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Running head: AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHEARPY

An Integrative Review: Effects of Oral Immunotherapy

Brooke Reamer
Bon Secours Memorial College of Nursing
Nursing Research
NUR 4222
Dr. Perkins
December 1, 2015
I pledge I have neither given nor received aid on this assignment.

AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

Abstract
The goal of this paper is to produce an integrative review of the effects of oral
immunotherapy on cow milk and peanut allergy symptoms in school age children. Food allergy
is a common and severe problem for many children, and possible treatments such as oral
immunotherapy are being explored. The research design of this undertaking is an integrative
review. Literature and peer-reviewed articles were obtained from database searches, notably
EBSCO. The search yielded numerous articles, but only five that met inclusion criteria were
utilized. All five articles demonstrated support of the PICOT question, and results showed the
effectiveness and safety of oral immunotherapy. The researcher was limited in that the review
could only reference five articles. The researcher was also an inexperienced undergraduate
nursing research student. This was the first integrative review undertaken by the researcher.
Future research would include more extensive use of articles and exploration of long term studies
of oral immunotherapy treatment.

AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

An Integrative Review: Effects of Oral Immunotherapy
The purpose of this paper is to review the literature and research related to the effects of
oral immunotherapy on peanut and milk allergy throughout immunotherapy treatment in school
age children. Food allergy is a common health concern, and it affects nearly four percent of
children in industrialized countries (Varshney, 2011). Adverse reactions include symptoms from
urticaria to anaphylactic shock. Treatment usually consists of avoiding allergens and having
epinephrine available in case of accidental exposure. Researchers are exploring other treatment
options, such as oral immunotherapy, in which increasing amounts of an allergen are ingested by
people with IgE-mediated allergy. Since this form of treatment is relatively new, researchers
must determine its efficacy and safety. The researcher in this study is interested to explore the
effects of oral immunotherapy on food allergies. The proposed PICOT question is: In school age
children, what is the effect of oral immunotherapy on peanut and milk allergy symptoms
throughout the immunotherapy treatment?
Research Design, Search Methods, & Search Outcomes
The research design is an integrative review conducted by a research student in an
undergraduate nursing program. The researcher used several databases from the online library of
Bon Secours Memorial College of Nursing, including PubMed, EBSCO, Ovid, and the American
Academy of Pediatrics Journals. EBSCO was the most effective search method and yielded the
most accurate articles. Search terms used were children, oral immunotherapy, and food
allergy. The EBSCO search yielded 13,517 articles, which had to be narrowed down using
additional terms, such as peanut allergy and milk allergy. Articles were also limited to the
past five years, which narrowed the search. The researcher selected articles based on relation to

AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

the PICOT question. Inclusion criteria of articles were sample of school age children, use of oral
immunotherapy, and use of either cow milk or peanut protein as independent variables. The
researcher excluded articles that did not meet these criteria and narrowed the search to five
quantitative articles pertaining to the PICOT question.
Findings/Results
The five peer-reviewed articles yielded results that support the efficacy and safety of oral
immunotherapy in cow milk and peanut allergy in school age children (Nozawa, Okamoto,
Moverare, Borres, & Kurihara, 2014; Salmivesi, Korppi, Makela, & Paassilta, 2012; Savilahti et
al., 2014; Varshney et al., 2011; & Yeung, Kloda, McDevitt, Ben-Shoshan, & Alizadehfar, 2012).
Table 1 shows a summary of the reviewed articles, including synthesized methods, results, and
implications. Two themes the researcher extracted from the literature review were the
effectiveness and safety of oral immunotherapy in cow milk allergy and the effectiveness and
safety of oral immunotherapy in peanut allergy.
Effectiveness and Safety of Oral Immunotherapy in Cow Milk Allergy
Oral immunotherapy in treatment of cow milk allergy has been shown to be effective and
relatively safe (Salmivesi et al., 2012; Savilahti et al., 2014; Yeung et al., 2012). Desensitization
was reached in the treatment groups. In the study by Salmivesi et al. (2012), twenty eight
children between the ages of six and fourteen years old participated. It was a randomized,
placebo-controlled, double-blind study with eighteen patients in the active treatment group and
ten in the placebo group. The variables measured were IgE antibody levels, which were drawn at
the first visit. The treatment group ingested pasteurized milk, while the placebo group had oat,
rice, or soy milk. The amount of milk protein was increased each day, from 0.06 to 6400

AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

milligrams. Children were monitored in an outpatient clinic. Parents were advised to observe for
allergic symptoms. Participants were required to have antihistamines, self-injectable epinephrine,
and corticosteroids at home in case of emergency. The researchers examined and interviewed
participants. Statistical analysis showed that there was no significant difference between the
children in the two treatment groups. Fishers exact test was used to categorize IgE levels.
Results showed that oral immunotherapy for cow milk allergy was effective (Salmivesi et
al., 2012). Sixteen of the children in the active group and eight of the children in the placebo
group completed the study. Before the study, children tolerated an average of six milligrams of
milk protein. After the study, participants in the treatment group were able to tolerate 960-6400
milligrams. Abdominal discomfort was the most commonly reported adverse effect in both
groups. Thirteen of the children in the active group were tolerant of 6400 milligrams cow milk
protein after one year. The researchers followed up three years after the study, where twelve of
the participants in the treatment group were still able to tolerate cow milk products. The
researchers of this study concluded that desensitization was successful.
The aim of another study was to determine the safety of oral immunotherapy with cow
milk allergy (Savilahti et al., 2014). Thirty two children ages six to seventeen years participated
in the study, and twenty six of them successfully completed it. Six children quit treatment due to
adverse reactions. The researchers explored the use of IgE and IgG4 epitope binding to
determine the safety of oral immunotherapy. Epitope binding to antibodies correlates with the
severity of an allergic reaction. Participants were prescribe antihistamines, corticosteroids, and
auto-injectable adrenaline. The maintenance dose was 7500 milligrams cow milk protein.
Normalized standardizations from peptide fluorescence intensities binding frequencies were used
for statistical analyses. A two-tailed Wilcoxon rank-sum test or Wilcoxon signed-rank test was

AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

used where applicable. Results demonstrated decreased IgE binding and increased IgG4 binding.
These results showed a correlation with decreased allergic response. The researchers concluded
that measuring IgE and IgG4 binding can predict oral immunotherapy outcomes, which could
improve the safety of treatment. A limitation of this study was lack of a control group.
A review of oral immunotherapy in treatment for cow milk allergy also demonstrated the
safety and efficacy of treatment (Yeung et al., 2012). The researchers compared oral
immunotherapy treatment to placebo treatment and the avoidance strategy. They searched
databases for journal articles, yielding sixteen randomized controlled studies that fit inclusion
criteria. Research revealed that milk oral immunotherapy is an effective way to desensitize
patients. There is lack of long term studies and concern regarding adverse reactions to treatment.
Most participants experienced milk allergic symptoms during treatment and few had
anaphylactic reactions requiring epinephrine treatment. The researchers concluded that oral
immunotherapy is effective short term, but long term success is not documented. The risks of
treatment may outweigh the benefits as the researchers found many studies underestimate
adverse reactions during treatment, though studies in this review showed treatment was relatively
safe.
Effectiveness and Safety of Oral Immunotherapy in Peanut Allergy
Two studies on oral immunotherapy in peanut allergy yielded similar results (Nozawa et
al., 2014; Varshney et al., 2011). Researchers aimed to explore the efficacy and safety of oral
immunotherapy for sever peanut allergic children (Nozawa et al., 2014). This study was specific
to Japanese children, aged five to fourteen years. Eighteen children from the Department of
Allergy in Kanagawa, Japan participated in this double-blind, placebo-controlled study.

AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

Participants ingested peanuts each day, increasing the dose by twenty percent each time, to reach
a maintenance dose of 3500-7000 milligrams. IgE, IgG, and IgG4 antibody levels were measured
through the study and up to three years after. Two children failed the study due to adverse
reactions. One hundred seventy three adverse reactions occurred in total throughout the study,
seventy four of which needing medication. IgE, IgG, and IgG4 levels to peanuts increased during
oral immunotherapy, and IgG4 levels remained high during the maintenance phase. Statistical
analysis was performed using Wilcoxon matched-pairs signed-rank test and Spearmans rank
correlation test. The two sided p-value was less than 0.05. The researchers concluded that peanut
oral immunotherapy is effective in treatment of sever peanut allergy in Japanese children.
Treatment was determined to be relatively safe, although numerous adverse reactions occurred.
The safety and efficacy of peanut oral immunotherapy in peanut allergic children was
explored again in another study (Varshney et al., 2011). This study was randomized double-blind,
placebo-controlled study. Twenty eight children participated, ages one to sixteen years. They
were recruited from the Allergy and Immunology clinics at Arkansas Childrens Hospital and
Duke University Medical Center. Build-up doses were used in the treatment group to build up to
a 4000 milligram maintenance dose of peanut flour. The food challenge occurred at four weeks
of maintenance therapy, where children were given 5000 milligrams of peanut or oat flour. Like
with most studies, adverse reactions occurred. Skin prick tests and antibody levels determined
the efficacy of the treatment. Fishers exact test and the Wilcoxon Rank-Sum Test were used for
statistical analyses. Throughout treatment, nine participants required antihistamine treatment and
two required epinephrine. One participant dropped out due to gastrointestinal symptoms, and
sixteen patients of the nineteen in the treatment group reached the maintenance dose. Skin prick

AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

test size decreased and peanut-specific antibodies IgG4 increased. Researchers concluded peanut
oral immunotherapy is effective and safe in children.
Discussion/Implications
The results of this integrative review addressed the effects of oral immunotherapy in
treatment of cow milk and peanut allergy in children. The researcher found evidence to answer
the PICOT question: In school age children, what is the effect of oral immunotherapy on peanut
and milk allergy symptoms throughout the immunotherapy treatment? All five articles
demonstrated that oral immunotherapy is effective in treating food allergy in children, and each
study found that treatment is relatively safe (Nozawa et al., 2014; Salmivesi et al., 2012;
Savilahti et al., 2014; Varshney et al., 2011, & Yeung et al., 2012). Themes included efficacy and
safety of cow milk oral immunotherapy and efficacy and safety of peanut oral immunotherapy.
All the articles yielded results in which desensitization was reached, although researchers used
varying methods. The review demonstrated lack of research in long term effectiveness, as well as
recognition of numerous adverse effects of oral immunotherapy (Yeung et al., 2012).
Implications of the integrative review include further research on the topic. Long term
studies must be performed, and researchers should find ways to reduce adverse events during
studies. Since the studies are performed on children with allergies, mild allergic reactions are
expected, and there is no way to predict whether an anaphylactic reaction will occur. Overall,
oral immunotherapy is a safe and effective form of treatment in cow milk and peanut allergy in
school age children. It is an alternative treatment, other than avoidance therapy and epinephrine
treatment for severe reactions, which should be considered in children suffering with severe
allergies, since it can prevent accidental exposure to allergens later on in life.

AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

Limitations
There were several limitations of this integrative review. The researcher was an
undergraduate level nursing student with lack of knowledge in the area of research. This was the
first undertaking of an integrative review for the researcher. Lack of time to put into research was
also a limitation, as the researcher was a full time student and worked throughout the project.
This review was limited to five articles published in the past five years, so there was a shortage
of research reviewed for the paper. Some articles yielded on the database searches could not be
obtained because they were not available to the public. In this case, other articles had to be
found.
Conclusion
The findings of this integrative review demonstrated the effects of oral immunotherapy
for use in school-age children with cow milk or peanut allergies. Results yielded two main
themes that the use of oral immunotherapy is effective and safe in treating children with cow
milk or peanut allergies. The use of laboratory tests and reports of allergic symptoms
demonstrated safe and effective desensitization in the undertaken review. Oral immunotherapy is
a relatively new therapy, so there is lack of research. The researcher should undertake additional
reviews over the next ten years to explore more studies, especially long term studies. The effects
of oral immunotherapy on children are safe and effective desensitization.

References
Nozawa, A., Okamoto, Y., Moverare, R., Borres, M.P., & Kurihara, K. (2014). Monitoring Ara

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AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

h1, 2 and 3-sIgE and sIgG4 antibodies in peanut allergic children receiving oral rush
immunotherapy. Pediatric Allergy & Immunology, 25, 323-328. doi: 10.1111/pai.12243
Salmivesi, S., Korppi, M., Makela, M., & Paassilta, M. (2012). Milk oral immunotherapy is
effective in school-aged children. Acta Paediatrica, 102, 172-176. doi: 10.1111/j.16512227.2012.02815.x
Savilahti, E.M., Kuitunen, M., Valori, M., Rantanen, V., Bardina, L., Gimenez, G.,
Sampson, H.A. (2014). Use of IgE and IgE4 epitope binding to predict the
outcome of oral immunotherapy in cows milk allergy. Pediatric Allergy &
Immunology, 25, 227-235. doi: 10.1111/pai.12186
Varshney, P., Jones, S.M., Scurlock, A.M., Perry, T.T., Kemper, A., Steele, P.,Burks, A.W.
(2011). A randomized controlled study of peanut oral immunotherapy (OIT): Clinical
desensitization and modulation of the allergic response. Journal of Allergy & Clinical
Immunology, 127(3), 654-660. doi: 10.1016/j.jaci.2010.12.1111
Yeung, J.P., Kloda, L.A., McDevitt, J., Ben-Shoshan, M., & Alizadehfar, R. (2012). Oral
immunotherapy for milk allergy. Pediatric Allergy & Immunology, 11, 1-41. doi:
10.1002/14651858.CD009542.pub2

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AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

Appendix
NUR 4122:Nursing Research
Table of Evidence

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AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

(Effectiveness of Oral Immunotherapy on Cow Milk and Peanut Allergy in Schoolaged Children)
Table 1
First
Auth
or
(Year
)

Conce
ptual
Frame
work

Design/
Method

Samp
le/
Settin
g

Noza
wa et
al.
(2014
)

n/a

Random
ized
controlle
d study;
measure
ments of
antibody
response
s

18
Japan
ese
childr
en, 514
yrs.
Old

Salmi
vesi
et al.
(2012
)

n/a

Random
ized
controlle
d study;
increasin
g cow
milk
protein
ingested

Savil
ahti

n/a

Experim
ental;

24
school
age
childr
en in
Tamp
ere
Unive
rsity
Hospi
tal of
Finlan
d
32
childr

Major
Varia
bles
Studie
d (and
their
definit
ion)
Increa
sing
peanut
dose
vs.
placeb
o

Measure
ment

Data
Analysis

Findings

Appraisa
l: Worth
to
practice

IgG4 and
IgE
antibodie
s
measure
d

Wilcoxon
signedrank test
and
Spearman
s rank
correlatio
n test; two
sided pvalue
<0.05
Fishers
exact test

16
children
desensitiz
ed; IgE
and IgG4
levels
increased
during
OIT.

OIT
protocol
for
peanut
allergy is
effective
and safe.

81% of
the
participan
ts were
able to
use milk
product
daily and
had
desensitiz
ation for
up to 3
yrs.
IgE
binding

OIT is
effective
for
school
age
children
with cow
milk
allergy.

Placeb
o vs.
cow
milk
protei
n
(increa
sing
levels
throug
h
study)

Parent
reports
of
allergic
symptom
s

IgE
and

Lab
values

Normaliz
ed

This
could be

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AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

et al.
(2014
)

analyzed
IgE and
IgG4
antibodi
es before
and after
therapy
for
binding

Varsh n/a
ney et
al.
(2011
)

Random
ized
controlle
d study;
lab
studies
and skin
prick
test used

Yeun
g et
al.
(2012
)

Review;
database
search
for
articles
(only
used
RCTs)

Review

en
from
outpat
ient
clinic

IgG4
levels
in
respon
se to
increa
sing
cows
milk
protei
n
ingest
ed
(bindi
ng

standardiz
ations
from
peptide
fluorescen
ce
intensities
; binding
frequenci
es; twotailed
Wilcoxon
rank-sum
test or
Wilcoxon
signedrank test
(when
applicable
)
28
Peanut SPT and Fishers
childr flour
lab
exact test,
en
doses studies at Wilcoxon
betwe vs.
regular
Ranken 1placeb intervals Sum Test,
16
o
througho p values
years
ut study <0.05
from
considere
outpat
d
ient
significan
clinics
t
Childr OIT
Depende Statistical
en
treatm nt on
heterogen
with
ent vs. article
eity
milk
placeb
assessed
allerg o vs.
with I2
y
avoida
test;
nce
pooled
strateg
risk ratio
y
for each
outcome

decreased
and IgG4
binding
increased
after OIT,
indicating
analysis
of these
antibodie
s binding
can
predict
OIT
success.

a good
way to
measure
whether
OIT is
successfu
l. It could
improve
the safety
of OIT.
This
study
lacks a
control
group.

Decrease
d SPT
size, IL5, and IL13 and
increased
IgG4

Peanut
OIT
results in
desensitiz
ation,
demonstr
ating
efficacy.

Studies
had
inconsiste
nt
methodol
ogical
rigor,
quality of
evidence
was low,

OIT has
been
shown to
be
effective,
but there
is a lack
of long
term
studies.

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AN INTEGRATIVE REVIEW: EFFECTS OF ORAL IMMUNOTHERAPY

with
MantelHaenzel
fixedeffect
model if
statistical
heterogen
eity low
(I2 <50%)

and
patients
usually
had mild
allergic
reactions
with OIT.

Adverse
effects
(usually
mild) are
common.