Asthma in children

Dr.Nurjannah,Sp.A

Topics
Inflammations and remodeling in asthma Classification of asthma Goal of asthma management Longterm management: When? Medications Side effects How early? Inhalation therapy: handicaps??

EVOLUTION OF ASTHMA
1950Reversible respiratory tract obstruction spontaneous or after bronchodilator treatment

1960-

Episodic, obstruction due to bronchial hyperresponsiveness (bronchial hyperactive)

1970-

Chronic conditions: recurrent bronchospasm due to narrowing respiratory tract as a stimuli response
Bronchospasm preventive concept
WHO, 1975

1990-an

Chronic inflammationcellular infiltrate, oedema, epithelial damage, fibrosis Anti-inflammatory drugs

OPERATIONAL DEFINITION

1989: 1992:

International Pediatric Consensus Statement on the Management of Childhood Asthma

Arch Dis Child 1992;67:240-8.

1998:

International Pediatric Consensus Statement on the Management of Childhood Asthma

Warner dkk. Pediatr Pulmonol 1998;25:1-7

Chronic inflammatory of respiratory tract Many cells and cellular elements play a role (mast cell, eosinophils, T lymphocytes)
GINA, 2002

2002

Complex definition difficult aplication and not practical

Diagnosis of Asthma
Cough

and/or wheezing that:

episodic, nocturnal (variability), reversibility

with atopic family

Inflammation
desquamation of epithelium Mucosal gland hyperplasia

Mucus plug

Basal membrane thickening

Oedema Smooth muscle constriction and hypertrophy

Barnes PJ

Netrophil and eosinophil infiltrations

Inflammation picture
Normal Asthma

Inflammation in asthma
Acute inflammation

Steroids Response

Chronic inflammation

Structure changes

Time

Barnes PJ

Topics
Konsep inflamasi dan remodeling pada asma Classification of asthma Tujuan tatalaksana Longterm management: Kapan? Obat Efek samping How early? Terapi inhalasi: kendala

Classification of asthma
Severity of attacks (Acute)
Mild Moderate Severe Respiratory arrest imminent

Class of disease (Chronic)

Infrequent episodic asthma Frequent episodic asthma Persistent asthma

Classification of disease
Clinical parameter , And lung function Infrequent episodic asthma Frequent episodic asthma Persistent asthma

Freq of attacks Duration of attacks Between episodes

< 1x /month < 1 week No symptoms

> 1x /month >1 week Symptoms (+)

Daily
Daily Frequent nocturnal symptoms

Sleep and activity

Physical exam Controller

Normal
Normal No need

May affect
May affect

Affect
Abnormal

Steroid/combination Steroid/combination

Lung function (No attacks)

Variability (attacks)

PEF/FEV1 >80% PEF/FEV1 60-80% >15% > 30%

PEF/FEV1 <60% Variability 20-30%

> 50%

Topics
Konsep inflamasi dan remodeling pada asma Klasifikasi asma Goal of asthma management Longterm management: Kapan? Obat Efek samping How early? Terapi inhalasi: kendala

Goal of asthma management

Minimal (ideally no) chronic symptoms Minimal (infrequent) exacerbations No emergency visits Minimal (ideally no) use of as needed 2agonist No limitations on activities (exercise) (Near) Normal lung function Minimal (or no) adverse effects from medicine

Last goal.

Improvement Quality of life

Asthma management
Allergen avoidance

Pharmacotherapy

COSTS

Immunotherapy

Education
GINA, 2002

Bahasan
Konsep inflamasi dan remodeling pada asma Klasifikasi asma Tujuan tatalaksana Longterm management: When?

Obat
Efek samping How early? Terapi inhalasi: kendala

Cost ?
Availability ?

When??
Classifications
Infrequent episodic asthma Frequent episodic asthma

Controller
No Yes

Reliever
Yes Yes

Persistent asthma

Yes

Yes

Topics
Konsep inflamasi dan remodeling pada asma Klasifikasi asma Tujuan tatalaksana Longterm management: Kapan? Medication How early? Efek samping Terapi inhalasi: kendala

Medications
Bronchodilators Antiinflammations Anti-remodeling Anti IgE Immunizations: ??

TREATING ASTHMA
with Bronchodilators alone

is like

Painting over rust

!!!

Anti-inflammations
Antihistamine Disodium Cromoglycate (DSCG) Corticosteroids Anti PDE 4 (Phosphodiesterase)

Long-term placebo-controlled trial of ketotifen in the management of preschool children with asthma
Loftus 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

Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with 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 a beneficial effect as maintenance treatment in children with asthma

Steroids ????

Corticosteroids
The most effective anti-inflammatory medications Improving lung function Airway hiperresponsiveness: Reducing symptoms Frequency and severity of exacerbations: Improving quality of life

Longterm management

Low dose steroid

Medium dose steroid

Low dose steroid + LABA

Low dose steroid + ALTR

Low dose steroid +TSR

High dose steroid

Medium dose steroid + LABA

Medium dose steroid + ALTR

Medium dose steroid + TSR

ORAL STEROID

Steroid efficacy in asthma

Benefit

Steroid dose

Side-effects

Benefit of steroid inhalation

Low dose Directly to respiratory tract Fast onset Minimal systemic side effects

Epithelial Repair Following Steroid Treatment

Before

After
P Howarth, 1999

Pathological feature

Laitinen LA et al, J Allergy Clin Immunol 1992

Bahasan
Konsep inflamasi dan remodeling pada asma Klasifikasi asma Tujuan tatalaksana Longterm management: Kapan? Obat Side effect

How early?
Terapi inhalasi: kendala

Longterm steroid

Side effects
hoarseness Iritation of pharynx Candidiasis Headache Growth disturbances??

Effect of FP in Children < 2 yrs old

GROWTH (SDS)
1.7 1.5

RATIO

1.3

1.1 0.9

Max Min Mean + SD Mean - SD Mean Plasebo FP 100 mcg/day FP 250 mcg/day

0.7

Ratio = (SDS+3) post / (SDS+3) pre R = -0.026 (p = 0.27) Teper AM et al. Pediatr Pulmonol 2004;37:1115

ICS and Growth

FP or Nedocromil Sodium for two years Growth velocity
cm/year
8 6 4 2 0
FP 100 g bid (n=87)
NS 4mg bid (n=87)

ns
6,0 6,2

ns
6,1 5,8

12 months
Roux C et al. Pediatrics, 2003;111:706-13

24 months

Bone Mineral Density

FP or nedocromil sodium for two years
FP 100 g bid (n=87) NS 4mg bid (n=87)

ns
% mean increase in BMD after 24 months
12 11.6 10 8 6 4 10.4

ns
8.9
8.5

2
0

Lumbar spine
Roux C et al. Pediatrics, 2003;111:706-13

Femoral neck

Corticosteroids
Foe
or

Friend

Bahasan
Konsep inflamasi dan remodeling pada asma Klasifikasi asma Tujuan tatalaksana Longterm management: Kapan? Obat Efek samping How early? Terapi inhalasi: kendala

Early Intervention
Early intervention can be applied soon after clinical asthma has occurred The goals: reducing asthma symptoms and exacerbations safely Repair processes to allow for normal lung growth and development to proceed.

Liu AH. J Allergy Clin Immunol 2004;113:S19-24.

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 and asthma control than delayed treatment and at lower maintenance doses (Selroos et al. Respir Med
2004;98:25462)

Improved growth of lung function and asthmatic child treated (Devulapalli et al. ERJ 2004;23:869-75)

Contra prophylaxis
Not all children with recurrent wheezing become asthma (after 6 years-old) Abnormal lung function did not indicate irreversible lower airways obstruction Not all studies proved the benefit of ICS in lung function at adulthood (Kaditis et al. Pediatr Pulmonol 2003;35:24152)

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 and clinical symptoms (Hofhuis et al. AJRCCM 2005;171:328-33)

Wheezing prevalence

Wheezers Low LFT

Transient

at birth

Non-Atopic Wheezers

Asthma

BHR of atopic asthma

Post RSV
0 3 6

Age (years)

11

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.
Taussig LM, et al. JACI 2003;111:661-75

Pro prophylaxis
Improvement of clinical symptoms and no side effect (Bisgaard AJRCCM 1999;160:126-31) Decreased of clinical symptoms, acute exacerbation, sleep disturbances, and improvement of lung function (OByrne et al. AJRCCM 2005;171:129-38) Significantly reduced asthma symptoms, -2 agonist using and improved FEV1 (Kaditis et al. Pediatr Pulmonol
2003;35:241-52)

Improved respiratory symptoms without side effects on growth and bone metabolism (Teper et al. Pediatr
Pulmonol 2004;37:1115)

Kejadian wheezing

Wheezers

Transient

Non-Atopic Wheezing berulang Wheezers Major : Dermatitis atopi Orang tua asma Minor Eosinofil darah Wheezing Rinitis alergika Asma: jika 2 major atau 1 major +2 minor

Asma

3 Umur (tahun)

11

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.
Taussig LM, et al. JACI 2003; 111:661-675

Management (research)
Anti IgE (Omalizumab)
rhuMAb-E25 (recombinant humanized monoclonal antibody)

Anti-interleukin (IL-4, IL-5)

research

Immunizations (genetic recombinant)

research

Topics
Konsep inflamasi dan remodeling pada asma Klasifikasi asma Tujuan tatalaksana Longterm management: Kapan? Obat Efek samping How early? Inhalation therapy: handicaps

Type of inhalation therapy

Metered dose inhaler (MDI)
With spacer Without spacer

Dry powder inhaler (DPI)

Turbuhaler, cyclohaler

Nebulizer
Jet Ultrasonic

MERAH

KUNING

MERAH
BIRU

Whats this ???

Whats this ???

Horse Frog

Limitations
Provider aspects
Miss perception Lost of patient

Community aspects
Dangerous Addictive Socio-cultural

Medications aspects
Availability Distribution Price

Tools
Algorithm complexity Equipment problems

Positive impact of inhalation therapy

INHALATION
Family Financial

ORAL

Quality of life
Patient

Quality of therapy

To another doctor Go abroad

(Low performance of Indonesian pediatricians )

Stable asthma Patient Get Patient

Conclusions
Asthma: Chronic inflammation and remodelling Ketotifen and Disodium cromoglycate: Insufficient evidence as longterm management Corticosteroids with/without combination: drug of choice as longterm management Indonesia: Guidelines of childhood asthma management

Harus Berjuang

Longterm steroid

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

Biochemical markers of bone metabolism

No significant:
serum osteocalcin PINP ALP BALP urine DPD/Cr ratio NTx/Cr ratio

400

350
300 250 Hasil 200 150 100 50

Kontrol Kasus Standard error

NTx/Cr (nmol/mmol)

ALP (IU/L)

P1NP (mg/L)

BALP (IU/L)

OSTEO (ng/m)l

DPD/Cr (nmol/mmol)

Petanda biokemis

Longterm steroid

No significant correlation between any of the biochemical markers and DEXA zscore (chronological or bone age)

Longterm steroid

Chronological age lumbar Spinal (L2-L4)

100 Reference Population Study Population

Cumulative Probability (%)

80

60

40

20 0

-4

-3

-2

-1

Z-score
Cumulative probability graphs of lumbar spinal density In study population vs. reference population

Longterm steroid

Bone Age Lumbar Spine (L2-L4)

100 Reference Population Study Population 80

Cumulative Probability (%)

60

40

20

0 -4 -3 -2 -1

Z-score

Cumulative probability graphs of lumbar spinal density In study population vs. reference population

Efikasi steroid

Keungtungan

dosis

Efek samping

Keuntungan steroid inhalasi

Dosis rendah Langsung ke sal respiratorik Onset (awitan) cepat Efek samping sistemik minimal

Modern view of Asthma

Allergen Macrophage/ dendritic cell Th2 cell Eosinophil Mucus plug Nerve activation Epithelial shedding Mast cell

Neutrophil

Subepithelial fibrosis Plasma leak Oedema Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy / hyperplasia

Mucus hypersecretion Hyperplasia

Vasodilatation New vessels

Barnes PJ

Rasionalisasi steroid + LABA

Smooth muscle dysfunction Airway inflammation

LABA

CS

Bronchoconstriction Bronchial hyperreactivity Hyperplasia Inflammatory mediator release

Inflammatory cell infiltration / activation Mucosa oedem Cellular proliferation Epithelial damage Basement membrane thickening

Symptoms / exacerbations

Evolving treatment options

Large use of short-acting 2-agonists 1975 ICS treatment introduced 1972 Adding LAA to ICS therapy
Kips et al, AJRCCM 2000 Pauwels et al, NEJM 1997 Greening et al, Lancet 1992 Single

inhaler therapy (Symbicort)

Fear of short-acting 2-agonists

1980

1985 1990
Bronchospasm Inflammation

2000

1995
Remodelling