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EAACI Food Allergy and Anaphylaxis Guidelines

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EAACI Food Allergy and Anaphylaxis Guidelines
1
EAACI Food Allergy and Anaphylaxis Guidelines
2
Diagnosis and management of food allergy
3
4
Short Title: Guidelines on food allergy
5
6
7
Key Words: Food allergy, anaphylaxis, oral food challenge, guidelines, evidence
based medicine, management, oral immunotherapy,
8
Word Count: 5, 923
9
10
Abbreviations:
11
APT Atopy patch test
12
BAT Basophil activation test
13
CRD Component-resolved diagnosis
14
DBPCFC Double-blind, placebo-controlled food challenge
15
EAACI European Academy of Allergy and Clinical Immunology
16
EoE Eosinophilic esophagitis
17
FA Food Allergy
18
FPIES Food protein-induced enterocolitis syndrome
19
GRADE Grading of Recommendations Assessment, Development and Evaluation
20
GERD Gastro-Esophageal Reflux Disease
21
HPF High power field
22
IgE Immunoglobulin E
23
IgG4 Immunoglobulin G4
24
LPT Lipid Transfer Proteins
25
LR Likelihood Ratio
26
NIAID National Institute of Allergy and Infectious Diseases
27
NPV Negative Predictive Value
28
NSAID Non Steroidal Anti-Inflammatory Drugs
29
OFC Oral food challenge
30
PPV Positive Predictive Value
1
31
PN Peanut
32
RCT Randomised controlled trials
33
SLIT Sublingual Immunotherapy
34
SPT Skin prick test
35
sIgE Specific IgE
36
US United States
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2
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ABSTRACT
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Food allergy can result in appreciable morbidity, impact negatively on quality of life
40
and prove costly in terms of medical care. These Guidelines have been prepared by
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the European Academy of Allergy and Clinical Immunology’s (EAACI) Guidelines for
42
Food Allergy and Anaphylaxis Group, building on previous EAACI position papers on
43
adverse reaction to foods and three recent systematic reviews on the epidemiology,
44
diagnosis and management of food allergy. These guidelines aim to provide
45
evidence-based recommendations for the diagnosis and management of food
46
allergy. While the primary audience is allergists, these guidelines are also likely to be
47
relevant to all other healthcare professionals who need to be aware that exposure to
48
foods may trigger allergic reactions, general physicians and relevant pediatric and
49
adult specialists need, in addition, a detailed understanding of the manifestations of
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food allergy, the role of diagnostic tests and the effective management of people with
51
food allergy. All healthcare professionals need appropriate training. Therefore, the
52
target audience is health care professionals (e.g. medical doctors, nurses,
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pharmacists and paramedics) who are involved in the diagnosis and management of
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food allergy, taking care of these patients in emergency departments, hospital and
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primary care. The acute management of non-life threatening reactions is covered in
56
these guidelines, but for guidance on the emergency management of anaphylaxis,
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readers are referred to the related EAACI Anaphylaxis Guidelines chapter.
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3
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Introduction
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Food allergy has been defined as the sub-group of adverse reactions in which
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“immunologic mechanisms have been demonstrated” (1, 2); this term therefore
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encompasses both immunoglobulin-E (IgE)-mediated and non-IgE-mediated food
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allergy. Food allergy can result in considerable morbidity and in some instances
65
results in life-threatening anaphylaxis. These guidelines aim to provide evidence-
66
based recommendations for the diagnosis and management of patients with
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suspected or confirmed food allergy of any age. Development of the guidelines has
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been based on three systematic reviews of the epidemiology, diagnosis and
69
management of food allergy (Appendices I, II, III) with weaker forms of evidence
70
being used where there were insufficient data from more robust studies or where
71
high level evidence is practically or ethically unobtainable. These guidelines builds on
72
the previous EAACI position paper on adverse reaction to foods (3) and is
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complementary to the other current food allergy guidelines (4), including the United
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States (US) National Institute of Allergy and Infectious Diseases (NIAID) guidelines
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(5). Distinctive features include a European focus and the placing of particular
76
emphasis on the practical issues associated with diagnosis and long-term
77
management of food allergy.
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Box 1: Key Terms
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Allergen
Any substance stimulating the production of
immunoglobulin IgE or a cellular immune response,
usually proteins.
Atopic eczema/ dermatitis
Chronic inflammatory skin disease characterized
by typical age related lesions with pruritus and
personal or family history of atopic disease.
Co-factors
Patient related external circumstances that are
associated with more severe allergic reactions that
may also lower the threshold of reactions. They are
known also as augmentation factors.
Eosinophilic
A chronic, immune/antigen-mediated disease
eosinophilicgastroenteropathies involving several tracts of the gut characterized
histologically
by
eosinophil-predominant
and esophagitis
inflammation.
Eosinophilic
esophagitis
is
characterized clinically by symptoms related to
esophageal dysfunction and histologically by
4
eosinophilic infiltration (≥15 eosinophils per high
power field (hpf)).
Food allergy
An adverse reaction to food triggered by an
immunological mechanism, involving specific IgE
(IgE mediated) or cell–mediated mechanisms (non
IgE mediated) or both IgE and cell mediated
mechanisms (mixed IgE and non IgE mediated).
Also known as food hypersensitivity.
Food desensitization
A short-term tolerance that might return to initial
levels of reaction after withdrawal of the treatment.
Oral tolerance
A state of local and systemic immune
unresponsiveness induced by oral administration of
innocuous antigens/ allergens
Oligo-allergenic Diet
An empirical elimination diet with minimal content
of main food allergens for the given population.
Oral tolerance induction
A state of local and systemic permanent immune
unresponsiveness induced by following oral
administration consumption of innocuous antigens
such as food proteins.
Prebiotic
Non-digestable substances that provide a
beneficial physiological effect for the host by
selectively stimulating the favourable growth or
activity of a limited number of indigenous bacteria.
Probiotic
Live microorganisms which, when administered in
adequate amounts, confer a health benefit on the
host
Sensitization
Presence of specific IgE to an allergen.
Symbiotics
A mixture of probiotics and prebiotics
81
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5
83
Methods
84
These Guidelines were produced using the Appraisal of Guidelines for Research &
85
Evaluation (AGREE II) approach (6, 7). This is a structured approach to guidelines
86
production that is designed to ensure appropriate representation of the full range of
87
stakeholders, a careful search for and critical appraisal of the relevant literature, a
88
systematic approach to the formulation and presentation of recommendations, and
89
steps to ensure that the risk of bias is minimized at each step of the process. We
90
provide below an overview of the approach used.
91
Clarifying the scope and purpose of the guidelines
92
The process began in January 2012 with a meeting to discuss the overall approach
93
to guidelines development, this included detailed discussions on the main aims of the
94
guidelines, the target conditions, agreeing the intended end-user for the
95
recommendations, agreeing the intended end-user group, and ensuring adequate
96
professional and lay representation in the guidelines development process.
97
Ensuring appropriate stakeholder involvement
98
Participants in the Food Allergy Diagnosis and Management Taskforce represented a
99
range of European countries, and disciplinary and clinical backgrounds (including
100
medical and nursing, hospital and primary care), and patient groups. The Food
101
Allergy Diagnosis and Management Taskforce continued to work together over the
102
ensuing 18 months through email discussions, teleconferences and several face-to-
103
face meetings.
104
Systematic reviews of the evidence
105
The initial full range of questions that were considered important were rationalized
106
through several rounds of iteration to agree to three key over-arching questions that
107
were then pursued through two formal systematic reviews of the evidence (8, 10)
108
(see Box 2).
109
Formulating recommendations
110
We graded the strength and consistency of key findings from these systematic
111
reviews to formulate evidence-linked recommendations for care (11) (Box 3). This
112
involved formulating clear recommendations and making clear the strength of
6
113
evidence underpinning each recommendation. Experts identified the resource
114
implications of implementing the recommendations, barriers and facilitators to the
115
implementation of each recommendation, advice on approaches to implementing the
116
recommendations and suggested audit criteria that can help with assessing
117
organizational compliance with each recommendation.
118
Peer review
119
A draft of these guidelines was externally peer-reviewed by invited experts from a
120
range of organizations, countries and professional backgrounds. Additionally the draft
121
guidelines is made available on the EAACI website for a 2 week period in June 2013
122
to allow all stakeholders to comment. All feedback will be considered by the Food
123
Allergy Diagnosis and Management Taskforce and, where appropriate, final revisions
124
will be made in the light of the feedback received.
125
Identification of evidence gaps
126
The process of developing these guidelines has identified a number of evidence gaps
127
and we plan in future to formally prioritize these. We plan furthermore to draft outline
128
research briefs that funders can use to commission research on these questions.
129
Editorial independence and managing conflict of interests
130
The production of these guidelines was funded and supported by EAACI. The
131
funders did not have any influence on the guidelines production process, its contents
132
or on the decision to publish. Taskforce members’ conflicts of interest were taken into
133
account by the Taskforce chair as recommendations were formulated.
134
Updating the Guidelines
135
We plan to update these guidelines in 2017 unless there are important advances
136
before then.
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7
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Box 2: Key over-arching questions addressed in the supporting systematic reviews
139
(8-10) Diagnosis and Management

What is the epidemiology (i.e. frequency, risk factors and outcomes) of food allergy in
Europe and how do these vary by time, place and person?

What is the diagnostic accuracy of tests aimed at supporting the clinical diagnosis of food
allergy?

What is the effectiveness of pharmacological and non-pharmacological interventions for
the management of acute, non-life-threatening food allergic reactions?

What is the effectiveness of pharmacological and non-pharmacological interventions for
the longer-term management of food allergy?
140
Box3: Assigning levels of evidence and recommendations according to new grading
system ((BMJ, 2001,) (12, 13))
Level of evidence for establishing diagnostic test accuracy
Level I
A systematic review of level II studies
Level II
A study of test accuracy with: an independent, blinded comparison with a valid
reference standard, among consecutive persons with a defined clinical
presentation
Level III-1*
A study of test accuracy with: an independent, blinded comparison with a valid
reference standard, among non-consecutive persons with a defined clinical
presentation
Level III-2*
A comparison with reference standard that does not meet the criteria required
for level II and III-1 evidence
Level III-3*
Diagnostic case-control study
Level IV
Study of diagnostic yield (no reference standard)
Level V
Case reports and expert opinion that include narrative literature, reviews and
consensus statements
Level of evidence for assessing effectiveness of interventions
Level I
Systematic reviews, meta-analysis, randomized control trials
Level II
Two groups, non-randomized studies (e.g. cohort, case-control)
Level III
One-group non-randomized (e.g. before and after, pre-test and post-test)
Level IV
Descriptive studies that include analysis of outcomes (single-subject design,
8
case-series)
Level V
Case reports and expert opinion that include narrative literature, reviews and
consensus statements
Grades of recommendation
Grade A
Consistent level I studies
Grade B
Consistent level II or III studies or extrapolations from level I studies
Grade C
Level IV studies or extrapolations from level II or III studies
Grade D
Level V evidence or troublingly inconsistent or inconclusive studies at any level
141
*For consistency with the Anaphylaxis Guidelines chapter level III-1 – level III-3 for
142
establishing diagnostic test accuracy were summarised as level III in this document.
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9
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Epidemiology
145
Reliable and up-to-date data on the epidemiology of food allergy in Europe are
146
lacking. In order to estimate the incidence and prevalence, time-trends, and potential
147
risk and prognostic factors for food allergy in Europe, we conducted a systematic
148
review of recent (i.e. 2000-2012) European studies (8). One hundred and nine
149
articles were assessed for eligibility and 75 (comprising of 56 primary studies) were
150
included in a narrative synthesis and 30 studies in a meta-analysis. Most of the
151
studies were graded as at moderate risk of bias.
152
153
A summary of the key findings is presented in Table 1. This reveals that the point
154
prevalence of self-reported food allergy was approximately six times higher than the
155
point prevalence of food allergy proven by food challenges. The prevalence of food
156
allergy was generally higher in children than in adults. While the incidence of food
157
allergy appeared to be stable over time, the prevalence may be increasing, this
158
possibly being due to secondary food allergy due to cross-reactions of food allergens
159
with inhalant allergens and/or better recognition, improved diagnosis and recording.
160
There were no consistent risk or prognostic factors for the development or resolution
161
of food allergy, but sex, age, country of residence, familial atopic history, and the
162
presence of other allergic diseases may play an important role in its etiology.
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164
Few studies employed double-blind placebo-controlled food challenge (DBPCFC) in
165
a population-based sample and so further studies are required to establish the actual
166
prevalence of objectively-confirmed food allergy in the general population. Further
167
studies are also needed to investigate the long-term prognosis of food allergy.
168
169
170
10
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Diagnosis
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173
Patient’s clinical history
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A careful dietary history is very important in diagnosing food allergy (D). A detailed
175
history can be very helpful in helping decide if one is more likely to be dealing with
176
food allergy or another diagnosis; it can also shed light on whether any suspected
177
reaction is likely to be IgE- or non-IgE- or non-immune mediated. It can inform
178
deliberations on which foods to test against. A small amount of literature (14) level III,
179
(15) level V (16) indicates the predictive value of the clinical history, either alone or in
180
combination with skin prick tests (SPT) or serum specific-IgE (sIgE) blood tests,
181
ranges from 50-100%. Structured questionnaires have the potential to be useful, but
182
more studies are needed to validate a predictive model of these instruments,
183
undertaking an impact assessment, in different ages and for the different clinical
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manifestations.
185
Structured questions on symptoms, foods and other background information (i. e. co-
186
factors) will enable informed decisions to be made with regard to further testing and
187
also highlight those who require more intensive nutritional and dietary support (D).
188
(see Appendix IV-A and IV-B.)
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Recommendations Box 3A
190
Clinical examination
191
The clinical presentation of food allergy involves a large spectrum of symptoms
192
varying
193
gastrointestinal (i.e. vomiting, colic, abdominal pain, diarrhoea, constipation) and
194
respiratory systems (rhinorrhea, sneezing, cough, dyspnea). There is often an
195
overlap with symptoms of other diseases and evaluation of severity and chronicity is
196
essential for a suspicion of food allergy. An adequate clinical examination should not
197
focus only on the main complaints but consists of a thorough examination of
198
nutritional status, growth especially in children as well as associated atopic
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symptoms such as atopic eczema/ dermatitis, asthma and allergic rhinitis.
200
The diagnostic workup of food allergy is summarized in Fig.1
from
skin
(urticaria,
angioedema,
11
atopic
eczema/
dermatitis)
to
201
Table 2: Food-induced allergic disorders (classified based on the underlying immunopathology)
Immunopathology
Disorder
Clinical features
Typical age group
Prognosis
IgE mediated
Urticaria/ angioedema
Triggered by ingestion or
direct contact
Children > adults
Depends on food
Rhinoconjunctivitis/ asthma
Accompanies
foodinducted allergic reaction,
but
rarely
isolated
symptoms
Infant/child > adult, except
for
occupational
disease
Depends on food
May be triggered by
ingestion of aerosolized
food protein
Mixed IgE and cell mediated
Anaphylaxis
Rapid
progressive,
multisystem reaction
Any age
Depends on food
Food-dependent,
exerciseinduced anaphylaxis
Food triggers anaphylaxis
only if ingestion is
followed temporally by
exercise
Onset in late childhood/
adulthood
Presumed persistent
Pollen food allergy syndrome
Pruritus,
mild
edema
confined to oral cavityanaphylaxis for some
pollen
related food
allergies mediated by
LTP
Onset after pollen allergy
established (adult >
young child)
Might be persistent; might
vary with seasons
Atopic eczema/ dermatitis
Associated with food in
30%-40% of children with
moderate
/
severe
eczema
Infant > child > adult
Usually resolves
12
Eosinophilic
disorders
Cell mediated
gastrointestinal
Symptoms vary depending
on the site of the
intestinal tract involved
and
degree
of
eosinophilic inflammation
Any age
Likely persistent
Dietary
proteininduced
proctitis/ proctocolitis
Mucus-laden, bloody stools
in infants
Infancy
Usually resolves
Food
protein-induced
enterocolitis syndrome
Chronic exposure: emesis,
diarrhea, poor growth,
lethargy
Infancy
Usually resolves
Reexposure
after
restriction:
emesis,
diarrhea, hypertension 2h
after ingestion
202
Modified from Sicherer SH, Sampson HA. Food Allergy. J Allergy Clin Immunol 2010;125:S120-121 . Permission Pending
13
203
Diagnostic tests for food allergy
204
The tests should be undertaken after a careful history/clinical assessment.
205
Determination of in vivo SPT and sIgE for food allergens are the first line tests to
206
assess IgE sensitization. However, it is well known that neither the patient history nor
207
the measurement of sensitization by itself can accurately diagnose food allergy.
208
Elimination diet for diagnostic purposes (D) and oral food challenges are still required
209
both for IgE and non-IgE mediated food allergy in order to define the clinical
210
relevance of the initial investigations. For some clinical manifestations such as food-
211
induced enteropathies, endoscopy and biopsy are often required to establish the
212
diagnosis.
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Specific IgE: In-vitro and skin tests
215
The determination of sensitization to suspected food allergens includes the
216
assessment of co- and cross-sensitization to related food or aeroallergens due to the
217
to the high levels of cross-reactive food allergies such as pollen food syndrome and
218
latex-food allergy. In order to avoid positive test outcomes without clinical relevance
219
only food and aeroallergens related to the clinical presentation, age, geographic
220
location and ethnic dietary habits of the patient should be investigated.
221
Specific IgE and SPT are scientifically valid tests which are commonly used in clinical
222
practice to establish or rule out IgE sensitization to foods. The allergens used in
223
these tests are traditionally based on food extracts, although not standardized and in
224
case of SPT increasingly based on fresh food. Currently there is not there is no
225
approved single protein for diagnostic procedure in the EU. Determination of total IgE
226
levels can be helpful in the interpretation of SPT or sIgE results, since very high IgE
227
levels can be associated with many positive SPTs or sIgE results that are not
228
clinically relevant.
229
SPT can be undertaken in patients of any age although expertise is needed in
230
interpreting skin reactivity that may be lower in infants and possibly the elderly, than
231
adults (17). The choice of tests should be guided by the detailed clinical history.
232
SPT should be undertaken by trained healthcare professionals, able to interpret
233
results and manage possible adverse reactions and are performed on the forearm
14
234
and upper back. Negative (saline) and positive (histamine 10mg/ml) controls are
235
required and the maximum wheal diameter is reported with an arbitrary positive cut-
236
off diameter ≥ 3mm after 15 minutes (18) There are numerous variables to be
237
considered when performing and interpreting SPT including lancets, recording of
238
wheal diameter, timing, age, sex, and site of testing (20, 21). In addition, it should be
239
considered that European parameters may differ from North American ones (22).
240
Intradermal skin testing for food allergy diagnosis is usually not recommended
241
because of low specificity, high potential for irritant reactions and risk for systemic
242
reactions, except in particular situations, e.g. alpha-gal allergy (23)
243
The use of good quality food allergen extracts, characterized by demonstration of
244
clinical efficacy and the presence of relevant allergens is strongly recommended
245
when available. Due to a possible under-representation of minor allergens or
246
instability of the allergenic proteins false negative reactions can occur. Therefore for
247
food allergens, where these types of extracts are not available and/or minor- or
248
instable allergens are relevant for the sensitization i.e. most fruits and vegetables,
249
fresh foods should be used preferentially.
250
In our systematic review we found reasonable sensitivity (70-100%), (although less
251
for most plant food allergies) but moderate specificity (40-70%) both for sIgE and
252
SPT using the DBPCFC as a reference test (9). Sensitivity and specificity of serum
253
IgE testing and SPT varied depending on the food being tested and due to the
254
heterogeneity of studies with respect to inclusion criteria for patients, their geographic
255
background, and their age and ethnicity, as well as recruitment processes. High
256
quality performance of these tests is observed for allergens such as peanut, egg,
257
milk, hazelnut, fish and shrimp, but less so for soy and wheat (B) (9). For other plant-
258
derived (carrot, celery, kiwi, lupine, maize and melon) or animal-derived foods
259
(chicken and pork) only single studies were included in the recent systematic
260
analysis.
261
Extract-based sIgE tests are good to confirm or rule out involvement of IgE in (self-)
262
reported food hypersensitivity. However, they are unable to differentiate between
263
clinical relevant allergy and tolerance. Raising the cut-off levels improves specificity
264
for some foods but that cannot replace oral challenges for the diagnosis of food
265
allergy. The estimation of likelihood ratios of history, sensitization and clinical
266
reaction is explained in appendix IV-C (including table IV-C).
15
267
Atopy patch test
268
The application of the Atopy Patch Test (APT) for foods (e.g. milk, egg, wheat and
269
soy) has been investigated to increase diagnostic specificity of delayed reactions in
270
patients with atopic eczema/dermatitis or eosinophilic esophagitis and with
271
detectable IgE sensitization to foods. Due to the lack of standardized test substances
272
and due to the lack of studies showing advantages of APT as compared to SPT or
273
sIgE, APTs are still not recommended (D) for routine diagnosis of food allergy. (24-
274
25).
275
276
Elimination diet
277
An elimination diet for diagnostic purposes consists of the avoidance of the food(s)
278
suspected of triggering allergic reactions based on the allergy-focused diet history,
279
clinical history and adjunct allergy testing, such as SPT and sIgE. The duration of the
280
avoidance should be no longer than necessary to achieve a significant relief of
281
symptoms, usually from 2 to 4 weeks for chronic manifestations. For non-IgE
282
mediated symptoms a longer period maybe required, for example, up to six weeks for
283
EoE. The diet should be thoroughly monitored and evaluated to establish or refute
284
the diagnosis and to prevent unnecessary food restrictions.
285
The avoidance phase should be followed by an OFC reintroducing the eliminated
286
food(s) under medical supervision must follow the avoidance phase. Assessing the
287
individual risk by history and allergy testing may also permit reintroduction into the
288
diet at home,, provided there is no risk for severe reactions; and that reported clinical
289
reaction is confirmed by OFC under medical supervision. If inadvertent immediate
290
symptoms continue to happen, or the effect of the avoidance is limited, the diet
291
needs to be carefully re-evaluated. All allergenic foods may not have been identified
292
or removed in some cases and co-factors may affect the outcome. In patients
293
suspected of cow’s milk allergy, the type of cow’s milk substitute should be
294
evaluated. Sometimes extensively hydrolysed formula is not effective in achieving
295
remission of symptoms and therefore, an amino acid based formula (see section on
296
Management) is required. If no results despite a properly performed elimination diet,
297
then food allergy to the eliminated foods is highly unlikely. Otherwise foods should be
16
298
added back into the diet after 2 to 4 weeks, in order to preserve the nutritional
299
balance of the diet and to prevent unnecessary dietary restrictions.
300
Recommendation Box 3C
301
17
302
Oral food challenges
303
OFCs are usually required to confirm the diagnosis of food allergy, to monitor food
304
allergy or to show oral tolerance to a given food (Table 3). There are guidelines
305
including one from the EAACI (26, 27) and a recent PRACTALL consensus (28) that
306
describe procedures of OFCs in detail. These recommendations deal with the many
307
variables involved in designing a patient specific challenge; these include patient
308
selection, safety criteria, type and quantity of the food allergen to be administered,
309
timings between doses, outcome criteria, observation periods and recipes to be
310
used. Some of the key recommendations are summarized in Table 4.
311
312
Oral food challenges can be performed in an open or blinded manner: Blinded
313
challenges can be single- or double-blinded. The double-blind, placebo-controlled
314
Food Challenge (DBPCFC) is considered the gold standard diagnostic test for the
315
diagnosis of food allergy. However, a negative open challenge of a regular age
316
appropriate serving or the negative outcome of the administration of a cumulative
317
dose of the previous challenge on another day (29), is required for confirming the
318
result of a negative DBPCFC (Fig 2). DBPCFC is time-consuming and resource-
319
intensive to undertake. A negative OFC may be useful as a first step in ruling out FA.
320
In patients with atopic eczema or suspected psychological symptoms the DBPCFC is
321
superior to an OFC. The food should be blinded for taste, smell, texture and
322
appearance (consistency, colour and shape). The placebo and the active food should
323
be sensory indistinguishable from each other.
324
In order to avoid severe reactions, patients receive the food in titrated doses often
325
with half-logarithmic dose increments, at set intervals. For many foods such as cow’s
326
milk, hen’s egg, peanut or tree nuts dose ranges from 3mg to 3g of food protein
327
seem sufficient in clinical practice (see Appendix IV D).
328
Food allergy challenges are usually stopped if objective clinical reactions are
329
observed or the last dose is consumed without clinical symptoms. Immediate
330
reactions usually appear within two hours after the last food intake, atopic eczema
331
may worsen several hours or during the following days of the oral challenge. Urticaria
332
and/or angioedema are the most common objective signs noted, gastrointestinal,
333
respiratory or cardiovascular system involvement are also common.
18
334
To optimize safety, procedures should be in place to deal with allergic reactions –
335
including anaphylaxis – and staff should be trained in the recognition and emergency
336
management thereof. Age- and weight-appropriate emergency medications that may
337
be required should be written-up on medication charts/electronic prescribing systems
338
prior to commencing the challenge. For patients with non-IgE mediated reactions
339
challenges tailored on the individual modalities of reactions should be designed. (See
340
appendix V- D for detailed recommendations on challenge tests and Box 4D for gaps
341
which were identified during the consensus process.)
342
Recommendation Box 3D
343
344
Promising novel diagnostic approaches
345
In molecular or component-resolved diagnostic tests (CRD), sIgE antibodies are
346
measured against individual allergenic molecules from foods with the potential to
347
improve the sensitivity of serum IgE testing and the specificity for selected food. For
348
peanut allergy, determination of sIgE for the major allergen, Ara h 2, showed
349
sensitivity to 100% and specificity to 70-80% in two recent studies (30, 31). The
350
determination of omega-5-gliadin proved to be of high diagnostic relevance in
351
exercise induced food allergy to wheat in a number of recent case reports and cohort
352
studies (32) as well as the determination of rGly m 4 for allergy to soy milk in birch
353
sensitized patients. For certain fruits (i.e. apple, peach, kiwi and melon), vegetables
354
(i.e. carrot and celery), tree nuts and peanut, soy, fish and shrimp, CRD are also
355
available and provide better insight into sensitization patterns. The technique of CRD
356
is promising and broadly studied, and some important clinical results are summarized
357
in Table 3. Since overall evidence from well-designed randomized controlled studies
358
on the diagnostic test accuracy of CRD is still lacking therefore, the diagnostic value
359
of most tests still remains inferior to OFCs and DBPCFC tests (see Box 3B)
360
Basophil activation tests (BAT) have been applied in the diagnosis of cow’s milk, egg
361
and peanut allergy (30, 33, 34) as well as in the diagnosis of pollen-food syndromes
362
in small clinical studies (35, 36). BAT has shown higher specificity and negative
363
predictive value than SPT and sIgE, without losing sensitivity or positive predictive
364
value. However, BAT requires a specialized laboratory setting and larger clinical
19
365
studies on its diagnostic performance are lacking, thus the use of this promising test
366
is still limited to research purposes on food allergy.
367
Another promising research area is the determination of IgE antibodies against
368
overlapping synthetic linear peptides of food allergens, as it has been performed for
369
milk (37-39), peanut (40, 41), egg (42) and shrimp ( 43,44).
370
Recommendation Box 3B
371
372
Diagnostic workup of gastrointestinal non IgE mediated symptoms including
373
eosinophilic esophagitis
374
Infants in the first months of life and usually to one year may present with
375
gastrointestinal food related clinical manifestations such ascolic, food protein
376
inducted enterocolitis syndrome (FPIES), protocolitis and enteropathy. Usually the
377
patients have negative food specific IgE with both in vivo (SPT) and in vitro testing.
378
(See Table 1) The diagnosis is based on symptoms, clinical history, and elimination
379
diet for up to three weeks as well as specifically designed OFCs (45). Endoscopy
380
with biopsies might be helpful in confirming bowel inflammation. Currently there is
381
scarce evidence that APT is helpful in diagnosing food allergy in such types of food
382
allergy.(46)
383
EoE is defined as a chronic, immune/antigen-mediated esophageal disease,
384
characterized clinically by symptoms related to esophageal dysfunction and
385
histologically by eosinophil-predominant inflammation (≥15 eosinophils per high
386
power field (hpf)) (47). All age groups can be affected and the current estimated
387
prevalence is around 1 in 24,000 adults. (48). Adult patients mostly present with
388
dysphagia, less frequently with retrosternal pain and food bolus impactation, whereas
389
the symptom presentation in children is much more variable and includes failure to
390
thrive, vomiting, regurgitation, thoracic and abdominal pain. EoE is diagnosed by an
391
upper endoscopy with two to four biopsies from both the proximal and distal
392
esophagus (47). Biopsies should be performed when the patient has been treated for
393
at least six weeks with double the standard dose proton pump inhibitors to rule out
394
esophageal eosinophilia caused by gastro-esophageal reflux disease (GERD) and to
395
exclude proton-pump inhibitor responsive esophageal eosinophilia. Other disorders
20
396
associated with esophageal eosinophilia such as Crohn’s disease, celiac disease,
397
achalasia, or eosinophilic gastroenteritis should be ruled out.
398
Approximately 15 – 43 % EoE patients are diagnosed with food allergies and
399
sensitization rate to aeroallergens is up to 80% (49). A close collaboration between
400
gastroenterologists and allergists is essential to optimize management of patients
401
with EOE (47, 48).
402
Recommendation 3-E
403
404
Unconventional tests (including specific IgG testing)
405
A number of expensive diagnostic alternative approaches are sometimes promoted
406
to physicians and often used by complementary and alternative medicine
407
practitioners in cases of suspected food allergy. Examples are bioresonance,
408
kinesiology, iridology, hair analysis, cytotoxic test, and IgG and IgG4 determination.
409
These tests are not currently validated and cannot be recommended in diagnosing
410
food allergy (50-54).
411
IgG-measurements cannot be correlated with any clinical symptoms or disease. Food
412
specific IgG4 levels indicate that the atopic individual has been repeatedly exposed
413
to high doses of food components, which are recognized as foreign proteins by the
414
immune system. Therefore, EAACI gave a clear recommendation not to use these
415
tests (54).
416
Recommendation Box 3F
417
418
Recommendations, gaps and research needs in diagnosis of food allergy are
419
summarized in Box 3 and 4 respectively.
420
21
Box 3: EAACI Recommendation on the DIAGNOSIS of food allergy
Key ref
Grade
Recommendations
Evidence
level
421
Detailed clinical history is essential for the diagnosis of food allergy.
IV
D
Expert Opinion
When taking a clinical history eliciting allergens, timing and chronicity, symptoms,
severity and signs, reproducibility, known risk (co)factors, family history, co-existing
medical problems including other allergic diseases should be addressed.
V
D
Expert Opinion
The use of structured questions on symptoms, foods and other background
information is recommended.
V
D
IgE sensitization does not always result in clinical relevant food allergy, therefore,
specific allergy testing should be directed by case history.
IV
D
Soares-Weiser Systematic Review 2013(9)
SPT and/or sIgE can be the test of choice for sensitization depending on local
availability and absolute and relative contraindications to SPT.
IV
D
Soares-Weiser Systematic Review 2013(9)
IgE sensitization to common food and appropriate aeroallergens is determined by SPT
and serum IgE tests are used as a support to the diagnosis of food allergy by clinical
history and/or food challenge.
I-III*
A-C
Soares-Weiser Systematic Review 2013(9)
Where available, standardized tests and procedures should be used.
IV
D
In the presence of a suggestive history, a negative SPT or sIgE needs to be
interpreted with caution particularly as these are expected in non-IgE mediated food
allergy.
IV
C
A- Patient’s clinical History
Expert Opinion
B -Determination of sensitization to food
22
Expert Opinion
Soares-Weiser Systematic Review 2013(9)
Where SPT and sIgE tests are inconclusive, CRD (if available) may provide additional
diagnostic information.
I – IV*
A – C*
Glaumann 2012(27), Eller 2012(30), Morita 2009
(31) Soares-Weiser 2013(9)
If clinical history combined with SPT and/or sIgE results are not highly predictive (see
figure 1), an OFC is required.
IV
D
Expert Opinion
Determination of total IgE is particularly useful in patients with severe eczema who
often show very high total IgE levels which indicates that positive specific IgE results
should be interpreted with care.
IV
D
Expert Opinion
The determination of the foods to be avoided should be based on the allergy-focused
diet history, clinical history and allergy testing (SPTs and/or sIgE).
V
D
Expert Opinion
For all of the individually avoided foods the results of the diagnostic elimination diet
should be carefully monitored and evaluated up to 2-4 weeks of avoidance.
V
D
Expert Opinion
Where the elimination diet leads to a significant relief of symptoms, it should be
continued until the provocation test is performed.
V
D
Expert Opinion
If no significant reduction of symptoms is obtained by elimination diet, the respective
food allergy is highly unlikely.
V
D
Expert Opinion
The OFC (particularly the double-blind placebo-controlled food challenge) is the gold
standard investigation for the objective diagnosis of IgE-and non-IgE mediated food
allergy.
IV
D
Expert Opinion
OFC’s should be used to demonstrate allergy or tolerance and in so doing facilitate
safe dietary expansion or appropriate allergen avoidance.
IV
D
Expert Opinion
C- Elimination diets for diagnostic purposes
D- Oral food challenge (OFC)
23
D
Bindslev-Jensen 2004(25)
The DBPCFC should be performed when symptoms are subjective, with delayed or
atypical symptoms, where patients and/or care givers are anxious, and considered in
all research settings.
IV
A negative DBPCFC should end with an open or cumulative ingestion of the food
based on a normal age appropriate portion to confirm oral tolerance.
IV
D
Expert Opinion
OFC must be performed in a specialist setting with emergency support immediately
available; where there is a moderate to high risk of a severe reaction, intensive care
support must be immediately available
IV
D
Expert Opinion
E -Diagnosis of EoE
IV
D
Liacouras 2011(44)
EoE is diagnosed by an upper endoscopy with 2-4 biopsies from both the proximal and
distal esophaguseal biopsies (43). Biopsies should be performed when the patient has
been treated for at least 6 weeks with double dose proton pump inhibitors to rule out
esophageal eosinophilia caused by gastro-esophageal reflux disease (GERD) and to
exclude proton-pump inhibitor responsive esophageal eosinophilia
IV
D
As Above, Dellon et al. 2013
The clinical utility of measuring serum food-specific IgE and skin prick test results to
generate a successful elimination diet needs further investigation. Future studies
should clearly document a clinical and histologic benefit from dietary interventions
guided by results from serum-IgE levels, skin prick testing or atopy patch testing.
IV
D
As Above
III
C
Stapel EAACI position paper 2008(54)
Sampson PRACTALL 2012 (27)
Every patient with EoE should be referred to an allergist / immunologist for workup
F-Unconventional tests, including specific IgG testing
There is no unconventional tests which can be recommended as an alternative or
complementary diagnostic tool in the work up of suspected food allergy, and their use
should be discouraged.
422
24
423
Management of food allergy
424
425
The over-arching key questions, which are answered in this part of the Guideline, are
426
summarized in Box1.The clinical management of food allergy includes short-term
427
interventions to manage acute reactions and long-term strategies to minimize the risk
428
of further reactions. The latter aim is primarily achieved through dietary modification,
429
education and behavioral approaches to avoid allergens and approaches to improve
430
outcomes if a further reaction does occur through pharmacological and non-
431
pharmacological management strategies. There is growing interest in the
432
effectiveness of potential immuno-modulatory treatment approaches, including
433
sublingual and oral immunotherapy (56).
434
435
Management of acute reactions
436
Most foods contain proteins, which may be allergenic and cause food allergy and, in
437
some cases, anaphylaxis. Recently severe reactions have been attributed to
438
carbohydrate with relevance to alpha gal as carbohydrate. (23) Assessment of the
439
risk of severe reactions is crucial in successfully managing food allergic patients. The
440
risks vary in different patient subgroups; for example patients with previous
441
anaphylaxis or severe asthma have a higher risk than other patients; known
442
cofactors include non-steroidal anti-inflammatory drugs (NSAID), exercise, infections,
443
and mastocytosis. For detailed guidance on the emergency management of
444
anaphylaxis, readers are referred to the EAACI Anaphylaxis Guideline chapter (73).
445
446
In our systematic review we found weak evidence to support the benefits of H1
447
antihistamines for children and adults with acute non-life threatening symptoms from
448
food allergy in three randomised trials and two non-randomised comparisons (10).
449
Importantly, there is no evidence for efficacy of antihistamines in the treatment of
450
more severe symptoms. Notably, the prophylactic administration of antihistamines
451
can mask early symptoms of anaphylaxis and lead to delayed treatment of
452
dangerous reactions with adrenaline (epinephrine).
453
Recommendation Box 5A
25
454
Long-term management strategies
455
Elimination diet and dietary interventions
456
Dietary avoidance is the key intervention in the management of food allergy resulting
457
in the resolution or strong decrease of symptoms and severe reactions. Little
458
research has been published about dietary eliminations due to the difficultly to
459
perform RCTs in subjects not suffering from food allergy due to ethical issues. The
460
findings from the few studies available (58-61) are mixed, and all had a high risk of
461
potential bias. The lack of evidence does not mean that elimination diets are not
462
effective, just that any recommendations made about elimination diets may need to
463
rely on expert opinion and experience rather than a high quality research base.
464
Dietary restrictions should eliminate the culprit food allergen(s) and be tailored to the
465
individual’s specific allergic and nutritional needs. This will cover a wide spectrum of
466
issues such as the nutritional needs of food allergic infants who are currently being
467
introduced to solid foods, which are very different form the nutritional needs of adults
468
with primary or secondary fruit and vegetable allergies.
469
Extensive and long-term avoidance should be carefully monitored as it can result in
470
nutritional compromises and impair quality of life. Ideally the patient should receive
471
proper counselling by a dietician with specific competence in food allergy. This is
472
particularly important in infants and children. In addition, it is crucial to take into
473
account that individual tolerance levels to the allergenic food may differ and change
474
overtime, especially in children, and may affect the stringency of avoidance advice.
475
In breast-fed infants suffering symptoms due to maternal intake of food allergens, the
476
mother should eliminate the foods in question and following a dietetic review, receive
477
a calcium supplement following a dietetic review if cow’s milk, cow’s milk substitutes
478
and derivatives are eliminated. (D)
479
Education is the key pillar of an effective long-term elimination diet. Patients, their
480
families, close relatives and caregivers should be aware of risk situations, and should
481
be instructed in reading labels and how to avoid the relevant food allergens both in
482
and outside the home, e.g. at restaurants. They should know that European Union
483
(EU) directives ask for the declaration of allergenic ingredients in foods and be
484
informed about precautionary labeled foods. They should also be provided with
485
information on possible substitute products for most food allergens. (D)
26
486
Cow's milk substitutes
487
In children with cow’s milk allergy, several substitutes are available. In infants and
488
young children these products are especially necessary to ensure a diet that is
489
adequate for growth and development. In infants younger than six months, such
490
formulas have to fulfil the general requirements for full nutrition until the introduction
491
of complementary foods. In addition, these substitutes may also be required in older
492
children to ensure a satisfactory caloric intake. There is some moderate level
493
evidence about some alternatives to cow’s milk. However, most of the research is of
494
low quality and there are a relatively small number of studies about each type of
495
alternative formula. There is some evidence to suggest that extensively hydrolyzed
496
formula, and amino acid-based formula may be useful long-term management
497
strategies. Soy formulas may be useful provided that nutritional evaluation regarding
498
the phytate and phyto-oestrogens content is considered. Rice hydrolyzed formulas
499
have been recently introduced to the market in some European countries and further
500
research is needed to compare these formula with extensively hydrolyzed formula
501
and soy formulas. Extensively hydrolysed cow’s milk formulas are the first choice as
502
an alternative to cow’s milk. However, as amino acid-based formulas are the only
503
completely non-allergenic formula, they can be effective in patients not responding to
504
extensively hydrolysed formulas and in subgroups of children. These include infants
505
with severe growth faltering (62, 63) those with, cow’s milk protein allergy with severe
506
symptoms and non-IgE mediated syndromes such as food protein induced
507
enterocolitis and enteropathies, eosinophilic gastroenteropathies.. Rice hydrolysed
508
formulas and soy formulas may be tolerated by the majority of subjects allergic to
509
cow’s milk. Soy formulas cannot be recommended until after 6 months of age but
510
they are tolerated by the majority of subjects allergic to cow’s milk. The substitutes
511
for cow’s milk should fulfil the criteria for documented hypoallergenicity and for
512
nutritional adequacy (62- 65). To achieve these requirements, the formula should be
513
investigated in consecutive patients with both IgE and non-IgE mediated cow’s milk
514
protein allergy (63). Few extensively hydrolyzed formulas have been investigated and
515
fulfill these criteria (68, 62). In addition, attention should be paid to taste and price as
516
reimbursement policies for these types of formulas differ across the EU.
517
Based on several reports partially hydrolysed cow’s milk based formulas are not
518
regarded safe for patients with cow’s milk protein allergy (68, 69).
27
519
There is less evidence regarding other mammalians milk. Goat and sheep’s milk are
520
very similar to the proteins in cow’s milk, and therefore should not be recommended
521
for patients with cow’s milk protein allergy (68, 69). Camel, donkey or mare’s milk
522
have been shown to be less cross-reactive than goat’s milk, although evidence for
523
recommendations is lacking as well as for chicken-based formula (71) or meat-based
524
formula (72).In summary, it is recommended that the choice of an appropriate cow’s
525
milk substitute should be assessed carefully balancing the following factors; age,
526
type of food allergy (IgE /non IgE) coexistence of gastrointestinal symptoms, history
527
of life threatening reactions and nutritional requirements as well as cost-effectiveness
528
Duration of elimination diets
529
Patients should be re-evaluated with diagnostic tests including OFCs at regular
530
intervals to assess whether they have developed tolerance depending on age and
531
the eliminated food. For allergy to cow’s milk and hen’s egg, re-evaluation in young
532
children is advised every 6-12 months, in older children every 12-18 months due the
533
natural course with development of tolerance to these allergens, whereas this may
534
be different for other food allergens such as nuts and shellfish. Inappropriate or
535
unnecessarily lengthy dietary eliminations should be avoided as such restrictions
536
may impair the quality of life, affect normal growth, and incur unnecessary health
537
care costs. There are currently no universal cut-off levels set for SPT or sIgE tests
538
indicating that the patient has developed tolerance to a food, so these evaluations
539
most often have to be based on re-challenges.
540
541
Probiotics and prebiotics
542
Probiotics have been investigated as another option for management of patients with
543
food allergy either added to formulas or given as a supplement to infants or children
544
most often with cow’s milk protein allergy.
545
The evidence about probiotic supplements efficacy by itself for prevention or
546
treatment is lacking and further research is needed to make recommendations in this
547
area. (73)
548
No studies meeting the inclusion criteria were identified about prebiotics or
549
synbiotics. (10)
550
Recommendation Box 5-B1.
551
28
552
Pharmacological treatment
553
Studies on the prophylaxis of FA with mast cell stabilizers have led to different
554
clinical results.(10). Four randomized trials and two non-randomized comparisons
555
found that mast cell stabilizers reduced symptoms of food allergy but three
556
randomized trials found no benefits. Overall, the evidence is not sufficient to
557
recommend mast cell stabilisers for the prophylactic treatment of food allergy.
558
559
Education and risk assessment
560
Education and training are a fundamental part of managing food allergies and should
561
be combined with a risk assessment of those patients at risk of severe reactions(74).
562
A personalised plan including an emergency plan should be issued as part of the
563
overall educational package offered to patients (family and caregivers). (See also
564
Anaphylaxis Guidelines) The plan should be designed to consider the many variables
565
that may influence the identification and treatment of allergic reactions: age of the
566
patient, literacy of patient and family, type and range of food allergy, concomitant
567
disease, geographic location and access to medical support. Training should cover
568
patient-specific avoidance strategies at home and in the social environment,
569
interpretation of warning signals, when and how to manage reactions including when
570
and how to administer self-injectable adrenaline if appropriate (3). All professionals
571
including family doctors, school nurses, dieticians, school teachers and nursery staff
572
should be trained. There is some evidence that a multi-disciplinary clinical approach
573
(10) and the provision of educational printed and online materials for food allergy (11)
574
have both been shown to improve knowledge, correct use of adrenaline auto-
575
injectors and reduce reactions. (See Anaphylaxis Guidelines)
576
Recommendation Box 5-B2
577
578
Co-factors
579
Several augmentation factors are known to increase the severity of some food
580
allergic reactions. Sometimes these factors are even obligatory to elicit symptoms of
581
food allergy. Among these factors the best characterized are physical exercise and
582
NSAID, although others have also been described (e.g. alcohol, fever, acute
29
583
infection, pollen season). The best known co-factor induced syndrome is wheat-
584
dependent-exercise induced anaphylaxis due to omega-5-gliadin sensitization (33);
585
other allergens such as lipid transfer proteins (LTP) seem to be relevant in certain
586
geographic areas (76, 77). Co-factors should be assessed in every history on
587
putative food allergy.
588
Recommendation Box 5-B6
589
590
Immunotherapy
591
Specific immunotherapy of food allergy
592
For the treatment of food allergy, specific immunotherapy with food allergens using
593
the subcutaneous, oral or sublingual route have been tried (10).
594
Most controlled studies have been performed with peanuts, hazelnut, hen’s egg or
595
cow’s milk. In pollen-associated food allergy both, the treatment with pollen allergens
596
using the subcutaneous or the sublingual route has been investigated but also oral
597
and sublingual immunotherapy with food allergens itself.
598
In regard to subcutaneous immunotherapy with food allergens two low quality
599
controlled crossover study suggest a better response to injection therapy than to
600
placebo. In regard to pollen-associated food allergy, three very low quality RCTs (78,
601
79, 80 ) and two non-randomized studies showed conflicting efficacy for the injection
602
treatment with pollen allergen.
603
In regard to sublingual immunotherapy with food allergens four randomized trials
604
found that sublingual immunotherapy with food allergens was associated with
605
improved tolerance and reduced symptoms for those with peanut, hazelnut and
606
peach allergies (82,83). One trial with birch pollen allergen found no benefit in
607
subjects with apple allergy (83).
608
In regard to oral immunotherapy two systematic review, eight randomized trials and
609
three non-randomized comparisons found that oral immunotherapy with food
610
allergens was associated with improved tolerance and reduced symptoms for
611
children and adults with various food allergies (10). However, usually around 90% of
612
participants suffered side effects, though these were usually not severe. Oral
30
613
immunotherapy was more efficacious for desensitization to cow’s milk than
614
sublingual immunotherapy (SLIT) but was accompanied by more systemic side
615
effects in one study (84). One randomized trial found no benefit. The two systematic
616
reviews suggested that so far oral immunotherapy should not be recommended as
617
routine treatment. In light of its potential benefit, it should be performed only in highly
618
specialized centres (combining staff with high expertise and adequate equipment)
619
and according to a clinical protocol approved by the local ethics committee (D).
620
621
The evidence from these studies supports the need for further exploration of
622
immunotherapy with food allergens (10), although, especially in subcutaneous and
623
oral immunotherapy the treatment seems to be associated with significant adverse
624
effects. In regard to pollen-associated food allergy there is conflicting evidence on
625
efficacy of subcutaneous and sublingual immunotherapy with pollen allergens;
626
therefore, this therapeutic intervention should be used only if primarily the pollen
627
allergy requires treatment.
628
Recommendation Box 5-B3
629
630
Anti-IgE treatment
631
Omalizumab is a humanized monoclonal anti-IgE antibody which is licensed for the
632
treatment of allergic asthma bronchiale. So far the effect of omalizumab and another
633
anti-IgE antibody (TNX-901) on the symptoms of food allergy have been described
634
(10). Increased thresholds of tolerance to food allergens was found in a subgroup of
635
participants. The studies suggest that the clinical benefits of omalizumab are
636
achieved early during therapy after a few doses of omalizumab in a pilot study.
637
Moreover, it was demonstrated that more rapid and higher doses of milk-protein
638
could be administered when omalizumab was used as an adjunct therapy (85).
639
Recommendation Box 5-B4
640
31
641
Challenges at regular intervals to assess achievements of tolerance
642
As food allergy can be outgrown spontaneously for some food allergens mainly in
643
children or can develop following pollen sensitivity, there is the need to re-evaluate
644
the patients regularly. Repeated IgE testing can be helpful to determine if
645
sensitization is decreasing (common in egg and milk allergy) or static and helps to
646
identify associated allergies (e.g. peanut, associated with tree nut, sesame (22)).
647
Currently, OFC are the only tests that can predict with adequate certainty the
648
achievement of tolerance although it has been shown that low food allergen specific
649
IgE levels at diagnosis and a decrease over time correlate with clinical tolerance. It is
650
therefore recommended that OFC should be performed at regular intervals in order to
651
avoid unnecessary dietary restrictions. The eliciting food may influence this process.
652
In cow’s milk and hen’s egg allergy the majority of children will become tolerant within
653
a few years while more patients with peanut or tree nut allergy may stay allergic
654
throughout their life. In cow’s milk or hen’s egg allergy intervals might be every 6-12
655
months. For peanut and tree nut allergy OFC for the determination of tolerance might
656
be considered every two years especially in the absence of an accidental reaction.
657
Recommendation Box 5-B5
658
659
Management of eosinophilic esophagitis
660
Symptomatic EoE patients should be treated not only for quality of life reasons but
661
also to reduce the risk for the occurrence of the potentially dangerous food bolus
662
impactions. Untreated eosinophil-predominant inflammation leads to esophageal
663
remodeling with narrowing of the esophageal caliber and a loss of function.
664
Treatment modalities include drugs, diets, and esophageal dilation. Swallowed
665
topical corticosteroids (budesonide or fluticasone) and diets have shown to reduce
666
symptoms and eosinophilic infiltration. The following diet types are available: amino-
667
acid based formula diet (necessitates often feeding tube), targeted elimination diet
668
(according to allergy workup) and empiric elimination diet. Esophageal dilation of
669
strictures can increase esophageal diameter and improve symptoms, however, it
670
does not influence the underlying inflammation. The long-term treatment strategies
671
are not yet defined. Close collaboration between allergists/immunologists and
672
gastroenterologists is advised. (17).
32
673
Recommendation Box 5-B6
674
675
Recommendations, gaps and research needs in the management of food
676
allergy are summarized in Box 5 and 6 respectively.
33
Box 5: EAACI recommendation of the on the MANAGEMENT of food allergy[U1]
Key ref
Grade
Recommendations
Evidence
level
677
A- Acute Management
The patient at risk of severe reactions should be properly and timely identified
IV
D
Expert Opinion
There is evidence to support the benefits of antihistamines for children and adults with
acute non-life threatening symptoms from food allergy.
III
C
(10)
The prophylactic application of antihistamines is not recommended
V
D
Expert Opinion
III
C
(10)
A sufficient elimination diet should be based on a proper allergy diagnosis identifying
the food allergen(s) responsible of the patient’s symptoms /reactions. The indications
should be re-evaluated at appropriate intervals
IV
D
(54-56)
Appropriate dietary avoidance diets is the key treatment in the management of food
allergy
IV
D
Expert Opinion
Patients with food allergy who are on long term elimination diets should have access to
appropriate nutritional counseling, ideally by a dietitian with competencies in food
allergy, and regular monitoring of growth
IV
D
Expert Opinion
Extensively hydrolysed cow’s milk formulas with documented hypoallergenicity can be
recommended as first choice for the treatment of cow’s milk allergy, especially in
I
A
(61-64)
Antihistamines and Mast Cell Stabilizers
Mast cell stabilisers are not recommended for the prophylactic treatment of food
allergy
B-Long-term management strategies
B1-Elimination Diet
34
infants and young children. Amino acid formulas can be recommended as well
especially for a subgroup of patients with more severe symptoms. ,
Soy formulas should not be recommended before 6 months of age and at any age in
the presence of gastrointestinal symptoms. From 6-12 months it can be considered on
a case-by-case basis.
I
B
(10)
Currently, probiotic supplements cannot be recommended for the management of food
allergy
I
D
(68-69)
Patients and caregivers need to be informed about the foods that should be avoided,
and practical advice given on avoidance measures, how to recognize a further reaction
and the self-management of these reactions
The diagnosis of food allergy should, with permission, be communicated to all relevant
care-givers
V
D
Expert opinion
V
D
Expert opinion
Patients/carers should be encouraged to join an appropriate patient support
organization
V
D
Expert opinion
All patients with food allergy require a management plan with appropriate education for
the patient, caregiver including school
V
D
Expert opinion
Education should cover allergen avoidance, symptom recognition and indication for
specific treatment and administration of specific mediation
V
D
Expert opinion
Absolute indications with adrenaline auto-injector include previous anaphylaxis to any
food,food allergy associated with persistent or severe asthma, exercise induced food
dependent anaphylaxis, and mastocytosis
IV
D
Expert Opinion ,
Guidelines Chapter
Refer
to
the
Anaphylaxis
IV-V*
C-D*
Expert Opinion ,
Guidelines Chapter
Refer
to
the
Anaphylaxis
B2- Education and Risk Assessment
Relative indications for adrenaline auto-injector with food allergy include (1) food
allergies that are likely to be persistent; (2) mild-to-moderate allergic reaction to peanut
and/or tree nut (3) mild-to-moderate reaction to very small amounts of food and (4)
specific high risk groups, eg adolescents, young adult males, poor access to medical
care .
35
Adrenaline should be immediately administered for cardiovascular symptoms and / or
respiratory symptoms such as altered voice, stridor or bronchospasm that is thought to
be induced by food allergy
IV
C
Refer to the Anaphylaxis Guidelines Chapter
Short acting beta agonists should be included in the management planfor all patients
with co-existing asthma and should be administered for bronchospasm after
adrenaline has been administered
V
D
Expert Opinion, Refer to the Anaphylaxis Guidelines
Chapter
Patient held glucocorticosteroids may be given with reactions to possibly prevent late
phase respiratory symptoms (self administered if travelling far from medical care,
otherwise in emergency center)
V
D
Expert Opinion, Refer to the Anaphylaxis Guidelines
Chapter
Any patient who has received adrenaline should be reviewed in an emergency
department
IV
D
Expert Opinion, Refer to the Anaphylaxis Guidelines
Chapter
Food allergen-specific immunotherapy for primary food allergy is a promising immunemodulatory treatment approach , but it is associated with risk of adverse reactions,
including anaphylaxis ; it is therefore not at present recommended for routine clinical
use. In light of its potential benefit, it should be performed only in highly specialized
centres (combining staff with high expertise and adequate equipment) and according
to a clinical protocol approved by the local ethics committee
III
C
(10)
Immunotherapy in patients with respiratory symptoms /allergy to inhalant allergens that
may also cause cross reactive food allergy, specific immunotherapy is recommended
for the treatment for the respiratory symptoms but currently not for the primary
treatment of crossreactive food allergy.
IV
D
Expert Opinion
IV
D
(10)
B3- Specific Immunotherapy
B4- Anti-IgE
The use of anti-IgE alone or in combination with specific immunotherapy is currently
not recommended for the treatment of food allergy even though it represents a
promising modality.
B5-Challenges at regular intervals to assess achievements of tolerance
36
OFC should be performed at regularly at intervals appropriate for the specific food and
patients history in order to assess achievement of tolerance.
V
D
Expert Opinion
Specific IgE testing (in vitro and Skin-prick-test) has limited value in guiding adequately
the timing of Oral Food Challenges for development of tolerance.
V
D
Expert Opinion
III-IV**
D
Expert Opinion
IV
D
(71,73)
B6- Cofactors
In food allergic reactions, the potential augmenting role of augmentation factors. ie
such as exercise, NSAID, omeprazol or alcohol intake, should be assessed in a
structured history
In allergic reactions occurring after exercise, NSAID or alcohol intake, underlying food
allergy to foods consumed in the previous hours should be assessed (especially
gliadin sensitization or LTP in southern Europe)
678
679
37
680
Conclusions and future perspectives:
681
Food allergy appears to be an increasing burden, which needs to be properly
682
addressed in a structured diagnostic and management approach. The overall body of
683
evidence indicates that patient’s clinical history through the use of structured
684
questions on symptoms, food and background information, should guide the allergy
685
testing as IgE sensitization does not always result in clinical relevant food allergy.
686
SPT and sIgE (and probably CRD) offer high sensitivity in relation to a range of
687
allergens implicated in immediate IgE mediated food allergy. Direct comparisons
688
among the tests are difficult for the limited body of evidence in which these tests
689
have been compared in the same population. In addition, there is greater variation in
690
the specificity of these tests, with specific IgE tending to a higher rate of false
691
positive. There is limited evidence for the APT reporting poorer test properties than
692
SPT and sIgE. Local decisions about which test to employ and prioritize should
693
consider the above considerations, the comparability of the population and the
694
relative availability, safety and costs of the tests.
695
An elimination diet based on an allergy focused clinical history and allergy testing
696
should be followed until a significant relief of symptoms is achieved and carefully
697
evaluated for nutritional factors and confounding variables. Given the tests limitation
698
OFC and ideally DBPCFC, still is the gold standard in IgE and non-IgE mediated food
699
allergy both for establishing a firm diagnosis and to determine threshold reactivity,
700
achievement of tolerance and response to food allergy immunotherapy. However,
701
facilities are lacking in this regard and reimbursement policies vary across national
702
European countries. Efforts should be provided to adequate equal diagnostic facilities
703
and capabilities to all food allergic patients in Europe.
704
The optimal management of food allergy consists of a multi-disciplinary and multi-
705
faceted approach, which encompasses treatment of acute episodes of the disease,
706
identification of patients at risk of severe reactions and long-term management
707
strategies in order to minimize recurrences of reactions and improve quality of life.
708
Although there are several management strategies available, the evidence of
709
effectiveness is very limited in this context. The data on pharmacologic treatment is
710
limited, H1-antihistamines can be considered only for alleviating acute non-life
711
threatening symptoms, whilst there is no evidence for any benefit from anti-
712
inflammatory drugs and mast-cells stabilizers. There is some evidence to
713
recommend some alternatives to cow’s milk formula in infants such as extensively
38
714
hydrolyzed formulas with documented hypoallergenicity and amino acids formulas.
715
However, as few extensively hydrolyzed formulas have been investigated with regard
716
to
717
formulas, including children with newly documented cow’s milk protein allergy, are
718
required. Dietary avoidance, which should be restricted to the properly identified
719
culprit food(s), is the cornerstone of treatment along with the provision of self-
720
injectable adrenaline for severe reactions. There is currently no evidence for
721
recommending probiotics and prebiotics with the aim to induce tolerance, although
722
there might be new findings in this field in the near future. Facilitated access to
723
allergy consultations, counseling by dietitians with competencies in food allergy,
724
psychological interventions as well as coordination among the several healthcare
725
professionals dealing with the various clinical manifestations of the disease should all
726
be ideally put in place for the effective treatment of these patients.
727
More proactive treatment is urgently needed. Findings suggest that immunotherapy
728
for
729
epicutaneous) or with heat-modified food, may help to increase threshold of reaction
730
in case of accidental exposure.
731
mediated food allergy but is associated with a significant risk of local and systemic
732
reactions. Overall, oral immunotherapy should be performed in highly specialized
733
clinical settings under supervision by an allergist with expertise in the field. As long
734
term strategy, further research is required into whether immunotherapy could be
735
offered in daily clinical practice.
hypoallergenicity, studies properly designed, for safety and efficacy of these
food
allergy
through
several
routes
(subcutaneous,
sublingual,
oral,
Oral immunotherapy may be valuable for IgE
736
737
Education is a key feature in the management of food allergy and should be heavily
738
promoted to patients, families and caregivers as well as to health professionals.
739
Developing and validating educational tools will further the establishment of vertical
740
and horizontal networks between Centres of Excellence, allergy specialists and
741
primary care practitioners as well as the implementation at the community level
742
through partnership with the patient’s organizations. (Community Guidelines chapter
743
to be finalized) Proper policies for reimbursement from national health systems and
744
insurance bodies for both the diagnostic procedures and the management strategies,
745
including education, should be implemented in the context of a public health
746
approach.
747
.
39
748
Box 6: Gaps and research needs in the diagnosis of food allergy
Gaps in the evidence
Plan to address
Priority
A-Patient’s clinical History
Lack of studies comparing the accuracy of predictions made using standardised
expertly compiled allergy-focused dietary history questionnaires to that obtained
following all stages of the food allergy diagnostic pathway including double-blind,
placebo-controlled oral food challenge.
More studies modelling the use of history and tests to predict the diagnosis of
different types of food allergy in both, children and adults.
Randomized control trials
1
Development of mathematical models
1
There is an urgent need for well-designed randomized
studies on both, routine diagnosis including CRD and
novel approaches including BAT, and linear IgE epitope
mapping
1
Need for studies on the procedure of avoidance diets
during the diagnostic phase
2
Need for more studies to harmonize protocols for open
and blinded challenges in relation to age
More studies needed to investigate the bias between
open v’s blinded challenges
More randomized controlled Trials
2
More research needed in secondary and third level
centres
More research needed in assessing inter and intra
individuals interpretation of symptoms
3
B- Determination of sensitization
Lack of well-designed studies
C-Elimination diets for diagnostic purposes
Lack of well-designed studies
D-Oral challenge tests
Lack of standardized protocols for open and blinded challenges in adults and children
Comparison between open v’s blinded challenges
Comparison of different challenge protocols – open v’s blinded in different age groups
and in children with different allergic disease.
Lack of evidence addressing the utility of different challenge protocols in different
clinical setting
Scarce evidence in validation of diagnostic criteria; subjective vs. objective during the
challenges
40
2
2
2
Lack of validated age-appropriate OFC recipes (active and placebo)
More studies for validation of recipes
2
Need of properly designed information and education
programmes on allergy diagnostic tests for health
professionals and the public
Need to facilitate access to qualified allergy services
Socio-economic evaluation of misdiagnosis of food
allergy:
A misdiagnosis compared to diagnosis in qualified
allergy centre
B. the overall costs of misdiagnosing compared to the
costs of establishing a qualified allergy service
2
E-Unconventional tests (including specific IgG testing)
Lack of knowledge among the public of the ineffectiveness of these test
Lack of understanding of the costs related to misdiagnosis
749
750
41
2
751
Box 7: Gaps and research needs in the management of food allergy
Gaps in the evidence
Plan to address
Priority
A- Acute Management
Biomarkers for identifying patients at risk of severe reactions
More research in biomarkers identification.
1
More research for the development of prophylactic drugs
2
High quality prospective studies of infants and young children on
e.g. efficacy, growth and quality of life
High quality prospective studies of adults on e.g. efficacy,
nutritional status and quality of life
High quality prospective randomised controlled trials of infants
and young children and adults with documented food allergy
Large cohort studies of cow’s milk allergic children comparing the
cost effectiveness of the two types of formulas in infants at
different ages and different clinical symptoms
High quality prospective randomised controlled trials of infants
and young children with documented food allergy
2
High quality prospective randomised controlled trials of infants
and young children and adults with documented food allergy
2
Randomized controlled study looking at the how different facets
of education impact on patients’ competency
2
Randomised controlled study comparing the impact of different
educational approaches to patients’ competency
2
Antihistamines and Mast Cell Stabilizers
Lack of effective prophylactic drugs in the management of food allergy
B- Long-term Management
B1-Elimination Diet
The long term effect of dietary avoidance on nutrition and quality of life
The possible effect of using modified food allergens e.g. baked milk and egg to
improve and accelerate tolerance
Indications for the use of amino acid formulas versus extensively hydrolysed
formulas
Long term nutritional drawback of rice and soy formulas
The effect of supplementation with different probiotic strains for management of
food allergy
1
2
2
B2- Education and Risk Assessment
The key areas (eg physician, clinical nurse specialist, dietician, simulation
training) that should feature in the education process to allow patients to achieve
competence in managing their food allergy
The optimal approach to educating patients and their caregivers
42
B3-Specific Immunotherapy
What is the: a) effectiveness; b) risks; c) cost-effectiveness and d) long-term
benefits and risks of food allergen-specific immunotherapy for primary food
allergy for specific food allergies?
Long term outcomes needs to be determined
Large multicenter trials for different allergens and route of specific
immunotherapy with foods
1
Clinical trials applying longer observation periods
1
What is the effectiveness, risks and cost-effectiveness and of allergen specific
immunotherapy to pollens in those with pollen associated food allergy?
Prospective Clinical studies
2
What is the efficacy of immunotherapy for pollen allergy in preventing the
development of pollen associated food allergy
Prospective Clinical Studies
2
Does the use of biologicals (e.g. anti-IgE) in the context of food allergen-specific
immunotherapy for primary food allergy a) enhance the effectiveness of
treatment and /or b) reduce the risks of severe adverse reactions?
B4-Anti-IgE
Prospective Clinical studies
1
Identification the subsets of patients that would benefit the most from
omalizumab.
Large multi-centre trials are however needed to confirm the
above findings
2
Effect of anti-IgE with desensitization to foods
On-going trials examining the use of omalizumab with
desensitization protocols.
2
Large cohort studies complemented by evaluation of biomarkers
for development of tolerance
2
Controlled data to assess epidemiology, co-factors and allergens, with
challenges
Controlled studies
2
Mechanisms involved in the amplifying role of cofactors
Pathophysiological studies in animal models and humans
2
B5- Challenges at regular intervals to assess achievements of tolerance
No evidence of the proper intervals in repeating challenges.
Lack of tests valuable in assess the development of tolerance
B6- Co-factors
43
Controlled data to assess epidemiology, co-factors and allergens, with
challenges
Controlled studies
2
Lack of relevant data for infections, menstrual cycle and stress
Observational studies
3
44
752
Acknowledgements
753
754
Authors’ contribution
755
756
Conflicts of interest
757
758
45
759
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57. Agata H, Kondo N, Fukutomi O, Shinoda S, Orii T. Effect of elimination diets
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on food-specific IgE antibodies and lymphocyte proliferative responses to food
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antigens in atopic dermatitis patients exhibiting sensitivity to food allergens.
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The Journal of allergy and clinical immunology 1993;91(2):668-679.
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58. Alonso A, Seoane MA, Iraneta SG, Scavini LM, Rodriguez SM. A citrus fruit-
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the International Association of Asthmology 1994;4(3):146-148.
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59. Lever R, MacDonald C, Waugh P, Aitchison T. Randomised controlled trial of
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advice on an egg exclusion diet in young children with atopic eczema and
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sensitivity to eggs. Pediatric allergy and immunology : official publication of the
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European Society of Pediatric Allergy and Immunology 1998;9(1):13-19.
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60. Chen JL, Bahna SL. Spice allergy. Annals of allergy, asthma & immunology :
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2011;107(3):191-199; quiz 199, 265.
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61. Hill DJ, Murch SH, Rafferty K, Wallis P, Green CJ. The efficacy of amino acid-
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based formulas in relieving the symptoms of cow's milk allergy: a systematic
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review. Clinical and experimental allergy : journal of the British Society for
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Safety and efficacy of a new extensively hydrolyzed formula for infants with
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cow's milk protein allergy. Pediatr Allergy Immunol 2008;19(4):348-354.
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63. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al.
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Diagnostic approach and management of cow's-milk protein allergy in infants
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Gastroenterol Nutr 2012;55(2):221-229.
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64. EEC – European Communities Commission amending Directive 91/321/EEC
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immunologic background and criteria for hypoallergenicity. Pediatr Allergy
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Immunol 2004;15(2):103-111.
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66. Muraro A, Dreborg S, Halken S, Host A, Niggemann B, Aalberse R, et al.
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studies and final recommendations. Pediatr Allergy Immunol 2004;15(4):291-
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69. Ellis MH, Short JA, Heiner DC. Anaphylaxis after ingestion of a recently
introduced hydrolyzed whey protein formula. J Pediatr 1991;118(1):74-77.
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70. Vita D, Passalacqua G, Di Pasquale G, Caminiti L, Crisafulli G, Rulli I, et al.
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comparison with goat's milk. Pediatr Allergy Immunol 2007;18(7):594-598.
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71. Jirapinyo P, Densupsoontorn N, Wongarn R, Thamonsiri N. Comparisons of a
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chicken-based formula with soy-based formula in infants with cow milk allergy.
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72. Galli E, Chini L, Paone F, Moschese V, Knafelz D, Panel P, et al. [Clinical
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comparison of different replacement milk formulas in children with allergies to
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cow's
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study].
Minerva
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73. Hol J, van Leer EH, Elink Schuurman BE, de Ruiter LF, Samsom JN, Hop W
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et al. The acquisition of tolerance toward cow's milk through probiotic
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supplementation: a randomised, controlled trial. J Allergy Clin Immunol
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2008;121(6):1448-1454.
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74. Muraro A, Roberts G, , Worm M, et al. Anaphylaxis: guidelines from the
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A, et al. Co-factor-enhanced food allergy. Allergy 2012;67(10):1316-1318.
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76. Romano A, Scala E, Rumi G, Gaeta F, Caruso C, Alonzi C, et al. Lipid transfer
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proteins: the most frequent sensitizer in Italian subjects with food-dependent
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exercise-induced anaphylaxis. Clinical and experimental allergy : journal of the
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British Society for Allergy and Clinical Immunology 2012;42(11):1643-1653.
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77. Miller JB. A double-blind study of food extract injection therapy: a preliminary
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report. Annals of allergy 1977;38(3):185-191.
78. Asero R. Effects of birch pollen-specific immunotherapy on apple allergy in
birch pollen-hypersensitive patients. Clin Exp Allergy 1998;28(11):1368-1373.
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79. Bucher X, Pichler WJ, Dahinden CA,Helbling A. Effect of tree pollen specific,
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subcutaneous immunotherapy on the oral allergy syndrome to apple and
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hazelnut. Allergy 2004;59(12):1272-1276.
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80. Mauro M, Russello M, Incorvaia C, Gazzola G, Frati F, Moingeon P,
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Birch-apple
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immunotherapy. Int Arch Allergy Immunol 2011;156(4):416-422.
birch
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81. Fernandez-Rivas M, Garrido Fernandez S, Nadal JA, Diaz de Durana MD,
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Garcia BE, Gonzalez-Mancebo E, et al. Randomized double-blind, placebo-
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controlled trial of sublingual immunotherapy with a Pru p 3 quantified peach
1020
extract. Allergy 2009;64(6):876-883.
1021
82. Garcia BE, Gonzalez-Mancebo E, Barber D, Martin S, Tabar AI, Diaz de
1022
Durana AM, et al. Sublingual immunotherapy in peach allergy: monitoring
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molecular sensitizations and reactivity to apple fruit and Platanus pollen.
53
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Journal of investigational allergology & clinical immunology : official organ of
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the International Association of Asthmology 2010;20(6):514-520.
1026
83. Kinaciyan T, Jahn-Schmid B, Radakovics A, Zwölfer B, Schreiber C, Francis
1027
JN, Ebner C, Bohle B. Successful sublingual immunotherapy with birch pollen
1028
has limited effects on concomitant food allergy to apple and the immune
1029
response to the Bet v 1 homolog Mal d 1. J Allergy Clin Immunol. 2007
1030
Apr;119(4):937-43.
1031
84. Keet CA, Wood RA, Matsui EC. Limitations of reliance on specific IgE for
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epidemiologic surveillance of food allergy. J Allergy Clin Immunol. 2012
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Nov;130(5):1207-1209.
1034
85. Nadeau KC, Schneider LC, Hoyte L, Borras I, Umetsu DT. Rapid oral
1035
desensitization in combination with omalizumab therapy in patients with cow's
1036
milk allergy. J Allergy Clin Immunol 2011;127(6):1622-1624.
1037
54
1038
Table1 Summary of the pooled prevalence of food allergy (FA) in Europe, by age and
1039
region: studies published 1 January 2000 – 30 September 20121
Point prevalence of
symptoms plus
Self-reported FA
Point prevalence of
sensitization to at least one
Percentage (95% CI)
sensitization to at least
Point
Point
one food allergen
prevalence of
prevalence of
Percentage (95% CI)
convincing
challenges or
clinical history
DBPCFC
or open food
positivity
food allergen
open food
Percentage (95% CI)
Lifetimeprevalence
Symptoms
Symptoms
challenges or
plus
plus skin
DBPCFC
Percentage
Point
Specific-
Skin prick
specific-
prick test
positivity
(95% CI)
prevalence
IgEpositivity
testpositivity
IgE
positivity
2
Percentage
positivity
(95% CI)2
All
17.3 (17.0-17.6)
5.9 (5.7-
10.7 (9.4-10.8)
3.0 (2.7-3.3)
6.1)
2.7 (1.7-
1.5 (1.3-
3.7)
1.7)
3.6 (2.8-
1.5 (1.3-
4.4)
1.7)
2.2 (0.8-
___6
2.6 (2.1-3.1)
0.9 (0.8-1.1)
2.6 (2.1-3.1)
1.0 (0.8-1.2)
___6
0.9 (0.8-1.0)
___6
3.1 (2.6-3.7)
Age
Children
17.4 (16.9-18.0)
(0-17
6.9 (6.6-
12.2 (11.4-
7.2)
13.1)
5.1 (4.8-
4.1 (3.2-5.1)
___6
17.2 (16.0-17.6)
yrs)
Adults (≥
3.0 (2.7-3.3)
5.3)
3.7)
18 yrs)
Region3
Western
23.8 (22.9-24.7)
Europe
41.6 (39.5-43.7)
Eastern
Europe
Southern
8.6 (8.2-9.0)
30.3 (28.7-31.9)
11.7 (9.8-13.6)
3.5)
___6
6
3.3 (1.2-
___
5.4)
9.8 (9.0-10.5)
3.5 (2.5-
___6
4.5)
14.5 (13.9-
1.8 (1.5-2.1)
Europe
19.2 (18.6-19.8)
5.0 (4.6-
2.6 (1.3-
1.4 (1.1-
3.8)
1.7)
6
6
___
6
___
6
___
5.4 (4.6-6.1)
6
___
___
___6
0.2 (0.1-0.3)
2.3)
2.6 (2.1-3.1)
1.1 (0.9-1.3)
1.6 (0.9-
___6
___6
6
___
4.2 (2.2-6.3)
15.2)
4
Northern
3.3 (3.1-
1.8 (1.3-
3.0 (2.1___6
3.9)
5.5)
2.3)
___6
Europe
___6
5
Europe
1040
1041
1
1042
1043
2
1044
1045
3
1046
4
1047
1048
5
The pooled prevalence of FA was based on random-effects meta-analysis for 30 clinically and methodologically comparable
studies
Where a study reported estimates for both open food challenges and DBPCFC, the DBPCFC estimates were always used;
otherwise open food challenges estimates were used if DBPCFC was not done in the study
European
region
were
classified
based
on
the
United
(http://unstats.un.org/unsd/methods/m49/m49regin.htm#europe accessed on December 28, 2012).
Nations
classification
We further added studies from Turkey into Southern Europe
For studies that included several European countries and gave overall estimate for all the countries and in which it was not
possible to calculate the frequency for each country studied
55
1049
6
No study undertaken for this group for this particular outcome
1050
1051
56
1052
Table 3: Indications of oral challenge tests
Indication
Rationale
Demonstrate Allergy
Equivocal diagnostic outcome despite use of detailed clinical
history and allergy testing.
Suspected food allergic reaction for which the cause is
uncertain despite allergy testing (e.g. composite meal eaten).
Determine threshold dose of causative allergen source.
Demonstrate tolerance
1. Allergy suspected to have been outgrown.
2. When allergy tests suggest tolerance, but food never eaten
and patients and/or parents too cautious to introduce at
home.
3. Cross-reactivity suspected, e.g. a patient with a low
positive IgE result to hazelnut but high positive birch pollen
sensitization.
4. When the diet is restricted due to a suspicion that one or
more foods is resulting in delayed allergic symptoms e.g.
eczema.
Monitor therapy for food
allergy
To monitor response to immunomodulatory treatment in
research setting.
1053
1054
57
1055
Table 4: Variables associated with oral food challenges
Challenge related variables:
Design


Open (Cumulative or
Incremental)
Blinded (Single or Double
blinded)
Form of challenge food
Design selected according to the indication and purpose
for which the challenge is being performed
The challenge food should closely replicate the usual
edible form of the food or form of the food implicated in
allergic reaction.
Food processing, and the food matrix can significantly
influence allergenicity of the food e.g baked vs raw egg.
For OFC’s performed to diagnose the Pollen Food
Syndrome, fresh fruit and vegetables should be used as
the responsible proteins are commonly heat labile.
Choice of food matrix
Strictly avoid use of allergenic ingredients for individual
patient
Minimise number of ingredients used
Provide adequate allergen protein in a manageable
portion size
For placebo foods sensory qualities should closely
replicate those of active challenge food
Doses

Number of doses

Initial dose
In most cases titrated often with half-logarithmic dose
increments. If a negative outcome is anticipated, and
there are no safety concerns, a single cumulative dose
is appropriate.
In clinical settings 3 mg of food protein (corresponding
to higher amounts of individual foods!) seems adequate
for the most common food allergens such as cow’s milk,
hen’s egg, peanuts and tree nuts. Low doses used for
threshold studies in research setting or for patients at
high risk of a severe reaction.
58

Top dose
Equivalent to an ‘age appropriate’ portion, 3 g of food
protein seems adequate for the most common food
allergens such as cow’s milk, hen’s egg, peanuts and
tree nuts. At least 15 minutes for immediate symptoms.
Adjust intervals depending on patient history

Total cumulative dose
Usually completed within 8 hours (immediate
symptoms) and 1-4 weeks (delayed symptoms)

Time intervals between
doses
15 – 30 minutes, but may be adjusted to the patient’s
history
1056
1057
59
1058
Figure 1 Algorithm on the diagnosis of food allergy
1059
1060
1061
1062
1063
1064
1065
1066
1067
1068
1069
60
1070
Figure 2: Algorithm for Oral Food Challenge:
1071
1072
1073
1074
1075
1076
1077
61
1078
Appendices:
1079
i.
Systematic Review of epidemiology of food allergy
1080
ii.
Systematic Review of diagnosis of food allergy
1081
iii.
Systematic Review of management of food allergy
1082
iv.
Tools to support the implementation:
1083
a. Key questions for patient’s clinical history
1084
b. Key observations
1085
c. Interpreting allergy tests
1086
d. Oral Challenges: recommended doses.
1087
1088
v.
Barriers and facilitators to implementation, audit criteria and resource
implications of recommendations
1089
1090
1091
1092
1093
1094
62
1095
Appendix IV: Tools to support Implementation:
1096
A: Key Questions in the patients´ history of possible food allergy
TABLE IV-A: Questions
Description of foodinduced allergic
symptoms
 What were the exact symptoms and timing there of? How were the
symptoms treated? What was the time of the resolution of
symptoms?
Eliciting food
allergen
 Which food induced the reaction? Is the allergen typical for age and
country?
Timing of the
reaction post
exposure
 How long after exposure did the reaction develop?
Reproducibility
 Is the reaction reproducible?
Food Processing
Does the reaction happen with processed and/or raw food
Route of allergen
exposure
What was the route of exposure to the food?
Amountof allergen
 How much of the food allergen did the patient have before
reacting?
Concomitant
diseases
 Does the patient have other medical conditions, including atopic
diseases?
Co-factors
 Did the patient exercise or take any alcohol or drugs before or after
eating the index food?
Co and Cross
reactivity
 Are related allergens eaten and tolerated?
 Is there cross-reactivity between inhalant allergens and food
allergens
Other foods
Is the patient allergic to latex
 Is the patient able to eat ... (name specific foods)?
Dietary intake
 Is the presence of a food allergy compromising dietary intake?
History of previous
elimination diets
 Did the patient follow elimination diets previously? Was it helpful?
1097
1098
63
1099
Appendix IV: Tools to support Implementation
1100
B: Key Observations:
TABLE IV-b: KEY OBSERVATIONS
 E.g milk and egg allergy are common in early childhood but comparatively rare in
adulthood. Shellfish and plant food allergies are more common in adulthood.
 An understanding of common regional allergens will guide subsequent allergy
testing
 Symptoms indicate possible underlying immunological mechanisms, namely IgE or
non-IgE-mediated.
 If the symptoms are not typical of an immune-mediated reaction then a differential
diagnosis must be considered.
 Confusing diagnostic scenarios in immediate-type reactions include: perioral
erythema and irritation provoked by contact with skin irritants (e.g. raw tomato,
citrus and berries), scromboid fish reactions, and chronic urticaria (for which food
allergy is a rare cause).
 In some children food allergy may masquerade as a food aversion or refusal, but
this may also be behavioural, due to oral tactile aversions, or odour sensitivity.
 A history of severe allergic reactions determines a different risk assessment and a
more stringent management plan.
 IgE-mediated allergic reactions usually occur within 20 minutes of the ingestion
and mostly within 2 hours.
 Non-IgE mediated immune reactions are typically more delayed in onset.
 Non-immune mediated reactions can be of both immediate and delayed onset
 Allergic reactions to a specific food should be consistent and develop every time
the patient is exposed to that food.
 In children, peanut reactions typically present after the first known exposure,
whereas other foods such as wheat, milk and fish, may present after multiple
exposures.
 However adults may have eaten peanuts and tree nuts for many years before
developing an allergy.
 Clinical reactivity may be influenced by processing of the food e.g. egg allergic
children commonly tolerate baked-egg protein whilst reacting to loosely cooked
egg. In adults, soy may be tolerated in some forms but soy milk may provoke
reactions in those with pollen-food syndrome.
 Patients with pollen-food syndrome usually tolerate cross reacting foods when
eaten cooked but develop symptoms when eaten raw.
 In breast-fed infants, food allergens may be transmitted via human milk.
 Allergic reactions may occur after exposure to airborne allergen vapour, typically
fish and milk.
 A proportion of patients will react after skin contact or inhalation.
 Different patients react to different doses of the food allergen.
 The dose of allergen eaten is also important to establish tolerance, e.g. if a child
has had a food regularly in very small amounts may not mean she/he would
tolerate the food if she/he ate a larger amount.
 The majority of children with food allergy will have eczema, and at least 25% will
go on to develop additional food allergies.
 Food allergic infants are at risk for the development of asthma; and asthma is a
risk factor for more severe-food induced allergic reactions in all age groups.
 Adults with food allergy will often be sensitised or allergic to pollen, and therefore
64
more likely to develop pollen-food syndrome. More than 50 % of those with birch
pollen allergy will report symptoms to plant foods due to cross-reactions.











Asthma, medication use (esp. ACEI, -blockers,
acetyl salicylate), alcohol intake and/or exercise are factors, which may increase
the severity of allergic reactions.
Allergy to just one food is increasingly uncommon. The patient with peanut allergy
is commonly sensetized to one or more tree nuts and or sesame.
People with pollen-food syndrome often report reactions to many different fruits,
nuts and vegetables
Some latex allergens are homologous to certain food allergens such as kiwi,
avocado and chestnuts
Ask specifically about common allergenic foods, including foods causing co- and
cross-reactivity with the index food.
Ask whether foods which might contain the suspected allergen are tolerated e.g. is
multi-grain bread tolerated if soy is suspected,
Ask if a child is able to consume age-appropriate quantities of specific foods e.g. a
5 year old should be able to consume a whole egg/full glass of milk before being
labelled as truly tolerant to the food.
In the absence of dietetic supervision, all children with food allergy are at a greatly
increased risk for nutritional compromise.
Adults, who are avoiding major food groups such as milk or wheat, will also have a
compromised nutritional intake.
Elimination diets without decrease of symptoms should be stopped.
1101
1102
1103
1104
1105
1106
1107
1108
1109
1110
1111
1112
65
1113
Appendix IV: Tools to support Implementation
1114
C: Interpreting Allergy Tests:
1115
The performance of allergy tests for the diagnosis of food allergy should ideally be
1116
validated against the gold standard investigation i.e. the DBPCFC.
1117
There are studies, in different clinical scenarios and geographic settings that assess
1118
the diagnostic ability of allergy tests (SPT and/or sIgE) as compared to the DBPCFC.
1119
These analyses allow for the generation of 2x2 tables and sensitivity and specificity
1120
values.
1121
Sensitivity refers to the proportion of patients with a condition who test positive. For
1122
the diagnosis of food allergy, sensitivity of SPT and Sp-IgE is variable and allergen
1123
specific e.g. for peanut modestly high at around >80%. Specificity refers to the
1124
proportion of persons without the condition who test negative; for food allergy the
1125
specificity of the SPT and PN-IgE is lower than the sensitivity, e.g. 30% to 50% for
1126
peanut.A highly sensitive test is good at ruling out a diagnosis when the test is
1127
negative. A specific test is good at confirming a diagnosis when the test is positive.
1128
The size of the test value (SPT and or Sp-IgE) that is to be considered ‘positive’
1129
dramatically alters the sensitivity/specificity of an investigation. Whilst it is useful to
1130
consider extreme values (both positive and negative) – as thesecarry better
1131
sensitivity or specificity – most patients seen in routine referral clinical settings .will
1132
not present with test results at the extreme. This may result in an equivocal
1133
diagnostic outcome (history depending) that can only be resolved through performing
1134
an OFC.
1135
As it is difficult to use sensitivity and specificity at the level of the individual, Positive
1136
and Negative predictive values are frequently utilized. The positive predictive value is
1137
the probability that a patient has food allergy if the test is positive (positive predictive
1138
value, PPV); the negative predictive value is probability that the patient does not
1139
have food allergy if the test is negative (negative predictive value, NPV). However,
1140
these predictive values are population dependent and influenced by the food allergen
1141
in question, background history, age, sex, geographic location, ethnicity, concomitant
1142
allergies e.g. eczema. It is therefore not easily possible to apply predictive values
1143
across different population and in different settings.
1144
66
1145
Given the above challenges, use is increasingly being made of likelihood ratios (LR)
1146
which offer a different diagnostic approach that is more practicable at the level of the
1147
individual patient. Indeed, the use of LR’s reflects the natural thought process that is
1148
undertaken by clinicians in routine medical diagnostic practice i.e. a determination is
1149
made of the pre-test probability of a condition (food allergy) being present prior to the
1150
test (in allergy, SPT and or sIgE); with the allergy test result known, a post-test
1151
probability is then determined by combining these two values and a decision
1152
regarding management can then be made. For the diagnosis of food allergy this
1153
crucial decision to be taken is whether the patient should undergo an OFC or not.
1154
1155
A LR reflects how many times more likely a given test result is seen in a patient who
1156
is allergic to that food compared with a patient who is tolerant. The further the LR is
1157
above 1 the stronger the evidence for the presence of the disease. A LR ‡10 is highly
1158
suggestive of food allergy. The pre-test probability is determined through combining
1159
the likely risk determined through clinical history, data on the local prevalence of the
1160
disease, personal clinical experience and published reports. Importantly, the use of
1161
the LR places emphasis on obtaining a robust clinical history as well as an
1162
understanding of the disease in a local setting.
1163
1164
The LR of the test – given only two allergy outcomes – can be calculated directly
1165
from sensitivity and specificity, LR [sensitivity/(1−specificity)]. The post-test
1166
probability is determined by this mathematical calculation or by using a simple
1167
statistically derived nomogram Fig. 1. A nomogram can simplify this calculation to
1168
percentages rather than odds
1169
The use of a LR has the advantage of giving us the ability to interpret allergy tests
1170
within the subject’s clinical context, as different patients in diverse clinical settings,
1171
but with the same test result, have different likelihoods of having food allergy
1172
67
1173
Figure IV-C. Using likelihood ratios (LR) to diagnose allergy –
1174
Likely Allergic
Test results high
Test resultslowmopderate
Test resultsnegativeorlow
Consider Challenge
Pre-test
Probability
Likelihood Post test
Ratio
Probability
1175
1176
Figure adapted from: Fagan TJ. Nomogram for Bayes theorem. N Engl J Med. 1975;293:257
1177
1178
The three arrows are examples of clinical situations which can occur in different
1179
patients as outlined in the table S1 below (Red arrow refers to scenario A, green to B
1180
and blue to C)- .
1181
1182
1183
Likely Tolerant - introduce
1184
1185
1186
1187
68
1188
Figure IV-D. An approach to diagnosing food allergy
Likelihood of clinical
allergy from history
Likelihood of clinical allergy from
specific IgE (KU/L) or SPT (mm) results
Low
(<0.35 or <3)
Intermediate
(0.35 to <15 or 3 to <8)
High
(15 or 8)
High
eg urticaria and
wheeze on 2
exposures
Possible allergy
Probable allergy
Allergy
Intermediate
eg urticaria on a single
exposure
Possible allergy
Possible allergy
Probable
allergy
Low
eg non-IgE symptoms
No allergy
Possible allergy
Possible
allergy
Children and adolescents in the possible allergy box require an OFC for a definitive diagnosis. Specific IgE and SPT
values are specific for peanuts. Values associated with a high likelihood of clinical allergy are lower for egg, milk and
fish Modified from Stiefel G, Roberts G. How to use serum specific IgE measurements in diagnosing and monitoring
food allergy. Arch Dis Child Educ Pract Ed 2012; 97: 29–36.
1189
1190
1191
69
1192
Table IV E: Clinical examples that relate to the diagnosis of peanut allergy:
1193
1194
1195
1196
1197
1198
1199
1200
1201
Scenario
History
Pre-test
probability
Test results
Management
A
5 yr old, British,
male. 3 previous
allergic reactions
soon after peanut
butter ingestion
At least
98%chance as
guided by history
SPT 8mm, LR
approx 17.3 (in
UK)
Strictly avoid
peanut.
B
8 yr old, French
female. No allergy
concerns. Sibling
peanut allergic. No
known peanut
exposure.
Epidemiological
risk 7%
No SPT
obtained.
PnIgE 2KU/L
LR approx 2.6
Post test
probability 25%,
consider OFC or
component
testing if not
readily available
C
4yrs old child, in UK,
with egg allergy and
early-onset
moderate eczema.
Never eaten peanut
Epidemiologic
risk of 30%
SPT 3mm, LR
40.3 in UK
Likely allergy
90%
Institute
comprehensive
education and
emergency plan
Footnote:
1. Values will differ by geographic location and should best be determined in the clinical
setting where they are applied. For example, Hazelnut values will perform differently
in parts of Europe where Birch pollen allergy is commonplace; this will also differ with
the age of the patient
2. The action to be taken with each post test LR will differ between clinics and is
influenced by local practice, the family’s preference, and the clinical scenario faced.
70
1202
Appendix IV: Tools for Implementation: Table IV-F: Recommended dosages for DBPCFC with milk, egg, peanut, wheat or soy
Pasteurized
Food
Protein(am
ount of food
protein in
an
incremental
dose of the
challenged
food)
Pasteurized
cow’s milk with 3.3%
protein content
Skim milk
powder
whisked
hen’s egg
with 36%
Soy drink
Hen’s egg
powder
Peanut butter
Peanut
flour
Gluten
powder
with 3.3%
with 50%
with 80%
protein content
Soy powder
with 50%
protein
content
protein
content
protein
content
with 24%
with 47%
protein
content
with 12.8%
protein
content
protein
content
protein
content
#mg
90.9 mg ≈ 0.1 ml
8.3 mg
23.4 mg
6.4 mg
12.5 mg
6.0 mg
3.8 mg
90.9 mg ≈ 0.1 ml
6.0 mg
10 mg
303.0 mg ≈ 0.3 ml
27.8 mg
78.1 mg
21.3 mg
41.7 mg
20.0 mg
12.5 mg
303.0 mg ≈ 0.3 ml
20.0 mg
30 mg
909.0 mg ≈ 0.9 ml
83.3 mg
234.4 mg
63.8 mg
125.0 mg
60.0 mg
37.5 mg
909.0 mg ≈ 0.9 ml
60.0 mg
100 mg
3,030.3 mg ≈ 3.0 ml
277.8 mg
781.3 mg
212.8 mg
416.7 mg
200.0 mg
125.0 mg
3,030.3 mg ≈ 3.0 ml
200.0 mg
300 mg
9,090.9 mg ≈ 9.1 ml
833.3 mg
2,343.8 mg
638.3 mg
1,250.0 mg
600.0 mg
375.0 mg
9,090.9 mg ≈ 9.1 ml
600.0 mg
1000 mg
30,303.0 mg ≈ 30.3
ml
2,777.8 mg
7,812.5 mg
2,127.7 mg
4,166.7 mg
2,000.0
mg
1,250.0 mg
30,303.0 mg ≈ 30.3 ml
2,000.0 mg
6,383.0 mg
12,500.0 mg
6,000.0
mg
3,750.0 mg
90,909.1 mg ≈ 90.9 ml
6,000.0 mg
3000 mg
90,909.1 mg ≈ 90.9
ml
23,437.5 mg
8,333.3 mg
1203
71
1204
1205
Appendix IV- G: Component resolved IgE studies included in the systematic review
1206
Reference ID
Target Food
Component specific IgE
Alessandri, 2012
Hen’s egg
Gal d 1, Gal d 2, Gal d 3,
Gal d 5
Ayuso, 2012
Shrimp
Pen a 1
Glaumann, 2012
Peanut
Ara h 1, Ara h 2, Ara h 3,
Ara h 8, Ara h 9
Flintermann, 2008
Hazelnut
Cor a 1, Bet v 1, Cor a 8,
Pru p 3
Jarlot, 2011
Hazelnut
Cor a 1, Bet v 1, Bet v 2,
Cor a 8
Masthof el al 2013
Hazelnut
Cor a 9 and Cor a 14
Ballmer-Weber, 2001
Carrot
Bet v 1, Bet v 2, Bet v 6
Ballmer-Weber, 2000
Celery
Bet v 1, Bet v 2
Reindl, 2000
Courgette
Bet v 1, Bet v 2
1207
72
Recommendation
Grade
Appendix V: DIAGNOSIS-Barriers and facilitators to implementation, audit criteria and resource implications of recommendations.
Evidence
level
1208
Barriers to
implementation
Facilitators to
implementation
Audit criteria
Patient’s clinical History
Detailed clinical history is essential for the diagnosis of
food allergy:
IV
C
When taking a clinical history eliciting allergens, timing
and chronicity, symptoms, severity and signs,
reproducibility, known risk (co)factors, family history, coexisting medical problems including other allergic
diseases should be addressed
Lack of standardized
questionnaire
Development of standardized
questionnaire
Training of health
professionals
Training of health
professionals
Health professionals
attitudes
Specific education of
healthcare professionals
Poor access to allergy
consultation
Improved access to allergy
consultation
% of patients excluded on the basis of
clinical history
The use of structured questions on symptoms, foods and
other background information is recommended (
APPENDIX TABLE 1)
Determination of sensitization
IV
C
IgEsensitisation does not always result in clinical relevant
food allergy, therefore, specific allergy testing should be
directed by case history
IV
C
73
% patients properly diagnosed with
food allergy
SPT and/or sIgE can be the test of choice depending on
local availability and absolute and relative
contraindications to SPT
IV
C
Lack of public information
Improved information to the
public
Lack of facilities and poor
access to allergy
consultation
Improvement of access to
allergy testing
Increase in allergy testing
Increase of facilities for allergy testing
Improvement of access to
allergy training of primary care
physicians
IgE sensitization to common food allergens is determined
by SPT and serum IgE tests and is used as a support to
the diagnosis of food allergy by clinical history and/or
food challenge. These tests are highly sensitive (75100%). However, specificity of these tests is moderate
(40-70%) and does not replace clinical history and food
challenges.
I-III*
A-C*
Health professionals
attitudes
Specific education of
healthcare professionals
Poor access to allergy
consultation
Improved access to allergy
consultation
Lack of public information
Improved information to the
public
% patients properly diagnosed with
food allergy
Where available, standardized tests and procedures
should be used
IV
C
SEE ABOVE
SEE ABOVE
SEE ABOVE
In the presence of a suggestive history, a negative SPT
or sIgE needs to be interpreted with caution particularly
as these are expected in non-IgE mediated food allergy
IV
C
SEE ABOVE
SEE ABOVE
SEE ABOVE
In case SPT and sIgE tests are inconclusive CRD (if
available) provides additional information
I–
IV*
A–
C*
Lack of facilities
Increase in availability of CRD
testing
% of patients properly diagnosed with
CRD testing
74
Difficulty in interpreting
Training of healthcare
professionals
Reimbursement policies
Costs
If clinical history with SPT and/or sIgE are not highly
predictive (see figure 1), a provocation test is require-
IV
C
Health professionals
attitudes
Specific education of
healthcare professionals
Poor access to allergy
consultation
Improved access to allergy
consultation
Lack of public information
Improved information to the
public
% patients properly diagnosed with
food allergy
Determination of total IgE is particularly useful in patients
with severe eczema who often show very high total IgE
levels which indicates thatpositive specific IgE results
should be interpreted with care.
IV
C
SEE ABOVE
SEE ABOVE
SEE ABOVE
BAT and determination of sIgE to linear epitopes are
promising techniques which should be further studied
V
D
Cost
Reduction of costs
Large cohort trials in food allergic
patients
Research projects
Elimination diets for diagnostic purposes
75
The determination of the foods to be avoided should be
based on the allergy-focused diet history, clinical history
and adjunct allergy testing, i.e. SPTs and/or sIgE
determination.
V
D
Health professionals
attitudes
Specific education of
healthcare professionals
Poor access to allergy
consultation
Improved access to allergy
consultation
Lack of public information
Improved information to the
public
% patients properly diagnosed with
food allergy
For all of the individually avoided foods the results of the
diagnostic elimination diet should be carefully monitored
and evaluated up to 2-4 weeks of avoidance.
V
D
Lack of consultation with
dieticians with
competence in food
allergy
Training of dieticians in food
allergy
Increase in % of dieticians with
competence in food allergy
In case the elimination diet leads to a significant relief of
symptoms, it should be continued until the provocation
test is performed..
V
D
Health professionals
attitudes
Specific education of
healthcare professionals
% patients properly diagnosed with
food allergy
Poor access to allergy
consultation
Improved access to allergy
consultation
Lack of public information
Improved information to the
public
SEE ABOVE
SEE ABOVE
If no significant reduction of symptoms is obtained by
elimination diet, the respective food allergy is highly
V
D
76
SEE ABOVE
unlikely. After the exclusion of confounding factors foods
should be reintroduced into the diet after 2-4 weeks.
Oral challenge tests
The Oral Food Challenge (particularly the double-blind
placebo-controlled food challenge) is the gold standard
investigation for the objective diagnosis of IgE-and nonIgE mediated food allergy.
IV
D
Health professionals
attitudes
Specific education of
healthcare professionals
National guidelines for food allergy.
Increase in number of OFC performed
Poor access to allergy
consultation and lack of
allergy services
Lack of public information
There are many OFC designs available: standardized
procedures should be used in order to achieve a safe
and objective challenge outcome that is patient/research
specific.
OFC’s should be performed in patients who have an
equivocal diagnosis of food allergy
IV
OFC’s should be used to demonstrate allergy or
tolerance and in so doing facilitate safe dietary expansion
or appropriate allergen avoidance.
IV
D
Improved access to allergy
consultation
Development of policies within the
context of the public health approach.
Improved information to the
public
Reimbursement policies
Proper reimbursement from
National Health systems and
Insurance bodies
Lack of information
among healthcare
professionals
Diffusion of proper information
SEE ABOVE
Training ofhealth professional
Lack of training
D
SEE ABOVE
77
SEE ABOVE
SEE ABOVE
The OFC may be performed as an open, single or
double-blinded challenge; variables such as clinical
history, food allergen, patient criteria (age, concomitant
food and other allergic disease, anxiety...), and research
criteria should guide the selection of the OFC.
The OFC, in additional to establishing a firm diagnosis
can be used to determine threshold reactivity, response
to OIT, spontaneous resolution of food allergy and the
exclusion of food allergy
IV
D
SEE ABOVE
SEE ABOVE
SEE ABOVE
IV
D
SEE ABOVE
SEE ABOVE
SEE ABOVE
The DBPCFC should be performed in the following
settings: when symptoms are subjective, with delayed or
atypical symptoms, where patients and/or care givers are
anxious, and considered in all research settings.
IV
D
SEE ABOVE
SEE ABOVE
SEE ABOVE
A negative DBPCFC should end with an open or
cumulative ingestion of the food to confirm oral tolerance.
IV
D
SEE ABOVE
SEE ABOVE
SEE ABOVE
OFC are not without risk, and must be performed in a
specialist setting with emergency support immediately
available. In patients with a moderate to high risk of a
severe reaction, intensive care support must be
immediately available
IV
D
SEE ABOVE
SEE ABOVE
SEE ABOVE
III
C
Miss information among
the public
Patient Organisations
Reduction in % of patients undertaking
unconventional testing
Unconventional tests (including specific IgG testing)
There is no unconventional approach which can be
recommended as an alternative or complementary
diagnostic tool in the work up of suspected food allergy,
and their use should be discouraged
Counteraction of “myths”
Poor access to allergy
consultation
78
1209
*Range of levels of evidence and grades are due to range of different foods tested
1210
79
Recommendation
Grade
APPENDIX V : MANAGEMENT-Barriers and facilitators to implementation, audit criteria and resource implications of recommendations.
Evidence
level
1211
Barriers to
implementation
Facilitators to
implementation
Audit criteria
Acute Management
The patient at risk of severe reactions should be
properly and timely identified (See Box 10
Anaphylaxis Chapter)
IV
D
Lack of epidemiological
data of inter and intra
individuals risk factors
Improved knowledge of
mechanisms underlying
severity an allergic reaction
Surveillance epidemiological
studies of acute episodes
Lack of biomarkers for
risk of severe reactions
Identification of biomarkers
to support clinical evaluation
Health professional
attitude
Education
Reduction of % of patients with
anaphylaxis using antihistamines
in patients
Large multi-centred trials
evaluating biomarkers in patients
with severe reactions
Antihistamines and Mast Cell Stabilizers
There is evidence to support the benefits of
antihistamines for children and adults with acute
non-life threatening symptoms from food allergy.
III
C
Lack of public
information
The prophylactic application of antihistamines is not
recommended
Mast cell stabilisers are not recommended for the
prophylactic treatment of food allergy
V
D
Health professional
attitude
Specific education of health
professionals
Reduction of % of patients with
anaphylaxis using antihistamines
in patients
III
C
Health professional
attitude
SEE ABOVE
Reduction of % of patients with
anaphylaxis using antihistamines
in patients
Elimination Diet
80
A sufficient elimination diet should be based on a
proper allergy diagnosis identifying the food
allergen(s) responsible of the patient’s symptoms
/reactions. The indications should be re-evaluated at
appropriate intervals
IV
D
Lack of proper allergy
diagnosis
Access to allergy services
Increase in allergy services
Lack of compliance
Counselling with proper
attractive menus, patients
and family
Appropriate Dietary avoidance diets is the key
treatment in the management of food allergy
Costs of alternative
foods
Pleasant food options
Availability of special food for
allergic consumer on the market
Psychological counselling
Difficulty in finding
alternative foods
IV
Increase in quality of life in patients
who receive psychological
counselling
D
Monotonous diet and
difficulty in finding a
pleasant replacement
Patients with food allergy who are on long term
elimination diets should have access to appropriate
nutritional counseling, ideally by a dietitian with
competencies in food allergy, and regular monitoring
of growth
Extensively hydrolysed cow’s milk formulas with
documented hypoallergenicity can be recommended
as first choice for the treatment ofcow’s milk allergy,
especially in infants and young children. Amino acid
IV
D
I
A
Lack of appropriately
train dietitian with
competencies in food
allergy
Education of food allergy
among dietitian’s training
% of patients suffer of dietary
compromises while on an
Elimination Diet
Cost of the alternative
formulas
Reduction of the costs
% of children with proper CMA
who receive first choice formulas
81
formulas can be recommended as well especially for
a subgroup of patients with more severe symptoms. ,
Improvement in
reimbursement polices
Reduction of cost documented by
companies
Availability of reimbursement of
formulas for special needs
Soy formulas should not be recommended before 6
months of age and at any age in the presence of
gastrointestinal symptoms.From 6-12 months it can
be considered on a case-by-case basis.
Health Professional
attitudes
Education
Reduction of cost documented by
companies
Reduction of the costs
I
B
Costs in developing
countries
Availability of reimbursement of
formulas for special needs
Improvement in
reimbursement polices
Currently, probiotic supplements cannot be
recommended for the management of food allergy
Public and Health
Professionals attitudes
I
Awareness of the results of
currently available studies
Large cohort studies to provide
evidence based conclusions
D
Lack of evidence based
benefit in large cohort
studies
Education and Risk Assessment
Patients and caregivers need to be informed about
the foods that should be avoided, and practical
advice given on avoidance measures, how to
V
D
Lack of awareness
among health
82
Allergy nurses and
Availability of tools designed for
dieticians with competencies education on food allergy
recognize a further reaction and the selfmanagement of these reactions
professionals
in food allergies
Patient Organisations
Patients/carers should be encouraged to join an
appropriate patient support organization
V
D
Lack of relevant patient
organisations
Establishment of patients’
organisations where needed
% of patients joining Patients
Organisations.
Denial of having a
disease requiring
external support.
Distribution of information of
the activities of Patient
Organisations at allergic
clinics
Presence of a food allergy Patient
Organisation in each European
Country
Increase in meetings organised by
Patient Organisation on Food
Allergy
All patients with food allergy require a management
plan with appropriate education for the patient,
caregiver including school
V
D
Lack of standardized
management plans
Standardized training
courses to educate patients
caregivers and schools
Reimbursement policies for
training courses
83
% of patient attending training
courses
Availability of reimbursement
policies for training
% of patients attending the ED
% of patients hospitalized because
of severe allergic reactions
% of patients who die because of a
further severe allergic reaction
Education should cover allergen avoidance,
symptom recognition and indication for specific
treatment and administration of specific medication
V
D
Lack of knowledge and
skills among parents,
schools and
professionals in
recognizing symptoms
Lack of allergy services
Absolute indications with adrenaline auto-injector
include previous anaphylaxis to any food, persistent
or severe asthma, exercise induced food dependent
anaphylaxis, and mastocytosis
IV
C
Scarce knowledge
among health
professionals about
proper management of
severe allergic
reactions
Costs of self injectable
84
Written plans
National and international policies
for education within the context of
a public health approach
Educational courses
Training courses
Development of tools for the
management of severe
reactions (ie. on-line training
courses, leaflets) to facilitate
education of health
professionals.
% of patients suffering from severe
reactions prescribed with selfinjectable adrenaline
% of patients with anaphylaxis who
present themselves to the ED
having already used an adrenaline
auto-injector
devices
Reduction of costs of selfinjectable adrenaline
Reimbursement
policies
Improvement of reimbursement
policies
Relative indications for adrenaline auto-injector with
food allergy include (1) food allergies that are likely
to be persistent; (2) mild-to-moderate allergic
reaction to peanut and/or tree nut (3) mild-tomoderate reaction to very small amounts of food and
(4) specific high risk groups, eg adolescents, young
adult males, poor access to medical care.
IV-V*
C-D* Scarce knowledge
among health
professionals about
proper management of
severe allergic
reactions
Costs of self injectable
devices
Reimbursement
policies
Adrenaline should be immediately administered for
cardiovascular symptoms and / or respiratory
symptoms such as altered voice, stridor or
bronchospasm that is thought to be induced by food
allergy lower threshold for administration can be
considered in patients with previous reactions and/or
with a history of exposure to known/likely allergen
IV
C
Scarce knowledge
among health
professionals about
proper management of
severe allergic
reactions
85
Development of tools for the
management of severe
reactions (ie. on-line training
courses, leaflets) to facilitate
education of health
professionals.
Reduction of deaths due to
anaphylaxis
Surveillance epidemiological
programmes
Written Plans
Short acting beta agonists should be included in the
management plan for all patients with co-existing
asthma and should be administered for
bronchospasm after adrenaline has been
administered
V
D
Scarce knowledge
among health
professionals about
proper management of
severe allergic
reactions
Development of tools for the
management of severe
reactions (ie. on-line training
courses, leaflets) to facilitate
education of health
professionals.
Reduction of deaths due to
anaphylaxis
Surveillance epidemiological
programmes
Written plans
Patient held glucocorticosteroids may be given with
reactions to possibly prevent late phase respiratory
symptoms
V
D
Often used as first line
treatment
Lack of evidence to
support intended use
Emphasis on adrenaline as
first line treatment
Compare outcomes of anaphylaxis
in patients who received
adrenaline treatment with and
Education of healthcare staff without glucocorticocosteroids
Clear protocols in
emergency department
May prevent biphasic
reactions
Any patient who has received adrenaline should be
reviewed in an emergency department
III
C
Lack of proper
information from the
patient
Education
% of patients presenting at ED
after having been administered
self-injectable adrenaline
III
C
Lack of established
requirements for
centres performing food
Identification of criteria for
centres of excellence
Increase in large multi-centre trials
for food allergen immunotherapy
Specific Immunotherapy
Food allergen-specific immunotherapy for primary
food allergy is a promising immune-modulatory
treatment approach (I), but it is associated with risk
86
of adverse reactions, including anaphylaxis (I); it is
therefore not at present recommended for routine
clinical use
allergen specific
immunotherapy
Increase in qualified allergy
centres
Increase in % of patients recruited
for proper food allergen
immunomodulatory treatment
Identification of criteria for
centres of excellence
Increase in large multi-centre trials
for food allergen immunotherapy
Increase in qualified allergy
centres
Increase in % of patients recruited
for proper food allergen
immunomodulatory treatment
Health professionals’
attitude
Identification of criteria for
centres of excellence
Increase in large multi-centre trials
for anti- IgE immunotherapy
Lack of proper
information among the
patients
Increase in qualified allergy
centres
Lack of proper
information among the
patients
Immunotherapy in patients with respiratory
symptoms /allergy to inhalant allergens that may
also cause cross reactive food allergy, specific
immunotherapy is recommended for the treatment
for the respiratory symptoms but currently not for the
primary treatment of cross-reactive food allergy.
IV
D
Lack of established
requirements for
centres performing food
allergen specific
immunotherapy
Lack of proper
information among the
patients
Anti-IgE
The use of anti-IgE alone or in combination with
specific immunotherapy is currently not
recommended for the treatment of food allergy even
though it represents a promising modality.
IV
D
87
Challenges at regular intervals to assess
achievements of tolerance
OFC should be performed at regularly intervals
appropriate for the specific food and patients history
in order to assess achievement of tolerance.
V
D
A lack of allergy
services
Reimbursement polices
Access to allergy services
Increase in number of OFC
Proper reimbursement from
National Health systems
and Insurance bodies
Increase in allergy services
National and EU polices fro OFC
reimbursement
Specific IgE testing (in vitro and Skin-prick-test)are
currently of little value in guiding adequately the
timing of Oral Food Challenges for development of
tolerance.
V
D
Knowledge among
health professionals
Education of health
professionals
Large multi-centre cohort studies
Lack of standardized
questionnaires
Development of properly
designed questionnaires
Large surveillance programmes on
incidence and prevalence of cofactors
Cofactors
In food allergic reactions, the potential augmenting
role of co-factors, ie such as exercise, NSAID,
omeprazol or alcohol intake, should be assessed in
a structured history
In allergic reactions occurring after exercise, NSAID
or alcohol intake, underlying food allergy to foods
consumed in the previous hours should be assessed
IIIIV**
D
IV
D
% of co-factors identified in severe
in patients suffering for severe
reactions
Lack of standardized
questionnaires
88
Development of properly
designed questionnaires
Large surveillance programmes on
incidence and prevalence of co-
(especially gliadin sensitization or LTP in southern
Europe)
factors
% of co-factors identified in severe
in patients suffering for severe
reactions
1212
1213
1214
89
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