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Influence of exposure to microbes and polluents on the development of atopy and asthma Prof. dr. K.Desager Department of Pediatrics University of Antwerp.

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Presentation on theme: "Influence of exposure to microbes and polluents on the development of atopy and asthma Prof. dr. K.Desager Department of Pediatrics University of Antwerp."— Presentation transcript:

1 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

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 2 minor criteria: allergic rhinitis Wheeze without cold eosinophilia 75% : active asthma at school age 1 major criterium Parental asthma atopic dermatitis of or en and 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,12mn= 431 questionnaires: prenatal, 3w, every 6 mths till 3yr clinical, eNO, SPT: 3 yr

7 CharacteristicNumber% Metropolitan102/15865 Sex (male)73/13853 Mother dd astma ever12/1478 Father dd asthma ever8/1386 Skin Prick Test positive15/11613 Positive mAPI18/11116 wheeze

8 Regional differences Characteristicmetropolitanruralp mAPI29%24%0.67 SPT18%4%0.045* parental asthma19%4%0.01* antibiotics yr148%55%0.48 passive smoke12%21%0.22 Outcome SPTOR95% Confidence intervals Parental asthma 4,1*1,115,7 Passive smoke 1,90,311,6 Region (metropolitan vs rural) 4,00,8 20,1

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% mAPI negativepositive eNO (ppb) < 3.4174 > 3.4710 (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% SPT negativepositive eNO (ppb) <4.9291 >4.944 (p < 0.05 )

12 Wheeze 2 yr Family history asthma or allergy + Birth weight+ Birth height+ Sex+ Pb cord blood+ DDE cord blood+ Antibiotics+ EffectPoint Estimate 95% Wald Confidence Limits Birth height1,6031,1962,149 DDE (fat, LOG)1,9301,0783,454 Number of days antibiotics1,0931,0381,150 polluents

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

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 1.Breastfeeding:because fecal pH?(3w) Lactobacilli/Streptococci Bifidobacteria Bacteroides 2.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 other species (Bjorksten B.,Cl.Exp.All.,1999) (Bjorksten B.,JACI,2001) (Kalliomaki, JACI,2001) (Ouwehand A.,JACI,2001)

18 Results: Breast feeding at age 3 weeks Log CFU/g (p<0.01 Kruskal-Wallis) Feeding Number(%) BF88 (57) BF+FF21 (14) FF45 (29) BF: breast feeding FF: formula feeding BFBF+FFFF

19 Results: Breast feeding at age 6 months Feeding Number (%) BF14 (10) BF+FF19 (13) FF109 (77) Log CFU/g (p<0.05, * P = 0.08, Kruskal-Wallis ) * BF: breast feeding FF: formula feeding BFBF+FFFF

20 Results: wheezing at age 1 year (p < 0.05 Mann-Whitney U ) Log CFU/g Wheezing Nr of children (%) Yes No 33 (21) 126 non-wheezers at 1 year wheezers Tot. Anaerobes 3w MCC 1 yr Bacteroides 6m Bacteroides 3w

21 mAPI at age 3 years Log CFU/g (p < 0.05 Mann-Whitney U ) mAPI Nr of children (%) Yes No 33 (27) 88 Bacteroides 3w Tot. Anaerobes 3w Neg.Pos.

22 Bacteroides culture 3 wks - mAPI mAPI Bacteroides colonisation NegPos Neg 597 Pos 3411 Specif. 63% Sens. 61% pos. mAPI prevalence = 16% (p < 0.05 Fisher exact)

23 Toll-like receptors and intestinal microflora Gr. pos bact. (Staf., PG)TLR 2Th2Asthma Bacteroides Lipoprotein * Gr. neg. bact. (E. coli, LPS)TLR 4Th1 (Agrawal S, J immunol., 2003) * (Netea M. et al., Eur. J. Imm., 2004)


25 2) 716 high school children: If atopic disease significantly higher Bacteroides vulgatus IgG titers (Fukuda S et al., J.Adolesc. Health, 2004) 1)

26 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”.

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

28 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)

29 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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