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CAN EARLY MANAGEMENT

PROGRAM OUR IMMUNE SYSTEM

HANY ALY, MD, FAAP


Professor of Pediatrics, Obstetrics &
Gynecology
Director, Newborn Services
Incidence of Infectious Diseases (%)
Infections over Time
100
Rheumatic fever
Mumps
Measles
Tuberculosis
HepA

50

0 Bach JF. N Engl J Med.


2002;347:911-920.
1950 1960 1970 1980 1990 2000
Autoimmune Diseases over Time
400
Incidence of Immune Disorders (%)

300
Crohn's disease (Th1)
Multiple sclerosis (Th1)
Type 1 diabetes (Th1)
Asthma (Th2)

200

100
1950 1960 1970 1980 1990 2000
Acquisition of Indigenous Flora
by the Newborn

• Fetus normally is in a sterile environment in


the uterus

• Newborn acquires its indigenous


microflora during delivery  maternal flora
provides the initial inoculum of colonizing
organisms
Acquisition of Indigenous Flora
by the Newborn

• Gestational age, mode of delivery, type of


feeding  all can affect formation of the
newborn’s indigenous flora
– VLBW infants: Intestinal colonization delayed,
development of anaerobic flora diminished
– Infants born by Cesarean Section delayed intestinal
colonization with anaerobic bacteria, and gut
colonization can be altered for as long as 6 months
after birth

Swanson D. Indigenous Flora. In Feigin RD et al., eds. Textbook of


Pediatric Infectious Diseases. 5th ed. Philadelphia: WB Saunders;
Intestinal Flora and Mode of Feeding
Breast feeding Formula feeding
Formula feeding

Log no. of Bacteria per gram feces


11 11
Log no. of Bacteria per gram feces

10 10
9 9
8 8
7 7
6 6
5 5
4 4
3 3
2 2
1 2 3 4 5 6 30 1 2 3 4 5 6 30
Days after birth Days after birth
Bifidobacteria Bacteroides Enterobacteria
Enterococci Lactobacilli Staphylococci

From: Yoshioka, H. Pediatrics 1983;72:317-321.


Microbiota Development
Weaning
Bifidobacteria
Relative Numbers of Anaerobes

(Anaerobic)

Bacteroides
Anaerobes Clostridia
Rapid accumulation of
anaerobic growth Coliforms
Staphylococcus
Klesiella
Salmonella
Facultative anaerobes Shigella
Lactobacillus
Streptococci
Enterococcus

Age
Day 1-3 Day 4 – 10 Day 11 - 120
Microbiota influenced by:
Genetics Microbiota influenced by: Adapted from: Rautava S. et al,
Mode of delivery Feeding type JPGN
Determinants of Intestinal Microflora

Ingested bacteria

Original
bacterial Newborn Environment
inoculum

Breast milk
(Including skin microbes)
Classification of Host Microbial Flora

 Normal resident flora: present routinely


in a specified anatomic location; quickly
re-established when disturbed
 Transient microbial flora: may colonize
the host for periods ranging from hours
to weeks, but does not permanently
establish itself

Tramont EC and Hoover DL. Innate Host Defense Mechanisms. In Mandell GL et al., eds.
Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone; 2000:31-
Acquisition of Indigenous Flora by the
Newborn is Influenced by:
• Host Factors
• Environmental Factors
• Type of Feeding
• Mode of Delivery
• Gestational Age
• Host Factors
Acquisition of Indigenous Flora
by the Newborn

• “Exposure to organisms from other people and


environmental sources contributes to the
formation of the neonate’s eventual normal
flora.”(Swanson D. pg 107)

– Premature infants with prolonged hospitalization


more frequently colonized with hospital flora than
term newborns

Swanson D. Indigenous Flora. In Feigin RD et al., eds. Textbook


of Pediatric Infectious Diseases. 5th ed. Philadelphia: WB
Adult Microbiota: A Complex Ecosystem
Esophagus
No own microbiota
Microbes from food and
oral cavity Stomach

Duodenum
104 CFU/g
Candida albicans
500 - 1000
103-104 CFU/g
Bacteroides
Helicobacter pylori
Lactobacillus
species
Candida albicans Streptococcus
Lactobacillus
Streptococcus
Jejunum
Colon 105-107 CFU/g
Bacteroides
1010-1011 CFU/g
Candida albicans
Bacteroides
Lactobacillus
Bacillus
Streptococcus
Bifidobacterium
Clostridium
Enterococcus Ileum
Eubacterium 107-108 CFU/g
Fusobacterium Bacteroides
Peptostreptococcus Clostridium
Ruminococcus Enterobacteriaceae
Streptococcus Enterococcus
Lactobacillus
Veillonella
Surface Areas of Exposure
to the Environment
• Skin 1-2 sq m
• Respiratory mucosa 100 sq m
• Intestinal mucosa 300 sq m
– Gut epithelium 0.03 mm
– Bacterial gut content up to 1012 / ml

Tightly regulated mucosal immunity is


needed to maintain health
GALT

Gut associate lymphoid tissue (GALT)


comprises 80% of immunologic cells in
the body

GALT is the largest immune organ


Two Arms of Defense to any Foreign
Substance (antigen) Entering the Body:

• Gut barrier (mechanical) function

• Immune function
• The innate immune response
• The adaptive immune response
Atopic Sensitization and Allergy Symptoms
Among Children Living on Farms and Children in
Same Rural Community from Non-farming Families

40

*
% Children

30
Farm
Non-farm *
20
*
10 *

0
Wheeze Hay fever Positive Positive
*P<0.05; bivariate analysis. RAST to RAST to
Outdoor Indoor
Allergens Allergens
Braun-Fahrlander CH. Clin Exp Allergy 1999;29:28-34.
Influence of Cesarean Delivery on Relative
Risk of Childhood Food Allergy
8 *
Adjusted Odds Ratio

CI = 1.9-32.0
7
6
5
4
3 CI = 1.0-7.0
2
1
0
No Maternal Hx Maternal Hx Vaginal Maternal Hx
Vaginal Delivery Delivery Cesarean Section
*P<0.01; adjusted for covariates.
Food Allergy to egg confirmed by testing at age 1 – 2.
Eggesbo M et al. J Allergy Clin Immunol 2003;112:420-426.
Childhood Antibiotics
and Risk of Allergy

• Oral broad spectrum antibiotics in the first 2


years of life: increased risks of eczema, allergic
rhinitis and asthma (OR: 2.07, p < 0.0001)

• Increased courses of antibiotics correlated with


atopic risk

• Peripartum antibiotics are associated with


increased risk for asthma and hay fever
McKeever TM, Am J Crit Care Med 2002,166:827

Farooqi IS and Hopkin JM. Thorax 1998;53:927-932.


Wicken K., et al. Clin Exp Allergy 1999;29:766-771.
von Mutius E. Eur Respir J 1999;14:4-11.
Intestinal Microflora is Altered
in Allergic Infants
• Reduced ratio of Bifidobacteria to clostridia in early gut
microflora precedes allergic disease
Kalliomaki M., et al. J Allergy Clin Immunol 2001;107:129-134.

• Allergic infants are less colonized with lactobacilli and


Bifidobacteria
Bjorksten B., et al. Clin Exp Allergy 1999;29:342-346.

• Allergic infants harbor adult like Bifidobacteria; healthy


infants have typical infant Bifidobacteria
Ouwehand AC., et al. J Allergy Clin Immunol 2001;108:144-145.
Intestinal Flora of Individuals with IBD
Differs from Normal Controls

• Increases in E. coli and bacteroides species


have been noted in patients with Crohn’s
disease compared to controls
Giaffer MH., et al. J Med Microbiol 1991;238-
243.

• Colonic biopsies from patients with active UC


have decreased anaerobic bacteria and
lactobacilli compared to controls
Fabia R., et al. Digestion 1993;54:248-255.
Intestinal Flora of Individuals with IBD
Differs from Normal Controls (cont.)

• Stool of patients with Crohn’s disease has


less Bifidobacteria compared to healthy
controls Favier
C., et al. Dig Dis Sci 1997;42:817-822.

• Stool of patients with active pouchitis has


less Bifidobacteria and lactobacilli and
more clostridia than controls
Ruseler-van Embden JGH., et al. Gut 1994;35:658-664.
“Modern” Lifestyle Has Decreased
Exposure to Bacteria

• More sterile processed


food
• Decreased intake in
foods produced by Less
natural fermentation exposure
• Increased hygiene to
measures bacteria
• Urban life
• Antibiotics
“Give us this day, our daily germs.”

Rook GA. Immunol Today 1998;19:113-11


Antigens Microflora
Intestinal Lumen

Epithelium
Intestinal Mucosa
Antigen Presentation Activated T cell

Th0

Th1 TReg Th2

TNF-α IL-4
IFN-γ TGF-β IL-5
IL-2 IL-10

Over Over
Expression Expression
Tolerance
IBD Allergy
Factors Favoring Factors Favoring
the Th1 Response the Th2 Response
• Healthy intestinal flora • Limited bacterial exposure
• Presence of older siblings • Urban/Western lifestyle
• Childhood infections • Indiscriminate antibiotic use
• Rural environment • Early exposure to
• Probiotics allergenic food proteins

Bacteria Antigens

Th1 Th2

Protective Allergy
Immunity
Bifidobacteria in Stool of Infants
mean log10 CFU/g stool After 7 Days of Feeding
11

10

6
Standard Formula + Breastmilk
Formula Probiotic

Adapted from Langhendries JP., et al. JPGN 1995;21:177-186.


Bifidobacteria Supplementation can Increase
Enteric Bifidobacteria (1 month follow up)
Stool After 1 Month of Feeding

70% *
Bifidobacteriain

60%
50%
40%
% Infants with

30%
20%
10%
0%
Supplemented Standard Breastmilk
formula
*P<0.05 compared to standard formula.
Adapted from Langhendries JP., et al. JPGN 1995;21:177-186.
Immune Benefits

• Cellular
• Humoral
B. lactis and Innate Cellular Immune
Response in Adults

90 * *
% Tumor cell killing

80

70

60

50
Baseline 3 wks intake 3 wks after intake

*P<0.05; compared to baseline.


Chiang BL., et al. European J Clin Nutr 2000;54;849-855.
Probiotics and Vaccination
Mix of Bifidobacteria (B. lactis) and Lactobacillus
Improves Response to Salmonella Vaccine in Adults
Serum specific Anti-Salmonella

120.0
typhi IgA Antibody Titre

Control *
100.0 Probiotics

80.0
*
60.0

40.0

20.0

0.0
Pre-vaccine day 14 day 24

*P< 0.001 compared to pre-vaccine

Link-Amster H., et al. Immunol Med Microbiol 1994;10:55-64.


B. lactis Enriched Formula and
% of infants that developed diarrhea Incidence of Diarrhea

40

30

20
31
10
*
7
0
Not supplemented Supplemented
*P=0.035

Saavedra JM, et al., Lancet 1994;344:1046-1049.


B. lactis Enriched Formula and
Incidence of Rotaviral Shedding
% of Infants that Shed Rotavirus

50

40

30

20 39 *
10
10
0
*P=0.025 Not supplemented Supplemented

Saavedra JM, et al., Lancet 1994;344:1046-1049.


Meta-analyses of Randomized Clinical Trials
on Probiotic Treatment of Acute Diarrhea

Incidence of Diarrhea > 3 days


Incidence Risk Reduction %

70
60
95%
50 CI = 0.3 – 0.5

40 95%
CI = 0.6 – 0.8
30
20
8 RCTs 15 RCTs
10
0
Szajewska, 2001 Allen, 2003

Adapted from: Szajewska H., et al. JPGN 2006;42:454-475.


Trends in Atopic Dermatitis Prevalence*

25

20
% Prevalence

15

10

0
1946 1958 1970 1994
*Secular trends in the UK
Eichenfield L., et al. Pediatrics 2003; 111: 608-616.
Immunologic Management of Antigens

Tolerance

Genetics

+ Antigens

Environment

Sensitization Allergy
Antigenic Exposure

• ~ 1 Ton of nutrients pass through GI


tract per year
• ~ 10 circulating intact proteins are
5

found 2-5 hrs after a meal (eg 3-10 ng/ml


beta lactoglobulin, ovalbumin, etc) free
of immune complexes

Should we expect more sensitization and


allergies?
Paganelli R. and Levinsky, RJ. J Immunol Methods 1980; 37:333-341.
Husby S., et .al. Scand J Immunol 1985; 22:83-92.
Risk Factors for Allergy

5
incidence of allergic symptoms
Odds Ratio of factors on

4 **
95%
CI = 1.0-14.2
*
3
95%
95% CI = 0.9-7.7
CI = 0.8-4.2
2
95%
CI = 0.3-0.9
1

0
Breast Feeding Parental Intact Protein Intact Protein
Asthma Formula Formula
(1st week) (any time)
*P<0.05; **P<0.0005
Marini A., et. al. Acta Paediatr Suppl 1996; 414:1-22.
Prevalence of Bifidobacteria in Stools of
Atopic and Healthy Infants
70% ***
Atopic **
60% Non-atopic
50% *
% of infants

40%
30%
20%
10%
0%
1 week 3 months 1 year
*P=0.02; **P=0.03; ***P=0.05 comparing prevalence at a given age

Björksten B., et al. J Allergy Clin Immunol 2001;108:516-520.


Conclusions

• The immune system is determined by:


– genetic factors
– environmental factors

• Any deviation from the “natural” life style is


adversely associated with life-long immune
responses
• These findings impose more responsibility on
neonatologists / pediatricians during management

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