Che cos’ è l’ asma bronchiale?

Malattia polmonare infiammatoria cronica caratterizzata

da iperreattività delle vie aeree.

L’ asma è un malattia allergica?

Si, ma non solo!

Asma estrinseco: scatenato da antigeni inalatori, frequente nei bambini. Tipicamente associato

con atopia.

Asma intrinseco: scatenato da fattori diversi in assenza di pregressa sensibilizzazione

e di una pregressa diatesi allergica, frequente negli adulti.

Prevalenza dell’asma in Italia

Circa 2.6 milioni di pazienti. 4.5% della popolazione

300 milioni di pazienti nel mondo

Prevalenza dell’asma

Quante forme di asma?

• Asma allergico: forma più comune, specialmente nei bambini, in risposta ai

pollini, peli, acari.

• Asma infettivo: nei bambini, come conseguenza di infezioni da virus

respiratori.

• Asma da sforzo: soprattutto in ambienti freddi e secchi.

• Asma professionale: assimilabile all’ asma allergico, ma in alcuni casi sembra

essere coinvolto un meccanismo da diretta neurotossicità (iperreattività del

sistema parasimpatico).

• Asma da farmaci: più comune in pazienti in cui è già presente una diatesi

asmatica. Tra gli agenti scatenanti più comuni l’ aspirina.

Il polmone sano

Bronco

Tappo mucoso

Infiltrato infiammatorio

Ipertrofia ghiandole mucose

Ipertrofia membrana basale

Ipertrofia tonaca muscolare

Il polmone asmatico

Reazioni da ipersensibilità

Patogenesi dell’ asma brochiale: fasi iniziali

Patogenesi dell’ asma brochiale: fasi intermedie

AIRWAY HYPERRESPONSIVENESS

Chemotaxis Eotaxin,

RANTES, MCP-4

CCR3

Survival IL-3, IL-5,

GM-CSF

VCAM-1 VLA4

Adhesion

Bone marrow

IL-4

IL-5

Airway vessel

Activation

Th2 cell

Basic proteins

Mediators

EOSINOPHIL RECRUITMENT IN ASTHMA

L’eosinofilo: una fabbrica di mediatori

Major Basic Protein-1

Eosinophil Peroxidase

Eosinophil-Derived Neurotoxin

Eosinophil Cationic Protein

Eosinophil

Mast cell

Allergen

Th2 cell

MODERN VIEW OF ASTHMA

Vasodilatation

New vessels

Plasma leak Oedema

Neutrophil

Mucus

hypersecretion

hyperplasia

Mucus plug

Macrophage

Bronchoconstriction

Hypertrophy/hyperplasia

Cholinergic reflex

Epithelial shedding

Subepithelial

fibrosis

Sensory nerve activation

Nerve activation

Ricordatevi che l’ asma è una malattia infiammatoria

cronica……….!!!!!

Bronco

Tappo mucoso

Infiltrato infiammatorio

Ipertrofia ghiandole mucose

Ipertrofia membrana basale

Ipertrofia tonaca muscolare

Il polmone asmatico

ASTHMA PATHOLOGY

• GROSS: VISCOUS SPUTUM / MUCUS

PLUGGING / HYPERINFLATION

• MICROSCOPIC: THICK BASEMENT

MEMBRANE / SM MUSCLE + / MUCOUS

GLANDS + / SUBMUCOSA OEDEMA AND

INFLAMMATION / MUCOSAL

DESTRUCTION AND METAPLASIA /

MUCUS ABNORMAL

• LATE FIBROSIS OF BRONCHIAL WALL

ASTHMA AND COPD

COPD IS NOT ASTHMA !

• Different causes

• Different inflammatory cells

• Different mediators

• Different inflammatory consequences

• Different response to treatment

Inflammation ASTHMA COPD

CELLS Mast cells Eosinophils CD4 T cells macrophages

Neutrophils CD4, CD8 T cells Macrophages++

MEDIATORS LTD4,histamineL-4, IL-5,

ROS +

LTB4’ IL-8, TNFa, ROS+++

EFFECTS All airways Little fibrosis Ep shedding

Periph airways Lung destruction Fibrosis + Sq metaplasia

Response steroids +++ ±

COPD ASTHMA

Neutrophils

No AHR

No steroid response

Eosinophils

AHR

Steroid response

~10%

“Wheezy bronchitis”

OVERLAP BETWEEN COPD AND ASTHMA

Asthma Definition

• A condition characterised by wide

variations over short periods of time in

resistance to air flow in intrapulmonary

airways

• Variability usually assessed by measuring

change in air flow rates ( ± > 15% FEV1)

ASTHMA PREVALENCE

• CURRENT 2 - 6% (CUMULATIVE 10%)

• ONSET <10y.o. in 50%

• INCREASED WITH “DEVELOPMENT”

• CHILDHOOD PREVALENCE NEAR 20%

IN IRELAND

• MORTALITY IRELAND < 100 / YEAR

Constitutional and environmental

factors which induce or incite

• Allergens

• Occupational chemical

• Viruses

• Genetic factors

• Prematurity

• Lack breast feeding

• ? Smoking

• Fumes, smoke, sprays

• Diurnal variation

• Exercise, cold air

• Fog

• Emotion

• Allergens, anaphylaxis

• Viruses

• Drugs - NSAID, Beta

ATOPY

• SUSCEPTIBILITY TO DEVELOP IGE

ANTIBODIES FROM EXPOSURE TO

COMMON ENVIRONMENTAL

ALLERGENS

• IGE - GLYCOPROTEIN : m.w. 190,000

daltons

FACTORS IN

INFLAMMATORY PROCESS

• MEDIATORS

• HISTAMINE

• LEUCOCYTE C F

• PROSTAGLANDINS

• LEUKOTRIENES

• PAF

• KININS

• CELL TYPES

• MAST CELLS

• MACROPHAGES

• EOSINOPHILS

• T LYMPHOCYTES

NEURAL MECHANISMS

PARASYMPATHETIC

AFFERENT SENSORY

HISTAMINE

KININS

EFFERENT

BRONCHOCONSTRICTOR

MUCUS SECRETION

ASTHMA

CLINICAL FEATURES

• SYMPTOMS: WHEEZE, COUGH, SPUTUM, DYSPNOEA,TIGHTNESS.

• PERIODICITY: DIURNAL, SEASONAL, PROVOKING FACTORS (COLD, EXERCISE, SMELLS.

• ASSOCIATED: NASAL/SINUS, “COLDS”, ALLERGIES.

• SMOKING AND OCCUPATION

EXAMINATION

• WHEEZES AND HYPERINFLATION

• TACHYCARDIA (>100 BPM)

• PULSUS PARADOXUS (>10 MMHG)

• PEAK FLOW (<100L/MIN OR <40% PREDICTED)

• CYANOSIS, SYNCOPE, HYPOTENSION, SILENT CHEST

• HYPOXEMIA (<8.5 KPA)

• HYPERCAPNIA EVEN MILD

CONFIRMING ASTHMA

• SPIROMETRY FEV1 & REVERSIBILITY

• TRIAL OF TREATMENT

• ?ALLERGY TESTS

• (CXR)

• CHALLENGE TEST: SPECIFIC/NON-S

TROUBLESOME ASTHMA

• INHALER TECHNIQUE/COMPLIANCE

• ALLERGENS - HDM, PETS, FOOD, DRUGS, DAMP HOUSE, ABPA.

• INFECTIONS

• AIR POLLUTION - SMOG, PASSIVE SMOKE,HYDROCARBONS

• SMOKING

• REFLUX DISEASE

• EXERCISE

• OCCUPATION (UP TO 10% OF PATIENTS)

A.B.P.A.

• ASTHMA PLUS

• FEVER

• CXR INFILTRATES

• SEVERE BLOOD EOSINOPHILIA

• POSITIVE SEROLOGY OR SKINPRICK

• ORGANISM IN SPUTUM

• COMPLICATIONS - APICAL FIBROSIS,

BRONCHIECTASIS

Definition of COPD

Chronic obstructive pulmonary disease is

defined as

‘a disease state characterised by the

presence of airflow obstruction due to

chronic bronchitis or emphysema; the

airflow obstruction is generally

progressive, may be accompanied by

airway hyper-reactivity, and may be

partially reversible’

American Thoracic Society 1995

Facts About COPD

• COPD is the 4th leading cause of death in the United States (behind heart disease, cancer, and cerebrovascular disease).

• In 2000, the WHO estimated 2.74 million deaths worldwide from COPD.

• In 1990, COPD was ranked 12th as a burden of disease; by 2020 it is projected to rank 5th.

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

0

0.5

1.0

1.5

2.0

2.5

3.0

Proportion of 1965 Rate

0.0

0.5

1.0

1.5

2.0

2.5

3.0

1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998

–59% –64% –35% +163% –7%

Coronary Heart

Disease

Stroke Other CVD COPD All Other Causes

Cost of COPD in United States

in 2000 31.9

20.7

11.2

0

5

10

15

20

25

30

35

Total Direct Indirect

American Lung Association, 2001

Costs

$Billions

10% of people with COPD responsible for >70% of COPD-related

medical care costs. In-patient hospitalization and emergency department

care accounts for >73% of this cost

COPD costs $1,522 per person per year (3 times asthma costs)

Risk Factors for COPD

Host Factors Genes (e.g. alpha1-antitrypsin deficiency)

Hyperresponsiveness

Lung growth

Exposure Tobacco smoke

Occupational dusts and chemicals

Infections

Socioeconomic status

Smoking prevalence - Europe

0 5 10 15 20 25 30 35 40 45 50 55

United States

Luxembourg

United Kingdom

Ireland

Italy

Germany (W)

Denmark

Spain

Greece

Germany (E)

France

Netherlands

European Union

Women

Men

News. Journal of the National Cancer Institute 1996 Volume 88: (17); 1190

Percentage of smokers by sex and country

Cigarette smoke

Alveolar macrophage

Neutrophil

PROTEASES

Alveolar wall destruction

(Emphysema)

Mucus hypersecretion

(Chronic bronchitis)

PROTEASE

INHIBITORS

Neutrophil chemotactic factors

CELLULAR MECHANISMS OF COPD

Neutrophil elastase Cathepsins

Matrix metalloproteinases

Cytokines (IL-8) Mediators (LTB4) 4 ) )

? CD8+

lymphocyte

-

MCP-1

SPUTUM CYTOKINES IN

COPD

COPD patients: 62.5 ±3.2y; FEV1 = 34.6±4 % predicted

0

2

4

6

8

L

[ T

NF

- (

nm

ol/

l)]

Controls (n=16)

Smokers (n=12)

COPD (n=14)

Asthma (n=22)

0

1

2

3

4

L

[IL

-8 (n

mo

l/l)

]

Controls (n=16)

Smokers (n=12)

COPD (n=14)

Asthma (n=22)

*

*

**

*

**

TNF- IL-8

Cigarette

smoke

Alveolar macrophage

Neutrophils

TNF- and IL-8 in COPD

4 ) ) TNF-

IL-8

Epithelial cells

TNF-

IL-8

NF-B

IL-8 gene

IL-8

Mucus secretion

NF-B

IL-8

Neutrophil

recruitment

TNF- a

REACTIVE OXYGEN SPECIES IN

COPD

Plasma leak Bronchoconstriction Isoprostanes

ANTIOXIDANTS Vitamins C and E

N-acetyl cysteine

Glutathione analogues

Nitrones (spin trap)

O2-, H202

OH., ONOO-

Anti-proteases

SLPI 1-AT

Proteolysis

Neutrophil elastase

Cathepsins

MMP-1, MMP-9,

MMP12

Granzymes,

perforins

Others……..

PROTEASE-ANTIPROTEASE IMBALANCE IN COPD

1-Antitrypsin

SLPI

Elafin

TIMPs

Alpha1-Antitrypsin Deficiency

• Enzyme prevents loss of lungs’ elastic

fibers

• Deficiency – Pan-lobular emphysema

• Homozygous – PiZZ – 15-30% of

normal AAT levels (PiMM) Earlier

development of COPD

– Airflow obstruction in early 40s

– Accelerated by 10 to 15 years

– occurs in 1:5000

• Heterozygous – PiMZ – 50-80% -

smokers

• Z allele – 3-5% population

Alpha1-Antitrypsin Deficiency

• Progressive SOB in young patients

• 60% emphysema under 40 yrs

• 2% of all cases of COPD

• Pneumothorax, Resp. failure, Cirrhosis

• Treatment – Stop smoking

– Avoid pollution/dust

– Recombinant AAT

– Gene therapy

– (long arm chr 14)

High resolution CT scan showing the characteristic basal

panlobular emphysema rather than the apical centrilobular

disease seen in smokers who have normal levels of 1-

antitrypsin.

SP

Mucus gland hyperplasia

Goblet cell hyperplasia

Mucus

Sensory nerve Cholinergic nerve ACh

N

E

Neutrophils

Epithelium

INFLAMMATION

Cytokines

ROS

• Acetylcholine

• Tachykinins

• Proteinases

neutrophil elastase

• Cytokines (TNF-)

• Oxidants

• Growth factors

• MUC genes

MUC5a, MUC8

MUCUS HYPERSECRETION IN COPD

ASTHMA v COPD Inflammation ASTHMA COPD

CELLS Mast cells Eosinophils CD4 T cells macrophages

Neutrophils CD8 T cells Macrophages++

MEDIATORS LTD4,histamineIL-4,IL-5,

ROS +

LTB4’ IL-8, TNFa, ROS+++

EFFECTS All airways Little fibrosis Ep shedding

Periph airways Lung destruction Fibrosis + Sq metaplasia

Response steroids +++ ±

COPD - SYMPTOMS

• COUGH AND MUCOID SPUTUM

• DYSPNOEA - SLOWLY PROGRESSIVE

• WHEEZE

• OEDEMA (IF COR PULMONALE)

• WINTER EXACERBATIONS

COPD - SIGNS

• HYPERINFLATION

• DECREASED EXPANSION CHEST

• PROLONGED EXPIRATION/±WHEEZE

• SIGNS PULMONARY HYPERTENSION AND/OR RVH (± CARDIAC FAILURE)

• CYANOSIS

• HYPERCAPNIA - ASTERIXUS, (PRE)-COMA

CONFIRMING COPD

• SPIROMETRY - GOLD GUIDELINES

• (DLCO)

• REVERSIBILITY (BETA2 AND INHALED

STEROID TRIAL)

• CXR - HYPERINFLATION/BULLAE

• ECG

• ABG - ACUTE V CHRONIC STABLE

• ALPHA-1 SCREEN (<45 YO OR F.H.)

0

100

200

300

400

500

1 2 3 4 5 6 7 8 9 10 11 12

13 14

Peak f

low

(L

/min

)

1 2 3 4 5 6 7 8 9 10 11 12

13 14

Peak f

low

(L

/min

)

Days

Prednisolone 30 mg o.m. x 14 days

Prednisolone 30 mg o.m. x 14 days

COPD

ASTHMA

0

100

200

300

400

500

TRIAL OF STEROIDS

Eliminate the irritant

• STOP SMOKING

• Counselling improves likelihood

• Smoking cessation program

• Pharmacotherapy

– Nicotine Replacement Therapy

– Bupropion (Zyban)

• Reduce exposure to environmental pollutants

Smoking Cessation

• Stops accelerated decline in FEV1

• Improves possibility of oxygen therapy benefits

• 3-6 months after quitting: end of cough/phlegm production

• 1 year: lung function increased 30mls

• 1 year: risk of Small Cell Lung Cancer halved

• 5 years: risk of any lung cancer halved

– No progression of COPD

– Sporting performance enhanced

• Methods of smoking cessation

– Counseling; Nicotine replacement; Behavior modification

– Hypnosis

BRONCHODILATORS IN

COPD • FEV/FVC <70% : 50%< FEV <80% LONG-

ACTING BRONCHODILATOR

• FEV/FVC <70% : 30%< FEV <50% AND EXACERBATION-INHALED STEROID

• FEV/FVC <70% ; FEV <30% ±RESP, FAILURE, ±CCF - LTOT ± SURGERY

• ANY SYMPTOMS AND FEV/FVC <70% SHOULD HAVE SHORT ACTING B/DILATOR

• SEE WWW.GOLDCOPD.COM

COPD MANAGEMENT

• PATIENT EDUCATION

• TREAT EXACERBATIONS EARLY -

ANTIBIOTICS, ±STEROIDS

• VACCINES

• (MUCOLYTICS)

• REHABILITATION PROGRAMMES

• LTOT ( >16 HOURS PER DAY)

• SURGERY - LVRS

COPD PROGNOSIS

• FEV1 < 1.0L 5 YSR - 69%

• 10 YSR - 40%

• RVF 5 YSR - 25%

MANAGING

EXACERBATIONS • ANTIBIOTICS

• CONTROLLED OXYGEN

• BRONCHODILATOR - BETA AGONIST ANTICHOLINERGIC, ±THEOPHYLLINE

• STEROIDS

• NIV BIPAP

• INTUBATION/VENTILATION

• TREAT HEART FAILURE IF PRESENT

• (RESPIRATORY STIMULANTS?)