asthma lecture 200705
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Asthma in children
Dr.Nurjannah,Sp.A
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Topics
Inflammations and remodeling in asthma
Classification of asthma
Goal of asthma management Longterm management:
When?
Medications
Side effects
How early?
Inhalation therapy: handicaps??
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EVOLUTION OF ASTHMA
Reversible respiratory tract obstruction
spontaneous or after bronchodilatortreatment
1950-
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Episodic, obstruction due to bronchial
hyperresponsiveness (bronchial hyperactive)
Chronic conditions: recurrent bronchospasm due to
narrowing respiratory tract as a stimuli response
Bronchospasm preventive concept WHO, 1975
Chronic inflammationcellular infiltrate, oedema,epithelial damage, fibrosis
Anti-inflammatory drugs
1970-
1960-
1990-an
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International Pediatric Consensus Statement on the
Management of Childhood Asthma
Arch Dis Child 1992;67:240-8.
International Pediatric Consensus Statement
on the Management of Childhood Asthma
Warner dkk. Pediatr Pulmonol 1998;25:1-7
1989:
1992:
1998:
OPERATIONAL DEFINITION
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Chronic inflammatory of respiratory tract
Many cells and cellular elements play a role(mast cell, eosinophils, T lymphocytes)
GINA, 2002
2002
Complex definitiondifficult aplication andnot practical
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Diagnosis of Asthma
Cough and/or wheezing that:
episodic,
nocturnal (variability),
reversibilitywith atopic family
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Inflammation
desquamation of epithelium
Mucus plug
Basal membrane
thickening
Netrophil and
eosinophil infiltrationsSmooth muscle
constriction and hypertrophy
Oedema
Mucosal gland
hyperplasia
Barnes PJ
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AsthmaNormal
Inflammation picture
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Inflammation in asthma
Barnes PJ
Chronic inflammation
Structure changes
Acute inflammation
Steroids
Response
Time
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Topics
Konsep inflamasi dan remodeling pada asma
Classification of asthma
Tujuan tatalaksana Longterm management:
Kapan?
Obat
Efek samping
How early?
Terapi inhalasi: kendala
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Classification of asthma
Severity of attacks
(Acute)
Mild
Moderate
Severe
Respiratory arrestimminent
Class of disease
(Chronic)
Infrequent episodicasthma
Frequent episodic
asthmaPersistent asthma
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Classification of disease
Clinical parameter ,
And lung function
Infrequent episodic
asthmaPersistent asthma
Frequent episodic
asthma
Freq of attacks < 1x /month Daily> 1x /month
Duration of attacks < 1 week Daily>1 week
Between episodes No symptoms
Frequent nocturnal
symptomsSymptoms (+)Sleep and activity Normal AffectMay affect
Physical exam Normal AbnormalMay affect
Controller No need Steroid/combinationSteroid/combinationLung function
(No attacks)PEF/FEV1 >80%
PEF/FEV1 15% > 50%> 30%
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Topics
Konsep inflamasi dan remodeling pada asma
Klasifikasi asma
Goal of asthma management Longterm management:
Kapan?
Obat
Efek samping
How early?
Terapi inhalasi: kendala
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Goal of asthma management
Minimal (ideally no) chronic symptoms
Minimal (infrequent) exacerbations
No emergency visits
Minimal (ideally no) use of as needed 2-
agonist
No limitations on activities (exercise)
(Near) Normal lung function
Minimal (or no) adverse effects from medicine
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Improvement Quality of life
Last goal
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Allergenavoidance
Immuno-
therapy
Pharmaco-
therapy
Education
Asthma management
COSTS
GINA, 2002
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Bahasan
Konsep inflamasi dan remodeling pada asma
Klasifikasi asma
Tujuan tatalaksana
Longterm management:
When?
Obat
Efek sampingHow early?
Terapi inhalasi: kendala
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Cost ?
Availabil ity ?
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When??
Classifications Controller Reliever
Infrequent
episodic asthma
No Yes
Frequent
episodic asthma
Yes Yes
Persistent
asthma
Yes Yes
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Topics
Konsep inflamasi dan remodeling pada asma
Klasifikasi asma
Tujuan tatalaksana Longterm management:
Kapan?
Medication
How early?
Efek samping
Terapi inhalasi: kendala
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Medications
Bronchodilators
Antiinflammations
Anti-remodeling
Anti IgE
Immunizations: ??
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TREATING ASTHMAwith Bronchodilatorsaloneis like
Paintingover rust
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Anti-inflammations
Antihistamine
Disodium Cromoglycate (DSCG)
Corticosteroids
Anti PDE 4 (Phosphodiesterase)
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Long -term p lacebo-con trol led tr ial of ketot i fen in the
management of preschoo l chi ldren with asthm aLoftus BG, Price JF
J Allergy Clin Immunol 1987; 79:350-5
The results suggest that:
Ketotifen has no place in the management
of young children with frequent asthma
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Inhaled disodium cromog lycate (DSCG) as
maintenance therapy in ch i ldren w ith asthma:
a systematic review.
Tasche MJA, Uijen JHJ, Bernsen RMD, de Jongste JC, van der Wouden JC.
Thorax 2000; 55:913-20
Insufficient evidence that DSCG has abeneficial effect as maintenance treatment
in children with asthma
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Steroids
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Corticosteroids
The most effective anti-inflammatorymedications
Improving lung function Airway hiperresponsiveness:
Reducing symptoms
Frequency and severity ofexacerbations:
Improving quality of life
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Steroid efficacy in asthma
Benefit
Steroid
dose
Side-effects
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Benefit of steroid inhalation
Low dose
Directly to respiratory tract
Fast onset
Minimal systemic side effects
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Epithelial Repair Following Steroid Treatment
Before After
P Howarth, 1999
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Pathological feature
Laitinen LA et al, J Allergy Clin Immunol1992
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Bahasan
Konsep inflamasi dan remodeling pada asma
Klasifikasi asma
Tujuan tatalaksana
Longterm management:
Kapan?
Obat
Side effect
How early? Terapi inhalasi: kendala
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Side effects
hoarseness
Iritation of pharynx
Candidiasis
Headache
Growth disturbances??
Longterm steroid
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Effect of FP in Children < 2 yrs old
Teper AM et al. Pediatr Pulmonol 2004;37:1115
0.7
0.9
1.1
1.3
1.5
1.7
Plasebo FP 100mcg/day
FP 250mcg/day
RAT
IO
Ratio = (SDS+3) post / (SDS+3) pre
R = -0.026 (p = 0.27)
MaxMin
Mean + SDMean - SD
Mean
GROWTH (SDS)
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ICS and Growth
6,25,8
6,16,0
0
2
4
6
8
cm/year
12 months 24 months
FP 100 g bid (n=87) NS 4mg bid (n=87)
Roux C et al. Pediatrics, 2003;111:706-13
FP or Nedocromil Sodium for two years
Growth velocity
ns ns
B Mi l D it
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Bone Mineral Density
11.6
8.9
10.4
8.5
0
2
4
6
8
10
12
%meanincreaseinBM
D
after24months
Lumbar spine
FP 100 g bid (n=87)
NS 4mg bid (n=87)
Femoral neck
Roux C et al. Pediatrics, 2003;111:706-13
FP or nedocromil sodium for two years
ns
ns
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Foe or Friend
Corticosteroids
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Bahasan
Konsep inflamasi dan remodeling pada asma
Klasifikasi asma
Tujuan tatalaksana Longterm management:
Kapan?
Obat
Efek samping
How early?
Terapi inhalasi: kendala
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Early Intervention
Early intervention can be applied soon
after clinical asthma has occurred
The goals: reducing asthma symptomsand exacerbations safely
Repair processes to allow for normal lung
growth and development to proceed.
Liu AH. J Allergy Clin Immunol 2004;113:S19-24.
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Why early treatment is important?
Airways inflammation is already present in
intermittent asthma(Vignola AM et al. AJRCCM 1998;157:4039).
Significantly better airway function andasthma control than delayed treatment and
at lower maintenance doses(Selroos et al. Respir Med2004;98:25462)
Improved growth of lung function andasthmatic child treated(Devulapalli et al. ERJ 2004;23:869-75)
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Contra prophylaxis
Not all children with recurrent wheezingbecome asthma (after 6 years-old)
Abnormal lung function did not indicateirreversible lower airways obstruction
Not all studies proved the benefit of ICS inlung function at adulthood(Kaditis et al. Pediatr Pulmonol 2003;35:241-52)
Early wheezing did not result deficit of lung
function in the future(Turner et al. AJRCCM 2004;169:921-7)
No significant difference in lung function andclinical symptoms(Hofhuis et al. AJRCCM 2005;171:328-33)
AsthmaTransient
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Fig. 6. Hypothetical peak prevalence by age for the 3 different wheezing phenotypes.
The prevalence for each age interval should be the area under the curve. This does not
imply that the groups are exclusive.
AsthmaNon-Atopic
Wheezers
Transient
Wheezers
Age (years)
Whee
zingprevalence
0 3 6 11
Taussig LM, et al. JACI 2003;111:661-75
Low LFT
at birth
Post
RSV
BHR of
atopic asthma
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Pro prophylaxis
Improvement of clinical symptoms and no sideeffect(Bisgaard AJRCCM 1999;160:126-31)
Decreased of clinical symptoms, acuteexacerbation, sleep disturbances, andimprovement of lung function(OByrne et al. AJRCCM 2005;171:129-38)
Significantly reduced asthma symptoms, -2agonist using and improved FEV1(Kaditis et al. Pediatr Pulmonol2003;35:241-52)
Improved respiratory symptoms without sideeffects on growth and bone metabolism(Teper et al. PediatrPulmonol 2004;37:1115)
AsmaN At iTransient
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Fig. 6. Hypothetical peak prevalence by age for the 3 different wheezing phenotypes.
The prevalence for each age interval should be the area under the curve. This does not
imply that the groups are exclusive.
AsmaNon-AtopicWheezers
Transient
Wheezers
Umur (tahun)
Keja
dianwheezing
0 3 6 11
heezing berulang Major :
Dermatitis atopi
Orang tua asma
Minor Eosinofil darah
Wheezing
Rinitis alergika
Asma: jika
2 major atau
1 major +2 minor
Taussig LM, et al. JACI 2003; 111:661-675
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Management (research)
Anti IgE (Omalizumab)
rhuMAb-E25 (recombinant humanized
monoclonal antibody) Anti-interleukin (IL-4, IL-5)
research
Immunizations (genetic recombinant) research
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Topics
Konsep inflamasi dan remodeling pada asma
Klasifikasi asma
Tujuan tatalaksana Longterm management:
Kapan?
Obat
Efek samping
How early?
Inhalation therapy: handicaps
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Type of inhalation therapy
Metered dose inhaler(MDI)
With spacer
Without spacer
Dry powder inhaler(DPI)
Turbuhaler, cyclohaler
Nebulizer
Jet
Ultrasonic
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MERAH
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KUNING
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MERAH
BIRU
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Whats this ???
h h ???
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Whats this ???Horse Frog
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Limitations
Provider aspects
Miss perception
Lost of patient Medications aspects
Availability
Distribution
Price
Community aspects
Dangerous
Addictive Socio-cultural
Tools
Algorithm complexity
Equipment problems
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Positive impact of inhalation therapy
Quality of life
Quality of therapy
INHALATION
ORAL
Patient
FamilyFinancial
To another doctor
Go abroad(Low performance
of Indonesian
pediatricians )
Stable asthma
Patient Get Patient
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Conclusions
Asthma: Chronic inflammation andremodelling
Ketotifen and Disodium cromoglycate:Insufficient evidence as longtermmanagement
Corticosteroids with/without combination:drug of choice as longterm management
Indonesia: Guidelines of childhood asthmamanagement
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Harus Berjuang
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Harus Berjuang
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Longterm steroid
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Bone densitometry
Bone densitometry
3/38 cases (7.9%) DEXA: chronological age
below -1.0 13/37 patients (35.1%) DEXA: lumbar spine
(L2-4) chronological age below -1.0
Longterm steroid
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Longterm steroid
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Biochemical markers of bone metabolism
No significant:
serum osteocalcin
PINPALP
BALP
urine DPD/Cr ratio NTx/Cr ratio
Longterm steroid
400
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Petanda biokemis
400
350
300
250
200
150
100
50
0 NTx/Cr(nmol/mmol)
ALP(IU/L)
P1NP(mg/L)
BALP(IU/L)
OSTEO(ng/m)l
DPD/Cr(nmol/mmol)
Hasil
KontrolKasusStandard error
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No significant correlation between any of
the biochemical markers and DEXA z-score (chronological or bone age)
ongterm steroid
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B A L b S i (L2 L4)
ongterm steroid
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Bone Age Lumbar Spine (L2-L4)
Cu
mulativeProb
ability(%)
Z-score-4 -3 -2 -1 0 1 2 3 4
0
20
40
60
80
100
Reference Population
Study Population
Cumulative probability graphs of lumbar spinal density
In study population vs. reference population
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Efikasi steroid
Keungtungan dosis
Efek samping
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Keuntungan steroid inhalasi
Dosis rendah
Langsung ke sal respiratorik
Onset (awitan) cepat
Efek samping sistemik minimal
Modern view of Asthma
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Modern view of Asthma
Mucus
hypersecretion
Hyperplasia
Eosinoph i l
Mast cel l
Allergen
Th2 cell
VasodilatationNew vessels
Plasma leakOedema
Neutrophi l
Mucus plug
Macrophage/dendri t ic cel l
Bronchoconstriction
Hypertrophy / hyperplasia
Cholinergicreflex
Epithelial shedding
Subepithelial
fibrosis
Sensory nerveactivation
Nerve activation
Barnes PJ
R i li i t id + LABA
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Rasionalisasi steroid + LABA
Smooth muscledysfunction
Airwayinflammation
BronchoconstrictionBronchial hyperreactivityHyperplasiaInflammatory mediator release
Inflammatory cellinfiltration / activation
Mucosa oedemCellular proliferationEpithelial damageBasement membrane thickening
Symptoms / exacerbations
LABA CS
Evolving treatment options
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Evolving treatment options
1975
1980
1985
1990 19952000
Large use ofshort-acting
2-agonists
Fear of
short-acting
2-agonists
Single
inhaler therapy
(Symbicort)
ICS treatment
introduced
1972
Adding
LAA to ICS therapy
Kips et al, AJRCCM 2000Pauwels et al, NEJM 1997
Greening et al, Lancet 1992
Bronchospasm Inflammation Remodelling
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