COPD IS NOT ASTHMA !

Different causes

Different inflammatory cells

Different mediators

Different inflammatory consequences

Different response to treatment

Kardos ERS 2003

A chronic
inflammatory disorder
of the airways
Many cells and cellular
elements play a role
Chronic inflammation
leads to an increase in
AHR with recurrent
episodes of wheezing,
coughing, SOB
Widespread, variable,
and often reversible
airflow limitation

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)

TRIGGERS

INFLAMMATION

Airway
Hyperresponsivenes

Symptoms

Normal
Smooth
muscle

Lumen

Epithelium

Submucosa

During an
attack

Normal airway
No thickening below
basement membrane

Inflamed
airway
Eosinophil infiltration

Shedding of
epithelial cells

Blood vessels
Formation of
mucus plugs

Vasodilatation increased
vascular permeability
with oedema

Collagen thickening

Airway Remodelling in Asthma:

Not an entirely reversible disease
Epithelial damage

Basement membrane
thickening

Smooth muscle
hyperplasia

P Jeffery, in: Asthma,

Academic Press 1998

Asthma Inflammatory Process

Allergen Exposure
Inflammatory mediators released

Glucocorticoids

Block activation of this pathway

Lipoxygenase
Chemotactic
Platelet-activating
factors
factor (PAF)
Histamine
Leukotrienes

BronchoIncreased
constriction
vascular
permeability

Increased
mucus
secretion

Arachidonic acid
Cyclooxygenase
Prostaglandins

Decreased
mucus
clearance

Symptoms of Asthma
Schleimer RP. Am Rev of Respir Dis. 1990;141(2 pt 2):S59

Chemotaxis

Smooth Muscle
Dysfunction

Bronchoconstriction
Bronchial hyperreactivity

Airway
Inflammation

Inflammatory cell infiltration/

activation

Hypertrophy/hyperplasia

Mucosal edema

Inflammatory mediator release

Cellular proliferation
Epithelial proliferation

Symptoms/Exacerbations

Epidemiology / pathology

KOMPONEN ASMA

Barnes PJ

Normal

Asthma

Constitutional and
environmental
factors
which
Fumes, smoke, sprays
Allergens
induce
or inciteDiurnal variation
Occupational
chemical
Viruses
Genetic factors
Prematurity
Lack breast feeding
? Smoking

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

EOSINOPHIL RECRUITMENT IN ASTHMA

IL-5

Th2 cell

IL-4

Adhesion
VCAM-1
VLA4
Chemotaxis
Eotaxin,
RANTES, MCP-4

Survival
IL-3, IL-5,
GM-CSF

Activation
Bone
marrow

CCR3

Airway vessel

Basic
proteins
Mediators
AIRWAY HYPERRESPONSIVENESS

MODERN VIEW OF ASTHMA

Allergen
Macrophage

Mast cell

Th2 cell

Mucus plug

Neutrophil
Eosinophil
Epithelial shedding
Nerve activation

Subepithelia
fibrosis
Plasma leak
Oedema
Mucus
Vasodilatation
hypersecretion
New vessels
hyperplasia

Sensory nerve
activation

Cholinergic
reflex
Bronchoconstriction
Hypertrophy/hyperplasia

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

 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 5 th.

CELLULAR MECHANISMS OF COPD

Cigarette smoke

Alveolar macrophage

CD8
lymphocyte
+

MCP-1

Neutrophil chemotactic factors

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

Neutrophil
PROTEASE
INHIBITORS

Neutrophil elastase
PROTEASES MatrixCathepsins
metalloproteinases

Alveolar wall destruction

(Emphysema)

Mucus hypersecretion
(Chronic bronchitis)

SPUTUM CYTOKINES IN COPD

COPD patients: 62.5 3.2y; FEV1 = 34.64 % predicted

TNF-

IL-8

*
L

ControlsSmokersCOPD Asthma
(n=16) (n=12) (n=14) (n=22)

**
[IL-8 (nmol/l)]

[ TNF- (nmol/l)]

**

*
L

ControlsSmokersCOPD Asthma
(n=16) (n=12) (n=14) (n=22)

TNF- and IL-8 in COPD

Cigarette
smoke

TNF-

Alveolar macrophage
4))

TNF-

NF-B

Epithelial
cells

IL-8

IL-8 gene
IL-8

Neutrophils

IL-8

OVERLAP BETWEEN COPD AND ASTHMA

COPD

ASTHMA

Neutrophils
No AHR

Eosinophils

~10%

No steroid response

AHR
Steroid response

Wheezy bronchitis

REACTIVE OXYGEN SPECIES IN

COPD
ANTIOXIDANTS
Anti-proteases
SLPI 1-AT

Vitamins C and E
N-acetyl cysteine
Glutathione analogues
Nitrones (spin trap)

NF-B

Proteolysis

IL-8

O2-, H202
OH., ONOO-

Mucus secretion

Isoprostanes

TNFa

Neutrophil
recruitment

Plasma leak

Bronchoconstriction

PROTEASE-ANTIPROTEASE IMBALANCE IN COPD

Neutrophil elastase
Cathepsins
MMP-1, MMP-9,
MMP12
Granzymes,
perforins
Others..

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
Progressive SOB in young patients
Deficiency
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 1antitrypsin.

MUCUS HYPERSECRETION IN COPD

Epithelium

Goblet cell
hyperplasia
CholinergicACh
nerve
N
E

Acetylcholine
Tachykinins
Proteinases

Mucus

neutrophil elastase

SP

Sensory nerve

Mucus gland hyperplasia

Cytokines
ROS

INFLAMMATION
Neutrophils

Cytokines
(TNF- )
Oxidants
Growth factors
MUC genes
MUC5a, MUC8

ASTHMA v COPD
Inflammation
CELLS

ASTHMA
Mast cells
Eosinophils
CD4 T cells
macrophages

MEDIATORS

LTD4,histamine LTB4
IL-8, TNFa,
IL-4,IL-5,
ROS+++
ROS +

EFFECTS

All airways
Little fibrosis
Ep shedding

Response steroids +++

COPD
Neutrophils
CD8 T cells
Macrophages++

Periph airways
Lung destruction
Fibrosis +
Sq metaplasia

DEFINISI
Inflamasi saluran napas
Gabungan obstruksi saluran napas kecil dan

kerusakan parenkim
Hambatan aliran udara ekspirasi
Progresif dan ireversibel /reversibel sebagian
Disertai efek ekstra pulmoner
Dapat dicegah

DAMPAK PADA INDIVIDU

FAKTOR YANG BERPERAN
Derajat keluhan
(sesak dan penurunan kapasitas latihan)
Efek sistemik dan gejala komorbid lain

KUALITAS HIDUP

Faktor risiko
Asap rokok (90% kasus perokok / mantan)
Polusi udara

- dalam ruangan
- luar ruangan
Stress oksidatif
Genetik
Tumbuh kembang paru
Sosial Ekonomi

ETIOLOGY AND RISK FACTORS

NOXIOUS AGENT

(tobacco smoke, pollutants, occupational agent)

AGING POPULATION

Genetic factors
Respiratory
infection
Others

Nutrition

COPD

Infections
Socio-economic status

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.)

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.)

TRIAL OF STEROIDS
Peak flow (L/min)

500
400

COPD
300

Prednisolone 30 mg o.m. x 14 days

200
100
0

Peak flow (L/min)

500

1
13

2
14

10

11

12

10

11

12

ASTHMA

400
300

Prednisolone 30 mg o.m. x 14 days

200
100
0

1
13

2
14

Days

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% LONGACTING 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%

Risk Factors for COPD

Host Factors
deficiency)

Genes (e.g. alpha1-antitrypsin

Hyperresponsiveness
Lung growth

Exposure

Tobacco smoke
Occupational dusts and chemicals
Infections
Socioeconomic status

MANAGING
EXACERBATIONS
ANTIBIOTICS
CONTROLLED OXYGEN
BRONCHODILATOR - BETA AGONIST

ANTICHOLINERGIC, THEOPHYLLINE
STEROIDS
NIV BIPAP
INTUBATION/VENTILATION
TREAT HEART FAILURE IF PRESENT
(RESPIRATORY STIMULANTS?)