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
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
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
University of Verona, Italy
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
University of Verona, Italy
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
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
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
University of Verona, Italy
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
University of Verona, Italy
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
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
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
University of Verona, Italy
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
University of Verona, Italy
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.
Introduction Genetic Factors Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style - psychology - treatment Conclusions
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
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
University of Verona, Italy
Attilio Boner
Smoking should always be avoided by anyone.
Introduction Genetic Factors Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style - psychology - treatment Conclusions
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
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
University of Verona, Italy
Attilio Boner
Early contact with:-Synthetic materials-Chlorinated pools-Pollution-Detergentsare important adjuvant factors.
ASTHMA ORIGINS
Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke
Other adjuvant factors
University of Verona, Italy
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
Introduction Genetic Factors Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style - psychology - treatment Conclusions
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
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
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.
LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY IS ASSOCIATED WITH ASTHMA IN 5-
YEARS-OLD CHILDREN Devereux AJRCCM 2006; 174: 499
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
LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY IS ASSOCIATED WITH ASTHMA IN 5-
YEARS-OLD CHILDREN Devereux AJRCCM 2006; 174: 499
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.
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
LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY IS ASSOCIATED WITH ASTHMA IN 5-
YEARS-OLD CHILDREN Devereux AJRCCM 2006; 174: 499
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.
Zinc deficiency in pregnant rats is associated with impaired
fetal lung growth.
Vojnik J Nutr 1977; 107: 862
LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY IS ASSOCIATED WITH ASTHMA IN 5-
YEARS-OLD CHILDREN Devereux AJRCCM 2006; 174: 499
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
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
Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke
Diet
University of Verona, Italy
Attilio Boner
“Early life (conception to 2 years) dietary exposure
might be particularly important in the development of
childhood asthma.”
ASTHMA ORIGINS
Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke
Diet
University of Verona, Italy
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.
Introduction Genetic Factors Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style - psychology - treatment Conclusions
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
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
Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke
Diet and life-style
University of Verona, Italy
Attilio Boner
“life-style might be particularly important in
the development of adolescent and adulthood
asthma.”
ASTHMA ORIGINS
Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke
Diet and life-style
University of Verona, Italy
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
Introduction Genetic Factors Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style - psychology - treatment Conclusions
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
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
University of Verona, Italy
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
University of Verona, Italy
Attilio Boner
Psychological factors maypredispose to wheeze and atopythrough neuro-immunological mechanisms.
Take it easyDon’t worry be happyMake love not war
Introduction Genetic Factors Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style - psychology - treatment Conclusions
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
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
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
During pregnancy potentially harmfull drugs have to be avoidedPharmachological prevention strategies need to be explored in humans
Introduction Genetic Factors Environmental Factors Conclusions
University of Verona, Italy
Attilio Boner
TO CHANGE ASTHMA NATURAL HISTORY: A MITH?
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%
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%
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.”
STRATEGIES FOR PREVENTING WHEEZING AND ASTHMA IN SMALL CHILDREN. Wickman Allergy 2003;58:742
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
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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