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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?)