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TO CHANGE ASTHMA NATURAL HISTORY: A MITH?

TO CHANGE ASTHMA NATURAL HISTORY: A MITH?. 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.

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TO CHANGE ASTHMA NATURAL HISTORY: A MITH?

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

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

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

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

  5. ATOPY ASTHMA 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 – 0 3.6 3.2 2.8 1.6 1.2 1 1 NONE M only F only F+M NONE M only F only F+M PARENTAL

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

  7. 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 * * * 0 2 4 6 8 10 12 14 16 18 Age, years

  8. REDUCED LUNG FUNCTION BOTH BEFORE BRONCHIOLITIS AND AT 11 YRS Turner Arch Dis Child 2002; 87: 417 . %VmaxFRC 3 2 1 0 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 Confirmed bronchiolitis (n = 16) Control (n = 162) Box and whisker plot for z scores for % V’maxFRCat 1 month

  9. 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 – 0 30 – 20 – 10 – 0 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

  10. 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

  11. 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. Good care of pregnancy is essential to allow a normal development of the lungs. Attilio Boner University of Verona, Italy

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

  13. alb 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

  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 • 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

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

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

  17. 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.

  18. FILLAGRIN LOSS-OF-FUNCTION MUTATIONS PREDISPOSE TO PHENOTYPES INVOLVED IN THE ATOPIC MARCH Marenholz JACI 2006; 118: 866 OR ratio for concomitant eczema and asthma OR ratio for concomitant eczema and allergic rhinitis 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 OR for non atopic eczema OR for atopic eczema 6.21 4.79 3.94 3.84 p=0.00001 p=0.0006 p=0.00001 p=0.00065 IN CHILDREN WITH FILAGGRIN LOSS-OF-FUNCTION MUTATION

  19. 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

  20. ASTHMA ORIGINS • 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

  21. TO CHANGE ASTHMA NATURAL HISTORY: A MITH? • Introduction • Genetic Factors • Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style - psychology - treatment • Conclusions Attilio Boner University of Verona, Italy

  22. PULMONARY FUNCTION IN THREE YEAR OLD CHILDREN: EFFECT OF EXPOSURE AND SENSITIZATION TO INDOOR ALLERGENSLowe JACI 2002; 109: 521Ab % mean difference in sRaw in mite sensitive vs non-sensitive 10 – 8 – 6 – 4 – 2 – 0 • Manchester Asthma and Allergy Study (birth cohort: 276 children) • specific airway resistance (sRaw) at 3 yrs of age +9.2% p=0.020

  23. 10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 to perennial allergen ALB 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 8.3 • 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 3.29 Early Current sensitization sensitisation (age <3)

  24. RISK FACTORS FOR ASTHMA AT 3.5 AND 7 YEARS OF AGEMitchell 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 – 0 2.1 • 871 children of European mothers enrolled at birth; • Data collected at birth, 12 months, 3.5 years of age and 7 years. 1.8 Contact with dog Sleeping in a previously used mattress in the first year

  25. p=0.005 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 0,24 0,23 0,14 0,13 p=0.005 p=0.0003 p<0.005 asthma Atopic dermatitis atopy Allergic rhinitis

  26. ALB EARLY LIFE ENVIROMENTAL CONTROL: EFFECT ON SYMPTOMS, SENSITIZATION AND LUNG FUNCTION AT AGE 3 YEARSWoodcock 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

  27. ALB EARLY LIFE ENVIROMENTAL CONTROL: EFFECT ON SYMPTOMS, SENSITIZATION AND LUNG FUNCTION AT AGE 3 YEARSWoodcock 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

  28. some of these new cases can be prevented 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 E D I C T E D - 1 - 2 - 3 - 4 - 5 - 6 - 4.3% - 5.5%

  29. 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 - 0 9.38% p<0.05 2.56% 9/96 3/117 CONTROL ACTIVE

  30. 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 – 0 p<0.001 for trend 4.17 FOR RELAPSE 3.38 FOR PERSISTANCE (+) SPT FOR MITES AT AGE 13 YEARS

  31. 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 – 0 • 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. 4.69 2.73 2.30 sIgE: MITE ASPERGILLUS CLADOSPORIUM

  32. 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

  33. 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 • Environmental strategies to delay sensitization might be helpful. • Early contact with cat and dog is not protective. Attilio Boner University of Verona, Italy

  34. TO CHANGE ASTHMA NATURAL HISTORY: A MITH? • Introduction • Genetic Factors • Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style - psychology - treatment • Conclusions Attilio Boner University of Verona, Italy

  35. membranous airway from an 8-month-old infant 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

  36. SMOKING MOTHER 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) 200 – 150 – 100 – 50 – 0 • 80 healthy infants tested shortly after birth (mean, 4.2+/-1.9 wk) • Urine cotinine • Expiratory flow-volume curves 150.4 p= 0.0007 74.3 YES NO

  37. PARENTAL SMOKING AND LUNG FUNCTION IN CHILDRENMoshammer 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%

  38. 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 – 0 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

  39. 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 – 0 • Between 1985 and 1996/1997 an 11-year community cohort study on the incidence of asthma • 3.786 subjects 3 Smoking mother

  40. 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 – 0 • Between 1985 and 1996/1997 an 11-year community cohort study on the incidence of asthma • 3.786 subjects 3 Smoking mother

  41. REGULAR SMOKING AND ASTHMA INCIDENCE IN ADOLESCENTS Gilliland AJRCCM 2006; 174: 1094 RR FOR NEW ONSET OF ASTHMA • 2,609children 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 4 – 3 – 2 – 1 – 0 3.9 In children smoking >300 cigarettes/year

  42. REGULAR SMOKING AND ASTHMA INCIDENCE IN ADOLESCENTS Gilliland AJRCCM 2006; 174: 1094 RR FOR NEW ONSET OF ASTHMA 10- 8 – 6 – 4 – 2 – 0 • 2,609children 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

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

  44. TO CHANGE ASTHMA NATURAL HISTORY: A MITH? • Introduction • Genetic Factors • Environmental Factors: - allergens - tobacco smoke - pollutants - diet - life-style - psychology - treatment • Conclusions Attilio Boner University of Verona, Italy

  45. 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 • Bedding type at 1mo • Wheeze at 7 yrs (n=6,378 ch) 5.2 2.5 synthetic pillow +synthetic quilt

  46. 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 – 0 • Sleeping environment of 863 infants evaluated at 1 month of life • Follow-up: 7 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

  47. Residential outdoor air pollution and allergen sensitization in schoolchildren in Norway Oftedal CEA 2007;37:1632 2 - 1 – 0 • 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 PM10 PM2.5 NO2 one interquartile increase of lifetime exposure to

  48. 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

  49. 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 – 0 • The relationship between types of traffic, traffic volume, and distance and wheezing among infants less than 1 year of age 2.5 In infants living very near (< 100 m) to stop-and-go bus and truck traffic

  50. 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 0 -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

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