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Influence of exposure to microbes and polluents on the development of atopy and asthma

Influence of exposure to microbes and polluents on the development of atopy and asthma. Prof. dr. K.Desager Department of Pediatrics University of Antwerp Dr C. Vael Department of Microbiology University of Antwerp. Hygiene hypothesis.

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Influence of exposure to microbes and polluents on the development of atopy and asthma

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  1. Influence of exposure to microbes and polluents on the development ofatopy and asthma Prof. dr. K.Desager Department of Pediatrics University of Antwerp Dr C. Vael Department of Microbiology University of Antwerp

  2. Hygiene hypothesis • Rising prevalence of atopic disorders in infants and children • ‘Westernized life style’ • Modified pattern of microbial exposure in young children

  3. Asthma phenotypes Martinez 2002

  4. Asthma Predictive Index < 3 yr and frequent episodes of wheeze and en 1 major criterium Parental asthma l l atopic dermatitis l l or of 2 minor criteria: allergic rhinitis l l Wheeze without cold l l eosinophilia l l 75% : active asthma at school age Castro - Rodriguez AJRCCM 2000;162: 1403 - 1406

  5. Aim to evaluate the bacterial flora of infants in relation to environmental pressure and to atopy

  6. Materials and methods Prospective cohort study: started 10/2002 • recruitment of 159 healthy neonates • cord blood polluents: Cd, Pb, DDE, PCB, dioxine • fecal sampling: 3w, 6m,12m n= 431 • questionnaires: prenatal, 3w, every 6 mths till 3yr • clinical, eNO, SPT: 3 yr

  7. wheeze

  8. Regional differences

  9. eNO • In 121 children eNO attempted. • technical difficulties: 14 • refusal: 11 children • leakage or irregular breathing: 43 • acceptable measurements: 38 (min 2 and max 5 attempts) • SPT: 15 positive SPT for at least one allergen • grass pollen: 6 • house dust mite: 10 • egg: 3 • cow’s milk: 2

  10. eNO - mAPI • children with positive mAPI were differentiated from those with negative mAPI at eNO of 3.4 ppb • sensitivity: 71% • specificity: 71% (p < 0.05 )

  11. eNO - SPT • cut-off value reflecting the best combination of sensitivity and specificity occurred at 4.9 ppb • sensitivity: 80% • specificity: 88% (p < 0.05 )

  12. polluents

  13. DDE - wheeze Sunyer Env Health Persp 2005; 113: 1787

  14. DDE - asthma • causal pathway DDE and asthma? • Immune system: associated with changes in • immune cells (Vine 2001) • immunoglobulins (Cooper et al. 2004; Vine 2001) • cytokines (Bilrha 2003; Daniel 2002) • hormone-like activity of DDE: • interfere with mast cells in airways that express estrogen/progesterone receptors, favoring the role of DDE in TH2 immune differentiation • Direct effect on the airway through altering b2-adrenergic responsiveness and increasing the production of prostaglandins

  15. conclusions • Region: No difference mApi, less sensitisation in rural region due to less parental asthma • eNo relationship with mAPI • Difficult to perform in 3 yr old • in agreement with data in older children, adults: atopy, family history • Prenatal exposure DDE related to wheeze 2 yrs • In agreement Sunyer

  16. Factors modifying infant gut flora • Breastfeeding: because fecal pH? (3w) Lactobacilli/Streptococci Bifidobacteria Bacteroides • Cesarian delivery: delayed colonization? Bifidobacterium (1w) Bacteroides (6m!) Clostridium perfringens(1m) (Harmsen H., J.Ped. Gastr.Nutr.,2000) (Gronlund M., J.Ped.Gastr.Nutr.,1999)

  17. Infant GI flora in allergy/atopy 3. Allergy/Atopy: Lactobacillus (24m) Bifidobacterium (1w,3m,12m,24m) Bacteroides (12m,24m) Enterococcus (1w,1m) Clostridia (3m) S. aureus (6m) Yeasts (3m) Early (<3m): Clostridium, Yeasts, Enterococcus, Bifidobacterium Late (>3m): Lactobacillus,Bifidobacterium,Bacteroides,S. aureus otherspecies (Ouwehand A.,JACI,2001) (Bjorksten B.,Cl.Exp.All.,1999) (Bjorksten B.,JACI,2001) (Kalliomaki, JACI,2001)

  18. Results: Breast feeding at age 3 weeks Log CFU/g FeedingNumber(%) BF 88 (57) BF+FF 21 (14) FF 45 (29) BF: breast feeding FF: formula feeding BF BF+FF FF (p<0.01 Kruskal-Wallis)

  19. Results: Breast feeding at age 6 months Log CFU/g * FeedingNumber (%) BF 14 (10) BF+FF 19 (13) FF 109 (77) BF: breast feeding FF: formula feeding BF BF+FF FF (p<0.05 , * P = 0.08, Kruskal-Wallis)

  20. Results: wheezing at age 1 year Log CFU/g Bacteroides 3w Wheezing Nr of children (%) YesNo 33 (21) 126 Bacteroides 6m Tot. Anaerobes 3w MCC 1 yr non-wheezers at 1 year wheezers (p < 0.05 Mann-Whitney U )

  21. mAPI at age 3 years Log CFU/g Bacteroides 3w Tot. Anaerobes 3w mAPI Nr of children (%) YesNo 33 (27) 88 Neg. Pos. (p < 0.05 Mann-Whitney U )

  22. Bacteroides culture 3 wks - mAPI (p < 0.05 Fisher exact) pos. mAPI prevalence = 16%

  23. Toll-like receptors and intestinal microflora Gr. pos bact. (Staf., PG) TLR 2 Th2 Asthma Bacteroides Lipoprotein * Gr. neg. bact. (E. coli, LPS) TLR 4 Th1 (Agrawal S, J immunol., 2003) * (Netea M. et al., Eur. J. Imm., 2004)

  24. 1) 2) 716 high school children: If atopic disease significantly higher Bacteroides vulgatus IgG titers (Fukuda S et al., J.Adolesc. Health, 2004)

  25. Conclusions: • Breastfeeding during the first year of life has an influence on the infant intestinal microflora. • Changes in the intestinal flora in the first month of life are associated with wheezing at the age of 1 year and mAPI at the age of 3 years. • Early postnatal intestinal colonization with Bacteroides fragilis is associated with a positive mAPI. Children with a positive mAPI have a 4 -10x higher risk of having subsequent asthma (age 6-13y). Funded by the Flemish government within the project : “Health and Environment, subdivision Asthma”.

  26. PCB’s: immunomodulating? Corrected breastfeeding, parity, education, smoking, fam history atopy, daycare Weisglas-Kuperus Tox lett 2004

  27. DDE - infections • decreased response to viruses, bacteria? • inconsistent results • moderate increase of acute infections during first year of life (Dallaire et al. 2004) • not in 343 German school children (Karmaus et al. 2003) • not in 207 Dutch infants (Weisglas-Kuperus et al. 1995)

  28. DDE – immunity, asthma • changes in T-cell– mediated immune cytokines related with allergy (IL-4) (Bilrha 2003; Daniel 2002) • similar effects: hexachlorobenzene (HCB) (Michielsen 1999) and polychlorinated biphenyls (PCBs) (Van Den Heuvel 2002) • cross-sectional study school children Germany DDE related with increases in total IgE and asthma (Karmaus 2001, 2003) • increase of asthma prevalence, mortality in adults was found among an older cohort of DDT sprayers (Beard 2003) • prevalence of wheeze increased with a variety of pesticides among current applicators (Hoppin 2002)

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