HOW EFFECTIVE IS PREVENTION HOW EFFECTIVE IS PREVENTION IN ASTHMA?IN ASTHMA?

Dr. A. Füsun KalpaklıoğluDr. A. Füsun Kalpaklıoğlu

AgeAgeEnvironEnvironmentment

GeneticsGenetics

Environmental InfluencesEnvironmental Influences• Cigarette smoking in pregnancy increases the

risk of wheezing in infancy

• Allergen specific T-helper cell programming is initiated early in life and is driven by ubiquitos dietary and inhalant allergens

• Early exposure to high levels of dietary allergens results in high zone tolerance

• Exposure to low levels of inhalant allergens triggers low zone tolerance with weak Th1-like immunity or Th2 polarised response.

• Some early respiratory infections, e.g. pertussis and RSV, may enhance IgE-sensitization

• Relatively lack of early microbial exposure may enhance the development of allergic diseases.

GeneticsGenetics • The atopic constitution is a major risk factor

for the development of IgE-sensitization

• Individuals with a family history of atopy have an increased risk of developing allergic diseases

• Double heredity means a four-fold, Single heredity means a two-fold risk to develop allergies

• Target organ sensitivity is a familial trait

• High IgE level in cord blood is specific for subsequent allergic disease but has a low sensitivity

• Early signs of atopic eczema, and presence of IgE antibodies to inhalant allergens, are important risk factors for later respiratory allergy

ADAM 33 gene

AgeAgeEnvironEnvironmentment

GeneticsGenetics

Immune Response

Th1

Lower airway injury

ASTHMAASTHMA

Abnormal repair

•Viral infections•Aeroallergens•Pollution

•Persistant inflammation•BHR•Remodelling•Lung maturation/differentiation

Atopy Th2

AllergensMicrobesInfectionsPollutionStress

Cytokine response

profile

Primary prevention

Secondary prevention

Prevention of

asthma in

sensitized

individual

Prevention of

allergen-specific

IgE response,

sensitization

Tersiary prevention

Prevention of the

onset of

symptoms in an

asthmatic

individual

CYTOKINE BALANCECYTOKINE BALANCE

ENVIRONMENTENVIRONMENT

Breast-feedingBreast-feeding

Kull I, et al. JACI 2004;114:755-60.

The association between infant feeding practices The association between infant feeding practices and subsequent atopy among children with a and subsequent atopy among children with a

family history of asthmafamily history of asthma•A cohort of children with a family history of asthma in Sydney, Australia, was followed from birth to age 5 years.•In 516 children evaluated at age 5 years, there was no significant association between the duration of breastfeeding or timing of introduction of solid foods and protection against asthma or other allergic disease.•However, breastfeeding for 6 months or more and introduction of solid foods after 3 months were both associated with an increased risk of atopy at age 5 years.•Longer duration of breastfeeding and later introduction of solid foods did not prevent the onset of asthma.

Mihrshahi S, CAPS Team. Clin Exper Allergy May 2007

The Link Between Housing & HealthThe Link Between Housing & Health

NHLBI Report 2007

Effectiveness of the Effectiveness of the Mite Avoidance InterventionMite Avoidance Intervention

Marks et al, JACI 2006; 118:53

0

5

10

15

20

25

30

35

40

ProbableAsthma

FrequentWheeze

PersistentWheeze

Late OnsetWheeze

TransientWheeze

Control

Active

Asthma and Wheezing at Age 5

by Mite Avoidance Treatment

Asthma by Size of Alternaria Skin Test Asthma by Size of Alternaria Skin Test Responses at Age 6 in Tucson, AZResponses at Age 6 in Tucson, AZ

0

10

20

30

40

50

60

Neg 3-4 mm 5-8 mm 9-12 mm >12 mm

%%Asthma

p<0.00001p<0.00001

Alternaria Response

Hygiene Hypothesis;Hygiene Hypothesis; Lack of intense infections in industrialized countries owing to improved hygiene, vaccination, and use of antibiotics may alter the immune system such that it responds inappropriately to innocuous substances. (increased allergy/asthma)

Atopic disease is the price paid by Atopic disease is the price paid by some members of the white some members of the white

community community [[as opposed to nativeas opposed to native Americans in Saskatchewan, Americans in Saskatchewan,

CanadaCanada]]

-Gerard JW, 1976

HYGIENE HYPOTHESISHYGIENE HYPOTHESIS

ExposureExposure to to StablesStables and/and/oror Farm Milk Farm Milk in in thethe First First YearYear of Lifeof Life

0

2

4

6

8

10

12

14

16

Asthma Asthma attacts past 12 mo

Exposed

Non-exposed%

Riedler et al, Lancet. 2001 Oct 6;358:1129-33.

* *

* p<0.0001

Inverse association of farm milk Inverse association of farm milk consumption with asthma and allergy in rural consumption with asthma and allergy in rural

and suburban populations across Europeand suburban populations across Europe• Cross sectional multi-centre study (PARSIFAL) including

14 893 children aged 5–13 years from five European countries (2823 from farm families and 4606 attending Steiner Schools as well as 5440 farm reference and 2024 Steiner reference children).

• Farm milk consumption ever in life showed a statistically significant inverse association with asthma. The associations were observed in all four subpopulations and independent of farm-related co-exposures. Other farm-produced products were not independently related to any allergy-related health outcome.

Waser M, et al. Clin Exper Allergy May 2007

Unpasteurized milk: health or hazard?Unpasteurized milk: health or hazard?

Endotoxin Exposure and IgE Endotoxin Exposure and IgE Mediated SensitizationMediated Sensitization

Ln total endotoxin recovered (EU/m2)

14121086420

Pre

dict

ed p

roba

bilit

y fo

r se

nsiti

satio

n1.0

.8

.6

.4

.2

0.0CCccc

7.4 54.6 403.4 2981 22000 1.2x106162755

0.01.0

0.2

0.4

0.6

0.8

1.0P

red

icte

d p

rob

abil

ity

fo

r s

ensi

tisa

tio

n

Endotoxin Load (EU/m2)

Simpson et al, AJRCCM September 2006

P=0.005

Endotoxin in inner-city homes: Endotoxin in inner-city homes:

Associations with wheeze and eczemaAssociations with wheeze and eczema

Perzanowski M et al. JACI 2006;117:1082-9

Response to endotoxin increases with Response to endotoxin increases with BMIBMI

Alexis N et al. JACI 2006;117:1185-6

Obesity&Asthma1.Development in early life

2.Mechanical factors promote asthma

3.GER resulting from obesity induces asthma

Data not to support the H.H.Pets

Brussee JE et al.Allergen exposure at 3 m and sensitization, wheeze and asthma at 4 y of age. JACI 2005;115:946-52.• 4146 children from the Prevention and Incidence

of Asthma and Mite Allergy study. • Early cat allergen exposure leads to persistent

wheeze.• Early dog allergen exposure leads to persistent

wheeze in children with maternal atopy.

Timing?Having cat before age 18 protects against adult asthma&atopy! de Meer Gea, et al. Jacı 2004;113:433-8.

Probiotics; beneficial microbes in the gut flora Probiotics; beneficial microbes in the gut flora may promote maturation of the immune may promote maturation of the immune

system away from proatopic statesystem away from proatopic state

Probiotics: Probiotics: Lactobacillus&Bifidobacterium

Rautava S et al. JACI 2002;109:119-21

NHLBI Report 2007

ISLE OF WIGHTISLE OF WIGHT

Arshad et al. JACI 2007;119:307-13

Becker, et al. JACI 2004;113:650-6

The Canadian Study: 2 yearsThe Canadian Study: 2 years

Chan-Yeung et al. JACI 2005;116:49-55

The Canadian Study: 7 yearsThe Canadian Study: 7 years

• 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;111:162-8

The Childhood Asthma PreventionThe Childhood Asthma Prevention Study (CAPS), Sidney Australia Study (CAPS), Sidney Australia

Marks GB et al. JACI 2006;118:53-61

連鎖過敏反應 (Allergy March)

若在嬰幼兒期間已誘發過敏感機制 (Sensitization) 及出現過敏症狀 ， 他們在成長過程中可能會增加患上其他過敏症的風險

(Sarrinen U.M. & Kajosaari 1995; Bergmann RL et al. 1998 ; Host A 2001 ;Spergel JM & Paller AS 2003 ;Rhodes et al. 2001; Sampson H.A. 2003 ; Halken S 2004; Wickman M. 2005; Hahn E. & Bacharier L.B.

2005)

濕疹

成年人過敏性哮喘或鼻炎

喘嗚 /

哮喘

鼻炎

哮喘 /

鼻炎 / 濕疹

因食物引起的 過敏症狀

誘發過敏激發過程

• 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.)

Year 3Year 3

Screening/Screening/EligibilityEligibility Run-inRun-in

Interim Efficacy Tests

PEAK PEAK (Prevention of Early Asthma in Kids)(Prevention of Early Asthma in Kids): : Study DesignStudy Design

YeYeaars rs 1 & 21 & 2 1 1 monthmonth

Randomize

TreatmentTreatment ObservationObservation

Guilbert et al, NEJM 2006;354:1985

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 Episode-free Days During the Entire StudyDuring the Entire Study

Treatment Treatment Observation Observation

Guilbert et al, NEJM 2006;354:1985

0

20

40

60

80

100

Number per 100 child

yearsPlaceboICS

ICS Effect During Treatment PhaseICS Effect During Treatment Phase

P<0.001

Asthma Exacerbations

Guilbert et al, NEJM 2006;354:1985

ETACETAC

Warner JO et al. JACI 2001;108:929-37

EPAACEPAAC

Th1

Th2

TCD4+IT

IMMUNE DEVIATION?ANERGY?BOTH?

IL-4IL-5IL-9

IL-2INF-g

Immunotherapy; Immunotherapy; MechanismsMechanisms

New sensitizations after 3 years:55% SIT group vs 100% control group.

Des Roches et al, JACI 1997

New sensitizations after 3 years: 25% SIT group vs 67% control group.

Pajno et al, Clin Exp Allergy 2001

New sensitizations after 4 years23% SIT group vs 68% control group.Purello D’Ambrosio et al, Clin Exp Allergy 2001

IT: Prevention of New SensitizationsIT: Prevention of New Sensitizations

Specific immunotherapy prevents the development Specific immunotherapy prevents the development of asthma in children with allergic rhinitis of asthma in children with allergic rhinitis

(the PAT study)(the PAT study)

205 children with rhinitis

age: 6-14 yrs

grass or birch allergy

3 yrs immunotherapy

SIT CONTROL

%60

19

4032

No asthma

Asthma

Moller C et al, JACI 2002

Niggemann et al, Allergy 2006;61:855-9

Asthma TreatmentAsthma Treatment

allergen avoidance

intermittent asthma mild persistent asthma

moderate persistent asthma severe persistent

asthma

pharmacotherapy

immünotherapy

Reduce Exposure to TriggersReduce Exposure to Triggers

Exercise

Weather

Odors

Airpollution Tobacco

smoke

Outdoormold &pollen

Indoormold

Petdander

Pests

Dustmites

Asthmaattack

Encasing MattressEncasing Mattress

Halken S et al. JACI 2003;111:169-76

ARIA UPDATE

NHLBI Report 2007

NHLBI Report 2007

Asthma Treatment and Asthma Prevention: Asthma Treatment and Asthma Prevention: a Tale of 2 Parallel Pathways a Tale of 2 Parallel Pathways

Martinez FD 2007, JACI, in press

Two (Provocative) IdeasTwo (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

Martinez FD

Nature begins with the cause and ends with the experience;

we need to operate in the reverse. -Leonardo da Vinci, 1512

THANK YOU!THANK YOU!

Preventive MeasuresGuidelines

Primary prevention• Avoid smoking and Environmental Tobacco Smoke,

particularly during pregnancy and early childhood (B). Remove tobacco smoke from work places (B)

• Avoid damp housing conditions (C) and reduce indoor air pollutants (C)

• Breast-feed exclusively until 4-6 months (B*). No special diet for lactating mothers (A)

• Reduce exposure to inhalant allergens in young children at high risk

• Eliminate sensitizing and highly irritating agents in occupational environments (C). Implement measures to prevent employee exposure

* WHO: exclusive breast-feeding for 6 months in general

Preventive MeasuresGuidelines

Secondary prevention• Treat atopic eczema topically, and possibly with

systemic pharmacotherapy to prevent respiratory allergy (D)

• Treat upper airways disease (rhinoconjunctivitis, sinusitis) to reduce risk of asthma (D)

• In young children sensitized to mites, pets or cockroaches, exposure should be reduced to prevent onset of allergic disease (B)

• Remove employees from occupational exposure if they have symptoms caused by occupational allergic sensitization (C)

Preventive MeasuresGuidelines

Tertiary prevention• Infants with cow’s milk allergy avoid cow’s milk proteins; if a

supplement is needed, use hypoallergenic formula, if available/affordable, to improve symptom control (B)

• Patients with asthma, rhinoconjunctivitis or eczema, who are allergic to indoor allergens, should eliminate or reduce the exposure to improve symptom control and prevent exacerbations (A-B)

• Environmental Tobacco Smoke aggravates asthma• Aim pharmacotherapy primarily towards the underlying

inflammatory process (A)• Avoid strictly ASA and other non-steroidal anti-inflammatory

drugs (NSAID) in patients who are sensitive to them (C)

Preventive MeasuresFurther actions for occupational allergies

• Risks of occupational allergy should be monitored and epidemiological information collected by a globally agreed questionnaire

• High risk allergy environments should be identified. In atopic employees who work in these environments, detection of sensitization by Skin Prick/Puncture Tests or IgE antibody measurements could prevent development of clinical allergy

• General principles of prevention of occupational allergies should be published by national regulatory and advisory authorities

Lung Function at Age 7 by Sensitization and Exposure to Aeroallergens at Age 3

FVCFVC FEV1FEV1 RatioRatio

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

Allergen ExposureAllergen Exposure

Genetic PredispositionGenetic Predispositionto Allergiesto Allergies

SensitizationSensitization

Genetic PredispositionGenetic Predispositionto Asthmato Asthma

AsthmaAsthma

Allergy,Allergy,No AsthmaNo Asthma

FEV1/FVC Ratio by Skin Test at Age 6

70

72

74

76

78

80

82

84

Yr11 Yr16 Yr22

NegativePos, Altern negAltern pos

%%

p=0.01p=0.01 p<0.001p<0.001 p=0.01p=0.01

Age (months)

Interferongammaresponses(Th1)

0 24-36

Allergic

Non-Allergic

Maturation of Immune Responses Maturation of Immune Responses in Infancyin Infancy

ICS Effect on IOS 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 Guilbert et al, NEJM 2006;354:1985

Busse PJ et al. JACI 2005;116:146-52

Wang Y et al. JACI 2006;118:143-51

Experimental LPS/Allergen Exposure

Wang Y et al. JACI 2006;118:143-51

Experimental LPS/Allergen Exposure

Encasing Mattress

Halken S et al. JACI 2003;111:169-76

Hijyen hipotezi

Long-lasting effect of sublingual immunotherapyin children with asthma due to house dust mite:

a ten-year prospective studyV.Di Rienzo, Clin Exp Allergy, 2003

60

pts

35 SLIT +drugs

25 onlydrugs

0 5 10YEARS

No More SLITNo More SLIT