Food allergy

Andras AratoAndras Arato

Food allergy
Andras AratoAndras Arato
Genetic predisposition for the
development of cow�s milk development of cow s milk
allergygy
Cow�s milk allergy ControlsCow s milk allergy Controls
Atopy in one of the 49% 32%Atopy in one of the
parents
49% 32%
A i bh 23% 3%** Atopy in both
parents
23% 3%
*** Atopy in both
parents +elevated
IgE in cord blood
38%
4,2%
***
IgE in cord blood
Genetic predisposition for the
development of cow�s milk development of cow s milk
allergygy
Cow�s milk allergy ControlsCow s milk allergy Controls
Atopy in one of the 49% 32%Atopy in one of the
parents
49% 32%
A i bh 23% 3%** Atopy in both
parents
23% 3%
*** Atopy in both
parents +elevated
IgE in cord blood
38%
4,2%
***
IgE in cord blood
Specific foods causing enteropathy
syndromes
� Cow s milk
�Soy
� Hydrolysates
� Wheat gluten
� Peanuts
� EggEgg
�Nuts
� Fish� Fish
� Multiple food allergy
Specific foods causing enteropathy
syndromes
� Cow s milk
�Soy
� Hydrolysates
� Wheat gluten
� Peanuts
� EggEgg
�Nuts
� Fish� Fish
� Multiple food allergy
Beta-lactoglobulin content of breast
milk, cow�s milk and hydrolasates
beta-lactoglobulin (ng/ml)
Cow�s milk 4000000Cow s milk 4000000
Partial hydrolasates 12400-32000
Extensive hydrolates 0.006-14.5
Breast milk 09-15Breast milk 0.9 1.5
One drop of cow�s milk contains so much
beta-lactoglobulin as 200 l breast milk
Beta-lactoglobulin content of breast
milk, cow�s milk and hydrolasates
beta-lactoglobulin (ng/ml)
Cow�s milk 4000000Cow s milk 4000000
Partial hydrolasates 12400-32000
Extensive hydrolates 0.006-14.5
Breast milk 09-15Breast milk 0.9 1.5
One drop of cow�s milk contains so much
beta-lactoglobulin as 200 l breast milk
Features of cow�s milk allergy Features of cow s milk allergy
� It is an adverse reaction to cow�s milk
proteins caused by immune respone to
these antigens.
T i diti i th j i f� Transitory condition, in the majority of
cases the patients can tolerate cows milk
after 2-3 years of age
Features of cow�s milk allergy Features of cow s milk allergy
� It is an adverse reaction to cow�s milk
proteins caused by immune respone to
these antigens.
T i diti i th j i f� Transitory condition, in the majority of
cases the patients can tolerate cows milk
after 2-3 years of age
FrequencyFrequency
� Allergy to cow�s milk is about 2,5% of the
general paediatric population (Schrandergeneral paediatric population (Schrander
JJ et al. Eur J Pediatr 1993, 152, 640-4.)
� In atopic infants, the prevalence is at least
five times higher
FrequencyFrequency
� Allergy to cow�s milk is about 2,5% of the
general paediatric population (Schrandergeneral paediatric population (Schrander
JJ et al. Eur J Pediatr 1993, 152, 640-4.)
� In atopic infants, the prevalence is at least
five times higher
The distribution of protein
fractions in cow�s milk
Percentage of total
protein content (%)
Responsible for the
symptoms (%)
C i 80 43Casein 80 43
Whey proteins
20
bovin lactoglobulin 9 82
alpha lactalbumin 4 41 p
proteases 4
bi 1 18bovin serum
albumins
1 18
bovin 2 27
immunoglobulins
The distribution of protein
fractions in cow�s milk
Percentage of total
protein content (%)
Responsible for the
symptoms (%)
C i 80 43Casein 80 43
Whey proteins
20
bovin lactoglobulin 9 82
alpha lactalbumin 4 41 p
proteases 4
bi 1 18bovin serum
albumins
1 18
bovin 2 27
immunoglobulins
Immune reactions in food
allergy I.
� Acute onset reaction (Type I. reaction)
anaphylaxis urticaria vomiting diarrhoea anaphylaxis, urticaria, vomiting,
diarrhoea,
wheezing
� IgE RAST mostly positive, but positive
reaction sometimes occur even in healthy
children. Prick test is frequently positive
� Correlation between the positive RAST � Correlation between the positive RAST
and positive prick test
Immune reactions in food
allergy I.
� Acute onset reaction (Type I. reaction)
anaphylaxis urticaria vomiting diarrhoea anaphylaxis, urticaria, vomiting,
diarrhoea,
wheezing
� IgE RAST mostly positive, but positive
reaction sometimes occur even in healthy
children. Prick test is frequently positive
� Correlation between the positive RAST � Correlation between the positive RAST
and positive prick test
Immune reactions in food
allergy II.
� Type III. (immuncomplex) reaction:
Immuncomplexes containing IgG may
cause allergic reactions, IgA containing
complexes do not cause reactionscomplexes do not cause reactions.
� Serum IgG anti-cow�s milk protein
antibodies b elevated in healthy antibodies can be elevated in healthy
infant after feeding of cow�s milk(especiall high 5 onths after he(especially high
5 months after the
introduction of cow�s milk.)
Immune reactions in food
allergy II.
� Type III. (immuncomplex) reaction:
Immuncomplexes containing IgG may
cause allergic reactions, IgA containing
complexes do not cause reactionscomplexes do not cause reactions.
� Serum IgG anti-cow�s milk protein
antibodies b elevated in healthy antibodies can be elevated in healthy
infant after feeding of cow�s milk(especiall high 5 onths after he(especially high
5 months after the
introduction of cow�s milk.)
Immune reactions in food
allergy III.
� Type IV (cell-mediated, delayed type)
reaction. This is the tipical reaction at the
intestinal form of food allergy
� Leucocyte igration inhibition test is � Leucocyte migration inhibition test is
pozitiv
� The number of immunoglobulin containing
cells in the lamina propria of smallcells in the lamina propria of small
intestinal mucosa is elevated.
Immune reactions in food
allergy III.
� Type IV (cell-mediated, delayed type)
reaction. This is the tipical reaction at the
intestinal form of food allergy
� Leucocyte igration inhibition test is � Leucocyte migration inhibition test is
pozitiv
� The number of immunoglobulin containing
cells in the lamina propria of smallcells in the lamina propria of small
intestinal mucosa is elevated.
Factors influencing the development of
mucosal immunity or tolerance
AtopyAge
Mucosal
immunity
Epithelial
permeability
Breast feeding
Oral tolerance
Intestinal bacteria
InfectionsDiet
Genetic predisposition
Factors influencing the development of
mucosal immunity or tolerance
AtopyAge
Mucosal
immunity
Epithelial
permeability
Breast feeding
Oral tolerance
Intestinal bacteria
InfectionsDiet
Genetic predisposition
Relationship among acut gastroenteritis,
lactose malabsorption and secundaerlactose malabsorption and secundaer
cow�s milk allergy
Acut gastroenteritisMucosal IgA
deficiency
Secundaer
lactose
Small intestinal damage
deficiency
malabsorptio
Deficiency of
Antigen load
y
suppression
Abrogation of g
tolerance
Protein sensitive
enteropathy
Local
sensitisation
Relationship among acut gastroenteritis,
lactose malabsorption and secundaerlactose malabsorption and secundaer
cow�s milk allergy
Acut gastroenteritisMucosal IgA
deficiency
Secundaer
lactose
Small intestinal damage
deficiency
malabsorptio
Deficiency of
Antigen load
y
suppression
Abrogation of g
tolerance
Protein sensitive
enteropathy
Local
sensitisation
Clinical symptomsClinical symptoms
� Anaphylaxis
� Skin manifestations: urticaria, pruritus,urticaria, pruritus,
exanthema, eczema
� Respiratory tract: wheezy bronchitis � Respiratory tract: wheezy bronchitis,
laryngitis, otitis
Gt i t ti l t t iti� Gastrointestinal tract: vomiting,
diarrhoea, haemorrhagic colitis, chronicdi h l b ti GERD diarrhoea, malabsorption,
GERD,
constipation failure to thrive
Clinical symptomsClinical symptoms
� Anaphylaxis
� Skin manifestations: urticaria, pruritus,urticaria, pruritus,
exanthema, eczema
� Respiratory tract: wheezy bronchitis � Respiratory tract: wheezy bronchitis,
laryngitis, otitis
Gt i t ti l t t iti� Gastrointestinal tract: vomiting,
diarrhoea, haemorrhagic colitis, chronicdi h l b ti GERD diarrhoea, malabsorption,
GERD,
constipation failure to thrive
Classification of gastrointestinalghypersensitivities
according their pathogenesisaccording their pathogenesis
IgE mediated Mixed (IgE and
non IgE)
Non IgE mediated
�Immediate
gastrointestinal
hypersensitivity
�Allergic eosinophil
oesophagitis
�Food induced
enteropathy
hypersensitivity
�Oral allergic
syndrome
�Allergic eosinophil
gastritis
All i i hil
�Food induced
enterocolitis
Fd i d d syndrome �Allergic eosinophil
gastroenterocolitis
�Food induced
proctitis
Classification of gastrointestinalghypersensitivities
according their pathogenesisaccording their pathogenesis
IgE mediated Mixed (IgE and
non IgE)
Non IgE mediated
�Immediate
gastrointestinal
hypersensitivity
�Allergic eosinophil
oesophagitis
�Food induced
enteropathy
hypersensitivity
�Oral allergic
syndrome
�Allergic eosinophil
gastritis
All i i hil
�Food induced
enterocolitis
Fd i d d syndrome �Allergic eosinophil
gastroenterocolitis
�Food induced
proctitis
Classification of cutaneous hypersensitivitiesypaccording their pathogenesis
IgE mediated Mixed (IgE and
non IgE)
Non IgE mediated
�Angiooedema
�Morbilliform rashes
�Atopic dermatitis �Contact dermatitis
�Dermatitis
�Urticaria
�Flushing
herpetiformis
Classification of cutaneous hypersensitivitiesypaccording their pathogenesis
IgE mediated Mixed (IgE and
non IgE)
Non IgE mediated
�Angiooedema
�Morbilliform rashes
�Atopic dermatitis �Contact dermatitis
�Dermatitis
�Urticaria
�Flushing
herpetiformis
Classification of respiratory hypersensitivitiesp y yp
according their pathogenesis
IgE mediated Mixed (IgE and
non IgE)
Non IgE mediated
�Acut
rhinoconjunctivitis
�Asthma �Food induced
haemosiderosis
(Heiner)�Acut bronchospasm (Heiner)
Classification of respiratory hypersensitivitiesp y yp
according their pathogenesis
IgE mediated Mixed (IgE and
non IgE)
Non IgE mediated
�Acut
rhinoconjunctivitis
�Asthma �Food induced
haemosiderosis
(Heiner)�Acut bronchospasm (Heiner)
Example of cutaneous reaction during cow's milk challenge through
human milk Infant before commencement fhuman milk. Infant before commencement of
challenge (A) and after appearance of reaction (B).
Jarvinen: J Pediatr, Volume 1999, 135, 506-512.
Example of cutaneous reaction during cow's milk challenge through
human milk Infant before commencement fhuman milk. Infant before commencement of
challenge (A) and after appearance of reaction (B).
Jarvinen: J Pediatr, Volume 1999, 135, 506-512.
Characteristic pH-tracing pattern of GOR
caused by cow�s milk allergy
Cow�s milk allergy
P i GORPrimary GOR
Cavataio F. Arch. Dis Child 1996, 75, 51-6.
Characteristic pH-tracing pattern of GOR
caused by cow�s milk allergy
Cow�s milk allergy
P i GORPrimary GOR
Cavataio F. Arch. Dis Child 1996, 75, 51-6.
Diagnosis IDiagnosis I.
� Exact history
symptomssymptoms,
atopy in the family
diet
� Exclusion of diseases causing the same � Exclusion of diseases causing the same
symptoms as cow�s milk allergy
Diagnosis IDiagnosis I.
� Exact history
symptomssymptoms,
atopy in the family
diet
� Exclusion of diseases causing the same � Exclusion of diseases causing the same
symptoms as cow�s milk allergy
Diagnosis IIDiagnosis II.
� Elimination of suspected food protein the
symptoms disappear and on challenge
reappear. So elimination diet and food
challenge remain the mainstay ofchallenge remain the mainstay of
diagnosis.
�RAST testing and prick test help the
diagnosis in children having IgE-mediated
reactions.
Diagnosis IIDiagnosis II.
� Elimination of suspected food protein the
symptoms disappear and on challenge
reappear. So elimination diet and food
challenge remain the mainstay ofchallenge remain the mainstay of
diagnosis.
�RAST testing and prick test help the
diagnosis in children having IgE-mediated
reactions.
Picture of small intestinal mucosa
in cow�s milk enteropathy
Picture of small intestinal mucosa
in cow�s milk enteropathy
Endoscopic view of the terminal ileum showing dense
lymphoid involvement filling the whole mucosa inlymphoid involvement filling the
whole mucosa in
children with food allergy
Kokkonen J et al. Am J Gastroenterol 2002, 97, 667-672
Endoscopic view of the terminal ileum showing dense
lymphoid involvement filling the whole mucosa inlymphoid involvement filling the
whole mucosa in
children with food allergy
Kokkonen J et al. Am J Gastroenterol 2002, 97, 667-672
Characterization of patients with
food allergy
Veres G, Westerholm-Ormio M, Kokkonen J, Arato A, Savilahti E.
J. Pediatr Gastroenterol Nutr 2003, 37, 27-34.
Characterization of patients with
food allergy
Veres G, Westerholm-Ormio M, Kokkonen J, Arato A, Savilahti E.
J. Pediatr Gastroenterol Nutr 2003, 37, 27-34.
Densities of positive cells labelled by different markers(cells/mm2) in the
duodenal lamina propria of patients with
t t d ( FA) d t t d f d ll tFA) d f t luntreated (uFA) and treated food allergy
tFA), and of controls.
Median, (25-75 percentile).
Veres G, Westerholm-Ormio M, Kokkonen J, Arato A, Savilahti E.
J. Pediatr Gastroenterol Nutr 2003, 37, 27-34.
Densities of positive cells labelled by different markers(cells/mm2) in the
duodenal lamina propria of patients with
t t d ( FA) d t t d f d ll tFA) d f t luntreated (uFA) and treated food allergy
tFA), and of controls.
Median, (25-75 percentile).
Veres G, Westerholm-Ormio M, Kokkonen J, Arato A, Savilahti E.
J. Pediatr Gastroenterol Nutr 2003, 37, 27-34.
Percentages of proliferating crypt cells (Ki-67), HLA-DR positive
staining of crypts and surface epithelium, and percentages of
ICAM 1 iti t t i th d d l l i i fICAM-1 positive structures in the duodenal lamina
propria of
patients with uFA, tFA), and of controls
Veres G, Westerholm-Ormio M, Kokkonen J, Arato A, Savilahti E.
J. Pediatr Gastroenterol Nutr 2003, 37, 27-34.
Percentages of proliferating crypt cells (Ki-67), HLA-DR positive
staining of crypts and surface epithelium, and percentages of
ICAM 1 iti t t i th d d l l i i fICAM-1 positive structures in the duodenal lamina
propria of
patients with uFA, tFA), and of controls
Veres G, Westerholm-Ormio M, Kokkonen J, Arato A, Savilahti E.
J. Pediatr Gastroenterol Nutr 2003, 37, 27-34.
Immunoperoxidase staining for IFN-. in
duodenal biopsy specimens
Untreated food allergyUntreated food allergy Treated food allergy Controls
Veres G, Westerholm-Ormio M, Kokkonen J, Arato A, Savilahti E.
J. Pediatr Gastroenterol Nutr 2003, 37, 27-34.
Immunoperoxidase staining for IFN-. in
duodenal biopsy specimens
Untreated food allergyUntreated food allergy Treated food allergy Controls
Veres G, Westerholm-Ormio M, Kokkonen J, Arato A, Savilahti E.
J. Pediatr Gastroenterol Nutr 2003, 37, 27-34.
Expression of IL-4 and IFN-. mRNA in celiac patients, untreated
and treated food-allergy patients, and normal controls (Co)gy p , ( )
detected by radioactive in situ hybridization
Veres G, Westerholm-Ormio M, Kokkonen J, Arato A,
Savilahti E JPGN 2003 37 27 34Savilahti E. JPGN 2003, 37, 27-34.
Expression of IL-4 and IFN-. mRNA in celiac patients, untreated
and treated food-allergy patients, and normal controls (Co)gy p , ( )
detected by radioactive in situ hybridization
Veres G, Westerholm-Ormio M, Kokkonen J, Arato A,
Savilahti E JPGN 2003 37 27 34Savilahti E. JPGN 2003, 37, 27-34.
The cow�s milk challenge test The cow s milk challenge test
� Skin prick test with milk. When the test is
negative, quick challenge can be done.
� The oral challenge begins with 1 ml of milk
and in 1/4 hour the dose i and in every 1/4 hour the dose is
increased (5, 10, 15, 30, 50, 100 ml)
� Since the beginning of challenge constant
medical observation is necessary for 6medical observation is necessary for 6
hours.
The cow�s milk challenge test The cow s milk challenge test
� Skin prick test with milk. When the test is
negative, quick challenge can be done.
� The oral challenge begins with 1 ml of milk
and in 1/4 hour the dose i and in every 1/4 hour the dose is
increased (5, 10, 15, 30, 50, 100 ml)
� Since the beginning of challenge constant
medical observation is necessary for 6medical observation is necessary for 6
hours.
Serum level of eosinophil cationic protein (sECP) is shown
for controls and for patient groups before the cow's milk p g p
challenge (0 hour) and 2 and 24 hours after the challenge
Hidvegi E, Cserhati E, Kereki E, Arato A.
JPGN 32, 475-479, 2001
Serum level of eosinophil cationic protein (sECP) is shown
for controls and for patient groups before the cow's milk p g p
challenge (0 hour) and 2 and 24 hours after the challenge
Hidvegi E, Cserhati E, Kereki E, Arato A.
JPGN 32, 475-479, 2001
Individual total IgE values in children with CMA who
had positive or negative reaction to cow�s milk at had positive or negative
reaction to cow s milk at
rechallenge and in controls.
total IgE
(kU/l)
100
positive (n=12)
negative (n=26)
control (n=30)
10
( )
1
Hidvegi E. Cserhati E. Kereki E. Savilahti E. Arato A Pediatr Allergy Immunol 2002,
13, 255-61.
Individual total IgE values in children with CMA who
had positive or negative reaction to cow�s milk at had positive or negative
reaction to cow s milk at
rechallenge and in controls.
total IgE
(kU/l)
100
positive (n=12)
negative (n=26)
control (n=30)
10
( )
1
Hidvegi E. Cserhati E. Kereki E. Savilahti E. Arato A Pediatr Allergy Immunol 2002,
13, 255-61.
Different laboratory parameters of cow milk allergic patients (n
= 27) and the control group (n = 20)* P < 0.03.** P < 0.01
Hidvegi E, Arato A, Cserhati E. et al. JPGN 36, 44-49, 2003
Different laboratory parameters of cow milk allergic patients (n
= 27) and the control group (n = 20)* P < 0.03.** P < 0.01
Hidvegi E, Arato A, Cserhati E. et al. JPGN 36, 44-49, 2003
Different laboratory parameters (mean � SD) of
hild ith t i t ( 20) d t ( children with transient (n = 20) and permanent (n =
7) cow milk allergy and of controls (n = 20)* P <
005** P <001 0.05.** P < 0.01.
Hidvegi E, Arato A, Cserhati E. et al. JPGN 36, 44-49, 2003
Different laboratory parameters (mean � SD) of
hild ith t i t ( 20) d t ( children with transient (n = 20) and permanent (n =
7) cow milk allergy and of controls (n = 20)* P <
005** P <001 0.05.** P < 0.01.
Hidvegi E, Arato A, Cserhati E. et al. JPGN 36, 44-49, 2003
No correlation between Z scores and the
length of the milk protein-free diet
Hidvegi E, Arato A, Cserhati E. et al. JPGN 36, 44-49, 2003
No correlation between Z scores and the
length of the milk protein-free diet
Hidvegi E, Arato A, Cserhati E. et al. JPGN 36, 44-49, 2003
TreatmentTreatment
� Strict avoidance of cow�s milk protein
� New approachesNew approaches
Immunotherapy -introducing antigen
specific hyporesponsiveness (Activation of
Th3 cells)
Stabilisation of intestinal mucosal barrier
(Peroral administration of probiotic(Peroral administration of probiotic
bacteria)
TreatmentTreatment
� Strict avoidance of cow�s milk protein
� New approachesNew approaches
Immunotherapy -introducing antigen
specific hyporesponsiveness (Activation of
Th3 cells)
Stabilisation of intestinal mucosal barrier
(Peroral administration of probiotic(Peroral administration of probiotic
bacteria)
Cow�s milk protein
elimination
� Formulas containing alternative protein
sources (soya is the most frequent)
� Extensively hydrolysated cow�s milk
protein formulasprotein formulas
casein
whey
S thetic amino acid deri d f las� Synthetic amino acid-derived formulas
Cow�s milk protein
elimination
� Formulas containing alternative protein
sources (soya is the most frequent)
� Extensively hydrolysated cow�s milk
protein formulasprotein formulas
casein
whey
S thetic amino acid deri d f las� Synthetic amino acid-derived formulas
Forms of cow�s milk protein
hydrolysates
� Extensively hydrolysed formulas
(They are containing peptides of molecular(They are containing peptides of
molecular
weight less than 1000 daltons)
� Partially hydrolysed formulas
(They are containing peptides even with
molecular weight between 8000-40000daltons) These formulas are)
contraindicated for the treatment of cow�s
milk allergygy
Forms of cow�s milk protein
hydrolysates
� Extensively hydrolysed formulas
(They are containing peptides of molecular(They are containing peptides of
molecular
weight less than 1000 daltons)
� Partially hydrolysed formulas
(They are containing peptides even with
molecular weight between 8000-40000daltons) These formulas are)
contraindicated for the treatment of cow�s
milk allergygy
Growth during first 24 months of infancy in patients
with cow's milk allergy with cow s milk allergy
Open circles = early onset
ld
o
Open squares = older onset
Solid circles = controls
Isolauri E et al. J Pediatr 1998. 132, 1004-9.
Growth during first 24 months of infancy in patients
with cow's milk allergy with cow s milk allergy
Open circles = early onset
ld
o
Open squares = older onset
Solid circles = controls
Isolauri E et al. J Pediatr 1998. 132, 1004-9.
Beta-lactoglobulin content of breast
milk, cow�s milk and hydrolasates
beta-lactoglobulin (ng/ml)
Cow�s milk 4000000Cow s milk 4000000
Partial hydrolasates 12400-32000
Extensive hydrolates 0.006-14.5
Breast milk 09-15Breast milk 0.9 1.5
One drop of cow�s milk contains so much
beta-lactoglobulin as 200 l breast milk
Beta-lactoglobulin content of breast
milk, cow�s milk and hydrolasates
beta-lactoglobulin (ng/ml)
Cow�s milk 4000000Cow s milk 4000000
Partial hydrolasates 12400-32000
Extensive hydrolates 0.006-14.5
Breast milk 09-15Breast milk 0.9 1.5
One drop of cow�s milk contains so much
beta-lactoglobulin as 200 l breast milk