AsthmaAetiology and Treatment

Julian VyasConsultant Respiratory Paediatrician

Starship Children’s Hospital, Auckland

“A chronic inflammatory disorder of the airways … in susceptible

individuals, inflammatory symptoms are usually associated with

widespread but variable airflow obstruction and an increase in airway

response to a variety of stimuli. Obstruction is often reversible, either

spontaneously or with treatment.”

BTS/SIGN guidelines 2002

“The diagnosis of asthma is a clinical one; there is no

standardised definition of the type, severity or frequency of

symptoms, nor of the findings on investigation. The absence

of a gold standard definition means that it is not possible to

make clear evidence based recommendations on how to

make a diagnosis of asthma.”

BTS/SIGN guidelines 2012

Definition

Childhood Asthma Definitions

• What is asthma?– Single disease

– Single final common pathway

• Asthma vs viral induced wheeze/ pre school wheeze

• Tendency to refer to “Asthma phenotype”– Suggests that a number of different processes result in

wheezing

• Ease/worth of differentiation complicated by absence of mechanisms to interrupt disease development

• Purpose of differentiation of pathophysiologies will become important when inflam modulation/ disease modifying Rx available.

ASTHMA

ASTHMA

The Global Burden of Asthma, GINA, 2003

Oz 28.8%

NZ 26.8%

Highest =

Wales 29.8%

• 15% of all New Zealanders

• Migrant > Indigenous

• Fatal 4.6 per 100,000

• Heavy burden on Maori

and Pacific Islanders

• Paed Hospitalisation rates

> adults by several times

Asthma in New Zealand

• 6-7 yr olds

– Maori 32%

– Euro 26%

– Pacific Islanders

21%

• Why such high

rates of asthma?

Asher et al. N Z Med J 2001;114:114-120

Regional variation

•Prevalence

•Hospitalisation

rates

15-20%

20-30%

> 30%

Asthma in New Zealand

Asthma aetiologyGenetic

Diet

Birth weight

Smoking

Allergy

Infection

GOR

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

Identical twins > non-identical

FH of asthma/atopy

Risk of asthma = x3 for 1 parent; x6

for both

17 poss genes variety of asthma

related factors

receptors, ECP, TGF

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

Antioxidant intake bronchial hyper-responsiveness

– Shaheen 2001: asthma severity negatively assoc with consumption of Selenium, red wine, apples

– Wood 2000: [8-isoPGF2] assoc with asthma severity;

• [Plasma antioxidant] (vit E, vit C, carotene, Zn, Se)

• Enzyme antioxidant activity (GSH peroxidase, SOD)

• Zn and Se assoc with severity asthma and [8-isoPGF2]

– Japan: decreased incidence ofasthma; increased fish oils

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

In utero exposure

abnormal lung growth, dilated bronchi, tortuous

bronchi, abnormal mucosa

increased neuroepithelial bodies (airway oxygen

sensors),

decreased fetal lung weight,

reduced number and size of fetal alveoli,

reduced peribronchial elastic tissue

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

Smoking during childhood…

..increases airway hyper-responsiveness

..effect less striking with age

..early airway responsiveness to histamine

(1/12) predicts FEV1 at 6 years

..reduced parental smoking assoc with improved

asthma symptoms; mainly if no FH atopy

Smoking

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

Increased wheezing in LBW infants

? Asthma

? viral induced wheezing

Barker hypothesis

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

Many known ”allergic” precipitants:

Cats (saliva)

HDM (D. pteronyssius faeces)

Cockroach

Trees

Grasses

Rodents

? Salicylates in food (!)

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

Good Bad

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

BadRSV “allergic type” residual effects

Anti-RSV IgE persists at least 12/12

[anti-RSV IgE] wheeze

(conc in wheezers > non-wheezers)

Anti-RSV IgE correlate with positive

allergen skin tests at 9 years

[histamine] at acute illness weak

correlation with severity of hypoxia - ?

Other mediators of wheeze

RSV+ LRTI assoc with LTC4 by ? IgE

dependent mechanism (83% IgE pos vs

29% IgE neg)

LTB4 (neut and eo chemoattractant) +

LTD 4 in 30% RSV-LRTI

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

BadRSV Infection; cellular response

Viral clearance in 7/7 (N cell med

immunity)

N response to viral inf = T lymps bind to

target cell receptors; ICAM-1 ligands.

Other viral infections release IFN-,

TNF-.

These cytokines amplify inflam

response to infection

RSV infection appears to block some of

these early cellular responses. ?

significance

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

GoodSome evidence that infection with

non-pathogenic mycobacterium can reduce

eczema in genetically modified mice

Asthma

CD4+

TH2

TH1

IFN-

IL-12IL-4

-

-

IL-2

IL-3

IFN-

TNF-

IL-4

IL-5

IL-6

IL-10

IL-13

Anderson. Trends Pharmacol Sci 1994; 15

ALLERGIC RESPONSE

INFLAMMATORY RESPONSE

IFN-

IL-12

IL-4

RSV

+

TB

+

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

Increased prevalence of GOR in children

with asthma

? GOR causes wheeze / ? Asthma causes GOR

Not the same as possetting

Can be clinically unexpected

Not just with aspiration – acid in lower oesophagus

can cause bronchspasm

pH probe needs to be related to symptoms

Asthma

Aetiology

– Genetic

– Diet

– Smoking

– Birth weight

– Allergy

– Infection

– GOR

Pathophysiology

www.azmacort.com

Stepwise management ofasthma in children aged 5-12 years

SIGN 2012

Step 1: Mild intermittent asthma

Step 5: Continuous or frequent use of oral steroids

Step 4: Persistent poor control

Step 3: Add-on therapy

Step 2: Regular preventer therapy

Stepwise management ofasthma in children aged 5-12 years

SIGN 2012

Step 1: Mild intermittent asthma

Inhaled short acting ß2 agonist as required

Stepwise management ofasthma in children aged 5-12 years

SIGN 2012

Step 2: Regular preventer therapy

Add inhaled steroid 200-400mcg/day *

(other preventer drug if inhaled steroid cannot be used)

200mcg is an appropriate starting dose for many patients

Step 1: Mild intermittent asthma

Start at dose of inhaled

steroid appropriate to

severity of disease.

* BDP or equivalent

Stepwise management ofasthma in children aged 5-12 years

SIGN 2012

Step 3: Add-on therapy

1. Add inhaled long-acting ß2 agonist (LABA)

2. Assess control of asthma:

• good response to LABA – continue LABA.

• benefit from LABA but control still inadequate – continue LABA and increase

inhaled steroid dose to 400mcg/day * (if not already on this dose).

• no response to LABA – stop LABA and increase inhaled steroid to

400mcg/day *. If control still inadequate, institute trial of other therapies (e.g.

leukotriene receptor antagonist or SR theophylline).

Step 1: Mild intermittent asthma

Step 2: Regular preventer therapyStart at dose of inhaled

steroid appropriate to

severity of disease.

* BDP or equivalent

Stepwise management ofasthma in children aged 5-12 years

SIGN 2012

Step 4: Persistent poor control

Increase inhaled steroid up to 800mcg/day *

Step 1: Mild intermittent asthma

Step 3: Add-on therapy

Step 2: Regular preventer therapyStart at dose of inhaled

steroid appropriate to

severity of disease.

* BDP or equivalent

Stepwise management ofasthma in children aged 5-12 years

SIGN 2012

Step 5: Continuous or frequent use of oral steroids

Use daily steroid tablet in lowest dose providing adequate control

Maintain high dose inhaled steroid at 800mcg/day *

Refer patient to respiratory paediatrician

Step 1: Mild intermittent asthma

Step 3: Add-on therapy

Step 2: Regular preventer therapyStart at dose of inhaled

steroid appropriate to

severity of disease.

* BDP or equivalent

Step 4: Persistent poor control

Stepwise management ofasthma in children under 5 years

SIGN 2012

Step 1: Mild intermittent asthma

Step 4: Persistent poor control

Step 3: Add-on therapy

Step 2: Regular preventer therapy

Stepwise management ofasthma in children under 5 years

SIGN 2012

Step 1: Mild intermittent asthma

Inhaled short acting ß2 agonist as required

Stepwise management ofasthma in children under 5 years

SIGN 2012

Step 2: Regular preventer therapy

Add inhaled steroid 200-400mcg/day * †

(leukotriene receptor antagonist if inhaled steroid cannot be used)

Step 1: Mild intermittent asthma

Start at dose of inhaled steroid

appropriate to severity of disease.

* BDP or equivalent† Higher nominal doses may be

required if drug delivery is difficult

Stepwise management ofasthma in children under 5 years

SIGN 2012

Step 3: Add-on therapy

In children aged 2-5 years consider addition of leukotriene

receptor antagonist

In children under 2 years consider proceeding to step 4

Step 1: Mild intermittent asthma

Step 2: Regular preventer therapy

Step 3: Add-on therapy

Step 2: Regular preventer therapy

Stepwise management ofasthma in children under 5 years

SIGN 2012

Step 4: Persistent poor control

Refer to respiratory paediatrician

Step 1: Mild intermittent asthma

Treatment Administration

Inhaled vs oral vs other

• Inhaled : large vol spacers, aerochambers, dry

powder, nebs

• Oral: monteleukast, theophyllines, salbutamol

• Other: sub cutaneous

Asthma

• Chronic inflammatory disorder

• “There’s a lot of it about”

• Rx stepwise

• Monitor symptom control

Diagnosis

DDx (other causes of wheezing and dyspnoea)

Infection: viral inf, mycoplasma, TB

Congenital: CF, PCD, immunodeficiency

Anatomical abnormality: TOF, airway malacia, airway stenosis, vasc ring

GOR

Foreign body

Laryngeal dysfunction

Diagnosis

Can be difficult

2 key questions:

“Are the symptoms significant”

“Is this something else, other than asthma”

Diagnosis

“Are the symptoms significant”

Symptoms / History:

– Episodic wheeze ± cough, increased with intercurrent RTI’s,

– Recognisable/predictable precipitants (e.g. cats etc, cold air,

exercise)

– Dry cough in wee small hours

– Periods when completely well

– Periods when admitted to hospital with breathing difficulties

– Response to inhalers and/or steroids

– Family history of atopy or asthma

Diagnosis

“Are the symptoms significant”

Signs:

– Polyphonic wheeze heard now/in the past

– Hyperinflation observed now/in the past

– Harrison’s sulcus (?)

Investigations:

– Normal CXR when well

– Obstructive lung function tests (spirometry), with bronchodilator

responsiveness - ??? Peak flow

Diagnosis

“Is this something else, other than asthma”

History/symptoms:

– Persistent symptoms even on best day

– Moist cough

– No response to bronchodilators and/or steroids

– Better with antibiotics

– FH of other lung disease e.g. CF, TB; or of early death in childhood

from “pneumonia”

– PMH:

• recurrent pneumonia/bronchitis;

• Infections elsewhere – purulent ear infections, abscesses, boils, chronic

diarrhoea

Diagnosis

“Is this something else, other than asthma”

Signs:

– Clubbing

– Chronic purulent ear infections, skin scars from infection

– smokers cough

– Focal chest signs, esp crackles >> wheeze

Investigations:

– Sputum culture +ve

– CXR abnormal when “well”

– Spirometry shows restrictive pattern, or no improvement with

bronchodilators, or steroids

What to remember

Asthma is:

• Multifactorial

• Common in NZ

• If no response to treatment (assuming proper Rx

use/techniques etc) or if picture not typical consider

other Dx – even if only to return to original Dx of

asthma

Questions