Asthma

Phenotypes

Jaichat Mekaroonkamol, MD.

In young children

©2014 MFMER | slide-3

1970’s 1980’s 1990’s present

Bronchospasm Bronchospasm

+ Inflammation

Bronchospasm

+ Inflammation

+ Remodeling

T cell Eosinophil

Th-2

IL-5 / IL-13

Th17

Dendritic cells

CHEST 2013; 144(3):1026–1032.

Asthma Timelines

©2014 MFMER | slide-4

Our understanding of asthma

continues to increase overtime

Bronchoconstriction

Airway Hyperesponsiveness

Inflammation and remodeling

Phenotypes and genetics

What Is a “Phenotype”

Henderson J et al. Arch Dis Child. 2009

• Phenotype:

Any observable characteristic of an

individual that is influenced by genetic

and environmental factors

• Clinical relevance:

May reflect causal pathways specific to

subgroups of patients with asthma, may lead

to improved management and

Help to predict prognosis

Natural history and Pathophysiology

Inception

• Genetics

• Allergens

• Infections

Progression

• Inflammation • Bronchospasm

• Remodeling

Exacerbations

• Lung functions

Stanley J. Szefler. J Allergy Clin Immunol 2014;133:3-13.)

Clinical relevance

Diagnosis

Management

Prognosis

Diagnosing Asthma

GINA 2011

Clinical features

• Nocturnal

• Exercise

• Go to the Chest

Pulmonary Function test

• Spirometer: FEV1

• Peak Expiratory Flow:PEF

Probability

Confirm DX

• Asthma, which typically

begins in childhood and

occurs throughout life

• Major burden from asthma that persists into adult life

• Many different

„„phenotypes‟‟ that are

associated with variable

disease courses.

Presentation of asthma

Stanley J. Szefler. J Allergy Clin Immunol 2014;133:3-13.)

Presentation of asthma

Presentation of asthma

Does my child have asthma?

Key symptom indicators

Middleton ed 8th .

Not all wheeze is asthma

Martinez FD, et al. N Engl J Med 1995

Wheezing phenotypes

Renato T Stein. Thorax 1997;52:946-52.

• Newborn infants between May 1980 and

October 1984

• A total of 1246 children were initially enrolled • 11 years follow up

Tucson study

Wheezing phenotypes

No wheezing in

first 6 years of

birth 51.5%

Renato T Stein. Thorax 1997;52:946-52.

Wheezing phenotypes

Renato T Stein. Thorax 1997;52:946-52.

Wheezing phenotypes

J Henderson. Thorax 2008;63:974–980

• Birth to 7 years from 6265 children

• Longitudinal birth cohort

• the ALSPAC study • 14,541 pregnant women

AVON study

Wheezing phenotypes

J Henderson. Thorax 2008;63:974–980

Wheezing phenotypes

TUCSON study, 1997 • Never(51%)

• Transient early wheezers (20%)

•Wheezed first 3 years

•Resolved by 6 years

• Persistent wheezers(14%)

•Wheezed first 3 years

•Still present at 6 years

•Late-onset wheezers(15%)

•Wheezed after 3 years of age

•Still wheeze at 6 years

AVON study, 2001 •Never(51%)

• Transient (16%)

• Persistent (7%)

• Intermediate(3%)

•Late-onset (15%)

• Prolonged early(9%)

Wheezing phenotypes

AVON study, 2001 •Never(51%)

• Transient (16%)

• Persistent (7%)

• Intermediate(3%)

•Late-onset (15%)

• Prolonged early(9%)

TUCSON study, 1997 • Never(51%)

• Transient early wheezers (20%)

•Wheezed first 3 years

•Resolved by 6 years

• Persistent wheezers(14%)

•Wheezed first 3 years

•Still present at 6 years

•Late-onset wheezers(15%)

•Wheezed after 3 years of age

•Still wheeze at 6 years

• Recurrent bronchial

obstruction (rBO) defined

as recurrent (at least two

episodes) doctor-

diagnosed wheeze

• Asthma from 2–10 years

and 10–16 years, defined

as at least two episodes of

doctor-diagnosed

asthma,symptoms and medication use,

Eur Respir J 2013; 41: 838–845

Asthma diagnosis and relapse rate

Eur Respir J 2013; 41: 838–845

1/3

9%

Wheezing phenotypes

Basic of classification

Examples of clinical features

Symptoms • Age at onset

• Natural history/disease course • Severity

Triggers • Viruses

• Exercise

• Allergens

AAIAT Annual Meeting 2014

Common clinical elements that define

phenotypes in pediatric asthma

Trigger-Based Pediatric Phenotypes

Virus-induced asthma

Exercise-induced asthma

Allergen-induced asthma

Stanley J. Szefler. J Allergy Clin Immunol 2014;133:3-13.)

Virus-induced asthma

• Most common presentation

of asthma in early life

• 90% of children younger

than 3 years with acute

wheezing

• HRV

• RSV

• Influenza virus

• Metapneumovirus

Stanley J. Szefler. J Allergy Clin Immunol 2014;133:3-13.)

Virus-induced asthma

M.L. Garcı´a-Garcı´a, PhD. Pediatric

Pulmonology 45:585–591 (2010)

Virus-induced asthma

M.L. Garcı´a-Garcı´a, PhD. Pediatric Pulmonology 45:585–591 (2010)

Virus-induced asthma

M.L. Garcı´a-Garcı´a, PhD. Pediatric Pulmonology 45:585–591 (2010)

Virus-induced asthma: RSV

Stéphane A. Régnier, Pediatr Infect Dis J 2013;32: 820–826.

Virus-induced asthma: RSV

Stéphane A. Régnier, Pediatr Infect Dis J 2013;32: 820–826.

Virus-induced asthma: HRV

Daniel J. Jackson, Am J Respir Crit Care Med, 2008

*P , 0.05 vs. Neither

+P , 0.05 vs. RSV only

COAST study

259 child followed prospectively from birth

Virus-induced asthma: HRV

Tuomas Jartti & Matti Korppi, Pediatr Allergy Immunol 2011; 22: 350–355.

Virus-induced asthma: HRV

YoshimichiOkayama, Frontiers in Microbiology, 2013

Virus-induced asthma: HRV

• Airway edema

• Hypersecretion • Bronchospasm

YoshimichiOkayama, Frontiers in Microbiology, 2013

Viral infection and Atopic Development

Renato T Stein, Lancet 1999; 354: 541–45

Viral infection and Atopic Development

Serum IgE

SPT

Renato T Stein, Lancet 1999; 354: 541–45

Viral infection and Atopic Development

Jartti T, Kuusipalo H, Pediatr Allergy Immunol 2010; 21: 1008–1014

62% 12% 15%

Rhino

virus RSV Entero

virus

Boca

virus

Other

virus

≥ 2

virus

No

virus

Sensitization

32% 9% 0% Atopic eczema

• Aeroallergen sensitization (respectively; 4.18; 2.00, 8.72) • Food allergen sensitization (respectively2.02; 1.08, 3.78)

Virus-induced asthma

The risk of asthma after

viral LRI is increased in

the presence of allergic

sensitization in early life

and if the infection is

more severe

Atopy-associated

mechanisms also

appear to be involved in

viral-induced acute

exacerbations of

asthma

Peter D. Sly, J Allergy Clin Immunol 2010; 125:1202-5

Trigger-Based Pediatric Phenotypes

Virus-induced asthma

Exercise-induced asthma

Allergen-induced asthma

Stanley J. Szefler. J Allergy Clin Immunol 2014;133:3-13.)

Exercise -induced asthma

• Exercise: a common trigger of symptoms

– Affects up to 90% of children with asthma

– May occur with other triggers

• Loss of water and heat from airway appears to

initiate pathologic/proinflammatory response to

exercise.

•Cysteinyl leukotrienes and other eicosanoids

from mast cells and eosinophils perpetuate the

underlying inflammatory processes

Mayoclinic, 2011

Exercise -induced asthma

Inflammation and irritation

of airways

Broncho

constriction

Overcooling of airways

Dry of airways

Mechanic irritation of

airways

Mayoclinic, 2011

Exercise -induced asthma

Typical pattern of EIA.

• Patients often

experience improvement

in lung function during

exercise.

• Exercise-induced

asthma does not fully

manifest until after

exercise

Expert Rev Clin Immunol, 2009

Exercise -induced asthma

Duke University Health System

Trigger-Based Pediatric Phenotypes

Virus-induced asthma

Exercise-induced asthma

Allergen-induced asthma

Stanley J. Szefler. J Allergy Clin Immunol 2014;133:3-13.)

Allergens -induced asthma

Kerstin Gerhold, AACI 2007

Lancet, 2006; 368: 763–70

• The German Multicentre Allergy Study followed

1314 children from birth to 13 years of age

• 90% of children with wheeze but no atopy lost their

symptoms at school age and retained normal lung

function at puberty.

• Sensitisation to perennial allergens (eg, house dust

mite, cat and dog hair) developing in the first 3

years of life was associated with a loss of lung function at school age

≤3 yr

≤5 yr

The chronic course

of asthma

characterised by

airway hyper-

responsiveness and

impairment of lung

function at school

age is determined by

continuing allergic

airway inflammation

beginning in the first 3 years of life.

on lung function at age 7 years

Lancet, 2006; 368: 763–70

Allergens -induced asthma

CACI 2010; 23:180-182

Allergens -induced asthma

Daniel J. Stoltz, Clin Exp Allergy, 2014

AR

Allergens -induced asthma

• Sensitization to perennial allergens

was more strongly associated with

asthma risk • cat, dog, cockroach, D.p., D.f., Alternaria

alternata

• sensitization to seasonal allergens

was more closely associated with

rhinitis risk. • ragweed, silver birch, timothy grass

Daniel J. Stoltz, Clin Exp Allergy, 2014

Allergens -induced asthma

Daniel J. Stoltz, Clin Exp Allergy, 2014

Allergens -induced asthma

Dog exposure at birth was

associated with a reduced

risk of asthma, regardless

of dog sensitization status

during the first 6 years of life (p = 0.05).

Daniel J. Stoltz, Clin Exp Allergy, 2014

Wheezing phenotypes

Brand, Eur Respir J, 2008

Wheezing phenotypes

Brand, Eur Respir J, 2008

A Schultz, Acta Pædiatrica 2010

• 132, 2–6 year old

• doctor diagnosed asthma and on maintenance

inhaled steroids (fluticasone) • followed up at three-monthly intervals for a year

• Initial (retrospective) classification

• EVW/MTW in the past year • Re-classification

The retrospectively determined phenotype was

independent of gender, atopy, smokers in the home and maternal smoking during pregnancy (all p values>0.05)

A Schultz, Acta Pædiatrica 2010

Phenotypic classification

- remained the same in

50(45.9%)

- altered in 59 (54.1%)

- similar number of

children EVW to MTW/

no wheeze

The prospectively determined phenotype was independent of

gender, atopy, smokers in the home and maternal smoking during pregnancy (all p values>0.05)

A Schultz, Acta Pædiatrica 2010

• History from parents of preschool children with

recurrent wheeze may be insufficient to provide

a reliable classification of wheezing phenotype

as EVW or MTW

• Atopy, family history of atopy and gender were

not helpful in predicting whether the phenotype would be stable or variable

A Schultz, Acta Pædiatrica 2010

Asthma Predictive Tools

JOSÉ A. CASTRO-RODRÍGUEZ, Am J Respir Crit Care Med. 2000

Asthma Predictive Tools

JOSÉ A. CASTRO-RODRÍGUEZ, Am J Respir Crit Care Med. 2000

Asthma Predictive Tools

Anina M. Pescatore, J Allergy Clin Immunol , 2014; 133:111-8

Asthma Predictive Tools

Classic API

• Sensitivity 63.2%, Specificity 70.4%, PPV 59.7%, NPV 73.4%

Allergy 2013; 68: 531-8

Anina M. Pescatore, J Allergy Clin Immunol , 2014; 133:111-8

Clinical relevance

Diagnosis

Management

Prognosis

Management

PRACTALL, 2008; 63: 5–34

Episodic viral wheeze

Systemic Steroid

Inhaled corticosteroid:

ICS

Leukotriene receptor antagonist:

LTRA

Pediatr Allergy Immunol 2013; 24: 237–243.

Risk of recurrent

wheezing

• prednisolone

(bold line)

• placebo

7-yr follow-up

Risk of recurrent wheezing

Pediatr Allergy Immunol 2013; 24: 237–243.

Risk of recurrent wheezing

hazard ratio 2.33; 95% CI 1.11–4.90

Pediatr Allergy Immunol 2013; 24: 237–243.

Risk of recurrent wheezing

hazard ratio 3.54; 95% CI 1.51–8.30

Pediatr Allergy Immunol 2013; 24: 237–243.

J Pediatr 2003;143:725-30

Prednisolone 1-2 MKD

3-5 days in acute viral induced wheeze

J Pediatr 2003;143:725-30

Episodic viral wheeze

Systemic Steroid

Inhaled corticosteroid:

ICS

Leukotriene receptor antagonist:

LTRA

Inhaled corticosteroid: Continuous

Pediatrics 2009;123:e519–e525

N Engl J Med 2006;354:1985-97.

PEAK study

N Engl J Med 2006;354:1985-97.

Fluticasone Placebo

N Engl J Med 2006;354:1985-97.

N Engl J Med 2006;354:1985-97.

Inhaled corticosteroid: Continuous

Pediatrics 2009;123:e519–e525

• 12-week, multicenter, doubleblind, randomized,

parallel-group study

• 480 asthmatic infants and children (64% boys)

• Ages 6 months to 8 years

• Moderate persistent asthma.

• Approximately 30% of children were previously on

inhaled corticosteroids that were discontinued

before the study.

Pediatrics 1999; 103:414–421

Inhaled corticosteroid: Continuous

Pediatrics 2009;123:e519–e525

Pediatric Pulmonology, 2004; 37:111–115

• Age less than 2 years

• Asthmatic symptoms (3/3)

• three or more episodes of wheeze

• clinical improvement after bronchodilators

• familial history of asthma

OR any other clinical finding indicating atopy (e.g.

AR or eczema) in first-degree relatives.

N Engl J Med 2006; 354:1998-2005.

• 411 infants enrolled and randomly 294 infants

• Single-center, randomized, double-blind,

prospective study of three years‟ Duration

• Budesonide (Pulmicort, AstraZeneca), at a dose of

400 μg per day, or matching placebo was

administered by pressurized metered-dose inhaler

and a spacer for two weeks

• Initiated after a three-day episode of wheezing

N Engl J Med 2006; 354:1998-2005.

early intervention with intermittent ICS therapy

• no effect on the progression from episodic to persistent

wheezing in young children • no short-term effect on wheezing

N Engl J Med 2006; 354:1998-2005.

finding that was unaffected by the presence or absence of atopic dermatitis

N Engl J Med 2006; 354:1998-2005.

N Engl J Med 2009; 360:339-53

• 129 childrens

• 1 to 6 years of age

• receive 750 μg of FP or

placebo twice daily

• beginning at the

onset of an URI and

continuing to 10 days • 6 to 12 months

• ≥ 3 wheezing episodes in

their lifetime, triggered by

URI or

• received at least one

course of rescue systemic

corticosteroids in the

previous 6 months (or two

in the preceding 12

months) or • Hospital admission

N Engl J Med 2009; 360:339-53

In preschool-age children with

moderate-to-severe virus-induced

wheezing, preemptive treatment with

high-dose fluticasone as compared with

placebo reduced the use of rescue oral corticosteroids

Treatment with fluticasone was

associated with a smaller gain in height and weight

N Engl J Med 2009; 360:339-53

Episodic viral wheeze

Systemic Steroid

Inhaled corticosteroid:

ICS

Leukotriene receptor antagonist:

LTRA

Pediatr Pulmonol. 2005; 40:285–291

P < 0.01 P < 0.05

P < 0.001 P < 0.01

P < 0.01 P < 0.05

Family history of atopy/ asthma

Patient history

of eczema/ dry cough

Pediatr Pulmonol. 2005; 40:285–291

Leukotriene receptor antagonist: LTRA

odds ratio 0.78

Post-bronchiolitis recurrent wheezing

Wan-Sheng Peng. Pediatric Allergy and Immunology, 2014; 25: 143–150.

Leonard B. Bacharier, J Allergy Clin Immunol. 2008

• Randomized, double-blind placebo-controlled

• Twelve-month trial

• 238 children

• Aged 12-59 months

• Moderate-severe intermittent wheezing

• Received 7-days: early in respiratory tract illnesses

• budesonide inhalation suspension (1mg twice

daily)

• montelukast (4mg daily)

• placebos

p=0.66 Exacerbation in 12 months

Leonard B. Bacharier, J Allergy Clin Immunol. 2008

Leonard B. Bacharier, J Allergy Clin Immunol. 2008

Clinical relevance

Diagnosis

Management

Prognosis

Avon study (ALSPAC)

J Henderson, Thorax 2008;63:974–980

• wheezing after 18 months (not three years) of age was

more strongly associated with the development of

asthma and atopy

Avon study (ALSPAC)

• Lung function is more impaired in children with prolong

early, intermediate-onset and persistent wheezing

• Airway hyperresponsiveness was greatest in the

intermediate and late-onset phenotypes

J Henderson, Thorax 2008;63:974–980

Avon study (ALSPAC)

• Lung function is more impaired in children with prolong

early, intermediate-onset and persistent wheezing

• Airway hyperresponsiveness was greatest in the

intermediate and late-onset phenotypes

J Henderson, Thorax 2008;63:974–980

Tucson study

Debra A. Stern, Lancet, 2008

Tucson study

Age at diagnosis was linearly associated with FEV1/FVC ratio at age 22

Debra A. Stern, Lancet, 2008

Tucson study • ¼ of active

asthma at age

22 were newly

diagnosed • 71% females

Asthma remittance by age 22 was higher among males

Debra A. Stern, Lancet, 2008

Tucson study

M-OR multinomial odds ratio (estimated using multinomial logistic regression) with

all risk factors listed in the table included in the model with the no asthma group as

the reference group. Models were additionally adjusted for ethnicity, sex and current smoking at age 22

Debra A. Stern, Lancet, 2008

Tucson study

M-OR multinomial odds ratio (estimated using multinomial logistic regression) with

all risk factors listed in the table included in the model with the no asthma group as

the reference group. Models were additionally adjusted for ethnicity, sex and current smoking at age 22

Debra A. Stern, Lancet, 2008

Tucson study

F/U at age 22 years: risk for chronic asthma

• Persistent wheezing in early life

• Asthma at age 6 years

• Sensitization to Alternaria sp

• Low lung function at 6 years

• Bronchial hyperresponsiveness to cold dry air

at age 6 years

Debra A. Stern, Lancet, 2008

Thorax, 2010; 65:1045e1052

Thorax, 2010; 65:1045e1052

Thorax, 2010; 65:1045e1052

Allergic

rhinoconjunctivitis

p<0.01

p<0.001

Thorax, 2010; 65:1045e1052

Positive Phadiatop

test

p<0.001

Thorax, 2010; 65:1045e1052

Persistent/ relapsing wheeze

associated with early allergic

sensitisation predominated in the

RSV cohort compared with controls

Thorax, 2010; 65:1045e1052

Spirometric function was reduced in subjects

with RSV with or without current asthma Thorax, 2010

Thorax, 2010

Small airway dysfunction (LCI) is related to

current asthma and airway inflammation but not to RSV bronchiolitis

J Allergy Clin Immunol 2012; 130:103-10

Trousseau study

Cross sectional analysis

Less than 36 months of age with recurrent wheezing

Trousseau study

Cross sectional analysis

Less than 36 months of age with recurrent wheezing

• 59.3%

• mild disease

• triggered by viral upper respiratory infections (URIs)

J Allergy Clin Immunol 2012; 130:103-10

Trousseau study

Cross sectional analysis

Less than 36 months of age with recurrent wheezing

• 28.5%

• Moderate to severe

disease

• Need high doses of

ICS

• Parents with asthma

• Girls

• Abnormal CXR

J Allergy Clin Immunol 2012; 130:103-10

Trousseau study

Cross sectional analysis

Less than 36 months of age with recurrent wheezing

• 12.2%

• Multiple wheezing triggers

(eg, URIs, exercise, cold air)

• Boys

• Atopy

J Allergy Clin Immunol 2012; 130:103-10

Trousseau study

J Allergy Clin Immunol 2012; 130:103-10

Trousseau study

J Allergy Clin Immunol 2012; 130:103-10

Trousseau study

83%

76%

90%

J Allergy Clin Immunol 2012; 130:103-10

J Allergy Clin Immunol, 2014

Take Home Message

• Asthma phenotypes may reflect causal pathways

specific to subgroups of patients with asthma, may

lead to improved management and help to predict

prognosis

• Several early-childhood wheezing phenotypes have

been described based upon the natural history and

associated risk factors

• Asthma predictive tools were low sensitivity but high

NPV

• Management of viral induced wheeze in young

children was controversy

• Lung function is more impaired in children with

persistent wheezing

THANKS!