ASTHMA

MANAGEMENT

LONG-TERM THERAPY
Inhalation therapy is
the mainstay therapy
Gaps between treatment goal and the
reality
THE GOAL
• no chronic symptoms
• no asthma attacks
• no emergency visits
• no need for quick relief (as
needed) ß2-agonist
• normal physical activity
including exercise
• lung function as close to
normal as possible
• no adverse effects from
medicine
THE REALITY
 Frequent chronic symptoms
 Some asthma attacks
 Some emergency visits
 Excessive use of ß2-agonist
as reliever
 Impaired physical activity
including exercise
 Some “ups” and “downs” in
lung function
 Frequent adverse effects from
medicine
Pathogenesis of asthma
 Pathogenesis of asthma
(NHLBI/WHO 1995)
Environmental risk factor

Inflammation
Symptoms

Airway
hyperresponsiveness Airflow limitation

Triggers
Asthma is an inflammatory
disease
 Inflammation
(–) (+)
 
Triggers

 

 
 

Normal Asthma

Bronchial hyperreactivity (-) Bronchial hyperreactivity

Symptoms (-) Symptoms (+)

 Ca++ Histamin
Ag
Ig E YY
Methyl Phosphatidyl Phosphatidyl
Phospholipid ethanolamine choline
transferase

Phospho
lipase A2 Ca ++ Histamin
Arachidonic acid ECF, NCF
lypoxygenase cyclooxygenase

5-HETE Leucotrienes Thromboxanes Prostaglandins

LTB4
LTC4 TXA2 PGD
LTD4 PGF2
LTE4
Mediator release in
asthma reactions
Diagnosis

Data

Analisis

Planning
 Data:
Diagnosis Batuk
Sesak
Mengi
Keluarga asma
Obat asma

Analisis
Asma
Pem.Fisik
Spirometri
APE
Tes Provokasi
Planning
 FVC / KVP
the total volume forcibly exhaled
FEV1 / VEP1
the amount exhaled in the first second
 6

4
Volume (liters)

3
FEV1 FVC
2

0 1 2 3 4 5 6
Time (sec)
Fig 2. Normal forced expiration curve
Peak Flow Meter /PEFR/APE
ASTHMA PROFILE
 ASTHMA PROFILE IN THE WORLD

Globally, over 150 million people diagnosed with asthma

Globally, over 180,000 people die from asthma each year

Globally, the economic burden of asthma are estimated

to be greater than TB and HIV/AIDS or combined

Major factors contributing to asthma morbidity and mortality

are underdiagnosis and inappropriate treatment
 PATIENT’S PROFILE
( Yayasan Asma Indonesia Wilayah SumateraUtara , 200, 93-95)

•More than one year 93 %

•Used anti inflammation 25 %
•Used objective values 9%
•Inhaller tehnique (poor ) 92 %
•Compliance 19 %
•Dose interval 17 %
 PATIENT’S PROFILE
( Yayasan Asma Indonesia Wilayah Sumatera Utara, 300, 96-99)

•More than one year 96 %

•Used anti inflammation 32 %
•Used objective values 7%
•Inhaller tehnique (poor ) 89 %
•Compliance 23 %
•Dose interval 21 %
Reflected in Indonesian Asthma Market
(IPMG Nov 2001)

3% 1%
5% Inhaled b2-agonist
Oral b2-agonist
11% Xanthines
NS Antiinflammatory
Inhaled Steroid
Anticholinergics
Antileukotriene
4% Other
46%

5%

25%
World Asthma Market
(IMS 2000)

1%
b2-agonist
16%
Xanthines
NS Antiinflammatory
30% Inhaled Steroid
Anticholinergics
Antileukotriene
5%
Other

6%

7%
35%
Change paradigm of
asthma
To/ To/
Symptoms Diseases
control control
Anti Inflammations is
the mainstay therapy
 Inflammation

Controller
Bronchial hyperreactivity
Reliever
Symptoms
Pathogenesis of asthma
Natural History of Asthma
 CURE
•UNCORRECT TREATMENT

CHRONIC ASTHMA
AIRWAY
REMODELLING

PERSISTENCE OF INFLAMMATION
AIRWAY REMODELLING CHRONIC ASTHMA
AIRWAY REMODELLING IN ASTHMA

•Desquamation of epithelium
•Increase in airway smooth muscle
•Vascular proliferation
•Collagen deposition
•Thickening of basement membrane
•Increase in bronchial glands
•Vascular congestion
•Oedema formation
•Cellular infiltration
Epithelial Damage

P Jeffery, in: Asthma, Academic Press 1998

 AIRWAY REMODELLING IN ASTHMA

e t ic ?
c oki n
a r ma
Ph Eosinophil

Desquamation of epithelium

MBP, ECP
Epithelium

Thickening of basement membrane

Increase in airway smooth muscle

Basement Membrane
Thickening

P Jeffery, in: Asthma, Academic Press 1998

Smooth Muscle Hyperplasia

P Jeffery, in: Asthma, Academic Press 1998

Fatal Asthma

Jeffery, 1994
FEV1
Symptom

Exacerbation
Symptom

od e lling
Rem

Time
Era of Asthma management

1930th : Xanthin
1960th : Beta2-agonist
1970th : Steroid inhallation
2000th : Combination
2003th : Single inhaler combination
Steroid depo ?
 Evolving treatment options
ICS treatment Adding
introduced LAßA to ICS therapy
Large use of 1972 Kips et al, AJRCCM 2000
Pauwels et al, NEJM 1997
short-acting
Greening et al, Lancet 1992 Single
ß2-agonists
inhaler therapy
1975
(Symbicort®)

“Fear” of
1980 short-acting
ß2-agonists

1985
2000
1990 1995

Bronchospasm Inflammation Remodelling

 Controller:
Anti inflammation

Non steroid Steroid

• sodium chromoglicate • budesonide (Pulmicort®)
(Intal®) (Inflamid®)
• beclomethasone dipropionat
• ketotifen
(Becotide®)
• sodium nedocromil
• triamcinolone acetonide
• fluticasone(Flexotide®)
 Mild Asthma has Airway
Inflammation
ICS Reverses Inflammation
E
E
BM

BM

Pre and post 3 month treatment with BUD 600 µg bd

Laitinen, J Allergy Clin Immunol, 1992
 Reliever
Bronchodilator
2 - agonist

• Xanthin
•Anticholinergic
 BRONCHODILATOR
Short Acting 2 AGONIST (SABA): Long Acting 2 AGONIST:
* salbutamol/albuterol (Ventolin ®) (LABA)

* terbutaline (Bricasma®) •salmoterol

* procaterol •formoterol
* fenoterol
* orciprenaline, etc

ANTICHOLINERGIC: XANTHINE:
* atropine sulfate * theophylline

* ipratropium bromide, etc

OTHER SYMPHATOMIMETIC:
* ephedrine
* adrenaline, etc
 GINA guidelines 1998/2002:
Focus on ICS and ß2-agonists

Mild Moderate Severe

Intermittent persistent persistent persistent

Short-acting ß2 prn

ICS

Long-acting ß2

Symbicort not specifically mentioned

Healthy
Healthy Subjects
Subjects Asthma
Asthma in
in Remission
Remission
Increased Membrane Basic Protein (MBP) positive area ( the red stain )
and epithelial shedding in the subject in clinical remission.
Van den Toom. AJRRCM 2001; 164: 2107-13
 Guidelines on Asthma:
Past and Current Trends

Mild Moderate Severe

Intermittent persistent persistent persistent

Short-acting ß-agonists2 prn

GINA 1998 LABA+ICS

(adapted) ICS
Current
evidences LABA+ICS
 The rationale behind fixed
combination therapy
 To increase adherence to controller
therapy
 To gain better control with less inhaled
steroid
ADULT PATIENTS & CAREGIVERS OF CHILDREN WITH ASTHMA
WERE ASKED “WHY THEY DID NOT TAKE THEIR INHALED
CORTICOSTEROID AS PRESCRIBED?”

 45% said they just forgot

 42% said that they felt well

Stahl AJRCCM, 2002
 Combinations once- or twice-daily dosing
offers convenient than single dosing
35
Change in morning PEF (L/min)

30

25

20

15 p<0.001
both treatments vs. budesonide alone
10

0
-5
-10 0 10 20 30 40 50 60 70 80 90
Treatment days

Symbicort® 160/4.5 µg Symbicort® 160/4.5 µg budesonide 200 µg

2 inhalations od 1 inhalation bid 2 inhalations od
Buhl et al, Am J Respir Crit Care Med 2001
Combination therapy

Symbicort®
Budesonide + Formoterol

Seretide®
Fluticasone + Salmoterol
The Beginning of
Treatment
 Exacerbation

The beginning of treatment ?

Stable condition

 Peak flow meter

Objective 600-700 ( normal )

value
300

0
 PEFR Monitoring:
A Major Tool in Asthma Self-Management
Chronic Diseases Monitor

Hypertension Blood pressure

Diabetes Serum glucose

Asthma PEFR
 THE GOALS FOR SUCCESSFUL
MANAGEMENT OF ASTHMA
( NHLBI / WHO, 1995)

• Achieve and maintain control of symptoms

•Prevent asthma exacerbations
• Maintain pulmonary function as close to normal
levels as posible
•Maintain normal activity levels, including exercise
•Avoid adverse effect for asthma medications

•Prevent development of irreversible airflow limitation

•Prevent asthma mortality
 MANAGEMENT

•ANTI INFLAMMATION, FIRST LINE, EARLY

•BRONCHODILATOR, OBJECTIVE VALUE

• MEDICINE , SELECTIVE
•TIME, PROPERLY

• TECHNIQUE, PROPERLY
•REHABILITATION, DO
•TRIGGER FACTORS, AVOID
THANK YOU
 Airway
Airway Remodelling
Remodelling in
in Asthma
Asthma
30

Subepithelial layer thickness (µm)

25

20

15

10
rs = 0.581
p < 0.001
5

0 0 2 4 6 8 10 12

Asthma severity score

Correlation between subepithelial layer thickness and asthma severity score

in 34 asthmatic patients.

Chetta CHEST 1997; 111:362-67

 GINA 2002
Systemic Glucocorticosteroid (Parenteral)
Systemic glucocorticosteroid speed resolution of exacerbations
and should be considered integral to the management of all
but the mildest exacerbation, especially if:
• The initial rapid acting inhaled ß2-agonist dose has failed
to achieve lasting improvement
• The exacerbation developed even though the patient was already
taking oral glucocorticosteroid
• Previous exacerbations required oral glucacorticosteroid

Intravenous administration may be considered if IV access is

desirable.
In patients being discharge from the emergency departement,
intramuscular administration may be helpful, specially if there
are concerns about compliance.
 STEP 4: SEVERE PERSISTENT
CONTROLLER:
Step
daily multiple medications RELIEVER down
• Inhaled steroid • Inhaled ß2- when
• Long-acting bronchodilator agonist p.r.n.
• Oral steroid controlled
Avoid or control triggers
STEP 3: MODERATE PERSISTENT
CONTROLLER: Patient education
daily medications RELIEVER
• Inhaled steroid and long- • Inhaled ß2- essential at every
acting bronchodilator
• Consider anti-leukotriene
agonist p.r.n. step
Avoid or control triggers
Reduce therapy
STEP 2: MILD PERSISTENT
CONTROLLER:
if controlled for at
daily medications RELIEVER least 3 months
• Inhaled steroid
• Or possibly cromone, oral theophylline or • Inhaled ß2-
anti-leukotriene agonist p.r.n. Continue
Avoid or control triggers monitoring
STEP 1: INTERMITTENT
Step up
CONTROLLER: RELIEVER
• Inhaled ß2-
if not controlled
none
agonist p.r.n. (after check on
inhaler technique
Avoid or control triggers
and compliance)
TREATMENT
GINA,
GINA, Guidelines 2002