asma na infância renato t. stein, m.d. pontifícia universidade católica porto alegre, brazil
TRANSCRIPT
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Asma na InfânciaAsma na Infância
Renato T. Stein, M.D.Renato T. Stein, M.D.PontifPontifícia Universidade Católicaícia Universidade Católica
Porto Alegre, BrazilPorto Alegre, Brazil
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Respiratory System DevelopmentRespiratory System Development
More vulnerable (irritants/virus, pollutants) in More vulnerable (irritants/virus, pollutants) in the first yearsthe first years Higher surface area-to-volume ratio (infants breath Higher surface area-to-volume ratio (infants breath
more air relative to body weight than older children)more air relative to body weight than older children) Smaller airways: more deposition of particulate Smaller airways: more deposition of particulate
mattermatter Major lung growth period (50-70% alveoli formed Major lung growth period (50-70% alveoli formed
after birth up to ~18 months old)after birth up to ~18 months old)
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Infant Pulmonary Function: PrematuresInfant Pulmonary Function: Prematures
Length (cm)
40 50 60 70 80 90 100
FV
C (
mL
)
0
200
400
600
800
1000
1200
1400
1600
Reduced Lung Function in Healthy Preterm Infants in the First Months of LifeFriedrich L, Stein RT, Jones MH et al. Am. J. Respir. Crit. Care Med. 2006
FV
CF
VC
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Infant Pulmonary Function: PrematuresInfant Pulmonary Function: Prematures
Length (cm)
40 50 60 70 80 90 100
FE
F25
-75
(mL
/s)
0
200
400
600
800
1000
1200
1400
1600
1800
Friedrich L et al. Am. J. Respir. Crit. Care Med. 2006
FE
F 2
5-75
FE
F 2
5-75
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Pulmonary Growth in Premature InfantsPulmonary Growth in Premature Infants
2D Graph 7
Momentos do teste
0 1 2 3
FE
F2
57
5 (
mL
/s)
200
300
400
500
600
700
800
PrematurosControles
2D Graph 5
Momentos do teste
0 1 2 3
FE
F7
5 (
mL
/s)
150
200
250
300
350
400
450
500
PrematurosControles
Friedrich L, Jones MH et al. . AJRCCM 2007
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Impact on Lung DevelopmentImpact on Lung Development
postnatalage
birth
lung function(centiles)
Allergens, pollutants, air toxics
Acute severe Viral Infections
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Different “Asthma” PhenotypesDifferent “Asthma” Phenotypes
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Transient Wheezing by Early Lung Function
Transient Wheezing by Early Lung Function
0
5
10
15
20
25
30
35
40
First Second Third Fourth
%%TransientTransientWheezingWheezing
p<0.0001p<0.0001
Quartiles of V’max FRC at 2 monthsQuartiles of V’max FRC at 2 months
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Persistent Wheezing by Early Lung Function
Persistent Wheezing by Early Lung Function
02
46
810
12
1416
1820
First Second Third Fourth
%%PersistentPersistentWheezingWheezing
n.sn.s..
Quartiles of V’max FRC at 2 monthsQuartiles of V’max FRC at 2 months
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60
70
80
90
100
7 10 14 21 28 35 42
age at review (years)
FE
V1/
FV
C
c
mwb
wb
a
sa
Lung Function over Time by Classification at Recruitment in the Melbourne Study
Lung Function over Time by Classification at Recruitment in the Melbourne Study
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Sears et al, NEJM 349:1414 (2003)Sears et al, NEJM 349:1414 (2003)
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FEV1 by Age in Asthmatics and Smokers (Busselton, Australia)FEV1 by Age in Asthmatics and Smokers (Busselton, Australia)
James et al, AJRCCM 2005, 171:109James et al, AJRCCM 2005, 171:109
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Lung Function at Ages 1, 6, 11 and 16 Years in the Tucson Study
Lung Function at Ages 1, 6, 11 and 16 Years in the Tucson Study
Age, years0 2 4 6 8 10 12 14 16 18
Z-S
core
s of
Adj
uste
d F
low
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
Never WheezeTransient EarlyLate OnsetPersistent
*
**‡
*
*
†
Morgan WJ et al. AJRCCM 2005Morgan WJ et al. AJRCCM 2005
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Hypothetical Representation of the Natural History of Asthma
Asthma Initial PhaseAsthma Initial Phase
InceptionInception
ExacerbationExacerbation
Progression
Progression
No AsthmaNo Asthma
PersistentPersistentAsthmaAsthma
Asthma,Asthma,Not Not
PersistentPersistent
No AsthmaNo Asthma
ProtectionProtection
Remission
Remission
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Hypothetical Representation of the
Natural History of Asthma
Asthma Initial PhaseAsthma Initial Phase
InceptionInception
ExacerbationExacerbation
Progression
Progression
No AsthmaNo Asthma
ChronicChronicAsthmaAsthma
Asthma,Asthma,Not ChronicNot Chronic
No AsthmaNo Asthma
ProtectionProtection
Remission
Remission
ICS?ICS?
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CAMP Study DesignCAMP Study Design
Children with “mild to moderate asthma” (symptoms or use of Children with “mild to moderate asthma” (symptoms or use of Albuterol Albuterol 2 times weekly or daily use of asthma medication)2 times weekly or daily use of asthma medication)
Treated for 4-6 years with Budesonide 200 Treated for 4-6 years with Budesonide 200 g bid (N=311) or g bid (N=311) or Nedocromil 8 mg bid (N=312) or matching placeboNedocromil 8 mg bid (N=312) or matching placebo
Primary outcome: mean change % predicted post Primary outcome: mean change % predicted post bronchodilator FEV1 4-6 years after initiation of treatmentbronchodilator FEV1 4-6 years after initiation of treatment
N Engl J Med 2000;343:1054-63
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Lung Function in the CAMP StudyLung Function in the CAMP Study
N Engl J Med 2000;343:1054-63
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What Is The PEAK Trial?
PEAK investigated if inhaled
corticosteroids (ICS),when initiated in
preschool-aged children at high risk for asthma,
can alter the natural history of asthma after ICS are discontinued
Guilbert TW et al. NEJM 2006
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• Randomized, multicenter, double-blind, parallelgroup, 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.)
Year 3Year 3
Screening/Screening/Eligibility Eligibility Run-inRun-in
Interim Efficacy Tests
PEAK: Study Design
Years 1 & 2Years 1 & 21 month1 month
Randomize
Treatment Treatment Observation Observation
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0.75
0.80
0.85
0.90
0.95
1.00
6 12 18 24 30 36
† † †
†
ICSPlacebop<0.05p<0.01
Pro
po
rtio
n o
f E
pis
od
e-f
ree
Da
ys
Months
Episode-free Days During the Entire Study
Treatment Treatment Observation Observation
Guilbert TW et al. NEJM 2006)
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0
20
40
60
80
100
Number per 100 child
yearsPlacebo
ICS
ICS Effect During Treatment Phase
P<0.001
Asthma Exacerbations
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ICS Effect on IOS (impulse oscillometry) Measures: Reactance at 5 HzICS Effect on IOS (impulse oscillometry) Measures: Reactance at 5 Hz
-0.45
-0.42
-0.39
-0.36
-0.33
End oftreatment
End ofobservation
PlaceboICS
p=0.008 p=0.83 * Greater dynamic lung compliance* Greater dynamic lung compliance
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ConclusionsConclusions Changes in airway function (remodeling?) occur Changes in airway function (remodeling?) occur
early in life in asthma, with little subsequent early in life in asthma, with little subsequent further deteriorationfurther deterioration
Daily ICS are effective in preventing exacerbations Daily ICS are effective in preventing exacerbations and controlling symptoms in 2-3 yr olds at high and controlling symptoms in 2-3 yr olds at high risk for asthmarisk for asthma
However, two years of treatment with daily ICS did However, two years of treatment with daily ICS did not change the natural history of asthma in these not change the natural history of asthma in these same children same children
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Asthma Phenotypes Asthma Phenotypes
Stein R et al. Thorax 1997
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Southern Brazil Study:Risk factors for Wheeze and AsthmaSouthern Brazil Study:Risk factors for Wheeze and Asthma
Wheeze in previous 12m OR (95% C.I.)
Active Asthma OR (95% C.I.)
Maternal Hx Asthma 3.1 (1.8-5.3)*** 5.6 (2.8-11.1)*** Paternal Hx Asthma 3.9 (2.1-7.3)*** 3.6 (1.6-7.9)*** Bronchiolitis < 2y 5.4 (2.9-9.9)*** 18.1 (9.1-36.0)*** Any positive skin test 2.7 (1.8-4.1)*** 6.3 (3.4-11.8)*** Humid household 1.5 (1.1-2.1)** 2.2 (1.3-3.8)** Maternal smoking 1.2 (0.9-1.7) 1.1 (0.6-2.0) Born before term 1.4 (0.8-2.3) 0.7 (0.3-1.8) Years of maternal schooling 0.98 (0.92-1.0) 0.9 (0.8-0.9)* ? 2 Siblings 1.1 (0.8-1.5) 0.5 (0.3-0.9)* Higher-load Ascaris (?100eggs/g)
1.8 (0.98-3.4) 2.4 (1.0-6.1)*
Pereira M et al. ERJ 2007
Risk increases > 50X for children Risk increases > 50X for children with both Bronchiolitis and Ascariswith both Bronchiolitis and Ascaris
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80
60
40
20
0Sp
utu
m e
osin
oph
ils
x 10
5 cel
ls/g
***
***
Atopicasthma
Non-atopicasthma
No atopy/no asthma
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IS Neutrophil concentration in asthma phenotypesIS Neutrophil concentration in asthma phenotypes
Pizzichini MM, et al. 2008
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IMMATURE IMMUNE SYSTEM Slow TH1
Th2-driven
Immunity
Allergen exposure
Airway Inflammatio
n
Altered Aw Function/BH
RASTHMAS
LRTI/ Bronchiolit
is
Airway Inflammatio
n
Altered Aw Function/BH
R
Intensification & low clearance
ALLERGIC PATHWAY
NON-ATOPIC/VIRUS PATHWAY
Environment
Genetic Predisposition
Genetic Predisposition