Food allergy diagnosis and intervention to improve children's health

Affecting 6-8% of children, food allergies can be life-threatening, and
especially common sources, such as peanut and cow*s milk, are extremely
difficult to avoid. In recent years, hospital admissions due to food
anaphylaxis have increased significantly from 1.2 to 4.0 per 100,000 people per
year. The main increase was seen in children <15 years of age with an annual
increase of 6.6 % from 2.1 to 9.2 admissions per 100,000. In children with
fatal anaphylaxis, milk was the causative allergen in 26% and peanut in 14% of
cases. The natural course of disease in children with peanut and cow*s milk
allergy differs. About 20% of young children with a peanut allergy will outgrow
this allergy by early adulthood. In children with an IgE-mediated cow*s milk
allergy about 50% will develop tolerance at the age of 5 years and 75% is
tolerant by early adolescence.

At present, there is no available, reimbursed treatment for food allergy in the
Netherlands. Therefore, there is a large unmet need for a safe treatment
intervention that increases tolerance levels to ensure that affected children
do not experience severe reactions to accidental exposure.
Oral immunotherapy (OIT) with food allergens is not a common treatment yet for
children with food allergies. Peanut allergic children treated with OIT show
good results regarding desensitization (no reaction while on daily peanut
intake); however, sustained unresponsiveness (the ability to still tolerate
peanut after a short period of avoidance) is less successful. Sustained
unresponsiveness is more successful in younger children and in children with
lower specific IgE to peanut. All studies investigating OIT are performed in
severe peanut allergic children, diagnosed using an oral food challenge (OFC)
test. However, not much is known about OIT in peanut allergic children with a
higher threshold to peanut. Oral food challenges are performed in the
diagnostic work-up to evaluate the threshold and the severity of the reaction.
At present, in the Erasmus MC-Sophia Children*s hospital / KinderHaven,
children with a mild allergic reaction to peanut after a relatively high
threshold (>2 peanuts) are offered to either avoid peanut or to introduce small
amounts of peanut according an introduction scheme with peanut flips (see
Appendix A). In this group of peanut allergic children, controlled, daily
intake of peanut snacks has shown promising results for tolerability.
Cow*s milk allergic children can benefit from introduction of baked milk (milk
in baked form, e.g. in cookies). Baked milk is less allergenic than pure dairy
and can be tolerated by approximately 70% of cow*s milk allergic children,
advancing tolerance to pure milk. Children with severe IgE-mediated symptoms to
dairy will usually first have an OFC with baked milk. If baked milk is
tolerated, it can be introduced on a daily base in their diet to improve
tolerance for cow*s milk. However, not all children are tolerant to baked milk.
In these cases the child needs to maintain a strict cow*s milk free diet.

The immunological mechanisms behind allergen immunotherapy or food introduction
are not completely understood, and there are no immunological markers to
predict outcome. Using state-of-art allergen-specific immunological
measurements, we have previously identified new immunological markers that
change early during successful immunotherapy for ryegrass pollen and bee venom.
In the current study, we will apply these measurements to investigate the
immune system in children with a peanut or cow*s milk allergy (as these have
distinct natural courses of disease) and evaluate immunological changes during
intervention through daily, controlled food intake in order to increase
tolerance.

Primary Objective:
- Evaluate changes in immune response during oral immunotherapy with either
peanut or baked milk in children with a mild peanut or cow*s milk allergy

Secondary Objective:
- Compare the immunological changes at baseline and over time between mild
peanut allergic children treated with peanut snacks versus severe peanut
allergic children remaining on a peanut free diet, as well as mild cow*s milk
allergic children treated with baked milk versus severe cow*s milk allergic
children remaining on a cow*s milk free diet.

This is a prospective single-center observational research study to investigate
immunological changes in mild and severe peanut and cow*s milk allergic
children who are on different diets.

Peanut allergic children: According to regular care (as described in the
introduction), children with a peanut allergy undergo an OFC with peanut to
evaluate the threshold and severity of their reaction to peanut. In case of a
mild reaction towards a relatively large dose of peanut (>= 300 mg peanut
protein which is equal to 2 peanuts), patient and parents are informed to start
introduction of peanut (according to a specific scheme) mild peanut allergy
group, n=30). If they had a reaction < 2 peanuts or if they have had a severe
reaction after a larger dose (treatment needed with adrenaline) they remain on
a diet free of peanut (severe peanut allergy group, n=15).

Cow*s milk allergic children: According to regular care (as described in the
introduction) children with a cow*s milk allergy undergo an OFC with baked milk
to evaluate the threshold and severity to baked milk. If they tolerate baked
milk or have a mild reaction after a relatively large amount of baked milk (>=
300 mg cow*s milk protein), patients and parents are advised to introduce baked
milk in the diet (according to an introduction scheme of baked milk) (mild
cow*s milk allergy group, n=30). In case of a reaction < 300 mg of cow's milk
protein or if they have had a severe reaction after a larger dose (treatment
needed with adrenaline) they remain on a strict cow*s milk free diet (severe
cow's milk allergy group, n=15).

Following the diagnosis and treatment decisions as described above (regular
patient care), all children (mild and severe allergic children) will be asked
to participate in this prospective study in order to evaluate immunological
changes between mild and severe forms of food allergy and the effect of
treatment over time. Enrolment in this study will not impact on their treatment
nor will it affect treatment decisions. All children will be asked to donate
blood (9-18 mL) before start of the study at t=0 (can be combined with regular
diagnostic testing before OFC), and at 4 and 12 months. At 12 months an OFC
with either peanut or cow*s milk will be repeated.

There is no perceived risk to the participants, investigators or institution.
Participants are having an additional 9-18 mL of blood sample
taken at 3 time points along with routine care. All blood sampling will follow
Good Clinical Practice.
This research will not provide a direct therapeutic benefit to the participant.
However, we hope it will contribute by improving diagnosis,
monitoring and treatment of allergies in the future. The project will aid in
identifying potential biomarkers of allergy and treatment options.
This project will have positive impacts in the field of Allergy by potentially
improving patient diagnosis and treatment.