to change asthma natural history: a mith? introduction genetic factors environmental factors...

TO CHANGE ASTHMA NATURAL HISTORY: A MITH?

Introduction Genetic Factors Environmental Factors Conclusions

University of Verona, Italy

Attilio Boner

TUCSON CHILDREN’S RESPIRATORY STUDY: 1980 TO PRESENT Taussig JACI 2003; 111:661

ALB

Lung Developmentand Physiology

TUCSON CHILDREN’S RESPIRATORY STUDY: 1980 TO PRESENT Taussig JACI 2003; 111:661

ALB

Lung Developmentand Physiology

Immunology

FAMILY HISTORY OF ASTHMA AND ATOPY: IN DEPTH ANALYSES OF THE IMPACT ON ASTHMA AND WHEEZE IN 7- TO 8- YEAR-OLD CHILDREN.

Bjerg Pediatrics 2007; 120: 741

A cohort of 3420 7- to 8- year-old children

SPTs

Questionnaires

Prevalence (%) of current asthma in relation to parental asthma, parental atopy, SPT

result, and combinations of these categories.

FAMILY HISTORY OF ASTHMA AND ATOPY: IN DEPTH ANALYSES OF THE IMPACT ON ASTHMA AND WHEEZE IN 7- TO 8- YEAR-OLD CHILDREN.

Bjerg Pediatrics 2007; 120: 741 FH of asthma and atopy and OR for current asthma in the

previous 12 months

NONE M only F only F+M

ASTHMA ATOPYPARENTAL

15 –14 –13 –12 –11 –10 –9 –8 –7 –6 –5 –4 –3 –2 –1 –0

NONE M only F only F+M

1 1.6

3.6

13.6

1.22.8

3.2

1

OR for parental asthma is

multiplicative.

OR for parental atopy is additive

Introduction Genetic Factors: - lung development - immunology Environmental Factors Conclusions


Attilio Boner


OUTCOME OF ASTHMA AND WHEEZING IN THE FIRST 6 YEARS OF LIFE

Morgan AJRCCM 2005; 172: 1253

A population-based birth cohort in Tucson

Maximal expiratory

flows at ages 2.4 mo and 6,

11, and 16 yr for the preschool

wheeze phenotypes Age, years

Never WheezeTransient EarlyLate OnsetPersistent

0 2 4 6 8 10 12 14 16 18

0.4

0.2

0.0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

Z-S

core

s o

f H

eig

ht

Ad

juste

d F

low

(+

/-se)

*

**

*

*

**

* **

REDUCED LUNG FUNCTION BOTH BEFORE BRONCHIOLITIS AND AT 11 YRS

Turner Arch Dis Child 2002; 87: 417

Control(n = 162)

Confirmedbronchiolitis

(n = 16)Box and whisker plot for z scores

for % V’maxFRC at 1 month

%VmaxFRCp=0.02

z score

3

2

1

0

-1

-2

-3

.

.

253 cohort membersVmaxFRC at 1

month of ageIndividuals with

bronchiolitis were prospectively identified

At 11 years of age lung function was repeated

% children with a history of asthma at

age 10 year30 –

20 –

10 –

0

16.2%

24.3%

p=0.01

Above the median

At-below the median

tPTEF/tE at age 3 days

% children with current asthma at age 10 year

30 –

20 –

10 –

07.5%

14.6%

p=0.005

Above the median

At-below the median

tPTEF/tE at age 3 days

REDUCED LUNG FUNCTION AT BIRTH AND THE RISK OF ASTHMA AT 10 YEARS OF AGE

Haland , Carlsen N Engl J Med 2006; 355: 1682

ASTHMA ORIGINS

Lung Development


Attilio Boner

Reduced lung development is apremorbid predisposing factor for:- Transient wheezing,- Bronchiolitis,- Persistent atopic wheezing,

Loss of lung function is characteristic of asthma.

ASTHMA ORIGINS

Lung Development


Attilio Boner

Reduced lung development is apremorbid predisposing factor for:- Transient wheezing,- Bronchiolitis,- Persistent atopic wheezing,

Loss of lung function is characteristic of asthma.

Good care of pregnancy is

essential to allow a normal

development of the lungs.

Introduction Genetic Factors: - lung development - immunology Environmental Factors Conclusions


Attilio Boner


One of the explanations for maintenance of a successful pregnancy is that both Th-2 (IL-4 and IL-13) and T regulatory (IL-10 and TGF-β) cytokines are generated by the conceptus to down-regulate maternal Th-1 immune responses to feto-paternal antigens which might otherwise lead to fetal rejection.

MATERNO-PLACENTO-FETAL INTERACTIONSWarner Arch Dis Child 2004;89:97

alb

14°wk

22°wk

Functional maturation of CD4+CD25+CTLA4+CD45RA+ T regulatory cells in human neonatal T cell responses to environmental antigens/allergens.

Thorton J Immunol 2004;173:3084

Neonatal T cell responses to allergens

differ markedly

from those occurring in

later life

1. In contrast to allergen-responsive adult CD4(+) T cell cultures, responding neonatal T cell cultures displays a high level of apoptosis.

2. In these cultures CD4+CD25+CTLA4+ T regulatory cells appears and exert a suppressive activity.

PRENATAL VERSUS POSTNATAL SENSITIZATION TO ENVIRONMENTAL ALLERGENS IN A HIGH-RISK BIRTH COHORT Rowe JACI 2007;119:1164

Prospectively studied HDM (house dust mite) specific sIgE and IgG4 and T-cell immunity in a cohort of 200 high-risk infants

Tracking antibody titers in individuals who are HDM SPT-

negative at age 24 months

Age (months)

0.35

PRENATAL VERSUS POSTNATAL SENSITIZATION TO ENVIRONMENTAL ALLERGENS IN A HIGH-RISK BIRTH COHORT Rowe JACI 2007;119:1164

Prospectively studied HDM (house dust mite) specific sIgE and IgG4 and T-cell immunity in a cohort of 200 high-risk infants

Tracking antibody titers in individuals who are HDM SPT-

positive at age 24 months

Age (months)

0.35

Skin barrier function and allergic risk. An intact epithelial barrier (a) prevents allergens fromreaching antigen presenting cells (APCs) in subepithelial tissues. Damage to this barrier (b) allow allergens to penetrate into the subepidermal layer and interact with APCs, leading to

allergic sensitization and, secondarily, to allergic manifestations in the host.

SKIN BARRIER FUNCTION AND ALLERGIC RISKHudson Nature Genetics 2006; 38: 399

IN CHILDREN WITH FILAGGRIN LOSS-OF-FUNCTION MUTATION

OR for non

atopic eczema

FILLAGRIN LOSS-OF-FUNCTION MUTATIONS PREDISPOSE TO PHENOTYPES INVOLVED IN THE

ATOPIC MARCH Marenholz JACI 2006; 118: 866

OR for atopic eczema

OR ratio for concomitan

t eczema and asthma

OR ratio for

concomitant eczema

and allergic rhinitis

7 –

6 –

5 –

4 –

3 –

2 –

1 –

0

3.94 p=0.0006

5

3.84p=0.0006

p=0.00001

p=0.00001

6.21

4.79

ASTHMA ORIGINS

Lung Development

Immunologic Maturation


Attilio Boner

The fetal life and the newborn period are prone to atopy.Sensitization starts early but postnataly.Defective skin barrier fuction predispose to allergy development.

ASTHMA ORIGINS

Lung Development

Immunologic Maturation


Attilio Boner

The fetal life and the newborn period are prone to atopy.Sensitization starts early but postnataly.Defective skin barrier fuction predispose to allergy development.

Good care of pregnancy

Allergen avoidance thereafter.

Immunomodulating natural factors?

Good care of the skin is probably important.

Introduction Genetic Factors Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style - psychology - treatment Conclusions


Attilio Boner


10 –

8 –

6 –

4 –

2 –

0

PULMONARY FUNCTION IN THREE YEAR OLD CHILDREN: EFFECT OF EXPOSURE AND SENSITIZATION TO INDOOR

ALLERGENS Lowe JACI 2002; 109: 521Ab

% mean difference in sRaw in mite sensitive vs non-

sensitiveManchester Asthma and Allergy Study (birth cohort: 276 children)

specific airway resistance (sRaw) at 3 yrs of age

+9.2%p=0.020

PERENNIAL ALLERGEN SENSITISATION EARLY IN LIFE AND CHRONIC ASTHMA IN CHILDREN: A BIRTH COHORT

STUDY Illi Lancet 2006; 368: 763

OR for BHR at school age

Early Current sensitization sensitisation

8.3

3.29

(age <3)to perennial allergen

10 –

9 –

8 –

7 –

6 –

5 –

4 –

3 –

2 –

1 –

0

ALB

1314 children from birth to 13 years of age (MAS study)

Allergen exposure at age 6 months, 18 months, and at 3, 4, and 5 yrs

Lung function at 7, 10, and 13 yrs

2.0 –

1.5 –

1.0 –

0.5 –

0

2.11.8

Contact with dog

Sleeping in a previously

used mattress in

the first year

RISK FACTORS FOR ASTHMA AT 3.5 AND 7 YEARS OF AGE Mitchell Clin Exp Allergy 2007;37:1747

871 children of European mothers enrolled at birth;

Data collected at birth, 12 months, 3.5 years of age and 7 years.

OR for asthma both at age 3.5 and 7 years

PREVENTION OF ALLERGIC DISEASE DURING CHILDHOOD BY ALLERGEN AVOIDANCE: THE ISLE OF WIGHT PREVENTION STUDY Arshad JACI 2007;119:307

Infants at higher risk because of family predisposition.

Randomized to prophylactic (n=58) and control (n=62) groups.

Prophylactic group: breast-fed or extensively hydrolyzed formula, acaricide and mattress covers.

Development of allergic disease at age 1,2,4 and 8 years.

OR in the prophylactic group at age 8 years

1 –

0,5 –

0

p=0.005p=0.005

p<0.005p=0.0003

0,24 0,230,14 0,13

asthma Atopic dermatit

is

Allergic rhinitis

atopy

Ln VmaxFRC GM & 95% CI at age 4 weeks1.0 –

0.8 –

0.6 –

0.4 –

0.2 –

0.0

EARLY LIFE ENVIROMENTAL CONTROL: EFFECT ON SYMPTOMS, SENSITIZATION AND LUNG FUNCTION AT AGE 3 YEARS Woodcock AJRCCM 2004;170:433

* *p=0.49

ALB

•Manchester cohort•128 active group•111 control group•Allergen level, symptoms, sensitization and lung function at 3 years of age

Ln sRaw GM & 95% CI at age 3 years

0.4 –

0.3 –

0.2 –

0.1 –

0.0 –

-.1

EARLY LIFE ENVIROMENTAL CONTROL: EFFECT ON SYMPTOMS, SENSITIZATION AND LUNG FUNCTION AT AGE 3 YEARS Woodcock AJRCCM 2004;170:433

**p=0.00

3

•Manchester cohort•128 active group•111 control group•Allergen level, symptoms, sensitization and lung function at 3 years of age ALB

IMPAIRED GROWTH OF PULMONARY FUNCTION IN CHILDREN SENSITIVE TO HOUSE DUST MITE

ULRIK AJRCCM 1999; 160: 40

408 children (7-17 years of age at

enrollment) reevaluated after 5

years

subjects with either persistent or new atopy

to HDM had lower FEV1 compared with

those whohad persistent (-) SPT

to HDM

ATOPY TO HDM

PERSISTENT NEWFEV1

%

PREDICTED

- 1

- 2

- 3

- 4

- 5

- 6 - 5.5%

- 4.3%

some of these new cases can be

prevented

PREVENTION OF SENSITIZATION TO HOUSE DUST MITE BY ALLERGEN AVOIDANCE IN SCHOOL AGE CHILDREN: A RANDOMIZED CONTROLLED STUDYArshad Clin. Exp. All. 2002; 32: 843 % ch. developing SPT

(+)to mites in the 12 mo

follow-up9.38%

2.56%

p<0.05

10 -

9 -

8 -

7 -

6 -

5 -

4 -

3 -

2 -

1 -

0

Study of prevention of Allergy in children of Europe, U.K., Greece and Lithuania(+) FH of atopy and SPT(+) to an aeroallergen but not to house dust miteCh.(5-7 yrs) - Cover mattress (n=117) - Control group (n=96)

3/1179/96

CONTROL ACTIVE

5 -

4 -

3 –

2 –

1 –

0

3.38

FORPERSISTANCE

A LONGITUDINAL, POPULATION-BASED, COHORT STUDY OF CHILDHOOD ASTHMA FOLLOWED TO ADULTHOOD.Sears NEJM 2003;349:1414

4.17

FORRELAPSE

(+) SPT FOR MITES AT AGE 13 YEARS

p<0.001 for trend

OR FOR WHEEZING AT AGE 26 YEARS

ARE ATOPY AND SPECIFIC IgE TO MITES AND MOLDS IMPORTANT FOR ADULT ASTHMA?

Jaakkola JACI 2006; 117: 642

Specific IgE to mites and molds;

All new diagnosed cases of asthma 21-63 years of age(1997-2000);

A random sample of control;

485 cases and 665 controls.

2.302.73

4.69

MITE

OR for new onset asthma

5 -

4 -

3 –

2 –

1 –

0ASPERGILLU

SCLADOSPORIU

MsIgE:

ASTHMA ORIGINS

Lung Development Immunologic Maturation

Allergens


Attilio Boner

•Early sensitization to allergens is a risk factor for more severe asthma and reduced lung function,•Sensitization can occur through the skin,•Sesitization can occur also later in life and is always a risk factor for asthma

ASTHMA ORIGINS

Lung Development Immunologic Maturation

Allergens


Attilio Boner

•Early sensitization to allergens is a risk factor for more severe asthma and reduced lung function,•Sensitization can occur through the skin,•Sesitization can occur also later in life and is always a risk factor for asthma

Environmental strategies

to delay sensitization might be helpful.

Early contact with cat and dog is not

protective.



Attilio Boner


AIRWAY ALVEOLAR ATTACHMENT POINTS AND EXPOSURE TO CIGARETTE SMOKE IN UTERO Elliot AIRCCM 2003; 167: 45

32 infants who died from sudden infant death syndrome

Compared with those without any exposure to cigarette smoke, the distance between alveolar attachments on airways was greater (p< 0.001) in infants exposed to cigarette smoke in utero

membranous airway from an 8-month-

old infant

80 healthy infants tested shortly after birth (mean, 4.2+/-1.9 wk)

Urine cotinine

Expiratory flow-volume curves

THE EFFECT OF MATERNAL SMOKING DURING PREGNANCY ON EARLY INFANT LUNG

FUNCTIONHanrahan Am. Rev. Respir. Dis. 1992; 145: 1129

YES NO

Flow at functional residual capacity (ml/s)

200 –

150 –

100 –

50 –

0

74.3

150.4p= 0.0007

SMOKING MOTHER

PARENTAL SMOKING AND LUNG FUNCTION IN CHILDREN Moshammer AJRCCM 2006;173:1255

20,000 children (aged 6-12 yr) from Europe and North America;

Exposure information by questionnaires;

SMOKING DURING PREGNANCY

-6% MEF25%

0 –

-1 –

-2 –

-3 –

-4 –

-5 –

-6 –

-7 –

-1% in FEV1

OR for asthma in the first 5 years of life

Smokingmother

only

1.3

MATERNAL AND GRANDMATERNAL SMOKING PATTERNS ARE ASSOCIATED WITH EARLY

CHILDHOOD ASTHMALi YF Chest 2005; 127: 1232

3 –

2 –

1 –

0

1.8338 children

with asthma diagnosed in the first 5 years of life

570 control subjects Grandmaternal

only smoking during the

mother’s fetal period

Grandmaternal and

maternal smoking

2.6

THE ADULT INCIDENCE OF ASTHMA AND RESPIRATORY SYMPTOMS BY PASSIVE SMOKING IN UTERO OR IN CHILDHOOD Skorge AJRCCM 2005; 172: 61

Between 1985 and 1996/1997 an 11-year community cohort study on the incidence of asthma

3.786 subjects

OR ratio for adult onset asthma

3 –

2 –

1 –

0

3

Smoking mother

THE ADULT INCIDENCE OF ASTHMA AND RESPIRATORY SYMPTOMS BY PASSIVE SMOKING IN UTERO OR IN CHILDHOOD Skorge AJRCCM 2005; 172: 61

Between 1985 and 1996/1997 an 11-year community cohort study on the incidence of asthma

3.786 subjects

OR ratio for adult onset asthma

3 –

2 –

1 –

0

3

Smoking mother

The adjusted attributable

fractions of the adult incidence of

asthma were

17.3% caused by maternal smoking and

9.3% caused by smoking by other

household members.

REGULAR SMOKING AND ASTHMA INCIDENCE IN ADOLESCENTS Gilliland AJRCCM 2006; 174: 1094

2,609 children with no lifetime history of asthma or wheezing

Followed annually in schools

Regular smoking was defined as smoking 300 cigarettes in the year

New cases of physician-diagnosed asthma

RR FOR NEW ONSET OF ASTHMA

3.94 –

3 –

2 –

1 –

0 In children smoking >300 cigarettes/year

RR FOR NEW ONSET OF ASTHMA

8.8

10-

8 –

6 –

4 –

2 –

0 In children smoking

>300 cigarettes/year andexposed to maternal smoking

during gestation

REGULAR SMOKING AND ASTHMA INCIDENCE IN ADOLESCENTS Gilliland AJRCCM 2006; 174: 1094

2,609 children with no lifetime history of asthma or wheezing

Followed annually in schools

Regular smoking was defined as smoking 300 cigarettes in the year

New cases of physician-diagnosed asthma

ASTHMA ORIGINS

Lung Development Immunologic Maturation Allergens

Exposure to Tobacco Smoke


Attilio Boner

Smoking should always be avoided by anyone.



Attilio Boner


Bedding type at 1mo

Wheeze at 7 yrs

(n=6,378 ch)

SYNTHETIC BEDDING AND WHEEZE IN CHILDHOOD. Ponsonby Epidemilogy 2003;14:37

7 –

6 –

5 –

4 –

3 –

2 –

1 –

0

OR for wheezing at 7 yrs

2.5

5.2

synthetic

pillow

+synthetic quilt

At age 7 years OR for

5 -

4 -

3 –

2 –

1 –

0

A prospective association between synthetic cocoon use in infancy and childhooh asthma.

Trevillian Paed Perin Epidem 2004:18:281

• Sleeping environment of 863 infants evaluated at 1 month of life

• Follow-up: 7 years

4.33

IN CH. SLEEPING IN A SYNTHETIC COCOON AT 1 MONTH OF AGE

RECENT WHEEZE AT AGE 7 YEARS

3.35NIGHT

WHEEZE AT AGE 7 YEARS

OR FOR SENSITIZATION TO D.farinae

NO2

1.88

Residential outdoor air pollution and allergen sensitization in schoolchildren in Norway Oftedal

CEA 2007;37:1632

1.61

1.46

PM10 PM2.5

2244 children 9-10 year old had lived in Oslo since birth

Exposure to outdoor air pollution: nitrogen dioxide (NO2), particulate matter (PM) with aerodynamic diameter <10 μm (PM10) and <2.5 μm (PM2.5)

2 -

1 –

0

one interquartile increase of lifetime

exposure to

LUNG FUNCTION GROWTH IN CHILDREN WITH LONG-TERM EXPOSURE TO AIR POLLUTANTS IN MEXICO CITY

Rojas-Martinez AJRCCM 2007;176:377

3,170 children aged 8 years at baseline.

Followed for 3 yrs and visited every 6 months.

Percentiles

Visits

Visits

Percentiles

OR for wheezing

3 –

2 –

1 –

0

2.5

The relationship between types of traffic, traffic volume, and distance and wheezing among infants less than 1 year of age

In infants living very near (< 100 m) to stop-and-go bus and truck traffic

IS IT TRAFFIC TYPE, VOLUME, OR DISTANCE? WHEEZING IN INFANTS LIVING NEAR TRUCK AND BUS TRAFFIC

Ryan JACI 2005; 116: 279

TRAFFIC EXPOSURE AND LUNG FUNCTION IN ADULTS: THE ATHEROSCLEROSIS RISK IN COMMUNITIES

STUDYKan Thorax 2007; 62: 8 73

15792 middle aged men and women.

Traffic density and distance to major roads were used as measures of traffic exposure.

IN WOMEN LIVING WITHIN 150 M FROM MAJOR ROAD

FEV1

-15.7 mL

0

-10 –

-20 –

-30 –FVC

-24.2 mL

European Community Respiratory Health Survey in 10 countries.

3.503 persons doing the cleaning in their homes and who were free of asthma at baseline.

In person using cleaning spray at least 4 days per

week

2.11

RR for new diagnosis of asthma

p.<0.05

2 –

1 –

0

THE USE OF HOUSEHOLD CLEANING SPRAYS AND ADULT ASTHMA Zock AJRCCM 2007;176:735

ASTHMA ORIGINS

Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke

Other adjuvant factors


Attilio Boner

Early contact with:-Synthetic materials-Chlorinated pools-Pollution-Detergentsare important adjuvant factors.

ASTHMA ORIGINS


Other adjuvant factors


Attilio Boner

Early contact with:-Synthetic materials-Chlorinated pools-Pollutionare important adjuvant factors.

no synthetic materials in early

llyfeAsk yourself what

you can do to prevent pollution



Attilio Boner


1.194 mother-child pairs

Maternal intake of vitamin D during pregnancy with FFQ

MATERNAL INTAKE OF VITAMIN D DURING PREGNANCY AND RISK OF RECURRENT WHEEZE IN CHILDREN AT 3 Y OF AGE Camargo Am J Clin Nutr 2007; 85: 788

Recurrent wheeze

In 3 yrs-old children of mothers in the highest

quartile of vitamin D intake (724 IU) versus the lowest quartile (356 IU) OR for

1 –

0

0.39p<0.001

Random sample of 2000 healthy pregnant women at approximately 12 wk gestation

Maternal vitamin D intake ascertained at 32 wk of gestation with FFQ

MATERNAL VITAMIN D INTAKE DURING PREGNANCY AND EARLY CHILDHOOD

WHEEZING Devereux Am J Clin Nutr 2007; 85: 853

Everwheeze

In 5 year old children of mothers in the highest versus the lowest quintiles of vit D intake OR for1 –

0

0.48

Persistent wheeze

Wheeze in previous

year

0.35 0.33

MATERNAL INTAKE OF VITAMIN D DURING PREGNANCY AND RISK OF RECURRENT WHEEZE IN CHILDREN AT 3 Y OF AGE Camargo Am J Clin Nutr 2007; 85: 788

MATERNAL VITAMIN D INTAKE DURING PREGNANCY AND EARLY CHILDHOOD WHEEZING Devereux Am J Clin Nutr 2007; 85: 853

1)

2)

“ using data from the two birth cohorts with maternal vitamin D assessment, we estimate that the population attributable risk for asthma incidence caused by vitamin D deficiency in pregancy is about 40% of all cases.” Weiss JACI 2007;120:1031

OR FOR WHEEZE WITHOUT A COLD IN THE LAST 12 MO AT 5 YEARS OF AGE

1

LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY IS ASSOCIATED WITH ASTHMA IN 5-

YEARS-OLD CHILDREN Devereux AJRCCM 2006; 174: 499

1

1-

1,861 children born to women recruited during pregnancy and followed up at 5 yr;

Maternal nutrient status by a food frequency questionnaire and plasma levels. 2 3 4 5

QUINTILES OF VIT E INTAKE IN THE MOTHER

0.500.56

0.53

0.22

p = 0.02 for trend

OR FOR ATOPIC SENSITIZATION

0.60

1-

in children of mothers with higher concentrations of tocoferol at 12 wk gestation


Maternal nutrient status by a food frequency questionnaire and plasma levels.



OR FOR EVER ASTHMA

1

1

1-

2 3 4 5

QUINTILES OF ZINC INTAKE

0.550.59

0.440.51

p = 0.04 for trend





OR FOR EVER ASTHMA

1

1

1-

2 3 4 5

QUINTILES OF ZINC INTAKE

0.550.59

0.440.51

p = 0.04 for trend





Zinc deficiency in pregnant rats is associated with impaired

fetal lung growth.

Vojnik J Nutr 1977; 107: 862



Major diet

source of Vit E

•Vegetable oils (sunflower, rapeseed, corn)•Margarine•Wheat germ•Nuts•Sunflower seeds

Major diet

source of Zinc

•Liver•Wheat germ•Lean red meat•Seeds•Nuts

1-

In animal models and

humans, vit E and Zinc

Th1 differentiation

Th1 cytokines

Th2 cytokines

1.924 children born to women recruited during pregnancy

Maternal diet during pregnancy was assessed by food frequency questionnaire

Followed up at 5 years by symptom questionnaire

MATERNAL FOOD CONSUMPTION DURING PREGNANCY AND ASTHMA, RESPIRATORY AND ATOPIC SYMPTOMS IN 5-YER-OLD CHILDREN

Willers Thorax 2007; 62: 773

Everwheeze

Maternal apple consumption highest versus lowest tertile OR for

1 –

0

0.63

Doctorasthma

Everasthma

0.54 0.47

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CHILDHOOD ASTHMA AND FRUIT CONSUMPTION

Okoko ERJ 2007;29:1161

2.640 primary school children aged 5–10 yrs;

Information about asthma symptoms and fruit consumption by questionnaire.

in children eating bananas

at least once a day, OR

for

0.66 0.69

0.80

Current wheeze

Ever wheeze

Ever asthma

1.00 –

0.80 –

0.60 –

0.40 –

0.20 –

0

2.640 primary school children aged 5–10 yrs;

Information about asthma symptoms and fruit consumption by questionnaire.

in children drinking apple juice concentrate at least once a day, OR

for

0.740.90

Current

wheeze

Ever wheez

e

Ever asthm

a

0.53

1.00 –

0.80 –

0.60 –

0.40 –

0.20 –

0

CHILDHOOD ASTHMA AND FRUIT CONSUMPTION

Okoko ERJ 2007;29:1161

DIET, WHEEZE, AND ATOPY IN SCHOOL CHILDREN IN MENORCA, SPAIN

Chatzi Pediatr Allergy Immunol 2007; 18: 480

A cross-sectional analysis was performed on 460 children at age 6.5 yr

Parents completed a questionnaire on allergic symptoms, and on food frequency.

0.38

OR FOR WHEEZING

p<0.05

1 –

0 In children consuming >40 g/day of fruity

vegetable (tomatoes, eggplants,

cucumber, green beans, zucchini)

Cross-sectional survey. 690 children aged 7-18

years in rural Crete. Questionaire on

respiratory and allergic symptoms and a 58-item food frequency qestionaire.

SPTs.

OR FOR WHEEZING3 –

2 –

1 –

0 nuts0.46

2.19

margarineHight intake > 3 times a

week

PROTECTIVE EFFECT OF FRUITS, VEGETABLES AND THE MEDITERRANEAN DIET ON ASTHMA AND ALLERGIES AMONG CHILDREN IN CRETE Chatzi Thorax 2007;62:677

In children of mothers with fish intake during pregnancy OR for

1 –

0

Maternal fish intake during pregnancy and atopy and asthma in infancy. Romieu Clin Exp All

2007;37:518

A cohort of women (n=462) enrolled during pregnancy

Offspring followed up to 6 years

0.73

0.68 0.5

5eczema at 1 yr

(+) SPT to HDM at age

6 yrs

Asthma at age 6 yrs

Predicted probability of skin prick test sensitivity to house dust mite (HDM) at 6 years of age

associated with weekly frequency of fish intake (long

scale)

The following changes in risk can be calculated for a change from:

1. once a month (0.25 per week) to once per week reduces the risk by 72%;

2. twice per month (0.5 per week) to once per week by 32%

3. once a week to 2.5 times per week by 47%.

Maternal fish intake during pregnancy and atopy and asthma in infancy. Romieu Clin Exp All

2007;37:518

DIET, WHEEZE, AND ATOPY IN SCHOOL CHILDREN IN MENORCA, SPAIN

Chatzi Pediatr Allergy Immunol 2007; 18: 480

A cross-sectional analysis was performed on 460 children at age 6.5.

Parents completed a questionnaire on allergic symptoms, and a food frequency.

0.43

OR FOR ATOPY

p.<0.05

1 –

0 Fish intake > 60 g/day

Relationship of fish and cod oil intake with adult asthma

Laerum ClinExpAll 2007;37:1616

16187 subjects aged 23-54 years

Postal questionnaire

OR FOR DOCTOR DIAGNOSED ASTHMA

IN ADULHOOD

Never had fish in childhood

2.03

2 –

1 –

0

X X XX

Linoleic acid (omega-6) (margarines)

Arachidonicacid cyclo-

oxygenase

PGE Inhibition on IL-2 INF-Y

No effect on IL-4 IL-5

Th0 Th2 IgE

+

+

2

POLYUNSATURATED FAT AND CYTOKINES

-

-

-

Linolenic acid (fish oil)

(omega-3)

Eicosapentaenoic acid

Consumption of cured meat

(times per month) 0 –

-20 –

-40 –

-60 –

-80 –

-100 –

-120 –

7,352 partecipants ≥ 45 years of age;

Cured meats, such as bacon, sausage, luncheon meats, and cured hams, are high in nitrites, which are added to meat products as a preservative, an antimicrobial agent, and a color fixative.

CURED MEAT CONSUMPTION, LUNG FUNCTION, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE AMONG UNITED STATES ADULTS Jiang AJRCCM

2007;175:798

-37.6 ml

-11.5 ml

-42 ml

-110 ml

1-2 3-4 5-13 >14

P<0,001 for trend

ml in FEV1

FAST FOODS – ARE THEY A RISK FACTOR FOR ASTHMA? Wickens Allergy 2005; 60: 1537

ISAAC1321 childrenSPTsEIABody mass

index

2 –

1

0

1.17

OR for current wheeze

<once/week >once/week

1.81

Consumption of

hamburger

ASTHMA ORIGINS


Diet


Attilio Boner

“Early life (conception to 2 years) dietary exposure

might be particularly important in the development of

childhood asthma.”

ASTHMA ORIGINS


Diet


Attilio Boner

“Early life (conception to 2 years) dietary exposure

might be particularly important in the development of

childhood asthma.”

Consumption of fresh fruit,

vegetables, and fish should be

increased.



Attilio Boner


BOTTLE FEEDING IN BED OR CRIB BEFORE SLEEP TIME AND WHEEZING IN EARLY CHILDHOOD. Celedon Pediatrics 2002;110:e77

448 ch with parental history of atopy followed from birth to 5 years

Parental report of wheeze

Bottle feeding in bed times in the first year

6 –

5 –

4 –

3 –

2 –

1 –

0

1 2 3 4 5 6

OR for asthma at age 5y

% ch who developed asthma in the 10 yrs follow-up

10 –

8 –

6 –

4 –

2 –

0

Low physical fitness in childhood is associated with the development of asthma in young adulthood: the Odense school child study.

Rasmussen ERJ 2000;16:866

• 757 healthy schoolchildren (mean age 9.7 yrs)

• Follow-up 10.5 yrs• Progressive

exercise test (maximal workload) on a bicycle ergometer

6.7%These children had

a significant (p=0.02) reduced

mean physical fitness at the time of enrolment into

the study.

OR for Development of Physician Diagnosed

Asthma2 –

1 –

0

0.93

in children with physical fitness > 1

W x Kg(-1)

Low physical fitness in childhood is associated with the development of asthma in young adulthood: the Odense school child study.

Rasmussen ERJ 2000;16:866

• 757 healthy schoolchildren (mean age 9.7 yrs)

• Follow-up 10.5 yrs• Progressive

exercise test (maximal workload) on a bicycle ergometer

The risk of developing

asthma during adolescence

was reduced

7% by increasing the

maximal workload 1 W

x Kg(-1)

LEISURE TIME ACTIVITY AND NEW ONSET OF WHEEZING DURING ADOLESCENCE

Vogelberg ERJ 2007;30:672

15 –

10 –

5 –

0

11.3%

% ADOLESCENTS

2.910 adolescents without earlier episodes of wheezing in childhood.

NEW ONSET OF WHEEZE IN THE PREVIOUS 12 MONTHS

% SUBJECTS WITH NEW ONSET OF WHEEZE IN THE PREVIOUS 12 MONTHS

12.9%

15 –

10 –

5 –

0

9.9%

YES ≤1/MONTH

8.2%

NO

13.9%

≥3/WEEK

P=0.02 P=0.001

VISITING DISCOTEQUES ON A REGULAR BASES SPORT ACTIVITY

LEISURE TIME ACTIVITY AND NEW ONSET OF WHEEZING DURING ADOLESCENCE

Vogelberg ERJ 2007;30:672

INCREASED INCIDENCE OF ASTHMALIKE SYMPTOMS IN GIRLS WHO BECOME OVERWEIGHT OR OBESE DURING THE SCHOOL YEARS Castro-Rodriguez AJRCCM 2001; 163: 1344

10 –

0

Prevalence of asthma and body mass index at mean ages of 6.3 and 10.9 yr in the Tucson cohort

In females who became overweight or obese between 6 and 11 yrs

Likelyhood to developnew asthma symptoms

at age 11-13 years

7 X

OVERWEIGHT, OBESITY, AND INCIDENT ASTHMA A Meta-analysis of Prospective Epidemiologic

Studies Beuther AJRCCM 2007; 175:661

Normal weight (BMI<25), overweight (BMI, 25-29,9), and obesity (BMI≥30);

7 studies (n = 333,102 subjects).

OR for incident asthma in adult

1.38

2 –

1.5 –

1 –

0.5 –

0

25-29.9

1.92

> 30

BMI

P<0,0001 for trend

OBESITY AND LEPTIN Weiss S

AJRCCM 2004; 169: 963Adipocites Leptin

Increased secretionin obesity

Signals satiety to the hypothalamus

Stimulate Th1, suppress Th2

Proliferation of lung and airway cells

Increase activity in sympatetic nerves

Release of catecholamines from adrenal medulla

In obese patients there is a

resistance to the effects of leptin

which may favor a Th2 polarization

and a reduction of lung size

In obese patients there is a

resistance to the effects of leptin

which may favor a Th2 polarization

and a reduction of lung size

ASTHMA ORIGINS


Diet and life-style


Attilio Boner

“life-style might be particularly important in

the development of adolescent and adulthood

asthma.”

ASTHMA ORIGINS


Diet and life-style


Attilio Boner

“life-style might be particularly important in

the development of adolescent and adulthood

asthma.”

No bottle feeding in the cribRegular physical activity to maintain good fitnessNo increase in BMI



Attilio Boner


influence of caregiver stress on wheeze in infancy

genetically predisposed birth-cohort (n=496)

Greater level of stress in caregivers

1 -1.6

PARENTAL STRESS AS A PREDICTOR OF WHEEZING IN INFANCY: A PROSPECTIVE

BIRTH-COHORT STUDYWright Am J Respir Crit Care Med 2002; 165: 358

RR of wheezing during the first 14 mo.

CHRONIC CAREGIVER STRESS AND IGE EXPRESSION, ALLERGEN-INDUCED PROLIFERATION, AND CYTOKINE

PROFILES IN A BIRTH COHORT PREDISPOSED TO ATOPY Wright JACI 2004; 113: 1051

Caregiver stress evaluated by Perceived Stress Scale in the first 2 yrs

Total IgE and proliferative response to HDM

OR in children (6-18 mo) forIgE > 100 vs < 100 UI/ml

With higher caregiver stress

3 -

2 –

1 –

0

2.03

BEHAVIOR PROBLEMS ANTECEDE THE DEVELOPMENT OF WHEEZE IN CHILDHOOD Calam Am J Respir Crit Care

Med 2005; 171: 323Psychologic factors at age 3 years and subsequent development of wheeze by age 5 in an unselected birth cohort study

Eyberg Child Behavior Inventory

Children who had never wheezed (n=397) and those developing late-onset wheezing (after age 3 years; n= 39)

% children with Intense Behavior

Problems30 –

20 –

10 –

0 Late onset wheezers

Never

wheezers

23.1%

6%

p<0.001

A TWIN STUDY OF POST-TRAUMATIC STRESS DISORDER SYMPTOMS AND ASTHMA

Goodwin AJRCCM 2007;176:983

Association between post-traumatic stress disorder (PTSD) symptoms and asthma.

Data from twins in the Vietnam Era Twin Registry.

Likelihood ratio of developing asthma

3 –

2 –

1 –

0

2.3P<0.001

In veterans in the highest quartile of PTSD compared to

those in the lowest

ASTHMA ORIGINS Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke Diet

Psychological factors


Attilio Boner

Psychological factors maypredispose to wheeze and atopythrough neuro-immunological mechanisms.

ASTHMA ORIGINS Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke Diet

Psychological factors


Attilio Boner

Psychological factors maypredispose to wheeze and atopythrough neuro-immunological mechanisms.

Take it easyDon’t worry be happyMake love not war



Attilio Boner


PRENATAL PARACETAMOL EXPOSURE AND RISK OF ASTHMA AND ELEVATED IMMUNOGLOBULIN E IN

CHILDHOOD Shaheen Clin. Exp. Allergy 2005; 35: 18 Population-based

Avon Longitudinal Study of Parents and Children

Paracetamol and aspirin use in late pregnancy (20-32 weeks)

Asthma, hayfever, eczema and wheezing in the offspring at 69-81 months

OR for different disease of offspring whose mothers took

paracetamol* versus those who never took it *

ASTHMA TOTAL IgE

*SOM

ETIMES

*MOSTDAYS

*SOM

ETIMES

*MOSTDAYS

2.0 –

1.5 –

1.0 –

5 –

0

1.221.62

1.14

1.52

The proportion of asthma

attributable to paracetamol use

in late pregnancy, assuming a

causal relation, was 7%.

ARE ORAL CONTRACEPTIVE USE AND PREGNANCY COMPLICATIONS RISK FACTORS FOR ATOPIC DISORDERS AMONG OFFSPRING? Brooks Pediatr. Allergy Immunol. 2004; 15: 487

Oral contraceptive use before pregnancy

OR for asthma in children

Follow-up 11-12 yrs of 1720 children

OR for having a mother who used contraceptive pills

In asthmatic children

2.0 –

1.5 –

1.0 –

5 –

0

1.81

Endobronchial biopsy from wheezy preschool children (aged 3 months to 5 years)

Subjects undergoing fibreoptic bronchoscopy to investigate stridor acted as non-asthma controls

EARLY DETECTION OF AIRWAY WALL REMODELLING AND EOSINOPHILIC INFLAMMATION IN PRESCHOOL

WHEEZERSSaglani AJRCCM 2007;176:858

WHEEZING CONTROLS

RETICULAR BASE MEMBRANETHICKNESS (μ)

4.6

3.8

p<0.055 –

4 –

3 –

2 –

1 –

0

LONG-TERM INHALED CORTICOSTEROIDS IN PRESCHOOL CHILDREN AT HIGH RISK FOR ASTHMA

Morgan NEJM 2006; 354: 1985

285 ch. 2-3 yrs old with (+) Asthma Predictive Index

Fluticasone Prop. 100 μg x 2 or placebo for 2 years

1 year follow-up without medication

Bimonthly proportion of episode-free days during the two year treatment

period and the observation period.

REVERSAL OF ALLERGEN-INDUCED AIRWAY REMODELING BY CYSLT1 RECEPTOR BLOCKADE

Henderson AJRCCM 2006; 173: 718

(1) Sensitized by intraperitoneal

ovalbumin

(2) Received intranasal OVA

periodically Days 14-73

(3) Montelukast or dexamethasone or

placebo from Days 73-163

Montelukast, but not dexamethasone, reversed the established increase in airway

smooth muscle mass and subepithelial collagen deposition

REVERSAL OF ALLERGEN-INDUCED AIRWAY REMODELING BY CYSLT1 RECEPTOR BLOCKADE

Henderson AJRCCM 2006; 173: 718

Controls on day 163 OVA sensitized and challenge mice in absence of Montelukas

OVA sensitized and challenge mice in presence of Montelukast

Collagen deposition

Introduction Genetic Factors Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style

- psychology - treatment


Attilio Boner


During pregnancy potentially harmfull drugs have to be avoidedPharmachological prevention strategies need to be explored in humans

Introduction Genetic Factors Environmental Factors Conclusions


Attilio Boner


Birth cohort 4089 ch

Families who lived according the Swedish primary prevention guidelines:

1.breastfeeding2.no tabacco smoke3.good ventilation & reduced dampness

*NO=exposed to >2 risk factors

STRATEGIES FOR PREVENTING WHEEZING AND ASTHMA IN SMALL CHILDREN. Wickman Allergy 2003;58:742

RECURRENT WHEEZING AT 2 YRS

living according to guidelines

YES NO*

30-

20-

10-

0

12.6%24.1%






RECURRENT WHEEZING AT 2 YRS

living according to guidelines

YES NO*

30-

20-

10-

0

12.6%24.1%

CAN ASTHMA AND ALLERGY BE PREVENTED

IN REAL LIFE? Carlsen Allergy 2003;58:730

“The present study shows that prevention of asthma and allergy may be very

effective.”






YES NO*

20-

10-

06.8%

17.9%

ASTHMA AT AGE 2

IN CHILDREN WITH HEREDITY TO ASTHMA, LIVING ACCORDING TO THE GUIDELINES

GAVE A THREEFOLDDECREASE IN ASTHMA AND IN CHILDREN

WITH NO HEREDITY A TWOFOLD REDUCTION Carlsen Allergy 2003;58:730

THE BRITISH 1958 COHORT.A MESSAGE FOR OBSTETRICIANS AND

PEDIATRICIANS. Boner AJRCCM 2007; 175: 298

“All effort should be made to prevent intrauterine insults that may perturb lung development:

1)No maternal smoking during pregnancy,2)No maternal undernutrition,3)No maternal hypertension which may cause

placental hypoxia,4)No oligodramnios,5)No harmfull drugs,6)No stress.

THE BRITISH 1958 COHORT.A MESSAGE FOR OBSTETRICIANS AND

PEDIATRICIANS. Boner AJRCCM 2007; 175: 298

In children may be of help:• Reduction of allergen exposure in early life,• Good care of the skin to maitain the barrier

function?• Regular consumption of fresh fruit, vegetables,

and fish,• Reduction of indoor and outdoor pollution,• No smoking,• No stress,• Regular physical activity.

Thank you for your attentionFORMAT 17-19/04/2008

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