Download - Asthma phenotypes in young children
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
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
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!