Phenotypes

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Development and Managementof Asthma in
ChildrenFernando D. Martinez, M.D.Arizona
Respiratory CenterThe University of Arizona
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An Epidemic No One Understands
When our first son developed asthma as a
3-year-old, my husband and I felt pretty much
blindsided. We were only a little less shocked
when the same thing happened to our second son,
at the same age. The disease turned out to be
tenacious, and for years both boys needed
inhalers or a nebulizer machine several times a
day to prevent asthma attacks that could keep
them up half the night, coughing and wheezing.
Denise Grady, New York Times November 28, 2006
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An Epidemic No One Understands
What caused all this? My husband and I were
mystified, because neither of us had asthma or
life-threatening allergies But we seem to have
been caught on a rising tide that no one fully
understandsbased on whats now known, could I
have done anything to prevent it? Was it bad that
we had cats when our children were born or that
we later gave them away? Asthma transformed me
and my husband from rather casual housekeepers
into mop-wielding fanatics. Im not sure it
helped.
Denise Grady, New York Times November 28, 2006
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Childhood Asthma What we Know That We Did Not
Know

• With the right therapeutic approach, most
  children with asthma can lead normal lives
• Childhood asthma is not a single disease
• Most cases of asthma start in the preschool years
• With rare exceptions, no single allergen causes
  childhood asthma
• No currently available medicine changes the
  course of the disease

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Childhood Asthma What we Know That We Did Not
Know

• With the right therapeutic approach, most
  children with asthma can lead normal lives
• Childhood asthma is not a single disease
• Most cases of asthma start in the preschool years
• With rare exceptions, no single allergen causes
  childhood asthma
• No currently available medicine changes the
  course of the disease

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Childhood Asthma 40 Years Ago
There was little that could be done to help the
asthmatic child preventive medications had yet
to be developed. The use of corticosteroids was
viewed with suspicion, and reserved for the most
intractable cases. Because asthma was widely
regarded as a psychosomatic disorder, some
extraordinary products were available for its
management, such as the combination of ephedrine,
theophylline and phenobarbitone in a single
tablet.
Ninan Russell, Paediatric Respiratory Reviews
2000 1 71
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Childhood Asthma 40 Years Ago
Asthma was therefore a life-long sentence to
chronic disability, punctuated by unpredictable,
frightening and difficult to treat acute
exacerbations. At its worst, the end result was a
severely disabled child, often with more or less
permanent dyspnoea, disturbed nights and day-time
somnolence, chest deformity, and inability to
enjoy normal childhood activitiesThese children
entered adult life having missed out on many of
the pleasures of normal childhood.
Ninan Russell, Paediatric Respiratory Reviews
2000 1 71
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Childhood Asthma What we Know That We Did Not
Know

• With the right therapeutic approach, most
  children with asthma can lead normal lives
• Childhood asthma is not a single disease
• Most cases of asthma start in the preschool years
• With rare exceptions, no single allergen causes
  childhood asthma
• No currently available medicine changes the
  course of the disease

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Different Asthma Phenotypes
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Transient Wheezing by Early Lung Function
plt0.0001
TransientWheezing
Quartiles of Vmax FRC at 2 months
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Atopic and Non-Atopic Wheezers
Illi et al, 2006 Lancet 368763
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Asthma and Wheezing Phenotypesin the Preschool
Years

• Transient Wheezers children who had MD-confirmed
  LRI with wheeze (WLRI) in early life but were not
  current wheezers at age 6
• Late Onset Wheezers current wheezers at age 6
  with no WLRI history
• Persistent Wheezers children with WLRI history
  who wheezed currently at age 6 yrs

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Clinical Outcomes of Wheezing Phenotypes in Early
Life
Morgan et al, AJRCCM. 20051721253
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Lung Function at Ages 1, 6, 11 and 16 Yearsby
Wheezing Phenotype

Morgan et al, AJRCCM. 20051721253
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Lung Function at Age 7 by Sensitization and
Exposure to Aeroallergens at Age 3
FVC
FEV1
Ratio
Illi et al, 2006 Lancet 368763
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Allergen Exposure
Genetic Predispositionto Allergies
Allergy,No Asthma
Sensitization
Genetic Predispositionto Asthma
Asthma
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Childhood Asthma What we Know That We Did Not
Know

• With the right therapeutic approach, most
  children with asthma can lead normal lives
• Childhood asthma is not a single disease
• Most cases of asthma start in the preschool years
• With rare exceptions, no single allergen causes
  childhood asthma
• No currently available medicine changes the
  course of the disease

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The Childhood Asthma Prevention Study (CAPS),
Sidney Australia

• Established in 1997
• Primary aims were to test whether in children at
  high risk of allergic disease the incidence of
  allergy and asthma at age 5 years could be
  reduced by the implementation of interventions
  directed at avoidance of HDM allergens, diet
  supplementation with omega-3 fatty acids, or a
  combination of these 2 interventions

Mihrshahi et al, JACI 2003111162
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Effectiveness of the Mite Avoidance Intervention
Marks et al, JACI 2006 11853
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Asthma and Wheezing at Age 5 by Mite
AvoidanceTreatment

Marks et al, JACI 2006 11853
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Asthma by Size of Alternaria Skin Test Responses
at Age 6 in Tucson, AZ
plt0.00001
Asthma
Alternaria Response
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FEV1/FVC Ratio by Skin Test at Age 6
p0.01
plt0.001
p0.01

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A Hypothesis

• Chronic asthma is caused by an alteration in the
  development of the immune system that makes the
  young child susceptible to becoming sensitized to
  the allergens she/he is raised around
• This susceptibility is NOT dependent on the
  concentration of the local allergen present in
  the environment
• Once the child is sensitized, exposure to the
  corresponding allergens may increased the risk of
  asthma symptoms and attacks

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Prevalence of Allergies by Endotoxin Exposure
Braun-Fahrländer et al. NEJM 347 (12) 869, 2002
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Endotoxin Exposure and IgE Mediated Sensitization
1.0
0.8
0.6
Predicted probability for sensitisation
P0.005
0.4
0.2
0.0
1.0
7.4
54.6
403.4
2981
22000
1.2x106
162755
Endotoxin Load (EU/m2)
Simpson et al, AJRCCM September 2006
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Maturation of Immune Responses in Infancy
Non-Allergic
Interferongamma responses(Th1)
Allergic
24-36
0
Age (months)
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Childhood Asthma What we Know That We Did Not
Know

• Childhood asthma is not a single disease
• Most cases of asthma start in the preschool years
• With rare exceptions, no single allergen causes
  childhood asthma
• With the right therapy, most children with asthma
  can lead normal lives
• No currently available medicine changes the
  course of the disease

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PEAK Study Design
Screening/ Eligibility
Run-in
Year 3
Years 1 2
1 month
Interim Efficacy Tests
Randomize

• Randomized, multicenter, double-blind,
  parallel group, placebo-controlled trial
• 285 two and three year olds at high-risk for
  asthma
• Fluticasone 44 ?g/puff or placebo (2 puffs
  b.i.d.)

Guilbert et al, NEJM 20063541985
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PEAK Primary Outcome

• Episode-free days during the observation-year
• No cough or wheeze
• No unscheduled clinic, urgent care, ER
  or hospital visits
• No use of asthma medications including
  bronchodilator
  pre-treatment before exercise

Guilbert et al, NEJM 20063541985
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Episode-free Days During the Entire Study
Guilbert et al, NEJM 20063541985
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ICS Effect During Treatment Phase
Asthma Exacerbations
Plt0.001
Guilbert et al, NEJM 20063541985
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ICS Effect on IOS MeasuresReactance at 5 Hz
p0.008 p0.83
Guilbert et al, NEJM 20063541985
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Asthma Treatment and Asthma Prevention a Tale
of 2 Parallel Pathways
Martinez FD 2007, JACI, in press
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Two (Provocative) Ideas

• Asthma-related airway remodeling and deficits in
  lung function growth occur mainly during the
  preschool years blocking the processes that
  cause these changes will drastically reduce
  persistent asthma
• In children with mild (moderate?) persistent
  asthma, intermittent, SABA-linked controller
  therapy may be as effective as daily therapy with
  ICS, and will be much more acceptable for parents
  and children alike

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