Alessandro Fiocchi Melloni Pediatria
Milano Una novità italiana:
l’idrolisato di riso.
Outline
1. CMA in Italy 2. CMA in Milan
3. Animal studies with HRF 4. HRF in severe CMA
5. HRF in CMA
6. Nutritional aspects
7,2
4,2
5,5
4,6
0,0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 8,0
1-3years 4-6years 7-12years 13-17years
%
Steinke M. Fiocchi A. and the REDALL group.
Perceived Food allergy in children. A Report on a representative telephone survey in 10 European countries. Int Arch Allergy Asthma Immunol 2007;143:290-5
Percentage of children reported with
food allergy in different ages
Foods reported to induce food allergy
6,7
13,5
9,7
18,1
8,4 3
11,4 7
19
38,5
29,5
0 5 10 15 20 25 30 35 40 45
fish seaf
ood
wheat
meat
eggs milk fruit legum
es vege
tables
nuts
others
%
Steinke M. Fiocchi A. and the REDALL group.
Perceived Food allergy in children. A Report on a representative telephone survey in 10 European countries. Int Arch Allergy Asthma Immunol 2007;143:290-5
Foods reportedly suspected (by country)
34,8 27,9
55,7 33,3
16,7 23,8
41,7 22,7
55,8 28,6
Milk %
21,7 27,9
27,3 15,2
27,1 9,5
14,6 0
14 7,1
Egg %
8,7 9,3
10,2 15,2
10,4 4,8
1 4,5
4,7 0
Meat %
13 4,7
2,3 3
0 4,8
2,1 4,5
2,3 0
Seafood %
7,4 7
1,1 6,1
8,3 4,8
19,8 0
4,7 0
Fish %
3,1 4,6
8,3 3,9
4,8 3
11,7 2,5
4,9 1,7
Prevalence %
CH Slo
Pol It
Gre Ger
Fld Dk
Bel Aus
Steinke M. Fiocchi A. and the REDALL group.
Perceived Food allergy in children. A Report on a representative telephone survey in 10 European countries. Int Arch Allergy Asthma Immunol 2007;143:290-5
3,9 3,8
3,3 3
2,5 2,4
1,5
0 0,5 1 1,5 2 2,5 3 3,5 4 4,5
18-29 n=5054
30-39 n=6432
40-49 n=7572
50-59 n=7175
60-69 n=6552
70-79 n=4792
80+
n=2384
Percentage of patients reported with food allergy in different ages
Steinke M. Fiocchi A. and the REDALL group.
Perceived Food allergy in children. A Report on a representative telephone survey in 10 European countries. Int Arch Allergy Asthma Immunol 2007;143:290-5
Foods reported to induce food allergy
Adults
9.1
5.4
10.9
6.6 8.3
26.2 28.6
6.0
16.1 13.7
20.4
0 10 20 30 40
Fish
Seafood
Whea t
Meat Eggs
Milk
Frui t
Legum es
Vegetables Nuts
Others
Valid cases: N=1290 in % IFAV/REDALL
Steinke M. Fiocchi A. and the REDALL group.
Perceived Food allergy in children. A Report on a representative telephone survey in 10 European countries. Int Arch Allergy Asthma Immunol 2007;143:290-5
Foods reportedly suspected (by country)
19.4 15.7
28.4 20.0
13.8 17.4
52.3 16.2
19.5 28.0
Milk
5.6 11.8
18.9 9.0
13.8 5.0
2.8 7.2
11.9 5.3
Eggs
5.6 21.6
5.4 9.0
10.0 5.0
1.1 1.8
7.6 6.7
Meat
9.3 18.6
10.8 14.5
3.8 11.6
12.7 1.8
6.8 12.0
Wheat
4.6 2.0
5.4 6.9
7.5 4.1
1.4 9.0
15.3 Seafoo 0.0
d
9.3 4.9
8.1 7.6
16.9 2.5
11.7 9.0
11.0 0.0
Fish
CH Slo
Pl I
Gr D
Fn Dk
B A
Steinke M. Fiocchi A. and the REDALL group.
Perceived Food allergy in children. A Report on a representative telephone survey in 10 European countries. Int Arch Allergy Asthma Immunol 2007;143:290-5
Outline
1. CMA in Italy 2. CMA in Milan 3. Animal studies
4. HRF in severe CMA 5. HRF in CMA
6. Nutritional aspects
Natural history of immediate-onset CMA
4 3 2
2 years 4 mo 1 year
Time after diagnosis
63%
53%
31%
Vanto
68%
Garcia-Ara
50%
Host
Tolerance Study
Høst A. Cow’s milk protein allergy and intolerance in infancy. Pediatric Allergy and Immunology 2003; 13 (s15), 23-8 Garcia-Ara MC. Cow's milk-specific immunoglobulin E levels as predictors of clinical
reactivity in the follow-up of the cow's milk allergy infants.
Clin Exp Allergy 2004;34:866-70 Vanto T. Prediction of the development of tolerance to milk in children with cow's milk
hypersensitivity. J Pediatr. 2004;144:218-22
Mean duration of disease:
1-3 years
The Milan Cohort:
Infants & Children Referrals with CMA
2001– 2006
Children with self-reported immediate symptoms to CM Full diagnostic evaluation
Entry criterion: positive DBPCFC with CM Presenting symptoms for referral :
1. Asthma and allergic rhinitis 2. Urticaria
3. GIT symptoms 4. Eczema (AEDS)
5. Anaphylaxis
Follow-up to tolerance
Fiocchi A, Terracciano L, Sarratud T, Veglia F, Bouygue GR, Martelli A, Ghiglioni D.
The fate of CMA: a prospective study. submitted
§
calcium integration
* when breastfed
Study protocol
9 9
9 9
9 9
9 9
9 30 months 9
9 27 months 9
9 9
9 9
9 9
9 9
24 months 9
9 9
21 months
9 9
9 9
9 9
9 9
9 9
18 months
9 9
15 months
9 9
9 9
9 9
9 9
9 9
12 months
9 9
9 months
9 9
9 9
9 9
9 9
9 9
6 months
9 9
9 3 months
9 9
9 9
9 9
9 9
9 Visit 1
DBPCFC Nutrition
indexes Verify
dietetic compliance Dietetician
sIgE beef sIgE
milk SPT
inhalant s ffSPT
cSPT Auxology
Ingestant allergens:
milk, egg white, egg yolk, rice, wheat,
codfish, beef, peanut, soy.
milk, cooked and raw beef allergens (case by
case)
inhalant allergens: grass, parietaria, ragweed,
dermatophagoides farinae,
dermatophagoides pteronyssinus, cat dander, dog dander,
alternaria
by specific questionnaire
haematology, BUN, retinol binding protein,
prealbumin, albumin, ferritin, blood amino acids
allocation to a dietetic group:
eHF, soy, HRF
Presented with suspicion of immediate-onset CMA = 298
DBPCFC – ve = 147 (exited the study) Confirmed at DBPCFC = 151
Lost to follow-up = 39 21 after diagnostic DBPCFC
18 after 2
ndDBPCFC
Enrolled N = 112 The Milan Infant and Children CMA Cohort
Fiocchi A, Terracciano L, Sarratud T, Veglia F, Bouygue GR, Martelli A, Ghiglioni D.
The fate of CMA: a prospective study. submitted
Profile of the child with long-term CMA
1. Presenting with asthma
1. Presenting with asthma
2. Multiple food sensitisations at ImmunoCAP
®Profile of the child with long-term CMA
1. Presenting with asthma
2. Multiple food sensitisations at ImmunoCAP
®3. Co-sensitisation to foods at SPT
Profile of the child with long-term CMA
1. Presenting with asthma
2. Multiple food sensitisations at ImmunoCAP
®3. Co-sensitisation to foods at SPT
4. Co-sensitisation to beef
Profile of the child with long-term CMA
1. Presenting with asthma
2. Multiple food sensitisations at ImmunoCAP
®3. Co-sensitisation to foods at SPT
4. Co-sensitisation to beef
5. Co-sensitisation to grass and dog dander
Profile of the child with long-term CMA
1. Presenting with asthma
2. Multiple food sensitisations at ImmunoCAP
®3. Co-sensitisation to foods at SPT
4. Co-sensitisation to beef
5. Co-sensitisation to grass and dog dander 6. Co-sensitisation to less prevalent allergens
Profile of the child with long-term CMA
Outline
1. CMA in Italy 2. CMA in Milan 3. Animal studies
4. HRF in severe CMA 5. HRF in CMA
6. Nutritional aspects
Results
RP HRF BetaL
Cas CMF
RP HRF BetaL
Cas CMF Challenge
80%
CMF
0 HRF
0 HRF
0 HRF
0 HRF
0 HRF
0 CMF
0 CMF
100%
CMF
100%
CMF
Fatal reactions Supplement
Piacentini GL. Allergenicity of a hydrolyzed rice infant formula in a guinea pig model.
Ann Allergy Asthma Immunol 2003; 91:61-4
Outline
1. CMA in Italy 2. CMA in Milan 3. Animal studies
4. HRF in severe CMA 5. HRF in CMA
6. Nutritional aspects
Patients
• 18 children (6F, 12M, median age 5 yrs, range 0.5–9.75)
• confirmed allergic to CM and soy
• DBPCFC-positive: 12/18 CM, 18/18 Soy
• DBPCFC con HRF
Fiocchi A.
Tolerance to a rice hydrolysate formula in children allergic to cow's milk and soy Clin Experim Allergy 2003; 33:1576-80
Results - synopsis
none 61%/nd
44%/11%
Rice/HRF
100%
77%
100%
Soy
100%
100%
100%
CM
Challenge + RAST+
SPT+
Fiocchi A.
Tolerance to a rice hydrolysate formula in children allergic to cow's milk and soy Clin Experim Allergy 2003; 33:1576-80
Open questions
Sensitisation to rice in CM-allergic children without soy allergy?
Levels of specific IgE to HRF?
Tolerance of HRF among children with CMA?
Fiocchi A.
Tolerance to a rice hydrolysate formula in children allergic to cow's milk and soy Clin Experim Allergy 2003; 33:1576-80
Outline
1. CMA in Italy 2. CMA in Milan 3. Animal studies
4. HRF in severe CMA 5. HRF in CMA
6. Nutritional aspects
Objective
Prospective assessment of clinical tolerance to a rice- based hydrolysate formula by children allergic to cow’s
milk proteins (CMP).
Research question:
can these children consume HRF safely?
The Italian CMA study group.
Children allergic to cow’s milk tolerate a rice hydrolysate formula.
Clin Exp Allergy 2006; 36:311-6
Patients
• Jan 2003 – Apr 2004
• 100 children (36F, 55M, mean age 3.17 ± 2.93 yrs, range 0.18–14.5)
• confirmed allergic to CM with immediate reactions
The Italian CMA study group.
Children allergic to cow’s milk tolerate a rice hydrolysate formula.
Clin Exp Allergy 2006; 36:311-6
Patients
54 AD
32 Urticaria
26 Asthma
2 Conjunctivitis
11 Angioedema
9 Rhinitis
1 Laryngospasm
16 Shock
24 Gastro-intestinal
Number Symptom
The Italian CMA study group.
Children allergic to cow’s milk tolerate a rice hydrolysate formula.
Clin Exp Allergy 2006; 36:311-6
Methods
•SPT with whole milk, alpha-lactalbumin (ALA), beta- lactoglobulin (BLG), alpha- and beta-casein (a-Cas, b- Cas) (Sigma Chemical, St. Louis, Mo).
• Specific IgE determinations: whole milk, ALA, BLG and Cas (Pharmacia, Uppsala, Sweden)
• Sensitisation to rice and HRF investigated by SPT and CAP test.
• Immunoblotting for CMP, rice and HRF (Heinz-Plada, Milan, Italy).
• DBPCFC with 24 g RHF powder masked in Neocate®
(equivalent to 180 mL reconstituted formula).
Results - sensitisation
5/88*
4/86 3/90
HRF
69/88 21/86
4/90 Rice
84/88 82/86
91/91 CM/ALA, BLG,
Cas
Immunoblotting+
CAP+
SPT+
* Tutti in classe I
The Italian CMA study group.
Children allergic to cow’s milk tolerate a rice hydrolysate formula.
Clin Exp Allergy 2006; 36:311-6
Results – sensitisation with CM proteins
39/88 78/86
76/90 Beta-Cas
52/88 65/86
75/90 BLG
54/88 Alfa-Cas
57/88 BSA
69/88 70/86
75/90 ALA
84/88 78/86
69/77 CM
Immunoblotting+
CAP+
SPT+
The Italian CMA study group.
Children allergic to cow’s milk tolerate a rice hydrolysate formula.
Clin Exp Allergy 2006; 36:311-6
Results – sensitisation with soy, rice and HRF
5/88*
4/86 3/90
HRF
69/88 21/86
4/90 Rice
70/88 35/86
4/20 Soy
Immunoblotting+
CAP+
SPT+
* Tutti in classe I
The Italian CMA study group.
Children allergic to cow’s milk tolerate a rice hydrolysate formula.
Clin Exp Allergy 2006; 36:311-6
a-Cas a-La BSA rice RHF MK eHF SH El Soy b-Cas b-Lg
Immunoblotting (pt 17)
The Italian CMA study group.
Children allergic to cow’s milk tolerate a rice hydrolysate formula.
Clin Exp Allergy 2006; 36:311-6
Immunoblotting (pt 22)
a-Cas a-La BSA rice RHF MK eHF SH El Soy b-Cas b-Lg
The Italian CMA study group.
Children allergic to cow’s milk tolerate a rice hydrolysate formula.
Clin Exp Allergy 2006; 36:311-6
Results - challenge
none Rice
none HRF
78/91 CM
Challenge +
The Italian CMA study group.
Children allergic to cow’s milk tolerate a rice hydrolysate formula.
Clin Exp Allergy 2006; 36:311-6
Open questions
Sensitisation to rice in CM-allergic children without soy allergy? Yes – no clinical significance
Levels of specific IgE to HRF?
Tolerance of HRF among children with CMA?
Open questions
Sensitisation to rice in CM-allergic children without soy allergy? Yes – no clinical significance
Levels of specific IgE to HRF? Low
Tolerance of HRF among children with CMA?
Open questions
Sensitisation to rice in CM-allergic children without soy allergy? Yes – no clinical significance
Levels of specific IgE to HRF? Low
Tolerance of HRF among children with CMA? High
Rice hydrolisate
• Hypoallergenic
Piacentini GL. Allergenicity of a hydrolyzed rice infant formula in a guinea pig model. Ann Allergy Asthma Immunol 2003; 91:61-4
• Tolerated by polyallergic
Fiocchi A. Tolerance to a rice hydrolysate formula in children allergic to cow's milk and soy. Clin Experim Allergy 2003; 33:1576-80
• Tolerated in CMA
Fiocchi A. Children allergic to cow’s milk tolerate a rice hydrolysate formula.
Clin Exp Allergy 2006; 36:311-6
More open questions
Sensitisation to HRF after prolonged use
Effect of HRF in prevention studies
Nutritional value of HRF
Outline
1. CMA in Italy 2. CMA in Milan 3. Animal studies
4. HRF in severe CMA 5. HRF in CMA
6. Nutritional aspects
Rice hydrolysate – nutritional value
16 infants - normal growth pattern with normal plasma biochemical parameters
D'Auria E. Nutritional value of a rice-hydrolysate formula in infants with cow's milk allergy: a randomized pilot study. J Intern Med Res 2003; 31: 1-8
• Doubts
Savino A. Z-score of weight for age of infants with atopic dermatitis and cow’s milk allergy fed with a rice-hydrolysate formula during the first two years of life.
Acta Paediatrica 2005; 94 S449; 1-6
• New data
Agostoni C. Growth of infants with IgE-mediated cow’s milk allergy fed different formulas in the complementary feeding period.
Pediatr Allergy Immunol 2007; in press
Growth in CMA with AD
• 58 infants with CMA and AD (open challenge)
• 15 rice-based hydrolysate formula (RHF)
• 17 soy-based formula (SF)
• 26 extensively hydrolysed casein formula (eHCF)
• The choice of the formula for each infant was based on allergometric tests, clinical features at the beginning of the diet and age.
Savino A. Z-score of weight for age of infants with atopic dermatitis and cow’s milk allergy fed with a rice-hydrolysate formula during the first two years of life.
Acta Paediatrica 2005; 94 S449; 1-6
Savino A. Z-score of weight for age of infants with atopic dermatitis and cow’s milk allergy fed with a rice-hydrolysate formula during the first two years of life. Acta Paediatrica 2005; 94 S449; 1-6
Growth in CMA with AD
1. Lack of biochemical data 2. Small number of children
3. No acceptable diagnosis of CMA 4 No randomisation
“For this reason, it is difficult to draw clear conclusions”
Savino A. Z-score of weight for age of infants with atopic dermatitis and cow’s milk allergy fed with a rice-hydrolysate formula during the first two years of life.
Acta Paediatrica 2005; 94 S449; 1-6
Growth in CMA with AD:
Methodological limitations
Agostoni C, Fiocchi A, Riva E, Terracciano L, Sarratud T, Martelli A, Lodi F, D’Auria E, Zuccotti GV, Giovannini M. Growth of infants with IgE-mediated cow’s milk allergy fed different
formulas in the complementary feeding period. Pediatr Allergy Immunol 2007; in press
Research question: is the type of milk in the complementary feeding period (6 to 12 months of age) associated with differences in the increase of standardized growth indices in infants with CMA?
Subjects: Infants with Ig-E mediated CMA breastfed at least four months and weaned in the 5 to 6 months period
Randomisation:
a. soy-formula (n= 32)
b. casein hydrolysate (n = 31) c. rice hydrolysate (n = 30)
Non-randomized group: breastfed up to 12 months (n = 32).
WA, LA and WL z-scores at 6, 9 and 12 months of age
Growth in complementary feeding period
and type of formula
Flow diagram of subjects progress through the study
Agostoni C, Fiocchi A, Riva E, Terracciano L, Sarratud T, Martelli A, Lodi F, D’Auria E, Zuccotti GV, Giovannini M. Growth of infants with IgE-mediated cow’s milk allergy fed different
formulas in the complementary feeding period. Pediatr Allergy Immunol 2007; in press Infants BF for at least 4 months with CMA
diagnosis n = 160
BF at 6 months n = 52
15 subjects left the study
n = 5, soyÆ secondary sensitization within 2 ws n = 10 (6 RHy, 4 CHy)Æ
bad acceptance/poor compliance within 4 ws
Soy n = 32
CHy n = 31
RHy n = 30
20 introduced a formula at 7 – 11 months and left the study
BF n = 32 WA, LA and WZ at 6, 9 and 12 months of age Randomized to a formula at 5-6 months
(FF) n = 108 (37 Soy , 35 CHy, 36 RHy)
WA z-scores
Agostoni C. Growth of infants with IgE-mediated cow’s milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol 2007; in press
-70 -60 -50 -40 -30 -20 -10 0 10 20 30 40
0 6 9 12
months
Soy=32 CHy=31 Rhy=30 BF =32
LA z-scores
Agostoni C. Growth of infants with IgE-mediated cow’s milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol 2007; in press
-80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
0 6 9 12
months
Soy=32 CHy=31 Rhy=30 BF =32
WL z-scores
Agostoni C. Growth of infants with IgE-mediated cow’s milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol 2007; in press
-50 -40 -30 -20 -10 0 10 20 30
0 6 9 12
months
Soy=32 CHy=31 Rhy=30 BF =32
Six to twelve months differences for WA (∆ WA), LA (∆ LA) and WL (∆ WL) z-scores
Agostoni C. Growth of infants with IgE-mediated cow’s milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol 2007; in press
0.286 -.09
.21 .08
∆ WL -.18
0.548 .01
.24 .23
∆ LA .11
0.023 -.10
.18 b .16 b
-.16 a
∆ WA
P BF = 32
RHy = 30 CHy = 31
Soy = 32
Growth in complementary feeding period and type of formula
Agostoni C. Growth of infants with IgE-mediated cow’s milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol 2007; in press
