Phenotypes by pengxiuhui

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									Development and Management
    of Asthma in Children

   Fernando D. Martinez, M.D.
      Arizona Respiratory Center
       The University of Arizona
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
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 understands…based on what’s 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. I’m not sure it helped.

           Denise Grady, New York Times November 28, 2006
    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
    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
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
   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 activities…These children entered adult life
having missed out on many of the pleasures of normal
childhood.

                Ninan & Russell, Paediatric Respiratory Reviews 2000; 1: 71
    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
Different “Asthma” Phenotypes
                 Transient Wheezing by
                  Early Lung Function
            40               p<0.0001
            35
            30

   %
            25
Transient   20
Wheezing
            15
            10
            5
            0
                 First      Second       Third       Fourth
                     Quartiles of V’max FRC at 2 months
Atopic and Non-Atopic Wheezers




                    Illi et al, 2006; Lancet 368:763
      Asthma and Wheezing Phenotypes
           in 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
                                  Clinical Outcomes of Wheezing
                                      Phenotypes in Early Life
                             80
                                                                                        Wheeze 1-3 times past year
                                                                                        Wheeze ge 4 times past year
% of Phenotype with Wheeze




                             60




                             40




                             20




       0
   Phenotypes: NW                  TEW LOW   PW   NW    TEW LOW   PW   NW    TEW LOW   PW        NW    TEW LOW   PW
            n: 355                 131  99   80   392   151 120   99   307   118  79   68        316   117  96   77
                                    Age 8                Age 11              Age 13                    Age 16




                                                        Morgan et al, AJRCCM. 2005;172:1253
Lung Function at Ages 1, 6, 11 and 16 Years
        by Wheezing Phenotype
                               0.4

                               0.2
   Z-Scores of Adjusted Flow




                               0.0
                                                                            †

                               -0.2                   *                                         *
                                                                                                     
                                                              *             *‡
                               -0.4

                               -0.6

                                                                                      Never Wheeze
                               -0.8
                                          *                                           Transient Early
                                                                                      Late Onset
                               -1.0
                                                                                      Persistent

                               -1.2
                                      0       2   4       6          8    10     12       14        16   18
                                                                   Age, years

                                                                  Morgan et al, AJRCCM. 2005;172:1253
Lung Function at Age 7 by Sensitization
and Exposure to Aeroallergens at Age 3
            FVC     FEV1         Ratio




                           Illi et al, 2006; Lancet 368:763
                         Allergen Exposure


Genetic Predisposition
     to Allergies

                                              Allergy,
                           Sensitization
                                             No Asthma

Genetic Predisposition
      to Asthma


                            Asthma
    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
        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 2003;111:162
    Effectiveness of the
Mite Avoidance Intervention




                   Marks et al, JACI 2006; 118:53
           Asthma and Wheezing at Age 5
            by Mite AvoidanceTreatment
    40

    35

    30

    25
%
    20
                                                                          Control
    15                                                                    Active

    10

     5

     0
         Probable   Frequent   Persistent Late Onset Transient
          Asthma     Wheeze     Wheeze     Wheeze     Wheeze

                                                Marks et al, JACI 2006; 118:53
     Asthma by Size of Alternaria Skin Test
      Responses at Age 6 in Tucson, AZ
       60
                  p<0.00001
       50

       40
  %
Asthma 30

       20

       10

        0
            Neg     3-4 mm    5-8 mm   9-12 mm   >12 mm
                      Alternaria Response
     FEV1/FVC Ratio by Skin Test at Age 6

    84                          p<0.001      p=0.01
                p=0.01

    82
    80
%   78                                                Negative
    76                                                Pos, Altern neg
                                                      Altern pos
    74

    72
    70
         Yr11            Yr16             Yr22
                     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
  Exposure to Stables and/or Farm Milk in
          the First Year of Life.

       16                                Exposed
   %                                     Non-exposed
       14
       12
       10
       8
       6             *                               *
       4
       2
       0
                   Asthma ever              Asthma attacks past 12 mo

                                                                        * p<0.0001
Riedler et al, Lancet. 2001 Oct 6;358:1129-33.
Prevalence of Allergies by Endotoxin Exposure




              Braun-Fahrländer et al. NEJM 347 (12): 869, 2002
            Endotoxin Exposure and IgE
              Mediated Sensitization
                Predicted probability for sensitisation   1.0
                                                           1.0




                                                          0.8
                                                            .8




                                                          0.6
                                                            .6




                                                          0.4
                                                            .4
                                                                   P=0.005



                                                          0.2
                                                            .2


                                                                                                                          CCccc
                                                           0.0
                                                          0.0
                                                               0
                                                             1.0     2
                                                                    7.4      4
                                                                            54.6      6
                                                                                    403.4    8
                                                                                            2981     10
                                                                                                   22000       12
                                                                                                             162755     14
                                                                                                                      1.2x106

                                                                               Endotoxin recovered (EU/m2)
                                                                          Ln total endotoxinLoad (EU/m2)
Simpson et al, AJRCCM September 2006
                 Maturation of Immune Responses
                             in Infancy

                      Non-Allergic
Interferon
gamma
responses
(Th1)

                                                    Allergic




             0                                            24-36
                                     Age (months)
    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
                PEAK: Study Design

    Screening/
     Eligibility Run-in          Treatment                Observation

               1 month       Years 1 & 2                   Year 3


                Randomize        Interim Efficacy Tests

• 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 2006;354:1985
    PEAK: Primary Outcome

 Episode-freedays 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 2006;354:1985
                                           Episode-free Days
                                         During the Entire Study
                                                  Treatment           Observation
                                                          †   †   †
Proportion of Episode-free Days



                                  1.00

                                  0.95

                                  0.90

                                  0.85
                                              ICS
                                  0.80        Placebo
                                          †   p<0.05
                                  0.75        p<0.01
                                              6      12       18    24   30    36
                                                              Months
         Guilbert et al, NEJM 2006;354:1985
    ICS Effect During Treatment Phase
                Asthma Exacerbations
         100

          80
Number per
 100 child 60
                                                      Placebo
  years
          40                                          ICS
          20

           0
                     P<0.001
                               Guilbert et al, NEJM 2006;354:1985
         ICS Effect on IOS Measures:
              Reactance at 5 Hz

          End of      End of
        treatment   observation
-0.33

-0.36
                                          Placebo
-0.39                                     ICS
-0.42

-0.45
        p=0.008      p=0.83
                           Guilbert et al, NEJM 2006;354:1985
Asthma Treatment and Asthma Prevention:
      a Tale of 2 Parallel Pathways




                    Martinez FD 2007, JACI, in press
            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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