smooth muscle hyperplasia

↑ Inflammatory cells (macrophages, CD8+ lymphocytes)

Changes in Pulmonary Arteries in COPD Patients


COPD: Pulmonary Vascular Changes

Normal COPD

COPD: Structure & Function

Alveolar Wall DestructionAir Spaces Enlargement

Alveolar AttachmentsLoss

HIGH VA/Q RATIOS

Capillary Network Reduction

Small AirwaysNarrowing-Distortion

Nonhomogeneous Inspired Air Distribution

LOW VA/Q RATIOS

Reduced Ventilation In Dependent Alveoli

AIR TRAPPING-LUNG HYPERINFLATION

Rodríguez-Roisin and MacNee. ERM 1998;7:103-6

AIRFLOW OBSTRUCTION

AIR TRAPPING

LUNG HYPERINFLATION

AIRFLOWOBSTRUCTION

Chronic hypoxiaChronic hypoxia

Pulmonary vasoconstrictionPulmonary vasoconstriction

MuscularizationMuscularization

Intimal Intimal hyperplasiahyperplasia

FibrosisFibrosis

ObliterationObliteration

Pulmonary hypertensionPulmonary hypertension

Cor pulmonaleCor pulmonale

Death

EdemaEdema

Pulmonary Hypertension in COPD


Assess for COPD:A Common Story

• Cough– intermittent or daily– present throughout day- seldom only nocturnal

• Sputum– Any pattern of chronic sputum production

• Dyspnea – Progressive and Persistent– "increased effort to breathe" "heaviness" "air hunger" or

"gasping" – Worse on exercise – Worse during respiratory infections

• Exposure to risk factors– Tobacco smoke – Occupational dusts and chemicals – Smoke from home cooking and heating fuels

59

Assess and Monitor COPD: Key PointsA clinical diagnosis of COPD should be

considered in any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease.

The diagnosis should be confirmed by spirometry. A post-bronchodilator FEV1/FVC < 0.70 confirms the presence of airflow limitation that is not fully reversible.

Comorbidities are common in COPD and should be actively identified.

60

Assess and Monitor COPD: Spirometry

Spirometry should be performed after the administration of an adequate dose of a short-

acting inhaled bronchodilator to minimize variability.

A post-bronchodilator FEV1/FVC < 0.70 confirms the presence of airflow limitation that is not fully reversible.

Where possible, values should be compared to age-related normal values to avoid overdiagnosis of COPD in the elderly.

SYMPTOMScoughcough

sputumsputumshortness of breathshortness of breath

EXPOSURE TO RISKFACTORS

tobaccotobaccooccupationoccupation

indoor/outdoor pollutionindoor/outdoor pollution

SPIROMETRYSPIROMETRY

Diagnosis of COPDDiagnosis of COPD

Spirometry: Normal and Patients with COPD

Age (years)

25 50 750

25

50

75

100


Dyspnea

Exercise Intolerance

Exacerbations

Hospitalizations

FE

V1

(% p

red

icte

d a

t ag

e 2

5 y

ea

rs)

Systemic Effects Respiratory Failure

Pulm Hypertension

Assess: Physical Examination

• Rarely diagnostic in COPD

• Physical signs of airflow limitation– rarely present until significant impairment of

lung function – low sensitivity and specificity

Assess: Additional Investigations > Stage II: Moderate COPD

• Bronchodilator reversibility testing– rule out asthma– establish best attainable lung function– gauge a patient's prognosis – guide treatment decisions

• Chest x-ray– seldom diagnostic unless obvious bullous disease– valuable in excluding alternative diagnoses– CT not routinely recommended

Hyperinflated Lungs : COPD

Apical bronchus of upper lobe

Luminal area Wall thickness

Computed Tomographic Measurements of Airways Dimensions

and Emphysema in Smokers

Assess: Additional Investigations > Stage II: Moderate COPD

• Arterial blood gas measurement– In advanced COPD: FEV1 <40% predicted or with

clinical signs suggestive of respiratory failure or right heart failure

– central cyanosis, ankle swelling, JVD – Respiratory failure

• PaO2 < 60 mm Hg +/- PaCO2 >50 mm Hg at sea level

• Alpha-1 antitrypsin deficiency screening– COPD at a young age– strong family history of the disease

Relationship between lung function and symptoms

Patients with poor lung function tend to have worse dyspnoea than those with less severe disease

Relationship between symptoms and health status

Health status encompasses respiratory symptoms as well as their impact on ability to function and on mood.

Relationship between Relationship between lung function and health statuslung function and health status

Patients with severely impaired lung function show worse health status than those with more mild disease.

Relationship between lung function and mortality

The risk of dying from COPD is higher in patients with poor lung function than in those with more mild disease.

Relationship between health status and mortality

Poor health status is associated with increased risk of death from COPD and small improvements may be associated with important differences in prognosis.

AIRFLOWLIMITATION

AirwayObstruction

StructuralChanges

MucociliaryDysfunction

Polivalent Nature of COPD

J COPD 2005;2:253-62

SystemicEffects

COPD and Co-MorbiditiesCOPD and Co-Morbidities

COPD patients are at increased risk for: • Myocardial infarction, angina• Osteoporosis• Respiratory infection• Depression• Diabetes• Lung cancer

COPD patients are at increased risk for: • Myocardial infarction, angina• Osteoporosis• Respiratory infection• Depression• Diabetes• Lung cancer

LiverLiverIL-6, TNF-IL-6, TNF-αα, IL-1, IL-1ββIL-6IL-6

CRPCRP

Cardiovascular diseaseCardiovascular disease Muscle wastingMuscle wasting

Skeletal Skeletal musclemuscle

OtherOtherInflammatory Inflammatory diseasesdiseases

CirculationCirculation

SYSTEMIC EFFECTS OF COPDSYSTEMIC EFFECTS OF COPD

COPD and Co-MorbiditiesCOPD and Co-Morbidities

COPD has significant extrapulmonary

(systemic) effects including:

• Weight loss

• Nutritional abnormalities

• Skeletal muscle dysfunction

COPD has significant extrapulmonary

(systemic) effects including:

• Weight loss

• Nutritional abnormalities

• Skeletal muscle dysfunction

Respiratory system

Target organs

Systemic inflammation

?

Insufficienza cardiaca cronicaCoronaropatia e Infarto miocardico

Vasculopatia periferica Embolia polmonare

Aritmie

Neoplasia polmonare

Sindrome metabolicaDiabete mellito

Osteoporosi

Depressione

Principali comorbidità

Effetti sistemici della BPCO

Infiammazione sistemica (aumento di PCR, IL-6, IL-8,TNF-α; cellule infiammatorie circolanti; stress ossidativo sistemico)

Alterazioni nutrizionali e cachessia (aumento del dispendio energetico

e del catabolismo, alterata composizione del corpo)

Alterazioni muscolo-scheletriche (perdita di massa muscolare; alterazioni della struttura e funzione, ridotta tolleranza allo sforzo)

Aspetti cardiovascolari (malattia aterosclerotica)

Alterazioni del metabolismo osseo (osteopenia, osteoporosi)

Alterazioni ematologiche (anemia normocitica, normocromica)

Relazione fra prognosi e comorbidità (BPCO - Malattie cardiovascolari)

• Le comorbidità hanno un importante effetto sulla prognosi del paziente con BPCO.• La coesistenza delle due malattie è condizione di peggioramento della prognosi.

• L'insufficienza respiratoria progressiva spiega solo un terzo circa

della mortalità legata alla BPCO; quindi fattori diversi dalla progressione

della malattia polmonare devono avere un ruolo di rilievo.

• I decessi dei pazienti con BPCO avvengono prevalentemente

a causa delle comorbidità piuttosto che per la BPCO.

• Nei pazienti affetti da BPCO il 40-50% dei casi di morte è imputabile

a cause cardiovascolari.

• Circa 1/3 dei pazienti affetti da cardiopatie è affetto anche da BPCO

che ne aumenta il rischio di morte.

• La riduzione del VEMS è un fattore di rischio di mortalità per tutte le cause.

Comorbidità: prospettive future

• Nel programmare la gestione del paziente è indispensabile tener conto di possibili condizioni morbose concomitanti, molto comuni nei pazienti di età >65 anni.

• Non è noto se l’applicazione contemporanea

di linee guida rivolte a differenti patologie interferisca con il raggiungimento degli obiettivi terapeutici di ciascuna condizione.

• In futuro la formulazione e l’implementazione di specifiche linee guida dovrà avvalersi di un contributo multidisciplinare comprendente in particolare il medico di medicina generale.

Translating COPD Guidelines into Primary Care

KEY POINTS

Spirometric confirmation is a key component of the diagnosis of COPD and primary care practitioners should have access to high quality spirometry.

Older patients frequently have multiple chronic health conditions. Comorbidities can magnify the impact of COPD on a patient’s health status, and can complicate the management of COPD.

Consider:Lung Disease –(other than airways disorders)Pulmonary embolismPleural effusionsLobar collapseDiaphragm weakness(Guillain Barre)

• Heart Disease –Myocardial infarctionCardiac rhythm disturbanceDissecting aneurysmLeft ventricular failure

• Systemic Disease –Blood loss/anaemia

• Foreign Body Aspiration

Patient presents with cough, wheeze,chest tightness or breathlessness

SUDDEN / RECENT Consider:Lung Disease -(other than airways disorders)Infiltration (Malignancy, Sarcoidosis)Fibrosing/allergic alveolitisEosinophilic pneumoniaDiaphragm Weakness(Motor Neurone Disease)Chest wall deformityAsbestosis

•Heart Disease -Chronic heart failure, valve disease,cardiomyopathy

•Systemic Disorders -Anaemia, obesity, hyperthyroidism

CHRONIC

Consider: Blood Tests or Chest X-Ray or ECG

www.theipcrg.org/guidelines/index.php

ERS Sep 2006 www.consultmarklevy.com

COPD: Making a diagnosis - Spirometry

YYYYYY

Mast cellMast cell

CD4+ cellCD4+ cell(Th2)(Th2)

EosinophilEosinophil

AllergensAllergens

Ep cellsEp cells

ASTHMAASTHMA

BronchoconstrictionBronchoconstrictionAHRAHR

Alv macrophageAlv macrophage Ep cellsEp cells

CD8+ cellCD8+ cell(Tc1)(Tc1)

NeutrophilNeutrophil

Cigarette smokeCigarette smoke

Small airway narrowingSmall airway narrowingAlveolar destructionAlveolar destruction

COPDCOPD

Reversible IrreversibleAirflow LimitationAirflow Limitation


Overlap between COPD and asthma

COPD ASTHMA–Neutrophils–No airway hyperreactivity–No bronchodilator response–No corticosteroid response

–Eosinophils–Airway

hyperreactivity–Bronchodilator

response–Corticosteroid

response

“Wheezy bronchitis”

~10%

Barnes, Chest 2000

Modifiche patologiche nelle vie aeree di pazienti con BPCO e asma

Modifiche patologiche nelle vie aeree di pazienti con BPCO e asma

eosinofili

membranabasale

Fabbri et al, AJRCCM 2003

Bronchite eosinofilica Bronchite eosinofilica

Una percentuale di pazienti con BPCO mostra un certo grado di eosinofilia nell’espettorato.

E’ possibile che la presenza di eosinofili nelle vie aeree sia correlata all’intensità del processo infiammatorio nella BPCO, che porta ad un reclutamento non specifico di queste cellule e alla loro attivazione.

Il maggiore impatto sul FEV1 avviene nei casi in cui sia la neutrofilia sia l’eosinofilia nell’espettorato sono più intense, con una relazione diretta fra i numeri di neutrofili ed eosinofili.

Una percentuale di pazienti con BPCO mostra un certo grado di eosinofilia nell’espettorato.

E’ possibile che la presenza di eosinofili nelle vie aeree sia correlata all’intensità del processo infiammatorio nella BPCO, che porta ad un reclutamento non specifico di queste cellule e alla loro attivazione.

Il maggiore impatto sul FEV1 avviene nei casi in cui sia la neutrofilia sia l’eosinofilia nell’espettorato sono più intense, con una relazione diretta fra i numeri di neutrofili ed eosinofili.

Maestrelli et al, Thorax 2001

Differenze nelle risposte infiammatorie fra asma e BPCO

Differenze nelle risposte infiammatorie fra asma e BPCO

Infiammazione Asma BPCO

Mediatori infiammatori

LTD4, istamina LTB4

IL-4, IL-5, IL-13 TNF-

Eotaxina, RANTES IL-8

Stress ossidativo +

Stress ossidativo +++

Infiammazione Asma BPCO

Mediatori infiammatori

LTD4, istamina LTB4

IL-4, IL-5, IL-13 TNF-

Eotaxina, RANTES IL-8

Stress ossidativo +

Stress ossidativo +++

Iperinflazione del polmone in asmaDonna di 38 anni, morta per assunzione di barbiturici, con una

lunga storia di ripetuti attacchi asmatici

Iperinflazione del polmone in asmaDonna di 38 anni, morta per assunzione di barbiturici, con una

lunga storia di ripetuti attacchi asmatici

Il muco occlude i lumi bronchiolari

Gli spazi aerei sono allargati, senza distruzione del tessuto

Enfisema panlobulareUomo di 62 anni deceduto per occlusione coronarica ma che aveva sintomi di malattia polmonare ostruttiva da 10 anni

prima di morire.

Enfisema panlobulareUomo di 62 anni deceduto per occlusione coronarica ma che aveva sintomi di malattia polmonare ostruttiva da 10 anni

prima di morire.

Gli spazi aerei dell’intero acino e del lobulo sono allargati con solo occasionali alveoli rimasti intatti

I bronchioli appaiono attenuati ecollassati e le strutture alveolari

non sono presenti

Differential Diagnosis: Differential Diagnosis: COPD and AsthmaCOPD and Asthma

COPD ASTHMA

• Onset in mid-life

• Symptoms slowly progressive

• Long smoking history

• Dyspnea during exercise

• Largely irreversible airflow limitation

• Onset early in life (often childhood)

• Symptoms vary from day to day

• Symptoms at night/early morning

• Allergy, rhinitis, and/or eczema also present

• Family history of asthma

• Largely reversible airflow limitation

Come distinguere l’asma dalla BPCO in base alla funzione polmonare?

Come distinguere l’asma dalla BPCO in base alla funzione polmonare?

Un valore post BD FEV1/FVC <70% suggerisce fortemente una BPCO

Una risposta al BD >12% (post BD FEV1-pre BD FEV1/pre-BD FEV1x 100) suggerisce fortemente un’asma

Che cosa ci dice una risposta positiva alla metacolina?

Un valore post BD FEV1/FVC <70% suggerisce fortemente una BPCO

Una risposta al BD >12% (post BD FEV1-pre BD FEV1/pre-BD FEV1x 100) suggerisce fortemente un’asma

Che cosa ci dice una risposta positiva alla metacolina?

Prevalence of hyperresponsiveness to different stimuli in asthma and COPD

6470362130

90/39*1181

7580826795909630

AcetylcholineMethacholineHistamine PropranololSO2

AMP Hyperventilation§

Fog

COPD Asthma Stimulus

* 90% in smokers, 39% in non-smokers. §Hyperventilation of cold air.

Postma and Kerstjens, AJCCRM 1998

Percentage of deaths with COPD as primary or secondary diagnosis according to the histamine

threshold in light, heavy, and never smokers

Hospers et al, Lancet 2000

0

20

40

60

80

>32 32 16 8 4 1

histamine threshold (g/L)

% C

OP

D d

ea

ths

Heavy smokers Light smokers Never smokers

Problemi con i criteri funzionali polmonari

Il rimodellamento nell’asma può causare un’ostruzione fissa.

I CSI riducono l’infiammazione, quindi riducono la risposta al BD, e ciò pone seri dubbi sul concetto di considerare solo una risposta post BD >12% come significativa.

Reversibilità e patologia sofferta

Sitkauskiene et al, Respir Med 2003

Ostruzione bronchiale reversibile e irreversibile quale predittore della

mortalità complessiva in asma e BPCO

La massima funzione polmonare ottenibile è il miglior indice spirometrico nella predizione della sopravvivenza a prescindere dai farmaci necessari per ottenerlo.

Ciò è vero tanto per l’asma quanto per la BPCO.

Hansen et al, AJRCCM 1999

Reversibility testinghttp://www.nice.org.uk/

Other Diff Dx to ConsiderOther Diff Dx to Consider Bronchiectasis

Large volumes of purulent sputum bacterial infection CXR/CT shows bronchial dilation, bronchial wall

thickening TB

History with the usual suspects BOO and BOOP

nonsmokers environmental exposures CT on expiration shows hypodense areas

Bronchiectasis Large volumes of purulent sputum bacterial infection CXR/CT shows bronchial dilation, bronchial wall

thickening TB

History with the usual suspects BOO and BOOP

nonsmokers environmental exposures CT on expiration shows hypodense areas

Congestive Heart FailureCongestive Heart Failure

Fine basilar crackles on auscultation Chest x-ray shows dilated heart,

pulmonary edema PFTs indicate restriction- not obstruction BNP can help

Fine basilar crackles on auscultation Chest x-ray shows dilated heart,

pulmonary edema PFTs indicate restriction- not obstruction BNP can help

Monitoring: This is a progressive disease

• Lung function worsens over time- even with best care

• Monitor symptoms and objective measures of airflow limitation for development of complications and to determine when to adjust therapy

• Spirometry should be performed if there is a substantial increase in symptoms or a complication

• ABG should be considered in all patients with an FEV1 <40% predicted or clinical signs of respiratory failure or right heart failure (JVD/edema)

Documents

Broncopneumopatia cronica ostruttiva (BPCO). COPD n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology