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

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)

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

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

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

Impact on Lung DevelopmentImpact on Lung Development

postnatalage

birth

lung function(centiles)

Allergens, pollutants, air toxics

Acute severe Viral Infections

Different “Asthma” PhenotypesDifferent “Asthma” Phenotypes

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

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

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

Sears et al, NEJM 349:1414 (2003)Sears et al, NEJM 349:1414 (2003)

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

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

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

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?

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

Lung Function in the CAMP StudyLung Function in the CAMP Study

N Engl J Med 2000;343:1054-63

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

• 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

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)

0

20

40

60

80

100

Number per 100 child

yearsPlacebo

ICS

ICS Effect During Treatment Phase

P<0.001

Asthma Exacerbations

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

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

Asthma Phenotypes Asthma Phenotypes

Stein R et al. Thorax 1997

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

80

60

40

20

0Sp

utu

m e

osin

oph

ils

x 10

5 cel

ls/g

***

***

Atopicasthma

Non-atopicasthma

No atopy/no asthma

IS Neutrophil concentration in asthma phenotypesIS Neutrophil concentration in asthma phenotypes

Pizzichini MM, et al. 2008

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