Cow's milk allergy
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Serious differences in extensively hydrolysed food for the treatment of cow’s milk allergy (CMA)
Not all extensively hydrolysed infant foods (eHF) are equally effective! This is the result of an analysis of different samples of commercial eHF, for the therapy of (CMA).
For infants with a CMA, eHF is the recommended first choice. It is assumed that the safety and suitability of eHFs has been thoroughly tested. However, documented allergic responses to eHFs have led to the hypothesis that some products may not be sufficiently hydrolysed and/or may be contaminated with cow‘s milk protein.
76 samples of commercially available whey and casein-based eHFs (eHF-W and eHF-C) from nine different manufacturers from different countries were tested. The following parameters were analysed:
Molecular weight distribution of peptides
Immunogenic peptides or proteins (IPP) derived from beta-lactoglobulin (BLG) or casein
The in vitro allergenicity induced by BLG
Results:
The eHFs were divided into three groups according to their content of immunogenic
peptides > 1,200 Dalton (DA): <5%, 5-15% and >15% (Fig. 1). 1,200 Da serves as a limit for the size of the peptides capable of binding an IgE molecule, which triggers the release of inflammatory mediators and cytokines.
For three eHFs there was a significant difference in the MW profile between or within products of the same brand.
In 22 of the eHFs a residual content of BLG-containing immunogenic peptides or proteins was found. 1 eHF-C and 2 eHF-W products tested positive for case in-derived immunogenic proteins and peptides.
In 9 eHFs (2 eHF-C / 7 eHF-W) the content of peptides >1,200 Da could be associated with both the residual content of BLG-immunogenic peptides or proteins and the BLG-induced in vitro allergenicity.
Conclusion: Significant differences between the eHFs investigated were found, with large variations in the MW profiles of the peptides, the residual content of BLG and casein IPP and the BLG-induced in vitro allergenicity. It is necessary to define the requirements for therapeutic eHFs more precisely and to establish stricter quality controls during the entire production process as well as standardised analytical methods.
Nutten S et al., Allergy 2019
Growth with a cow’s milk allergy
Children with a cow‘s milk allergy (CMA) are smaller and weigh less than those
who suffer from peanut or walnut allergies. This fact remains until early adolescence. This finding is the result of a recent longterm
study.
The data of paediatric patients with a persistent IgE-mediated allergy to cow‘s milk, peanuts or tree nuts were examined. The diagnosis was based on clinical symptoms, food specific IgE levels, prick tests and provocation tests. To be admitted, the children had to have at least one clinical examination during three defined time frames between 2 and 12 years, during which height and weight were also recorded.
Between November 1994 and March 2015, 191 children were recorded,111 with CMA, 80 with nut allergies (61% and 51.3% male). The difference in size was more pronounced at the age of 5–8 and 9–12 years. For 53 children, whose data was
recorded even >13 years, the difference was even more striking.
One explanation could be that children affected by CMA often have other allergies and therefore tend to avoid foods other than milk. Although the handling of CMA improves, it usually disappears during childhood. However, in children with persistent forms, greater attention should be paid to age-appropriate growth. Further studies are needed to find out which other factors play a role and to what extent the differences in height and weight remain in adulthood.
Robbins et al., J Allergy 2020
HMO-enriched eHF for CMA is well tolerated
The aim of a study was to assess whether an extensively hydrolysed formula (eHF) enriched with 2 human milk oligosaccharides (HMO) is well tolerated by infants with cow‘s milk allergy and supports normal growth.
For the RCT study, infants, 0–6 months, with diagnosed CMA were enrolled at 44 sites. The test diet was a whey-based eHF with 2 Fucosyllactose (2‘FL) and Lacto-N-neotetraose (LNnT), protein content 2.20g/100 kcal. A currently marketed eHF (Althéra®, Nestlé Health Science) without HMO, protein content 2.47 g/100 kcal,
served as a control food.
The infants received a milk-protein-free supplementary diet from the age of 4–6 months. Weight, height and head circumference were monitored monthly from admission (V0) to follow-up after 4. The primary study outcome was weight gain per day from V0 to V4. Secondary endpoints were Z-scores for weight for age, height for age and head circumference for age, as well as clinical tolerance, number of adverse events (AE) and drug use up to 12 months of age.
194 of the children examined were randomly switched to test (n=97) or control food (n=97). The mean age at V0 was 3.2 ± 1.7 months; 99 (51.0%) were male. At V4 the per-protocolcohort (PP) included 137 infants (73 test, 64 control). The daily weight gain of the test diet was no less from V0 to V4 than that of the control diet (19.38 g/d vs. 20.12 g/d; p= 0.0049). At no time were there significant group differences for any of the anthropometric parameters.
In the study group, the rate of lower respiratory tract infections in the test group between V0 and V6 was reduced by 38.1% (12/73 vs. 17/64); upper respiratory tract infections were reduced by 14.8% (35/73 vs. 36/64). Otitis media was reduced by 100% (0/73 vs. 7/64). The use of antibiotics was 20.3% lower in the study group (20/73 vs. 22/64) and of antipyretics 24.9% (30/73 vs. 35/64). However, the small sample size does not allow stable statistical conclusions about these secondary outcomes.
Conclusion: The infants fed with the HMO enriched test formula achieved normal growth.
The PP analysis indicates a reduced risk of respiratory tract and ear infections as well as a reduced need for antibiotics and antipyretics.
Vandenplas Y et al., PAAM 2019
Safety of AF food in practice
Special foods based on amino acids (AF)
are used for children suffering from cow‘s
milk allergy (CMA), multiple food allergies
or malabsorption. They are recommended by
the professional societies when extensively
hydrolysed foods (eHF) are not effective.
The aim of a first post-market safety study with AF foods, was to examine the frequency and type of adverse events (AE) in children receiving AF foods. The second objective was to study the demographic and clinical characteristics of children with AE.
The study took place between February 2017 and May 2018 at 30 locations in the USA. Children at ≤ 12 months were enrolled and with a gestational age > 37 weeks. They received a uniform AF food (Alfamino® Infant) for 4 months. The data of 144 children were collected at the beginning, 88 could be followed over the 4 months. 100 (69%) had a diagnosed CMA, 84 of them were classified as severe CMA due to a medical diagnosis, anaphylaxis or the unsuccessful eHF use.
6 severe AE were reported in 6 children (3 of them with severe CMA), for none of the SAEs a possible or definite association with the study food was seen.
SE were reported in 58 (40%) children (31 of them with severe CMA = 90 SE). 122 AU (78%) were reported as unrelated, 14 (9%) as unlikely, 17 (11%) as possible and only 1 (<1 %) as definite to AF food.
Vomiting and constipation were the most frequently mentioned AE in a possible connection to food. No anaphylactic case was observed during the study.
Of the interviewed nursing staff, 91 of 114 were satisfied with Alfamino® (80%).
This prospective postmarket study of an AF diet showed no unexpected safety problems in children with CMA, severe CMA or malabsorption in both the general and severe CMA group.
Cekola P et al., Annual Meeting der NASPGHAN, 2019
Not all extensively hydrolysed infant foods (eHF) are equally effective! This is the result of an analysis of different samples of commercial eHF, for the therapy of (CMA).
For infants with a CMA, eHF is the recommended first choice. It is assumed that the safety and suitability of eHFs has been thoroughly tested. However, documented allergic responses to eHFs have led to the hypothesis that some products may not be sufficiently hydrolysed and/or may be contaminated with cow‘s milk protein.
76 samples of commercially available whey and casein-based eHFs (eHF-W and eHF-C) from nine different manufacturers from different countries were tested. The following parameters were analysed:
Molecular weight distribution of peptides
Immunogenic peptides or proteins (IPP) derived from beta-lactoglobulin (BLG) or casein
The in vitro allergenicity induced by BLG
Results:
The eHFs were divided into three groups according to their content of immunogenic
peptides > 1,200 Dalton (DA): <5%, 5-15% and >15% (Fig. 1). 1,200 Da serves as a limit for the size of the peptides capable of binding an IgE molecule, which triggers the release of inflammatory mediators and cytokines.
For three eHFs there was a significant difference in the MW profile between or within products of the same brand.
In 22 of the eHFs a residual content of BLG-containing immunogenic peptides or proteins was found. 1 eHF-C and 2 eHF-W products tested positive for case in-derived immunogenic proteins and peptides.
In 9 eHFs (2 eHF-C / 7 eHF-W) the content of peptides >1,200 Da could be associated with both the residual content of BLG-immunogenic peptides or proteins and the BLG-induced in vitro allergenicity.
Conclusion: Significant differences between the eHFs investigated were found, with large variations in the MW profiles of the peptides, the residual content of BLG and casein IPP and the BLG-induced in vitro allergenicity. It is necessary to define the requirements for therapeutic eHFs more precisely and to establish stricter quality controls during the entire production process as well as standardised analytical methods.
Nutten S et al., Allergy 2019
Growth with a cow’s milk allergy
Children with a cow‘s milk allergy (CMA) are smaller and weigh less than those
who suffer from peanut or walnut allergies. This fact remains until early adolescence. This finding is the result of a recent longterm
study.
The data of paediatric patients with a persistent IgE-mediated allergy to cow‘s milk, peanuts or tree nuts were examined. The diagnosis was based on clinical symptoms, food specific IgE levels, prick tests and provocation tests. To be admitted, the children had to have at least one clinical examination during three defined time frames between 2 and 12 years, during which height and weight were also recorded.
Between November 1994 and March 2015, 191 children were recorded,111 with CMA, 80 with nut allergies (61% and 51.3% male). The difference in size was more pronounced at the age of 5–8 and 9–12 years. For 53 children, whose data was
recorded even >13 years, the difference was even more striking.
One explanation could be that children affected by CMA often have other allergies and therefore tend to avoid foods other than milk. Although the handling of CMA improves, it usually disappears during childhood. However, in children with persistent forms, greater attention should be paid to age-appropriate growth. Further studies are needed to find out which other factors play a role and to what extent the differences in height and weight remain in adulthood.
Robbins et al., J Allergy 2020
HMO-enriched eHF for CMA is well tolerated
The aim of a study was to assess whether an extensively hydrolysed formula (eHF) enriched with 2 human milk oligosaccharides (HMO) is well tolerated by infants with cow‘s milk allergy and supports normal growth.
For the RCT study, infants, 0–6 months, with diagnosed CMA were enrolled at 44 sites. The test diet was a whey-based eHF with 2 Fucosyllactose (2‘FL) and Lacto-N-neotetraose (LNnT), protein content 2.20g/100 kcal. A currently marketed eHF (Althéra®, Nestlé Health Science) without HMO, protein content 2.47 g/100 kcal,
served as a control food.
The infants received a milk-protein-free supplementary diet from the age of 4–6 months. Weight, height and head circumference were monitored monthly from admission (V0) to follow-up after 4. The primary study outcome was weight gain per day from V0 to V4. Secondary endpoints were Z-scores for weight for age, height for age and head circumference for age, as well as clinical tolerance, number of adverse events (AE) and drug use up to 12 months of age.
194 of the children examined were randomly switched to test (n=97) or control food (n=97). The mean age at V0 was 3.2 ± 1.7 months; 99 (51.0%) were male. At V4 the per-protocolcohort (PP) included 137 infants (73 test, 64 control). The daily weight gain of the test diet was no less from V0 to V4 than that of the control diet (19.38 g/d vs. 20.12 g/d; p= 0.0049). At no time were there significant group differences for any of the anthropometric parameters.
In the study group, the rate of lower respiratory tract infections in the test group between V0 and V6 was reduced by 38.1% (12/73 vs. 17/64); upper respiratory tract infections were reduced by 14.8% (35/73 vs. 36/64). Otitis media was reduced by 100% (0/73 vs. 7/64). The use of antibiotics was 20.3% lower in the study group (20/73 vs. 22/64) and of antipyretics 24.9% (30/73 vs. 35/64). However, the small sample size does not allow stable statistical conclusions about these secondary outcomes.
Conclusion: The infants fed with the HMO enriched test formula achieved normal growth.
The PP analysis indicates a reduced risk of respiratory tract and ear infections as well as a reduced need for antibiotics and antipyretics.
Vandenplas Y et al., PAAM 2019
Safety of AF food in practice
Special foods based on amino acids (AF)
are used for children suffering from cow‘s
milk allergy (CMA), multiple food allergies
or malabsorption. They are recommended by
the professional societies when extensively
hydrolysed foods (eHF) are not effective.
The aim of a first post-market safety study with AF foods, was to examine the frequency and type of adverse events (AE) in children receiving AF foods. The second objective was to study the demographic and clinical characteristics of children with AE.
The study took place between February 2017 and May 2018 at 30 locations in the USA. Children at ≤ 12 months were enrolled and with a gestational age > 37 weeks. They received a uniform AF food (Alfamino® Infant) for 4 months. The data of 144 children were collected at the beginning, 88 could be followed over the 4 months. 100 (69%) had a diagnosed CMA, 84 of them were classified as severe CMA due to a medical diagnosis, anaphylaxis or the unsuccessful eHF use.
6 severe AE were reported in 6 children (3 of them with severe CMA), for none of the SAEs a possible or definite association with the study food was seen.
SE were reported in 58 (40%) children (31 of them with severe CMA = 90 SE). 122 AU (78%) were reported as unrelated, 14 (9%) as unlikely, 17 (11%) as possible and only 1 (<1 %) as definite to AF food.
Vomiting and constipation were the most frequently mentioned AE in a possible connection to food. No anaphylactic case was observed during the study.
Of the interviewed nursing staff, 91 of 114 were satisfied with Alfamino® (80%).
This prospective postmarket study of an AF diet showed no unexpected safety problems in children with CMA, severe CMA or malabsorption in both the general and severe CMA group.
Cekola P et al., Annual Meeting der NASPGHAN, 2019
