TO CHANGE ASTHMA NATURAL HISTORY: A MITH? University of Verona, Italy

TO CHANGE ASTHMA NATURAL HISTORY: A MITH? University of Verona, Italy
Introduction Genetic Factors Environmental Factors Conclusions Attilio Boner University of Verona, Italy

TUCSON CHILDREN’S RESPIRATORY STUDY:
1980 TO PRESENT Taussig JACI 2003; 111:661 Lung Development and Physiology ALB

TUCSON CHILDREN’S RESPIRATORY STUDY:
1980 TO PRESENT Taussig JACI 2003; 111:661 Lung Development and Physiology Immunology ALB

A cohort of 3420 7- to 8- year-old children
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 Prevalence (%) of current asthma in relation to parental asthma, parental atopy, SPT result, and combinations of these categories. A cohort of to 8- year-old children SPTs Questionnaires

OR for parental asthma is multiplicative.
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 15 – 14 – 13 – 12 – 11 – 10 – 13.6 OR for parental asthma is multiplicative. OR for parental atopy is additive 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 3.6 3.2 2.8 1.6 1 1 1.2 NONE M only F only F+M NONE M only F only F+M ASTHMA ATOPY PARENTAL

Introduction Genetic Factors: lung development immunology Environmental Factors Conclusions Attilio Boner University of Verona, Italy

* * * * * * * * * * A population-based birth cohort in Tucson
OUTCOME OF ASTHMA AND WHEEZING IN THE FIRST 6 YEARS OF LIFE Morgan AJRCCM 2005; 172: 1253 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 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 * * * * * Z-Scores of Height Adjusted Flow (+/-se) * * Never Wheeze Transient Early Late Onset Persistent * * * Age, years

Individuals with bronchiolitis were prospectively identified
REDUCED LUNG FUNCTION BOTH BEFORE BRONCHIOLITIS AND AT 11 YRS Turner Arch Dis Child 2002; 87: 417 . 3 2 1 %VmaxFRC p=0.02 253 cohort members VmaxFRC at 1 month of age Individuals with bronchiolitis were prospectively identified At 11 years of age lung function was repeated . z score -1 -2 -3 Control (n = 162) Confirmed bronchiolitis (n = 16) Box and whisker plot for z scores for % V’maxFRC at 1 month

REDUCED LUNG FUNCTION AT BIRTH AND THE RISK OF ASTHMA AT 10 YEARS OF AGE
Haland , Carlsen N Engl J Med 2006; 355: 1682 % children with a history of asthma at age 10 year % children with current asthma at age 10 year 30 – 20 – 10 – 30 – 20 – 10 – p=0.01 24.3% p=0.005 16.2% 14.6% 7.5% Above the median At-below the median Above the median At-below the median tPTEF/tE at age 3 days tPTEF/tE at age 3 days

University of Verona, Italy
ASTHMA ORIGINS Lung Development Reduced lung development is a premorbid predisposing factor for: Transient wheezing, Bronchiolitis, Persistent atopic wheezing, Loss of lung function is characteristic of asthma. Attilio Boner University of Verona, Italy

ASTHMA ORIGINS Lung Development Good care of pregnancy is
Reduced lung development is a premorbid 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. Attilio Boner University of Verona, Italy

Introduction Genetic Factors: lung development immunology Environmental Factors Conclusions Attilio Boner University of Verona, Italy

MATERNO-PLACENTO-FETAL INTERACTIONS
Warner Arch Dis Child 2004;89:97 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. 22°wk 14°wk alb

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 In contrast to allergen-responsive adult CD4(+) T cell cultures, responding neonatal T cell cultures displays a high level of apoptosis. In these cultures CD4+CD25+CTLA4+ T regulatory cells appears and exert a suppressive activity. Neonatal T cell responses to allergens differ markedly from those occurring in later life

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 0.35 Age (months) Tracking antibody titers in individuals who are HDM SPT-negative at age 24 months

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 0.35 Age (months) Tracking antibody titers in individuals who are HDM SPT-positive at age 24 months

SKIN BARRIER FUNCTION AND ALLERGIC RISK
Hudson Nature Genetics 2006; 38: 399 Skin barrier function and allergic risk. An intact epithelial barrier (a) prevents allergens from reaching 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.

FILLAGRIN LOSS-OF-FUNCTION MUTATIONS PREDISPOSE TO PHENOTYPES INVOLVED IN THE ATOPIC MARCH
Marenholz JACI ; 118: 866 OR ratio for concomitant eczema and asthma OR ratio for concomitant eczema and allergic rhinitis 7 – 6 – 5 – 4 – 3 – 2 – 1 – OR for non atopic eczema OR for atopic eczema 6.21 4.79 3.94 3.84 p= p=0.0006 p= p= IN CHILDREN WITH FILAGGRIN LOSS-OF-FUNCTION MUTATION

ASTHMA ORIGINS Lung Development Immunologic Maturation The fetal life and the newborn period are prone to atopy. Sensitization starts early but postnataly. Defective skin barrier fuction predispose to allergy development. Attilio Boner University of Verona, Italy

ASTHMA ORIGINS Immunologic Maturation Good care of pregnancy
Lung Development Immunologic Maturation Good care of pregnancy Allergen avoidance thereafter. Immunomodulating natural factors? Good care of the skin is probably important. The fetal life and the newborn period are prone to atopy. Sensitization starts early but postnataly. Defective skin barrier fuction predispose to allergy development. Attilio Boner University of Verona, Italy

Introduction Genetic Factors Environmental Factors: - allergens tobacco smoke pollutants diet life-style psychology treatment Conclusions Attilio Boner University of Verona, Italy

% mean difference in sRaw in mite sensitive vs non-sensitive
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-sensitive Manchester Asthma and Allergy Study (birth cohort: 276 children) specific airway resistance (sRaw) at 3 yrs of age 10 – 8 – 6 – 4 – 2 – +9.2% p=0.020

8.3 3.29 1314 children from birth to 13 years of age (MAS study)
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 10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 1314 children from birth to 13 years of age (MAS study) Allergen exposure at age 6 months, months, and at 3, 4, and 5 yrs Lung function at 7, 10, and 13 yrs 8.3 3.29 Early Current sensitization sensitisation (age <3) ALB to perennial allergen

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 OR for asthma both at age 3.5 and 7 years 2.0 – 1.5 – 1.0 – 0.5 – 871 children of European mothers enrolled at birth; Data collected at birth, 12 months, years of age and 7 years. 2.1 1.8 Contact with dog Sleeping in a previously used mattress in the first year

OR in the prophylactic group
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 – 0,24 0,23 0,14 0,13 p=0.005 p=0.005 p=0.0003 p<0.005 asthma Atopic dermatitis Allergic rhinitis atopy

Ln VmaxFRC GM & 95% CI at age 4 weeks
EARLY LIFE ENVIROMENTAL CONTROL: EFFECT ON SYMPTOMS, SENSITIZATION AND LUNG FUNCTION AT AGE 3 YEARS Woodcock AJRCCM 2004;170:433 1.0 – 0.8 – 0.6 – 0.4 – 0.2 – 0.0 Ln VmaxFRC GM & 95% CI at age 4 weeks * Manchester cohort 128 active group 111 control group Allergen level, symptoms, sensitization and lung function at 3 years of age * p=0.49 ALB

Ln sRaw GM & 95% CI at age 3 years
EARLY LIFE ENVIROMENTAL CONTROL: EFFECT ON SYMPTOMS, SENSITIZATION AND LUNG FUNCTION AT AGE 3 YEARS Woodcock AJRCCM 2004;170:433 Ln sRaw GM & 95% CI at age 3 years * Manchester cohort 128 active group 111 control group Allergen level, symptoms, sensitization and lung function at 3 years of age 0.4 – 0.3 – 0.2 – 0.1 – 0.0 – -.1 * p=0.003 ALB

PERENNIAL ALLERGEN SENSITISATION EARLY IN LIFE AND CHRONIC ASTHMA IN CHILDREN: A BIRTH COHORT STUDY
Illi Lancet 2006; 368: 763 * * * * * * * * * * * * NS S/LE SHE NS S/LE SHE NS S/LE SHE NS S/LE SHE NS S/LE SHE NS S/LE SHE FVC (% predicted) FEV1 (% predicted) FEV1/FVC MEF75 (% predicted) MEF50 (% predicted) MEF25 (% predicted) Effect of allergen sensitisation and exposure at < 3 years on lung function at age 7 years. NS= Not sensitised to dust mites or cat dander. S/LE= sensitised to dust mites cat dander and low exposure to these allergens. S/HE= Sensitised to dust mites or cat dander and high exposure to these allergen.

had persistent (-) SPT to HDM
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 who had persistent (-) SPT to HDM ATOPY TO HDM PERSISTENT NEW F E V1 % P R D I C T - 1 - 2 - 3 - 4 - 5 - 6 - 4.3% - 5.5% 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 STUDY Arshad Clin. Exp. All. 2002; 32: 843 % ch. developing SPT (+) to mites in the 12 mo follow-up 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 mite Ch.(5-7 yrs) - Cover mattress (n=117)  - Control group (n=96)  10 - 9 - 8 - 7 - 6 - 5 - 4 - 3 - 2 - 1 - 9.38% p<0.05 2.56% 9/96 3/117 CONTROL ACTIVE

OR FOR WHEEZING AT AGE 26 YEARS
A LONGITUDINAL, POPULATION-BASED, COHORT STUDY OF CHILDHOOD ASTHMA FOLLOWED TO ADULTHOOD.Sears NEJM 2003;349:1414 OR FOR WHEEZING AT AGE 26 YEARS 5 - 4 - 3 – 2 – 1 – p<0.001 for trend 4.17 FOR RELAPSE 3.38 FOR PERSISTANCE (+) SPT FOR MITES AT AGE 13 YEARS

ARE ATOPY AND SPECIFIC IgE TO MITES AND MOLDS IMPORTANT FOR ADULT ASTHMA?
Jaakkola JACI 2006; 117: 642 OR for new onset asthma 5 - 4 - 3 – 2 – 1 – Specific IgE to mites and molds; All new diagnosed cases of asthma 21-63 years of age ( ); A random sample of control; 485 cases and 665 controls. 4.69 2.73 2.30 sIgE: MITE ASPERGILLUS CLADOSPORIUM

ASTHMA ORIGINS Lung Development Immunologic Maturation Allergens 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 Attilio Boner University of Verona, Italy

ASTHMA ORIGINS Allergens Environmental strategies
Lung Development Immunologic Maturation Allergens 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 University of Verona, Italy

membranous airway from an 8-month-old infant
AIRWAY ALVEOLAR ATTACHMENT POINTS AND EXPOSURE TO CIGARETTE SMOKE IN UTERO Elliot AIRCCM 2003; 167: 45 membranous airway from an 8-month-old infant 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

residual capacity (ml/s)
THE EFFECT OF MATERNAL SMOKING DURING PREGNANCY ON EARLY INFANT LUNG FUNCTION Hanrahan Am. Rev. Respir. Dis. 1992; 145: 1129 Flow at functional residual capacity (ml/s) 80 healthy infants tested shortly after birth (mean, 4.2+/-1.9 wk) Urine cotinine Expiratory flow- volume curves 200 – 150 – 100 – 50 – 150.4 p= 74.3 YES NO SMOKING MOTHER

SMOKING DURING PREGNANCY
PARENTAL SMOKING AND LUNG FUNCTION IN CHILDREN Moshammer AJRCCM 2006;173:1255 SMOKING DURING PREGNANCY 0 – -1 – -2 – -3 – -4 – -5 – -6 – -7 – 20,000 children (aged 6-12 yr) from Europe and North America; Exposure information by questionnaires; -1% in FEV1 -6% MEF25%

MATERNAL AND GRANDMATERNAL SMOKING PATTERNS ARE ASSOCIATED WITH EARLY CHILDHOOD ASTHMA
Li YF Chest 2005; 127: 1232 OR for asthma in the first 5 years of life 3 – 2 – 1 – 2.6 338 children with asthma diagnosed in the first 5 years of life 570 control subjects 1.8 1.3 Grandmaternal only smoking during the mother’s fetal period Grandmaternal and maternal smoking Smoking mother only

THE ADULT INCIDENCE OF ASTHMA AND RESPIRATORY SYMPTOMS BY PASSIVE SMOKING IN UTERO OR IN CHILDHOOD Skorge AJRCCM 2005; 172: 61 OR ratio for adult onset asthma 3 – 2 – 1 – Between 1985 and 1996/1997 an 11-year community cohort study on the incidence of asthma 3.786 subjects 3 Smoking mother

THE ADULT INCIDENCE OF ASTHMA AND RESPIRATORY SYMPTOMS BY PASSIVE SMOKING IN UTERO OR IN CHILDHOOD Skorge AJRCCM 2005; 172: 61 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. OR ratio for adult onset asthma 3 – 2 – 1 – Between 1985 and 1996/1997 an 11-year community cohort study on the incidence of asthma 3.786 subjects 3 Smoking mother

RR FOR NEW ONSET OF ASTHMA
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 4 – 3 – 2 – 1 – 3.9 In children smoking >300 cigarettes/year

REGULAR SMOKING AND ASTHMA INCIDENCE IN ADOLESCENTS Gilliland AJRCCM 2006; 174: 1094
RR FOR NEW ONSET OF ASTHMA 10- 8 – 6 – 4 – 2 – 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 8.8 In children smoking >300 cigarettes/year and exposed to maternal smoking during gestation

ASTHMA ORIGINS Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke Smoking should always be avoided by anyone. Attilio Boner University of Verona, Italy

SYNTHETIC BEDDING AND WHEEZE IN CHILDHOOD
SYNTHETIC BEDDING AND WHEEZE IN CHILDHOOD. Ponsonby Epidemilogy 2003;14:37 7 – 6 – 5 – 4 – 3 – 2 – 1 – OR for wheezing at 7 yrs Bedding type at 1mo Wheeze at 7 yrs (n=6,378 ch) 5.2 2.5 synthetic pillow +synthetic quilt

RECENT WHEEZE AT AGE 7 YEARS NIGHT WHEEZE AT AGE 7 YEARS
A prospective association between synthetic cocoon use in infancy and childhooh asthma Trevillian Paed Perin Epidem 2004:18:281 At age 7 years OR for 5 - 4 - 3 – 2 – 1 – Sleeping environment of 863 infants evaluated at 1 month of life Follow-up: years 4.33 3.35 RECENT WHEEZE AT AGE 7 YEARS NIGHT WHEEZE AT AGE 7 YEARS IN CH. SLEEPING IN A SYNTHETIC COCOON AT 1 MONTH OF AGE

Residential outdoor air pollution and allergen sensitization in schoolchildren in Norway Oftedal CEA 2007;37:1632 2 - 1 – 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) OR FOR SENSITIZATION TO D.farinae 1.88 1.61 1.46 NO2 PM10 PM2.5 one interquartile increase of lifetime exposure to

Rojas-Martinez AJRCCM 2007;176:377
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 Percentiles Visits

IS IT TRAFFIC TYPE, VOLUME, OR DISTANCE
IS IT TRAFFIC TYPE, VOLUME, OR DISTANCE? WHEEZING IN INFANTS LIVING NEAR TRUCK AND BUS TRAFFIC Ryan JACI 2005; 116: 279 OR for wheezing 3 – 2 – 1 – The relationship between types of traffic, traffic volume, and distance and wheezing among infants less than year of age 2.5 In infants living very near (< 100 m) to stop-and-go bus and truck traffic

IN WOMEN LIVING WITHIN 150 M FROM MAJOR ROAD
TRAFFIC EXPOSURE AND LUNG FUNCTION IN ADULTS: THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY Kan Thorax 2007; 62: 8 73 IN WOMEN LIVING WITHIN 150 M FROM MAJOR ROAD -10 – -20 – -30 – 15792 middle aged men and women. Traffic density and distance to major roads were used as measures of traffic exposure. -15.7 mL FEV1 -24.2 mL FVC

THE USE OF HOUSEHOLD CLEANING SPRAYS AND ADULT ASTHMA Zock AJRCCM 2007;176:735
2 – 1 – RR for new diagnosis of asthma 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. 2.11 p.<0.05 In person using cleaning spray at least 4 days per week

ASTHMA ORIGINS Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke Other adjuvant factors Early contact with: Synthetic materials Chlorinated pools Pollution Detergents are important adjuvant factors. Attilio Boner University of Verona, Italy

ASTHMA ORIGINS Other adjuvant factors
Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke Other adjuvant factors Early contact with: Synthetic materials Chlorinated pools Pollution are important adjuvant factors. no synthetic materials in early llyfe Ask yourself what you can do to prevent pollution Attilio Boner University of Verona, Italy

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 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 1.194 mother-child pairs Maternal intake of vitamin D during pregnancy with FFQ 1 – 0.39 p<0.001 Recurrent wheeze

MATERNAL VITAMIN D INTAKE DURING PREGNANCY AND EARLY CHILDHOOD WHEEZING Devereux Am J Clin Nutr 2007; 85: 853 In 5 year old children of mothers in the highest versus the lowest quintiles of vit D intake OR for Random sample of healthy pregnant women at approximately wk gestation Maternal vitamin D intake ascertained at 32 wk of gestation with FFQ 1 – 0.48 0.35 0.33 Ever wheeze Wheeze in previous year Persistent wheeze

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

LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY IS ASSOCIATED WITH ASTHMA IN 5-YEARS-OLD CHILDREN Devereux AJRCCM 2006; 174: 499 OR FOR WHEEZE WITHOUT A COLD IN THE LAST 12 MO AT 5 YEARS OF AGE 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. 1- 1 p = 0.02 for trend 0.56 0.50 0.53 0.22 1 2 3 4 5 QUINTILES OF VIT E INTAKE IN THE MOTHER

LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY IS ASSOCIATED WITH ASTHMA IN 5-YEARS-OLD CHILDREN Devereux AJRCCM 2006; 174: 499 OR FOR ATOPIC SENSITIZATION 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. 1- 0.60 in children of mothers with higher concentrations of  tocoferol at 12 wk gestation

QUINTILES OF ZINC INTAKE
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 1,861 children born to women recruited during pregnancy and followed up at 5 yr; Maternal nutrient status by a food frequency questionnaire and plasma levels. 1- 1 p = 0.04 for trend 0.59 0.55 0.51 0.44 1 2 3 4 5 QUINTILES OF ZINC INTAKE

QUINTILES OF ZINC INTAKE
LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY IS ASSOCIATED WITH ASTHMA IN 5-YEARS-OLD CHILDREN Devereux AJRCCM 2006; 174: 499 Zinc deficiency in pregnant rats is associated with impaired fetal lung growth. Vojnik J Nutr 1977; 107: 862 OR FOR EVER ASTHMA 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. 1- 1 p = 0.04 for trend 0.59 0.55 0.51 0.44 1 2 3 4 5 QUINTILES OF ZINC INTAKE

OR for wheeze in absence of a cold in the second year
ANTIOXIDANT INTAKE IN PREGNANCY IN RELATION TO WHEEZE AND ECZEMA IN THE FIRST TWO YEARS OF LIFE Martindale AJRCCM ; 171: 121 OR for wheeze in absence of a cold in the second year 2000 women Prospective investigation of the influence of maternal antioxidant intake in pregnancy determined by food frequency questionnaire at 34 weeks gestation Development of asthma and eczema in children (questionnaire) Follow up the 1,924 singleton children 6, 12 and 24 months of age 1 1 p for trend = 0.006 0.61 0.47 1° tertile 2° tertile 3° tertile Vitamin E maternal intake

In animal models and humans, vit E and Zinc
LOW MATERNAL VITAMIN E INTAKE DURING PREGNANCY IS ASSOCIATED WITH ASTHMA IN 5-YEARS-OLD CHILDREN Devereux AJRCCM 2006; 174: 499 Vegetable oils (sunflower, rapeseed, corn) Margarine Wheat germ Nuts Sunflower seeds Major diet source of Vit E In animal models and humans, vit E and Zinc 1- Liver Wheat germ Lean red meat Seeds Nuts Major diet source of Zinc Th1 differentiation Th1 cytokines Th2 cytokines

Maternal apple consumption highest versus lowest tertile OR for
MATERNAL FOOD CONSUMPTION DURING PREGNANCY AND ASTHMA, RESPIRATORY AND ATOPIC SYMPTOMS IN 5-YER-OLD CHILDREN Willers Thorax 2007; 62: 773 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 apple consumption highest versus lowest tertile OR for 1 – 0.63 0.54 0.47 Ever wheeze Ever asthma Doctor asthma

0.80 0.66 0.69 CHILDHOOD ASTHMA AND FRUIT CONSUMPTION
Okoko ERJ 2007;29:1161 in children eating bananas at least once a day, OR for 1.00 – 0.80 – 0.60 – 0.40 – 0.20 – 2.640 primary school children aged 5–10 yrs; Information about asthma symptoms and fruit consumption by questionnaire. 0.80 0.66 0.69 Current wheeze Ever wheeze Ever asthma

CHILDHOOD ASTHMA AND FRUIT CONSUMPTION
Okoko ERJ 2007;29:1161 in children drinking apple juice concentrate at least once a day, OR for 1.00 – 0.80 – 0.60 – 0.40 – 0.20 – 2.640 primary school children aged 5–10 yrs; Information about asthma symptoms and fruit consumption by questionnaire. 0.90 0.74 0.53 Current wheeze Ever wheeze Ever asthma

DIET, WHEEZE, AND ATOPY IN SCHOOL CHILDREN IN MENORCA, SPAIN
Chatzi Pediatr Allergy Immunol 2007; 18: 480 1 – OR FOR WHEEZING 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 p<0.05 In children consuming >40 g/day of fruity vegetable (tomatoes, eggplants, cucumber, green beans, zucchini)

PROTECTIVE EFFECT OF FRUITS, VEGETABLES AND THE MEDITERRANEAN DIET ON ASTHMA AND ALLERGIES AMONG CHILDREN IN CRETE Chatzi Thorax 2007;62:677 3 – 2 – 1 – OR FOR WHEEZING 0.46 2.19 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. nuts margarine Hight intake > 3 times a week

In children of mothers with fish intake during pregnancy OR for
Maternal fish intake during pregnancy and atopy and asthma in infancy. Romieu Clin Exp All 2007;37:518 In children of mothers with fish intake during pregnancy OR for A cohort of women (n=462) enrolled during pregnancy Offspring followed up to 6 years 1 – 0.73 0.68 0.55 eczema at 1 yr (+) SPT to HDM at age 6 yrs Asthma at age 6 yrs

Maternal fish intake during pregnancy and atopy and asthma in infancy
Maternal fish intake during pregnancy and atopy and asthma in infancy. Romieu Clin Exp All 2007;37:518 The following changes in risk can be calculated for a change from: once a month (0.25 per week) to once per week reduces the risk by 72%; twice per month (0.5 per week) to once per week by 32% once a week to 2.5 times per week by 47%. 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)

DIET, WHEEZE, AND ATOPY IN SCHOOL CHILDREN IN MENORCA, SPAIN
Chatzi Pediatr Allergy Immunol 2007; 18: 480 1 – A cross-sectional analysis was performed on 460 children at age 6.5. Parents completed a questionnaire on allergic symptoms, and a food frequency. OR FOR ATOPY 0.43 p.<0.05 Fish intake > 60 g/day

2.03 X X X X Relationship of fish and cod oil intake with adult asthma
Laerum ClinExpAll 2007;37:1616 OR FOR DOCTOR DIAGNOSED ASTHMA IN ADULHOOD 16187 subjects aged years Postal questionnaire 2 – 1 – 2.03 X X X X Never had fish in childhood

+ - + - Linoleic acid (omega-6) (margarines) Eicosapentaenoic acid
POLYUNSATURATED FAT AND CYTOKINES Linoleic acid (omega-6) (margarines) + - Linolenic acid (fish oil) (omega-3) Eicosapentaenoic acid Arachidonic acid cyclo- oxygenase + - Inhibition on IL-2 INF-Y PGE 2 No effect on IL-4 IL-5 Th Th IgE

Consumption of cured meat
CURED MEAT CONSUMPTION, LUNG FUNCTION, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE AMONG UNITED STATES ADULTS Jiang AJRCCM 2007;175:798 Consumption of cured meat (times per month) 0 – -20 – -40 – -60 – -80 – -100 – -120 – 1-2 3-4 5-13 >14 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. -11.5 ml -37.6 ml -42 ml P<0,001 for trend -110 ml ml in FEV1

FAST FOODS – ARE THEY A RISK FACTOR FOR ASTHMA?
Wickens Allergy 2005; 60: 1537 2 – 1 OR for current wheeze 1.81 ISAAC 1321 children SPTs EIA Body mass index 1.17 <once/week >once/week Consumption of hamburger

ASTHMA ORIGINS Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke Diet “Early life (conception to 2 years) dietary exposure might be particularly important in the development of childhood asthma.” Attilio Boner University of Verona, Italy

Consumption of fresh fruit, vegetables, and fish should be increased.
ASTHMA ORIGINS Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke Diet “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 University of Verona, Italy

Bottle feeding in bed times in the first year 1 2 3 4 5 6
BOTTLE FEEDING IN BED OR CRIB BEFORE SLEEP TIME AND WHEEZING IN EARLY CHILDHOOD. Celedon Pediatrics 2002;110:e77 6 – 5 – 4 – 3 – 2 – 1 – OR for asthma at age 5y 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

% ch who developed asthma in the
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 % ch who developed asthma in the 10 yrs follow-up 10 – 8 – 6 – 4 – 2 – 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.

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 OR for Development of Physician Diagnosed Asthma 2 – 1 – The risk of developing asthma during adolescence was reduced 7% by increasing the maximal workload 1 W x Kg(-1) 757 healthy schoolchildren (mean age 9.7 yrs) Follow-up 10.5 yrs Progressive exercise test (maximal workload) on a bicycle ergometer 0.93 in children with physical fitness > 1 W x Kg(-1)

NEW ONSET OF WHEEZE IN THE PREVIOUS 12 MONTHS
LEISURE TIME ACTIVITY AND NEW ONSET OF WHEEZING DURING ADOLESCENCE Vogelberg ERJ 2007;30:672 15 – 10 – 5 – % ADOLESCENTS adolescents without earlier episodes of wheezing in childhood. 11.3% NEW ONSET OF WHEEZE IN THE PREVIOUS 12 MONTHS

% SUBJECTS WITH NEW ONSET OF WHEEZE
LEISURE TIME ACTIVITY AND NEW ONSET OF WHEEZING DURING ADOLESCENCE Vogelberg ERJ 2007;30:672 % SUBJECTS WITH NEW ONSET OF WHEEZE IN THE PREVIOUS 12 MONTHS 15 – 10 – 5 – P=0.001 13.9% P=0.02 12.9% 9.9% 8.2% YES NO ≤1/MONTH ≥3/WEEK VISITING DISCOTEQUES ON A REGULAR BASES SPORT ACTIVITY

INCREASED INCIDENCE OF ASTHMALIKE SYMPTOMS IN GIRLS WHO BECOME OVERWEIGHT OR OBESE DURING THE SCHOOL YEARS Castro-Rodriguez AJRCCM 2001; 163: 1344 10 – Likelyhood to develop new asthma symptoms at age years Prevalence of asthma and body mass index at mean ages of 6.3 and 10.9 yr in the Tucson cohort 7 X In females who became overweight or obese between 6 and 11 yrs

1.92 1.38 OVERWEIGHT, OBESITY, AND INCIDENT ASTHMA
A Meta-analysis of Prospective Epidemiologic Studies Beuther AJRCCM 2007; 175:661 2 – 1.5 – 1 – 0.5 – OR for incident asthma in adult P<0,0001 for trend Normal weight (BMI<25), overweight (BMI, 25-29,9), and obesity (BMI≥30); 7 studies (n = 333,102 subjects). 1.92 1.38 > 30 BMI

OVERWEIGHT, OBESITY, AND INCIDENT ASTHMA
A Meta-analysis of Prospective Epidemiologic Studies Beuther AJRCCM 2007; 175:661 A similar increase in the OR of incident asthma due to the overweight and obesity was observed in men and women 2 – 1.5 – 1 – 0.5 – OR for incident asthma in adult P<0,0001 for trend Normal weight (BMI<25), overweight (BMI, 25-29,9), and obesity (BMI≥30); 7 studies (n = 333,102 subjects). 1.92 1.38 > 30 BMI

OBESITY AND LEPTIN Weiss S AJRCCM 2004; 169: 963
Adipocites Leptin 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 Increased secretion in obesity 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 “life-style might be particularly important in the development of adolescent and adulthood asthma.” Attilio Boner University of Verona, Italy

ASTHMA ORIGINS Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke Diet and life-style “life-style might be particularly important in the development of adolescent and adulthood asthma.” No bottle feeding in the crib Regular physical activity to maintain good fitness No increase in BMI Attilio Boner University of Verona, Italy

PARENTAL STRESS AS A PREDICTOR OF WHEEZING IN INFANCY: A PROSPECTIVE
BIRTH-COHORT STUDY Wright Am J Respir Crit Care Med ; 165: 358 RR of wheezing during the first 14 mo. influence of caregiver stress on wheeze in infancy genetically predisposed birth-cohort (n=496) 1.6 1 - Greater level of stress in caregivers

OR in children (6-18 mo) for
CHRONIC CAREGIVER STRESS AND IGE EXPRESSION, ALLERGEN-INDUCED PROLIFERATION, AND CYTOKINE PROFILES IN A BIRTH COHORT PREDISPOSED TO ATOPY Wright JACI 2004; 113: 1051 OR in children (6-18 mo) for IgE > 100 vs < 100 UI/ml 3 - 2 – 1 – Caregiver stress evaluated by Perceived Stress Scale in the first 2 yrs Total IgE and proliferative response to HDM 2.03 With higher caregiver stress

% children with Intense Behavior Problems
BEHAVIOR PROBLEMS ANTECEDE THE DEVELOPMENT OF WHEEZE IN CHILDHOOD Calam Am J Respir Crit Care Med 2005; 171: 323 Psychologic factors at age 3 years and subsequent development of wheeze by age 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 Problems 30 – 20 – 10 – 23.1% p<0.001 6% Late onset wheezers Never wheezers

Likelihood ratio of developing asthma
A TWIN STUDY OF POST-TRAUMATIC STRESS DISORDER SYMPTOMS AND ASTHMA Goodwin AJRCCM 2007;176:983 3 – 2 – 1 – Likelihood ratio of developing asthma Association between post-traumatic stress disorder (PTSD) symptoms and asthma. Data from twins in the Vietnam Era Twin Registry. 2.3 P<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 Psychological factors may predispose to wheeze and atopy through neuro-immunological mechanisms. Attilio Boner University of Verona, Italy

ASTHMA ORIGINS Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke Diet Psychological factors Take it easy Don’t worry be happy Make love not war Psychological factors may predispose to wheeze and atopy through neuro-immunological mechanisms. Attilio Boner University of Verona, Italy

Shaheen Clin. Exp. Allergy 2005; 35: 18
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 months OR for different disease of offspring whose mothers took paracetamol* versus those who never took it * The proportion of asthma attributable to paracetamol use in late pregnancy, assuming a causal relation, was 7%. 2.0 – 1.5 – 1.0 – 5 – 1.62 1.52 1.22 1.14 *MOST DAYS *MOST DAYS *SOMETIMES *SOMETIMES ASTHMA TOTAL IgE

OR for having a mother who used contraceptive pills
ARE ORAL CONTRACEPTIVE USE AND PREGNANCY COMPLICATIONS RISK FACTORS FOR ATOPIC DISORDERS AMONG OFFSPRING? Brooks Pediatr. Allergy Immunol ; 15: 487 OR for having a mother who used contraceptive pills 2.0 – 1.5 – 1.0 – 5 – Oral contraceptive use before pregnancy OR for asthma in children Follow-up yrs of 1720 children 1.81 In asthmatic children

* * * * * * * * * * A population-based birth cohort in Tucson
OUTCOME OF ASTHMA AND WHEEZING IN THE FIRST 6 YEARS OF LIFE Morgan AJRCCM 2005; 172: 1253 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 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 * * * * * Z-Scores of Height Adjusted Flow (+/-se) * * Never Wheeze Transient Early Late Onset Persistent * * * Age, years

RETICULAR BASE MEMBRANE
EARLY DETECTION OF AIRWAY WALL REMODELLING AND EOSINOPHILIC INFLAMMATION IN PRESCHOOL WHEEZERS Saglani AJRCCM 2007;176:858 Endobronchial biopsy from wheezy preschool children (aged 3 months to years) Subjects undergoing fibreoptic bronchoscopy to investigate stridor acted as non-asthma controls RETICULAR BASE MEMBRANE THICKNESS (μ) 5 – 4 – 3 – 2 – 1 – p<0.05 4.6 3.8 WHEEZING CONTROLS

285 ch. 2-3 yrs old with (+) Asthma Predictive Index
LONG-TERM INHALED CORTICOSTEROIDS IN PRESCHOOL CHILDREN AT HIGH RISK FOR ASTHMA Morgan NEJM 2006; 354: 1985 Bimonthly proportion of episode-free days during the two year treatment period and the observation period. 285 ch. 2-3 yrs old with (+) Asthma Predictive Index Fluticasone Prop μg x or placebo for years 1 year follow-up without medication

(2) Received intranasal OVA periodically Days 14-73
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 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 Collagen deposition OVA sensitized and challenge mice in presence of Montelukast

Introduction Genetic Factors Environmental Factors: - allergens tobacco smoke pollutants diet life-style psychology treatment During pregnancy potentially harmfull drugs have to be avoided Pharmachological prevention strategies need to be explored in humans Attilio Boner University of Verona, Italy

Introduction Genetic Factors Environmental Factors Conclusions Attilio Boner University of Verona, Italy

STRATEGIES FOR PREVENTING WHEEZING AND ASTHMA IN SMALL CHILDREN
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: breastfeeding no tabacco smoke good ventilation & reduced dampness *NO=exposed to >2 risk factors RECURRENT WHEEZING AT 2 YRS 30- 20- 10- 24.1% 12.6% YES NO* living according to guidelines

24.1% 12.6% CAN ASTHMA AND ALLERGY BE PREVENTED IN REAL LIFE?
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: breastfeeding no tabacco smoke good ventilation & reduced dampness *NO=exposed to >2 risk factors RECURRENT WHEEZING AT 2 YRS 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.” 30- 20- 10- 24.1% 12.6% YES NO* living according to guidelines

STRATEGIES FOR PREVENTING WHEEZING AND ASTHMA IN SMALL CHILDREN
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: breastfeeding no tabacco smoke good ventilation & reduced dampness *NO=exposed to >2 risk factors ASTHMA AT AGE 2 IN CHILDREN WITH HEREDITY TO ASTHMA, LIVING ACCORDING TO THE GUIDELINES GAVE A THREEFOLD DECREASE IN ASTHMA AND IN CHILDREN WITH NO HEREDITY A TWOFOLD REDUCTION Carlsen Allergy 2003;58:730 20- 10- 17.9% 6.8% YES NO*

No maternal smoking during pregnancy, No maternal undernutrition,
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: No maternal smoking during pregnancy, No maternal undernutrition, No maternal hypertension which may cause placental hypoxia, No oligodramnios, No harmfull drugs, No stress.

In children may be of help:
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 attention
FORMAT 17-19/04/2008

TO CHANGE ASTHMA NATURAL HISTORY: A MITH? University of Verona, Italy

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