Transcript Slide 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
Hygiene hypothesis

Rising prevalence of atopic
disorders in infants and
children

‘Westernized life style’

Modified pattern of microbial
exposure in young children
Asthma phenotypes
Martinez 2002
Asthma Predictive Index
< 3 yr and frequent episodes of wheeze
and
en
or
of
1 major criterium
l Parental asthma
l atopic dermatitis
2 minor criteria:
l allergic rhinitis
l Wheeze without cold
l eosinophilia
75% : active asthma at school age
Castro-Rodriguez AJRCCM 2000;162: 1403-1406
Aim
to evaluate the bacterial flora
of infants in relation to
environmental pressure and
to atopy
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
30
25
102/158
65
Sex (male)
73/138
53
Mother dd astma ever
12/147
8
Father dd asthma ever
8/138
6
Skin Prick Test positive
15/116
13
Positive mAPI
18/111
16
20
15
10
5
0
m
th
12 s
m
th
s
18
m
24 ts
m
th
s
36
m
th
s
Metropolitan
k
%
6
Number
3w
Characteristic
wheeze
Regional differences
Characteristic
metropolitan
rural
p
mAPI
29%
24%
0.67
SPT
18%
4%
0.045*
parental asthma
19%
4%
0.01*
antibiotics yr1
48%
55%
0.48
passive smoke
12%
21%
0.22
Outcome SPT
OR
95%
Confidence intervals
Parental asthma
4,1*
1,1
15,7
Passive smoke
1,9
0,3
11,6
Region (metropolitan vs rural)
4,0
0,8
20,1
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
eNO - mAPI
• children with positive
mAPI
mAPI were
differentiated from
those with negative
negative positive
mAPI at eNO of 3.4 eNO < 3.4 17
4
ppb
(ppb)
• sensitivity: 71%
> 3.4 7
10
• specificity: 71%
(p < 0.05 )
eNO - SPT
• cut-off value reflecting
the best combination
of sensitivity and
specificity occurred at eNO <4.9
(ppb)
4.9 ppb
• sensitivity: 80%
>4.9
• specificity: 88%
(p < 0.05 )
SPT
negative positive
29
1
4
4
polluents
Wheeze 2 yr
Family history asthma or
allergy
+
Birth weight
+
Birth height
+
Sex
+
Pb cord blood
+
DDE cord blood
+
Antibiotics
+
Effect
Point
Estimate
95% Wald
Confidence Limits
Birth height
1,603
1,196
2,149
DDE (fat, LOG)
1,930
1,078
3,454
Number of days antibiotics
1,093
1,038
1,150
DDE - wheeze
Sunyer Env Health Persp 2005; 113: 1787
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
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
Factors modifying infant gut flora
1. Breastfeeding:
because fecal pH?
(3w)
Lactobacilli/Streptococci
Bifidobacteria
Bacteroides
(Harmsen H., J.Ped. Gastr.Nutr.,2000)
2. Cesarian delivery:
delayed colonization?
Bifidobacterium
Bacteroides
(1w)
(6m!)
Clostridium perfringens
(1m)
(Gronlund M., J.Ped.Gastr.Nutr.,1999)
Infant GI flora in allergy/atopy
3. Allergy/Atopy:
Lactobacillus
Bifidobacterium
Bacteroides
Enterococcus
(24m)
(1w,3m,12m,24m)
(12m,24m)
(1w,1m)
Clostridia
S. aureus
Yeasts
(3m)
(6m)
(3m)
other species
(Ouwehand A.,JACI,2001)
(Bjorksten B.,Cl.Exp.All.,1999)
(Bjorksten B.,JACI,2001)
(Kalliomaki, JACI,2001)
Early (<3m):
Late (>3m):
Clostridium, Yeasts, Enterococcus, Bifidobacterium
Lactobacillus,Bifidobacterium,Bacteroides,S. aureus
Results: Breast feeding at age 3 weeks
Log CFU/g
Bifidobacteria
Enterococcus
Clostridium
10,00
Feeding
Number(%)
8,00
6,00
BF
88 (57)
BF+FF
21 (14)
FF
45 (29)
4,00
2,00
BF: breast feeding
0,00
FF: formula feeding
0
enkel
BV
BF
1
BV
en FV
BF+FF
2
FV
FF
(p<0.01 Kruskal-Wallis)
Results: Breast feeding at age 6 months
Log CFU/g
Stafylococcus
Bacteroides *
Lactobacillus
10,00
Feeding
Number (%)
8,00
BF
14 (10)
BF+FF
19 (13)
FF
109 (77)
6,00
4,00
2,00
BF: breast feeding
FF: formula feeding
0,00
,00
1,00
2,00
BF
BV
BF+FF
BV+FV
FF
FV
(p<0.05 , * P = 0.08, Kruskal-Wallis)
Results: wheezing at age 1 year
Log CFU/g
Bacteroides
Bacteroides
3w3w
Bacteroides
Bacteroides
6m6m
Tot.Anaeroben
Tot. Anaerobes
3w
3w
Gr Neg aeroob
MCC
12m
10,00
8,00
Wheezing
Nr of children (%)
1 yr
6,00
Yes
4,00
No
33 (21) 126
2,00
0,00
0
neen
non-wheezers
1
piepen
12m
at
1 year
ja
wheezers
(p < 0.05 Mann-Whitney U )
mAPI at age 3 years
Log CFU/g
Bacteroides
logBBE
3w
logCAA
Tot. Anaerobes
3w
10,00
mAPI
8,00
Nr of children (%)
6,00
Yes
No
33 (27)
88
4,00
2,00
0,00
,00
Neg.
1,00
Pos.
mAPI
(p < 0.05 Mann-Whitney U )
Bacteroides culture 3 wks - mAPI
mAPI
Bacteroides
colonisation
Neg
Pos
Neg
59
7
Pos
34
11
Specif.
Sens.
61%
63%
(p < 0.05 Fisher exact)
pos. mAPI prevalence = 16%
Toll-like receptors and intestinal microflora
Gr. pos bact. (Staf., PG)
Bacteroides Lipoprotein *
Gr. neg. bact. (E. coli, LPS)
TLR 2
Th2
TLR 4
Asthma
Th1
(Agrawal S, J immunol., 2003)
* (Netea M. et al., Eur. J. Imm., 2004)
1)
Figure 1 Scattergram showing faecal concentrations of bacteroides and Escherichia coli versus
serum total IgE concentration in each individual. Regression lines with 95% confidence intervals
(broken lines); Spearman's rho and p values are given for both slopes. HSG, highly sensitised
group; SG, sensitised group.
Kirjavainen, P V et al. Gut 2002;51:51-55
Copyright ©2002 BMJ Publishing Group Ltd.
2) 716 high school children:
If atopic disease
significantly higher Bacteroides vulgatus IgG titers
(Fukuda S et al., J.Adolesc. Health, 2004)
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”.
PCB’s: immunomodulating?
Corrected breastfeeding, parity, education, smoking, fam history atopy, daycare
Weisglas-Kuperus Tox lett 2004
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)
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)