The Effect of Per Oral Immunotherapy Treatment in Severe IgE Mediated Milk, Peanut and Egg Allergy in Adults
Phase: NA
Conditions: Food Allergy
Sponsor: Helsinki University Central Hospital

 
1
 
 
 
- The effect of per oral immunotherapy treatment in severe IgE mediated  
milk, peanut and egg allergy in adults. 
 
NCT03361072 
 
7 May 2017 

 
2
Paula Kauppi  
 
 
Version 2 
HUS Ethical Comittee 
Supplement 
Per oral immunotherapy treatment in severe food allergy in adults (Aikuisten vaikean 
ruoka-allergian siedätyshoito) 7 May 2017 
 
 
 
- The effect of per oral immunotherapy treatment in severe IgE mediated  
milk, peanut and egg allergy in adults. 
 
 
 
Summary 
 
Prospective study on per oral immunotherapy treatment in IgE mediated milk, peanut or 
egg allergy in adults (>18 year olds).   
 
 
1. Background  
 
In Finland, the estimated prevalence of physician-diagnosed food allergy in 1-4 year old 
children is 9%, and the most common allergen is milk (Pyrhönen K 2009). The overall food 
allergy has been reported to be 3.7% (Sicherer SH 2006). Hen’s egg allergy is among the 
most common food allergies in childhood. In addition, it predicts later development of 
allergic disease such as asthma. Most of the egg and milk allergy is transient and 
disappears in childhood. Currently, the standard of care for food allergy includes strict 
allergen avoidance. However, oral immunotherapy (OIT) has been under investigation in 
children milk, egg, and wheat allergy. Previously, induction of clinical egg tolerance has 
been reported with egg oral immunotherapy in children aged from 3 to 13 years (Vickery 
BP 2010). In adults, strict avoidance is still the standard care but there is also growing 
interest in treatment of severe food allergy with oral immunotherapy or anti-IgE (Sicherer 
SH 2006, Sicherer SH 2010). 
 
In respiratory allergy, the administration of allergen immunotherapy is known to alter the 
natural history of allergic disease and to induce tolerance against allergens (Durham SR 
1999). Oral immunotherapy has been introduced also into treatment of allergic rhinitis with 
good results. However, there is very little information on oral immunotherapy in severe 
food allergy in adults and no information on the effect of oral immunotherapy on asthma in 
adults.  
 
In the study of Buchanan et al., 7 subjects were enrolled into egg oral immunotherapy study 
(Buchanan AD 2007). All the study subjects (mean age 3.7 years) completed the study. All 
the study subjects had atopic dermatitis and 43% had asthma. All patients had history of 
egg-ingestion reactions but none had a history of anaphylaxis to egg. Cumulative egg dose 
at first treatment varied between 17.6-1012 mg and the initial daily home dose varied 

 
3
between 25-200 mg. Mean baseline egg-specific IgE-level in the study was 24 kU/L (SD 
44 kU/L) and 24-month level 12 kU/L (SD 19 kU/L).  
 
In the study of Vickery et al., 8 patients were enrolled into egg oral immunotherapy study 
(Vickery BP) (median age 5 years). Of these, 75% had atopic dermatitis and 38% asthma. 6 
of these 8 patients completed the study. 83% of these six patients developed allergic 
symptoms during the initial dose escalation day, and 50% developed allergic symptoms 
during the build-up phase. The mean baseline egg-white specific IgE level was 25 kU/L. 
 
Allergen components Ara h2 and Ara h6 have been estimated to be the best predictive 
components for symptomatic peanut allergy. In studies on  adults, the threshold for 
allergic symptoms in the challenge tests pre-OIT have varied from 5-50 mg  or from 6-
100 mg. In the study of Syed et al. symptom threshold in four adult patients (18- 45 
years) before OIT were 6mg (peanut specific IgE 20.9 kU/l), 25mg (peanut specific IgE 
20.6 kU/l), 100mg (peanut specific IgE 264 kU/l), 50mg (peanut specific IgE 149 kU/l).  
 
In a Cochrane review on egg allergy it was agreed that OIT can desensitize a large 
number of egg-allegic patients but the long-term tolerance was unknown. However, 
sustained unresponsiveness in food allergy has been reported to increase by longer 
duration of immunotherapy in egg allergy. In a study with 5-18 year old children, 
sustained unresponsiveness increased from 27.5% (immunotherapy for two years) to 
50.0% when OIT was continued for four years.  
 
In the same Cochrane review side effects were brought into discussion since sixty nine 
per cent of the participants presented with mild-to-severe adverse effects during OIT. 
Five of the 100 participants required epinephrine. This safety issue has been further 
studied in peanut allergy OIT, where 352 treated patients received 240 351 doses of 
peanut and experienced 95 reactions that were treated with epinephrine. Only three 
patients received two doses of epinephrine and none required more intensive treatment. A 
total of 298 patients achieved the maintenance dose (thus with a success rate of 85%). In 
addition to OIT also sublingual immunotherapy has been studied in peanut allergy. OIT 
was reported to be far more effective than sublingual therapy but also with more adverse 
reactions.   
 
In milk allergy, accordingly, OIT was more effective than sublingual therapy but also 
with more adverse reactions.  Only one of the 10 patients receiving sublingual therapy 
passed the milk challenge after immunotherapy. With oral immunotherapy six out of ten 
(sublingual therapy first and then continued with oral immunotherapy) and eight out of 
ten passed the milk challenge after OIT. In a Cochrane review on OIT for milk allergy, 
the conclusions were similar to peanut allergy. OIT is effective but is associated with side 
effects and long-term tolerance has not been established.  
 
 
This is the second part of the oral immunotherapy study in adults at Skin and Allergy 
Hospital. The preliminary results for oral immunotherapy since 2012 are presented in the  
paragraph 4. 

 
4
 
 

 
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3. Study plan 
 
3.1. Subjects 
 
We study 100 subjects. All subjects are adults having no other severe chronic diseases.  
 
(a) 
30 patients ( >18 year olds) that have IgE mediated severe milk allergy 
 
(b) 
30 patients ( >18 year olds) that have IgE mediated severe peanut allergy 
 
(c) 
30 patients ( >18 year olds) that have IgE mediated severe egg allergy 
 
(d) 
up to 10 patients whose oral immunotherapy against milk allergy has started as 
individually given treatment for clinical need 
 
 
 
The diagnosis of milk allergy is verified with positive history, skin prick test (>5 mm), egg 
and milk allergen specific IgE antibodies (>5.0 kU/l). In addition, food allergy is verified 
with an open label (milk allergy) or blind (peanut and egg allergy) allergen specific 
challenge test.  
 
Atopic subjects may have simultaneously other allergies. Intermittent mild asthma, and 
mild and moderate persistent asthma are tolerated and treatment with inhaled steroids and 
other asthma medication is allowed. Atopic subjects may have additional skin symptoms. 
Quality of life, anxiety and patient history data is collected by questionnaires. All patients 
undergo a spirometry with a bronchodilatator test, fractionale exhaled nitric oxide and a 
methacholine challenge before and a year after oral immunotherapy. Those with test results 
diagnostic for asthma (FEV1 response in a bronchodilator test > 12%/200ml and/ or PD20 
<600 µg/ml methacholine in methacholine provocation test) (Crapo) are treated with 
asthma medication before hyposensibilisation treatment is started.   
 
Exclusion criteria: adults with instabile cerebrovascular or heart disease, active 
autoimmune disease or cancer, or current use of betablocking agents. In addition, poorly 
controlled asthma or FEV1 < 70% (FEV1< -2SD)  are not tolerated.  
 
 
3.2. Allergen specific challenge test 
 
In egg allergy, increasing doses are given every 60 minutes during the egg or peanut 
allergen challenge. The protocol is done in a double-blind manner (day A, day B and one to 
seven days in between the two challenge days).  
 
 
 

 
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3.2.1. Food challenges. 
 
For milk allergy, increasing doses are given every 60 minutes (5 drops of  milk, 1 ml of 
milk, 10 ml of milk, 50ml  and 80 ml of milk). The challenge can be done as an open step-
wise challenge during two days (Vlieg-Boerstra 2011).  
 
The given doses in the peanut allergen challenge test are 5mg, 25mg, 50mg, 200mg and 
1000mg of peanut protein. The 50mg of peanut protein is similar to ¼ peanut. The 
maximum dose of 1000mg peanut protein is approximately 5 peanuts. 
 
Accordingly, the challenge test in egg protein allergy is started with 5mg egg protein 
(150mg of meat ball) and then followed by 25mg of egg protein, 50mg, 500mg and 
1000mg of egg protein.  
 
The patient is followed for signs and symptoms of allergic reaction for two hours after the 
last dose of allergen. In the case of allergic reaction, the patient is treated with normal 
procedures: 0,5 mg epinephrine im in anaphylaxis, followed by corticosteroids 
(prednisolon 40mg po, methylprednisolon 40-80mg iv), cetirizin 10mg po and 0,9% NaCl 
iv, salbutamol and ipratropiumbromide as inhalation (Atrodual® 2,5ml)(Akuuttihoito-
opas).  
 
 
3.3. Study protocol 
 
 
 
In milk allergy, increasing doses are given using the following schedule. If the subject does 
not tolerate a given dose and symptoms are mild, then that dose or the previously tolerated 
one is repeated, and the protocol proceeds as outlined. If the subject experiences significant 
symptoms, then the protocol is stopped, and the highest tolerated dose is used as the 
starting daily one. 
 
The schedule for oral immunotherapy against milk allergy:  
 
 
Day no 
Milk, diluted (1:10 
drops) 
Milk, 
dropps 
Milk, 
ml 
1 
5 
 
 
7 
10 
 
 
14 
20 
 
 
21 
 
5 
 
28 
 
10 
 
35 
 
20 
 
42 
 
 
1 
49 
 
 
2 
56 
 
 
5 

 
7
63 
 
 
10 
70 
 
 
20 
84 
 
 
40 
98 
 
 
80 
112 
 
 
160 
126 
 
 
200 
 
 
Similarly, in egg and peanut allergy, increasing doses are given using the predefined 
schedule. If the subject does not tolerate a given dose and symptoms are mild, then that 
dose or the previously 
tolerated one is repeated, 
and 
the 
protocol 
proceeds as outlined. If 
the subject experiences 
significant 
symptoms, 
then the protocol is 
stopped, and the highest 
tolerated dose is used as 
the starting daily one. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Product 
Week 
Dose 
 
Protein  
(mg)  
Egg protein 
liquid 
1mg/ml 
(vihreä) 
1  
0,1 ml 
0,1 
2  
0,2 ml 
0,2 
3  
0,4 ml 
0,4 
 
4  
1 ml 
1  
6 
2 ml 
2  
Egg protein 
8 hoitaja 
0,4 ml 
4 

 
8
The schedule for oral 
immunotherapy against 
egg allergy:  
 
 
liquid 
10mg/ml 
(punainen) 
10  
0,8 ml 
8 
12  
1,2 ml 
12 
14  
2,5 ml 
25 
16 
5 ml 
50 
18   
10 ml 
100 
20  
20 ml  
200 
Egg protein 
 
22    
1 dose (spoon) 
350 
24 
2 dose 
600 
26 
3 dose 
1050 
32  
3 dose 
1050 

 
9
 
 
 
 
The schedule for oral immunotherapy against peanut allergy:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Product 
Week 
Tea spoon or  
number/day 
(1 tl=2g) 
Protein  
(mg)  
Margarine 
contain 
peanut 
protein 
1    vo 
1 teespoon 
0,1 
2  
2 
0,2 
3  
4 
0,4 
 
4   vo 
1 
1  
6 
2 
2  
8 
3 
3  
10   vo 
5 
5  
12 
6 
6  
 
14   vo 
1 
10 
16 
2,5 
25 
18    
5 
50 
Peanut 
20  vo 
¼ peanut 
50 
22  vo 
½  
100 
24 
¾  
150 
26 
1 peanut 
200 
28 vo 
1,5  
300 
30 
2  
400 
32 vo 
3 peanuts 
600 
34 
4 
800 

 
10
All the patients undergoing oral immunotherapy are prescribed with emergency medication 
such as antihistamine tablets, prednisolon tablets (40mg for three days in adults), 
epinephrine autoinjector (300 µg per dose) and salbutamol or terbutaline inhalator. 
 
After escalating doses of allergen during the first phase of oral immunotherapy, the 
treatment is continued with the highest tolerated maintenance dose until one year of 
therapy. Spirometry with a bronchodilatator test, fractionale exhaled nitric oxide, a 
methacholine challenge and immunological parameters are studied a year after oral 
immunotherapy. 
 
After one year of oral immunotherapy we have given the option to be followed further if 
the patient is willing to continue the immunotherapy. Spirometry with a bronchodilatator 
test, fractionale exhaled nitric oxide, and immunological parameters are studied once a year 
if the oral immunotherapy continues.  
 
3.3. 3. Immunological parameters 
Serum samples are taken for allergen component evaluation. Egg white specific IgE and 
ovomucoid and ovalbumin specific IgE (Pharmacia Diagnostics AB, Uppsala, Sweden) 
before and after one year of oral immunotherapy for egg allergic patients. Casein, -
lactalbumin and ß2-lactoglobulin specific IgE are studied for milk allergy before and after 
one year of immunotherapy. Similarly, IgE against peanut, Ara h 2, Ara h 3, Ara h 8, and 
Ara h 9 are studied in peanut allergy. 
 
 
 
3.3. 4. Statistical methods 
Frequencies, means, medians, proportions and standard deviations are calculated for all the 
data. Pairwise IgE results, methacholine challenge test results are analyzed using the t-test 
or Wilcoxon signed rank test. The published reports on milk oral immunotherapy have 
been done in rather small number of study subjects, of which all have been children. The 
estimated numbers (50) of study subjects in this study tolerate also withdrawing of some of 
the subjects. 

 
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4. Preliminary results since 2012 
 
 
Milk allergy 
 
Eight patients (62 %) have continued oral milk immunotherapy from 4 – 96 months with 
a mean of 23.5 months. Five (38 %) patients in total have discontinued the desensitization 
due to allergic reactions (4) or pregnancy (1). The dose range of oral immunotherapy at 
the current time point is from 3 ml (initiation phase) to 130ml (maintenance dose). 
Maximum dose has been 200ml. Six patients have reached the maintenance dose while 
two are still on the initiation phase. Overall milk and casein IgE levels have decreased in 
patients receiving the maintenance dose, indicating a possible decease in immunologic 
reactions against the allergen. 
 
Egg allergy  
 
Three adult patients have received oral immunotherapy because of severe egg allergy. All 
these patients are women and their symptom history for egg allegy had persisted already 
since childhood. Two of them have asthma persisted since childhood.  Of these, two 
patients have continued successfully the therapy.  However, exacerbation of atopic eczema 
has led to decreasing the dose of boiled egg white.  With one patient the oral 
immunotherapy was discontinued because of exacerbation of atopic eczema after one year 
of immunotherapy. The two patients with beneficial immunotherapy results have been 21 
and 20 years old women, when the one with cessaction of therapy was 40 year old. 
 
Peanut allergy 
 
In all peanut allergic patients, the Ara h2 level was increased before the immunotherapy 
with results ranging from 0.5-324 kU/l. The threshold for allergic symptoms in the 
challenge tests pre-OIT (oral immunotherapy) has varied from 5 to 50 mg. Oral 
immunotherapy has led to increased allergen tolerance by means of increasing the 
threshold for symptoms in our six adult patients. However, one patient had an 
anaphylactic reaction during OIT at the dose of 50 mg; at the initiation phase and the 
dose was given at hospital. This prompts careful patient selection and follow-up during 
OIT for adult patients.  
 
 
4. Study group 
 
 
Paula Kauppi, MD, PhD, Chief Specialist of the Adult Allergy Department, Skin and 
Allergy Hospital, Helsinki University Central Hospital 
 
Auli Hakulinen, MD, Skin and Allergy Hospital, Helsinki University Central Hospital 
Timo Helin, MD, Skin and Allergy Hospital, Helsinki University Central Hospital 
Helena Voutilainen, MSc, nutritionist 
Hilkka Viiitanen, MD, Skin and Allergy Hospital, Helsinki University Central Hospital 

 
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Jarkko Mäntylä, MD, in trainee, Skin and Allergy Hospital and Heart and Lung Center, 
Helsinki University Hospital 
Tuuli Thomander, Medical student, University of Kuopio 
 
5. Budget 
 
 
 
Costs of patient visits are managed by normal clinical work. 
 
 
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