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

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Presentation on theme: "TO CHANGE ASTHMA NATURAL HISTORY: A MITH? Introduction Genetic Factors Environmental Factors Conclusions University of Verona, Italy Attilio Boner."— Presentation transcript:

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

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

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

4 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 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.

5 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 ATOPY PARENTAL 15 – 14 – 13 – 12 – 11 – 10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 NONE M only F only F+M OR for parental asthma is multiplicative. OR for parental atopy is additive

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

7 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 Wheeze Transient Early Late Onset Persistent Z-Scores of Height Adjusted Flow (+/-se) * * * * * * * * * *

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

9 % children with a history of asthma at age 10 year 30 – 20 – 10 – % 24.3% p=0.01 Above the median At-below the median t PTEF /t E at age 3 days % children with current asthma at age 10 year 30 – 20 – 10 – 0 7.5% 14.6% p=0.005 Above the median At-below the median t PTEF /t E 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

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

11 ASTHMA ORIGINS Lung Development University of Verona, Italy Attilio Boner 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.

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

13 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 INTERACTIONS Warner Arch Dis Child 2004;89:97 alb 14°wk 22°wk

14 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.

15 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

16 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

17 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. SKIN BARRIER FUNCTION AND ALLERGIC RISK Hudson Nature Genetics 2006; 38: 399

18 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 concomitant eczema and asthma OR ratio for concomitant eczema and allergic rhinitis 7 – 6 – 5 – 4 – 3 – 2 – 1 – p= p= p=

19 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.

20 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.

21 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?

22 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-sensitive Manchester Asthma and Allergy Study (birth cohort: 276 children) specific airway resistance (sRaw) at 3 yrs of age +9.2% p=0.020

23 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 (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

24 2.0 – 1.5 – 1.0 – 0.5 – 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: 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

25 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=0.005 p<0.005p= ,24 0,23 0,14 0,13 asthmaAtopic dermatitis Allergic rhinitis atopy

26 Ln VmaxFRC GM & 95% CI at age 4 weeks 1.0 – 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

27 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=0.003 Manchester cohort 128 active group 111 control group Allergen level, symptoms, sensitization and lung function at 3 years of age ALB

28 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. NS S/LE SHE FVC (% predicted) FEV 1 (% predicted) FEV 1 /FVC MEF 75 (% predicted) MEF 50 (% predicted) MEF 25 (% predicted) PERENNIAL ALLERGEN SENSITISATION EARLY IN LIFE AND CHRONIC ASTHMA IN CHILDREN: A BIRTH COHORT STUDY Illi Lancet 2006; 368: 763 * * * * * * * * * * * *

29 IMPAIRED GROWTH OF PULMONARY FUNCTION IN CHILDREN SENSITIVE TO HOUSE DUST MITE ULRIK AJRCCM 1999; 160: children (7-17 years of age at enrollment) reevaluated after 5 years subjects with either persistent or new atopy to HDM had lower FEV 1 compared with those who had persistent (-) SPT to HDM ATOPY TO HDM PERSISTENT NEW FEV1%PREDICTEDFEV1%PREDICTED % - 4.3% some of these new cases can be prevented

30 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 9.38% 2.56% p< 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) 3/117 9/96 CONTROL ACTIVE

31 – 2 – 1 – FOR PERSISTANCE A LONGITUDINAL, POPULATION-BASED, COHORT STUDY OF CHILDHOOD ASTHMA FOLLOWED TO ADULTHOOD. Sears NEJM 2003;349: FOR RELAPSE (+) SPT FOR MITES AT AGE 13 YEARS p<0.001 for trend OR FOR WHEEZING AT AGE 26 YEARS

32 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 years of age ( ); A random sample of control; 485 cases and 665 controls MITE OR for new onset asthma – 2 – 1 – 0 ASPERGILLUSCLADOSPORIUM sIgE:

33 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

34 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.

35 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?

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

37 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 FUNCTION Hanrahan Am. Rev. Respir. Dis. 1992; 145: 1129 YES NO Flow at functional residual capacity (ml/s) 200 – 150 – 100 – 50 – p= SMOKING MOTHER

38 PARENTAL SMOKING AND LUNG FUNCTION IN CHILDREN Moshammer AJRCCM 2006;173: ,000 children (aged 6-12 yr) from Europe and North America; Exposure information by questionnaires; SMOKING DURING PREGNANCY -6% MEF 25% 0 – -1 – -2 – -3 – -4 – -5 – -6 – -7 – -1% in FEV 1

39 OR for asthma in the first 5 years of life Smoking mother only 1.3 MATERNAL AND GRANDMATERNAL SMOKING PATTERNS ARE ASSOCIATED WITH EARLY CHILDHOOD ASTHMA Li YF Chest 2005; 127: – 2 – 1 – 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

40 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 subjects OR ratio for adult onset asthma 3 – 2 – 1 – 0 3 Smoking mother

41 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 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.

42 REGULAR SMOKING AND ASTHMA INCIDENCE IN ADOLESCENTS Gilliland AJRCCM 2006; 174: ,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 – 2 – 1 – 0 In children smoking >300 cigarettes/year

43 RR FOR NEW ONSET OF ASTHMA – 6 – 4 – 2 – 0 In children smoking >300 cigarettes/year and exposed to maternal smoking during gestation REGULAR SMOKING AND ASTHMA INCIDENCE IN ADOLESCENTS Gilliland AJRCCM 2006; 174: ,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

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

45 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?

46 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 synthetic pillow +synthetic quilt

47 At age 7 years OR for – 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 3.35 NIGHT WHEEZE AT AGE 7 YEARS

48 OR FOR SENSITIZATION TO D.farinae NO Residential outdoor air pollution and allergen sensitization in schoolchildren in Norway Oftedal CEA 2007;37: PM 10 PM children 9-10 year old had lived in Oslo since birth Exposure to outdoor air pollution: nitrogen dioxide (NO 2 ), particulate matter (PM) with aerodynamic diameter <10 μm (PM 10 ) and <2.5 μm (PM 2.5 ) – 0 one interquartile increase of lifetime exposure to

49 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

50 OR for wheezing 3 – 2 – 1 – 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

51 TRAFFIC EXPOSURE AND LUNG FUNCTION IN ADULTS: THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY Kan Thorax 2007; 62: 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 FEV mL – -20 – -30 – FVC mL

52 European Community Respiratory Health Survey in 10 countries 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.< – 1 – 0 THE USE OF HOUSEHOLD CLEANING SPRAYS AND ADULT ASTHMA Zock AJRCCM 2007;176:735

53 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 -Detergents are important adjuvant factors.

54 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 are important adjuvant factors. no synthetic materials in early llyfe Ask yourself what you can do to prevent pollution

55 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?

56 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 – p<0.001

57 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 Ever wheeze In 5 year old children of mothers in the highest versus the lowest quintiles of vit D intake OR for 1 – Persistent wheeze Wheeze in previous year

58 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

59 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: ,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 QUINTILES OF VIT E INTAKE IN THE MOTHER p = 0.02 for trend

60 OR FOR ATOPIC SENSITIZATION 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

61 OR FOR EVER ASTHMA QUINTILES OF ZINC INTAKE 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.

62 OR FOR EVER ASTHMA QUINTILES OF ZINC INTAKE 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

63 1° tertile 2° tertile 3° tertile Vitamin E maternal intake OR for wheeze in absence of a cold in the second year 1010 p for trend = 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 ANTIOXIDANT INTAKE IN PREGNANCY IN RELATION TO WHEEZE AND ECZEMA IN THE FIRST TWO YEARS OF LIFE Martindale AJRCCM 2005; 171: 121

64 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

65 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 Ever wheeze Maternal apple consumption highest versus lowest tertile OR for 1 – Doctor asthma Ever asthma

66 CHILDHOOD ASTHMA AND FRUIT CONSUMPTION Okoko ERJ 2007;29: 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 Current wheeze Ever wheeze Ever asthma 1.00 – 0.80 – 0.60 – 0.40 – 0.20 – 0

67 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 Current wheeze Ever wheeze Ever asthma – 0.80 – 0.60 – 0.40 – 0.20 – 0 CHILDHOOD ASTHMA AND FRUIT CONSUMPTION Okoko ERJ 2007;29:1161

68 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 OR FOR WHEEZING p< – 0 In children consuming >40 g/day of fruity vegetable (tomatoes, eggplants, cucumber, green beans, zucchini)

69 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 WHEEZING 3 – 2 – 1 – 0 nuts margarine Hight 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

70 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 eczema at 1 yr (+) SPT to HDM at age 6 yrs Asthma at age 6 yrs

71 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

72 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 OR FOR ATOPY p.< – 0 Fish intake > 60 g/day

73 Relationship of fish and cod oil intake with adult asthma Laerum ClinExpAll 2007;37: subjects aged years Postal questionnaire OR FOR DOCTOR DIAGNOSED ASTHMA IN ADULHOOD Never had fish in childhood – 1 – 0 X XX X

74 Linoleic acid (omega-6) (margarines) Arachidonic acid cyclo- oxygenase PGE Inhibition on IL-2 INF-Y No effect on IL-4 IL-5 Th0 Th2 IgE POLYUNSATURATED FAT AND CYTOKINES Linolenic acid (fish oil) (omega-3) Eicosapentaenoic acid

75 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: ml ml -42 ml -110 ml >14 P<0,001 for trend ml in FEV 1

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

77 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.”

78 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.

79 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?

80 BOTTLE FEEDING IN BED OR CRIB BEFORE SLEEP TIME AND WHEEZING IN EARLY CHILDHOOD. Celedon Pediatrics 2002;110:e 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 – OR for asthma at age 5y

81 % 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: 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.

82 OR for Development of Physician Diagnosed Asthma 2 – 1 – 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: 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)

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

84 % 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

85 INCREASED INCIDENCE OF ASTHMALIKE SYMPTOMS IN GIRLS WHO BECOME OVERWEIGHT OR OBESE DURING THE SCHOOL YEARS Castro-Rodriguez AJRCCM 2001; 163: – 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 develop new asthma symptoms at age years 7 X

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

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

88 OBESITY AND LEPTIN Weiss S AJRCCM 2004; 169: 963 Adipocites Leptin Increased secretion in 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

89 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.”

90 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 crib Regular physical activity to maintain good fitness No increase in BMI

91 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?

92 influence of caregiver stress on wheeze in infancy genetically predisposed birth- cohort (n=496) Greater level of stress in caregivers PARENTAL STRESS AS A PREDICTOR OF WHEEZING IN INFANCY: A PROSPECTIVE BIRTH-COHORT STUDY Wright Am J Respir Crit Care Med 2002; 165: 358 RR of wheezing during the first 14 mo.

93 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) for IgE > 100 vs < 100 UI/ml With higher caregiver stress – 1 –

94 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 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 Problems 30 – 20 – 10 – 0 Late onset wheezers Never wheezers 23.1% 6% p<0.001

95 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 – P<0.001 In veterans in the highest quartile of PTSD compared to those in the lowest

96 ASTHMA ORIGINS Lung Development Immunologic Maturation Allergens Exposure to Tobacco Smoke Diet Psychological factors University of Verona, Italy Attilio Boner Psychological factors may predispose to wheeze and atopy through neuro-immunological mechanisms.

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

98 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?

99 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 * ASTHMA TOTAL IgE *SOMETIMES *MOST DAYS *SOMETIMES *MOST DAYS 2.0 – 1.5 – 1.0 – 5 – The proportion of asthma attributable to paracetamol use in late pregnancy, assuming a causal relation, was 7%.

100 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 yrs of 1720 children OR for having a mother who used contraceptive pills In asthmatic children 2.0 – 1.5 – 1.0 – 5 –

101 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 Wheeze Transient Early Late Onset Persistent Z-Scores of Height Adjusted Flow (+/-se) * * * * * * * * * *

102 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 WHEEZERS Saglani AJRCCM 2007;176:858 WHEEZING CONTROLS RETICULAR BASE MEMBRANE THICKNESS (μ) p< – 4 – 3 – 2 – 1 – 0

103 LONG-TERM INHALED CORTICOSTEROIDS IN PRESCHOOL CHILDREN AT HIGH RISK FOR ASTHMA Morgan NEJM 2006; 354: 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.

104 REVERSAL OF ALLERGEN-INDUCED AIRWAY REMODELING BY CYSLT 1 RECEPTOR BLOCKADE Henderson AJRCCM 2006; 173: 718 (1) Sensitized by intraperitoneal ovalbumin (2) Received intranasal OVA periodically Days (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

105 REVERSAL OF ALLERGEN-INDUCED AIRWAY REMODELING BY CYSLT 1 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

106 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 avoided Pharmachological prevention strategies need to be explored in humans

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

108 Birth cohort 4089 ch Families who lived according the Swedish primary prevention guidelines: 1.breastfeeding 2.no tabacco smoke 3.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* % 24.1%

109 Birth cohort 4089 ch Families who lived according the Swedish primary prevention guidelines: 1.breastfeeding 2.no tabacco smoke 3.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* % 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.”

110 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.breastfeeding 2.no tabacco smoke 3.good ventilation & reduced dampness *NO=exposed to >2 risk factors YES NO* % 17.9% 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

111 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.

112 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.

113 Thank you for your attention FORMAT 17-19/04/2008


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