WORKING
P A P E R
Prevalence, Natural
History, Diagnosis, and
Treatment of Food Allergy
A Systematic Review of the
Evidence
JENNIFER J. SCHNEIDER CHAFEN,
SYDNE NEWBERRY, MARC RIEDL,
DENA M. BRAVATA, MARGARET MAGLIONE,
MARIKA SUTTORP, VANDANA SUNDARAM,
NEIL M. PAIGE, ALI TOWFIGH,
BENJAMIN J. HULLEY, PAUL G. SHEKELLE
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WR-757-1
August 2010
Prepared for the National Institute of Allergy and Infectious Diseases
Prevalence, Natural History, Diagnosis, and
Treatment of Food Allergy: A Systematic Review
of the Evidence
Prepared for:
National Institute on Allergy and Infectious Diseases
6610 Rockledge Drive, MSC 6612
Bethesda, MD 20892-6612
Prepared by:
RAND Corporation
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Santa Monica, CA 90407
Director, Southern California EPC:
Paul Shekelle, M.D., Ph.D.
Associate Director, Southern California EPC:
Margaret Maglione, M.P.P.
Content Expert:
Marc Riedl, M.D.
Literature Reviewers:
Dena M. Bravata, M.D., M.S.
Benjamin J. Hulley, B.S.
Sydne Newberry, Ph.D.
Neil Paige, M.D.
Jennifer J. Schneider Chafen, M.D.
Vandana Sundaram, M.P.H.
Ali Towfigh, M.D.
Programmer:
Elizabeth Roth, M.A.
Staff Assistants:
Jerome Hawkins, B.S.
Breanne Johnsen, B.S.
Aneesa Motala, B.A.
TABLE OF CONTENTS
EXECUTIVE SUMMARY .......................................................................................................................... 1
INTRODUCTION ........................................................................................................................................... 1
METHODS ................................................................................................................................................... 1
RESULTS ..................................................................................................................................................... 2
CONCLUSIONS .......................................................................................................................................... 13
INTRODUCTION ...................................................................................................................................... 15
METHODS.................................................................................................................................................. 17
RESULTS.................................................................................................................................................... 33
SECTION I. WHAT IS THE DEFINITION OF FOOD ALLERGY? .................................................. 35
KEY QUESTION A. DEFINE FOOD ALLERGY. ............................................................................................ 35
SECTION II. INCIDENCE AND PREVALENCE OF DIFFERENT TYPES OF FOOD
ALLERGIES; INCLUDING THE SYMPTOMS AND NATURAL HISTORY OF DIFFERENT
TYPES ......................................................................................................................................................... 50
INTRODUCTION TO KEY QUESTIONS B, C, D, AND E ................................................................................ 50
KEY QUESTION B/C: WHAT ARE THE INCIDENCE/PREVALENCE OF IGE-MEDIATED FOOD ALLERGY AND
IMMUNOLOGIC BUT NON-IGE-MEDIATED ADVERSE REACTIONS TO FOOD? ............................................... 52
KEY QUESTION D/E: WHAT ARE THE SYMPTOMS AND NATURAL HISTORY OF IGE-MEDIATED AND OF
IMMUNOLOGIC BUT NON-IGE MEDIATED ADVERSE REACTIONS TO FOOD? ................................................ 66
SECTION III. DIAGNOSIS OF FOOD ALLERGY: WHAT TOOLS ARE AVAILABLE AND
HOW RELIABLE ARE THEY?............................................................................................................... 80
KEY QUESTIONS F AND G: WHAT TOOLS ARE CURRENTLY USED TO DIAGNOSE IGE-MEDIATED AND NONIGE-MEDIATED FOOD ALLERGY? .............................................................................................................. 80
SECTION IV. MANAGEMENT, TREATMENT AND PREVENTION OF FOOD ALLERGY .... 157
KEY QUESTION H. WHAT METHODS ARE CURRENTLY USED TO MANAGE PATIENTS DIAGNOSED WITH IGEMEDIATED FOOD ALLERGY?.................................................................................................................... 160
KEY QUESTION I. WHAT METHODS ARE CURRENTLY USED TO MANAGE PATIENTS DIAGNOSED WITH NONIGE-MEDIATED REACTIONS TO FOOD, AND HOW DO THEY DIFFER FROM METHODS USED TO MANAGE
PATIENTS DIAGNOSED WITH IGE-MEDIATED FOOD ALLERGY? ................................................................ 214
KEY QUESTION J. WHAT ARE THE APPROPRIATE METHODS OF DIAGNOSIS AND TREATMENT OF ACUTE AND
LIFE-THREATENING, IGE-MEDIATED FOOD ALLERGIC REACTIONS?......................................................... 214
CONCLUSIONS....................................................................................................................................... 245
REFERENCE LIST………………………………………………………………………………………248
LIST OF FIGURES
FIGURE 1: LITERATURE FLOW ....................................................................................................................... 33
FIGURE 2: CONCEPTUAL MODEL OF KEY QUESTIONS .................................................................................... 34
FIGURE 3: NUMBERS OF STUDIES WITH A “YES” RESPONSE TO THE QUADAS DOMAIN QUESTION ............ 82
FIGURE 4: ROC CURVE FOR SPT. SIGE, APT FOR COW’S MILK .................................................................. 137
FIGURE 5: ROC CURVE FOR SPT AND SIGE FOR HEN'S EGG ........................................................................ 138
FIGURE 6: FIGURES 6A, 6B, AND 6C ............................................................................................................ 139
FIGURE 7: DISTRIBUTION OF PREVENTION RCTS BY COUNTRY .................................................................. 158
FIGURE 8: DISTRIBUTION OF PREVENTION RCTS BY INTERVENTION .......................................................... 159
FIGURE 9: DISTRIBUTION OF MANAGEMENT/TREATMENT RCTS BY COUNTRY .......................................... 159
FIGURE 10: DISTRIBUTION OF MANAGEMENT/TREATMENT RCTS BY INTERVENTION ................................ 160
FIGURE 11: TREATMENT/MANAGEMENT - SUMMARY OF EVIDENCE BY FOOD TYPE .................................... 233
FIGURE 12: SUMMARY OF EVIDENCE BY SPECIFIC CLINICAL CONDITION ................................................... 243
ii
LIST OF TABLES
TABLE 1: ORGANIZATION OF REPORT ............................................................................................................ 25
TABLE 2: CRITERIA FOR ASSIGNING GRADE OF EVIDENCE ............................................................................. 31
TABLE 3: REVIEWS INCLUDING FOOD ALLERGY DEFINITIONS ........................................................................ 35
TABLE 4: WEB SITES WITH FOOD ALLERGY DEFINITIONS ............................................................................... 36
TABLE 5: TERMS ASSOCIATED WITH IGE-MEDIATED CONDITIONS ................................................................ 36
TABLE 6: TERMS ASSOCIATED WITH NON-IGE-MEDIATED CONDITIONS ........................................................ 37
TABLE 7: TERMS ASSOCIATED WITH MIXED IGE AND NON-IGE-MEDIATED CONDITIONS ............................... 37
TABLE 8: SYSTEMATIC REVIEWS AND META-ANALYSES OF THE PREVALENCE OF FOOD ALLERGIES ........... 54
TABLE 9: PREVALENCE OF PEANUT AND TREE NUT ALLERGY IN 2002 BY AGE .............................................. 56
TABLE 10: PREVALENCE OF PEANUT AND TREE NUT ALLERGY BY RACE, ETHNICITY, AND SEX BY AGE ......... 58
TABLE 11: PREVALENCE OF SEAFOOD ALLERGY BY RACE/ETHNICITY AND SEX/AGE .................................... 59
TABLE 12: PREVALENCE OF FOOD ALLERGY IN NATIONAL US STUDIES COMPARED TO SYSTEMATIC
REVIEWS .............................................................................................................................................. 61
TABLE 13: US STUDIES OF THE INCIDENCE OF ANAPHYLAXIS DUE TO FOOD ................................................ 65
TABLE 14: US STUDIES OF THE NATURAL HISTORY OF PEANUT ALLERGY ................................................... 72
TABLE 15: US STUDIES OF THE NATURAL HISTORY OF EOSINOPHILIC ESOPHAGITIS .................................... 77
TABLE 16: STUDIES OF ALLERGIES TO SPECIFIC FOODS, NON US/CANADA .................................................. 78
TABLE 17: DIAGNOSTIC TEST PROPERTIES..................................................................................................... 80
TABLE 18: STUDIES OF FOOD CHALLENGE TESTS ......................................................................................... 87
TABLE 19: SUMMARY OF COW'S MILK ALLERGY STUDIES WITH SKIN PRICK TESTS..................................... 96
TABLE 20: SUMMARY OF HEN'S EGG ALLERGY STUDIES WITH SKIN PRICK TESTS ....................................... 99
TABLE 21: SUMMARY OF PEANUT ALLERGY ASSESSMENTS WITH SKIN PRICK TESTS ................................ 101
TABLE 22: SUMMARY OF SOY ALLERGY ASSESSMENTS WITH SKIN PRICK TESTS....................................... 102
TABLE 23: SUMMARY OF WHEAT ALLERGY ASSESSMENTS WITH SKIN PRICK TESTS ................................. 103
TABLE 24: SIGE MEASURES OF COW’S MILK ALLERGY USING FOOD CHALLENGE AS REFERENCE ............ 108
TABLE 25: SIGE MEASURES OF HEN’S EGG ALLERGY USING FOOD CHALLENGE AS REFERENCE ............... 113
TABLE 26: SIGE MEASURES OF PEANUT ALLERGY USING FOOD CHALLENGE AS REFERENCE .................... 116
TABLE 27: SIGE MEASURES OF SOY ALLERGY USING FOOD CHALLENGE AS REFERENCE .......................... 117
TABLE 28: SIGE MEASURES OF WHEAT ALLERGY USING FOOD CHALLENGE AS REFERENCE..................... 119
TABLE 29: APT STUDIES OF COW'S MILK ..................................................................................................... 130
TABLE 30: APT STUDIES OF HEN’S EGG ...................................................................................................... 132
TABLE 31: APT STUDIES OF SOY ................................................................................................................. 133
TABLE 32: APT STUDIES OF WHEAT/CEREAL............................................................................................... 134
TABLE 33: COMBINATION OF SPT AND APT COMPARED WITH INDIVIDUAL TESTS ..................................... 142
TABLE 34: COMBINATION OF SPT AND SIGE COMPARED WITH INDIVIDUAL TESTS..................................... 145
TABLE 35: COMBINATION OF APT AND ANTIGEN-SPECIFIC IGE COMPARED WITH INDIVIDUAL TESTS ....... 147
TABLE 36: COMBINATION OF SPT AND APT AND ANTIGEN-SPECIFIC IGE COMPARED WITH INDIVIDUAL
TESTS ................................................................................................................................................ 149
TABLE 37: SENSITIVITY AND SPECIFICITY OF SPT AND APT IN EE............................................................. 153
TABLE 38: RECOMMENDATIONS ON FOOD AVOIDANCE BY PROFESSIONAL SOCIETIES ............................... 167
TABLE 39: FOOD ALLERGY PREVENTION SYSTEMATIC REVIEWS AND META-ANALYSES .............................. 171
TABLE 40: FOOD ALLERGY PREVENTION CONTROLLED TRIALS: STUDY INFORMATION ................................ 174
TABLE 41: FOOD ALLERGY PREVENTION CONTROLLED TRIALS: PATIENT CHARACTERISTICS ...................... 176
TABLE 42: FOOD ALLERGY PREVENTION CONTROLLED TRIALS: INTERVENTION CHARACTERISTICS AND
OUTCOMES REPORTED ........................................................................................................................ 180
TABLE 43: FOOD ALLERGY TREATMENT SYSTEMATIC REVIEWS AND META-ANALYSES ............................... 195
TABLE 44: FOOD ALLERGY TREATMENT/MANAGEMENT CONTROLLED TRIALS: STUDY INFORMATION........ 197
TABLE 45: FOOD ALLERGY TREATMENT/MANAGEMENT CONTROLLED TRIALS: PATIENT CHARACTERISTICS 199
TABLE 46: FOOD ALLERGY TREATMENT/MANAGEMENT CONTROLLED TRIALS: INTERVENTION
CHARACTERISTICS AND OUTCOMES REPORTED .................................................................................. 206
TABLE 47: SAFETY DATA FOR ALLERGEN SPECIFIC IMMUNOTHERAPY ........................................................ 212
TABLE 48: COHORT STUDIES ON ANAPHYLAXIS: STUDY INFORMATION ....................................................... 216
TABLE 49: COHORT STUDIES ON ANAPHYLAXIS: PATIENT CHARACTERISTICS ............................................. 216
iii
TABLE 50: COHORT STUDIES ON ANAPHYLAXIS: INTERVENTION CHARACTERISTICS AND OUTCOMES
REPORTED .......................................................................................................................................... 216
TABLE 51: TREATMENT/MANAGEMENT - SPECIFIC FOOD ALLERGY STUDIES: STUDY INFORMATION ............ 226
TABLE 52: TREATMENT/MANAGEMENT - SPECIFIC FOOD ALLERGY STUDIES: PATIENT CHARACTERISTICS .. 227
TABLE 53: TREATMENT/MANAGEMENT - SPECIFIC FOOD ALLERGY STUDIES: INTERVENTION
CHARACTERISTICS AND OUTCOMES REPORTED .................................................................................. 230
TABLE 54: SPECIFIC CLINICAL CONDITIONS ASSOCIATED WITH FOOD ALLERGIES: DESIGN AND PATIENT
CHARACTERISTICS ............................................................................................................................. 241
TABLE 55: SPECIFIC CLINICAL CONDITIONS ASSOCIATED WITH FOOD ALLERGIES: INTERVENTION
CHARACTERISTICS AND OUTCOMES REPORTED .................................................................................. 242
APPENDICES
APPENDIX A: SEARCH STRATEGIES .............................................................................................. 277
APPENDIX B: SCREENING FORM..................................................................................................... 293
APPENDIX C: STUDY DESIGN DEFINITIONS ................................................................................ 295
APPENDIX D: CRITERIA FOR ASSESSING THE QUALITY OF STUDIES OF DIAGNOSTIC
ACCURACY............................................................................................................................................. 297
APPENDIX E. EXCLUDED STUDIES: INCIDENCE/PREVALENCE, NATURAL HISTORY ... 302
APPENDIX F: FOOD ALLERGY TREATMENT/MANAGEMENT CONTROLLED TRIALS:
STUDY QUALITY CHARACTERISTICS ........................................................................................... 334
APPENDIX G: ABBREVIATIONS USED IN THIS REPORT........................................................... 336
APPENDIX H: EVIDENCE TABLES-DIAGNOSIS STUDIES.......................................................... 339
APPENDIX I. EXCLUDED STUDIES AT SCREENER LEVEL ....................................................... 355
APPENDIX J. EXCLUDED STUDIES: DIAGNOSIS.......................................................................... 374
APPENDIX K. EXCLUDED STUDIES: TREATMENT/MANAGEMENT/PREVENTION .......... 396
APPENDIX L. ASSESSED FOR THEIR DEFINITION OF FOOD ALLERGY ............................. 405
iv
Executive Summary
Introduction
The US federal government is interested in coordinating the development of guidelines
for diagnosing and managing food allergy. A meeting was held on July 19, 2007, entitled
“Guidelines for the Diagnosis and Management of Food Allergy.” It was jointly
organized by a Coordinating Committee comprising The National Institutes of Allergy
and Infectious Diseases (NIAID), American Academy of Allergy Asthma and
Immunology (AAAAI), and the Food Allergy and Anaphylaxis Network (FAAN). The
attendees included representatives of over twenty professional societies, patient advocacy
groups, and several NIH Institutes. They concurred that evidence-based clinical
guidelines were needed and outlined steps for their development.
The first step in developing the guidelines is a systematic review of the scientific and
clinical literature. To carry out this step, the NIAID contracted with the Southern
California Evidence-based Practice Center (EPC) based at RAND.
Methods
Under the auspices of the Coordinating Committee, the NIAID and the food allergy
Expert Panel developed an extensive set of key questions, which were further refined in
discussions with the EPC. These questions and the corresponding answers are detailed in
the Results section of this executive summary. The EPC was provided with a list of
specific medical conditions that were either comorbid with food allergy or qualified as
food-allergy conditions. Literature searches were performed on PubMed, the Cochrane
Database of Systematic Reviews, the Cochrane Database of Abstracts of Reviews of
Effects (DARE), the Cochrane Central Register of Controlled Trials (Central), and the
World Allergy Organization Journal. The principle search topics were diagnosis and
testing techniques for food allergies in general, and in the case of the PubMed searches,
the specific IgE and non-IgE-related reactions mentioned in the list provided. In most
cases, searches were limited to the years 1988 to the present, with no language
restrictions. We also sought supplemental publications from experts on our team and
others involved in the review process.
Researchers screened all titles found through our searches or that were submitted by
experts. We established screening criteria to facilitate the identification of articles
concerning definitions, diagnoses, prevention, treatment, management, and other topics
as per the NIAID’s and Expert Panel’s questions. Articles were included/excluded based
on article type (included: original research or systematic reviews; excluded:
background/contextual reviews, non-systematic reviews, commentary, or other types of
articles) and study purpose (included: studies that looked at incidence/prevalence/natural
history; diagnosis; treatment/management/prevention; excluded: studies that either were
not about food allergy or were about some aspect not listed in the “included” category).
1
Included studies were categorized in two ways. First they were categorized by the food(s)
of concern: multiple foods, milk, egg, peanut/tree nut, fish/shellfish, soy, wheat, and/or
other foods, as specified. Studies were then categorized by medical condition, e.g.,
anaphylaxis, eczema, if specified.
Accepted articles were reviewed by topic teams and data were abstracted. The teams
reached consensus on inclusion of final article sets for each topic area as well as
consensus on data items abstracted from these articles.
The evidence is reported in several forms. Evidence tables offer a detailed description of
the studies that we identified, addressing each of the topic areas. They provide
information consistent with established criteria about the study design, patient
characteristics, inclusion and exclusion criteria, interventions evaluated, and the
outcomes. The study sample size offers a measure of the weight of the evidence. (In
general, larger studies provide a more precise estimate of the effect in question, although
the specific patient population has greater influence on the applicability of any given
study.) Narrative text summarizes the findings and provides qualitative analysis of the
key questions as they relate to the topic area.
Results
Key Question A. What is the definition of food allergy?
i. What definitions of food allergy are currently being used?
ii. Describe conditions that are described as non-immunologic adverse reactions
to food.
iii. Describe conditions that are described as immunologic, but not IgE-mediated,
adverse reactions to food.
iv. Describe conditions that are described as immunologic and IgE-mediated
adverse reactions to food (and which are considered by some authorities to be
equivalent to food allergy).
v. Compare adverse reactions to food that are non-immunologic, immunologic
and not IgE-mediated, and immunologic and IgE-mediated.
In the NIAID and Expert Panel’s original definition, for a condition to be considered a
food allergy, it must be:
a) an adverse immune response that occurs reproducibly on exposure to a given food and
b) distinct from other adverse responses to food, such as food intolerance, pharmacologic
reactions, and toxin-mediated reactions. The NIAID also specified that while food
allergy is frequently defined as a disorder caused by IgE-mediated reactions to food, we
should review literature on non–IgE-mediated immunologic mechanisms as well.
Non-immunologic adverse reactions to food are also discussed, only as they compare
with similar immune mechanism caused symptoms.
In order to provide definitions of food allergy currently being used, we assessed whether
or not the characteristics outlined above were included in published reviews of food
2
allergy. We abstracted such information from several dozen existing review articles,
along with what medical conditions they considered as “food allergy.” We also abstracted
information from the web sites of 57 professional societies and other related
organizations on a list provided by the technical Expert Panel (TEP). Only 19 of the 57
web sites provided a definition of food allergy.
Only 31.0 percent of definitions included in review articles mentioned reproducibility,
and 45.1 percent mentioned a particular given food. 78.9 percent mentioned IgE –
mediated reactions and 66.2 percent mentioned non-IgE medicated immunologic
mechanisms. The web site definitions were less clear. Only 42.1 percent mentioned IgEmediated reactions and 15.8 percent mentioned non-IgE-mediated immunologic
mechanisms.
The NIAID and the Expert Panel developed the explicit list of conditions (below) that are
either comorbid with food allergy or qualify as allergic reactions to food. These medical
conditions are described in detail in the body of our report.
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Classic food-related anaphylaxis
Laryngeal edema
Heiner’s Syndrome (pulmonary hemosiderosis)
Asthma
Food-associated, exercise-induced syndromes
Colitis
Eosinophilic Esophagitis/Gastroenteritis
Cow’s milk allergy syndrome:
п‚ћ Induced colitis (and blood in the stools)
п‚ћ Food-induced enterocolitis syndrome
п‚ћ Food-induced proctocolitis syndrome
п‚ћ Milk protein allergy of infancy
Gastrointestinal hypersensitivity (e.g., vomiting, colic, diarrhea)
Contact dermatitis
Eczema, atopic dermatitis
Generalized flushing
Oral Allergy Syndrome
Rhinitis, rhinoconjunctivitis conjunctivitis
Urticaria
Angioedema
3
Key Questions B & C: What are the incidence/prevalence of
IgE-mediated food allergy (B) and immunologic but non-IgEmediated adverse reactions to food (C)?
B & C. i. Incidence and prevalence in the adult and pediatric populations
B & C. ii. Incidence and prevalence for specific foods
B & C. iii. Age- or gender-specific changes in specific foods
Two previously-published, acceptable quality systematic reviews found that the
prevalence of food allergy overall and allergy to specific foods varied depending on the
definition used, and even within the same definition; estimates of prevalence varied
widely. Improving the knowledge base on this topic will require better standardization of
the definition of a food allergy. For example, the reviews reported a pooled overall
prevalence of 13 percent and 12 percent for adults and for children, respectively, of selfreport of food allergy to any food. Pooled results for allergy to any food were far lower
when assessed by sensitization or food challenge; being about three percent (data
stratified by age were not reported). For specific foods, pooled results showed that
prevalence was highest for milk (3 percent by symptoms, 0.6 percent and 0.9 percent for
Skin Prick Test (SPT) and food challenge) and lowest for fish (0.6 percent by symptoms,
0.2 percent by SPT and 0.3 percent by food challenge).
B & C. iv. Incidence and prevalence of co-morbid conditions
We did not identify any US or Canada studies that had nationally representative
populations that assessed the co-occurrence of other conditions in patients with food
allergy in general. We did identify several studies that assessed the co-occurrence of
other conditions in samples of patients with specific allergies or conditions. The most
common co-occurring conditions included asthma, rhinitis, and eczema. All of these
conditions are conditions that can be caused by allergy.
B & C. v. Risk factors for development of food allergy
In general, we did not identify any studies specifically addressing risk factors for the
development of food allergy, as do exist for conditions such as heart disease, lung cancer,
etc. Experimental studies of early life allergen exposure or avoidance suggest that these
are believed to be potential risk factors for food allergy; however, the findings on these
factors are mixed. One case-controlled study from England reported that household
exposure to peanut-containing skin lotions was a significant risk factor for developing
food allergy. In addition, there are studies of prevention where infants or pregnant
mothers are classified as “high risk” for atopy. This is usually due to a family history of
atopy. One family-based study from Chicago reported a strong familial clustering of
food allergy. There are emerging data about genetic associations but results are too
preliminary to reach conclusions.
4
Key Question D & E: What are the symptoms and natural
history of IgE-mediated (D) and of immunologic but non-IgE
mediated (E) adverse reactions to food?
D & E. i. Symptoms and natural history
We identified no published studies from the US or Canada on the natural history of food
allergy conditions that reported data from nationally representative or even communitybased populations. The only published studies of natural history came from selected
populations, usually from a single clinic or hospital. Such patient populations may not be
representative of the general patient population with a specific food allergy. Nonetheless,
to assist the Expert Panel, we summarized the published studies we did identify, keeping
in mind that their findings may not necessarily be extrapolated to all patients with the
condition. Detailed descriptions of these natural history studies are contained in the
results section of main report.
D & E. ii. Relationship between IgE-mediated and immunologic but non-IgEmediated food allergy and comorbid conditions.
No additional studies other than those previously described in section B were found.
D & E. iii. Differences in populations related to socioeconomic status (SES), access
to health care, stress.
We did not find any US studies that specifically addressed differences in incidence,
prevalence, or natural history related to socioeconomic status, access to health care, or
stress. A US National Study did report data stratified by race, and some investigators use
race as a proxy for socioeconomic status and access to health care. Those data are
presented in the tables reporting the US National data. In addition, two US studies
already presented (of infant feeding practices and of the NHIS/NHDS databases) reported
that black males were more likely to have parent-reported food allergy and the rates of
food allergy in Hispanics was lower than in non-hispanics. One cohort study from
Sweden reported that the risk of sensitization to food allergens decreased with increasing
socioeconomic status, with an odds ratio of 0.65 (95% confidence interval 0.41,1.02,
p=0.03 for trend) in the highest as compared to the lowest socioeconomic group.
Key Questions F & G. What tools are currently used to
diagnose IgE-mediated food allergy (F) and non-Ige-mediated
adverse reactions (G)?
We combined questions F and G because it can be difficult to distinguish an IgEmediated from a non-IgE-mediated allergy prior to diagnostic workup, based on history
alone; thus, with the exception of a small number of distinct non-IgE-mediated conditions
such as eosinophilic esophagitis and celiac disease, IgE-mediated and non-IgE-mediated
allergies are usually not addressed separately in the literature. In responding to these
questions, we reviewed articles that attempted to establish the validity of each of the
diagnostic methods, i.e., against a gold standard, or attempted to optimize methodology.
5
We included only articles that reported the sensitivity and specificity of the diagnostic
test(s) in question, provided: a description of the generalizability of the population, and
had a prospective design. For a small number of questions for which no studies could be
identified that met these criteria, studies of lesser quality were included.
F & G. i. Patient history and physical examination
It is generally accepted that the diagnosis of food allergy must begin with a careful
history and physical exam, the results of which guide the use of any further diagnostic
tests. One study that met our screening criteria reported a physical finding (umbilical
erythema) in patients with suspected cow’s milk protein intolerance with a low sensitivity
but a specificity of 1.
F & G. ii. Immediate skin testing
Skin prick testing (SPT) is the preferred method of skin testing for suspected IgEmediated (immediate) allergies as recommended by the AAAAI and ECAAI (European
Academy of Allergy and Clinical Immunology). Both organizations recommend against
intracutaneous testing for food allergies, citing increased risk of serious reaction and no
increase in sensitivity or specificity. Additionally, both the AAAAI and ECAAI
recommend against using skin scratch tests due to their low specificity compared to skin
prick tests.
No standard exists for administering or interpreting skin prick tests; the studies that
utilized skin prick tests and that met our inclusion criteria used several different methods
to define a positive test, from measuring the absolute wheal size to measuring the wheal
size relative to the negative control. The type of allergen used for SPTs also varies
greatly: Both fresh foods and a variety of commercial preparations are used. Two studies
that specifically addressed the comparability of these tests met our inclusion criteria. For
cow’s milk allergy testing, a large study reported a high degree of concordance between a
commercial cow milk allergen (ALK) and milk powder. Another large study of peanut
preparations reported a high false negative rate with a commercial peanut extract
(Allerbio) compared to fresh peanut, which was 100 percent sensitive compared to
double-blind placebo controlled food challenge (DBPCFC, widely considered the gold
standard).
F & G. iii. In vitro testing
The sensitivity and specificity of serum antigen-specific IgE (sIgE) assays for food
allergies varied by food, assay system, and study. For example, for cow’s milk sIgE, the
sensitivity ranged from 0.57 to 0.89 and the specificity ranged from 0.49 to 1 when the
performance of the test was compared to the use of a food challenge. For peanut allergy,
the five studies that satisfied inclusion criteria reported similar maximum sensitivities
(0.44-0.60) with one exception: If the decision point was set at the lower limit of
detection of the test, the sensitivity rose to 0.98. Studies that compared the performance
of several sIgE assay systems found discrepancies, especially for particular foods (wheat
and soy), such that one assay might diagnose a particular patient as being allergic
whereas another test might find the same patient not to be allergic to the food.
6
F & G. iv. Atopy patch testing
The atopy patch test (APT) is generally used to assess delayed, or non-IgE-mediated,
reactions to an allergen. Seven studies addressing the specificity and sensitivity of APT
met our selection criteria, all using food challenge as a reference test. No studies
specifically addressed the methodology of atopy patch tests; however, by convention, the
standard test is performed by applying a food for 48 hours and with the final reading of
the test performed 72 hours after the food was first applied. Additionally, some studies
reported checking for immediate reactions 15-30 minutes after the food was applied. No
studies compared the use of different food preparations. The sensitivity and specificity of
the APT may vary by the timing of the reaction to oral food challenge, but the variation
was not consistent either between foods or between studies of the same food. The
sensitivity and specificity of this test may also vary by the presence of atopic dermatitis
and the age of the patient.
F & G. v. Elimination diets used for diagnosis
We found no studies that used elimination diets as the primary means of diagnosis.
F & G. vi. Oral food challenges used for diagnosis
Oral food challenge tests under controlled conditions are widely used as the gold standard
for food allergy diagnosis (at least when implemented under double blind conditions with
placebo controls). However, several issues remain to be clarified about these tests,
including the actual need for blinding, the effect of the form of food used (e.g., raw vs.
cooked, fresh vs. freeze-dried, whole vs. extracts), the optimal time intervals before
assessing reactions, and when the tests are needed (given the expense, time, and potential
risks involved). A small number of studies that satisfied our inclusion criteria examined
issues related to the use of double-blind placebo-controlled food challenge (DBPCFC).
One study found no difference in the prevalence of positive responses between doubleblind- and open tests. Other studies report “positive” reaction in as many as 13 percent of
patients when given placebo. In an effort to overcome problems in assessing outcomes of
food challenges, two studies assessed the performance of alternative outcome measures,
facial thermography and gastric juice analysis, with good results. These findings we
considered to be preliminary. Another study examined the use of intestinal, rather than
oral, challenge for persons with GI complaints. This test had high specificity but low
sensitivity; its practicality was not discussed. Finally, a study that assessed the use of
symptom diaries found that external evaluation of the entries increased the objectivity of
diagnosis.
Although we did not specifically conduct a search for all published studies of food
challenge testing that reported adverse events, we did track the reporting of adverse
events in the published studies of food challenge testing that satisfied our inclusion
criteria. We also identified several studies that explicitly addressed the risk of serious
adverse (anaphylactic) reactions to blinded food challenges. These studies concluded that
the actual risks are quite small.
7
We performed a meta-analysis using Receiver Operator Characteristic curve methods to
compare the diagnostic accuracy of SPT, sIgE, and APT for those foods where sufficient
data existed (milk, eggs, wheat) and across food types. There was no evidence to
conclude that any test was more accurate than any other test.
F & G. vii. Additional diagnostic tests other than those previously described
Only seven studies that met the inclusion criteria examined a test other than DBPCFC,
SPT, APT, or sIgE.
One study found that combining an assessment of beta-lactoglobulin-mediated
lymphocyte proliferation with that of cow’s milk sIgE was more sensitive than other tests
in detecting cow’s milk allergy diagnosed by food challenge.
One study found that the measurement of IgG4 had a sensitivity and specificity
comparable to that of other in vitro tests.
Two studies assessed the use of a basophil histamine release assay for diagnosis of
allergy to cow’s milk and hen’s egg. Sensitivities ranged from 0.66 to 0.75. Specificities
ranged from 0.66 to 0.80.
The findings of three studies suggest that endomysial antibodies may be a better predictor
than anti-gliadin antibodies of celiac disease, a non-IgE-mediated condition (Because
guidelines already exist for celiac disease, a review of the diagnosis and treatment of
celiac disease was not within the scope of this report. However, the evidence regarding
differential diagnosis of celiac disease vs. IgE and non-IgE-mediated allergic conditions
with similar manifestations is within the scope of the report).
An active area of investigation is whether the combination of two or more tests improves
the sensitivity or specificity of diagnosis. Of eight studies that tried to improve diagnostic
specificity or sensitivity by combining two or more tests, five paired the APT with SPT,
sIgE, or both, in an attempt to capture both immediate and delayed responses to antigen.
Pairing the APT with SPT, sIgE, or both, improved sensitivity and specificity over the
use of individual tests in most studies; however, the small number of studies that
calculated the proportion of patients for whom two or more tests could obviate the need
for DBPCFC found these proportions to be quite small.
The diagnosis of eosinophilic esophagitis is defined as esophageal biopsy with the
finding of greater than 20 eosinophils per high power field; the gold standard for
establishing food allergy as the causal mechanism is resolution of esophageal
eosinophilia and symptoms following elimination of the food from diet followed by
recurrent esophageal eosinophilia with food challenge. One study that did not meet all
inclusion criteria reported high negative predictive value but variable positive predictive
value for a combination of APT and SPT for a wide variety of foods.
8
F &G. viii. Diagnostic tools used by different groups of clinicians to make the
diagnosis of food allergy.
A small number of studies indirectly addressed this question. A 2006 case-based survey
of pediatricians found that understanding of allergy diagnosis was generally poor among
pediatricians who reported that they do not manage allergy cases but better among those
who do. A 2007-8 survey conducted among allergists and primary care physicians, which
had poor response rate, found that non-allergists and allergists differed greatly in their use
of the various allergy tests. No statistical differences were found between allergists and
non-allergists in the use of medical history, food diaries, or elimination diets. However,
allergists were significantly more likely than non-allergists to use percutaneous skin
testing (SPT and APT), sIgE, and food challenge. Allergists were significantly less likely
to report using intradermal tests, sIgG4, and sublingual tests than non-allergists (tests that
have shown poor PPV compared with DBPCFC). The two groups also differed in their
ranking of the most common food allergens, which would affect the diagnostic tests
conducted. Finally, a 2009 study conducted in the allergy department of a large regional
tertiary care hospital found that patients referred by primary care physicians for suspected
food allergy based on the use of sIgE tests were usually able to tolerate the suspected
foods on double-blind-placebo-controlled food challenge.
F & G. ix. What tools are used for longitudinal assessment of patients and what are
the criteria for such assessments?
No studies that met the inclusion criteria examined the use of diagnostic tests for
longitudinal assessment of patients.
Key Question H. What methods are currently used to manage
patients diagnosed with IgE-mediated food allergy?
H. i. Dietary avoidance (including cross-reacting allergens and issues of breast
feeding and delay of solids) in the context of preventing food allergy.
H i a. What are the effects of early versus delayed introduction of certain foods into
an infant’s diet?
The quality of evidence for this key question is low given only two controlled trials of
relatively low quality address this question. While both found some association between
delayed solids and decreased incidence of atopic symptoms, their findings should be
interpreted with caution given that one study was of poor quality and the other evaluated
delayed introduction of solid foods in conjunction with breastfeeding, making it difficult
to determine the independent effect of delayed introduction of foods. In summary, we
found insufficient evidence to support the association between delayed introduction of
solid foods in infants and the incidence of atopic disease.
H i. b. What is the effect of maternal diets during pregnancy and lactation on the
development of, and clinical course of, food allergy?
One high quality systematic review and one comparative study evaluated the effect of
maternal diet during pregnancy and lactation on the development of food allergy. We
9
found conflicting evidence on maternal diet during pregnancy and/or lactation and its
effect on atopic disease among children at high risk for atopic disease. While the
systematic review (which included two trials) reported no evidence to support a
protective effect of maternal diet, the comparative study found significantly reduced
incidence of atopic dermatitis in children whose mothers had a restricted diet during
lactation; however, this study was of poor quality. Given these conflicting findings, we
conclude that there is insufficient evidence to determine the effect of restricting maternal
diet in reducing the risk of atopic disease in infants.
H i. c. What is the effect of breastfeeding infants on the development of, and clinical
course of, food allergy?
Four studies evaluated the effects of breastfeeding in combination with other
interventions but only one comparative study compared breastfeeding alone with cow’s
milk formula. That study found lower risk of atopic dermatitis at one year of age in
infants who were exclusively breast fed. The quality of evidence for this key question is
low.
H i. d. What are the effects of special diets in infants and young children (e.g.,
formula, hydrolyzed formula) on the development of, and clinical course of, food
allergy?
The quality of evidence for the key question on special diets in infants and young
children is moderate to high. The quality of evidence on use of soy formulas is moderate
given that this was addressed by a high quality review that included only three small
RCTs; the evidence suggests that there is little difference between soy formula and cow's
milk formula for the prevention of allergies in high risk infants. The quality of evidence
on use of hydrolyzed formulas is high given that two systematic reviews and four other
RCTs address this question; there is some evidence that hydrolyzed formulas
(particularly extensively and partially hydrolyzed formulas) may reduce infant and
childhood allergy, asthma, and cow's milk allergy syndrome in high risk infants when
compared with cow milk formula.
H i. e. What are the recommendations by professional organizations regarding the
avoidance of food allergens during pregnancy, lactation, and early life in order to
prevent food allergy?
The American Academy of Allergy Asthma and Immunology (AAAAI) developed a
brochure for parents, which was updated in 2009. It includes these specific guidelines:
п‚· Try to wait until babies are 6 months old before you give them solid foods.
п‚· Wait until they are 1 year old before giving them milk and other dairy (like cheese
and yogurt).
п‚· Toddlers should not eat eggs until they are 2 years old.
п‚· Children should not eat peanuts, nuts or fish until they are 3 years old.
п‚· Talk to your doctor about a plan for introducing these foods.
Additional Information Relevant to H.i. Systematic review of the association of
caesarean delivery and allergic diseases.
10
There may be a positive association between caesarian delivery and the development of
allergic disease later in life; however, the total body of evidence on this issue has
significant methodologic concerns necessitating further investigation.
Additional Information Relevant to H.i. Studies on the use of probiotics for the
prevention of food allergies.
The quality of evidence for this key question is moderate given five high quality RCTs
that address this question but provide some mixed results. The use of probiotics in the
prenatal and early neonatal period may be associated with mild reductions in the
cumulative incidence of allergic skin disease in children. However, these results are
interpreted with caution since the trials with the most significant results used probiotics in
conjunction with breastfeeding and/or hypoallergenic formula and thus the independent
effects of probiotics cannot be established in these trials.
H ii. What methods are currently used in the management of existing food allergy?
H ii. a. What are the data on the effects of allergen avoidance based on both the
primary literature the recommendations of key organizations? This question should
include the effect on nutritional status.
Allergen avoidance is a common treatment strategy for food allergy and may work.
However, this intervention has not been adequately studied, and the quality of evidence
for this key question is low, given that only one non-randomized comparative study of
poor quality addresses this question. Confounding this key question is that allergen
avoidance diets are commonly used as a diagnostic test in addition to a treatment
strategy. If a patient is placed on an allergen avoidance diet and continues to have
symptoms, it is not clear if the allergen avoidance diet is ineffective or if the patient did
not in fact, have an allergy to that particular food. Complete absence of cow milk protein
may result in decreased energy, protein, and fat consumption while formula and milkrestricted diets may lead to micronutrient deficiencies. The quality of evidence for this
key question is low, given that only one small observational study addressed this topic.
H ii. b. What are the data on the benefits and adverse effects of immunotherapy
with foods (e.g., parenteral, oral, sublingual) to treat food allergy?
The quality of evidence for this key question—does immunotherapy improve clinical
symptoms—is high given six RCTs pf allergen-specific immunotherapy (five with oral
exposure and one with sublingual) and four RCTs of specific-immunotherapy with crossreactive allergens (sublingual and subcutaneous).. Allergen-specific immunotherapy and
specific-immunotherapy with cross reactive allergens improve clinical symptoms of food
allergy . The safety of such treatment was reported in only four of six studies of allergenspecific immunotherapy. While symptoms such as local reactions and gastrointestinal
symptoms were common, being reported in 35% and 50% of subjects, no serious safety
problems were reported. However, as case reports were not specifically searched for in
our Medline search, it is possible that a specific search for case reports of harms of
allergen-specific immunotherapy might identify some events.
11
H ii. c. How effective are current standards for food labeling for prevention of food
allergic reactions?
Since the implementation of the Food Allergen Labeling and Consumer Protection Act of
2004, no study has explicitly assessed its effect on the frequency of severe symptoms
from accidental exposure (e.g., peanut). The identified studies, all of which predated the
legislation, mostly assessed knowledge and preferences for food labeling.
H ii. d. What are the allergenic cross-reactivities (with other foods or non-food
allergens) of foods (i.e. other legumes in peanut allergic patients, tree nuts in peanut
allergic patients, etc)? What are the clinical consequences?
One small RCT evaluated the incidence of adverse reactions or allergies to soy formulas
in infants with cow’s milk allergy syndrome and found low rates of adverse events in
both the soy formula and the placebo formula. We conclude that there is insufficient
evidence to evaluate the allergenic cross-reactivities of foods.
H ii. e. What are the effects of food allergen avoidance, and other food allergy
management strategies, on co-morbid conditions such as, but not limited to, atopic
dermatitis, asthma, and eosinophilic gastrointestinal disorders?
The quality of evidence for the effect of food allergen avoidance in treating atopic
dermatitis is high given that we found two high quality systematic reviews addressing
this topic. Both reported no evidence supporting the use of allergen avoidance in treating
atopic dermatitis. We did not find any controlled studies specifically addressing food
allergen avoidance in other co-morbid conditions.
Additional Information Relevant to H ii. Pharmacological management of food
allergies
We identified four RCTs that evaluate pharmacologic agents (astemizole, cromolyn, and
steroids) to treat food allergy and one study that used probiotics to treat rectal bleeding
caused by food allergy. Given the heterogeneity of the pharmacologic interventions and
allergic conditions evaluated, we conclude that there is insufficient evidence to evaluate
the extent to which pharmacologic therapy is useful in treating food allergies.
H ii. f. What are the effects of co-morbid conditions on the clinical course of, and
management of, food allergy?
No studies were found on the effects of co-morbid conditions on the clinical course of
food allergy.
Key Question I. What methods are currently used to manage
patients diagnosed with non-IgE-mediated reactions to food,
and how do they differ from methods used to manage patients
diagnosed with IgE-mediated food allergy?
The literature does not readily separate on the basis of IgE and non-IgE mediated
reactions. To the extent possible, we have described interventions for both in H above.
12
Key Question J. What are the appropriate methods of
diagnosis and treatment of acute and life-threatening, IgEmediated food allergic reactions?
There were no specific trials evaluating methods for the diagnosis of acute or lifethreatening allergic reactions to food. We found no RCTs evaluating the management of
these serious reactions to food, but did find three cohort studies on this topic. We
conclude that there is very little data on effective strategies for the prevention or
management of life-threatening food allergies. Anaphylaxis reaction to food allergy is
seen most frequently in patients with a peanut allergy—however the literature is
insufficient to conclude regarding methods to prevent or treat this.
Conclusions
A principal conclusion of this review is that the quality of evidence is poor for most
aspects of food allergy. After screening more than 11,000 titles from which we identified
and read in more detail over 1,200 published papers, we found very few areas where we
could draw anything more than tentative conclusions. Central to the problem of
synthesizing the literature on food allergy is the lack of an agreed-upon criteria for
diagnosis. This lack of standardized, operational criteria means that results of incidence,
prevalence, and natural history cannot be compared across studies, that there is no single
“gold standard” to use for assessing the sensitivity, specificity, and other properties of
diagnostic tests, and that studies of treatments may not be comparable due to differing
methods used to identify patients with food allergy for inclusion in the study. The lack of
standardized criteria for what constitutes a diagnosis of food allergy is a major limitation
to further understanding of this.
With that limitation in mind, there are a few consistent findings that we can point to.
First, while the prevalence of food allergies varies from study to study and depends
greatly on the criteria used for diagnosis, in general it is not much more than 10%, and
may be much lower. For specific foods, allergy to cow’s milk is generally greater than
allergies to other foods, at least in children, but the prevalence of cow’s milk allergy
declines in adults, while the prevalence of allergies to other foods generally remains more
constant. Allergies to other foods are common in patients with one identified food
allergy, and other conditions such as asthma and atopic dermatitis are extremely common
in individuals identified as food-allergic. Cow’s milk allergy clearly lessens in
prevalence over time, as does egg allergy. While there are documented cases of some
patients “outgrowing” their allergy, in general this does not happen for nuts, peanuts, and
shellfish; although reactions to any particular exposure can be variable. In fact, shellfish
allergy often appears in adulthood. The natural history of other food allergies – soy, egg,
etc., has not been well studied in US populations.
Second, with regard to diagnosis, the double-blind placebo-controlled food challenge
remains the gold standard, although concerns exist regarding its practicality, validity, and
13
safety. As a result, simpler, less intensive tests are often used. The skin prick test is one
such method. Studies assessing its utility are plagued by lack of standardization of how
to administer the test and what constitutes a positive test. Compared to a food challenge,
sensitivities of 60%-95% and specificities of 40%-95% are commonly reported, and
depend on food type and wheal size, among other things. Blood tests for antigen-specific
IgE are also commonly used, and also suffer from differing thresholds being used to
classify a test as “positive”, along with differences in the type of test and type of food.
Compared to a food challenge, sensitivities of 44%-57% are reported, with specificities
of 95% to 100%. Atopy patch testing is commonly used to assess delayed immunologic
response, but also suffers from lack of standardization. A number of other tests have
been proposed as useful for diagnosing food allergies, but few have been subjected to
rigorous assessment. Combinations of tests offer some benefits, but the incremental
value, and optimal sequencing, of series of tests remains uncertain.
Third, with regard to treatment, special diets in infancy seem to help reduce the
occurrence of childhood atopic diseases in high-risk babies, some forms of
immunotherapy with or without desensitization improve some symptoms of food allergy.
While no studies have explicitly assessed the effect of changes in the legislation
governing food labeling (requiring description of potential allergenic ingredients) on
reducing symptomatic episodes of food allergy, studies conducted prior to
implementation of this legislation consistently found that parents could not understand
the existing food labels; these findings support the need for the new labeling; studies will
be needed to assess its effect.
Fourth, the most common treatment for food allergies—allergen avoidance—was
evaluated in only one small non-randomized comparative study, which suggested that it
may be an effective means of reducing allergy symptoms. A key gap in the food allergy
literature is a detailed evaluation of how to assess a “failed” trial of allergen avoidance.
Some forms of allergen specific immunotherapy improve some symptoms of food
allergy. Given the potential for anaphylaxis and other significant side effects, coupled
with the fact that only four of the six studies of this treatment strategy specifically
reported side effects, future studies of immunotherapy should systematically assess and
report on common and serious side effects.
The importance of guidelines for the diagnosis and management of food allergy are made
clear by two studies we identified as part of this literature review. One demonstrated that
having a child with food allergy affected meal preparation and family social activities,
while the other study assessed the care for acute food allergy reactions treated in the
Emergency Department and found both care that is probably not adequate, and variations
in care across sites. Effective practice guidelines will be a first step at improving care for
food allergies.
14
Introduction
Over the past decade, the occurrence of food allergies may have increased, with
prevalence estimates as high as 13 percent in US adults.1 Studies of the severity and
prevalence in the scientific literature have been in conflict, and this situation has been
further compounded by anecdotal self-reporting. As currently employed, the term “food
allergy” can cover a range of reactions that may vary depending on the amount of the
triggering food, as well as the developmental stage of the allergic individual. Based on
these parameters, suggested treatments and interventions may differ.
While reactions can sometimes be relatively mild, perhaps no more than quickly
disappearing hives, more severe reactions can result in anaphylactic shock and death.
Such a scale of consequences supports the need for precise, accurate treatment guidelines.
The necessity is further heightened by the fact that diagnosis and treatment of true food
allergies can be confounded by the occurrence of “food intolerance,” conditions in which
symptoms may resemble those of a true allergy but are not actually caused by allergens.
One example of such a condition is lactose intolerance, which produces gastrointestinal
distress (as do many food allergies), but in which the underlying cause is a mutation that
results in the inability to synthesize an enzyme needed to digest lactose, a constitutent of
dairy products.
Many guidelines for food allergy diagnosis and management are available. For example,
professional medical organizations have created clinical guidelines, such as those of the
American Gastroenterological Association, published in 2001.2 However, no
comprehensive set of medical guidelines currently exists for all food allergies,
coordinated at the federal level. Several states have developed or implemented food
allergies guidelines for their public schools; however, these guidelines are more in the
nature of risk management policies to contain known allergens, such as peanuts. For
example, at the federal level, in 2008, H.R. 2063 The Food Allergy and Anaphylaxis
Management Act of 2008 was passed in the House of Representatives. It would have
established nation-wide guidelines for schools, but it was not voted on by the Senate and
did not become law.
On July 19, 2007, a meeting was held entitled “Guidelines for the Diagnosis and
Management of Food Allergy.” It was jointly organized by the NIAID, American
Academy of Allergy, Asthma and Immunology (AAAAI), and the Food Allergy and
Anaphylaxis Network. The attendees included representatives of over twenty professional
societies, patient advocacy groups, and several NIH Institutes. They concurred that
evidence-based clinical guidelines were needed and outlined steps for their development.
The first step is a systematic review of the scientific and clinical literature. To carry out
this step, the NIAID contracted with the Southern California Evidence-based Practice
Center (EPC), based at RAND, for a systematic review of the literature. We now present
this draft report as our contribution to the guideline development process. A draft
version of this report underwent peer review; this final report incorporates the revisions
in response to that review. We now present this final report as our contribution to the
15
guideline development process. This report will serve as the basis for the further
development of guidelines according to the NIAID’s processes..
16
Methods
Key Questions
This systematic review was conducted at the request of the National Institute of Allergy
and Infectious Diseases (NIAID). The following key questions were originally posed in
the Request for Task Order (RFTO):
A. Define Food Allergy:
i. What definitions of food allergy are currently being used?
ii. Describe conditions that are described as non-immunologic adverse
reactions to food.
iii. Describe conditions that are described as immunologic, but not IgEmediated, adverse reactions to food.
iv. Describe conditions that are described as immunologic and IgE-mediated
adverse reactions to food (and which are considered by some authorities to
be equivalent to food allergy).
v. Compare adverse reactions to food that are non-immunologic,
immunologic and not IgE-mediated, and immunologic and IgE-mediated.
Include criteria for differential diagnosis of these conditions.
B. What is the incidence/prevalence of IgE-mediated food allergy? The
following should be addressed:
i. What is the incidence/prevalence of IgE-mediated food allergy in the
pediatric and adult populations? Provide a comparison.
ii. Describe the incidence/prevalence of IgE mediated allergy to specific
foods in the pediatric and adult populations.
iii. Describe age- or gender-specific changes in the specific foods that elicit
allergic reactions in children and adults.
iv. What is the incidence/prevalence of co-morbid conditions among the food
allergic population? Co-morbid conditions should include, but are not
limited to, atopic dermatitis, asthma and eosinophilic gastrointestinal
disorders (eosinophilic esophagitis, eosinophilic colitis, eosinophilic
gastroenteritis, etc).
C. What is the incidence/prevalence of immunologic, but non-IgE-mediated
adverse reactions to foods? The following should be addressed:
i. What is the incidence/prevalence of immunologic but non-IgE-mediated
adverse reactions to food in the pediatric and adult populations? Provide a
comparison.
ii. Describe the incidence/prevalence of immunologic but non-IgE-mediated
adverse reactions to specific foods in the pediatric and adult populations.
iii. What is the incidence/prevalence of co-morbid conditions among this
population?
17
iv. What is the relationship between the natural history of IgE-mediated food
allergy and the natural history of co-morbid conditions such as, but not
limited to, atopic dermatitis, asthma, and eosinophilic gastrointestinal
disorders?
v. What are the risk factors for the development of non-IgE-mediated food
allergy?
D. What are the symptoms and natural history of IgE-mediated food allergy?
The following should be addressed:
i. Describe the symptoms and natural history of IgE-mediated food allergy
in the pediatric and adult populations (including the incidence/prevalence
of unintentional exposure, risk factors for the development of disease,
severity of reactions, relationship with environmental factors and
exposures). Provide a comparison.
ii. What is the relationship between IgE-mediated food allergy and comorbid conditions (including atopic dermatitis, other eczematous skin
disorders, asthma, and eosinophilic gastrointestinal disorders)?
iii. Where do health disparities in the food allergic population exist?
E. What are the symptoms and natural history of immunologic but non-IgEmediated adverse reactions to food? The following should be addressed:
i. Describe the symptoms and natural history of immunologic but non-IgEmediated adverse reactions to food in the pediatric and adult populations
(including the incidence/prevalence of unintentional exposure, risk factors
for the development of disease, severity of reactions, relationship with
environmental factors and exposures). Provide a comparison.
ii. What is the relationship between immunologic but non-IgE-mediated
adverse reactions to foods and co-morbid conditions (including atopic
dermatitis, other eczematous skin disorders, asthma, and eosinophilic
gastrointestinal disorders)?
iii. Describe where health disparities exist in this food allergic population.
F. What tools are currently used to diagnose IgE-mediated food allergy? The
following should be addressed:
i. Patient history and physical examination
ii. Immediate skin testing (for IgE antibody)
iii. In vitro testing:
a. total serum IgE
b. allergen-specific serum IgE
c. basophil activation
d. other tests (e.g. IgG antibody levels in serum)
iv. Atopy patch testing
v. Elimination diets used for diagnosis
18
vi. Oral food challenges used for diagnosis:
a. foods used
b. method of challenge
c. criteria for positive and negative result
vii. Additional diagnostic tests besides the ones listed above
viii. Diagnostic tools used by different groups of clinicians to make the
diagnosis of food allergy.
ix. What tools are used for longitudinal assessment of patients and what are
the criteria for such assessments?
G. What tools are currently used to diagnose immunologic but non-IgEmediated adverse reactions to food, and how is a differential diagnosis made?
i. In vivo and in vitro assays for diagnostic testing.
ii. Oral food challenges used for diagnosis.
H. What methods are currently used to manage patients diagnosed with IgEmediated food allergy? The following should be addressed:
i. Dietary avoidance (including cross-reacting allergens and issues of breast
feeding and delay of solids) in the context of preventing food allergy.
a. What are the effects of early versus delayed introduction of
certain foods, notably allergenic foods, into an infant’s diet?
This question should include the effect on nutritional status.
b. What is the effect of maternal diets during pregnancy and
lactation on the development of, and clinical course of, food
allergy?
c. What is the effect of breast feeding infants on the
development of, and clinical course of, food allergy?
d. What are the effects of special diets in infants and young
children (e.g., formula, hydrolyzed formula) on the
development of, and clinical course of, food allergy?
e. What are the recommendations by professional organizations
regarding the avoidance of allergens (food and non-food) by
people with food allergy?
ii. Management of existing food allergy.
a. What are the current recommendations on strictness of
allergen avoidance for established IgE-mediated food
allergy?
b. What are the data on the benefits and adverse effects of
immunotherapy with foods (e.g., parenteral, oral, sublingual)
to treat food allergy?
19
c. How effective are current standards for food labeling for
prevention of food allergic reactions?
d. What are the allergenic cross-reactivities (with other foods or
non-food allergens) of foods (i.e. other legumes in peanut
allergic patients, tree nuts in peanut allergic patients, etc)?
What are the clinical consequences?
e. What are the effects of food allergen avoidance, and other
food allergy management strategies, on co-morbid conditions
such as, but not limited to, atopic dermatitis, asthma, and
eosinophilic gastrointestinal disorders?
f. What are the effects of these co-morbid conditions on the
clinical course of, and management of, food allergy?
I. What methods are currently used to manage patients diagnosed with nonIgE-mediated reactions to food, and how do they differ from methods used to
manage patients diagnosed with IgE-mediated food allergy?
These conditions include food protein-induced enteropathy, milk colitis, Heiner’s
syndrome, etc. Celiac disease, a special case of immune reaction to food that is
not often included in the definition of food allergy is excluded because clinical
guidelines for the management of this condition already exist.
J. What are the appropriate methods of diagnosis and treatment of acute and
life-threatening, IgE-mediated food allergic reactions?
i. Describe signs, symptoms and diagnostic tests that distinguish foodinduced acute allergic reactions and anaphylaxis from asthma or other
diseases within the differential diagnosis. This should include acute food
allergic reactions that occur only when accompanied by exercise.
ii. What are differences on the severity and ultimate outcome of acute food
allergic reactions, of administration of epinephrine auto-injections by self
administration versus by a bystander?
iii. What are the effects of medication administration by different patient care
personnel (e.g., trained ambulance personnel vs. untrained EMTs vs.
personnel in hospital emergency rooms, etc.) on the severity and ultimate
outcome of acute food allergic reactions?
iv. What is the time course of acute food allergic reactions, and what are the
effects of delays between onset of acute food allergic reaction and seeking
medical care on the severity and ultimate outcome of acute food allergic
reactions?
v. What medications treat or prevent delayed or biphasic food allergic
reactions?
vi. Describe all medications used to treat acute food allergic reactions,
including their documented effectiveness in treating specific symptoms.
Medications shall include, but are not limited to:
20
a.
b.
c.
d.
epinephrine and route
antihistamines and route
corticosteroids and route
fluids and route
vii. What is the risk of death from acute food allergic reactions?
viii. What populations are at greatest risk of death?
Refinement of Key Questions
In consultation with the NIAID and the Expert Panel, we refined the original key
questions to allow for greater tractability. The following refinements were made:
A. Define Food Allergy:
Regarding sub-question A.i, searching for definitions, per se, in Medline would be
problematical. The NIAID asked that we search for definitions currently used by major
organizations, such as the AAAAI. In addition, we performed Google searches using
terms such as “food allergy and definition.” We also looked for definitions in highimpact review articles.
Regarding subquestions ii, iii, and iv, the NIAID agreed that information for descriptions
should come from widely-used textbooks.
Sub-question A.v asked us to include “criteria for a differential diagnosis.” This is not an
evidence review question, but rather a guideline Expert Panel question. We can search for
published studies that test different criteria for distinguishing between various clinical
conditions, but interpreting any such results into criteria for a differential diagnosis is a
role of the Expert Panel.
B. What is the incidence/prevalence of IgE-mediated food allergy?
The NIAID agreed that the scope be confined to the US and Canada. In addition, because
there was some suggestion that some of the conditions of interest could be either IgE- or
non-IgE-mediated, it was agreed that the conditions would not be so divided. The list of
conditions considered in this review appears below.
C. What is the incidence/prevalence of immunologic, but non-IgE-mediated
adverse reactions to foods?
With input from our researcher reviewers, the NIAID, and their technical Expert Panel
(TEP), we developed the explicit list of conditions (below).
After much discussion and preliminary research, the RAND EPC developed a list of food
allergy conditions, in collaboration with the NIAID and the Expert Panel. Central to the
challenge is that the overarching condition of interest, “food allergies,” is not an index
21
term in Medline, (for example, the way heart failure or urinary tract infection is). The
index term in Medline is “Food Hypersensitivity.” Electronic searches using this index
term, “food hypersensitivity,” identified thousands of unrelated articles, while missing
many important ones (most on non-IgE-mediated conditions). Therefore, both RAND
and the NIAID were convinced that the only feasible way to search was to identify
specific conditions as the search subjects. In order to identify which conditions should be
considered within the domain of “food allergy” for the search, the NIAID and RAND
jointly agreed to the strategy of assessing the frequency with which particular conditions
were “included” in or “excluded” from the topic of “food allergy” as reported in a
comprehensive set of review articles on this topic. Four RAND researchers collected data
on food allergy definitions, and the medical conditions included, from 85 review articles,
using a one-page form (see Appendix L). Each review article was independently
abstracted by two reviewers, who then came to consensus and submitted one form for
each article.
In addition, the NIAID provided RAND with a list of organizations (suggested by the
Expert Panel) that might have their own definition of food allergy. RAND abstracted
information from the web sites of the 57 professional societies and other related
organizations on the Expert Panel’s list. Where available, we abstracted each
organization’s definition of food allergy; however, only 19 of the 57 web sites provided a
definition. We also abstracted the internet address; whether, how often, and in what
context the site mentions food allergy; and a link to guidelines on food allergy if the
organization had developed or endorsed them.
The results of the above tasks were presented to the Expert Panel on March 18, 2009.
Officials and the Chair of the Expert Panel selected the final list shown here:.
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
Asthma
Atopic dermatitis, eczema
Classic food-related anaphylaxis
Food-associated, exercise-induced syndromes
Colitis
Eosinophilic Esophagitis/Gastroenteritis
Cow’s milk allergy syndrome:
Induced colitis (and blood in the stools)
Food-induced enterocolitis syndrome
Food-induced proctocolitis syndrome
Milk protein allergy of infancy
Gastrointestinal hypersensitivity (e.g., vomiting, colic, diarrhea)
Laryngeal edema
Contact dermatitis
Generalized flushing
Oral Allergy Syndrome
Rhinitis, rhinoconjunctivitis conjunctivitis
Urticaria
Angioedema
22
п‚·
Heiner’s Syndrome (pulmonary hemosiderosis)
D. What are the symptoms and natural history of IgE-mediated food allergy?
Per the NIAID’s clarification of sub-question D.iii, regarding “health disparities,” we
considered issues such as socio-economic status, access to healthcare, and stress.
E. What are the symptoms and natural history of immunologic but non-IgE
mediated adverse reactions to food?
We limited our review for questions D and E to the conditions included in the list above.
F. What tools are currently used to diagnose IgE-mediated food allergy?
The NIAID re-stated this and its sub-questions as a two-part question: first, identify what
tools are currently being used, including those of which the NIAID may have initially
been unaware; and second, evaluate the utility of the tools. For sub-question F.viii, the
objective was to understand if differences existed among physicians of different
specialties or in different health care settings in the tools being used; it was agreed that
the search should be limited to tools used by physicians.
G. What tools are currently used to diagnose immunologic but non-IgE-mediated
adverse reactions to food, and how is a differential diagnosis made?
As with questions B, C, and E above, we limited the review for this question to the predetermined explicit list of conditions and their diagnosis. However, as will be described
below, since it would not be apparent whether a patient had an IgE-mediated or non-IgEmediated condition prior to diagnosis, questions F and G were considered together, with a
focus on differential diagnosis.
H. What methods are currently used to manage patients diagnosed with IgE
mediated food allergy?
After discussions with the NIAID, this question and its sub-questions were refined to
address two concerns: addressing prevention strategies for people at risk for food
allergies, and addressing the management of patients with a diagnosis of food allergy.
The subsection on pregnant women with a history of food allergy (i.e., prevention
strategies) was further refined to make explicit the distinction between management of
already allergic pregnant and/or nursing women themselves, and prenatal management
directed at trying to prevent allergies developing in offspring.
I. What methods are currently used to manage patients diagnosed with
non-IgE mediated reactions to food, and how do they differ from methods used to
manage patients diagnosed with IgE-mediated food allergy?
23
Again, in consultation with experts and the NIAID, we agreed to focus on the specific list
of conditions above.
J. What are the appropriate methods of diagnosis and treatment of acute and life
threatening, IgE-mediated food allergic reactions?
The NIAID and their guideline Expert Panel helped us to specify the list of medications
in sub-question J.vi, as follows:
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
Epinephrine (intramuscular, subcutaneous and intravenous)
H1 Blockers
H2 Blockers
Corticosteroids (intravenous and oral)
Glucagon
Alpha adrenergic agonists (intravenous)
Beta adrenergic agonists (intravenous and inhaled)
Vasopressors
Anti-IgE
Anti-leukotrienes
Charcoal
Oxygen
Intravenous fluids, including normal saline
Atrovent
Report Section by Key Question
Table 1 illustrates the task order questions and how we organized the report to address
the NIAID’s priorities. On a conference call with the NIAID in May 2009, RAND
reported that most studies found through the literature searches discuss food allergy
conditions without regard to whether they are IgE vs. non-IgE mediated. This is
especially true for incidence / prevalence studies. RAND requested further guidance
regarding where to discuss the findings of such studies. The NIAID advised not to use
IgE vs. non-IgE categories for now, but rather to categorize by conditions refined in
question C above. The guideline Expert Panel will further classify and categorize during
guideline development.
24
Table 1: Organization of report
KEY QUESTION
REPORT SECTION
Preliminary
Material
Introduction
A
Section I. What is the definition of food allergy?
B, C, D & E
Section II. Incidence and Prevalence of different types of food allergies; including
what are the symptoms and natural history of different types
F&G
Section III. Diagnosis of Food Allergy: What tools are available and how reliable
H I&J
Section IV. Management, Treatment, and Prevention of Food Allergy
Methods
Evidence Sources and Searches
Literature Searches
Literature searches were performed on PubMed, the Cochrane Database of Systematic
Reviews, the Cochrane Database of Abstracts of Reviews of Effects (DARE), the
Cochrane Central Register of Controlled Trials (Central), and the World Allergy
Organization Journal. The principle topics covered were diagnosis and testing techniques
for food allergies in general, and in the case of the PubMed searches, specific IgE- and
non-IgE-related reactions to food allergies/hypersensitivity, as indicated previously. In
most cases searches were limited to the years 1988 to the present (by agreement with the
NIAID that the prior 20 years should contain all or nearly all of the data relevant to the
current diagnosis and management of food allergy), with no language restrictions. Older
studies were included by reference mining or at the suggestion of experts. Complete
search strategies are presented in Appendix A.
Pubmed
PubMed is a service of the US National Library of Medicine (NLM) that includes over 18
million citations from MEDLINE and other life science journals for biomedical articles
back to 1948. PubMed includes links to full text articles and other related resources.
MEDLINE is the largest component of PubMed. Approximately 5,200 journals published
in the US and more than 80 other countries have been selected and are currently indexed
for MEDLINE. A distinctive feature of MEDLINE is that the records are indexed with
NLM's controlled vocabulary, the Medical Subject Headings (MeSH). MeSH
terminology provides a consistent way to retrieve information that may use different
terminology for the same concepts.
Cochrane Collaboration
The Cochrane Collaboration is an international, non-profit, independent organization,
established to ensure that up-to-date, accurate information about the effects of healthcare
interventions is readily available worldwide. It produces and disseminates systematic
reviews of healthcare interventions and promotes the search for evidence in the form of
25
clinical trials and other studies of the effects of interventions. The Collaboration produces
the Cochrane Central Register of Controlled Trials (Central), the Cochrane Database of
Systematic Reviews, and the Cochrane Database of Abstracts of Reviews of Effects
(DARE).
DARE
DARE contains structured abstracts of high-quality systematic reviews published in the
scientific literature. DARE also contains references to other reviews that may be useful
for background information. The reviews are identified by searching through key medical
journals, bibliographic databases, and less widely available “gray literature” which
includes non-peer reviewed materials. DARE includes papers that review the
effectiveness of healthcare interventions or organization. The quality of the database
content relies upon ensuring that all reviewers work to specified guidelines, and that
independent checks on the review process are carried out. DARE is produced by contract
with the Centre for Reviews and Dissemination (CRD) at the University of York, UK.
Title & Abstract Screening
The principal investigator reviewed all titles and abstracts resulting from the literature
searches regarding the key questions other than diagnosis; these latter titles were
reviewed by two RAND researchers. The principal investigator resolved any questions or
needs for clarification that arose throughout the process. Reviewers screened all titles
identified through our searches or submitted by content experts for pertinence to the key
questions. We established screening criteria to facilitate the identification of articles
concerning definitions, diagnoses, and other topics as per the NIAID and Expert Panel’s
questions. At the title screening stage, we marked for exclusion citations that were
unrelated to any of the medical conditions listed above; we generally retained ambiguous
citations.
Study Screening and Abstraction
Articles retrieved based on their titles moved on to the screening phase. Articles were
dual-reviewed, and we employed the following techniques to improve the reliability and
accuracy of our method:
п‚· Reviewers were trained in principles of evidence-based medicine using a
“training set” of articles to encourage consistent application of the definitions
and criteria of the project.
 The principal investigator served as the “gold standard” reviewer.
п‚· Specific definitions were used for both exclusion criteria and categorization.
п‚· A second review of a random subset of articles from all reviewers was
conducted.
Seven researchers, all trained in conducting systematic reviews, participated in the
process. These seven reviewers divided into teams of at least two people each to examine
which studies merited inclusion in our report, according to the criteria set forth on a Food
26
Allergies Screener form specifically designed for the review (see Appendix B for copy of
form). If the reviewers had questions, they turned to the PI for a final determination.
Articles were included/excluded based on the following:
п‚·
п‚·
Article Type
п‚ћ Included: Original data or systematic reviews.
п‚ћ Excluded: Background/contextual reviews; non-systematic
reviews, commentary or other types of articles.
Study Purpose
п‚ћ Included: Studies that looked at incidence/prevalence/natural
history; diagnosis; treatment/management/prevention.
п‚ћ Excluded: Studies that either were not about food allergy or had
some other purpose than listed above in “included.”
Included studies were then categorized by the food(s) of concern. These categories
included multiple foods, milk, egg, peanut/tree nut, fish/shellfish, soy, wheat, and/or
other foods, as specified. Studies were then categorized by the medical conditions listed
earlier; those that did not pertain to at least one of the explicit conditions were excluded
at this point. We then asked a series of questions, keyed to particular types of studies. A
number of possible answers were provided with checkboxes, and spaces were included to
specify other, unlisted answers. The questions, divided by study types, were as follows:
п‚·
п‚·
п‚·
Incidence/prevalence/natural history studies
п‚ћ From where were the patients identified?
п‚ћ How were the patients selected?
п‚ћ In which country was the study performed/did patients reside?
п‚ћ How was food allergy assessed?
Diagnosis studies
п‚ћ How were the patients identified?
п‚ћ What diagnostic tests were performed?
п‚ћ What reference tests were performed?
п‚ћ Were data reported on sensitivity or specificity or positive/negative
predictive value or false positive/false negative rate?
Treatment/management/prevention studies
п‚ћ Who was the target of the intervention?
п‚ћ What were the specific interventions?
п‚ћ What was the study design?1
Accepted articles were reviewed and abstracted by the topic teams. The teams reached
consensus on inclusion of final article sets for each topic area as well as consensus on
data items abstracted from these articles. Because of the large number of articles and the
1
Studies presenting original data were classified as either: controlled trials, cohort studies, case series,
case-control studies, decision analyses, or individual case reports. Definitions of these study designs are
included in Appendix C.
27
short time for our review, in practice, not all articles were dual-abstracted even though
team members worked together closely.
Incidence, Prevalence, and Natural History Questions
For Key Questions B-E, we first searched for high quality systematic reviews or metaanalyses, which we assessed using the AMSTAR criteria:3
AMSTAR criteria:
01. Was an a priori study design provided?
02. Was there duplicate study selection and data extraction?
03. Was a comprehensive literature search performed?
04. Was the status of publication (gray literature) used as an inclusion criterion?
05. Was a listed of studies (included/excluded) provided?
06. Were the characteristics of the included studies provided?
07. Was the scientific quality of the included studies assessed and documented?
08. Was the scientific quality of the included studies used appropriately in formulating conclusions?
09. Were the methods used to combine the findings of studies appropriate?
10. Was the likelihood of publication bias assessed?
11. Was the conflict of interest stated?
Where these were found, in general we did not review the individual studies included in
the review or meta-analysis. An exception to this rule was made for some US nationwide
studies of prevalence, which were included in a high quality review but which we also
reviewed separately as they concerned the population of most interest to the NIAID and
Expert Panel.
In addition to applying the AMSTAR criteria, we searched for studies of acceptable
design and execution to support generalization to a broad population. As detailed in the
results section, this process consisted mainly of identifying studies where the population
sampled was national in scope or came from a clearly identified community.
For these studies, we extracted relevant information about the study design, the
population, the data sources, how food allergy was defined, and the findings. We created
evidence tables for related studies and summarized them narratively.
Diagnostic Studies
For Key Questions F & G on tools for diagnosis, our initial screening identified 264
articles (studies) that evaluated diagnostic methods. Of these, three were systematic
reviews and 153 appeared on initial screening to evaluate the method(s) by reporting the
sensitivity and specificity (or positive and negative predictive value or receiver-operating
characteristics) or providing the data to perform this calculation.
These articles underwent additional screening to assess study quality using two of the 8
criteria recommended by Lijmer4 and later incorporated into the Standards for the
Reporting of Diagnostic Accuracy (STARD)5 criteria: prospective (vs. retrospective) data
collection and a modification of generalizability of the population, in that studies that did
28
not specify how the subjects were assembled were excluded. [The STARD initiative
aims to improve the quality of reporting of studies of diagnostic accuracy by applying a
checklist of 25 criteria (see Appendix D). STARD is not intended as a tool for assessing
the overall quality of a diagnostic study. The 8-item checklist used by Lijmer and
colleagues as well as a tool such as the 14-item Quality Assessment of Studies of
Diagnostic Accuracy (QUADAS),6 which relies on similar criteria, can be used for that.]
The QUADAS criteria are also shown in Appendix D for this project. Prospective data
collection was defined by its distinction from the sole reliance on medical or
administrative records for identification of patients and diagnostic test data (however,
studies were included if medical record abstraction was used to identify a population of
patients seen for a suspected food allergy or other condition of interest and all relevant
diagnostic tests were then prospectively performed on that population). Population
generalizability was defined very liberally by requiring that there be some statement
about how the subjects were assembled. Studies stating “A total of 170 infants who had
come to the allergy service for the first time and who were selected consecutively over a
4-year period” were included at this stage, whereas studies were excluded if they used
vague statements such as “one thousand patients with a typical history of an acute allergic
reaction to nut were included”, “108 individuals with suspected shrimp allergy were
included”, and “children younger than 4 years who attended the outpatient pediatric
dermatology department because of atopic dermatitis and suspected food allergy were
recruited.” Studies that met the criteria of prospective data collection and a defined
population were given priority in our synthesis because they are less susceptible to bias.
Only in certain cases, such as an explicit key question (or sub-question) for which we
found no studies that met these selection criteria, did we include studies of lesser quality.
The studies that met the initial inclusion criteria were further evaluated using QUADAS.
Treatment, Management, and Prevention Studies
For Key Questions H-J on topics related to the prevention, treatment, and management of
food allergies, we first sought high-quality systematic reviews. From each of the
systematic reviews, the following information was abstracted: study question, databases
searched, interventions evaluated, inclusion/exclusion criteria, total number of
publications included, outcomes reported, and the 11 AMSTAR quality criteria3
displayed on the previous page. We did not perform additional data abstraction on
individual studies that were already included in a systematic review.
For those key questions not addressed in a systematic review, a single investigator
abstracted the following information from each controlled trial: study purpose, design,
food/condition of interest, population of interest, intervention evaluated, and outcomes
evaluated. Although study data were abstracted by a single investigator, they were
checked by a second reviewer. If a clear consensus could not be reached as a group, we
consulted with the project principal investigator for further input.
From each included controlled trial, we also abstracted study quality information based
on the Jadad scale.7 The Jadad scale measures quality on a scale that ranges from 0 to 5,
assigning points for randomization, blinding, and accounting for withdrawals and
29
dropouts.7 Across a broad array of meta-analyses, an evaluation found that trials scoring
0-2 report exaggerated results compared with trials scoring 3-5.8 If studies were
appropriately randomized, were blinded, performed intention to treat analyses, and had
follow up rates in excess of 50 percent, we generally considered them to be of good
quality. Studies lacking two or more of these qualities were considered to be of fair
quality and studies with fewer than two of these qualities were considered to be of poor
quality.
For those key questions not addressed by either a systematic review or high quality
controlled trials, we sought information from observational studies. We first sought
observational studies with more than 100 patients, since observational studies with small
sample sizes have very limited ability to provide information that supplements trials and
is also valid. However, if still unable to address a key question, we included
observational studies with fewer than 100 patients. Specifically, small observational
studies were included for safety of immunotherapy and nutritional status for allergy
avoidance. From these observational studies, we abstracted the same study design,
population, intervention, and outcome information as for the controlled trials. Because all
of the observational studies in this review lack a comparison group, we initially
considered them to be of poor quality but then upgraded the quality rating if the study had
a high level of follow up (>90 percent), large sample sizes (>500 patients), and made
attempts to reduce bias either through study design or statistical analysis.
Summarizing the Evidence
In addition to assessing the quality of each of the included studies, for each key question
we assessed the quality of the body of evidence based on GRADE.9 GRADE was
developed to help rate the quality of evidence for studies of the treatment of a condition.
We assessed the overall quality of evidence for outcomes using a method developed by
the Grade Working Group, which classified the grade of evidence across outcomes
according to the following criteria:
o High = Further research is very unlikely to change our confidence on the
estimate of effect.
o Moderate = Further research is likely to have an important impact on our
confidence in the estimate of effect and may change the estimate.
o Low = Further research is very likely to have an important impact on our
confidence in the estimate of effect and is likely to change the estimate.
o Very Low = Any estimate of effect is very uncertain.
GRADE also suggests using the following scheme for assigning the “grade” or strength
of evidence:
30
Table 2: Criteria for assigning grade of evidence
Type of evidence
Randomized trial = high
Observational study = low
Any other evidence = very low
Decrease grade if:
п‚·
Serious (-1) or very serious (-2) limitation to study quality
п‚·
Important inconsistency (-1)
п‚·
Some (-1) or major (-2) uncertainty about directness
п‚·
Imprecise or sparse data (-1)
п‚·
High probability of reporting bias (-1)
Increase grade if:
п‚·
Strong evidence of association-significant relative risk of > 2 (< 0.5) based on consistent evidence
from two or more observational studies, with no plausible confounders (+1)
п‚·
Very strong evidence of association-significant relative risk of > 5 (< 0.2) based on direct evidence
with no major threats to validity (+2)
п‚·
Evidence of a dose response gradient (+1)
п‚·
All plausible confounders would have reduced the effect (+1)
For example, if a key question was addressed by one or more systematic reviews of high
quality and the conclusions of that review are unlikely to be changed by the addition of
new RCT data, the quality of the body of evidence was deemed to be high. Similarly, if
the key question was addressed by several RCTs, which provide robust, consistent
evidence and the conclusions of those RCTs are unlikely to be changed by the addition of
new RCT data, the quality of the body of evidence was deemed to be high. If the
systematic review or RCT evidence was inconclusive or highly likely to be changed by
future studies, the quality of the body of evidence was considered to be moderate. If the
RCT evidence was inconclusive, subject to significant methodologic concerns, or not
directly applicable to the key question, the quality of the body of evidence was
considered to be low.
Recently an adaptation of GRADE has been proposed for use with diagnostic studies.10
We used this adaptation to assess the quality of the evidence for diagnosis.
Given the heterogeneity of the included trials, with one exception we were not able to
perform quantitative syntheses of the data. Instead we present narrative summaries of the
included studies by key question, by common allergenic foods, and by common clinical
allergic conditions.
31
Meta-Analysis of Diagnostic Studies
We examined the distribution of sensitivity and specificity pairs by food allergy, test
type, and food allergy by test type. ROC curves were estimated by transforming
sensitivity and specificity pairs using logistic transforms and regressing logit sensitivities
on logit specificities. Studies were weighted by sample size. ROC curves were calculated
by back transforming predicted values from these regression models. We calculated the
lower and upper 95% confidence bounds for the ROC curves by re-estimating the curves
on bootstrap samples. The bootstrap was also used to test differences in AUC for subsets
of the studies. The bootstrap incorporated the clustering of observations within studies by
resampling at the study level rather than the sensitivity-specificity pair level.
Narrative Data Synthesis
The remaining data we found would not support statistical pooling of results across
studies (meta-analysis) because the studies were judged clinically too heterogeneous to
combine; therefore, our synthesis of the data is narrative. (An obvious exception is the
situation where an existing meta-analysis has already been performed that pooled those
studies on a particular topic judged sufficiently similar to do so.) We report the evidence
in several forms. First, the evidence tables offer a detailed description of the studies that
we identified, addressing each of the topic areas. The evidence tables provide detailed
information consistent with established criteria about the study design, patient
characteristics, inclusion and exclusion criteria, interventions evaluated, and the
outcomes.
Throughout the report, summary tables report on systematic reviews and original studies
in an abbreviated form, using summary measures of the main outcomes. Narrative text
summarizes the findings and provides qualitative analysis of the key questions as they
relate to the topic area.
Peer Review
A draft version was sent to members of the Expert Panel and to the NIAID staff. After
receiving and attending to any comments received, the final report was prepared and
submitted.
32
Results
This section presents the results of the literature synthesis. Figure 1 presents the flow of
articles. A conceptual model used to guide the analysis is shown in Figure 2.
Figure 1: Literature Flow
33
Figure 2: Conceptual model of Key Questions
34
Section I. What is the definition of food allergy?
Key Question A. Define Food Allergy.
i. What definitions of food allergy are currently being used?
In the NIAID and Expert Panel’s original definition, for a condition to be considered a
food allergy, it had to satisfy the following criteria: a) an adverse immune response that
occurs reproducibly on exposure to a given food and is b)distinct from other adverse
responses to food, such as food intolerance, pharmacologic reactions, and toxin-mediated
reactions. In addition, the NIAID initially specified that while food allergy is frequently
defined as a disorder caused by IgE-mediated reactions to food, we should review
literature relevant to adverse reactions to foods that arise from non–IgE-mediated
immunologic mechanisms (but not non-immunologic mechanisms).
In order to assess the definitions of food allergy currently being used, we reviewed all
review articles on food allergy published in the past decade (1998-2008). We identified
85 articles, of which 71 (81.7 percent) defined food allergy (see Appendix L). We
identified six key characteristics in the draft NIAID definition, and then assessed whether
or not each characteristic was included in each review article definition. The specifics
included in the definitions are shown in Table 3.
Table 3: Reviews including food allergy definitions
Definition – Key Characteristic
Immune response
Reproducibility
Particular food
Separate from food intolerance, pharmacologic,
or toxinmediated reactions
IgE-mediated reactions
Non-IgE-mediated immunologic mechanisms
Proportion of Reviews including
characteristic (N=71)
62 (87.3%)
22 (31.0%)
32 (45.1%)
35 (49.3%)
56 (78.9%)
47 (66.2%)
Also at the suggestion of the NIAID, we examined the Web sites of 57 organizations
concerned with food allergy (suggested by the Expert Panel). These organizations
included the American Academy of Allergy, Asthma, and Immunology (AAAAI),
American Academy of Pediatrics (AAP), American College of Allergy, Asthma &
Immunology (ACAAI), Centers for Disease Control and Prevention (CDC), and the Food
and Drug Administration (FDA). Nineteen of those sites contained definitions of food
allergy, as shown in Table 4.
35
Table 4: Web sites with food allergy definitions
Definition – Key Characteristic
Immune response
Reproducibility
Particular given food
Separate from food intolerance —
pharmacologic or toxinmediated reactions
IgE-mediated reactions
Non-IgE-mediated immunologic mechanisms
Proportion of sites/definition
including characteristic (N=19)
18 (94.7%)
1 (5.3%)
9 (47.4%)
6 (31.6%)
8 (42.1%)
3 (15.8%)
From each article, we also abstracted the medical conditions associated with the
definitions of the terms IgE-mediated, Non-IgE mediated, as well as those identified as
Mixed IgE- and Non-IgE mediated (as part of the previously described process to identify
the conditions that should be included within this review of “food allergy”). The results
are shown below in Table 5 through Table 7.
Table 5: Terms associated with IgE-mediated conditions
Condition
Angioedema
Asthma
Atopic dermatitis
Colitis
Food related eosinophilic esophagitis
Food related exercise induced
Gastrointestinal hypersensitivity
Generalized flushing
Laryngeal edema
Oral allergy syndrome
Rhinitis
Rhinoconjunctivitis
Urticaria
* Note: Not all reviews specified a list of conditions
36
Proportion of reviews including
this condition as “food
allergy”(N=71)
31 (43.7%)
28 (39.4%)
21 (29.6%)
0
2 (2.8%)
15 (21.1%)
22 (31.0%)
5 (7.0%)
3 (4.2%)
35 (49.3%)
20 (28.2%)
14 (19.7%)
38 (53.5%)
Table 6: Terms associated with Non-IgE-mediated conditions
Condition
Proportion of reviews including
this condition as “food
allergy”(N=71)
Asthma
5 (7.0%)
Atopic dermatitis
11 (15.5%)
Celiac disease
19 (26.8%)
Classic food related anaphylaxis
47 (66.2%)
Contact dermatitis
9 (12.7%)
Cow milk induced colitis
6 (8.5%)
Dermatitis herpetiformis
17 (12.7%)
Eosinophilic esophagitis
5 (7.0%)
Eosinophilic gastroenteritis
5 (7.0%)
Food-induced proctocolitis
24 (33.8%)
Heiner’s syndrome
15 (21.1%)
Inflammatory bowel disease
1 (1.4%)
Milk protein allergy, infants
7 (9.9%)
Protein-induced enterocolitis
29 (40.9%)
* Note: Not all reviews specified a list of conditions
Table 7: Terms associated with mixed IgE and non-IgE-mediated conditions
Condition
Proportion of reviews including
this condition as “food
allergy”(N=71)
Allergic eosinophilic esophagitis
20 (28.2%)
Allergic eosinophilic gastroenteritis
22 (31.0%)
Asthma
11 (15.5%)
Atopic dermatitis
21 (28.6%)
Contact dermatitis
2 (2.8%)
* Note: Not all reviews specified a list of conditions
Key Question A (continued)
ii.
Describe conditions that are described as non-immunologic adverse reactions
to food.
iii.
Describe conditions that are described as immunologic, but not IgEmediated, adverse reactions to food.
iv.
Describe conditions that are described as immunologic and IgE-mediated
adverse reactions to food (and which are considered by some authorities to be
equivalent to food allergy).
v.
Compare adverse reactions to food that are non-immunologic, immunologic
and not IgE-mediated, and immunologic and IgE-mediated.
37
In the course of reviewing the literature, we determined that classifying conditions as
“IgE-Mediated” and “Non-IgE-Mediated” might engender some controversy; thus,
throughout the remainder of this report, with the consent of the NIAID staff who guided
us on the review and the preparation of the report, we will not deliberately categorize
study findings in this way, but rather will present the results by condition as described in
the literature. The following constitutes a brief, basic overview of the medical conditions
studied in this report.
Anaphylactic Conditions
Classic food-related anaphylaxis
Anaphylaxis is a rapid-onset, life-threatening systemic reaction to allergens in which the
affected individual may experience cardiovascular shock and/or serious respiratory
compromise due to airway obstruction or broncho-constriction. Typically IgE-mediated,
food-induced anaphylaxis is believed to involve previously sensitized mast cells and
basophils.11 Mast cells have higher concentrations of tryptase, but samples from victims
of food-related anaphylaxis have shown a lack of elevated tryptase (victims of other
kinds of anaphylaxis, by contrast, have elevated tryptase). This finding suggests that
basophils may play the more predominant role.12, 13 However, the findings are not
definitive enough to support using tryptase as a diagnostic marker.12
The most common food triggers of anaphylaxis are peanuts and tree nuts; dairy; eggs; fin
fish, and shellfish. Incidence is variable depending on age, regional diets, food
preparation, amount of exposure, and timing of first exposure.12, 14 Most fatalities are
associated with a lack of immediate access to epinephrine; oral antihistamines alone can
not prevent death. Despite this understanding, physicians often fail to prescribe selfadministered epinephrine to individuals with a history of anaphylactic reactions to a food,
and emergency responses can vary by region.12, 15, 16
Food-induced anaphylaxis is caused by contact with the proteins in allergens, not by
inhaling olfactory volatiles (which do not contain proteins). For example, inhaling a
sufficient quantity of peanut dust may cause anaphylaxis; however, merely smelling
peanuts can not.17, 18
The NIH and National Library of Medicine’s Medline Plus lists the following symptoms
and signs of anaphylaxis. This list is general and does not distinguish between foodinduced anaphylaxis and other causes, such as insect venom- or drug-induced
anaphylaxis. The primary cause of death for food-induced anaphylaxis is respiratory
collapse.12
Symptoms:
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Abdominal pain or cramping
Abnormal (high-pitched) breathing sounds
Anxiety
Confusion
38
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Cough
Diarrhea
Difficulty breathing
Fainting, light-headedness, dizziness
Hives, itchiness
Nasal congestion
Nausea, vomiting
Sensation of feeling the heart beat (palpitations)
Skin redness
Slurred speech
Wheezing
Signs:
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Abnormal heart rhythm (arrhythmia)
Fluid in the lungs (pulmonary edema)
Hives
Low blood pressure
Mental confusion
Rapid pulse
Skin that is blue from lack of oxygen or pale from shock
Swelling (angioedema) in the throat that may be severe enough to block the airway
Swelling of the eyes or face
Weakness
Wheezing
Food-associated, exercise-induced syndromes
Food-dependent exercise-induced anaphylaxis (FDEIA) is a relatively rare variant of
exercise-induced anaphylaxis.19 FDEIA is an IgE-mediated reaction that requires a
sequence of activities to be triggered. First, individuals ingest the food to which they are
allergic; then, they exercise within a triggering window, generally two to four hours.14
The symptoms resemble those of classic food-related anaphylaxis and can be fatal if left
untreated. On the AAAAI Web site, Anna Feldweg, M.D. and Al Sheffer, M.D. (authors
of a forthcoming chapter on “Exercise Anaphylaxis” for the Joint Council Parameters on
Anaphylaxis), warned that FDEIA can be unpredictable—sometimes no reaction is
observed with the combination of specific food and exercise; sometimes a severe clinical
reaction occurs. They recommend patients who begin to display symptoms be told to stop
exercising “immediately, without exception.”
Generalized flushing
Generalized Flushing is a sudden and transient reddening of the face, neck, and less
frequently, other parts of the upper body and abdomen. While a flushing reaction may
39
occur when foods that are natural blood vessel dilators (such as hot spices and vinegars)
are ingested, flushing is also a common sign of food allergies.12, 14, 20, 21
The following foods may cause generalized flushing as part of allergic reaction:
Alcohol
пЂј
Avocadoes
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Cantaloupes
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Chocolate
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Dairy Products
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Lima Beans
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Monosodium glutamate
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Soy Sauce`
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Spinach
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Tomatoes
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Occurrences of food allergy-related generalized flushing are very common in children
and often develop simultaneously with gastrointestinal or respiratory symptoms. Flushing
is a frequent part of food-induced anaphylaxis, and thus is IgE-mediated.
Occurrences of non-food allergy-related generalized flushing, especially when
accompanied by sweating, vomiting, and diarrhea, may suggest scombroid fish poisoning
(most often from consuming contaminated tuna and mackerel). Upper body flushing,
with watery diarrhea, is also a symptom of carcinoid syndrome.
Laryngeal edema
Laryngeal edema is an intense inflammation of the larynx (voice box), and ranges in
symptomatology from a moderate swelling of the throat, resulting in a “dry staccato” or
croupy cough, to acutely hindered breathing caused by severe obstruction of the upper
airway. Recurrence of laryngeal edema is often mistaken for the common cold or
laryngitis, but more serious incidents can be life threatening.11, 22-25
The following foods may cause laryngeal edema as part of allergic reaction (not an
exhaustive list):
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Celery
Cheese
Eggs
Fish
Milk
Peanuts
Shellfish
Tree nuts
Wheat
Occurrences of food allergy-related laryngeal edema come on quite suddenly and most
commonly affect children between the ages of 2 and 8, but may also occur in older
40
children and adults. The first signs are drooling, noisy breathing, high fever, and airway
distress. Laryngeal edema is a frequent part of food-induced anaphylaxis, and thus is IgEmediated.
Occurrences of non-food allergy-related laryngeal edema, especially when occurring
without additional skin and gastro-intestinal symptoms, may suggest allergic reaction to
external factors such as bee stings and latex.
Gastrointestinal Conditions
Many of the gastrointestinal reactions to food have overlapping symptoms and allergen
triggers; without detailed histories and specialized diagnostic tools, ranging from serum
radioallergosorbent and skin prick tests to histological samples, they can be difficult to
distinguish from each other and from conditions with other causes. They can be IgE- or
non-IgE mediated. IgE-mediated conditions will often occur rapidly as part of
anaphylaxis, while non-IgE mediated symptoms are more often slowly developing and
chronic.26
Sicherer offers this definition: “Gastrointestinal food allergies are a spectrum of disorders
that result from adverse immune responses to dietary antigens. The named disorders
include immediate gastrointestinal hypersensitivity (anaphylaxis), oral allergy syndrome,
allergic eosinophilic esophagitis, gastritis, and gastroenterocolitis; dietary protein
enterocolitis, proctitis, and enteropathy; and celiac disease. Additional disorders
sometimes attributed to food allergy include colic, gastroesophageal reflux, and
constipation”.27
The World Allergy Organization offers a Web page of definitions and a chart of food
triggers linked to age and anaphylaxis:
http://www.worldallergy.org/public/allergic_diseases_center/foodallergy
Colitis
(see also Cow’s milk allergy syndrome)
Two major allergy textbooks with recent copyright dates (2008 and 2009 respectively) do
not list colitis in their indexes.11, 28 Nevertheless, the medical literature linking colitis and
food allergy goes back decades. The introduction to one of the earliest papers covers
much of what is currently known: “Simple colitis associated with varying degrees of
diarrhea, abdominal soreness, cramping, tenesmus and mucus frequently is due to
specific food allergies. Wheat, egg, milk, fish, honey, various vegetables, fruits and other
foods and condiments have been incriminated. Milk allergy, especially, is a common
cause of colitis.”29
Eosinophilic Esophagitis/Gastroenteritis
Eosinophilic esophagitis (EE) involves “a localized eosinophilic inflammation of the
esophagus.”30, 31 It affects both children and adults, although symptoms may vary with
age.30 “In children it is responsible for feeding disorders, vomiting, reflux symptoms and
41
abdominal pain and in adults it causes dysphagia and esophageal food impactions,”
according to Ferguson and Foxx-Orenstein.32
While food allergens have been implicated in EE, the precise etiology remains unknown.
It appears that both IgE and non-IgE mediated reactions occur, with non-IgE cellmediated responses predominating.30, 33 According to DeBrosse and Rothenberg, “Recent
advances have highlighted the role of Th2(T-helper type 2 cell)-driven cytokines in the
development of EGID (eosinophil-associated gastrointestinal disorders), and clinical
studies have verified that children and adults with EGID often have positive skin testing
to food allergens.”34
Eosinophilic gastroenteritis is “a general term that describes a constellation of symptoms
and a pathologic infiltration of the GI tract by eosinophils.”30 It is also both IgE- and nonIgE mediated and linked to food allergies.35, 36 Together with EE, it is part of the group of
diseases dubbed EGIDs.37 EGIDs often have similar symptoms (vomiting, regurgitation,
nausea, heartburn) to gastroesophageal reflux disease or dysphagia, and it is
recommended clinicians also consider a possible diagnosis of EE when encountering
such symptoms.30 According to an UpToDate report, “It is becoming increasingly
apparent that the esophagus (normally devoid of eosinophils) is an immunologically
active organ which, similar to the colon, is capable of recruiting eosinophils in response
to a variety of stimuli.”31, 38
Regarding EE, the Metcalfe text cautions that many patients continue to have symptoms
after elimination of the suspect foods.11 The chapter on EE recommends a specific aminoacid based diet, citing studies that showed a 95 percent successful resolution in
children.39, 40 Elemental diet and other treatments are also discussed in Pasha, et. al.41 As
for EG, elemental diets are also recommended, though such diets have not been as
“uniformly successful” as they have been for EE.30
Cow’s Milk Allergy Syndrome
(see also Colitis; Gastrointestinal hypersensitivity)
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Induced colitis (blood in the stools)
Food-induced enterocolitis (and blood in the stools)
Food-induced proctocolitis syndrome
Milk protein allergy in infancy
All of these terms are part of a constellation of symptoms/diagnoses, associated with an
early-life allergy to cow’s milk, which is a major concern in pediatric practice.42 The
current research is summarized in a review abstract by Heine and colleagues, “Cow's
milk allergy affects approximately two percent of infants under 2 years of age. Apart
from IgE-mediated atopic manifestations, T cell-mediated reactions have been
demonstrated in infants with cow's milk allergy. The clinical spectrum ranges from
immediate-type reactions, presenting with urticaria and angioedema to intermediate and
late-onset reactions, including atopic dermatitis, infantile colic, gastro-oesophageal
42
reflux, oesophagitis, infantile proctocolitis, food-associated enterocolitis and
constipation. The exact mechanisms of these disorders are still poorly understood.
Double-blind, placebo controlled food challenge, the definitive diagnostic test for cow's
milk allergy, is increasingly being replaced by the measurement of food-specific
antibodies, in combination with skin-prick or atopy patch testing. The treatment of cow's
milk allergy relies on allergen avoidance and hypoallergenic formulae, or maternal
elimination diets in breast-fed infants.”43
Sicherer describes a non IgE-mediated condition called Dietary Protein-Induced
Proctitis/Proctocolitis in this manner: “Infants with dietary protein-induced
proctitis/proctocolitis seem generally healthy but have visible specks or streaks of blood
mixed with mucus in the stool… The disorder manifests in the first several months of
life, with a mean age at diagnosis of 2 months…The lack of systemic symptoms,
vomiting, diarrhea, and growth failure help to differentiate this disorder from other
gastrointestinal food allergies that may also include colitis. Cow milk proteins and, less
commonly, soy protein are the common triggers. Most infants present while being
breastfed and are symptomatic as a result of maternally ingested proteins excreted in
breast milk. The disorder has also been noted in infants who take casein hydrolysates.”27
Jones and Burks describe Food protein-induced entereocolitis syndrome as a condition
in infancy that manifests with vomiting and diarrhea severe enough to cause dehydration
and shock.26 The condition is linked to both cow’s milk and soy protein, although some
studies also report reactions to solid food, including rice, oats, other cereal grains and
poultry.27 While the disorder is not associated with IgE antibodies, a few patients may
eventually establish IgE antibody responses. Due to the severity of the condition, Sicherer
warns: “Caution is needed when performing oral food challenges because approximately
20 percent of reactions lead to shock.”27
Regarding milk protein allergy in infancy, Arvola and colleagues concluded, “Cow's
milk allergy among (infants with rectal bleeding) is more uncommon than previously
believed. Cow's milk challenge is thus essential in infants who become symptom-free
during a cow's milk-free diet to reduce the number of false-positive cow's milk-allergy
diagnoses”.44
Paajanen and colleagues pursued the idea of cow’s milk allergy in young adults and
concluded: “Food-related gastrointestinal symptoms in young adults are caused by
unspecific and unknown traits of altered mucosal immune response rather than by cow
milk, as is often suspected by the patient.”45
Gastrointestinal hypersensitivity (e.g., vomiting, colic, diarrhea)
Immediate gastrointestinal hypersensitivity is a textbook term that refers specifically to
an IgE-mediated food allergy, in which upper GI symptoms may occur within minutes,
with lower GI symptoms occurring either immediately or with a delay of up to several
hours.26 According to Sicherer, “The usual offenders are milk, egg, peanut, soy, wheat,
and seafood. Similar to other IgE-dependent allergic disorders, allergy to milk, egg,
43
wheat, and soy generally resolves, whereas allergies to peanuts, tree nuts, and seafood are
more likely to persist.”27
Sicherer offers a cautionary note about food allergy linkage with colic: “There is some
evidence that infantile colic is associated with CMA (cow’s milk allergy), but the
strength of the relationship is not well-defined. Infants who are experiencing symptoms
of CMA have a high rate (44 percent) of colic, and hypoallergenic formulas are more
efficacious for colic than antacids or low-lactose formula. However, the role of allergy as
opposed to other causes among those with colic and without other symptoms of food
allergy remains controversial and in need of additional study.”27
Oral Allergy Syndrome
According to the World Allergy Organization, oral allergy syndrome (OAS) “is a form of
contact urticaria from ingesting a food (usually fresh fruit) confined to the lips, mouth
and throat, which most commonly affects patients who are allergic to pollens. Symptoms
include itching of the lips, tongue, roof of the mouth and throat, with or without facial
swelling, and/or tingling of the lips, tongue, roof of the mouth and throat.”46
Sicherer writes, “Individuals with oral allergy syndrome, an IgE antibody-mediated
disorder, experience prompt oral pruritus and sometimes angioedema of the lips, tongue,
and palate when ingesting certain fresh fruits and vegetables. The expression of this
allergic response requires initial sensitization via the respiratory route to pollens that
contain proteins that are homologous to those found in particular fruits and vegetables.
Individuals with this syndrome, therefore, usually have a history of seasonal allergic
rhinitis (hayfever). Examples of the associated pollens and foods include reactions to
melons in individuals with ragweed allergy and reactions to apples, peaches, and cherries
in those with birch pollen allergy. The proteins are labile, and cooked forms of the fruits
and vegetables generally do not induce symptoms. Similarly, it is assumed that systemic
reactions are averted because the proteins are easily digested. However, 9 percent of
individuals experience symptoms beyond the mouth, and one percent to two percent
experience severe reactions. Allergy skin tests using fresh extracts of the implicated food
are characteristically positive.”27
Heiner’s Syndrome (pulmonary hemosiderosis)
Jones and colleagues offer this definition: “a rare syndrome in infants characterized by
recurrent pneumonia with pulmonary infiltrates, hemosiderosis, gastrointestinal blood
loss, iron-deficiency anemia, and failure to thrive. Symptoms are associated with non-IgE
mediated hypersensitivity to cow’s milk with evidence of peripheral eosinophilia and the
presence of cow’s milk precipitins on diagnostic testing. Deposits of immunoglobulins
and C3 may also be found on lung biopsy. Strict dietary elimination of milk results in
reversal of syndromes.”26 The World Allergy Organization says that egg and pork have
also been found to be involved, but does not cite a specific source.46 In a review of eight
cases, Moissidis and colleagues found, “Milk elimination resulted in remarkable
improvement in symptoms within days and clearing of the pulmonary infiltrate within
weeks.”47
44
Skin Conditions
Fasano offers a good general summary of the inter-relationship of various dermatologic
adverse food reactions, and why differential diagnosis can be challenging: “Cutaneous
reactions to foods represent one of the most common presentations of food allergy in
children. IgE-mediated (urticaria, angioedema, flushing, pruritus), cell-mediated (contact
dermatitis, dermatitis herpetiformis), mixed IgE- and cell-mediated (atopic dermatitis),
and nonimmune-mediated (irritant contact dermatitis, Frey's syndrome) reactions to foods
have all been reported.”48
Contact dermatitis
Skypala and Venter give this textbook definition: “an inflammation of the epidermis and
dermis that occurs as a result of direct contact between a substance and the surface of the
skin. This type of cutaneous reaction is most commonly seen in occupational food
handlers, involving the hands, but it can also involve the face, especially around the
mouth, in children. This type of skin reaction may be IgE- and/or cell-mediated, and
symptoms therefore may be immediate (within 10 minutes to two hours) or delayed (2-48
hours). Research has reported contact dermatitis with a wide variety of foods, including
raw and processed foods, spices, food additives, and a variety of nuts.”49 Several articles
also implicate mangos.50
Amadoa and Jacobs summarize means of direct and indirect exposure, including kissing
(5 percent of cases) and contact with particles that become aerosolized during cooking.
They include a full list of food triggers involving non-food substances, including metals
present in foods (nickel, cobalt, chrome) and fragrances, such as Peru balsam.51 The
North American Contact Dermatitis Group’s analysis of food-associated contact
dermatitis concluded, “nickel, Myroxilon pereirae, and propylene glycol were the most
common allergens identified with a food source. Of food-related occupational disease,
irritation was more common than allergy.”52
Eczema, atopic dermatitis
Incorvaia and colleagues state: “the pathogenesis of [atopic dermatitis] is linked to a
complex interaction between skin barrier dysfunction and environmental factors such as
allergens and microbes. In particular, an important advance was the demonstration that
the mutation of the skin barrier protein filaggrin is related strictly to allergen sensitization
and to the development of asthma in subjects with AD. The altered skin barrier function,
caused by several factors, results in the passage of allergens through the skin and to
systemic responses. A pivotal role in such a response is exerted by Langerhans cells
which, via their immunoglobulin E (IgE) receptor, capture the allergens and present them
to T cells. When T helper type 2 (Th2) cells are activated, the production of a
proinflammatory cytokines and chemokines pattern sustains the persistence of
inflammation. Known AD-related cytokines are interleukin (IL)-5, IL-13 and tumor
necrosis factor (TNF)-alpha, with emerging importance for IL-17, which seems to drive
airway inflammation following cutaneous exposure to antigens, and IL-31, which is
expressed primarily in skin-homing Th2 cells. Skin-homing is another crucial event in
45
AD, mediated by the cutaneous lymphocyte-associated antigens (CLA) receptor, which
characterizes T cell subpopulations with different roles in AD and asthma.”53
According to Waterish, “the role of food allergy in the pathogenesis of atopic dermatitis
is still controversial; however, there is no doubt that, particularly in infants and young
children, food allergens can induce atopic dermatitis or aggravate skin lesions. In adults,
food allergy as a cause or a trigger of atopic dermatitis is very rare. However, in foodallergic patients with atopic dermatitis, the ingestion of the food item can provoke the
whole spectrum of IgE-mediated symptoms, from oral allergy syndrome to severe
anaphylaxis.”54
While dietary exclusion is frequently recommended for such reactions, which have been
attributed to milk and other foods,55 there are some counter-examples in the literature.
Bath-Hextall and colleagues performed a systematic review of randomized controlled
trials to assess the effects of dietary exclusion for the treatment of established atopic
eczema. They concluded, “Despite their frequent use, we find little good quality evidence
to support the use of exclusion diets in atopic eczema.”56 Schafer concludes: “Atopic
eczema is not necessarily associated with allergic sensitization. Sensitization to house
dust mites, however, seems to be clinically relevant. The impact of food allergy on atopic
eczema is difficult to assess on the basis of epidemiological studies, and more detailed
studies are needed.”57
Urticaria
(see also Angioedema)
According to Bindslev-Jensen and colleagues, “IgE and non-IgE mediated reactions of
the skin exclusive of eczema usually present as urticaria and/or angioedema.”11 In
contact urticaria, wheals appear only on the skin where direct contact has been made with
the trigger; in acute urticaria, wheals can appear anywhere.11 Burks notes, “Acute
urticaria is a common manifestation of an allergic skin response to food, but food is
rarely a cause of chronic urticaria.”58
Muller gives a precise description: “Urticarial lesions are polymorphic, round or
irregularly shaped pruritic wheals that range in size from a few millimeters to several
centimeters. Lesions can develop anywhere on the body and are spread by scratching,
combining into large, fiery-red patches. Sometimes a vascular wheal phenomenon causes
lesions to appear hyperemic in the center with a white halo along the circumference.”59
In their guidelines, the British Association of Dermatologists state, “For clinical purposes
it is often more helpful to classify urticaria by presentation than by etiology, which is
often difficult to establish. It is usually possible to distinguish clearly recognizable
patterns of urticaria on the clinical presentation, supported, where appropriate, by
challenge tests and skin biopsy…The presentation of urticaria in childhood is similar to
that in adults. Clinical and etiological classifications should be complementary rather
than exclusive: for example, chronic ordinary urticaria (COU) is most appropriate when
the etiology remains uncertain. Where there is evidence of histamine-releasing
autoantibodies the patient has autoimmune COU (synonym, chronic autoimmune
46
urticaria) but where there is no evidence of functional autoantibodies the patient has
idiopathic COU (synonym, chronic idiopathic urticaria).”60
Bindslev-Jensen and Osterballe include a chart with urticaria triggering foods identified
through a literature survey.11 In descending order, they are:
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cow’s milk
egg
peanut
additives
mustard
cod fish
wheat
goat’s milk
kiwi
sesame seeds
soy
hazelnut
cashew
apple
orange
celery
shrimp
potato
garlic
pea
corn
walnut
pineapple
In addition, Raap and colleagues describe one patient who developed urticaria in
response to lychee fruit.61
Charlesworth advises: “Urticaria and angioedema are frustrating problems for both
physicians and their patients; however, the problem can best be approached by
considering urticaria as a symptom that may be part of a larger clinical spectrum. The
physical examination and medical history remain the two most important pieces of
information. The allergist frequently overlooks the value of a skin biopsy as an aid in
sorting out the pathophysiology of urticaria and the biopsy results may help to classify
urticaria into subgroups which respond differently to treatment.”62
47
Angioedema
(See also Urticaria)
Muller and colleagues summarize the distinction between angioedema and urticaria:
“Urticaria (i.e., pruritic, raised wheals) and angioedema (i.e., deep mucocutaneous
swelling) occur in up to 25 percent of the US population. Vasoactive mediators released
from mast cells and basophils produce the classic wheal and flare reaction. Diagnosis can
be challenging, especially if symptoms are chronic or minimally responsive to therapy.”59
The same authors also give a more precise description: “Angioedema, which can occur
alone or with urticaria, is characterized by nonpitting, nonpruritic, well-defined,
edematous swelling that involves subcutaneous tissues (e.g., face, hands, buttocks, and
genitals), abdominal organs, or the upper airway (i.e., larynx). Angioedema tends to
occur on the face and may cause significant disfigurement. Laryngeal angioedema is a
medical emergency requiring prompt assessment. Acute intestinal and stomach swelling
may mimic symptoms of an abdominal surgical emergency.”59
Respiratory and Related Conditions
Rhinitis, rhinoconjunctivitis, conjunctivitis
The “Guideline on the Clinical Development of Medicinal Products for the Treatment of
Allergic Rhino-Conjunctivitis” produced by the European Medicines Agency summarizes
these conditions in its introduction: “Allergic rhino-conjunctivitis is an allergen-induced
inflammatory response. The non-infective, seasonal (SAR) and perennial allergic rhinoconjunctivitis (PAR) are the most common types and result from an immunological
response mediated by IgE. There is also a Th2 cell component accounting for chronic
symptoms. Histamine is a well-known mediator responsible for the signs and symptoms
of SAR but many other mediators including leukotrienes and prostaglandin D2 are
involved. SAR is caused by allergens released by tree, grass or weed pollination (and
spores and moulds), whereas PAR results from allergens such as animal dander, dust
mites and less frequently from allergens such as cockroaches or mould spores. Asthma
and allergic rhino-conjunctivitis are common co-morbidities. Symptoms are both nasal
and non-nasal. The most prominent nasal symptoms are itching, sneezing, rhinorrhoea
and congestion. Non-nasal symptoms commonly associated with allergic rhinitis include
tearing, eye itching and redness. Allergic rhino-conjunctivitis is most prevalent during
school age years. Allergic rhino-conjunctivitis is rare before 5 years of age.”63
Malik and colleagues write that patients, influenced by the Internet, have come to believe
in a frequent association between rhinitis and food. Instead, their review states, it is a
relatively rare reaction: “Food allergy usually presents with multi-system involvement,
most commonly cutaneous and gastrointestinal symptoms. Food allergy induced rhinitis
is less common, and isolated rhinitis due to food allergy is extremely rare. Treatment for
rhinitis due to food allergy is therefore rarely indicated.”64
Eigenmann and James concur, “Chronic or recurrent rhinitis, mostly in pre-school
children, is sometimes associated to allergic reactions mostly to milk. While some
48
patients claim of a significant decrease of the symptoms on an avoidance diet, a clear
relation has not been reproduced by validated studies. Some patients also link
consumption of milk-protein-containing products to increased amounts of secretion of the
nose and the upper respiratory tract. Again there is no evidence of an allergy-related
mechanism.”65
49
Section II. Incidence and Prevalence of different types of
food allergies; including the symptoms and natural
history of different types
Introduction to Key Questions B, C, D, and E
The Key Questions B-E are thematically related in that they concern issues about
estimation of incidence, prevalence, symptoms, natural history, and co-morbid conditions
in the general population. For this reason, the selection of articles for review is critically
dependent on the sample of patients contributing data to the article and the degree to
which conclusions about the general population may be inferred. In this case, as
described in the section entitled “Refinement of Key Questions,” the general population
of interest for this report is the US and Canada. Because genetic or environmental factors
are likely important in determining factors such as incidence, prevalence, and natural
history, and these factors certainly vary from country to country, the EPC was directed to
restrict the articles to those from the US or Canada. A list of non-US/Canada articles
identified but not included in this synthesis, their titles, and the countries of origin, is
included in Appendix E.
In addition to restriction based on country of origin, how a sample of patients is selected
is vitally important in being able to draw conclusions about the general population. From
what population the subjects were sampled, and the degree to which people sampled
actually participated in the study (the dropout rate), are the two most important factors in
determining the validity of applying the results from a study to the population as a whole.
Ideally, a random sample of US and/or Canadian residents would be selected for study
and all or nearly all would agree to participate. As the population from which the sample
is drawn is more restricted, and as the drop out rate rises, inference to the general
population becomes more problematic. No universally agreed upon threshold defines
how big the dropout rate or how narrow the sample population can be; however, in
general, dropout rates above 30 percent (i.e., retention rates below 70 percent) are a cause
for concern, and most authorities would require at a minimum that the sampled
population represent a community. Thus, studies that assess factors such as incidence,
prevalence, and natural history within a defined geographic region – such as a state or a
city or a metropolitan statistical area, in general, have greater validity as estimates of the
population parameters than studies that assess samples of patients derived from a
particular clinic or hospital. For this synthesis, we aimed to include studies with samples
drawn from a recognizable community-based population, and did not include studies of
patients from single clinics or hospitals. When no community-based studies were
available for certain key questions, we relaxed this requirement and summarized the
available data from hospital/clinic studies, and supplied the appropriate caveat that
inference to the general population is problematic.
50
A third critical factor when considering studies of incidence, prevalence, natural history,
and risk factors is the criteria used to make the diagnosis. In the case of food allergies,
the diagnostic criteria varied in the identified articles from symptoms (assessed by direct
questioning, survey, or by proxy) to skin prick tests or serum IgE or IgG levels (the latter
with thresholds that varied from article to article in terms of making the diagnosis), to
food challenges, to medical record review, to ICD codes in administrative databases.
Each of these methods has certain advantages and limitations. Patient and parent report of
symptoms with ingestion of various foods does not correlate well with other tests for food
allergies. Wood and colleagues used dietary questionnaires to assess symptoms of
possible food allergy in 457 young adults who were part of a population-based
epidemiologic cohort, and then also assessed these same young adults with skin prick
testing (SPT).66 Twenty-two percent of subjects reported an illness to food nearly every
time they ate it, with dairy products, fruits, and seafood topping the list. Thirteen percent
of subjects were sensitized to at least one food allergen extract, with peanut, shrimp, and
whole grain topping the list. Only seven subjects who reported illness in response to a
food had a positive SPT to the same food. In a study of cow’s milk allergy, Eggesbo and
colleagues compared children with a parentally perceived reaction to milk to children
with a parentally perceived reaction to egg and to children with no perceived reaction to
food.67 All children were then subjected to a diagnostic test protocol, which included
SPT, egg- and milk-specific Serum IgE, and food challenges. Among 54 children with
parentally perceived reactions to milk, 33 percent had cow’s milk allergy confirmed or
deemed “possible.” Among 32 children with parentally perceived reactions to egg (but
not milk), one had cow’s milk allergy identified on double blind placebo-controlled food
challenge (DBPCFC) and two other children had “possible” cow’s milk allergy. Among
17 children with no parentally perceived reaction to food, one had a positive DBPCFC
reaction to cow milk. In a study of 15 patients with DBPCFC sensitivies to cow’s milk,
egg, wheat and rye flour, none had a positive skin prick test or specific IgE to food.68
Consequently, different criteria for the diagnosis of food allergy will identify different
proportions of subjects as allergic. We did not exclude articles based on their method of
making the diagnosis. However, the results of studies vary by the diagnostic criteria used,
which then limits the conclusions that can be drawn.
Description of the Evidence
For these key questions, we identified 415 articles from our overall literature search,
which was unrestricted to country of origin. Of these, 92 were from the US or Canada,
58 were the United Kingdom, Australia, or New Zealand, 185 were from Scandinavia or
Europe, 31 were from the Mediterranean countries, 20 were from Japan, Korea, or China,
and 34 were from other countries. Among the 92 from the US or Canada, 48 contained
data from community-based populations. Two recent studies were available only as
abstracts and were therefore excluded. Across all studies, the largest proportion
concerned multiple food allergies, followed by roughly equal proportions of studies
solely about cow’s milk allergy syndrome, asthma and eczema, and then only a small
number of studies about any other condition.
51
Key Question B/C: What are the incidence/prevalence of IgEmediated food allergy and immunologic but non-IgE-mediated
adverse reactions to food?
i.
ii.
iii.
Incidence and prevalence in the adult and pediatric populations
Incidence and prevalence for specific foods
Age- or gender-specific changes in specific foods
Prior Systematic Reviews and Meta-Analyses
We identified two prior systematic reviews/meta-analyses relevant to these key questions,
using the criteria proposed by Whitlock and colleagues.69 Both publications resulted
from the same literature search and screening process, which was comprehensive and in
general followed the methods used by the Cochrane Collaboration. MEDLINE,
EMBASE, and the Cochrane Database were searched using multiple key words from
1990-2005. Articles were selected if they included data about the prevalence of food
allergies from community-based populations; articles from clinic-based populations and
articles that estimated the proportion of patients with asthma, eczema, or allergic rhinitis
due to food allergy were excluded. Both publications scored acceptably on the
AMSTAR3 criteria for evaluating systematic reviews. Details of each publication are
presented in Table 8. Although studies from numerous countries were included, and data
from the US and Canada were not reported separately, we nevertheless discuss the results
of these systematic reviews/meta-analyses here, and then compare and contrast their
findings with the more limited data from original research studies based in the US.
The first publication from this effort was a meta-analysis of the prevalence of food
allergy overall, stratified by adults and by children, and separate analyses of the
prevalence for each of the five main foods: cows’ milk, hen’s egg, peanut, fish, and
shellfish.1 Data were further stratified by the method used to establish the diagnosis of
food allergy: self-report, sensitization (either skin prick test or serum IgE levels), or
DBPCFC. Data were pooled across studies, although the authors acknowledge that for
most pooled analyses, there was substantial heterogeneity in the results. Given that
caveat, the authors report a pooled overall prevalence of 13 percent and 12 percent for
adults and for children, respectively, of self-report of food allergy to any food. Note that
these numbers plus all others reported here were taken from the authors’ graphs, in that
the numerical pooled result was not actually presented in the publication. Pooled results
for allergy to any food were far lower when assessed by sensitization or food challenge,
being about three percent (data stratified by age were not reported). For specific foods,
pooled results showed that prevalence was highest for milk (3.5 percent by symptoms,
0.6 percent by SPT, and 0.9 percent for food challenge) and lowest for fish (0.6 percent
by symptoms, 0.2 percent by SPT, and 0.3 percent by food challenge) (Table 8). Again, it
is worth noting that for most pooled analyses, there was statistically significant
heterogeneity in the results, indicating unexplained differences between studies, and
52
additionally, the 95% confidence intervals for many pooled results were quite wide,
indicating a lack of precision in the estimate. The authors note the need for better data
and suggest that future studies should use similar methods to minimize the influence of
different methods on the results seen across studies.
The second publication presented this group’s findings for other foods of interest: fruits,
vegetables/legumes, tree nuts, wheat, and soy.70 Additional data on cereals and seeds
were presented in an online supplement. Data in most cases were summarized
narratively, presenting ranges of prevalence reported in different studies. Results are
summarized in Table 8. In general, as with the previous analysis, the prevalence of food
allergy was much higher when assessed using self-report than when using sensitization or
food challenge. Reported prevalence for these foods was much lower than for the five
foods in their prior assessment.
In sum, prior acceptable quality systematic reviews (from the same literature search)
found that the prevalence of food allergy overall and allergy to specific foods varied
depending on the definition used, and even within the same definition, estimates of
prevalence varied widely. Improving the knowledge base on this topic will require better
agreement on an acceptable definition of food allergy for use in studies of prevalence.
53
Table 8: Systematic Reviews and Meta-Analyses of the Prevalence of Food Allergies
Medline,
EMBASE
Cochrane
1990-2005
Prevalence
of food
allergy in
asthma,
eczema, or
allergic
rhinitis;
estimates
from
selected
populations
not
representati
ve of a
community
33
Egg
Fish
Shellfish
01. Can’t
Answer
02. Yes
03. Yes
04. Yes
05. Yes
06. Yes
07. No
08. No
09. Yes
10. No
11. Yes
Milk
Prevalence of food allergy Findings
Self Report of
Symptoms
Children
Adults
All Ages
Symptoms and Skin
Prick Test or
Serum IgE
All Ages
Double-Blind
Placebo-Controlled
Food Challenge
All Ages
0.75%
3.5%*
1%
0.6%
1.1%
3%
0.75%
0.6%
0.9%
0.2%
0.6%
01. Can’t
Answer
02. Yes
03. Yes
04. Yes
05. Yes
06. Yes
07. No
08. No
09. Yes
10. No
11. Yes
3%
N.E.
0.9%
0.3%
0.3%
N.E.
Symptoms
Skin Prick Test
Challenge Test
Meta-Analysis
Adults
Children
12%
13%
0.028.5%
0.024.2%
0.14.3%
1.22%
(Sympto
ms)
N.E.
Soy
Fruits
Vegetable
s/ legumes
Tree nuts
(not
peanuts)
Wheat
Soy
AMSTAR
Criteria
Wheat
To assess the
prevalence of
allergy to
plant foods
Prevalence
of food
allergy in
asthma,
eczema, or
allergic
rhinitis;
estimates
from
selected
populations
not
representati
ve of a
community
Total
Publications
Included
51
Tree Nuts
Zuidmeer,
200870
Excludes
Peanut
To assess the
prevalence of
food allergy
Databases
Searched/
Years
Medline,
EMBASE
Cochrane
1990-2005
Vegetables/
Legumes
Rona,
20071
Food
Allergies
Included
Cow’s
Milk
Hen’s Egg
Peanut
Fish
Shellfish
Overall
Study
Question
Fruits
Author/
Year
0.0113.7%
0.012.7%
0.10.3%
04.1%
0.044.5%
0.14.3%
0.21.3%
0.21.2%
00.5%
00.6%
0.030.2%
00.7%
0.1%
(Sympto
ms)
N.E.
0.4%
(symptoms)
2%
(sensitization)
N.E.
N.E.
0.5%
(symptoms)
0.4%
(sensitization)
N.E.
Note: Almost all analyses had marked heterogeneity and wide 95% confidence intervals, indicating unexplained differences between studies
* Greater prevalence in children than adults, not specifically estimated but it appears to be about 6-7 percent in children and 1-2 percent in adults.
N.E. Not estimated
54
Data from US National Studies
We next describe the prevalence data from US studies that included representative samples of the
entire population. (We did not identify any national Canadian studies). No studies were
identified that assessed the prevalence of cow’s milk or egg allergy.
Peanut or tree nut allergy
We identified two US studies of prevalence of peanut or tree nut allergy.71, 72 The two studies
were from a nationwide, cross-sectional telephone interview of households. A random sampling
of telephone numbers was generated by computer. A preliminary study71 was conducted between
April and June 1997 and a subsequent larger study72 was conducted from June to August 2002.
The results from the 2002 study were similar to those of the 1997 study. In the 2002 study, a
total of 9,252 households were contacted; 4,397 refused to participate or were ineligible for the
study (language barrier or confusion about the study). A total of 4,855 households representing
13,493 individuals participated in the study. The participation of barely over half the families
contacted is a limitation of this study. A total of 155 (3.2 percent of households) reported one or
more individual with peanut allergy, tree nut allergy or both. The authors reported the prevalence
of peanut and tree nut allergy by age, race, and, gender:
55
Table 9: Prevalence of peanut and tree nut allergy in 2002 by age
Type of nut allergy
Any nut*
Both peanut and
TN
Isolated peanut
Isolated TN
Unspecified nut
Age
Total Sample
Population,
n = 13,493
n
% (95% CI)
n
% (95% CI)
n
% (95% CI)
n
% (95% CI)
n
% (95%
CI)
0-5 y
869
9
1.0 (0.4-1.7)
1
0.1 (0.0-0.3)
7
0.8 (0.2-1.4)
1
0.1 (0.0-0.3)
0
0
6-10 y
851
9
1.1 (0.4-1.8)
2
0.2 (0.0-0.6)
5
0.6 (0.1-1.1)
2
0.2 (0.0-0.6)
0
0
11-17 y
1228
10
0.8 (0.3-1.3)
4
0.3 (0.0-0.6)
2
0.2 (0.0-0.4)
3
0.2 (0.0-0.5)
1
0.1 (0.0-0.2)
18-20 y
579
5
0.9 (0.1-1.6)
0
0
3
0.5 (0.0-1.1)
2
0.4 (0.0-0.8)
0
0
21-30 y
1491
19
1.3 (0.7-1.8)
3
0.2 (0.0-0.4)
6
0.4 (0.1-0.7)
10
0.7 (0.3-1.1)
0
0
31-40 y
1556
18
1.2 (0.6-1.7)
3
0.2 (0.0-0.4)
7
0.5 (0.1-0.8)
7
0.5 (0.1-0.8)
1
0.1 (0.0-0.2)
41-50 y
1809
19
1.1 (0.6-1.5)
4
0.2 (0.0-0.4)
4
0.2 (0.0-0.4)
10
0.6 (0.2-0.9)
1
0.1 (0.0-0.2)
51-60 y
1352
24
1.8 (1.1-2.5)
8
0.6 (0.2-1.0)
6
0.4 (0.1-0.8)
6
0.4 (0.1-0.8)
4
0.3 (0.0-0.6)
61-64 y
355
7
2.0 (0.5-3.4)
0
0
1
0.3 (0.0-0.8)
5
1.4 (0.2-2.6)
1
0.3 (0.0-0.8)
1345
22
1.6 (1.0-2.3)
2
0.2 (0.0-0.4)
6
0.5 (0.1-0.8)
9
0.7 (0.2-1.1)
5
0.4 (0.1-0.7)
Child (<18 y), age
not specified
179
9
5.0 (1.8-8.3)
2
1.2 (0.0-2.7)
3
1.7 (0.0-3.6)
1
0.6 (0.0-1.7)
3
1.7 (0.0-3.6)
Adult (>18 y), age
not specified
1394
12
0.9 (0.4-1.4)
3
0.2 (0.0-0.5)
2
0.1 (0.0-0.3)
1
0.1 (0.0-0.2)
6
0.4 (0.1-0.8)
485
3
0.6 (0.1-1.8)
3
0.6 (0.1-1.8)
≥65 y
Age not known
Overall
13493
166
1.2 (1.0-1.4)
32
0.2 (0.2-0.3)
52
72
Table adapted from Sicherer, 2003
56
0.4 (0.3-0.5)
57
0.4 (0.3-0.5)
25
0.2 (0.1-0.3)
Peanut allergy was noted in 0.4 percent of the population, while allergy to any nut was reported
as 1.2 percent. Although the rate of allergy was reported lowest among black subjects, it was not
significantly lower than that among white subjects (p=0.25). There is an overall predominance of
peanut/tree nut allergy reported in children compared with adults (p=0.02) and, among adults,
predominance among females (p=0.0008). In contrast, in children, allergy to any nut was higher
among males.
57
Table 10: Prevalence of peanut and tree nut allergy by race, ethnicity, and sex by age
Type of nut allergy
Any nut*
Both peanut and
TN
Isolated peanut
Isolated TN
Unspecified nut
Total
Population
n
% (95% CI)
n
% (95% CI)
n
% (95% CI)
n
% (95% CI)
n
% (95% CI)
White
9867
113
1.2 (0.9-1.4)
25
0.3 (0.2-0.4)
37
0.4 (0.3-0.5)
42
0.4 (0.3-0.6)
9
0.1 (0.0-0.2)
Black
Age
1222
9
0.7 (0.3-1.2)
3
0.3 (0.0-0.5)
3
0.3 (0.0-0.5)
2
0.2 (0.0-0.4)
1
0.1 (0.0-0.2)
Hispanic
765
10
1.3 (0.5-2.1)
2
0.3 (0.0-0.6)
3
0.4 (0.0-0.8)
5
0.7 (0.1-1.2)
0
0
Other
825
12
1.5 (0.6-2.3)
1
0.1 (0.0-0.4)
5
0.6 (0.1-1.1)
6
0.7 (0.2-1.3)
0
0
Not Reported
814
22
2.7 (1.6-3.8)
1
0.1 (0.0-0.4)
4
0.5 (0.0-1.0)
2
0.3 (0.0-0.6)
15
1.8 (0.9-2.8)
15
0.98 (0.49-1.48)
5
0.33 (0.04-0.61)
2
0.13 (0.0-0.31)
Sex/age
Male (<18 y)
Female (<18
y)
1526
26
1.70 (1.05-2.35)
4
0.26 (0.01-0.52)
1473
10
0.68 (0.26-1.10)
4
0.27 (0.01-0.54)
3
0.20 (0.00-0.43)
2
0.14 (0.00-0.32)
1
0.07 (0.0-0.20)
Male (>18 y)
4338
37
0.85 (0.58-1.13)
7
0.16 (0.04-0.28)
12
0.28 (0.12-0.43)
15
0.35 (0.17-0.52)
3
0.07 (0.0-0.15)
Female (>18
y)
4962
82
1.65 (1.30-2.01)
16
0.32 (0.16-0.48)
22
0.44 (0.26-0.63)
35
0.71 (0.47-0.94)
9
0.18 (0.6-0.30)
Table adapted from Sicherer, 200372
58
The authors reported the symptoms of peanut or tree allergy as follows: throat tightness, 53
percent; dyspnea, 41 percent; wheezing, 29 percent; angioedema, 51 percent; urticaria, 47
percent, vomiting, 17 percent, diarrhea, 6 percent; and loss of consciousness, 6 percent.
Seafood allergy
We identified one US study of the prevalence of seafood allergy.73 The study was a nationwide,
cross-sectional telephone interview of households. A random sampling of telephone numbers
was generated by computer. The study was conducted between October and December, 2002. A
total of 10,966 households were contacted: 3,585 refused to participate, and an additional 1,592
were ineligible (language barrier, confusion, and hearing problems). A total of 5,789 households
(67.3 percent participation rate) representing 14,948 individuals participated in the study. A total
of 327 households (5.9 percent) reported one or more individual with allergy to seafood. The
authors reported the prevalence of fish, shellfish, and seafood allergy by age, race, and, gender
(Table 11).
Table 11: Prevalence of seafood allergy by race/ethnicity and sex/age
Type of allergy
Fish
Age
White
Total Sample
Population, n
= 14,498
11176
Shellfish
Both fish and shellfish
Any seafood
n
% (95% CI)
n
% (95% CI)
n
% (95% CI)
n
% (95% CI)
28
0.3 (0.2-0.4)
197
1.8 (1.5-2.0)
12
0.1 (0.0-0.2)
213
1.9 (1.6-2.2)
Black
1508
16
1.1 (0.6-1.7)
47
3.1 (2.3-4.1)
7
0.5 (0.2-1.2)
56
3.7 (2.8-4.8)
Other
1909
11
0.6 (0.3-1.0)
41
2.2 (1.6-2.9)
4
0.2 (0.0-0.5)
48
2.5 (1.9-3.3)
5.4 (3.3-8.2)
Refused/Not
Reported
355
3
0.9 (0.2-2.5)
18
5.0 (3.0-7.8)
2
0.6 (0.0-2.0)
19
Male (<18 y)
1936
4
0.2 (0.0-0.4)
13
0.7 (0.3-1.0)
2
0.1 (0.0-0.3)
15
0.8 (0.4-1.2)
Female (<18 y)
1726
3
0.2 (0.0-0.4)
7
0.4 (0.1-0.7)
2
0.1 (0.0-0.3)
8
0.5 (0.1-0.8)
Male (>18 y)
Female (>18
y)
5018
11
0.2 (0.1-0.4)
93
1.9 (1.5-2.2)
5
0.1 (0.0-0.2)
99
2.0 (1.6-2.4)
5726
39
0.7 (0.5-0.9)
183
3.2 (2.7-3.7)
15
0.3 (0.1-0.4)
207
3.6 (3.1-4.1)
Table adapted from Sicherer, 200473
The total lifetime prevalence rate for reported seafood allergy in the total populations was 2.3
percent, and it was 0.4 percent, 2.0 percent, and 0.2 percent for fish allergy, shellfish allergy, and
both, respectively. The rates for children were significantly lower than for adults, as follows: fish
allergy, 0.2 percent versus 0.5 percent (p=0.02); shellfish allergy, 0.5 percent versus 2.5 percent
(p<0.001); and any seafood allergy, 0.6 percent versus 2.8 percent (p=0.001). Female subjects
reported a higher rate of shellfish (2.6 percent vs. 1.5 percent, P<0.001) and fish allergy (0.6
percent vs. 0.2 percent, p<0.001) than male subjects. However, the differences in prevalence rate
by age and sex indicate a tendency toward a higher rate of seafood allergy in boys compared
with girls (0.8 percent vs. 0.5 percent, P=NS) and women compared with men (3.6 percent vs.
59
2.0 percent, p<0.001). Regarding race or ethnicity, the highest rates of seafood allergy were
reported in black subjects.
The authors reported the symptoms of shellfish allergy as follows: urticaria, 60 percent; edema,
70 percent; vomiting, 20 percent; diarrhea, 21 percent; cough, 19 percent; dyspnea, 54 percent;
wheezing, 32 percent; oral pruritis, 39 percent; throat tightness, 51 percent; and lightheadedness,
34 percent. Multiple reactions commonly occurred in each subject.
The authors reported the symptoms of finfish allergy as follows: urticaria, 69 percent; edema, 71
percent; vomiting, 27 percent; diarrhea, 23 percent; cough, 23 percent; dyspnea, 48 percent;
wheezing, 47 percent; oral pruritis, 52 percent; throat tightness, 62 percent; and lightheadedness,
45 percent. Multiple reactions commonly occurred in each subject.
Two additional studies deserve mention here because they analyze national US databases for
issues related to food allergy. In the first, investigators at the Center for Food Safety and
Applied Nutrition analyzed data from the Infant Feeding Practices Study II, a longitudinal
national mail survey of pregnant women who gave birth to a healthy single child of at least 35
weeks duration, beginning in the third trimester of pregnancy and periodically thereafter up to
age 1 of the infant.74 In this analysis, probable food allergy was defined as a doctor-diagnosed
food allergy or food-related symptoms of swollen eyes or lips or hives. In this study of 2441
mothers, 60 percent completed all serial questionnaires with detailed questions about problems
with food. About 500 infants were characterized as having a food-related problem, and 143 were
classified as probable food allergy. Infants were statistically significantly more likely to be
classified as “probable food allergy” if they had a family history of food allergy, were male,
black, or live in a rural or urban (as opposed to suburban) area on univariate analysis.
Multivariate analyses were not reported.
The second study was a National Center for Health Statistics data brief that used data from both
the 2007 National Health Intervention Survey (NHIS) and the 1998-2006 National Hospital
Discharge Survey (NHDS) to estimate the prevalence of food allergy in children and number of
hospital discharges for children.75 Both national databases are probability samples which when
weighted can produce national estimates.2 ICD codes for allergic rhinitis due to food, allergic
gastroenteritis and colitis, contact dermatitis due to skin contact, dermatitis due to foods taken
internally, and anaphylaxis shock with specific codes for peanuts, fish etc, and food additives
were included. While contact dermatitis and reactions due to food additives are outside the
scope for this report, because this study reports national data and because the cases are likely to
represent a minority of the sample, we include it here, but note the inclusion of these other
conditions as a potential limitation.
The national estimate for the prevalence of food allergy in children was 3.9 percent, with higher
prevalence in children less than 5 (4.7 percent) than others aged 5-17 years (3.7 percent).
Prevalence in girls and boys was similar (4.1 percent vs. 3.8 percent, respectively). Rates in
Hispanics were lower than in non-Hispanic whites or blacks (3.1 percent vs. 4.1 percent and 4.0
percent, respectively). Comparing these data to those collected back to 1997 showed a
2
“Food Allergy was assessed by an affirmative answer to the signle question “During the past 12 months, has
(child) had any kind of food or digestive allergy?”
60
statistically significant upward trend, from about 3.5 percent to 3.9 percent. Children classified
as having food allergy also reported having asthma (29 percent), eczema or skin allergy (27
percent), or respiratory allergy (32 percent). The national estimate of hospital discharges was
9,537 per year, and this represented a more than 3-fold increase since 1998-2000. However, as
the authors note, increases could be due to increased awareness or reporting, or a real increase in
children experiencing food-related reactions.
Lastly, as this report was being finalized a new publication appeared that assessed several
different national US surveys (National Health Interview Survey, National Hospital Ambulatory
Medical Case Survey, National Hospital Discharge Survey, and National Health and Nutrition
Examination Survey). These surveys used self-report, utilization data, and food-specific IgE.
The surveys estimated the prevalence of food allergy in the US at 3.3 percent in 1997 and 3.9
percent in 2007, and in 2005-2006 9.3 percent, 6.7 percent, 12.2 percent, and 5.2 percent of
children had serum IgE to peanut, egg, milk, and shrimp, respectively. The author concludes that
there are increasing reports of food allergy in the US, although data are unable to establish how
much is due to increased awareness and how much to a true increase in clinical disease.76
Comparison of US national studies with Prior Meta-Analyses
In Table 12, we present the data from the multinational meta-analysis with the data from the US
National Studies. Some of the estimates from the two sources are similar for some foods; for
example, shellfish has an estimated prevalence based on symptoms of 0.99 percent, 1.20 percent,
and two percent from three different studies. For other foods, the estimated prevalence based on
symptoms of allergy to cow’s milk was three percent in the meta-analysis but 0.40 percent in the
US National Study. The extent to which this and other differences are due to true differences in
prevalence in the US compared to other countries or due to differences in the way food allergy is
measured is unknown.
Table 12: Prevalence of Food Allergy in National US studies Compared to Systematic Reviews
Specific Foods
Author/Year
Milk
Zuidmeer, 200870
Symptoms
Skin Prick
IgE
Challenge
Test
Rona, 20071
Symptoms
Skin Prick
IgE
Challenge
Test
Symptoms
Skin Prick
IgE
Challenge
Test
Sicherer, 200473
Eggs
Peanut Tree nut
Shellfish
Fish
3%
0.60%
0.90%
0.60%
0.75%
0.90%
1%
0.90%
0.30%
61
Fruits
0.02-8.5%
0.02-4.2%
0.1-4.3%
0-4.1%
0.01-4.5%
0.1-4.3%
1.20%
0.60%
NE
0.60%
0.20%
0.30%
2%
0.40%
Sicherer, 200372
0.40%
Symptoms
Skin Prick
IgE
Challenge
Test
0.40%
Anaphylaxis
We next describe a discrete body of literature that assessed the incidence of anaphylaxis related
to food from US representative samples. This assessment comprised seven articles, which all
used administrative databases or medical record review to identify cases of anaphylaxis (Table
13).
The first study used medical records to assess all 133 persons having an anaphylactic event in
Olmsted County, Minnesota (MN) from 1983 to 1987.77 The diagnosis of anaphylaxis was made
on the basis of at least one symptom of “generalized mediator release” (flushing, pruritis,
urticaria, etc) and one symptom involving the oral/gastrointestinal tract, respiratory, or
cardiovascular system. The authors found a rate of 30 cases per 100,000 person-years. In 36
percent of cases, an “ingestant” was identified as the trigger. The implicated foods were fish,
shellfish, tree nuts, eggs, peanuts, and seeds.
The second study was a retrospective cohort study that examined the management of food related
acute allergic reactions as part of the Multicenter Airway Research Collaboration (MARC), a
division of the Emergency Medicine Network (EMNet). Chart reviews of Emergency
Department (ED) visits for food allergy at 21 EDs in 9 US states and four Canadian provinces
were performed. Cases with ICD-9 codes specifying diagnoses of dermatitis due to food, allergy
due to unspecified food, allergy due to specified foods, other anaphylactic shock, and allergy,
unspecified were included. Anaphylaxis cases were further identified using specific criteria
determined by the authors to define the condition. These criteria included involvement of two or
more organ systems from a specified list as well as automatic inclusion of the case as
anaphylaxis if hypotension (systolic blood pressure (BP) less than 100 milimeters (mm) mercury
(Hg)) was present. Overall, the screening process identified and reviewed in detail the records of
678 patients from 5,296 charts identified as carrying a diagnosis of an acute allergic reaction to
food.
The third study assessed cases of anaphylaxis in persons aged up to 18 years who were members
of Group Health Cooperative, a health maintenance organization (HMO) in Washington state.78
Using an algorithm that assessed symptoms, timing, and response to treatment, the authors
searched administrative databases to indentify possible cases of anaphylaxis, which they then
reviewed in more detail using the medical record. The authors found 67 cases of anaphylaxis for
a rate of 10.5 cases per 100,000 person-years. A food trigger was identified in 51 percent of
cases.
The fourth article was a cross sectional study of patients hospitalized for anaphylaxis in Florida
in 2001. Data from the Florida Agency for Health Care Administration were used, which
includes almost all non-federal Florida hospitals. To be included in the study a record needed to
have an ICD-9 code with a principal diagnosis of anaphylactic shock, allergic shock,
62
anaphylactic reaction, anaphylaxis not otherwise specified or due to the adverse effect of a
correct medicinal substance that was administered properly, anaphylactic shock due to an
adverse reaction to a nonpoisonous food, anaphylaxis due to anesthesia, or toxic effect of other
substances (including venom). A total of 464 cases were identified in the study, 363 of which
were classified as white non-Hispanic. Using this total figure and Florida’s estimated population
in 2001, an incidence of 2.8 hospitalizations for anaphylaxis per 100,000 population was
calculated. A rate of 19.8 cases of anaphylaxis per 100,000 patients hospitalized for all causes
was also tabulated. Food-related cases made up 75 of the 464 cases of anaphylaxis (16 percent).
The overall incidence of hospitalizations for anaphylaxis increased with age, although specific
values were not cited.79
The fifth study was designed as a retrospective cohort to characterize anaphylaxis
hospitalizations in New York State in patients younger than 20 years. The Statewide Planning
and Research Cooperative System (SPARCS) database, which contains information about all
New York State acute care hospitalizations, was used to extract data. Using ICD-9 codes, cases
in which anaphylaxis, as well as angioedema, urticaria, or �allergy unspecified’ were the
principal diagnoses were identified. The authors reported finding 1,972 cases of anaphylaxis in
persons younger than 20 years over the study period, 22 percent of whom were black youth. The
incidence of anaphylaxis increased over the study period from 1 per 100,000 person years in
1990 to 4.7 per 100,000 person years in 2006. About 66 percent or 1302 of the cases of
anaphylaxis were food related.80
The last study was a retrospective cohort study attempting to identify cases of anaphylaxis
occurring in patients living in Rochester, MN between 1990 and 2000. Data were extracted from
the records of the Rochester Epidemiology Project, which links and indexes the records of
almost all of the medical providers in Olmsted County, MN. Cases of anaphylaxis were initially
identified using ICD-9 codes. These cases were then reviewed further to confirm cases of
anaphylaxis using predefined criteria. There were 211 cases of anaphylaxis identified, which led
to a calculated incidence of 49.8 per 100,000 person years. Of these 211 cases of anaphylaxis, 75
were determined to be food related (36 percent). Blacks accounted for six cases, and Hispanic
persons accounted for one case of the 211 total cases. The incidence of adult cases of
anaphylaxis was found to be 42 per 100,000 person years compared to the incidence of pediatric
cases of 70 per 100,000 person years.81
The most recent study used data from the National Electronic Injury Surveillance System
(NEISS) to demonstrate, in a self-described pilot study, the feasibility of estimating food allergic
and anaphylactic events resulting in visits to US emergency departments.82 NEISS collects data
from 98 hospital EDs that are geographically distributed throughout the US, have at least six
beds, and provide 24 hour emergency services. Psychiatric and penal institutions are excluded.
NEISS represents a stratified probability sample that can use weights to estimate use in EDs
across the country. Two months of data (August-September 2003) were used in this pilot study.
Medical records were reviewed to identify food-related adverse events. Symptom key words
(flushing, rash, pruritus, wheeze) as well as voice hoarseness, congestion, sneezing, etc. were
used combined with medical record indication of “food allergic reaction” and no mention of food
spoilage, food poisoning, medication use, gastrointestinal infection, etc. From cases so identified,
additional information was extracted. This study identified 173 visits meeting their criteria, of
63
which 23 were for anaphylaxis. Using their population weights, the author estimated that across
the US, during this 2 month period, there were 2,333 visits to EDs for food related anaphylaxis.
Using a US population estimate of about 300 million, this yields an incidence estimate of about
4-6 cases/100,000 person-years. Of these 23 cases, fish or shellfish were implicated in 8 and
nuts were implicated in 7. Children/teenagers accounted for 43 percent of anaphylactic events.
Interestingly, epinephrine was given in only 62 percent of anaphylactic events (antihistamines
were given in 86 percent).
Although not from a representative sample, two additional articles are noted here because of the
specific focus on severe anaphylactic reactions or death due to foods. Sampson and colleagues
reported on 13 children aged 2-17 years, six of whom died and seven who nearly died. Peanuts
were responsible in four patients, other nuts in six patients, eggs in one patient, and milk in two
patients.83 In a subsequent article, Bock, Munoz-Furlong and Sampson reported on an additional
32 deaths. Nearly all were caused by peanut or nuts.84
In summary, seven studies found wide differences in the rates of hospitalization or ED visits for
anaphylaxis, as assessed by ICD codes or medical record review, from 1/100,000 population to
as high as 70/100,000 population. These differences may be due to differences in the study
methods or differences in the populations (Florida, New York, Washington, Minnesota). The
proportion of anaphylaxis cases thought to be due to foods also varied from 16 percent to 35
percent to 51 percent to 65 percent, depending on the study. One study reported that the number
of hospitalizations for anaphylaxis increased with increasing age, while another study reported
total cases of anaphylaxis were almost twice as high in children as in adults. We identified no
estimate of the incidence of anaphylaxis in a population that could be representative of the US
population as a whole, although a recent pilot study demonstrated the potential to estimate the
incidence of anaphylaxis that presents to US emergency departments. In case series of deaths in
the US, nearly all were attributed to peanuts or nuts.
64
Table 13: US Studies of the Incidence of Anaphylaxis due to Food
Study
Author/Year Design Population
Years of
Inclusion Data sources
How Anaphylaxis
Defined
Sample
Size
Incidence of
Anaphylaxis
Overall / Food
Related
Incidence of
Anaphylaxis Adult /
Pediatric
Yocum, 199977
Cohort
Individuals residing in
Olmstead County,
Minnesota
1983-1987
medical record
review
2 or more symptoms from a
specified list
133
30 per 100,000
person-years; meal
triggered
NS (not specified)
Clark, 200415
cohort
ED visits for acute food
allergies in US and Canada
1999
medical record
review
involvement of two or more
organ systems from
specified list
678
346 out of
678(51%) / 346 out
of 678(51%)
NS (not specified)
Bohlke, 200478
cohort
children and adolescents to
age 18, members of Group
Health Cooperative HMO
1991-1997
medical record
review
algorithm of organ systems
involved and timing plus
response to treatment
67
10.5 per 100,000
person-years; food
trigger in 51%
All < 19 years old
Mulla, 200779
cross
sectional
hospitalizations for
anaphylaxis in Florida
2001
hospitalized for
anaphylaxis
ICD-9 codes
464
19.8 per 100,000
hospitalized / 75 out
of 464
NS (not specified)
Lin, 200880
cohort
hospitalizations in NY State
in patients younger than 20
years
1990-2006
administrative
database
ICD-9 codes
4,341
1 per 100,000
person years (1990)
- 4.7 per 100,000
person years (2006)
/ 1302 out of 1972
all <20 years old
Decker, 200881
cohort
individuals residing in
Rochester, Minnesota
1990-2000
administrative
database
ICD-9 codes and specified
list of symptoms
211
49.8 per 100,000
person-years / 75
out of 211
42 per 100,000 (adult) 70
per 100,000 (pediatric)
Ross, 82
cohort
ED visits to any of 98
hospital EDs that participate
in the National Electronic
Injury Surveillance System,
which is a nationally
representative probability
sample of EDs in the US
AugustSeptember
2003
Medical Record
Review
Specific keywords, use of
phrase “food allergic
reaction” no mention that
symptoms were caused by
food poisoning medication
use, etc.
173 food
allergic
events; 23
anaphylaxis
events
2,333 nationwide
over 2 months; 4.6
per 100,000 personyears
44 percent of cases in
children/teenagers
65
Key Question D/E: What are the symptoms and natural history
of IgE-mediated and of immunologic but non-IgE mediated
adverse reactions to food?
i.
Symptoms and natural history
We identified no published studies from the US or Canada on the natural history of food
allergy conditions that reported data from nationally representative or even communitybased populations. The only published studies of natural history came from selected
populations, usually from a single clinic or hospital. Such patient populations may not be
representative of the general patient population with a specific food allergy. Nonetheless,
to assist the NIAID and the Expert Panel, we summarize here the published studies we
did identify, keeping in mind that their findings may not necessarily be extrapolated to all
patients with the condition.
Cow’s milk allergy
We identified one US study on the natural history of IgE-mediated Cow’s Milk Allergy.85
All cases came from those seen between 1993 and 2004 by one of the authors. Among
1,368 patients with food allergy, 1,073 were diagnosed with milk allergy. Fifty-three
patients with non-IgE mediated disease were excluded, and 213 patients were also
excluded because they had only one visit. A retrospective record review and analysis
was conducted for the remaining 807 patients. The diagnosis of Cow’s Milk Allergy was
made on the basis of a history of symptoms clearly associated with exposure to milk, a
positive oral food challenge, and/or clear improvement in eczema or other symptoms
with milk avoidance. Determination of an IgE-mediated allergy was based on a skin
prick test with a wheal diameter of 3 mm or greater and/or a Cow’s Milk-specific(s)IgE
of 0.35 or greater kU/L (kiloUnits per liter, an arbitrary measure of reactivity in
immunosorption assays for antigen-specific IgE).
The median age at the initial visit was 13 months, and patients were followed for a
median of 54 months. About two-thirds of patients were male. Initial symptom
presentation was as follows: skin (85 percent) including urticaria, angioedema, eczema,
or other unspecific rash; gastrointestinal (46 percent) including vomiting, diarrhea,
bloody stools, and/or gastroesophageal reflux; lower respiratory tract (14 percent)
including wheezing, cough, stridor, or difficulty breathing; and upper respiratory tract (6
percent) including rhinitis and nasal congestion. About half of patients had one organ
system affected, and half had more than one organ system affected.
Most patients had other atopic conditions: 49 percent had asthma, 40 percent had allergic
rhinitis; and 71 percent had eczema. Nearly all patients (91 percent) had an allergy to
another food in addition to cow’s milk (defined as having had a “clear symptomatic
reaction to the food and/or having had a positive skin prick test or food-specific IgE
level”): egg was most common at 79 percent, followed by peanut (73 percent), tree nut
(51 percent), soy (41 percent), and wheat (35 percent).
66
These 807 patients underwent a total of 289 milk challenges, 68 of which were conducted
at home and 221 were in the clinic. Three sets of criteria were used to define acquisition
of milk tolerance: 1) passing a milk challenge, 2) passing a challenge or a Cow’s Milk
sIgE level of less than 3 kU/L and no reaction in the last 12 months, and 3) a sIgE less
than 15 kU/L and no reaction in the past 12 months. Using these three definitions, the
proportion of patients who outgrew their allergy at 4 years was 5 percent, 19 percent, and
26 percent, respectively. The proportion who outgrew their allergy by 8 years was 21
percent, 42 percent, and 56 percent. Beyond 10 years, the number of assessed subjects
dropped to under 100 (only 60 and 18 subjects were assessed at 12 and 16 years,
respectively). Predictors of the acquisition of tolerance included lower peak IgE level
(lower levels associated with greater acquisition of tolerance), the absence of asthma or
allergic rhinitis, and never having been formula fed. Another US-based study also
reported that the rate of decline of sIgE levels over time predicted the development of
tolerance to cow’s milk in children with food-challenge-assessed cow’s milk allergy,86
albeit in a highly selected patient population.
Tree Nut Allergy
We identified one US study on the natural history of tree nut allergy.87 All cases came
from a retrospective chart review of patients from a university-based pediatric allergy
clinic. The diagnosis of tree nut allergy was made if the patient had a clear-cut history of
an allergic reaction on ingestion and a confirmation positive test response for tree nut IgE
or a history of a positive tree nut SPT or positive tree nut IgE level of greater than
0.35kU/L without a history of ingestion. Cases meeting this definition were then invited
for DBPCFC if they are 4 years of age or older and had a current tree nut IgE level of less
than 10kU/L and no history of an acute reaction in the past year. A total of 278 patients
were enrolled, of which 65 percent of whom were males, and their allergies had been
diagnosed at a median of 1.3 years. Nearly all patients (96 percent) had another atopic
condition, with 66 percent having atopic dermatitis. Of the 278 patients, 4 had reported a
reaction to tree nut in the prior year, and 106 had tree nut IgE levels above the threshold,
and 51 had elevated IgE levels and a history of reaction to ingestion. Of the remaining
117 who were eligible for a challenge test, 78 declined (67 percent), 39 consented, and of
these 23 passed the challenge. The study confirmed that some children can outgrow an
allergy to tree nut over time.
Egg Allergy
We identified one US study on the natural history of egg allergy.88 All cases came from a
retrospective chart review of patients from a university-based pediatric allergy clinic.
Chart review was done by a single abstractor. The diagnosis of egg allergy was made if
the patient had a clear clinical history of an IgE-mediated allergic reaction to egg
ingestion, or if a patient had an egg IgE of greater than 2 kU/L without known tolerance
to egg. A total of 881 patients were identified, of whom 68 percent were male. The
median age at initial visit was 14 months and the median duration of follow-up was 59
months. Most patients had other atopic conditions: 54 percent had asthma, 55 percent
had allergic rhinitis, and 81 percent had eczema. Almost all patients (93 percent) had
allergies to other foods, with peanut (74 percent) and milk (72 percent) being most
67
common. In just over half, skin manifestations were the presenting symptoms. Over
time, many patients became tolerant to egg, with tolerance values ranging from 26
percent to 55 percent at age 8 and 48 percent to 76 percent at age 12, depending on the
definition used for tolerance. However, only 67 patients contributed data to the tolerance
estimates at age 12.
Wheat Allergy
We identified one US study on the natural history of wheat allergy.89 All cases came
from a retrospective chart review of patients from a university-based pediatric allergy
clinic. Chart review was done by one of three abstractors. The diagnosis of wheat
allergy was made if patients had a clinical history consistent with an IgE-mediated
allergic reaction on wheat ingestion and a positive wheat IgE test. Between 1993 and
2007, 103 patients were identified. Of these, 66 percent were male, the median age at the
initial visit was 19 months and the median deviation of follow-up was 31 months. Most
patients had other atopic conditions: 87 percent had eczema, 67 percent had asthma, and
60 percent had allergic rhinitis. Most patients also had allergies to other foods, with milk
(70 percent), egg (56 percent), and soy (50 percent) being most common. Skin reactions
were the predominant symptoms, in more than half of cases. Over time, many patients
became tolerant, with half or more of patients being tolerant at age 8, depending on the
definition used for tolerance.
IgE-mediated wheat allergy may be indistinguishable from celiac disease based on
symptomatology. Celiac disease is a non-IgE mediated condition, while wheat allergy is
IgE-mediated. As guidelines for celiac disease already exist, studies of the natural
history of this condition were excluded from this report.
Peanut Allergy
We identified five US studies of the natural history of peanut allergy.90-94 Details of the
five studies are in Table 14. All five studies involved selected populations from
specialist clinics. One study assessed 102 children with adverse reactions to peanuts prior
to age 4.92 The authors reported this population was 68 percent male and they were
followed for a median of 5.9 years. The authors categorized the symptoms on peanut
exposure. Non-life-threatening reactions (experienced by 73 percent of the population)
included 1) contact reactions without ingestion or skin-limited symptoms on ingestion,
consisting of hives or urticaria, erythematous flushing, cutaneous pruritis, cutaneous
angioedema, or atopic dermatitis; 2) respiratory, including rhinitis, sneezing, eye
symptoms, and an abnormal sensation in the mouth and throat; and 3) gastrointestinal
symptoms like emesis, diarrhea, and abdominal pain and cramping. Life-threatening
symptoms (which occurred in 27 percent of the population) consisted of throat tightness
and angioedema, laryngeal angioedema, angioedema in the mouth, cough, wheeze,
shortness of breath, noisy breathing, tachypnea, voice change, hypotension, and loss of
consciousness. Follow-up data were available for 83 patients. Of these, 50 (60 percent)
reported a total of 115 accidental exposures to peanuts with adverse reactions, for a rate
of 0.33 adverse reactions due to accidental exposure per year. Of the 61 patients who had
initial reactions that were judged non-life-threatening, 43 had at least one subsequent
reaction, and of these, 19 had potentially life-threatening symptoms (31 percent of the
68
original 61), while 24 continued to have non-life-threatening symptoms. Of the 22
patients who had initial life-threatening symptoms, 17 had at least one subsequent
reaction, and of these reactions, 12 were considered to include life-threatening symptoms
(55 percent of the original 22) and five were considered non-life-threatening. Four
children were selected for a double-blind placebo controlled food challenge based on a
low level of sIgE and a history suggesting they had lost their allergy to peanuts. All four
passed the test; their ages were 10 years, 8 years, 6 years, and 4 years.
The second study assessed 223 patients from two university clinics and one private
practice, although 95 percent of all patients came from the Johns Hopkins clinic.93 In this
sample, 63 percent of patients were male and the median age at initial diagnosis was 1.5
years of age; the median age at the time of this evaluation was 6.5 years. In this
population, the following characteristics of the initial peanut reactions were noted: rash or
hives on the face only (19 percent), eczema (6 percent), hives or angioedema (19
percent), respiratory symptoms only (2 percent), gastrointestinal symptoms only (2
percent), skin and respiratory symptoms (6 percent), skin and gastrointestinal symptoms
(3 percent), gastrointestinal and respiratory symptoms in (1 percent), and symptoms in all
three organ systems (11 percent). Thirty percent of patients were identified on the basis
of a positive skin prick test or RAST (an immunosorption test for sIgE) without
symptoms. Associated allergic disorders were common: 59 percent of patients had
asthma, 60 percent of patients had allergic rhinitis, and 58 percent of patients had atopic
dermatitis. Concurrent allergy to another food or a history of other food allergies were
present in 70 percent and 76 percent of patients, respectively. Only five percent of
patients had no identifiable additional atopic disorder. Among concurrent food allergies,
egg (39 percent), milk (30 percent), and tree nuts (39 percent) were most commonly
reported. Among all patients, based on the history and a low level of peanut sIgE, 126
persons were deemed eligible for an oral peanut challenge. Forty one patients declined,
leaving 85 patients to undergo either open peanut challenge (67 percent of cases) or
DBPCFC (33 percent of cases). Of these patients, 48 passed the challenge.
The third study was drawn from the same general patient population as the prior study,
and assessed 68 patients who had “outgrown” their peanut allergy.94 These patients were
invited to undergo a DBPCFC, of whom 21 accepted. On the basis of answers to a
questionnaire and the food challenges in the selected patients, the authors determined that
forty seven of these patients continued to tolerate peanut ingestion. Eighteen patients
were classified as “indeterminate” because they ate only limited amounts of peanuts and
declined the food challenge. Three patients had recurrence of their peanut allergy: one
was confirmed in the food challenge test, one was not given the food challenge test due to
high peanut IgE levels, and the third case of recurrence was based on convincing history
alone.
The fourth study assessed 140 children diagnosed with peanut allergy at the Duke
University pediatric allergy clinic.91 As in the other studies, most children were male.
Most patients also had other allergic disorders: 82 percent had a past or current history of
atopic dermatitis, 62 percent had asthma, and 57 percent had allergic rhinitis. Accidental
ingestions were common, occurring in 39 percent of patients, with a mean of 1.8
69
accidental ingestions per patient. Four patients (3 percent) became tolerant at a median
age of 55 months; in two patients, tolerance was demonstrated by physician-supervised
challenge tests.
The last study on development of tolerance to peanut was substantially older, assessing
patients between 1973 and 1985.90 Since data come from the same center as the study by
Vander Leek92 summarized above, and have a common author, it is not completely clear
whether some of the subjects in the older study were also included in the newer study.
Nonetheless, in this study, 32 children who had a positive reaction to a DBPCFC were
found at two to 14 years after their original diagnosis (out of 46 sought). Of these, 16 had
experienced an accidental ingestion in the year prior to contact that had resulted in
symptoms, eight more had an accidental ingestion between one and five years prior to
contact, and eight patients had avoided peanuts entirely since their original diagnosis.
One patient was described, who, by report, was able to tolerate small amounts of peanut;
however, after an accidental ingestion produced a severe reaction, the patient resumed
total avoidance. No patient developed tolerance.
One US case report also described a patient who had resolution of peanut allergy at age 3
years and 4 months after being diagnosed at age 8 months on the basis of skin symptoms
and a positive skin prick test.95
Is the prevalence of peanut allergy increasing?
We identified two studies that assessed the change in prevalence over time of peanut
allergy in children. The first report assessed prevalence in the Isle of Wight.96 and the
second study, in two reports, assessed prevalence in Montreal, Canada97, 98. Both studies
were limited by low response rates-in the Isle of Wight study the response rate was 43
percent, a severe limitation, and in the Montreal the response rate in the first study was 56
percent and 64 percent in the second.
Both studies used a combination of symptoms and SPT to make the diagnosis of food
allergy, and the Isle of Wight study did open oral food challenges on 24 children, while
the Montreal studies used peanut-specific IgE and DBPCFC in selected children.
The Isle of Wight study found the prevalence of reported peanut allergy at 0.5 percent in
1989 and 1.0 percent in 1994-1996, a non-statistically significant difference. The
prevalence of sensitization increased from 1.1 percent to 3.3 percent, a statistically
significant difference. Although the authors concluded that sensitization to peanuts was
rising, the very low response rate makes us unable to draw any conclusions.
The two studies from Montreal both assessed a random sample of children within a
random sample of elementary schools in Montreal, in 2000-2002 and again in 2005-2007.
Children reporting no difficulties eating peanuts, about 94 percent in each sample, were
not assessed further. Symptoms, SPT, peanut-specific IgE levels and selected use of
DBPCFC were used to classify the other children as peanut-allergic or not. The
prevalence in 2000-2002 was 1.50 percent compared to 1.63 percent in 2005-2007. This
70
difference, and a difference based on a Bayesian sensitivity analysis, were not statistically
significant, but credible set intervals varied from a 0.38 percent decrease to a 70 percent
increase, meaning definitive conclusions could not be drawn.
Risk factors for peanut allergy
We identified no US studies using community-based sampling that assessed risk factors
for peanut allergy (other than familial associations of allergic disorders). At the request
of the Expert Panel, we discuss two articles from England that concern risk factors for
peanut allergy. These studies are included with the caveat that they are outside the a
priori inclusion criteria for this review.
The first study assessed patients that were part of the Avon Longitudinal Study of Parents
and Children99. This study used a case control design, with patients identified as having
peanut allergy initially coming from responses to survey items about food avoidance
and reactions to foods, previous hospitalizations, and clinical investigations. Mothers of
49 children were interviewed, and 36 of these underwent further testing (2 did not
participate because they had prior anaphylactic reactions, the remainder either could not
be located or their parents refused consent). Twenty-nine of these children had a positive
skin test to peanut. Double blind food challenge was positive in 23 children. Both the 49
child sample and the 23 child sample were considered as "cases". Controls were 70
children who had eczema ("atopic controls") and 140 children without peanut allergy.
Stored cord blood of the 23 children with peanut allergy did not contain detectible
peanut-specific IgE. Based on retrospective recall of the parents, using multivariate
logistic regression, the consumption of soy milk or soy formula, rashes over the joints
and skin creases, and the presence of an oozing, crusted rash were all independently
associated with the presence of peanut allergy (with odds ratios of 2.61, 2.60, and 5.66,
respectively). An additional analysis related the use of peanut-oil containing creams to
children with peanut allergy
The second study, from some of the same investigators, used a similar case control
design and assessed children attending a food allergy clinic in London.100 In this study,
high risk controls had a diagnosis of egg allergy, and low risk controls were recruited
from the general pediatric clinic. Environmental household peanut exposure (defined as
peanut intake across all members of the household) was much higher in cases than in
either high risk controls or low risk controls. There was no significant difference in
infant intake of peanut during the first year of life between cases and controls.
71
Table 14: US Studies of the Natural History of Peanut Allergy
Author/Year
Population
Criteria for
Diagnosis
Sample Size
Years of
Study
Population
Characteristics
Natural
History
Accidental exposure to
peanut during follow up
= 60%
Mean adverse reactions
due to accidental
exposure = 0-33/year
4 children selected on
the basis of a low serum
peanut-specific IgE had
food challenges that
were negative at ages
10, 8, 6 and 4 years
8 patients selected due
to low peanut-specific
IgE had negative food
challenges at a median
age = 6 years
Vander Leek,
200092
Children with adverse reactions
to peanuts before age 4, seen at
the National Jewish Medical &
Research Center
1) Convincing history
of clinical peanut
hypersensitivity
and/or a positive food
challenge test and
2) Positive skin prick
test
102, of which 83 contributed
data to the analysis
Not Stated;
Mean duration of
follow-up = 5.9 years
Male =
69%
Age at beginning of study =2-4 years
Initial symptoms non-lifethreatening =
73%
Skolnick, 200193
Children with a diagnoses of
peanut allergy at two university
clinics & one private practice,
age 4 years or older (95% from
Johns Hopkins University)
History of acute
reaction to peanut &
positive skin test,
RAST, or challenge;
“in some cases
positive results to
RAST or skin test
with no history of ever
ingesting peanuts”
223; of which 85
participated in oral peanut
challenge
1998-2000
Male =
63%
Median age at diagnosis = 1.5 years
Median age at evaluation =6.5 years
Fleischer, 200494
Children with a diagnoses of
peanut allergy at two university
clinics & one private practice,
age 4 years or older (88% from
Johns Hopkins University)
History of acute
reaction to peanut &
positive skin test,
RAST, or challenge;
“in some cases
positive results to
RAST or skin test
with no history of ever
ingesting peanuts”
68
1997-2003
Male =
59%
Median age at diagnosis = 1.1 years
Median age at evaluation =8.5 years
Clearly tolerate peanuts
= 47/68 (6%)
Indeterminate = 18/68
(26%)
Recurrence = 3/38 (4%)
Green, 200791
Children diagnosed as having
peanut allergy at the Duke
University pediatric clinic
between 2000-2006
Convincing clinical
history and foodspecific IgE or food
challenge
140
2000-2006
Male =
66%
Median age at first visit =28 months
Bock, 198990
Children aged 2 to 14 years seen
at the National Jewish Center for
Immunology and Respiratory
Medicine
All had symptoms and
a positive double
blind oral good
challenge
32
1973-1985
Male=
not stated
Median age at diagnosis = 7
Median age at evaluation = not
stated
Accidental exposure to
peanuts after diagnosis
= 39%
Developed tolerance =
3%
No patient developed
tolerance
72
Asthma
We identified six US studies assessing the relationship of food allergies to asthma.101-104 In
addition, two studies already discussed, both dealing with fatal or near fatal anaphylaxis to foods
in US children, reported that all or almost all patients who died had co-occurring asthma.83, 84
Furthermore, as already noted in numerous studies, co-occurring asthma is highly prevalent
among patients diagnosed with food allergy.
The first of two studies assessed cross-sectionally the association between the presence of food
allergies (based on self-report) and the severity of asthma in adults attending the general medical
clinic at Mt. Sinai Hospital.101 Among 203 adults with asthma, 22% reported convincing
symptoms to at least one food. These patients were more likely than the non-food allergic
asthma patients to have had a hospitalization for asthma and increased emergency department
visits for asthma.
The second study assessed the presence of food sensitization (as measured by sIgE of greater
than 0.35 kU/L) in 504 random serum samples from the National Cooperative Inner City Asthma
Study.102 This study included children between 4 and 9 years of age recruited from EDs and
clinics in inner-city areas of the US. Skin prick testing was also performed. Forty-five percent
of children were sensitized to at least one food, and four percent had sIgE levels that had a
greater than 95% positive predictive value for food allergy. The most common sensitizations
were to milk, wheat, and peanut, whereas the most common sIgEs with a 95 percent positive
predictive value for food allergy were peanut and egg. Sensitized asthmatic children had a
higher rate of hospitalization than non-sensitized asthmatic children and also required more
steroid use.
The third study examined the medical records of 72 patients admitted to the pediatric intensive
care unit of the Cleveland Clinic from 1992 to 2002. All patients had been admitted for asthma,
and they were compared to 108 patients admitted for asthma but not requiring ICU admission
and another 108 ambulatory care asthma patients.103 When compared on self-reported food
allergy documented in the medical record, in a model adjusting for age, ethnicity, tobacco
exposure, and other factors, the presence of food allergy was significantly much more likely in
patients admitted to the ICU than in either of the comparison groups (adjusted odds ratio
compared to non-ICU hospital admission 3.27 (95% CI 1.45-7.40); adjusted odds ratio compared
to ambulatory asthmatic patients 7.36 (95% CI 2.54-21.39).
The fourth study assessed a convenience-sample of families with and without food allergies
living in Chicago, Illinois. Food allergy was defined as typical symptoms plus an SPT or sIgE
test. Asthma was assessed by parental report of a physician diagnosis. The adjusted odds ratio
of having asthma was about 5.105
The last study surveyed members of Kaiser Permanente Northwest who had either been
hospitalized with asthma during the prior four years or who had failed at least two prescriptions
for medications used to treat asthma in the prior year. Nine hundred fourteen subjects provided
data, although what proportion this was of the total population was not reported. Subjects
completed a survey and some had spirometry. All subjects had a physician-made diagnosis of
73
asthma. Among the 914 subjects, 400 reported having a reaction to food on the survey. The
most commonly reported foods were milk (21.5 percent), eggs (8.5 percent), red wine (8.5
percent), chocolate (7.5 percent), and peanuts (7.2 percent). The presence of self reported food
allergy was significantly associated with greater asthma severity (32 percent to 26 percent, odds
ration of 1.4), as was the odds of hospitalization for asthma (odds ratio = 1.5)
A related study reported changes in airway hyper-responsiveness to methacholine before and
after DBPCFC in 26 patients with both food allergy and asthma.106 This study concluded that
food-induced allergic reactions can increase airway reactiveness.
Atopic dermatitis
We identified one US study of the natural history of food hypersensitivity in children with atopic
dermatitis presented in two papers.107, 108 Initially, these authors studied 113 children referred for
evaluation of severe atopic dermatitis. Ninety-three of these children had at least one reaction to
a standard battery of food antigens on skin prick testing. Sixty three tested children had a
positive reaction to DBPCFC. Egg, peanut, and milk were the most common foods provoking a
reaction. In a follow up study, seventy five children with a mean age of 8 (range 3-18) were
identified, all diagnosed with a DBPCFC. In addition to atopic dermatitis, these patients had
other atopic diseases: 44 percent had allergic rhinitis and asthma; 27 percent had allergic
rhinitis; and four percent had asthma. Sixty percent of the patients were allergic to a single food,
28 percent were allergic to two foods, eight percent were allergic to three foods, and three
children (four percent) were allergic to four foods. Milk, peanut, and egg were the most likely to
produce positive food challenges. No additional data were reported about the patients (such as
gender or symptoms).
After their initial diagnosis, all children were placed on allergen-restricted diets; compliance by
history was 90 percent. After one or two years, patients underwent repeat food challenge tests.
Twenty six percent of patients lost all evidence of symptomatic food hypersensitivity, and
overall, 31 percent of the 1,221 food sensitivities were lost, or, as the authors described it,
“outgrown” after one year of food avoidance. All patients who “outgrew” their reactivity to a
specific food had the food reintroduced into their diets with no recurrence of symptoms and no
worsening of atopic dermatitis, at a follow-up from six months to four years. Patients who
developed skin and respiratory tract symptoms at the initial food challenge were much less likely
to “outgrow” their food allergy than patients whose initial symptoms were limited to skin only or
skin and gastrointestinal tract symptoms.
An additional article about the relationship of atopic dermatitis and food allergy assessed
consecutive children presenting to a university dermatology clinic with persistent eczematous
rash. Sixty-three patients were studied, with a median age of 2.8 years. Twenty two of the
children had food-specific IgE levels of 0.7 kUA/L to each of milk, egg, wheat, soy, peanut and
fish, and were not studied further. Of the remaining 41 patients, 10 did not undergo additional
evaluation due to loss to follow up on patient preference. Of the remaining 31 patients, 19
underwent DBPCFC and 14 had open food challenges with 18 positive challenges in 11 patients.
Two patients were considered food allergic based on food-specified IgE being above a threshold
with 95 percent predictive value for a positive food challenge, and 6 and 5 patients were
diagnosed as food allergic based on a convincing history and either a positive skin test or
74
elevated sIgE. In all, 23 of 63 children (37 percent) with atopic dermatitis were considered to
have food allergy.109
Chronic urticaria and angioedema
We identified one US study of the national history of chronic urticaria and angioedema. All
subjects were patients of the same allergy clinic. Eighty six patients with chronic urticaria or
angioedema were identified. There was a slight preponderance of females (48 females, 38
males) and mean age of onset was 33 years of age. Eleven patients were lost to follow up. Of
the remaining, 27 patients had their symptoms resolve in a 3 year period. The authors note that
testing for allergies was rarely helpful.110
Eosinophilic Esophagitis
We identified three US studies of the natural history of eosinophilic esophagitis.111-113 Details of
the three studies are presented in Table 15. All studies involved selected populations from
university-affiliated or referral specialty clinics. All studies used symptoms plus a positive
biopsy on endoscopy to make the diagnosis. The first study112 assessed 71 patients, the second
study111 assessed 89 patients, and the third study assessed 562 patients.113 In all three studies, the
majority of patients were male, and in two of the studies, 90 percent or more where white. Most
children were diagnosed within the first three years of life. Symptoms in the study of 89 patients
included emesis in 53, abdominal pain in 22, heartburn in 19, dysphagia in 14, diarrhea in 14,
airway symptoms in 12, cough in 10 and chest pain in 6. In the study of 562 patients, symptoms
were grouped into age-related categories as “refusal to eat” in toddlers, gastroesophageal reflux
and vomiting symptoms in young school-age children, and dysphagia and food impaction in
older children. Two of the studies differed on the report of implicated foods. The leading foods
in the one study were egg, peanut, and soy (39 percent, 39 percent, and 34 percent
respectively),111 while in the other study the leading foods were milk, egg, and wheat (17
percent, 11 percent, and 10 percent, respectively).113 The third study did not report specific
prevalence for foods, but did note that 60 percent of tested patients had food allergies. In two
studies with adequate follow-up over several years, most patients remained symptomatic, and
resolution was uncommon (8/57, or 14 percent in one study, 11/562, or two percent in the other),
but the two studies differed in reports of progression of eosinophilia to other parts of the
gastrointestinal tract (77 percent in one study versus 0 percent in the other).
We briefly mention two additional studies here. Among 565 patients (5 percent in all, median
age = 50 years) scheduled for outpatient elective upper endoscopy at Walter Reed hospital, 385
(68 percent) agreed to and received a biopsy to assess the prevalence of eosionophilic
esophagitis, and completed a survey about symptoms and comorbid conditions. Of these, 25 (6.5
percent) had histologic evidence of eosinophilic esophagitis, and of these, 4 (16 percent) reported
food allergies as a comorbidity.114 Sixty eight patients with biopsy-proven eosinophilic
esophogitis at the Cleveland Clinic were identified from a registry. Of these, 28 had been
referred for an allergy evaluation, and of these 26 completed the evaluation. Thirteen of these
patients had a positive skin test for at least one food, with peanut, egg, soybean, and cow milk
being most common.115
75
Exercise-induced anaphylaxis
We identified one US study of the natural history of exercise-induced anaphylaxis.116 Six
hundred seventy one patients were identified at a single Asthma and Allergic Diseases Center
from 1980 until approximately 1993. Inclusion criteria included being age 18 or older and
speaking English. A survey was mailed to all patients; 365 responded (54 percent). Of these
365, 279 (76 percent) met the criteria for exercise-induced asthma (which included report of
anaphylactic symptoms, urticaria, and/or angioedema with symptoms consistent with upper
respiratory obstruction) or had cardiovascular collapse during exercise. Patients with symptoms
that included an elevation in core body temperature were excluded. Nearly three quarters of
patients were female. The mean age was 37 years with an onset of symptoms at age 26, and the
mean duration of symptoms was 10.6 years. The average number of episodes per year at the
time of initial presentation was 14.5, but this frequency decreased to 8.3 at the time of the
survey. Approximately one third of subjects had no attacks in the 12 months prior to the survey.
The most frequently occurring symptoms were pruritis (92 percent), urticaria (86 percent),
angioedema (72 percent), flushing (70 percent), and shortness of breath (51 percent). Thirty
seven percent of patients reported a food trigger. The most commonly reported food triggers
were shellfish (16 percent), alcohol (11 percent), tomatoes (8 percent), cheese (8 percent), and
celery (7 percent). About one half of subjects reported seasonal rhinitis or dust allergies. Asthma
was reported by 19 percent, and 10 percent had eczema.
76
Table 15: US Studies of the Natural History of Eosinophilic Esophagitis
Author/Year
Population
Criteria for
Diagnosis
Years of
Study
Sample Size
Population
Characteristics
Dauer, 2005112
Pediatric patients
diagnosed with
eosinophilic
esophagitis at the
Mayo Clinic
Not specifically
stated, but all
but one patient
underwent
endoscopy with
biopsy
71
1992-2003
Male:
Assa’ad, 2007111
Pediatric patients
diagnosed with
eosinophilic
esophagitis at
Cincinnati
Children’s Hospital
Symptoms;
biopsy at
endoscopy
89; 57 contributed
to data follow-up
1997-2004;
Mean duration
of follow-up=
7.6 years
Male:
79%
White:
94%
Age at diagnosis:
Mean =
6 years
Mode =
1 year
Spergel, 2009113
Pediatric patients
diagnosed with
eosinophilic
esophagitis at
Children’s Hospital
in Philadelphia
Symptoms;
biopsy at
endoscopy
562
1996-2006;
Mean duration
of follow-up=
3.2 years
Male:
75%
White:
90%
Age at diagnosis:
Mean =
6 years
Mode =
0-3 years
77
Foods with
positive skin
prick test or
atopy patch test
65% SPT or RAST
performed in 47
Age at diagnosis:
patients. 60% of
Mean =
10.5 years patients had food
Mode =
12 year allergies. Most
common were milk,
peanuts, & soy
beans.
Egg =
Peanut =
Soy =
Beans =
Cow Milk =
Pea =
Mustard =
Milk =
Egg =
Wheat =
Soy =
Corn =
Peanut =
39%
39%
34%
29%
29%
29%
26%
17%
11%
10%
8%
8%
5%
Natural
History
Of 96 patients
treated with
swallowed
fluticasone,
follow up data
available for
only 26. 17 of
these had
“complete
response.”
Resolved =
8/57
Resolved with
Relapse =
30/57
Persisted =
19/57
Resolved =
11/562
Partial
Resolution =
33/562
Progression to
eosinophilia
in colon or
stomach = 0
Table 16: Studies of Allergies to Specific Foods, Non US/Canada
Food
Country
Reference
Asparagus
Buckwheat
Celery
Cow Milk
Cow Milk
Cow Milk, Egg &
Atopic Dermatitis
Egg
Egg
Kiwi
Legume
Melon
Mustard
Mustard
Mustard
Peanut
Peanut
Peanut
Sesame
Sesame
Sesame
Sesame
Snail
Soy Bean
Zucchini
Spain
China
France
Australia
Italy
117
Europe
Turkey
Norway
Spain
Spain
Spain
France
Spain
France
Australia
UK & Israel
UK
Israel
Israel
France
Israel
Spain
Europe
Switzerland
55
118
119
120
121
122
123
124
125
126
127
128
129
130
131
99
132
133
134
135
136
137
138
78
Other conditions/foods
We did not identify any US or Canadian studies of the natural history of other conditions or
foods. Of note, we did identify such reports from other countries. Table 16 lists these studies.
ii.
Relationship between IgE-mediated and immunologic but non-IgE-mediated
food allergy and comorbid conditions.
No additional studies other than those described above in section B-D iv were found.
iii.
Differences in populations related to socioeconomic status, access to health care,
stress.
We did not find any US studies that specifically addressed differences in incidence, prevalence,
or natural history related to socioeconomic status, access to health care, or stress. The US
National Study did report data stratified by race, and some investigators use race as a proxy for
socioeconomic status and access to health care. Those data are presented in tables 10 and 11
reporting the US National data. In addition, two US studies already presented (of infant feeding
practices and of the NHIS/NHDS databases) reported that black males were more likely to have
parent-reported food allergy and the rates of food allergy in Hispanics was lower than in nonHispanics. One cohort study from Sweden reported that the risk of sensitization to food
allergens decreased with increasing socioeconomic status, with an odds ratio of 0.65 (95%
confidence interval 0.41,1.02, p=0.03 for trend) in the highest as compared to the lowest
socioeconomic group.139
Genetics
There is emerging evidence of a genetic association with food allergy. A family-based study of
food allergy in Chicago reported strong familial aggregation and suggested that both genetic and
environmental factors contributed to this.140 Three genetic association studies reported a
relationship between certain genes (SPINK5, FOXP3, and NLRP3) and food allergy, and the
NLRP3 association was reported specific for food-induced anaphylaxis.141-143
Lastly, recent studies have suggested that filaggrin mutations associated with severe atopic
dermatitis may subsequently confer greater risk of allergic senisitization to foods.144 In a recent
systematic review of 24 studies, filaggrin gene defects were associated with an increased odds of
developing atopic eczema, allergic rhinitis, and the co-occurrence of allergic rhinitis or asthma in
patients with atopic eczema. Evidence was inconclusive regarding an association between
filaggrin gene mutations and asthma in patients without atopic eczema, and in this review no
studies were identified assessing fillagrin gene mutations and food allergies or anaphylaxis.145
79
Section III. Diagnosis of Food Allergy: What tools are
available and how reliable are they?
Key Questions F and G: What tools are currently used to diagnose
IgE-mediated and non-IgE-mediated food allergy?
General Principles for Studies of Diagnostic Tests
Before proceeding to a description of the findings of our literature review, it will be valuable to
review a few principles of how diagnostic tests are assessed. At its most fundamental level, an
assessment of a diagnostic test can be depicted as shown in Table 17.
Table 17: Diagnostic test properties
Reference Test or Gold Standard
Positive
Study Test
Negative
Positive
Negative
True Positives (TP)
False Positives (FP)
(Type I error)
PPV
TP/(TP+FP)
False Negatives (FN) True Negatives (TN)
(Type II error)
NPV
TN/(TN+FN)
Sensitivity
TP/(TP+FN)
Specificity
TN/(FP+TN)
In this table, the “study test” is the diagnostic test being assessed and is compared to a reference
test or “gold standard,” that is, a test that is assumed to diagnose the condition of interest with
100 percent certainty. Each participant is assessed with both the reference test and the study test.
Subjects testing positive by both tests are denoted "True Positives" (TP) and those testing
negative by both tests are denoted "True Negatives" (TN). Subjects who test positive by the
study test but negative by the reference test are "False Positives" (FP), whereas those who test
negative by the study test, but positive by the gold standard are "False Negatives" (FN). Four
statistics are commonly produced from these frequencies that can be used to gauge the usefulness
of a test. The sensitivity of a test is the number of true positives divided by the total number of
positives as defined by the reference test or TP/(TP+FN) and is a measure of the proportion of
subjects with a condition who are identified by a given test. A test with a 100-percent sensitivity
is positive for all individuals with a given diagnosis. The specificity of a test is the number of
true negatives divided by the total number of negatives as defined by the reference test, or
TN/(FP+TN). A 100 percent specific test is negative for all people who do not have the
condition by the reference standard (i.e., no false positives). The positive predictive value (PPV)
of a test is the proportion of patients with a positive result by the study test who are correctly
diagnosed or TP/(TP+FP). A 100% PPV means that all subjects with a positive study test result
have the condition according to the reference test (i.e., no false positives). Finally, the negative
predictive value (NPV) of a test is the proportion of patients with a negative test result who were
correctly identified (compared to the reference test) or TN/(TN+FN). For a test with 100% NPV,
80
all subjects with a negative test result do not have the condition (according to the reference
standard).
With an understanding of these measures, the general outline of the issues in studies of
diagnostic tests can be appreciated. First, is the reference test an adequate gold standard upon
which to compare the study test? Second, is the study test defined in sufficient detail that it can
be replicated: the conditions used for the test and the criteria for a positive or a negative result?
Third, is the interpretation of the two tests made independently, such that investigators were
blinded to the results of other tests when interpreting a given test? Fourth, from what population
were the subjects drawn and to whom do the study apply?
The same principles as discussed in the section introducing studies of the natural
history/incidence/prevalence apply here. Studies where the patients came from a defined
population, “all patients referred from primary care…” or “consecutive patients evaluated for the
possibility of food allergy” give readers a better sense of whom the results apply to than vague
statements like “46 patients were assessed.” The extent to which the defined population
represents the kinds of patients for whom the diagnosis is uncertain increases the usefulness of
the results. Likewise, performing the assessment of the study test in only those patients for
whom the diagnosis is already known does not represent the real-life situation in which the study
test will be used.
Search Results
Two hundred sixty-four articles were initially identified as diagnostic studies. Among the articles
screened, 153 articles reported sensitivity and specificity or provided data that allowed us to
calculate those values. The articles were further selected based on two criteria derived from the
above discussion of principles: We chose studies that were prospective and had a defined
population, at least at the level of “consecutive patients referred”. However, we also included
evidence of lower quality for several conditions and tests that were specifically identified by the
key questions for which no studies of higher quality were available.
In this section, we report the findings of these studies according to the type of test, the test(s)
used as the gold standard (reference), and the specific food(s) involved. In general, for each
study, we report the sensitivity and specificity of the test(s) compared to the reference as well as
the positive predictive value and negative predictive value when provided.
Using the QUADAS criteria, we assessed the quality of all studies that met the inclusion criteria.
QUADAS is a tool for the assessment of quality of studies of diagnostic methodologies.7
Characteristics assessed include description of the population, blinding, comparison to a gold
standard, the timing of the diagnostic test compared with the gold standard, and description of
the methodology. Although the complete tool includes 14 items (domains), we excluded two
items that would be difficult to apply to tests of food allergy. The criteria and scoring are
provided in Appendix D. The results are reported in Figure 3 below and in the evidence table in
Appendix H. Two domains were almost universally satisfied by the studies: “Was the reference
standard independent of the index test?” and “Was the execution of the index test described
81
sufficiently?” (34 of 38 studies) Two domains were satisfied in 33 out of 38 of the studies: “Is
the time period between reference standard and index test short enough?” and “Did patients
receive the same reference standard?” One domain satisfied 31 out of 38 of the studies: “Was the
execution of the reference standard described sufficiently?” The following domains were
satisfied in 30 out of 38 of the studies: “Is the reference standard likely to correctly classify the
target condition?” and “Were the index test results interpreted independent of the reference
standard?” One domain satisfied 26 out of 38 of the studies: “Were patients representative of
those who will receive the test?” One domain satisfied 22 out of 38 of the studies: “Were
selection criteria clearly described?” The domains least satisfied were the following: “Were the
reference standard results interpreted independent of the index test?” (12 of 38 studies) and
“Were withdrawals from the study explained?” (11 of 38 studies).
Figure 3: Numbers of Studies with a “Yes” Response to the QUADAS Domain Question
History and Physical Examination
It is generally accepted that the diagnosis of food allergy must begin with a careful history and
physical exam, the results of which guide the use of any further diagnostic tests; however, only
one study on this topic met our inclusion criteria. This study investigated the use of umbilical
erythema as an indication of cow's milk protein intolerance (CMPI) in 796 children (aged 1
month to 10 years) consecutively referred to the gastroenterology clinic at an Italian hospital
with suspected CMPI. Of these children, 384 were diagnosed with CMPI via elimination diet
and subsequent DBPCFC, and of these, 36 children had umbilical erythema, yielding a
sensitivity of 0.09. There were no cases of children with umbilical erythema and without CMPI,
resulting in a specificity of 1.0 (this study satisfied 10 of the 12 QUADAS domains assessed).146
82
The quality of evidence for the history and physical examination is very low, meaning any
estimate of effect is very uncertain, due to a near total absence of data, but we discuss it here at
the request of the NIAID and Expert Panel.
Food Challenge Tests
Oral food challenge tests, in which individuals with suspected food allergies are administered
increasing amounts of the suspect foods (usually following a period of prescribed avoidance)
under controlled conditions, are widely used as the gold standard for food allergy diagnosis (at
least when implemented under double blind conditions with placebo controls). However, several
issues remain to be clarified about food challenge tests: the need for blinding, the effect of the
form of food used (e.g., raw vs. cooked, fresh vs. freeze-dried, whole vs. extracts), whether the
test is truly a gold standard, and when the tests are needed (given the expense, time, and potential
risks involved).147
Five studies that assessed various aspects of food challenge tests satisfied the inclusion criteria
(four of these five studies are described in Table 18; the fifth is described in more detail later in
this section).
Double-blind versus Open Challenge
Isolauri (1996) placed 183 Finnish children (2-36 months of age) on cows’ milk elimination diets
(substituting cow’s milk with breast milk or special formula) and then randomly assigned them
to open or double-blind placebo controlled cow’s milk challenge.148 The placebo consisted of
NeocateВ® formula, and the challenge formula consisted of 10gm skimmed cow milk powder per
milliliter (ml) of the placebo formula (beta-lactoglobulin concentration in the placebo compared
with cow’s milk was 0.24 g/L vs. 4x106 g/L). The challenge involved administering
increasing doses of the milk, beginning with 10 ml, and continuing for a week (day one in the
clinic, the remainder at home) or until a clinical reaction occurred. Children were examined at
the time of reaction and/or at 7 and 14 days. The open challenge used a commercial formula that
contained 124,000пЃ­g/L beta-lactoglobulin. A positive challenge was defined as an unequivocal
adverse reaction. The rate of positive reactions was identical between the blinded and open
challenge groups (54 percent, 99 children). No differences were seen between blinded and open
tests in the time to acute or delayed reaction or in the doses required to elicit their respective
reactions. Although all placebo challenges were negative, one child subsequently showed a
positive clinical reaction to open cow’s milk feeding, resulting in a one percent false negative
challenge (this study satisfied 10 of the 12 QUADAS domains assessed).
Mehl (2006) conducted DBPCFC in 437 children (referred to an allergy department in Germany
for suspected allergy to milk, egg, wheat, or soy) as a standard for assessing the utility of the
atopy patch test (APT) compared with tests of immediate (IgE-mediated) reactivity. Although
this study is described in much greater detail below, it seems worth noting that 10 of 341 (three
percent) placebo challenges gave positive reactions (this study satisfied 9 of the 12 QUADAS
domains assessed).149
83
A 2007 study found that of 123 DBPCFC administered to 105 children, nearly 13 percent of
positive reactions were reactions to placebo.150 Of these reactions, 65% actually involved
objective symptoms (e.g., urticaria). A variety of reasons were suggested for positive placebo
reactions, including hypersensitivity due to recent withdrawal from allergy medication and
inadvertent exposure to the allergen. The authors cited the rate of positive placebo reactions as
supportive of the need for DBPCFC. Another study published in 2007 compared open food
challenges with DBPCFC in those children with a positive open challenge.151 Among 41
children who received both, 11 children had a positive response during a one-day open food
challenge and 8 of these had a positive response on DBPCFC. Two of the three children with a
positive open challenge but a negative DBPCFC had reported subjective symptoms on the open
challenge. Thirty children had positive reactions to 35 open challenges of one week’s duration,
and of these 20 were also positive on DBPCFC. All those with a negative DBPCFC had reported
subjective symptoms. This study, like others of its kind, was limited by the refusal, of about one
third of the children with a positive open challenge to receive a DBPCFC. A 2009 case report
described a 15-month old child referred for assessment of egg allergy who had a positive
reaction to placebo presentation during a DBPCFC.152 Subsequent investigation revealed that the
child was inadvertently exposed to egg during the placebo portion of the test because the
accompanying parent kissed the child immediately after having eaten an egg sandwich. Lastly, a
research letter reported on 5 cases (out of 242 children) who had passed an open food challenge
or DBPCFC but who had symptoms when consuming the food at home, with all 5 children
subsequently having a positive DBPCFC.153 These cases were interpreted as “false negative”
initial challenges.
Use of Alternative Outcomes to Improve Assessment of Reactivity.
Positive reactions to food challenges are typically some combination of signs or symptoms
indicative of an adverse reaction to that food and condition. Two studies meeting the inclusion
criteria investigated subjective measure of food challenge outcome.
Clark (2007) examined the use of facial thermography to improve the objective assessment of
clinical symptoms in response to challenge among 24 children with confirmed egg allergy.154
The children were administered increasing amounts of egg (cooked egg to children with
confirmed allergy to cooked egg; uncooked egg to all others) at 10-minute intervals.
Thermography was performed in a temperature-controlled room by a technician blinded to other
responses to the challenge. The sensitivity was 0.92 for the test (no specificity could be
calculated, as the entire sample had the disease). The median time of onset to the rise in nasal
temperature was 20 minutes, compared with a median 67-minute time to onset for
gastrointestinal symptoms (this study satisfied 7 of the 12 QUADAS domains).
Hwang (2008) tested the use of a gastric juice leukocyte counts and several other assessments as
a more rapid, reliable response to cow’s milk challenge (than vomiting and diarrhea) among 16
Korean infants with suspected cow’s milk-protein-induced enterocolitis (CMPIE).155 Prior to
beginning the challenge, other possible causes of the symptoms were ruled out, infants were
switched to hydrolyzed protein formula and/or breast milk, and weight was stabilized. Among
the children, 15 had elevated levels of leukocytes in their gastric juice in response to the
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challenge, compared with 14 who exhibited vomiting. Results of other tests (shown in Table 18)
were considered less reliable (this study satisfied 8 of the 12 QUADAS domains assessed).
Endoscopic Allergen Provocation
Bischoff (1996) assessed 375 adults seen in a university gastroenterology clinic, 275 of whom
had Crohn’s disease, 82 of whom had ulcerative colitis, and 38 of whom had other diseases.
Patients were classified as “suspected intestinal food allergy” of they met at least three of the
following: symptoms related to food, elevated total serum IgE, sIgE for specific foods, peripheral
or tissue eosinophilia, improvement of symptoms after treatment with disodium cromoglycate or
presence of an atopic disorder in a first degree relative of the patient. In 13 such patients, in
whom an elimination diet did not produce a clean result, investigators performed colonoscopic
allergen provocation by administering allergens and observing the mucosa for 20 minutes and
then taking a biopsy.156 Investigators conducted 34 intestinal food allergen provocations in 12
individuals. In 50 percent of provocations, the provocation test and the history were both
positive, and in 6 percent of provocations, tests were negative. In 41 percent of provocations a
positive history could not be confirmed by provocation. (see Table 18). The routine use of such
a test was not discussed (this study satisfied 4 of the 12 QUADAS domains assessed).
Risks and Pitfalls of Food Challenges
Several studies that did not meet the initial inclusion criteria examined problems involved with
food challenges. Niggemann and Beyer157 have reviewed the pitfalls in double-blind, placebocontrolled oral food challenges, which, in addition to those mentioned above, include the
problem of determining what constitutes a reaction (short of anaphylaxis) and the time interval
between administration of the test food and the clinical reaction; they conclude more
standardization is needed. In a study of food challenges for adult patients with subjective
symptoms (mainly abdominal), Gellerstedt reported that changing the method used for
interpreting patient symptom diaries to assess a positive reaction resulted in four of 25 patients
previously classified as “negative” now being classified as “positive”.158 No other studies of
variability in interpretation were identified.
The 2009 Work Group Report on Oral Food Challenge Testing reviewed the literature on factors
that can affect the outcomes of food challenge tests. The report found that reactivity to a food can
depend on how the food is presented. For suspected milk, egg, and peanut/legume allergy,
reactivity can depend on whether the food is left in its natural state, cooked, or baked, as well as
the fat content of the food or vehicle. For suspected fruit or vegetable allergy, method of
preparation as well as variety, ripeness, and storage time affect reactivity.159
As described, concerns exist regarding the safety of conducting oral food challenges. The actual
risks involved in DBPCFC have been investigated in several studies. A 1994 study in which 320
children with atopic dermatitis underwent DBPCFC found that 59 percent of the children with
positive food challenges developed respiratory symptoms; however, only 7 percent had a
decrease in forced expiratory volume of more than 20 percent.160 Likewise, a 2004 study that
retrospectively assessed the results of DBPCFC among 584 challenges found that of the foods
tested, all produced comparable reactions; all reactions were reversible with short-acting
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antihistamines with or without epinephrine, пЃў-agonists, and/or corticosteroids; and no child had
cardiovascular symptoms or required hospitalization.161
Summary
A small number of studies that satisfied our inclusion criteria examined issues related to the use
of DBPCFC. One study found no difference in the prevalence of positive responses between
double-blind- and open tests. Other studies reported positive reactions to placebo in up to 13
percent of patients. In an effort to overcome problems in assessing outcomes of food challenges,
two studies assessed the performance of alternative outcome measures, facial thermography and
gastric juice analysis, with good results. Finally, another study examined the use of intestinal,
rather than oral, challenge for persons with GI complaints. This test had high specificity but low
sensitivity; its practicality was not discussed. The quality of these studies varied widely:
QUADAS domains satisfied ranged from 4 to 10 out of 12.
A number of studies and reviews have discussed the potential pitfalls and safety issues involved
in administering DBPCFC. Pitfalls include the rate of positive reactions to placebo and the many
factors that can affect reactivity to a suspected allergen. The quality of evidence regarding
DBCFC is judged moderate, meaning further research is likely to have an important impact on
our confidence in the estimate of effect. While this test is the gold standard at present, there are
numerous issues about its standardization that need attention.
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Table 18: Studies of Food Challenge Tests
Study
Population
Isolauri, 1996148 183 Finnish children (age 2-36 months) referred to a
specialist for evaluation of atopic dermatitis (AD)
randomized to open or DBPC cow’s milk challenge
(following 4 weeks milk elimination)
Clark, 2007154
24 UK children (2.6-14 years) with history of egg allergy
(positive history, SPT, and sIgE) challenged with cooked
(CE) or uncooked egg (UE)
Reference Test
DBPCFC
Test and Results
Open food challenge: 54% positive tests for
both open and DBPC challenges (99+), 49
immediate and 50 delayed
Objective
symptoms of
DBPCFC
Facial Thermography at 10-min. intervals:
Sensitivity: 0.92
Specificity: 1
based on comparison to objective symptoms
of DBPCFC
Gastric Juice Analysis:
15/16 GJA+ (>10 leukocytes/field)
14/16 vomiting+
5/16+ Peripheral absolute neutrophil count
12/16+ Fecal white blood cells
0/16+ C-reactive protein (>1mg/dL)
Colonoscopic Provocation
13 patients underwent a total of 34 tests.
Provocation and history both positive: 50%
Provocation and history both negative: 6%
Provocation positive, history negative: 3%
Provocation negative, history positive: 41%
Hwang, 2008155
16 Korean children (14-44 days) admitted to hospital
with suspected CMPIE (vomiting, diarrhea, failure to
thrive, lethargy). Infants switched to protein hydrolysate
formula and/or breast milk, other factors ruled out (e.g.,
infection), and weight stabilized prior to challenge
Objective
symptoms of
DBPCFC
Bischoff,
1996156
375 randomly selected patients in GI clinic (Germany)
with clinical criteria of intestinal food allergy (3 of the
following 6 (clinical history): Hx of food-related GI
symptoms, increased total sIgE, food sIgE, eosinophilia,
improvement w/ cromoglycate, clinical atopy; and 1 of
the following 2: +response to provocation or + response
to elimination)
Clinical history
and +
elimination
response
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Skin Prick Tests
Skin prick testing (SPT) is the preferred method of skin testing as recommended by the
AAAAI162 and EAACI.163 Both organizations recommend against intracutaneous testing for food
allergies, citing increased risk of serious reaction and no increase in sensitivity or specificity.
Additionally, both the AAAAI and EAACI recommend against using skin scratch tests due to
their low specificity compared to skin prick tests. A 2005 systematic review of systemic
reactions to skin testing found that five of seven fatal reactions were from intracutaneous testing
and recommended against it for that reason.164 This section reviews the evidence on the use of
SPT for diagnosis of food allergy.
Administration and Interpretation of SPTs
There is no standard for administering or interpreting skin prick tests162 indeed, the studies
utilizing skin prick tests that met our inclusion criteria used several different methods to define a
positive test. The most common approaches either measured the absolute wheal size or
measured the wheal size relative to the negative control.
Types of Allergens
Heterogeneity is also seen in the type of allergen used for SPTs: Both fresh foods and
commercial preparations are used. Two studies that specifically addressed the comparability of
these tests met our inclusion criteria. For milk preparation, a study of 183 children with AD and
suspected CMA reported a high degree of concordance of SPT results between a commercial
cow milk allergen (ALK) and milk powder with Cohen's Kappa of 0.86, 95% CI 0.77-0.95 (this
study satisfied 10 of the 12 QUADAS domains assessed).148 In comparison, a study of peanut
preparations in 393 children with suspected food allergy reported a high false negative rate with
a commercial peanut extract (Allerbio) compared to fresh peanut, which was 100 percent
sensitive (this study satisfied 10 of the 12 QUADAS domains assessed).165
Cow's Milk Allergy
Twelve studies of the use of skin prick tests in cow’s milk allergy met our inclusion criteria and
are described in Table 19 (although two, Roehr, 2001 and Mehl, 2006, may share all or some
participants); all of these used food challenge as the reference test.
A small 1988 study of 26 children (aged 1-48 months) consecutively referred to a Danish
hospital allergy clinic diagnosed 20 of the 26 children with cow’s milk allergy via open food
challenge to compare the sensitivity and specificity of skin prick tests with those of sIgE and a
novel basophil histamine release assay.166 The skin prick test was performed with raw cow’s
milk extract, and any wheal size greater than that of the histamine control was considered
positive; sensitivity was 0.80, specificity was 0.66, PPV was 0.89, and NPV was 0.5 (this study
satisfied 8 of the 12 QUADAS domains assessed).
A 2001 study of 170 children (aged 1-12 months) consecutively seen at a Madrid university
hospital allergy clinic diagnosed 67 of the 170 children with cow’s milk allergy (161 based on
DBPCFC and 9 based on history of severe reaction to exposure) to compare the sensitivity and
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specificity of skin prick tests using whole milk as well as three of its component proteins (пЃЎlactalbumin[ALA], пЃў-lactoglobulin[BLG], and casein) with that of sIgE to test immediate
hypersensitivity.167 When at least one of the four skin prick tests was positive, the sensitivity
(0.99) and NPV (0.97) were highest. Specificity and PPV were highest for casein (0.87) (this
study satisfied 8 of the 12 QUADAS domains assessed).
In a 2003 study, 151 children consecutively referred to a Bologna university hospital pediatric
allergy clinic with multiple atopic symptoms received a food challenge, skin prick tests, and two
different commercial sIgE tests to compare the results.168Among the challenges, 27 responded
positively to cow’s milk A positive skin prick test, defined as a wheal diameter of 3mm or
greater, was obtained in 17 of 22 children. The test had a sensitivity of 0.77, a specificity of 0.88,
a PPV of 0.63 and a NPV of 0.94 (this study satisfied 10 of the 12 QUADAS domains assessed).
In a 2004 study of a 3-year-old birth cohort of 495 children in Denmark, parents completed a
questionnaire that included questions about food hypersensitivities.169 Based on the responses,
children were given open food challenges and skin prick tests (as well as APT, sIgE, and
basophil histamine release assessments). Three of 8 children had positive challenge responses to
cow’s milk; 2 of the 3 had positive skin prick tests, defined as a wheal diameter 3mm or larger.
The test had a sensitivity of 0.66, a specificity of 0.80, a PPV of 0.66 and a NPV of 0.80 (this
study satisfied 8 of the 12 QUADAS domains assessed).
In another 2004 study of 48 children (3-29 months) consecutively recruited to a French pediatric
hospital allergy clinic with AD, open food challenges were administered based on the results of
skin prick tests, atopy patch tests, and/or sIgE measures.170 Skin prick tests were performed with
fresh milk; positive tests were defined as wheal diameters ≥3mm greater than negative control
and at least 50% greater than positive control. The test had a sensitivity of 0.59, a specificity of
0.50, a PPV of 0.91 and a NPV of 0.56 (this study satisfied 10 of the 12 QUADAS domains
assessed).
In a study of 98 children admitted consecutively to a Berlin pediatric hospital pneumonology
ward with atopic dermatitis, 71 received a DBPCFC for cow’s milk and a skin prick test with
fresh milk to compare the results of skin prick test with that of atopy patch test, sIgE, and
combinations of the tests.171 Among the challenges, 45 of 71 were positive. A positive skin prick
test, defined as a wheal diameter of 3mm or greater with no reaction to the negative control, was
obtained in 43 of 98 children. The test had a sensitivity of 0.78, a specificity of 0.69, a PPV of
0.81 and a NPV of 0.64 (this study satisfied 9 of the 12 QUADAS domains assessed).
Among a cohort of 6209 infants recruited for a study of the effects of various infant formulae on
the development of cow’s milk allergy,172 239 (ages 6-7 months) showed symptoms that
subsided with elimination of cow’s milk and received a milk challenge, skin prick tests, and sIgE
measurements; 118 reacted positively to the challenge. The sensitivity and specificity of the skin
prick test was assessed at three different wheal diameter cutoff points: ≥3, 6, and 8mm. The
maximum sensitivity (0.61) and NPV (0.67) were found at a cutoff of 3mm; The maximum
specificity (0.98) and PPV (0.92) were found at a cutoff of 8mm (this study satisfied 11 of the 12
QUADAS domains assessed).
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In a study of 437 children (aged 3 months to 17 years) consecutively referred to a German
allergy clinic with suspected food allergy, 168/437 were diagnosed with cow’s milk allergy via
DBPCFC.149 This study used fresh milk samples, but did not report the definition of a positive
test used. They report sensitivity of the test of 0.85, specificity of 0.70, PPV of 0.73, and NPV of
0.83. They also report the decision points (wheal sizes) necessary for achieving 0.95 PPV (9.2
mm) and 0.99 PPV (14.5 mm) (this study satisfied 9 of the 12 QUADAS domains assessed).
This study appears to share at least some participants with reference 176, described above.
A study of 183 children with atopic dermatitis referred to a Finnish allergy clinic with suspected
cow’s milk allergy used a mix of open and double blind food challenges to establish 99/183
cases of cow’s milk allergy.148 This study reported the following results with respect to DBPCFC
(and open food challenge): sensitivity 0.48 (0.47), specificity 0.86 (0.83), likelihood ratio of
positive test 3.46 (2.70), likelihood ratio of negative test 0.60 (0.64). Skin testing was not
performed during the elimination period in 40 cases due to persistent atopic dermatitis, but these
participants appear to have been included in the calculation of sensitivity and specificity as
negative test results (this study satisfied 10 of the 12 QUADAS domains assessed).
A study of 37 children (aged 1.5-84 months) consecutively referred to a Turkish allergy clinic
with suspected cow’s milk allergy found 23/37 cases of cow’s milk allergy via DBPCFC (or
history of anaphylaxis due to milk in 6/23 patients).173 This study used a commercial milk
allergen (ALK) and reported the sensitivity and specificity of SPT with respect to early reactions
(occurring within two hours of food challenge) and late reactions (occurring two hours after food
challenge). The study reported 100 percent sensitivity of the SPT to patients with early reactions
to food challenge (19/19) compared to 50 percent sensitivity of the SPT to patients with late
reactions (2/4). The SPT was 50 percent specific to both early and late reactions (this study
satisfied 10 of the 12 QUADAS domains assessed).
A study of 104 children consecutively referred to an Italian pediatric allergy clinic for evaluation
of suspected CMA (mean age 3.6, with standard deviation of 2.9, 71 percent male) compared the
effectiveness of three milk proteins (lactalbumin, beta-lactoglobulin, and casein) with fresh milk
for the detection of CMA using SPT. The study reported that fresh milk produced the largest
mean wheal diameters and highest sensitivity (96.4 percent) whereas casein had the highest
specificity (96 percent). When a positive test was defined as a positive reaction to any of the
three milk proteins, the sensitivity was 89.3 percent, which rose to 96.4 percent if milk was
included. This study also reported optimal decision points for each milk protein to achieve a
95% PPV: 5 mm for lactalbumin, 3 mm for casein, 4 mm for beta-lactoglobulin, and 8 mm for
fresh milk (this study satisfied 7 of the 12 QUADAS domains assessed).174
A 2007 study that included all children (3-48 months of age) referred to a Naples pediatric
gastroenterology clinic for suspected food-allergy related symptoms performed open food
challenges with fresh CM based on the results of skin prick tests, APT, and sIgE.175 Among 55
children challenged with CM, 31 had positive reactions (10 early and 21 late reactions). Skin
prick tests with wheal diameters of ≥3mm were defined as positive if participants had no
reactions to the control substance. The test had a sensitivity of 0.45, a specificity of 0.70, a PPV
of 0.67 and a NPV of 0.51 (this study satisfied 11 of the 12 QUADAS domains assessed).
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Hen's Egg Allergy
Eight studies of the use of skin prick tests in hen's egg allergy met our inclusion criteria and are
described in Table 20.
In a 2003 study, 151 children consecutively referred to a Bologna university hospital pediatric
allergy clinic with multiple atopic symptoms received a food challenge, skin prick tests, and two
different commercial sIgE tests to compare the results.168Among the challenges, 40 responded
positively to hen’s egg. A positive skin prick test, defined as a wheal diameter of 3mm or
greater, was obtained in 31 of 34 children. The test had a sensitivity of 0.91, a specificity of 0.77,
a PPV of 0.65 and a NPV of 0.95 (this study satisfied 10 of the 12 QUADAS domains assessed).
In a 2004 study of a 3-year-old birth cohort of 495 children in Denmark, parents completed a
questionnaire that included questions about food hypersensitivities.169 Based on the responses,
children were given open food challenges and skin prick tests (as well as APT, sIgE, and
basophil histamine release assessments). Eight of 14 children had positive challenge responses to
hen’s egg; 9 of 14 had positive skin prick tests, defined as a wheal diameter 3mm or larger. The
test had a sensitivity of 0.88, a specificity of 0.83, a PPV of 0.88 and a NPV of 0.83 (this study
satisfied 8 of the 12 QUADAS domains assessed).
In another 2004 study of 48 children (3-29 months) consecutively recruited to a French pediatric
hospital allergy clinic with AD, open food challenges were administered based on the results of
skin prick tests, atopy patch tests, and/or sIgE measures.170 Skin prick tests were performed with
fresh egg; positive tests were defined as wheal diameters ≥3mm greater than negative control and
at least 50% greater than positive control. The test had a sensitivity of 0.93, a specificity of 0.50,
a PPV of 0.97, and a NPV of 0.66 (this study satisfied 10 of the 12 QUADAS domains assessed).
In a study of 98 children admitted consecutively to a Berlin pediatric hospital pneumonology
ward with atopic dermatitis, 42 received a DBPCFC for hen’s egg and a skin prick test with
whisked egg white and yolk to compare the results of skin prick test with that of atopy patch
test, sIgE, and combinations of the tests.171 Of the 42 challenges, 28 were positive. A positive
skin prick test, defined as a wheal diameter of 3mm or greater with no reaction to the negative
control, was obtained in 31 of 98 children. The test had a sensitivity of 0.89, a specificity of 0.57,
a PPV of 0.81 and a NPV of 0.73 (this study satisfied 9 of the 12 QUADAS domains assessed).
In a study of 437 children (aged 3 months to 17 years) consecutively referred to a German
allergy clinic with suspected food allergy, 193/437 were diagnosed with hen's egg allergy via
DBPCFC.149 This study used fresh egg samples (yolk and white), but did not report the
definition of a positive test used. They report sensitivity of the test of 0.93, specificity of 0.54,
PPV of 0.79, and NPV of 0.81. They also report the decision points (wheal sizes) necessary for
achieving 0.95 PPV (9.0 mm) and 0.99 PPV (11.9 mm) (this study satisfied 9 of the 12
QUADAS domains assessed).
A study of 107 children (ages 1-19 months) with AD and no prior egg exposure referred to an
Italian allergy clinic for management of AD used open egg challenge to find a 72/107 children
with egg allergy.176 The SPT used a commercial extract of albumin and yolk and reported
sensitivities for a range of wheal sizes (though they do not describe whether they use an absolute
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wheal size, or one relative to the negative control) (this study satisfied 8 of the 12 QUADAS
domains assessed). Data are shown in Table 20.
A study of 104 patients (ages 12-15 months) with IgE-mediated cow’s milk allergy (by history
and SPT/sIgE) with no prior egg exposure consecutively seen at a Spanish hospital found 38/104
children with egg allergies.177 They performed skin prick tests with commercial extracts of six
egg allergens: egg white, yolk, ovalbumin, ovomucoid, ovotransferrin, and lysozyme (this study
satisfied 11 of the 12 QUADAS domains assessed). Results are reported in Table 20. This study
also reported receiver-operating characteristic (ROC) curves, which were used to generate the
area under the curve and optimal decision points (the diagnostic cutoff points that optimize
sensitivity and/or specificity of the test).
A 2007 study that included all children (3-48 months of age) referred to a Naples pediatric
gastroenterology clinic for suspected food-allergy related symptoms performed open food
challenges with fresh HE based on the results of skin prick tests, APT, and sIgE.175 Among 28
children challenged with HE, 19 had positive reactions (5 early and 14 late reactions). Skin prick
tests with wheal diameters of ≥3mm were defined as positive if participants had no reactions to
the control substance. The test had a sensitivity of 0.58, a specificity of 0.67, a PPV of 0.79 and a
NPV of 0.43 (this study satisfied 11 of the 12 QUADAS domains assessed).
Peanut Allergy
Three studies of the use of skin prick tests in suspected peanut allergy met our inclusion criteria
and are described in Table 21.
A 2002 study of 393 children referred to a French allergy clinic with suspected food allergy
found a rate of 177/393 peanut allergic children with DBPCFC.165 This study used a fresh peanut
mix for the skin prick tests and defined a positive test as a wheal greater than 3 mm larger than
the negative control. The study reported a sensitivity/specificity for two wheal sizes. For wheals
3 mm larger than negative control, sensitivity was 1.00, specificity was 0.66, PPV was 0.74, and
NPV was 1.00. For wheal diameter 16 mm larger than the negative control, sensitivity was 14.7,
specificity was 1.00, PPV was 1.00, and NPV was 0.55. This study did not monitor for late
reactions to food challenge. The study reported ROC curves for both commercial and raw peanut
extracts (this study satisfied 10 of the 12 QUADAS domains assessed).
A 2004 study consecutively recruited 48 children (3-29 months of age) with AD and suspected
food allergy to a French pediatric hospital allergy clinic to compare the performance of skin
prick tests, APT, and sIgE. Open food challenges were administered based on the results of skin
prick tests, atopy patch tests, and/or sIgE measures.170 Oral challenges and skin prick tests were
performed with fresh ground peanut; positive skin prick tests were defined as wheal diameters
≥3mm greater than negative control and at least 50% greater than positive control. The test had a
sensitivity of 0.70, a specificity of 0.50, a PPV of 0.60, and a NPV of 0.55 (this study satisfied 10
of the 12 QUADAS domains assessed).
A study was conducted among 84 children who were consecutively recruited from children
attending a Sydney pediatric hospital allergy clinic based on positive skin prick test for peanut
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allergy using a commercial extract and a wheal size cutoff of 3mm larger than the saline
control.178 All participants without a history of having ingested peanut in the preceding 3 months
were given an open in-hospital challenge along with sIgE measures and an immediate skin
application food test (I-SAFT, a rapid topical test used to assess sensitivity to very small
quantities of allergen). The purpose of the study was to assess the clinical usefulness of available
in vitro and in vivo tests, alone or in combination, compared with food challenge. The sensitivity
and specificity of the skin prick test were assessed at two different wheal diameter cutoffs: 8mm
and 15mm. For wheal diameter 8mm larger than the negative control, sensitivity was 0.75,
specificity was 0.67, PPV was 0.78, and NPV was 0.63. For wheal diameter 15 mm larger than
the negative control, sensitivity was 0.06, specificity was 1.00, PPV was 1.00, and NPV was 0.40
(this study satisfied 9 of the 12 QUADAS domains assessed).
A fourth study for which only 44 percent of the participants had their allergy confirmed by food
challenge or history (and no data were provided to assess the performance characteristics of the
index test) also assessed the use of skin prick test to diagnose peanut allergy.179 The results of the
skin prick test alone were not considered predictive of reaction to peanuts.
Soy Allergy
Two studies of the use of skin prick tests in soy allergy met our inclusion criteria and are
described in Table 22.
In a study of 98 children admitted consecutively to a Berlin pediatric hospital pneumonology
ward with atopic dermatitis, 25 received a DBPCFC for soy milk and a skin prick test to compare
the results of skin prick test with that of atopy patch test, sIgE, and combinations of the tests.171
Four of the 25 food challenges were positive. A positive skin prick test was defined as a wheal
diameter of 3mm or greater with no reaction to the negative control. Four of 98 children had
positive skin prick tests to soy milk. The test had a sensitivity of 0.67, a specificity of 0.53, a
PPV of 0.60 and a NPV of 0.60 (this study satisfied 9 of the 12 QUADAS domains assessed).
In a study of 437 children (aged 3 months to 17 years) consecutively referred to a German
allergy clinic with suspected food allergy, 37/437 were diagnosed with soy allergy via
DBPCFC.149 This study used fresh soy samples, but did not report the definition of a positive
test. They reported a sensitivity for the test of 0.29, specificity of 0.85, PPV of 0.33, and NPV of
0.82 (this study satisfied 9 of the 12 QUADAS domains assessed).
Wheat Allergy
Three studies of the use of skin prick tests in wheat allergy met our inclusion criteria and is
described in Table 23.
In a study of 98 children admitted consecutively to a Berlin pediatric hospital pneumonology
ward with atopic dermatitis, 35 received a DBPCFC for wheat and a skin prick test with wheat
powder dissolved in water to compare the results of skin prick test with that of atopy patch test,
sIgE, and combinations of the tests.171 Of the 35 challenges, 18 were positive. A positive test,
defined as a wheal diameter of 3mm or greater with no reaction to the negative control, was
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obtained in 20 of the 98 children. The test had a sensitivity of 0.67, a specificity of 0.53, a PPV
of 0.60 and a NPV of 0.60 (this study satisfied 9 of the 12 QUADAS domains assessed).
In a study of 437 children (aged 3 months to 17 years) consecutively referred to a German
allergy clinic with suspected food allergy, 159/437 were diagnosed with wheat allergy via
DBPCFC.149 This study used wheat samples, but did not report the definition of a positive test
used. They report a sensitivity for the skin prick test of 0.75, specificity of 0.64, PPV of 0.49,
and NPV of 0.85 (this study satisfied 9 of the 12 QUADAS domains assessed).
A 2004 study consecutively recruited 48 children (3-29 months of age) with AD and suspected
food allergy to a French pediatric hospital allergy clinic to compare the performance of skin
prick tests, APT, and sIgE. Open food challenges were administered based on the results of skin
prick tests, atopy patch tests, and/or sIgE measures.170 Oral challenges and skin prick tests were
performed with fresh wheat powder; positive skin prick tests were defined as wheal diameters
≥3mm greater than negative control and at least 50% greater than positive control. The test had a
sensitivity of 0.75, a specificity of 0.50, a PPV of 0.75, and a NPV of 0.50 (this study satisfied 10
of the 12 QUADAS domains assessed).
IgE-mediated wheat allergy may be indistinguishable from celiac disease based on history and
symptomatology alone. In particular, individuals with gastrointestinal symptoms consistent with
for food allergy and negative work up for IgE-mediated food allergy may benefit from evaluation
for celiac disease. The tests used commonly for the evaluation of celiac disease (CD) differ from
those used for other allergic diseases. The diagnosis of celiac disease is suggested when biopsy
of the small intestine reveals the presence of villous atrophy and crypt hyperplasia (scoring
systems for intestinal biopsy include the Alexander's classification and the ESPGAN criteria; no
studies validating these criteria satisfied our screening criteria) with the diagnosis confirmed by
resolution of symptoms and histological abnormalities following removal of wheat from the diet
and recurrence of either on rechallenge with wheat. No studies examining the reliability of this
standard met our inclusion criteria. Additionally, no studies were identified that directly
compared the diagnosis of IgE-mediated wheat allergy to celiac disease in individuals presenting
with suspected wheat allergy (of either type).
Other Food Allergies
Two other studies that examined the performance characteristics of the skin prick test met the
inclusion criteria.
A 2000 study enrolled 53 consecutive adults (15-69 years) who were referred to a Madrid
university hospital allergy clinic complaining of reaction to melon.180 Allergy to melon as well as
related foods was confirmed by open food challenge followed by DBPCFC using fresh foods
unless the patient had a history of anaphylaxis associated with the food(s). Nineteen patients had
positive DBPCFC or history of anaphylaxis in response to melon. Thirty six had positive skin
prick tests, defined as wheal diameter ≥3mm. They reported a sensitivity for the test of 0.79,
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specificity of 0.38, PPV of 0.42, and NPV of 0.77 (this study satisfied 9 of the 12 QUADAS
domains assessed).
A 2005 study enrolled 100 consecutive patients who presented to a Bangkok university pediatric
allergy clinic with urticaria over a 2-year period.181 Among 36 with suspected food
hypersensitivity (to CM, HE, wheat, or shrimp), DBPCFC was performed on 22, and another 5
had a history of anaphylaxis in response to one of the foods. Skin prick tests were performed
with one or more of the fresh foods in question. The definition of a positive skin prick test was
not provided. The test (for all four foods combined) had a sensitivity of 0.83, a specificity of
0.38, a PPV of 0.28 and a negative predictive value of 0.89 (this study satisfied 8 of the 12
QUADAS domains assessed).
Risks and Pitfalls to Skin Prick Testing
A systematic review of systemic reactions from skin testing from 2006 found that while skin
prick testing is generally safe, testing with fresh foods was not without risk, particularly for
patients with prior history of anaphylaxis, small children, pregnant women, uncontrolled
asthmatics, and high degree of reactivity. The authors concluded that while the risk of fatality
from skin prick testing was "extremely remote,” physicians performing such tests should be
aware of this risk and prepared to deal with potentially fatal reactions.164
A critique of the studies included in the analysis is that none actually confirmed the
concentrations of the suspected allergen proteins in the foods or extracts. Of thirteen studies, five
relied on commercial extracts only,148, 173, 176, 177 six used only fresh foods (although preparation
was not always specified),149 and two used both commercial extracts and fresh.165, 174
Summary
The reported sensitivity and specificity of skin prick testing varies greatly. There also are
important issues regarding the standardization of the procedure in terms of the test allergen used
and the interpretation of the wheal. Due to inconsistency of results and limitations in study
design and execution, the overall quality of evidence is judged to be low, meaning further
research is likely to have an important impact in our confidence in the estimate of effect. The
studies of SPT included in this report satisfied 7 to 11 of the 12 QUADAS domains assessed.
95
Table 19: Summary of Cow's Milk Allergy Studies with Skin Prick Tests
Study
Population
Reference Test
Assay
Prahl,
1988166
26 children (aged
Open food challenge
1-63 months)
consecutively
referred to a Danish
university hospital
allergy clinic for
suspected cow milk
allergy
Skin prick test with
raw cow’s milk,
positive test defined
as wheal diameter ≥
histamine (positive)
control
GarciaAra,
2000167
170 infants (aged
1-12 months)
consecutively seen
at a Madrid
children’s hospital
allergy service for
suspected cow milk
allergy
Skin prick test with
alpha-lactalbumin
(ALA), betalactoglobulin
(BLG), whole milk,
and casein; positive
test defined as a net
wheel diameter
3mm>negative
control
Roehr,
2001171*
Open controlled
challenge tests
performed in 161
infants; remaining 9
had history of severe
allergic reaction to
cow’s milk protein and
evidence of milk sIgE
98 children (2
71 DBPCFC with cow
months-11 years) milk based on history
consecutively
admitted to a Berlin 45/71 diagnosed with
university hospital
milk allergy
pneumonology
ward with atopic
dermatitis
Saarinen, 239 infants (6-7
239 open challenges
months) from a
2001172
prospective Finnish 118/239 positive
birth cohort study
on the effect of
infant formulae on
development of
cow’s milk allergy
with symptoms that
disappeared on
withdrawal of milk
Ricci,
2003168
151 children
consecutively
referred to a
university hospital
pediatric allergy
clinic in Bologna
for suspected food
allergy (CM and
HE)
FC (blinding not
specified)
27 positive for CM
Skin prick test with
fresh milk; positive
test defined as a net
wheel diameter ≥
3mm with no
reaction to negative
control; 43/98
positive reactions
Skin prick test with
Cow’s milk
formula, whole
milk, or protein
fractions; a positive
test was defined as
a wheal diameter of
≥3
SPT with foods,
preparation not
specified
Cutoff: wheal
diameter≥3mm
96
Results
Se
Sp
PPV
NPV
0.8
0.66
0.89
0.50
Se
Sp
PPV
NPV
Milk
0.72
0.62
0.60
0.73
ALA
0.66
0.64
0.59
0.70
BLG
0.84
0.53
0.59
0.81
Casein
0.55
0.87
0.78
0.71
≥1
0.99
0.38
0.56
0.97
Se
Sp
PPV
NPV
0.78
0.69
0.81
0.64
CM
formul
a
Se
Sp
PPV
NPV
≥3
0.61
0.76
0.71
0.67
≥6
0.37
0.93
0.83
0.60
≥8
0.19
0.98
0.92
0.55
Cow’s milk: 17/22 positive
Se
Sp PP NP
V V
0.77 0.8 0.6 0.9
8
3 4
Study
Population
Osterball 495 children 3
e, 2004169 years of age with
and without AD
(members of a
Danish birth
cohort) whose
parents responded
to a questionnaire
about food
hypersensitivity
RancГ©,
2004170
Mehl,
2006149*
Canani,
2007175
Reference Test
Assay
OFC to assess both
early and late
reactions:
3/8 positive for CM
Skin prick test
performed with
fresh CM
Cutoff: ≥3mm
48 children, 3-29
months,
consecutively
recruited to a
French pediatric
hospital allergy
clinic with AD
OFC (based on results
of APT, SPT, or sIgE)
or sIgE
Skin prick test
performed with
fresh CM
Cutoff: ≥3mm
larger than negative
control and ≥50%
larger than positive
control
437 German
children (aged 3
mos to 17 years)
consecutively
referred to a
specialist for
suspected food
allergy (excluding
those with a clear
history of food
related symptoms).
391 patients had
history of AD.
DBPCFC (except
patients under 1 year of
age with clear history
of immediate
reactions) guided by
SPT, sIgE, and clinical
history.
Skin prick test with
fresh food samples,
definition of
positive tests not
reported.
All children 3-48
months referred to
Pediatric
gastroenterology
center in Naples for
suspected FArelated symptoms
OFC with fresh CM,
based on reactions to
SPT, APT, and sIgE:
89 challenges
performed in 60
patients
CM: 31/55 positive (10
early reax, 21 late
reax)
Results
2/8 positive
Se
0.66 0.80 0.66 0.80
Se
97
Sp PP NP
V V
0.59 0.5 0.9 0.5
0
1 6
Se
Sp
PPV
NPV
0.85
0.7
0.73
0.83
Decision Points
168/437 diagnosed
with cow’s milk
allergy by DBPCFC
SPT with fresh CM
Positive reaction:
≥3mm with no
reaction to control
Sp PPV NPV
Se
PPV
wheal
n
0.95
9.2 mm
19/437
0.99
14.5 mm
2/437
Sp PP NP
V V
0.45 0.7 0.6 0.5
0
7 1
Study
Isolauri,
1996148
Population
183 Finnish
children (ages 2-36
months) with AD
and suspected
CMA
Reference Test
Assay
Results
Patients randomized to Commercial cow
DBPCFC (Open)
DBPCFC (n=118) and milk allergen
positive % negative %
open FC (n=65)
(ALK) and milk
SPT
n=64 (35)
n=54 (30)
powder. Reactions
positive
48 (47)
14 (17)
99/183 confirmed with read at 15 minutes
CMA by oral
with wheals greater negative
52 (53)
86 (83)
challenge.
than half the
histamine reactions
size were
FC
Se
Sp
considered positive.
Blind
0.48
0.86
Open
0.47
0.83
Also reports concordance of SPT
with ALK and milk powder: Cohen's
kappa=0.86 with 95% CI=[0.77,
0.95].
Keskin,
2005173
37 consecutive
children (age 1.584 months) with
suspected CMA
referred to Turkish
allergy clinic at a
tertiary care center
excluding children
with chronic
disease.
DBPCFC preceded by
at least 2 weeks of
elimination of CM
(except in 6 patients
with history of
anaphylactic reaction
to cow's milk).
Reactions were
categorized as early
(within 2 hours of test)
or late.
Skin prick test with
SPT
commercial
allergen (ALK)
positive
wheal greater than
or equal to 3mm
negative
larger than negative
control was
considered positive
23/37 had positive
challenges or history of
anaphylactic reaction
Calvani,
2007174
104 children
consecutively
referred to an
Italian pediatric
allergy clinic for
evaluation of
suspected CMA
Food challenge (70
SPT with:
open and 34 DBPCFC) - lactalbumin
- casein
28/104 tests were
- beta-lactoglobulin
positive
- fresh milk
with positive tests
defined as mean
wheal diameters 3mm
≥ the negative
control.
positive
neg
early
late
19
2
7
0
2
7
Reaction
Se
Sp
PPV
NPV
All
91
50
75
78
Early
100
50
73
100
Late
50
50
22
78
Test
Se
Sp
PPV NPV
lactalbumin
75
80
58
90
casein
61
96
85
87
betalactoglobulin
75
82
60
90
fresh milk
96
65
50
98
≥1 protein
positive
89
71
53
95
≥1 SPT
positive
96
61
47
98
Table Notes: AD atopic dermatitis; APT atopy patch test; CMA cow’s milk allergy; DBPCFC double blind placebo-controlled
food challenge; FC food challenge; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; Se
sensitivity; Sp specificity; SPT skin prick test; *these two studies appear to share some participants
98
Table 20: Summary of Hen's Egg Allergy Studies with Skin Prick Tests
Study
Roehr,
2001171
Ricci,
2003168
Population
98 children (2
months-11 years)
consecutively
admitted to a Berlin
university hospital
pneumonology ward
with atopic dermatitis
Reference Test
DBPCFC on 42
children based on
history
28/42 diagnosed
with egg allergy
151 children
FC (blinding not
consecutively referred specified)
to a university
40 positive for HE
hospital pediatric
allergy clinic in
Bologna for suspected
food allergy (CM and
HE)
Osterball 495 children 3 years
e, 2004169 of age with and
without AD
(members of a Danish
birth cohort) whose
parents responded to
a questionnaire about
food hypersensitivity
Assay
Skin prick test with
raw egg white and
yolk; positive test
defined as a net wheel
diameter ≥ 3mm with
no reaction to negative
control; 31/98 positive
reactions
Results
Se
Sp
PPV
NPV
0.89
0.57
0.81
0.73
SPT with foods,
preparation not
specified
Cutoff: wheal
diameter≥3mm
31/34 positive
OFC to assess both
early and late
reactions:
8/14 positive for
HE
Skin prick test
performed with fresh
HE
Cutoff: ≥3mm
9/14 positive
RancГ©,
2004170
48 children, 3-29
months, consecutively
recruited to a French
pediatric hospital
allergy clinic with
AD
OFC (based on
results of APT,
SPT, or sIgE) or
sIgE
Skin prick test
performed with fresh
whole HE
Cutoff: ≥3mm larger
than negative control
and ≥50% larger than
positive control
Canani,
2007175
All children 3-48
months referred to
Pediatric
gastroenterology
center in Naples for
suspected FA-related
symptoms
OFC with fresh HE,
based on reactions
to SPT, APT, and
sIgE: 89 challenges
performed in 60
patients
19/28 positive for
HE (5 early, 14 late
reactions)
SPT with fresh HE
Positive reaction:
≥3mm with no
reaction to control
99
Se
Sp PPV NPV
0.91 0.77 065 0.95
Se
Sp PPV NPV
0.88 0.83 0.88 0.83
Se
Sp PPV NPV
0.93 0.50 0.97 0.66
Se
Sp PPV NPV
0.58 0.67 0.79 0.43
Study
Mehl,
2006149
Monti,
2002176
Population
Reference Test
437 German children
(aged 3mos to 17
years) consecutively
referred to specialist
for suspected food
allergy (excluding
those with a clear
history of food related
symptoms). 391
patients had history of
AD.
DBPCFC (except
patients under 1
year of age with
clear history of
immediate
reactions) guided
by SPT, sIgE, and
clinical history.
107 children (age 119 months) with
atopic dermatitis and
no prior egg exposure
referred to an Italian
allergy clinic for
management of AD.
Open egg
challenge,
monitoring for early
and late reactions
(up to 8 days)
DiГ©guez, 104 patients (ages 1215 months) with IgE
2008177
mediated CMA (by
history and SPT/sIgE)
with no prior egg
exposure
consecutively seen in
the allergy clinic of a
Spanish hospital
Assay
Skin prick test with
fresh food samples,
definition of positive
tests not reported.
193/437 diagnosed
with egg allergy
SPTs were performed
with commercial
extracts of albumin
and yolk; they
reported the absolute
measure of the wheal
72/107 children had diameter.
positive food
challenges.
Open oral challenge SPTs with egg white,
with egg
yolk, ovalbumin
components.
(OVA), ovomucoid
(OVM), ovotransferrin
38/104 were egg
(OVT), and lysozyme
allergic by oral
commercial extracts
challenge.
(Bial-Aristegui
laboratories). Wheal of
3 mm or larger was
regarded as positive.
Results
Se
Sp
0.93
0.54
PPV NPV
Eff
0.79
0.79
0.81
PPV
wheal
n
0.95
9.0 mm
68/437
0.99
11.9 mm
31/437
SPT w/Yolk
Wheal
Se
Sp
PPV
NPV
≥3 mm
66.6
88.6
92.3
56.3
≥4 mm
26.4
94.3
90.5
38.4
≥5 mm
4.2
100
100
33.6
PPV
NPV
SPT w/Albumin
Wheal
Se
Sp
≥3 mm
87.5
85.7
92.6
77
≥4 mm
62.5
91.4
93.7
54.2
≥5 mm
18
100
100
37.2
Allergen
Area Under
Curve
(95% CI)
Optimal
Decision
Point
Egg White 0.83 (0.7-0.96)
6 mm
Yolk
0.73 (0.59-0.88)
3 mm
OVA
0.55 (0.36-0.75)
3 mm
OVM
0.82 (0.70-0.94)
5 mm
OVT
0.55 (0.37-0.72)
Lysozyme 0.60 (0.43-0.96)
Wheal
Se
Sp
PPV
NPV
3 mm
0.95
0.4
0.59
0.89
6 mm
0.81
0.73
0.73
0.81
3 mm
0.67
0.85
0.83
0.71
5 mm
0.58
0.97
0.95
0.69
Egg white
OVM
Table Notes: AD atopic dermatitis; APT atopy patch test; CMA cow’s milk allergy; DBPCFC double blind placebo-controlled
food challenge; FC food challenge; NPV negative predictive value; Ova ovalbumin; OVM ovomucoid; OVT ovotransferrin; OFC
open food challenge; PPV positive predictive value; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp specificity; SPT
skin prick test
100
Table 21: Summary of Peanut Allergy Assessments with Skin Prick Tests
Study
Population
Reference Test
Assay
Wainstei 84 children
n,
consecutively
2007178
recruited in a
Sydney pediatric
hospital allergy
clinic with positive
SPT (defined as a
wheal 3x3mm>
control)
DBPCFC or
documented recent
reaction to peanut
51/84 peanut
allergic by FC
SPT performed with
commercial whole
peanut extract;
geometric mean of
wheal calculated; two
wheal diameter cutoffs
used to calculate
sensitivity and
specificity: ≥8mm and
≥15mm
RancГ©,
2004170
48 children, 3-29
months,
consecutively
recruited to a French
pediatric hospital
allergy clinic with
AD
OFC (based on
results of APT,
SPT, or sIgE) or
sIgE
Skin prick test
performed with raw
peanut, crushed to
powder and mixed with
vehicle
Cutoff: ≥3mm larger
than negative control
and ≥50% larger than
positive control
RancГ©,
2002165
393 children
consecutively
referred to a French
hospital with
suspected peanut
allergy
DBPCFC preceded
by elimination diet.
Patients monitored
for reactions for 4
hours following
test.
SPT performed with
commercial extract
(Allerbio) and fresh
peanut mix with wheals
3 mm greater than
negative control
defined as positive
tests.
177/393 peanut
allergic by FC
Results
Wheal
(mm)
Se
Sp
PPV
NPV
0.78
0.63
1.00
0.40
≥8
0.75
0.67
(95% CI)
0.62.86
0.48.82
≥ 15
0.06
1.00
(95% CI)
0.01.16
0.891.00
Se
Sp PPV NPV
0.70 0.50 0.60 0.55
The commercial extract was falsely
negative in 32/171 patients,
whereas the raw extract yielded a
100% sensitivity, so only data from
the raw extracts was reported
Wheal
(mm)
Se
Sp
PPV
NPV
≥3
100
66.1
73.7
100
(95% CI)
98-100
59-73
68-79
98-100
≥ 16
14.7
100
100
55.2
(95% CI)
10-21
98-100
87-100
50-61
Table Notes: AD atopic dermatitis; APT atopy patch test; DBPCFC double blind placebo-controlled food challenge; FC food
challenge; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; Se sensitivity; sIgE antigenspecific immunoglobulin E; Sp specificity; SPT skin prick test
101
Table 22: Summary of Soy Allergy Assessments with Skin Prick Tests
Study
Population
Reference Test
Assay
Roehr,
2001171
98 children (2 months11 years)
consecutively admitted
to a Berlin university
hospital
pneumonology ward
with atopic dermatitis
DBPCFC on 25
children for soy
based on history
Mehl,
2006149
437 German children
(aged 3mos to 17
years) consecutively
referred to specialist
for suspected food
allergy (excluding
those with a clear
history of food related
symptoms). 391
patients had history of
AD.
DBPCFC (except
patients under 1 year
of age with clear
history of immediate
reactions) guided by
SPT, sIgE, and
clinical history.
Skin prick test with soy
milk; positive test
defined as a net wheel
diameter ≥ 3mm with
4/25 diagnosed with no reaction to negative
soy allergy
control; 4/98 positive
reactions to soy milk
Skin prick test with
fresh food samples,
definition of positive
tests not reported.
Results
Se
Sp
PPV
NPV
0.50
0.90
0.50
0.90
Se
Sp PPV NPV
0.29 0.85 0.33 0.82
37/437 diagnosed
with wheat allergy
Table Notes: AD atopic dermatitis; APT atopy patch test; DBPCFC double blind placebo-controlled food challenge; NPV
negative predictive value; OFC open food challenge; PPV positive predictive value; Se sensitivity; sIgE antigen-specific
immunoglobulin E; Sp specificity; SPT skin prick test
102
Table 23: Summary of Wheat Allergy assessments with Skin Prick Tests
Study
Population
Reference Test
Assay
98 children (2
months-11 years)
consecutively
admitted to a
Berlin university
hospital
pneumonology
ward with atopic
dermatitis
DBPCFC on 35
children for wheat
based on history
RancГ©,
2004170
48 children, 3-29
months,
consecutively
recruited to a
French pediatric
hospital allergy
clinic with AD
OFC (based on
Skin prick test
results of APT, SPT, performed with wheat
or sIgE) or sIgE
powder dissolved in
water
Cutoff: ≥3mm larger
than negative control
and ≥50% larger than
positive control
Mehl,
2006149
437 German
children (aged
3mos to 17 years)
consecutively
referred to
specialist for
suspected food
allergy (excluding
those with a clear
history of food
related symptoms).
391 patients had
history of AD.
DBPCFC (except
patients under 1 year
of age with clear
history of immediate
reactions) guided by
SPT, sIgE, and
clinical history.
Roehr,
2001171
Skin prick test with
wheat powder dissolved
in water; positive test
defined as a net wheel
diameter ≥ 3mm with
no reaction to negative
control; 20/98 positive
reactions to wheat
18/35 diagnosed
with wheat allergy
Skin prick test with
fresh food samples,
definition of positive
tests not reported.
Results
Se
Sp
PPV
NPV
0.67
0.53
0.60
0.60
Se
Sp PPV NPV
0.75 0.50 0.75 0.50
Se
Sp
0.75
0.64
PPV NPV
0.49
0.85
159/437 diagnosed
with wheat allergy.
Table Notes: AD atopic dermatitis; DBPCFC double blind placebo-controlled food challenge; NPV negative predictive value;
PPV positive predictive value; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp specificity; SPT skin prick test
In Vitro (Immune) Tests
A variety of in vitro tests of immune response have been developed because such tests are safe,
relatively non-invasive, simple, and have the potential to provide rapid through-put at relatively
low cost. Tests that measure total or allergen-specific IgE are generally used for suspected IgEmediated reactions. This section describes studies that have assessed the use of these tests.
Total IgE
The most general in vitro test of atopy is that of total IgE. Two studies that met our inclusion
criteria included measures of total IgE.182, 183 In one study, which enrolled 34 children (3-51
months of age) suspected of having cow’s milk allergy and used elimination and food challenge
as the reference, total IgE had a sensitivity of 0.58 and a specificity of 0.73 (this study satisfied 8
of the 12 QUADAS domains assessed).183
103
In the other study, which enrolled 49 patients (1-51 years of age) with strong initial SPT
response to whole spices and used SPT as the reference test to assess allergy to various spices,
fruits, and vegetables, no correlation was found between total IgE levels and results of SPT.182
Neither of these studies found a difference in total IgE levels between allergic and non-allergic
individuals (this study satisfied 7 of the 12 QUADAS domains assessed). The quality of this
evidence is considered to be very low due to sparseness of data.
Allergen-Specific IgE
Assays to measure antigen-specific IgE (sIgE) have undergone several improvements since their
first use in the early 1990s. The “first generation” of sIgE assays used a radioallergosorbic test
(RAST) in which a patient’s serum was incubated with a quantity of the antigen in question.
After removing unbound serum, the researcher would then add radio labeled antibody (IgG) that
specifically recognizes the IgE in antigen-bound IgE complexes, separate unbound IgG after
some incubation period, and count the radioactivity bound to the plates. Levels of reactivity are
expressed as kilo-units of antibody per liter (kUA/L). Newer, more sensitive, variations of the test
– the second and third generation - have since been developed. The second generation of test is
referred to as the fluorescent enzyme immunoassay (FEIA) (e.g., UniCAPВ®), and the third
generation is referred to as the chemiluminescent enzyme immunoassay (CLEIA) (e.g., Immulite
2000В®). The major innovations consist of the chemical reaction (signal) used to detect the bound
IgG-IgE-antigen complexes and automation involving application of the test antigens to solid
surfaces. Although the threshold of sensitivity for these tests is advertised as 0.35 kU/L for the
CAP and 0.l for the Immulite, published studies establish their own cutoff levels of sIgE
considered indicative of a positive test, and a number of studies have aimed to establish the level
that optimized sensitivity and/or specificity of the test.
Twenty-five studies that met our inclusion criteria assessed the use of measures of sIgE or
compared various automated systems for measuring sIgE for the diagnosis of allergy to specific
foods. Among the studies that employed sIgE assays, 20 used a food challenge alone or
combined with strong clinical history as the reference, three used the immediate SPT as the
reference, and two used another measure of sIgE or another test as the reference. The studies are
summarized according to the specific food for which reactivity was assessed. Studies aimed at
determining whether combining sIgE with another test (e.g., SPT) is superior to using one test
alone are described in a subsequent section.
Food challenge/history as reference test
Cow’s Milk Allergy
Fifteen studies that met the inclusion criteria assessed the use of sIgE to diagnose cow’s milk
allergy with food challenge/history as a reference and are summarized in Table 24 (three of these
studies—Roehr, 2001, Celik-Bilgili, 2005, and Mehl, 2006—may share at least some
participants).
104
A small 1988 study of 26 children (aged 1- 48 months) consecutively referred to a Danish
hospital allergy clinic diagnosed 20 of the 26 children with cow’s milk allergy via open food
challenge to compare the sensitivity and specificity of skin prick tests, sIgE, and a novel basophil
histamine release assay.166 The sIgE was measured using a commercial extract of raw cow’s milk
in the RAST assay; sensitivity was 0.80, specificity was 0.66, PPV was 0.89, and NPV was 0.5
(this study satisfied 8 of the 12 QUADAS domains assessed).
A 1990 study enrolled 34 children with suspected cow’s milk allergy (3-51 months). Allergies
were confirmed in 19 with food challenge: 14 showed immediate response and five showed
delayed response.183 Cow’s milk-sIgE determination with the RAST demonstrated a sensitivity
of 0.63 and specificity of 0.80 (this study satisfied 8 of the 12 QUADAS domains assessed).183
In a 2001 study of 98 children admitted consecutively to a Berlin pediatric hospital
pneumonology ward with atopic dermatitis, 71 received a DBPCFC with fresh milk to compare
the results of skin prick test, atopy patch test, sIgE, and combinations of the tests.171 Among the
challenges, 45 of 71 were positive. sIgE was determined using the Pharmacia CAP FEIA; a
positive test was considered any value above the detection limit of 0.35 kU/L. Among the 98
children tested, 54 expressed CM sIgE. The test had a sensitivity of 0.84, a specificity of 0.38, a
PPV of 0.70 and a NPV of 0.59 (this study satisfied 9 of the 12 QUADAS domains assessed).
The 2001 cohort study that identified infants who appeared to react to cow’s milk formula
compared the sensitivity and specificity of sIgE using three different cutoff points as well as sIgE
levels in response to three different forms of milk.172 The maximum sensitivity (0.72) and NPV
(0.61) were found at a cutoff of ≥0.35kU/ml; the maximum specificity (0.98) and PPV (0.94)
were found at a cutoff of ≥3.5kU/ml (this study satisfied 11 of the 12 QUADAS domains
assessed).
A 2001 study of 170 children (aged 1-12 months) consecutively seen at a Madrid university
hospital allergy clinic diagnosed 67 of the 170 children with cow’s milk allergy (161 based on
DBPCFC and 9 based on history of severe reaction to exposure) to compare the sensitivity and
specificity of sIgE using whole milk as well as three of its component proteins (пЃЎlactalbumin[ALA], пЃў-lactoglobulin[BLG], and casein) with that of the SPT to test immediate
hypersensitivity.167 When at least one of the four sIgE levels was positive, the sensitivity (0.85)
and NPV (0.83) were highest. Specificity and PPV were highest for ALA (0.84 and 0.74,
respectively) (this study satisfied 8 of the 12 QUADAS domains assessed).
A 2003 study enrolled 35 children (2-57 months) referred for persistent, non-specific digestive
symptoms to compare the utility of sIgE and APT in these children.184 Using food challenge
(open, or if equivocal, blinded), they determined that 24 children had cow’s milk allergy and 11
did not. Cow’s milk-sIgE was positive in three of the 24 with CMA (0.6 kUI/L, 0.36 kUI/L, and
0.49 kUI/L) and negative in all 11 without evidence of cow’s milk allergy (sensitivity: 0.13;
specificity: 1) (this study satisfied 8 of the 12 QUADAS domains assessed).
A 2006 study measured cow’s milk sIgE in 437 children (3 mos-14 years) using the CAP
system.149 Sensitivity was 0.87, specificity was 0.49; PPV was 0.62; NPV was 0.79; and
efficiency was 0.68 (this study satisfied 8 of the 12 QUADAS domains assessed).
105
A 2005 study enrolled 501 children with suspected food allergy (1 mo-16.1 years) to assess the
predictive value of specific sIgE for cow’s milk and other foods using the CAP system.185 Food
challenge was used to confirm allergy in children older than 1 year. Sensitivity for cow’s milk
was 0.83, specificity was 0.53; PPV was 0.63; NPV was 0.76. The 90 percent predictive decision
point was 88.8kU/L. The patient population may possibly be the same patient population as or
may overlap with that of Mehl and coworkers (this study satisfied 9 of the 12 QUADAS domains
assessed).
A second 2005 study enrolled 37 children (1.5-84 mos) with suspected cow’s milk allergy
referred to a Turkish hospital clinic and measured cow’s milk sIgE, using a cutoff of 0.7kU/L.173
The sensitivity was 0.74, specificity was 0.79, PPV was 0.85, and NPV was 0.65. Subgroup
assessment of children with immediate vs. late-onset reactions showed that the sensitivity and
PPV for sIgE, like those of the SPT, were much lower for late-onset reactions than for earlyonset, consistent with a non-IgE-mediated mechanism for late-onset reactions (this study
satisfied 10 of the 12 QUADAS domains assessed).
A 2001 study enrolled 100 children (3 mos-14 years) with suspected IgE-mediated food allergy
to assess the performance characteristics of the Pharmacia CAP System FEIA for six different
foods, including milk.186 Sixty-two children were diagnosed with milk allergy (1/3 based on
positive challenge, the remainder based on clinical history). They tested 95 percent predictive
decision points (the serum sIgE levels above which patients had a 95 percent probability of
having a positive reaction to the food on a challenge test) for sIgE determined previously with a
retrospective sample. Sensitivity and specificity were assessed at the 90 percent and 95 percent
predictive decision points. At the 90 percent predictive decision point (15 kUA/L the test had a
sensitivity of 0.57, a specificity of 0.94, a PPV of 0.95 and a NPV of 0.53 (this study satisfied 9
of the 12 QUADAS domains assessed).
In a 2003 study, 151 children consecutively referred to a Bologna university hospital pediatric
allergy clinic with multiple atopic symptoms received a food challenge, skin prick tests, and two
different commercial sIgE tests to compare the results of the two commercial tests.168 Among the
challenges, 27 responded positively to CM. A positive test was defined as a sIgE value
≥0.35kU/L. The Pharmacia UniCAP test was slightly more sensitive, with a sensitivity of 0.91, a
specificity of 0.70, a PPV of 0.44 and a NPV of 0.97; the Centaur test had a sensitivity of 0.82, a
specificity of 0.74, a PPV of 0.45 and a NPV of 0.94 (this study satisfied 10 of the 12 QUADAS
domains assessed).
In a 2004 study of a 3-year-old birth cohort of 495 children in Denmark, parents completed a
questionnaire that included questions about food hypersensitivities.169 Based on the responses,
children were given open food challenges, skin prick tests, atopy patch tests, sIgE, and basophil
histamine release assessments. Three of 8 children had positive challenge responses to cow’s
milk. The test system was a Magic Lite, with a positive result being defined as a value greater
than 1.43 sU/ml. The test had a sensitivity of 0.66, a specificity of 0.40, a PPV of 0.40 and a
NPV of 0.66 (this study satisfied 8 of the 12 QUADAS domains assessed).
106
In another 2004 study of 48 children (3-29 months) consecutively recruited to a French pediatric
hospital allergy clinic with AD, open food challenges for CM allergy were administered based
on the results of skin prick tests, atopy patch tests, and/or sIgE measures.170 Tests were
performed with a Pharmacia CAP FEIA system; positive tests were defined as values
≥0.35kU/L. The test had a sensitivity of 0.31, a specificity of 0.66, a PPV of 0.83 and a NPV of
0.15 (this study satisfied 10 of the 12 QUADAS domains assessed).
A 2007 study that included all children (3-48 months of age) referred to a Naples pediatric
gastroenterology clinic for suspected food-allergy related symptoms performed open food
challenges with fresh CM based on the results of skin prick tests, APT, and sIgE.175 Among 55
children challenged with CM, 31 had positive reactions (10 early and 21 late reactions). A
positive test was defined as a value ≥0.35kU/L. The test had a sensitivity of 0.23, a specificity of
0.74, a PPV of 0.54 and a NPV of 0.42 (this study satisfied 11 of the 12 QUADAS domains
assessed).
Finally, a 2008 study enrolled all 1800 children (0-18 years of age) seen between 1994 and 2006
for suspected CM allergy.187 The aim of the study was to assess the utility of CM sIgE values in
the first year of life for predicting persistent CM allergy at 3 years of age. The reference test was
food challenge or positive history combined with sIgE. Based on positive challenge or history or
a cutoff of ≥1kU/L, 135 children were considered CM allergic in their first year. Based on
challenge, 56 children had persistent allergy after the age of 3. A sIgE value ≥3kU/L in the first
year of life had the following performance characteristics for predicting persistent allergy:
sensitivity: 0.68; specificity: 0.70; PPV: 0.83; NPV 0.52 (this study satisfied 8 of the 12
QUADAS domains assessed).
The sensitivity and specificity of sIgE measurement for the diagnosis of CMA varies widely
among studies. In general, the sensitivity and NPV tend to be lower than the specificity and PPV.
Again, this finding is consistent with an allergy that can be mediated by either IgE- or non-IgEmediated mechanisms.
107
Table 24: sIgE Measures of Cow’s Milk Allergy Using Food Challenge as Reference
Study
Population (age range)
Reference Test
Assay System
Prahl, 1988 166
26 children (aged 1-63 months)
Open food challenge RAST with
consecutively referred to a Danish
20/26 positive
commercial
university hospital allergy clinic
raw cow’s
for suspected cow milk allergy
milk extract
Tainio, 1990183
Roehr, 2001171*
34 children w/ suspected CMA (351 mos)
98 children (2 months-11 years)
consecutively admitted to a Berlin
university hospital pneumonology
ward with atopic dermatitis
Open challenge
19/34 positive (14
immediate and 5
delayed
71 DBPCFC with
cow milk based on
history
RAST
Results
Se
Sp
PPV
NPV
0.8
0.66
0.89
0.50
(sIgE positive in 16/18 with CMA
and 2/18 without CMA)
Se
Sp
0.63 0.8
CAP
Se
Sp PPV NPV
0.84 0.38 0.70 0.59
45/71 diagnosed with
milk allergy
Saarinen,
2001172
239 infants (6-7 months) from a
prospective Finnish birth cohort
study on the effect of infant
formulae on development of cow’s
milk allergy with symptoms that
disappeared on withdrawal of milk
239 open challenges
118/239 positive
CAP using
whole CM
and/or CM
protein
fractions
CM
formula
cutoff
Se
Sp PPV NPV
≥0.35
0.61 0.76 0.71 0.67
≥0.7
0.37 0.93 0.83 0.60
≥3.5
0.19 0.98 0.92 0.55
(sIgE positive in 84/116 with
CMA and 60/117 without CMA
at a cutoff of 0.35)
Garcia-Ara,
2001167
170 infants (aged 1-12 months)
consecutively seen at a Madrid
children’s hospital allergy service
for suspected cow milk allergy
Open controlled
challenge tests
performed in 161
infants; remaining 9
had history of severe
allergic reaction to
cow’s milk protein
and evidence of milk
sIgE
CAP FEIA
using milk,
ALA, BLG,
and casein;
positive test
defined as
sIgE≥0.35
Antigen
Se
Sp PPV NPV
CM
0.84 0.56 0.61 0.81
ALA
0.55 0.84 0.74 0.70
BLG
0.59 0.80 0.70 0.71
Casein
0.71 0.75 0.70 0.76
≥1
0.85 0.56 0.61 0.83
CM by
cutoff
108
≥0.35
0.84 0.56 0.61 0.81
≥0.7
0.74 0.71 0.67 0.83
≥2.5
0.48 0.95 0.90 0.69
≥5
0.30 0.99 0.95 0.64
Study
DeBoisseau,
2003184
Ricci, 2003
168
Population (age range)
35 children (2-57 months) referred
for diagnosis of non-specific
persistent digestive symptoms.
151 children consecutively referred
to a university hospital pediatric
allergy clinic in Bologna for
suspected food allergy (CM and
HE)
Reference Test
Food challenge (open
unless results
equivocal)
24/35 positive
FC (blinding not
specified)
27 positive for CM
Assay System
CAP-RAST
Results
sIgE positive in 3/24 with CMA,
positive in 0/11 w/o CMA
Se
Sp
0.89 1.00
Pharmacia
UniCAP vs.
ADVIA
Centaur
cutoff>0.35kU
/L
UniCAP
Se Sp PPV NPV
0.91 0.70 0.44 0.97
ADVIA Centaur
Se Sp PPV NPV
0.82 0.74 0.45 0.94
Osterballe,
2004169
Canani, 2007175
Rottem, 2008187
RancГ©, 2004 170
Mehl, 2006149*
495 children 3 years of age with
and without AD (members of a
Danish birth cohort) whose parents
responded to a questionnaire about
food hypersensitivity
All children 3-48 months referred
to Pediatric gastroenterology
center in Naples for suspected FArelated symptoms
All individuals seen between 1994
and 2006 for suspected milk
allergy at an Israeli university
medical center (1800 infants and
children 0-18 years of age)
OFC to assess both
early and late
reactions:
3/8 positive for CM
Magic Lite
sIgE
Cutoff: 1.43
sU/ml
OFC with fresh CM,
based on reactions to
SPT, APT, and sIgE:
89 challenges
performed in 60
patients
CM: 31/55 positive
(10 early reax, 21
late reax)
Food challenge or
suggestive history
Pharmacia
CAP RAST
Positive test
≥0.35kU/L
48 children, 3-29 months,
consecutively recruited to a French
pediatric hospital allergy clinic
with AD
OFC (based on
results of APT, SPT,
or sIgE) or sIgE
437 children referred to specialist
for diagnosis of suspected food
allergy.
DBPCFC (except
patients under 1 year
of age with clear
history of immediate
reactions) guided by
SPT, sIgE, and
clinical history.
168/437 positive
109
Immulite sIgE
to whole milk
and
components
Cutoff ≥1
kU/L
135 children
considered
positive; 56
children had
persistent
allergy past 3
years of age
Pharmacia
Upjohn CAP
FEIA
Cutoff: ≥0.35
kU/L
RAST
Se
Sp PPV NPV
0.66 0.40 0.40 0.66
Se
Sp PPV NPV
0.23 0.74 0.54 0.42
Cutoff ≥3 kU/L at 1 year of
age as prediction of persistent
milk allergy at age 3:
Se
Sp PPV NPV
0.68 0.70 0.83 0.
CM sIgE ≥3 kU/L at 1 year of
age was considered predictive of
persistent CM allergy at 3 years
of age
Se
Sp PPV NPV
0.31 0.66 0.83 0.15
Se
Sp PPV NPV
0.87 0.49 0.62 0.79
Study
Celik-Bilgili,
2005185
Keskin, 2005173
Sampson,
2001186
Population (age range)
501 children (1 mo-16.1 yr)
37 children referred for suspected
CMA
100 consecutive children (0.4-14.3
yrs)
Reference Test
Food challenge in
children >1 year of
age
Assay System
CAP-RAST
DBPCFC preceded
by at least 2 weeks of
elimination of CM
(except in 6 patients
with history of
anaphylactic reaction
to cow's milk).
Reactions were
categorized as early
(within 2 hours of
test) or late.
ImmunoCAP
FEIA
23/37 had positive
challenges or history
of anaphylactic
reaction
Food challenge or
strong history
62/100 positive, 1/3
based on food
challenge
Results
Se
Sp PPV NPV
0.83 0.53 0.63 0.76
Predictive decision points:
90%: 88.8 kU/L
Cutoff point≥0.7kU/L
Se
Sp PPV NPV
0.74 0.79 0.85 0.65
ImmunoCAP
FEIA
Decision Point (kUA/L) 15
Se
Sp PPV NPV
0.57 0.94 0.95 0.53
Table Notes: AD atopic dermatitis;; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test *Roehr,
2001, Mehl, 2006, and Celik-Bilgili, 2005 may share some participants
Hen’s Egg Allergy
Ten studies attempted to assess the value of sIgE for diagnosing allergy to hen’s egg; however,
one did not report study characteristics for specific foods.188 Of the remaining four studies, one
assessed sIgE for both egg white protein (albumin) and yolk, and three assessed sIgE for total
egg protein. These studies are summarized in Table 25.
A 2001 study used the CAP system to assess the 90-percent predictive decision points for egg
sIgE in 75 children (0.14-14.3 years) (1/3 diagnosed by positive challenge, the remainder by
strong history).186 At a cutoff of 7kUA/L, the sensitivity was 0.61, specificity was 0.95, PPV was
0.98, and NPV was 0.38 (this study satisfied 9 of the 12 QUADAS domains assessed).
In another 2001 study, 98 children were admitted consecutively to a Berlin pediatric hospital
pneumonology ward with atopic dermatitis; 71 received a DBPCFC with hen’s egg to compare
the results of skin prick test, atopy patch test, sIgE, and combinations of the tests.171 Among the
challenges, 28 of 42 were positive. sIgE was determined using the Pharmacia CAP FEIA; a
positive test was considered any value above the detection limit of 0.35 kU/L. Among the 98
children tested, 36 expressed hen’s egg sIgE. The test had a sensitivity of 0.96, a specificity of
110
0.36, a PPV of 0.75 and a NPV of 0.83 (this study satisfied 9 of the 12 QUADAS domains
assessed).
A 2002 study in 107 children (1-19 months) with atopic dermatitis and with no known previous
exposure to egg used the RAST to measure both albumin- and yolk sIgEs.176 Using a cutoff of
greater than 99kU/L for albumin sIgE, the test had a specificity of 1, a sensitivity of 16.6 percent,
PPV of 100 percent and NPV of 36.8 percent. Using a cutoff of ≥17.5 kU/L for yolk sIgE, the
test had a specificity of 1, sensitivity of 23.6 percent, PPV of 100 percent and NPV of 39 percent
(this study satisfied 7 of the 12 QUADAS domains assessed).
A 2005 study of 501 children (1 mo-16.1 yr) with suspected egg allergy used the CAP system to
assess the predictive value of sIgE levels for egg.185 The sensitivity was 0.97, specificity was
0.51, PPV was 0.80, and NPV was 0.89. The predicted probabilities (of a positive challenge)
were 90 percent for a cutoff of 6.3, 95 percent for a cutoff of 12.6, and 99 percent for a cutoff of
59.2 kU/L for all children. Dividing children into those less than 1 year and those 1 year or older,
the predictive probabilities were different. In children less than 1 year, the decision point using a
95 percent predicted probability was 10.9 kU/L, while it was 13.2kU/L for children over 1 year
of age. Choosing a 90 percent predicted probability, this difference was 4.2 and 6.7kU/L,
respectively (i.e., the titer was higher in older children) (this study satisfied 10 of the 12
QUADAS domains assessed).
A study of 437 children used the CAP system to assess the predictive value of sIgE for egg.149
They reported a sensitivity of 0.96, specificity of 0.48, PPV 0.79, and NPV 0.85 (this study
satisfied 9 of the 12 QUADAS domains assessed).
In a 2003 study, 151 children consecutively referred to a Bologna university hospital pediatric
allergy clinic with multiple atopic symptoms received a food challenge, skin prick tests, and two
different commercial sIgE tests to compare the results of the two commercial tests.168 Among the
challenges, 40 responded positively to HE. A positive test was defined as a sIgE value
≥0.35kU/L. The Pharmacia UniCAP test was slightly more sensitive, with a sensitivity of 0.94, a
specificity of 0.64, a PPV of 0.55 and a NPV of 0.96; the Centaur test had a sensitivity of 0.88, a
specificity of 0.52, a PPV of 0.46, and a NPV of 0.90 (this study satisfied 10 of the 12 QUADAS
domains assessed).
In a 2004 study of a 3-year-old birth cohort of 495 children in Denmark, parents completed a
questionnaire that included questions about food hypersensitivities.169 Based on the responses,
children were given open food challenges, skin prick tests, atopy patch tests, sIgE, and basophil
histamine release assessments. Eight of 14 children had positive challenge responses to hen’s
egg. The test system was a Magic Lite, with a positive result being defined as a value greater
than 1.43 sU/ml. The test had a sensitivity of 0.63, a specificity of 0.66, a PPV of 0.71 and a
NPV of 0.57 (this study satisfied 8 of the 12 QUADAS domains assessed).
In another 2004 study of 48 children (3-29 months) consecutively recruited to a French pediatric
hospital allergy clinic with AD, open food challenges were administered based on the results of
skin prick tests, atopy patch tests, and/or sIgE measures.170 Tests were performed with a
Pharmacia CAP FEIA system; positive tests were defined as values ≥0.35kU/L. The test had a
111
sensitivity of 0.65, a specificity of 0.75, a PPV of 0.96 and a NPV of 0.21 (this study satisfied 10
of the 12 QUADAS domains assessed).
A 2007 study that included all children (3-48 months of age) referred to a Naples pediatric
gastroenterology clinic for suspected food-allergy related symptoms performed open food
challenges with fresh hen’s egg, based on the results of skin prick tests, APT, and sIgE.175
Among 28 children challenged with hen’s egg, 19 had positive reactions (5 early and 14 late
reactions). A positive test was defined as a value ≥0.35kU/L. The test had a sensitivity of 0.32, a
specificity of 0.67, a PPV of 0.67 and a NPV of 0.32 (this study satisfied 11 of the 12 QUADAS
domains assessed).
Thus, four studies found high sensitivity and NPV but relatively low specificity for egg sIgE,
whereas two other studies observed a lower sensitivity but high specificity. The aim of at least
two of the studies was to identify threshold values that would maximize the positive predictive
value (specificity), in order to minimize the proportion of individuals who might needlessly be
consigned to avoidance of egg.
112
Table 25: sIgE Measures of Hen’s Egg Allergy Using Food Challenge as Reference
ID/Author,
Population (age range)
Reference Assay System
Results
Yr.
Test
75 consecutive children
Food
Sampson,
Pharmacia CAP Decision Point (kUA/L) 7
(0.4-14.3 yrs)
challenge
2001186
FEIA
Se Sp PPV NPV
or strong
0.61 0.95 0.98 0.38
history
Roehr,
2001171
Monti,
2002176
98 children (2 months-11
years) consecutively
admitted to a Berlin
university hospital
pneumonology ward with
atopic dermatitis
107 children (1-19 mos)
DBPCFC
Pharmacia CAP
FEIA
Decision Point (kUA/L) 0.35
Se Sp PPV NPV
0.96 0.36 0.75 0.83
Open egg
challenge,
monitoring
for early
and late
reactions
(up to 8
days)
RAST
Celik-Bilgili,
2005185
501 children (1 mo-16.1
yr)
Food
challenge
in children
>1 year of
age
CAP system
Ricci,
2003168
151 children consecutively
referred to a university
hospital pediatric allergy
clinic in Bologna for
suspected food allergy
(CM and HE)
FC
(blinding
not
specified)
40 positive
for HE
Pharmacia
UniCAP vs.
ADVIA Centaur
cutoff>0.35kU/L
Albumin>99kU/L
Yolk ≥17.5 kU/L
Specificity: 1
Se
Sp PPV NPV
0.97 0.51 0.80 0.89
Predictive decision points:
All ages:
90%: 6.3 kU/L
95%: 12.6
99%: 59.2
< 1 year:
95%: 10.9 kU/L
90%: 4.2
≥1 year:
95%: 13.2kU/L
90%: 6.7kU/L
UniCAP
Se Sp PPV NPV
0.94 0.64 0.55 0.96
ADVIA Centaur
Se Sp PPV NPV
0.88 0.52 0.46 0.90
Osterballe,
2004169
495 children 3 years of age
with and without AD
(members of a Danish
OFC to
assess
both early
113
Magic Lite sIgE
Cutoff: 1.43
sU/ml
Se
Sp PPV NPV
0.63 0.66 0.71 0.57
ID/Author,
Yr.
Population (age range)
birth cohort) whose
parents responded to a
questionnaire about food
hypersensitivity
Canani,
2007175
All children 3-48 months
referred to Pediatric
gastroenterology center in
Naples for suspected FArelated symptoms
RancГ©, 2004
48 children, 3-29 months,
consecutively recruited to
a French pediatric hospital
allergy clinic with AD
170
Mehl,
2006149
437 children referred to
specialist for diagnosis of
suspected food allergy.
Reference
Test
and late
reactions:
8/14
positive
for HE
Assay System
OFC with
fresh CM,
based on
reactions
to SPT,
APT, and
sIgE: 89
challenges
performed
in 60
patients
HE: 19/28
positive (5
early reax,
14 late
reax)
OFC
(based on
results of
APT, SPT,
or sIgE) or
sIgE
DBPCFC
(except
patients
under 1
year of age
with clear
history of
immediate
reactions)
guided by
SPT, sIgE,
and
clinical
history.
Pharmacia CAP
RAST
Positive test
≥0.35kU/L
Pharmacia
Upjohn CAP
FEIA
Cutoff: ≥0.35
kU/L
RAST
Results
Se
Sp PPV NPV
0.32 0.67 0.67 0.32
Se
Sp PPV NPV
0.65 0.75 0.96 0.21
Se
Sp PPV NPV
0.96 0.48 0.79 0.85
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
114
Peanut Allergy
Five studies assessed the performance of peanut sIgE in children with positive challenge or
strong suggestive clinical history. These studies are summarized in Table 26.
The first, a 2001 study, measured peanut sIgE in 68 children (2 percent diagnosed by positive
challenge; the remainder by strong history).186 Using a cutoff of 14 kUA/L gave a sensitivity of
0.57 and a specificity of 1 (this study satisfied 9 of the 12 QUADAS domains assessed).
The second study measured sIgE among 363 children with suspected peanut allergy (177 with
positive challenges, 186 with negative challenge).165 The median peanut sIgE was 10 in children
with a positive challenge (range 0-100) and 0 in children with negative challenge (range 0-56).
The area under the ROC curve was 0.87 9(5% CI, 0.84, 0.91). The cutoff for a specificity and
PPV of 1 was 57 kUA/L, a cutoff that would have avoided the need for challenge in 27 children.
However, no threshold provided 100 percent sensitivity (the lower limit of detection, 0.35kUA/L,
provided a sensitivity of 96.6%). At a cutoff of 15 kUA/L, the specificity was 95 percent and the
sensitivity was 44 percent. Levels of sIgE were not associated with severity of challenge reaction
(this study satisfied 10 of the 12 QUADAS domains assessed).
The third study was a 2004 study of 48 children (3-29 months) consecutively recruited to a
French pediatric hospital allergy clinic with AD; open food challenges were administered based
on the results of skin prick tests, atopy patch tests, and/or sIgE measures.170 Tests were
performed with a Pharmacia CAP FEIA system; positive tests were defined as values
≥0.35kU/L. The test had a sensitivity of 0.53, a specificity of 0.66, a PPV of 0.89 and a NPV of
0.21 (this study satisfied 10 of the 12 QUADAS domains assessed).
The fourth study was conducted among 84 children who were consecutively recruited from
children attending a Sydney pediatric hospital allergy clinic based on positive skin prick test for
peanut allergy using a commercial extract and a wheal size cutoff of 3mm larger than the saline
control.178 All participants without a history of having ingested peanut in the preceding 3 months
were given an open in-hospital challenge along with sIgE measures and an immediate skin
application food test (I-SAFT, a rapid topical test used to assess sensitivity to very small
quantities of allergen). The purpose of the study was to assess the clinical usefulness of available
in vitro and in vivo tests, alone or in combination, compared with food challenge. The sensitivity
and specificity of the UniCAP FEIA test were measured using cutoffs of 0.35 and 10 kU/ml. At a
cutoff of 0.37 kU/ml, the sensitivity was 0.98, with a specificity of 0.33. At a cutoff of 10 kU/ml,
the sensitivity dropped to 0.54, and the specificity rose to 1.00 (this study satisfied 9 of the 12
QUADAS domains assessed).
The fifth study was a 2008 study of 324 consecutive children referred to a pediatric allergy clinic
in Boulder CO for suspected allergy to peanuts, tree nuts, or seeds (age range 2.4 months-40.2
years).189 The reference test consisted of clinical history, a questionnaire, and the results of SPT
or sIgE; 72 percent had a convincing history of peanut allergy. When a positive test was defined
as a sIgE value ≥0.13 kU/L, the test had a sensitivity of 0.60, a specificity of 0.96, a PPV of 0.99
and a NPV of 0.35 (this study satisfied 5 of the 12 QUADAS domains assessed).
115
Finally, an additional study for which only 44 percent of the participants had their allergy
confirmed by food challenge or history (and no data were provided to assess the performance
characteristics of the index test) also assessed the use of sIgE levels to diagnose peanut
allergy.179 sIgE levels alone were not considered predictive of reaction to peanuts in this study.
Table 26: sIgE Measures of Peanut Allergy Using Food Challenge as Reference
ID/Author,
Population (age range)
Reference
Assay
Results
Yr.
Test
System
68 consecutive children 93
Food
Sampson,
Pharmacia
Decision Point (kUA/L) 14
mos-14 yrs)
challenge or
2001186
CAP FEIA
Se Sp PPV NPV
strong history
0.57 1.00 1.00 0.36
363 children, 177 with
RancГ©,
DBPCFC
Pharmacia
Decision Point (kU kUA/L) 15
positive challenge, 186 with preceded by
2002165
CAP FEIA
Se Sp PPV NPV
negative challenge
elimination
0.44 0.95 ND ND
diet. Patients
monitored for
reactions for
4 hours
following
test.
Maloney,
2008189
RancГ©,
2004170
Wainstein,
2007178
All individuals referred to
pediatric allergy clinic in
Boulder CO for suspected
allergy to peanut, tree nut,
seeds; 324 patients (2.4
months – 40.2 years)
48 children, 3-29 months,
consecutively recruited to a
French pediatric hospital
allergy clinic
84 children consecutively
recruited in a Sydney
pediatric hospital allergy
clinic with positive SPT
(defined as a wheal
3x3mm> control)
177/363
peanut
allergic by
FC
Clinical
history,
questionnaire,
and/or SPT or
sIgE
72% had
convincing
history of
peanut
allergy
OFC (based
on results of
APT, SPT, or
sIgE) or sIgE
DBPCFC or
documented
recent
reaction to
peanut
51/84 peanut
allergic by
FC
ImunoCAP
sIgE
Decision Point: ≥13 kU/L
Se
Sp PPV NPV
0.60 0.96 0.99 0.35
Pharmacia
Upjohn
CAP FEIA
Pharmacia
CAP FEIA
Decision Point: ≥0.35kU/L
Se
Sp PPV NPV
0.53 0.66 0.89 0.21
Se
Sp
PPV NPV
0.37 0.98 0.33 0.70 0.92
CI
0.9- 0.181.0 .52
10
0.54 1.00 1.00 0.58
CI 0.39- 0.890.67 1.00
Table Notes: AD atopic dermatitis; CM cow’s milk; ALA α-lactalbumin; APT atopy patch test; BLA β-lactoglobulin; CM cow’s
milk; CMA cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent
enzyme immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value;
RAST radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
116
Soy Allergy
Four studies assessed the performance of soy sIgE as an assessment of allergy to soy.
The first study assessed soybean sIgE in 100 children, 25 of whom were diagnosed with soy
allergy (84 percent by food challenge, the remainder by strong history). Using the 95% decision
point determined in a previous retrospective study (65 kUA/L), they found a sensitivity of 0.24, a
specificity of 0.99, PPV 0.86, and NPV of 0.78. Using the 90% cutoff point (30 kUA/L) produced
a sensitivity of 0.44, specificity of 0.94, PPV of 0.73 and NPV of 0.82 (this study satisfied 6 of
the 12 QUADAS domains assessed).186
In the second study, 98 children were admitted consecutively to a Berlin pediatric hospital
pneumonology ward with atopic dermatitis; 25 received a DBPCFC with soy milk to compare
the results of skin prick test, atopy patch test, sIgE, and combinations of the tests.171 Among the
challenges, 4 of the 25 were positive. sIgE was determined using the Pharmacia CAP FEIA; a
positive test was considered any value above the detection limit of 0.35 kU/L. Among the 98
children tested, 12 expressed sIgE in response to soy milk. The test had a sensitivity of 0.75, a
specificity of 0.52, a PPV of 0.23 and a NPV of 0.92 (this study satisfied 9 of the 12 QUADAS
domains assessed).
In the third study, soy sIgE was assessed using the CAP system in 501 children, 189 of whom
underwent challenge for suspected soy allergy (confirmed in 38 children). The sensitivity was
0.69, specificity was 0.50, PPV was 0.22, and NPV was 0.88.185 However, the relationship
between sIgE titer and positive food challenge was highly variable (this study satisfied 10 of the
12 QUADAS domains assessed).
The fourth study assessed the performance of soy sIgE compared with food challenge in 425
children (180 challenged with soy; 37 positive challenges). The test had a sensitivity of 0.65, a
specificity of 0.50, PPV of 0.22, and NPV of 0.86 (this study satisfied 9 of the 12 QUADAS
domains assessed).149
Table 27: sIgE Measures of Soy Allergy Using Food Challenge as Reference
ID/Author, Yr. Population (age range)
Assay
Results
System
100 children (3 mos-14 yrs): 21
Sampson,
Pharmacia
95% Decision Point (kUA/L): 65
with positive food challenge and CAP FEIA
2001186
Se Sp PPV NPV
4 with strong history
0.24 0.99 0.86 0.78
90% Decision Point (kUA/L): 30
Se Sp PPV NPV
0.44 0.94 0.73 0.82
Roehr, 2001
171
Celik-Bilgili,
2005185
98 children (2 months-11 years)
consecutively admitted to a
Berlin university hospital
pneumonology ward with atopic
dermatitis; 4 of 25 with a
positive DBPCFC to soy
501 children (1 mo-16.1 yrs),
189 administered food challenge,
Pharmacia
CAP FEIA
Cutoff: 0.35 kUA/L
Se
Sp PPV NPV
0.75 0.52 0.23 0.92
Pharmacia
CAP FEIA
117
Cutoff: 0.35 kUA/L
of which 38 were positive
Se
Sp PPV NPV
0.69 0.50 0.22 0.88
Mehl, 2006
149
425 children (3 mos-14 yrs) , 37
with positive challenge to soy
Pharmacia
CAP FEIA
Se
Sp PPV NPV
0.65 0.50 0.22 0.86
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
Wheat Allergy
Five studies assessed the performance of wheat sIgE in patients with positive food challenges.
The first assessed wheat sIgE in 100 children, 23 diagnosed with wheat allergy (74 percent by
food challenge, the remainder by strong history). Using the 95% decision point determined in a
previous retrospective study, they found a sensitivity of 0.13, a specificity of 1, PPV 1, and NPV
of 0.76 for a cutoff point of 100 kUA/L. Using the 90% cutoff point (26 kUA/L) produced a
sensitivity of 0.61, specificity of 0.92, PPV of 0.74 and NPV of 0.87 (this study satisfied 9 of the
12 QUADAS domains assessed).186
In the second study, 98 children were admitted consecutively to a Berlin pediatric hospital
pneumonology ward with atopic dermatitis; 35 received a DBPCFC with wheat powder to
compare the results of skin prick test, atopy patch test, sIgE, and combinations of the tests.171
Among the challenges, 18 of the 35 were positive. sIgE was determined using the Pharmacia
CAP FEIA; a positive test was considered any value above the detection limit of 0.35 kU/L.
Among the 98 children tested, 21 expressed sIgE in response to wheat. The test had a sensitivity
of 0.67, a specificity of 0.53, a PPV of 0.57 and a NPV of 0.57 (this study satisfied 9 of the 12
QUADAS domains assessed).
The third study assessed wheat sIgE using the CAP system in 501 children, 178 of whom
underwent challenge for suspected wheat allergy (confirmed by challenge in 62). The sensitivity
was 0.79, specificity was 0.38, PPV was 0.41, and NPV was 0.77.185 However, at no level of
antibody titer was the proportion with positive food challenge greater than 75 percent (this study
satisfied 10 of the 12 QUADAS domains assessed).
The fourth assessed the performance of wheat sIgE compared with food challenge in 423
children, of whom 159 underwent challenge for suspected wheat allergy (confirmed in 57). The
test had a sensitivity of 0.82, a specificity of 0.34, PPV of 0.41, and NPV of 0.77 (this study
satisfied 9 of the 12 QUADAS domains assessed).149
The fifth study was a 2004 study of 48 children (3-29 months) consecutively recruited to a
French pediatric hospital allergy clinic with AD; open food challenges were administered based
on the results of skin prick tests, atopy patch tests, and/or sIgE measures.170 Tests were
performed with a Pharmacia CAP FEIA system; positive tests were defined as values
≥0.35kU/L. The test had a sensitivity for wheat of 0.40, a specificity of 0.50, a PPV of 0.66 and
a NPV of 0.25 (this study satisfied 10 of the 12 QUADAS domains assessed).
118
Table 28: sIgE Measures of Wheat Allergy Using Food Challenge as Reference
ID/Author,
Population (age range)
Reference
Assay
Results
Yr.
Test
System
Sampson,
100 children (3 mos-14 yrs), Food
Pharmacia
95% Decision Point (kUA/L): 100
2001186
17 with positive food
challenge or CAP FEIA
Se Sp PPV NPV
challenge and 6 with strong
strong
0.13 1.00 1.00 0.76
history
history
90% Decision Point (kUA/L): 26
Se Sp PPV NPV
0.61 0.92 0.74 0.87
98 children (2 months-11
years) consecutively
admitted to a Berlin
university hospital
pneumonology ward with
atopic dermatitis; 18/35 with
a positive DBPCFC to soy
48 children, 3-29 months,
consecutively recruited to a
French pediatric hospital
allergy clinic
Roehr,
2001171
RancГ©,
2004170
Celik-Bilgili,
2005185
Mehl, 2006
149
501 children (1 mo-16.1
yrs), 178 administered wheat
challenge, of which 62 were
positive
423 children (3 mos-14 yrs),
159 administered wheat
challenge; 57 positive
DBPCFC
Pharmacia
CAP FEIA
OFC (based
on results
of APT,
SPT, or
sIgE) or
sIgE
Food
challenge in
children >1
year of age
Pharmacia
Upjohn
CAP FEIA
DBPCFC
(except
patients
under 1
year of age
with clear
history of
immediate
reactions)
guided by
SPT, sIgE,
and clinical
history.
Pharmacia
CAP FEIA
Pharmacia
CAP FEIA
Se
Sp PPV NPV
0.67 0.47 0.57 0.57
Se
Sp PPV NPV
0.40 0.50 0.66 0.25
Cutoff: 0.35 kUA/L
Se
Sp PPV NPV
0.79 0.38 0.41 0.77
Se
Sp PPV NPV
0.82 0.34 0.41 0.77
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
119
Allergy to Other Foods
Two studies that met the inclusion criteria assessed the use of sIgE measurement to diagnose
allergy to other foods.
A 2000 study enrolled 53 consecutive adults (15-69 years) who were referred to a Madrid
university hospital allergy clinic complaining of reaction to melon.180 Allergy to melon as well as
related foods was confirmed by OFC followed by DBPCFC using fresh foods unless the patient
had a history of anaphylaxis associated with the food(s). Nineteen patients had positive DBPCFC
or history of anaphylaxis in response to melon. Twenty three patients had positive reactions
based on sIgE levels (a positive test was defined as a sIgE level ≥0.35 kU/L . They reported a
sensitivity for the test of 0.53, specificity of 0.62, PPV of 0.44, and NPV of 0.70 (this study
satisfied 9 of the 12 QUADAS domains assessed).
A 2008 study of 324 consecutive children referred to a pediatric allergy clinic in Boulder CO for
suspected allergy to peanuts, tree nuts, or seeds (age range 2.4 months-40.2 years) assessed the
efficacy of the skin prick test and sIgE.189 The reference test consisted of clinical history, a
questionnaire, and the results of SPT or sIgE. When a positive test was defined as a sIgE value
≥18.5 kU/L, the test for walnut allergy had a sensitivity of 0.17, a specificity of 0.98, a PPV of
0.99 and a NPV of 0.56 (this study satisfied 5 of the 12 QUADAS domains assessed).
Skin Prick Test as Reference Test
Three studies examined the performance of antigen sIgE measurements in patients with food
allergy diagnosed using skin prick test (SPT) (or SPT and history).188, 190, 191 Although these
studies included patients with positive SPT results to common food allergens, including cow’s
milk, hen’s egg, peanut and other tree nuts, wheat, soy, and finfish or shellfish, each used a
mixed panel for sIgE assays; thus, no study reported sensitivity or specificity by specific food.
One study compared the performance of several different sIgE assay systems in diagnosing food
or inhalant allergy in a group of 193 5-year-old children, 20 of whom had at least one positive
SPT to a food allergen (17 of these children also had clinical signs of atopy).190 Among the 20
children with positive SPT, 15 had a positive reaction in the Phadiatop PediatricВ® (PP) test (a
test designed primarily for children under 7) and the RAST mixed food panel, and 18 had a
positive PhadiatopВ® test (a test designed primarily for children over 7). Among the 17 clinically
atopic children with positive SPT, all had a positive PhadiatopВ® test; however two had a
negative PP test, and three had a negative RAST mixed food test. P had a sensitivity of 0.86, a
specificity of 0.94, and an efficacy of 0.92 (this study satisfied 8 of the 12 QUADAS domains
assessed).
The performance of the Phadiatop Infant sIgE test was examined among 147 children, 61 of
whom had SPT+ tests for a food or aeroallergen.188 Of these 61, 56 had a positive sIgE test, and
64 of 78 without an IgE-mediated allergy had negative results, for a sensitivity of 0.92,
specificity of 0.82, PPV of 0.8 and NPV of 0.93. Thirteen children with a negative SPT and
120
positive sIgE were retested after two years: 12 of the 13 were diagnosed with an IgE-mediated
allergy in blinded testing (this study satisfied 3 of the 12 QUADAS domains assessed).
The performance of two sIgE systems (the second generation Pharmacia UniCAPВ® and the third
generation Immulite 2000) was compared using a population of 118 whites, 15 years and older
who were referred for workup of suspected allergy.191 Of the 118, 63 were diagnosed as allergypositive (for food, inhalants, or both) based on SPT and clinical symptoms/history; the remainder
were diagnosed as allergy-negative. Isolated food allergy was diagnosed in seven patients, and
combined inhalant and food allergy was diagnosed in two additional patients. The two sIgE food
panels were positive in six and seven of the nine patients with food allergy. Of note, two patients
with peanut allergy were missed by the second generation sIgE system. Compared with the SPT,
the 3rd generation system had 94 percent total agreement, 0.571 relative sensitivity, and 1.0
relative specificity. The 2nd generation system had a total agreement (with SPT) of 0.924, relative
sensitivity of 0.643, and relative specificity of 0.967 percent. When the results of single food
sIgE tests were compared to SPTs, negative sIgE tests for egg white, cow’s milk, codfish, wheat,
peanut, and soy agreed with negative SPTs for 0.95-1.0 of patients and 0.89-0.99 of patients for
3rd and 2nd generation tests respectively. Sensitivity data are inconclusive because of the small
number of patients (this study satisfied 7 of the 12 QUADAS domains assessed).
Other sIgE Test(s) as Reference Test
Two recent studies compared the performance of sIgE assay systems against each other.
One study compared the performance of three different systems (as well as clinical data) on 50
patients (2.92-18 years)-the Phadia ImmunoCAP, Turbo-MP, and the Immulite 2000-for
assessment of allergy to cow’s milk, hen’s egg, peanut, as well as three aeroallergens.192 Each
system used slightly different forms of the antigens (e.g., skimmed cow’s milk vs. freeze-dried
cow’s milk vs. whole cow’s milk). Of the 50 patients, 42 had diagnosed food allergies. Each
system provided significantly different measurements of sIgE for the same serum samples.
Immulite 2000 showed higher sIgE for all antigens compared with ImmunoCAP. Turbo-MP
overestimated egg. Differences were also seen for cow’s milk and peanut. Thus the predictive
values associated with clinical evidence of allergy for the 2nd generation ImmunoCAP cannot be
applied to the 3rd generation instruments (this study satisfied 7 of the 12 QUADAS domains
assessed).
A second study also compared the Immulite 2000 with the UniCAP system among 283 Korean
patients (1-76 years) (645 paired tests).193 sIgE for cow’s milk, egg white, peanut, and shrimp
were compared. Correlations between the two systems were good (0.85 or greater) for cow’s
milk, egg, and peanut, but not for shrimp. However agreement about whether a particular result
was positive or negative for a particular food was slightly different (0.946 for egg, 0.889 for
cow’s milk, 0.75 for peanut, and 0.563 for shrimp). Sensitivity and specificity were not
compared for food allergens (this study satisfied 9 of the 12 QUADAS domains assessed).
Differences in the determination of sIgE between the different assays were also reported on a
study of serum samples assessing Immunocap turbo RAST and Immulite.194
121
Summary
The reported sensitivity and specificity of sIgE assays for food allergies varied by food, assay
system, and study. Studies that compared the performance of several assay systems found
discrepancies, especially for particular foods (wheat and soy), such that one assay might
diagnose a particular patient as being allergic whereas another test might find the same patient
not to be allergic to the food.
The quality of evidence regarding sIgE is judged as low, meaning further research is likely to
have an important impact on our confidence in the estimate of effect, due to important
inconsistencies in study results and limitation of the studies in terms of patient populations,
standardization of the test, and in some cases the gold standard test.
Immunoglobulin G(IgG)4
One study that met the inclusion criteria assessed the use of levels of serum IgG4 to common
foods in diagnosing food allergy among 68 patients with a history suggestive of food allergy (age
range 10-71 years) and 22 controls in an Italian academic hospital allergy clinic. Based on
history and elimination diet as the reference standard, the use of food-specific IgG levels had a
sensitivity of 0.81 and a specificity of 0.87, with a NPV of 0.99 (this study satisfied 10 of the 12
QUADAS criteria assessed).195
In Vitro Basophil Histamine Release
A small 1988 study of 26 children (aged 1-48 months) consecutively referred to a Danish
hospital allergy clinic diagnosed 20 of the 26 children with cow’s milk allergy via open food
challenge to compare the sensitivity and specificity of skin prick tests and sIgE with a novel
basophil histamine release assay.166 The tests were performed with raw cow’s milk extract.
Histamine release was measured both from basophils and from leukocytes. Histamine release
was considered positive in 17 of 26 children tested, 15 with a positive challenge test and 2 with a
negative challenge: sensitivity was 0.75, specificity was 0.66, PPV was 0.88, and NPV was 0.44,
in fair agreement with the SPT and RAST (this study satisfied 8 of the 12 QUADAS domains
assessed).
In a 2004 study of a 3-year-old birth cohort of 495 children in Denmark, parents completed a
questionnaire that included questions about food hypersensitivities.169 Based on the responses,
children were given open food challenges and basophil histamine release assays (as well as APT,
sIgE, and skin prick tests). Three of 8 children had positive challenge responses to cow’s milk
and 8 of 14 had positive challenge responses to hen’s egg;. The test for cow’s milk had a
sensitivity of 0.66, a specificity of 0.80, a PPV of 0.66 and a NPV of 0.80; the test for hen’s egg
had a sensitivity of 0.71, a specificity of 0.80, a PPV of 0.71 and a NPV of 0.80 (this study
satisfied 8 of the 12 QUADAS domains assessed).
122
Serum Eosinophil Cationic Protein
One study that met the inclusion criteria compared the measurement of serum eosinophil cationic
protein (SCEP) with that of other in vitro and in vivo tests to diagnose cow’s milk allergy.172
Among a cohort of 6209 Finnish infants recruited for a study of the effects of various infant
formulae on the development of cow’s milk allergy, 239 (ages 6-7 months) showed symptoms
that subsided with elimination of cow’s milk and received a milk challenge, skin prick tests, sIgE
measurements, and the SCEP; 118 reacted positively to the challenge. The SCEP was measured
using the Pharmacia CAP system on day 4 of the challenge. Three different cutoff values were
tested: 15.0, 20.0, and 24.7 micrograms(g )/L. At a cutoff of ≥15.9g/L, t he sensitivity was
0.27 (specificity 0.74; PPV 0.67; NPV 0.34)); at a cutoff value of 24.7пЃ­g/L , the sensitivity was
0.13 (specificity 0.98; PPV 0.93; NPV 0.37).
Atopy Patch Tests
The atopy patch test is regarded as useful for assessing suspected non-IgE-mediated (delayed
hypersensitivity) reactions to an allergen. Seven studies addressing the specificity and sensitivity
of atopy patch tests (APT) alone met our selection criteria, all using food challenge as a
reference test. These studies applied foods (fresh or from powders) with aluminum cups, with
occlusion times of 48 hours, and final results read 72 hours after application of the food.
Additionally, six studies checked for immediate reactions 15-30 minutes after the initial
application of the food. Two studies of APT methodology met our criteria; one compared
different occlusion times and one compared the use of different allergen preparations.
APT Test Performance by Food
Cow's Milk
Eight studies of APT in the diagnosis of food allergy to cow's milk met our inclusion criteria, the
results of these studies are reported in Table 29 and described below.
In a study of 98 children admitted consecutively to a Berlin pediatric hospital pneumonology
ward with atopic dermatitis, 71 received a DBPCFC for cow’s milk and an APT with fresh milk
to compare the results of the APT with that of the skin prick test, sIgE, and combinations of the
tests.171 Among the challenges, 45 of 71 were positive. A positive APT, defined as erythema
with infiltration after 48 and 72 hours, was obtained in 22 of 98 children. The test had a
sensitivity of 0.47, a specificity of 0.96, a PPV of 0.95 and a NPV of 0.51 (this study satisfied 9
of the 12 QUADAS domains assessed).
Among a cohort of 6209 Finnish infants recruited for a study of the effects of various infant
formulae on the development of cow’s milk allergy,172, 239 (ages 6-7 months) showed symptoms
that subsided with elimination of cow’s milk and received a milk challenge, skin prick tests, and
sIgE measurements; 118 reacted positively to the challenge. The sensitivity and specificity of the
APT were assessed for three different antigens: whole cow’s milk (0.37, 0.77), cow’s milk
123
protein fractions (0.26, 0.92), and either one or a mixture of both (0.43, 0.72). All three antigens
had relatively low PPVs (0.60-0.77) and NPVs (0.56-0.57) (this study satisfied 11 of the 12
QUADAS domains assessed).
A study of 183 Finnish children (ages 2-36 months) with AD and suspected CMA using a mix of
double blind placebo controlled and open food challenges (with 99/183 confirmed allergic)
reported sensitivity and specificity of 0.61 and 0.81 respectively for the DBPCFCs and 0.59 and
0.83 respectively for the open food challenges (this study satisfied 10 of the 12 QUADAS
domains assessed).148
A study of 437 German children (aged 3 mos to 17 years) consecutively referred to a specialist
for suspected food allergy (excluding those with a clear history of food related symptoms) using
DBPCFC as a reference (except in patients under 1 year of age or those with clear history of
immediate reactions) confirmed 168/437 cases of milk allergy. The overall sensitivity and
specificity of the APT were 0.31 and 0.95, with a PPV and NPV of 0.86 and 0.60 respectively.
This study also reported the sensitivity of the test according to the timing of the reaction to
challenge, with sensitivities of 0.27, 0.45, and 0.36 for immediate, late, and combined reactions
to food challenge respectively. This study reported results stratifying by atopic dermatitis
(391/437) finding sensitivity and specificity of 0.32 and 0.93 respectively in children with AD,
and 0.30 and 1.0 in children without. The study also reported that the sensitivity of APT
increased with age, and was 1.0 for children 3-6 years of age (this study satisfied 9 of the 12
QUADAS domains assessed).149
A study of 37 children referred to a Turkish allergy clinic with suspected CMA used DBPCFC
(except in the case of six patients with clear history of anaphylaxis to milk) to confirm 23 cases
of allergy to cow's milk. This study reported the overall sensitivity and specificity of the APT in
the diagnosis of milk allergy was 0.73 and 0.86 respectively with a PPV of 0.89 and NPV of
0.67. Comparing immediate and late reactions to milk challenge, the sensitivities were 0.72 and
0.75, specificities were both 0.86, PPVs were 0.87 and 0.60, and NPVs were 0.71 and 0.92 (this
study satisfied 10 of the 12 QUADAS domains assessed).173
In a 2004 study of a 3-year-old birth cohort of 495 children in Denmark, parents completed a
questionnaire that included questions about food hypersensitivities.169 Based on the responses,
children were given open food challenges and APT (as well as skin prick tests, sIgE, and
basophil histamine release assessments). Three of 8 children had positive challenge responses to
cow’s milk. A positive APT was defined as any erythema or slight infiltration after 72 hours. The
APT had a sensitivity of 0.00, a specificity of 1.00, a PPV of 1.00 and a NPV of 0.00 (this study
satisfied 8 of the 12 QUADAS domains assessed).
A 2007 study that included all children (3-48 months of age) referred to a Naples pediatric
gastroenterology clinic for suspected food-allergy related symptoms performed open food
challenges with fresh CM based on the results of skin prick tests, APT, and sIgE.175 The aim of
the study was to compare the effect of using of fresh foods with those of commercial extracts on
the diagnostic accuracy of the APT. Among 55 children challenged with CM, 31 had positive
reactions (10 early and 21 late reactions). Occlusion time was 48 hours and tests were read 24
124
hours later. A positive test was defined as including erythema and slight infiltration or more.
Using commercial extracts, the test had a sensitivity of 0.06, a specificity of 0.96, a PPV of 0.67
and a NPV of 0.43; using fresh milk, the test had a sensitivity of 0.65, a specificity of 0.96, a
PPV of 0.95 and a NPV of 0.67. The study also found that accepting a positive APT or a positive
SPT or sIgE test as indication of an allergic reaction maximized the performance characteristics
of the tests (sensitivity 0.90; specificity 0.52; PPV 0.72; NPV 0.80) (this study satisfied 11 of the
12 QUADAS domains assessed).
A 2004 study of 48 children (3-29 months) with AD consecutively recruited to a French pediatric
hospital allergy clinic aimed to determine the optimal occlusion time for the APT in children
with AD. As a reference standard, open food challenges were administered based on the results
of skin prick tests, atopy patch tests, and/or sIgE measures.170Tests were performed in duplicate
on either side of children’s backs and read after occlusion times of 24 and 48 hours. The results
comparing occlusion times are reported below. At 48 hours, the test had a sensitivity of 0.89, a
specificity of 0.96, PPV of 0.94, and NPV of 0.92 (this study satisfied 10 of the 12 QUADAS
domains assessed).
Hen's Egg Allergy
Five studies of atopy patch tests in the diagnosis of hen's egg allergy met our criteria and are
summarized in Table 30.
In a 2004 study of a 3-year-old birth cohort of 495 children in Denmark, parents completed a
questionnaire that included questions about food hypersensitivities.169 Based on the responses,
children were given open food challenges and APT (as well as skin prick tests, sIgE, and
basophil histamine release assessments). Eight of 14 children had positive challenge responses
to hen’s egg. A positive APT was defined as any erythema or slight infiltration after 72 hours.
The APT had a sensitivity of 0.63, a specificity of 0.80, a PPV of 0.83 and a NPV of 0.57 (this
study satisfied 8 of the 12 QUADAS domains assessed).
A 2007 study that included all children (3-48 months of age) referred to a Naples pediatric
gastroenterology clinic for suspected food-allergy related symptoms performed open food
challenges with fresh egg based on the results of skin prick tests, APT, and sIgE.175 The aim of
the study was to compare the effects of using fresh foods with those of commercial extracts on
the diagnostic accuracy of the APT. Among 28 children challenged with egg, 19 had positive
reactions (5 early and 14 late reactions). Occlusion time was 48 hours and tests were read 24
hours later. A positive test was defined as including erythema and slight infiltration or more.
Using commercial extracts, the test had a sensitivity of 0.05, a specificity of 1.00, a PPV of 1.00
and a NPV of 0.33; using fresh HE, the test had a sensitivity of 0.84, a specificity of 1.00, a PPV
of 1.00 and a NPV of 0.75. The study also found that accepting a positive APT or a positive SPT
or sIgE test as indication of an allergic reaction maximized the performance characteristics of the
tests (sensitivity 0.95; specificity 0.44; PPV 0.78; NPV 0.80) (this study satisfied 11 of the 12
QUADAS domains assessed).
125
A 2004 study of 48 children (3-29 months) with AD consecutively recruited to a French pediatric
hospital allergy clinic aimed to determine the optimal occlusion time for the APT in children
with AD. As a reference standard, open food challenges were administered based on the results
of skin prick tests, atopy patch tests, and/or sIgE measures.170 Tests were performed in parallel
on the children’s backs and read after occlusion times of 24 and 48 hours. The results comparing
occlusion times are reported below. At 48 hours, the test had a sensitivity of 0.97, a specificity of
0.71, PPV of 0.95, and NPV of 0.83 (this study satisfied 10 of the 12 QUADAS domains
assessed).
In a study of 98 children admitted consecutively to a Berlin pediatric hospital pneumonology
ward with atopic dermatitis, 42 received a DBPCFC for hen’s egg and an APT with egg white
and yolk to compare the results of the APT with that of the skin prick test, sIgE, and
combinations of the tests.171 Among the challenges, 28 of 42 were positive. A positive APT,
defined as erythema with infiltration after 48 and 72 hours, was obtained in 17 of 98 children.
The test had a sensitivity of 0.57, a specificity of 0.93, a PPV of 0.94 and a NPV of 0.52 (this
study satisfied 9 of the 12 QUADAS domains assessed).
A study of 437 German children (aged 3 mos to 17 years) consecutively referred to a specialist
for suspected food allergy (excluding those with a clear history of food related symptoms) using
DBPCFC as a reference (except in patients under 1 year of age or those with clear history of
immediate reactions) confirmed 193/437 cases of hen's egg allergy. The overall sensitivity and
specificity of the APT were 0.41 and 0.87, with a PPV and NPV of 0.86 and 0.43 respectively.
This study also reported the sensitivity of the test according to the timing of the reaction to
challenge, with sensitivities of 0.45, 0.17, and 0.36 for immediate, late, and combined reactions
to food challenge respectively. This study reported results stratifying by atopic dermatitis
(391/437) finding sensitivity and specificity of 0.40 and 0.91 respectively in children with AD,
and 0.60 and 0.85 in children without. The study also reported that the sensitivity of APT was
not affected by age (this study satisfied 9 of the 12 QUADAS domains assessed).149
Peanut Allergy
One study of atopy patch tests in the diagnosis of peanut allergy met our inclusion criteria. A
2004 study of 48 children (3-29 months) with AD consecutively recruited to a French pediatric
hospital allergy clinic aimed to determine the optimal occlusion time for the APT in children
with AD. As a reference standard, open food challenges were administered based on the results
of skin prick tests, atopy patch tests, and/or sIgE measures.170 Tests were performed in parallel
on the children’s backs and read after occlusion times of 24 and 48 hours. At 24 and 48 hours,
the test for peanut reactivity had a sensitivity of 0.13 and 0.71; a specificity of 0.97 and 0.82;
PPV of 0.67 and 0.66; and NPV of 0.72 and 0.85, respectively (this study satisfied 10 of the 12
QUADAS domains assessed).
126
Soy Allergy
Two studies of atopy patch tests in the diagnosis of soy allergy met our inclusion criteria and is
summarized in Table 31.
In a study of 98 children admitted consecutively to a Berlin pediatric hospital pneumonology
ward with atopic dermatitis, 25 received a DBPCFC and an APT with soy milk to compare the
results of the APT with that of the skin prick test, sIgE, and combinations of the tests.171 Among
the challenges, 4 of 25 were positive. A positive APT, defined as erythema with infiltration after
48 and 72 hours, was obtained in 6 of 98 children. The test had a sensitivity of 0.75, a specificity
of 0.86, a PPV of 0.50 and a NPV of 0.95 (this study satisfied 9 of the 12 QUADAS domains
assessed).
A study of 437 German children (aged 3 mos to 17 years) consecutively referred to a specialist
for suspected food allergy (excluding those with a clear history of food related symptoms) using
DBPCFC as a reference (except in patients under 1 year of age or those with clear history of
immediate reactions) confirmed 37/437 cases of soy allergy. The overall sensitivity and
specificity of the APT were 0.23 and 0.86, with a PPV and NPV of 0.30 and 0.82 respectively.
The sensitivity and specificity of the APT did not vary according to the timing of the reaction to
food challenge. Stratifying by atopic dermatitis (391/437), sensitivity and specificity were 0.25
and 0.88 respectively in children with AD, and 0.0 and 0.86 in children without. The sensitivity
of APT increased with age, and was 1.0 in children older than 6 years (this study satisfied 9 of
the 12 QUADAS domains assessed).149
Wheat Allergy
Four studies of atopy patch tests for the diagnosis of wheat allergy met our inclusion criteria and
are summarized in Table 32.
In a study of 98 children admitted consecutively to a Berlin pediatric hospital pneumonology
ward with atopic dermatitis, 25 received a DBPCFC and an APT with wheat to compare the
results of the APT with that of the skin prick test, sIgE, and combinations of the tests.171 Among
the challenges, 18 of 35 were positive. A positive APT, defined as erythema with infiltration
after 48 and 72 hours, was obtained in 17 of 98 children. The test had a sensitivity of 0.89, a
specificity of 0.94, a PPV of 0.94 and a NPV of 0.89 (this study satisfied 9 of the 12 QUADAS
domains assessed).
A study of 437 German children (aged 3 mos to 17 years) consecutively referred to a specialist
for suspected food allergy (excluding those with a clear history of food related symptoms) using
DBPCFC as a reference (except in patients under 1 year of age or those with clear history of
immediate reactions) confirmed 159/437 cases of wheat allergy. The overall sensitivity and
specificity of the APT were 0.27 and 0.89, with a PPV and NPV of 0.58 and 0.69 respectively.
This study also reported the sensitivity of the test according to the timing of the reaction to
challenge, with a sensitivities of 0.22, 0.29, and 0.50 for immediate, late, and combined reactions
to food challenge respectively. The sensitivity of APT increased with age, and was 1.0 in
children older than 6 years (this study satisfied 9 of the 12 QUADAS domains assessed).149
127
A study of 90 children with food challenge confirmed cow's milk allergy, but with residual
symptoms after milk elimination (and elimination of eggs, nuts, fruits, chocolate, and fish) tested
for cereal (wheat, rye, barley, oats) allergy. In the 44 children tested for wheat allergy by open
food challenge, 30 children had confirmed wheat allergy (66/90 children were positive for any
cereal allergy). For wheat allergy, the sensitivity was 0.70, specificity was 0.71, PPV 0.84, and
NPV 0.69; for any cereal allergy, the sensitivity was 0.67, specificity 0.79, PPV 0.90, and NPV
0.46 (this study satisfied 9 of the 12 QUADAS domains assessed).196
A 2004 study of 48 children (3-29 months) with AD consecutively recruited to a French pediatric
hospital allergy clinic aimed to determine the optimal occlusion time for the APT in children
with AD. As a reference standard, open food challenges were administered based on the results
of skin prick tests, atopy patch tests, and/or sIgE measures.170 Tests for wheat allergy were
performed in parallel on the children’s backs and read after occlusion times of 24 and 48 hours.
The results comparing occlusion times are reported below. At 48 hours, the test for reaction to
wheat had a sensitivity of 0.83, a specificity of 0.94, PPV of 0.71, and NPV of 0.97 (this study
satisfied 10 of the 12 QUADAS domains assessed).
APT Performance Under Different Conditions
Two studies that met the inclusion criteria examined the performance of APT under different
conditions.
Fresh Foods vs. Commercial Extracts
A 2007 study that included all children (3-48 months of age) referred to a Naples pediatric
gastroenterology clinic for suspected food-allergy related symptoms performed open food
challenges with fresh foods based on the results of skin prick tests, APT, and sIgE.175 The aim of
the study was to compare the effects of using fresh foods with those of commercial extracts on
the diagnostic accuracy of the APT. Among 55 children challenged with cow’s milk, 31 had
positive reactions (10 early and 21 late reactions). Occlusion time was 48 hours and tests were
read 24 hours later. A positive test was defined as including erythema and slight infiltration or
more. Using commercial extracts, the test had a sensitivity of 0.06, a specificity of 0.96, a PPV
of 0.67 and a NPV of 0.93; using fresh cow’s milk, the test had a sensitivity of 0.65, a specificity
of 0.96, a PPV of 0.95 and a NPV of 0.67. Similar results were found for hen’s egg: fresh hen’s
egg had a sensitivity of 0.84, compared with 0.05 for commercial extracts (this study satisfied 11
of the 12 QUADAS domains assessed).
Occlusion Times
A 2004 study of 48 children (3-29 months) with AD consecutively recruited to a French pediatric
hospital allergy clinic aimed to determine the optimal occlusion time for the APT in children
with AD. As a reference standard, open food challenges were administered based on the results
of skin prick tests, atopy patch tests, and/or sIgE measures.170 Tests were performed in parallel
on the children’s backs and read after occlusion times of 24 and 48 hours. At 24 hours, the test
for CM had a sensitivity of 0.18, a specificity of 1.00, a PPV of 1.00 and a NPV of 0.63. At 48
hours, the test had a sensitivity of 0.89, a specificity of 0.96, PPV of 0.94, and NPV of 0.92. The
128
tests for reactivity to HE, wheat, and peanut gave similar results (see Tables 30-32) (this study
satisfied 10 of the 12 QUADAS domains assessed).
Reproducibility
Finally, one study that did not meet the inclusion criteria assessed the reproducibility of the test
within the same individuals by applying duplicate test foods on the right and left side of the back.
This 2008 study enrolled a cohort of 277 Italian children in two age groups.197 The younger
children (mean age 8.7 years) underwent duplicate testing with fresh food extracts of CM, HE,
tomato, and wheat flour. The older group (mean age 12.9 years) was tested with duplicate
samples of commercial extracts of the same foods. For both the fresh and commercial foods,
25% to 75% of the tests were positive on one side and negative on the other (Cohen’s Kappa
0.38 for fresh tomato to 0.81 for fresh CM).
Summary
Two studies that met the inclusion criteria specifically addressed the methodology of atopy patch
tests. One showed that applying a food for 48 hours (with the final reading of the test performed
72 hours after the food was first applied) provided better sensitivity and specificity than applying
the food for 24 hours (with the final reading at 48 hours). Additionally, some studies reported
checking for immediate reactions 15-30 minutes after the food was applied. One study
compared the use of different food preparations and found that fresh foods provided superior
sensitivity but not specificity. The sensitivity and specificity of the atopy patch test may vary by
the timing of the reaction to oral food challenge (early vs. late), but the variation was not
consistent either between foods or between studies of the same food. The sensitivity and
specificity of this test may also vary by the presence of atopic dermatitis and the age of the
patient. The QUADAS scores for included studies ranged from 8 to 10 out of 12. The quality of
evidence is judged to be very low, meaning any estimate of effect is uncertain, due to sparseness
of data, important inconsistency in study results, and limitations of the studies in terms of study
populations, and lack of standardization of the test itself.
129
Table 29: APT studies of cow's milk
Study
Population
Reference Test
Roehr,
2001171
Saarinen,
2001 172
Isolauri,
1996148
Assay
Result
98 children (2
71 DBPCFC with cow
months-11 years) milk based on history
consecutively
admitted to a Berlin
45/71 diagnosed with
university hospital
milk allergy
pneumonology ward
with atopic
dermatitis
One drop of fresh cow’s
milk placed on filter
paper and applied to
patients’ backs using
12mm aluminum cups;
occlusion time, 48 hours,
read 20 minutes after
removal of the cup, and
then again at 72 hours;
erythema with
infiltration constituted
positive reaction .
22/98 positive
239 infants (6-7
239 open challenges
months) from a
prospective Finnish
118/239 positive
birth cohort study on
the effect of infant
formulae on
development of
cow’s milk allergy
with symptoms that
disappeared on
withdrawal of milk
CM formula powder,
bovine serum albumin,
crystallized bovine BLG,
and bovine casein were
each dissolved in saline,
and filter papers were
soaked in the solutions
before being applied to
the back under aluminum
cup. Occlusion time, 48
hours, results read 48
hours after removal of
cups; marked erythema
(>half the size of the
cup) and erythema with
induration constituted
positive response.
183 Finnish children Patients randomized to
(ages 2-36 months) DBPCFC (n=118) and
with AD and
open FC (n=65)
suspected CMA
99/183 confirmed with
CMA by oral challenge.
humidified powdered
DBPCFC (Open)
skim cow milk applied to
APT
Positive % Negative %
patient's backs with
n = 64 (35) n = 54 (30)
aluminum cups,
61 (59)
19 (17)
Positive
occlusion time of 48
hours, results read at 15
39 (41)
81 (83)
Negative
minutes after cup
removal and again at 72
FC
Se
Sp
hours
Osterballe 495 children 3 years OFC to assess both early
, 2004169 of age with and
and late reactions:
without AD
3/8 positive for CM
(members of a
Danish birth cohort)
whose parents
responded to a
questionnaire about
food hypersensitivity
130
APT scored after 72
hours; positive test
ranged from erythema
and slight infiltration to
papules and vesicles
Cow’s milk:
0/8 positive
Se
Sp
0.47
0.96
PPV NPV
0.95
0.51
Se
Sp
PPV NPV
Whole
CM
and/or
protein
fraction
s
0.43
0.72
0.60
0.57
Whole
CM
0.37
0.77
0.61
0.56
CM
protein
fraction
s
0.26
0.92
0.77
0.57
Blind
61
81
Open
59
83
Se
Sp PPV NPV
0.0 1.00 0.0 0.62
Study
RancГ©,
2004 170
Canani,
2007 175
Mehl,
2006149
Keskin,
2005173
Population
Reference Test
Assay
Result
48 children, 3-29
OFC (based on results of
months,
APT, SPT, or sIgE) or
consecutively
sIgE
recruited to a French
pediatric hospital
allergy clinic
APT scoring compared
after 24- and 48-hour
occlusion times; positive
test required a minimum
of erythema and slight
infiltration
All children 3-48
months referred to
Pediatric
gastroenterology
center in Naples for
suspected FA-related
symptoms
OFC with fresh CM,
HE, and wheat powder
based on reactions to
SPT, APT, and sIgE: 89
challenges performed in
60 patients
CM: 31/55 positive (10
early reax, 21 late reax)
APT performed with
fresh foods compared
with commercial
extracts; Occlusion time
48 hours
Results read at 72 hours
Positive test defined as a
minimum of erythema
and slight infiltration
437 German children
(aged 3 mos to 17
years) consecutively
referred to a
specialist for
suspected food
allergy (excluding
those with a clear
history of food
related symptoms).
391 patients had
history of AD.
DBPCFC (except
patients under 1 year of
age with clear history of
immediate reactions)
guided by SPT, sIgE,
and clinical history.
One drop fresh CM put
Reaction Se
Sp PPV NPV
on filter paper and
Overall
31
95
86
60
applied to back with
aluminum cups. Checked Immediate 27
at 20 minutes for
Late
45
immediate reactions.
Combined 36
Cups removed at 48
hours and read 20
AD+
32
93
minutes later, then again
AD30 100
24 hours later (72 hours
sensitivity
of
APT increased with
after application).
age, and was 100% for children 36 years of age.
37 consecutive
children (age 1.5-84
months) with
suspected CMA
referred to Turkish
allergy clinic at a
tertiary care center
excluding children
with chronic disease.
DBPCFC preceded by at
least 2 weeks of
elimination of CM
(except in 6 patients
with history of
anaphylactic reaction to
cow's milk). Reactions
were categorized as
early (within 2 hours of
test) or late.
168/437 diagnosed with
cow’s milk allergy by
DBPCFC
23/37 had positive
challenges or history of
anaphylactic reaction
Se
Sp PPV NPV
24 hr 0.18 1.00 1.00 0.63
48 hr 0.89 0.96 0.94 0.92
Se
Sp
PPV NPV
Fres
h
0.65 0.96 0.95 0.67
Extr
act
0.06 0.96 0.67 0.43
cow's milk powder
SPT
positive
mixed with saline,
early
late
applied with aluminum
positive
13
3
cups to packs. Children
examined after 30
negative
5
1
minutes for immediate
reactions. Cups removed
after 48 hours and read
Reaction Se
Sp PPV
72 hours after
All
73
86
89
application.
2
12
NPV
67
Immediate
72
86
87
71
Late
75
86
60
92
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
131
neg
Table 30: APT studies of hen’s egg
Study
Population
Reference Test
Assay
Result
Roehr,
2001171
98 children (2 months- DBPCFC in 42
11 years)
children
consecutively admitted
to a Berlin university 28/42 positive
hospital
pneumonology ward
with atopic dermatitis
One drop of fresh whisked egg
Se Sp PPV NPV
white and yolk placed on filter paper
and applied to patients’ backs using 0.57 0.93 0.94 0.52
12mm aluminum cups; occlusion
time, 48 hours, read 20 minutes after
removal of the cup, and then again
at 72 hours; erythema with
infiltration constituted positive
reaction .
17/98 positive
Osterballe,
2004169
495 children 3 years of
age with and without
AD (members of a
Danish birth cohort)
whose parents
responded to a
questionnaire about
food hypersensitivity
APT scored after 72 hours; positive
Se Sp PPV NPV
test ranged from erythema and slight
0.63 0.80 0.83 0.57
infiltration to papules and vesicles
Hen’s egg:
6/13 positive
RancГ©,
2004 170
48 children, 3-29
OFC (based on
months, consecutively results of APT, SPT,
recruited to a French
or sIgE) or sIgE
pediatric hospital
allergy clinic
APT scoring compared after 24- and
Se Sp PPV NPV
48-hour occlusion times; positive
24 hr 0.15 0.83 0.86 0.12
test required a minimum of
48 hr 0.97 0.71 0.95 0.83
erythema and slight infiltration
Canani,
2007 175
All children 3-48
months referred to
Pediatric
gastroenterology
center in Naples for
suspected FA-related
symptoms
OFC with fresh CM,
HE, and wheat
powder based on
reactions to SPT,
APT, and sIgE: 89
challenges
performed in 60
patients
HE: 19/28 positive
(5 early, 14 late
reactions)
APT performed with fresh foods
compared with commercial extracts;
Occlusion time 48 hours
Results read at 72 hours
Positive test defined as a minimum
of erythema and slight infiltration
437 German children
(aged 3mos to 17
years) consecutively
referred to specialist
for suspected food
allergy (excluding
those with a clear
history of food related
symptoms). 391
patients had history of
AD.
DBPCFC (except
patients under 1 year
of age with clear
history of immediate
reactions) guided by
SPT, sIgE, and
clinical history.
One drop fresh HE (white and yolk)
put on filter paper and applied to
back with aluminum cups. Checked
at 20 minutes for immediate
reactions. Cups removed at 48
hours and read 20 minutes later,
then again 24 hours later.
Mehl,
2006149
OFC to assess both
early and late
reactions:
8/14 positive for HE
193/437 diagnosed
with egg allergy
Se
Sp PPV NPV
Fresh
0.84 1.00 1.00 0.75
Extract
0.05 1.00 1.00 0.33
Reaction
Se
Sp
Overall
41
87
Immediate
45
Late
17
Combined
36
AD+
40
91
AD-
60
85
PPV NPV
86
there was no effect of age on
sensitivity.
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
132
43
Table 31: APT studies of soy
Study
Population
Reference Test
Roehr,
2001171
98 children (2
DBPCFC in 25
months-11 years)
children
consecutively
admitted to a Berlin 4/25 positive
university hospital
pneumonology ward
with atopic
dermatitis
Mehl,
2006149
437 German
children (aged 3mos
to 17 years)
consecutively
referred to specialist
for suspected food
allergy (excluding
those with a clear
history of food
related symptoms).
391 patients had
history of AD.
Assay
Result
One drop of soy milk
Se Sp PPV NPV
placed on filter paper and
0.75 0.86 0.50 0.95
applied to patients’ backs
using 12mm aluminum
cups; occlusion time, 48
hours, read 20 minutes after
removal of the cup, and
then again at 72 hours;
erythema with infiltration
constituted positive
reaction .
6/98 positive
DBPCFC (except
patients under 1 year
of age with clear
history of immediate
reactions) guided by
SPT, sIgE, and clinical
history.
One drop soy milk put on
Reaction Se Sp PPV NPV
filter paper and applied to
Overall
23 86
30
82
back with aluminum cups.
AD+
25 88
Checked at 20 minutes for
immediate reactions. Cups
AD0
86
removed at 48 hours and
No
difference
seen
in the
read 20 minutes later, then
sensitivity
of
the
test
by reaction
again 24 hours later.
timing
37/437 diagnosed with
wheat allergy
sensitivity of APT increased with
age, and was 100% for children
older than 6 years of age.
Table Notes: AD atopic dermatitis; ALA О±-lactalbumin; APT atopy patch test; BLG ОІ-lactoglobulin; CM
cow’s milk; CMA cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food
challenge; FEIA fluorescent enzyme immunoassay; HE hen’s egg; NPV negative predictive value; OFC open
food challenge; PPV positive predictive value; RAST radioallergosorbent test; Se sensitivity; sIgE antigenspecific immunoglobulin E; Sp Specificity; SPT skin prick test
133
Table 32: APT studies of wheat/cereal
Study
Population
Reference Test
Assay
Result
Roehr,
2001171
98 children (2
months-11 years)
consecutively
admitted to a Berlin
university hospital
pneumonology ward
with atopic
dermatitis
RancГ©,
2004 170
48 children, 3-29
OFC (based on
months,
results of APT, SPT,
consecutively
or sIgE) or sIgE
recruited to a French
pediatric hospital
allergy clinic
APT scoring compared after 24Se Sp PPV NPV
and 48-hour occlusion times;
24 hr 0.25 1.00 1.00 0.94
positive test required a
48 hr 0.83 0.94 0.71 0.97
minimum of erythema and
slight infiltration
Mehl,
2006149
437 German
children (aged 3mos
to 17 years)
consecutively
referred to specialist
for suspected food
allergy (excluding
those with a clear
history of food
related symptoms).
391 patients had
history of AD.
DBPCFC (except
patients under 1 year
of age with clear
history of immediate
reactions) guided by
SPT, sIgE, and
clinical history.
One drop wheat powder
Reaction Se Sp PPV NPV
(Kröner) dissolved in water, put
Overall
27 89
58
69
on filter paper and applied to
Immediate 22
back with aluminum cups.
Checked at 20 minutes for
Late
29
immediate reactions. Cups
Combined 50
removed at 48 hours and read
20 minutes later, then again 24
hours later.
sensitivity of APT increased with
age, and was 100% for children
older than 6 years of age.
90 children (2.5-36
months) w/CMA
(both IgE- and nonIgE-mediated)
controlled via
elimination but w/
residual symptoms
that did not respond
to elimination of
eggs, nuts, fruits,
chocolate, fish.
Open food challenge
preceded by
elimination diet.
Immediate reactions
were those occurring
within an hour of the
last dose. Each child
only tested with one
cereal (reason of
choice not reported.
Jarvinen,
2003196
DBPCFC performed One drop of wheat powder
with wheat powder dissolved in water placed on
on 35 children
filter paper and applied to
patients’ backs using 12mm
18/35 positive
aluminum cups; occlusion time,
48 hours, read 20 minutes after
removal of the cup, and then
again at 72 hours; erythema
with infiltration constituted
positive reaction .
17/98 positive
159/437 diagnosed
with wheat allergy.
Se
Sp
PPV NPV
0.89 0.94 0.94 0.89
wheat flour mixed with isotonic
Food
Se
saline was applied to the back
Wheat
70
with aluminum cups. Cups were
All Cereals 67
removed after 48 hours and
reactions read 72 hours after the
cups were applied. Presence of
edema or eczema was
considered a positive reaction.
Sp
71
84
53
79
90
46
30/44 OFCs were
positive for wheat
66/90 OFCs were
positive for all
cereals (wheat, rye,
barley, oats)
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
134
PPV NPV
Immediate Skin Application Test
Immediate skin application testing (I-SAFT) is a rapid assessment of topical allergic response to
very small quantities of allergen that has been used to predict the likelihood of a strong response
to oral challenge. One study compared response to I-SAFT with that of SPT, APT, and sIgE in
diagnosing peanut allergy.178 The study was conducted among 84 children who were
consecutively recruited from children attending a Sydney pediatric hospital allergy clinic based
on positive skin prick test for peanut allergy using a commercial extract and a wheal size cutoff
of 3mm larger than the saline control. All participants without a history of having ingested
peanut in the preceding 3 months were given an open in-hospital challenge. Prior to the
challenge, one gram of commercial peanut butter on a cardboard square was applied directly to
the skin; the response was read after 15 minutes. A positive score consisted of the appearance of
any wheal in the area. The test had a sensitivity of 0.50 (95% CI 0.36, 0.64); specificity of 0.82
(95% CI 0.65, 0.93); PPV of 0.81 and NPV of 0.51 (this study satisfied 9 of the 12 QUADAS
domains assessed).
135
Meta-analysis comparing different diagnostic tests
To summarize and compare the results of studies of SPT, sIgE, and APT, where possible we
constructed Receiver Operator Characteristic (ROC) curves for each test, both within and across
food types. ROC curves plot sensitivity versus 1-specificity and are useful when assessing
whether different tests reporting different results, are actually different, since simply changing
the threshold for a positive test will make any data appear “different” by trading off sensitivity
for specificity. Twelve studies provided data on SPT, 11 studies provided data on sIgE, and 8
studies provided data on APT.
For three foods, cow’s milk, hen’s egg, and wheat, there were sufficient data to construct ROC
curves. Figure 4 shows the results for cow’s milk, figure 5 shows the results for hen’s egg.
There were sufficient data to compare SPT and sIgE for diagnostic accuracy, within cow's milk
and hen's egg, and across all food types. Figure 6a shows the data across all food types, with an
area under the curve of 0.85 for SPT and 0.81 for sIgE, this difference is not statistically
significant. Figure 6b shows the data for cow's milk, with an area under the curve of 0.84 for
SPT and 0.78 for sIgE, this difference is not statistically significant. Figure 6c shows the data for
hen's egg, with an area under the curve of 0.87 for SPT and 0.85 for sIgE, also a non-significant
difference. Neither is there any statistically significant difference in diagnostic accuracy for the
tests across foods (data not shown). In prior sections of this report, the most likely explanation
for variations in reported sensitivity and specificity of SPT and sIgE across foods is differences
in the criteria for a positive test. Our Receiver Operator Characteristic curves are most consistent
with the hypothesis that all IgE-based tests are operating on the same curve.
The quality of this evidence is considered moderate meaning future research may change our
confidence in the estimate of effect.
136
.2
.4
Sensitivity
.6
.8
1
Figure 4: ROC curve for SPT. sIgE, APT for Cow’s Milk
0
.2
.4
.6
1 - Specificity
APT
sIgE
SPT
.8
APT studies
sIgE studies
SPT studies
137
1
0
.2
Sensitivity
.4
.6
.8
1
Figure 5: ROC curve for SPT and sIgE for Hen's egg
0
.2
.4
.6
1 - Specificity
sIgE
SPT
.8
sIgE studies
SPT studies
138
1
Figure 6: Figures 6a, 6b, and 6c
139
Use of Combined Tests
Eleven studies compared the diagnostic value of combining two or more types of tests with using
only one test. Combining test results could be accomplished in one of two ways: 1) a positive
result on either one test or another (others) (referred to as parallel testing in some studies); or 2)
a positive result on two or more tests (referred to as serial testing in some studies). Some studies
assessed parallel testing, some assessed serial testing, and some assessed both. The findings of
these studies are summarized here.
Skin Prick Test and Atopy Patch Test
Six studies assessed the combination of SPT and atopy patch test (APT) (Table 33).
The combination of SPT and APT (both in serial and in parallel) was compared with that of each
alone for the diagnosis of cow’s milk allergy in 183 patients (2-36 months), some with
immediate onset reactions and some with delayed onset reactions to cow’s milk (reference was
food challenge).148 The SPT tended to be positive in those with immediate responses and
negative in those with delayed responses. When both tests were required to be positive, they
displayed a sensitivity of 0.24 and specificity of 0.94; when one or the other was positive, the
sensitivity was 0.72 and the specificity 0.86. In comparison, the SPT alone had a sensitivity of
0.48 and a specificity of 0.86; the APT alone had a sensitivity of 0.61 and specificity of 0.81.
The responses to the SPT and APT were both positive in only 0.15 and both negative in only
0.38 of participants. Cohen’s  statistic for concordance was 0.03 (95% CI -0.13, 0.19)
indicating no agreement. The authors concluded that use of both tests was superior to use of only
one in diagnosing cow’s milk allergy and pinpointing the type (McNemar chi square test for
SPT: 8.17, p=0.004) vs. chi square test for APT 6.25, p=0.01) (this study satisfied 10 of the 12
QUADAS domains assessed).
The combined use of APT and SPT (in serial) was compared with individual tests and other
combinations of tests in a study of 98 children admitted consecutively to a Berlin pediatric
hospital pneumonology ward with atopic dermatitis and suspected allergy to cow’s milk, hen’s
egg, wheat, or soy. All children received DBPCFC based on previous history and all received
SPT, APT, and sIgE.171 Combining the SPT and APT did not improve the PPV or NPV over that
of the individual tests (this study satisfied 9 of the 12 QUADAS domains assessed).
The use of both APT and SPT in serial was compared with individual tests in 37 children with
suspected cow’s milk allergy (some with immediate and some with delayed-onset symptoms)
diagnosed with food challenge.173 Combining both tests provided a sensitivity of 1, specificity of
0.5, PPV of 0.76 and NPV of 1. In comparison, the SPT alone had a sensitivity of 0.91 and a
specificity of 0.5 and the APT had a sensitivity of 0.73 and a specificity of 0.86 (the significance
of these differences was not tested statistically) (this study satisfied 10 of the 12 QUADAS
domains assessed). However, the authors concluded that while the addition of APT could help
rule out cow’s milk allergy in some children, positive responses to both tests was not an adequate
substitute for food challenge.
140
The use of SPT and APT were compared with the use of both tests (in parallel and in serial) in
diagnosing cereal allergy in children who had cow’s milk allergy but who had residual symptoms
after cow’s milk withdrawal.196 As shown in Table 29, the use of both tests in serial provided
greater sensitivity and NPV than either test alone, whereas the SPT alone had the best specificity
and PPV. The APT was as sensitive as the SPT for immediate hypersensitivity but far more
efficient for detecting delayed hypersensitivity (this study satisfied 9 of the 12 QUADAS
domains assessed). The authors concluded that the APT aids in diagnosis of cereal allergy,
especially if the primary test was a SPT, but that diagnosis still required food challenge for
confirmation.
The performances of SPT, APT, and both tests in serial were compared in diagnosing allergy to
cow’s milk, egg, wheat, and soy in 437 children (ages 3 mos to 14 years) who had received
DBPCFC (this study satisfied 9 of the 12 QUADAS domains assessed).149 The combination of
tests was superior to either test alone for all foods.
Finally, a study that enrolled all children (3-48 months) referred to an Italian pediatric
gastroenterology center for evaluation of suspected food hypersensitivity compared the
combination of SPT and APT in parallel to that of the individual tests for diagnosing allergy to
cow’s milk and hen’s egg.175 The study found that accepting a positive APT or a positive SPT as
indication of an allergic reaction increased the sensitivity of testing for allergy to cow’s milk and
hen’s egg (sensitivity for cow’s milk 0.87; specificity 0.65; PPV 0.77; NPV 0.79; sensitivity for
hen’s egg: 0.95, specificity 0.67; PPV 0.86; NPV 0.86)( this study satisfied 11 of the 12
QUADAS domains assessed).
141
Table 33: Combination of SPT and APT compared with Individual Tests
Study
Population
SPT
APT
Results
Results
Isolauri,
Se Sp
Se Sp
1995148
SPT+/or APT
Results
Either test +:
Se
0.61 0.81
0.48 0.86
Sp
0.72 0.86
Both tests +:
Se
Sp
0.92 0.24
Roehr,
2001171
98 children (2 months11 years) consecutively
admitted to a Berlin
university hospital
pneumonology ward
with atopic dermatitis
Cutoff
Milk
Milk
0.47
0.96
0.95
0.51
Se
Sp
PPV
NPV
0.74
1.00
1.00
0.74
Sp
PPV
NPV
0.89
0.94
0.73
Sp
PPV
NPV
1.00
1.00
0.94
Sp
PPV
NPV
0.90
0.92
0.82
NPV
0.78
0.69
0.81
0.64
PPV
NPV
Se
Sp
PPV
NPV
Se
0.73
0.57
0.93
0.94
0.52
0.84
NPV
Se
Sp
PPV
NPV
Se
0.50
0.90
0.75
0.86
0.50
0.95
0.67
PPV
NPV
Se
Sp
PPV
NPV
Se
0.60
0.89
0.94
0.94
0.89
0.86
Hen’s Egg
Se
0.50
Sp
0.57
0.81
Sp
0.90
PPV
Wheat
Se
0.67
Mehl, 2006149
NPV
PPV
Se
Jarvinen,
2003196
PPV
Sp
Soy
37 children referred for
suspected CMA
Sp
Se
0.89
Keskin,
2005173
Milk
Se
Sp
0.53
0.60
Cutoff point≥3mm
Hen’s Egg
Hen’s Egg
Soy
Soy
Wheat
Wheat
Cutoff:>1+
Se
Sp
PPV
NPV
Se
Sp
PPV
NPV
Se
Sp
PPV
NPV
0.91
0.50
0.75
0.65
0.91
0.50
0.75
0.76
1.00
0.50
0.76
1.00
90 children (2.5-36
months) w/CMA (both
IgE- and non-IgEmediated) controlled via
elimination but w/
residual symptoms that
did not respond to
elimination of eggs,
nuts, fruits, chocolate,
fish. DBPCFC was
reference.
SPT cereal
437 children referred to
specialist for diagnosis
of suspected allergy to
CM, egg, wheat, soy (3
mos-14 yrs), confirmed
with DBPCFC
CM:
Se
APT cereal
Sp PPV NPV
0.23 1.0 1.0
0.32
Se
Sp PPV NPV
0.67 0.79 0.9
0.46
SPT+APT
Cereal:
Se
Sp PPV NPV
0.73 0.83 0.92 0.53
Wheat:
Se
Sp PPV NPV
0.17 1.0
Se
Wheat:
1.0
0.36
Se
Sp PPV NPV
0.7 0.71 0.84 0.53
Sensitivity decreased
with age; specificity
increased with age
CM:
Sp PPV NPV
0.85 0.70 0.73 0.83
Se
Sp PPV NPV
0.31 0.95 0.86 0.60
Wheat:
Se
Sp PPV NPV
0.77 0.17 0.85 0.59
CM:
Se
Sp PPV NPV
0.69 0.97 0.92 0.86
Egg:
Se
Sp PPV NPV
0.93 0.54 0.79 0.81
Egg:
Se
Egg:
Sp PPV NPV
0.41 0.87 0.86 0.43
Se
Sp PPV NPV
0.85 0.89 0.92 0.80
Wheat:
Se
Sp PPV NPV
0.75 0.64 0.49 0.85
Wheat:
Se
Sp PPV NPV
0.27 0.89 0.58 0.69
Soy:
142
Wheat:
Se
Sp PPV NPV
0.43 0.90 0.50 0.86
Se
Sp PPV NPV
0.29 0.85 0.33 0.82
Soy:
Soy:
Se
Sp PPV NPV
0.23 0.86 0.30 0.82
Canani,
2007175
All children 3-48
months referred to
Pediatric
gastroenterology center
in Naples for suspected
FA-related symptoms
Reference Test:
OFC with fresh CM,
HE, and wheat powder
based on reactions to
SPT, APT, and sIgE: 89
challenges performed in
60 patients
CM: 31/55 positive (10
early reax, 21 late reax)
HE: 19/28 positive
(5 early reax, 14 late
reax)
SPT with fresh foods
Positive reaction
≥3mm with no
reaction to control
Cow’s milk:
Se
Sp
PPV NPV
0.45 0.70 0.67 0.51
Hen’s Egg:
Se
Sp
APT with fresh food
Cow’s milk:
Se
Sp
PPV NPV
0.65 0.96 0.95 0.67
Hen’s Egg:
Se
Sp
PPV NPV
0.84 1.00 1.00 0.75
Se
Sp PPV NPV
0.14 0.96 0.43 0.82
APT or SPT
Cow’s milk:
Se
Sp
PPV NPV
0.87 0.65 0.77 0.79
Hen’s Egg:
Se
Sp
PPV NPV
0.95 0.67 0.86 0.86
PPV NPV
0.58 0.67 0.79 0.43
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
143
SPT and Antigen-specific IgE
Three studies compared the performance of combining SPT with sIgE with that of the tests alone
(Table 34).
One study reported that the use of RAST to measure sIgE did not improve the predictive value of
SPT alone for diagnosis of cow’s milk allergy in 135 children (5 mos to 13 years), half of whom
had been diagnosed as cow’s milk allergic and the other half as not allergic with food challenge
(this study satisfied 9 of the 12 QUADAS domains assessed).198 These authors did not report the
predictive value of RAST alone.
The combination of SPT and sIgE was compared with individual tests and other combinations of
tests in a study of 98 children admitted consecutively to a Berlin pediatric hospital
pneumonology ward with atopic dermatitis and suspected allergy to cow’s milk, hen’s egg,
wheat, or soy. All children received DBPCFC based on previous history and all received SPT,
APT, and sIgE.171 Combining the SPT and sIgE did not improve the PPV or NPV over that of the
individual tests (this study satisfied 9 of the 12 QUADAS domains assessed).
The third study compared the performance of SPT (using both raw and commercial extracts),
sIgE (measured by CAP FEIA), and the two tests combined for measuring peanut allergy.165
They reported that the performance characteristics of raw extracts were superior to those of the
commercial extracts. They also found that the combination of SPT and sIgE was superior to that
of either test alone, and that the predictive values of the combined tests would avoid the need for
DBPCFC in patients with SPT wheal diameter <3 and sIgE<57 (indicating a negative result) or
with wheal diameter ≥16 OR sIgE≥57 (indicating a positive result) (this study satisfied 10 of the
12 QUADAS domains assessed).
144
Table 34: Combination of SPT and sIgE compared with Individual Tests
Study
Population
SPT
sIgE
SPT+sIgE
Results
Results
Results
Hill, 1988198
135 children referred SPT≥4=positive
RAST
Se Sp PPV NPV
to specialist with
PPV: 1
Predictive value not
0.54 0.91 0.86 0.66
CMA (5 mos-13
NPV: 0.65
reported
yrs); ВЅ CMA+ by
food challenge
Roehr, 2001171
98 children (2
Cutoff: ≥0.35 kU/L
Cutoff≥3mm (no
months-11 years)
reaction to control)
consecutively
Milk
Milk
Milk
admitted to a Berlin
Se
Sp
PPV NPV
Se
Sp
PPV NPV
Se
Sp
PPV NPV
university hospital
0.78 0.69 0.81
0.64
0.84 0.38 0.70
0.59
0.85 0.56 0.83
0.30
pneumonology ward Hen’s Egg
Hen’s Egg
Hen’s Egg
with atopic
Se
Sp
PPV NPV
Se
Sp
PPV NPV
Se
Sp
PPV NPV
dermatitis
0.89
0.57
0.81
0.73
Soy
Se
Sp
PPV
NPV
0.50
0.90
0.50
0.90
Wheat
Rance, 2002165
363 children referred
for suspected peanut
allergy
0.96
0.36
0.75
0.83
Soy
Se
Sp
PPV
NPV
0.75
0.52
0.23
0.92
Wheat
Se
Sp
PPV
NPV
0.67
0.53
0.60
0.60
NPV for raw extract
=1
SPT>3mm:
specificity 74%
PPV=1 for
SPT≥16mm:
0.96
0.43
0.86
0.75
Soy
Se
Sp
PPV
NPV
1.00
0.91
0.50
1.00
Se
Sp
PPV
NPV
0.71
0.50
0.63
0.60
Wheat
Se
Sp
PPV
NPV
0.67
0.47
0.57
0.57
CAP FEIA PPV=1
for kUA/L≥57
sIgE+SPT
Predictive values of
nearly 1 for the
following cutoffs:
+ Dx: SPT≥16 and
sIgE≥57
-Dx: SP<3 and
sIgE<57
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
Atopy Patch Test and Antigen-specific IgE
Two studies assessed the performance of combining the results of APT and sIgE (Table 35). The
combination of APT and sIgE was compared with individual tests and other combinations of
tests in a 2001 study of 98 children admitted consecutively to a Berlin pediatric hospital
pneumonology ward with atopic dermatitis and suspected allergy to cow’s milk, hen’s egg,
wheat, or soy (the results of combining tests were reported only for suspected milk and egg
allergy). All children received DBPCFC based on previous history and all received SPT, APT,
and sIgE.171 sIgE reactions were assessed at two different cutoff points, and at two different time
points (early and delayed), in an attempt to assess the utility of combining tests to distinguish
IgE-mediated (early) vs. non-IgE-mediated (delayed) allergy. For cow’s milk allergy, the APT
had a PPV of 0.95; combining the APT with sIgE or SPT improved the PPV to 1.00. Combining
APT with sIgE also slightly improved the PPV for both early and late reactions to cow’s milk
over that of APT, SPT, or sIgE alone and improved the NPV for late reactions over that of APT,
SPT, or sIgE alone. For hen’s egg allergy, the combination of APT and sIgE had no advantage
over individual tests.
145
The second study assessed the effect of combining the results of APT and sIgE for the same four
foods.149 The addition of APT to sIgE resulted in increased sensitivity and/or specificity in
diagnosis over the use of either sIgE or APT alone. These authors attempted to calculate the
proportion of children who could be spared a DBPCFC by the use of combined tests; they found
that setting the PPV of the test at 0.99, only 0.05 -7 of children would fulfill the criteria, and
setting it at 0.95, between 0.06 and 0.14 would fulfill the criteria for being able to avoid food
challenge (this study satisfied 9 of the 12 QUADAS domains assessed).
146
Table 35: Combination of APT and Antigen-specific IgE Compared with Individual Tests
Study
Population
APT
sIgE
APT+sIgE
Results
Results
Results
Roehr, 2001171
98 children (2
Milk-Early reactions
Milk-Early reactions
Milk-Early reactions
months-11 years)
Se
Sp
PPV NPV
Se
Sp
PPV NPV
Se
Sp
PPV
consecutively
0.26 0.96 0.88
0.56
≥0.35 0.85 0.38 0.59
0.71
≥0.35 0.64 1.00 1.00
admitted to a
≥17.5 0.22 0.96 0.86
0.54
≥17.5 0.06 1.00 1.00
Berlin university Milk-Late reactions
hospital
Se
Sp
PPV NPV
Milk-Late reactions
Milk-Late reactions
pneumonology
0.78 0.96 0.93
0.86
Se
Sp
PPV NPV
Se
Sp
PPV
ward with atopic
≥0.35
0.83
0.38
0.48
0.77
≥0.35
0.92
1.00
1.00
dermatitis
≥17.5 0.17
Se
Sp
PPV
NPV
0.44
0.93
0.89
0.57
Se
Sp
PPV
NPV
0.80
0.93
0.89
0.87
Sp PPV NPV
0.31 0.95 0.86 0.60
Egg:
Se
Wheat:
0.27 0.89 0.58 0.69
Soy:
Se
0.23 0.86 0.30 0.82
1.00
0.90
0.89
Egg-Early reactions
Sp
PPV
NPV
≥0.35 0.94
0.36
0.65
0.83
≥0.35 0.94
0.83
0.94
0.83
≥17.5 0.28
1.00
1.00
0.52
≥17.5 0.35
1.00
1.00
0.54
Se
Sp
PPV
Se
Egg-Late reactions
NPV
Se
Sp
PPV
NPV
≥0.35 1.00
0.38
0.53
1.00
≥0.35 1.00
0.83
0.89
1.00
≥17.5 0.20
1.00
1.00
0.64
≥17.5 0.50
1.00
1.00
0.87
Se
CM:
Sp PPV NPV
0.87 0.49 0.62 0.79
Se
Sp PPV NPV
0.82 0.34 0.41 0.77
Se
Sp PPV NPV
0.74 0.94 0.90 0.83
Egg:
Sp PPV NPV
0.96 0.48 0.79 0.85
Se
Se
Se
Sp PPV NPV
0.91 0.83 0.91 0.83
Wheat:
Se
Sp PPV NPV
0.62 0.81 0.65 0.85
Soy:
Sp PPV NPV
0.65 0.50 0.22 0.86
Se
Sp PPV NPV
0.31 0.85 0.27 0.87
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
Skin Prick Test and Atopy Patch Test and Antigen-specific IgE
Five studies compared the performance characteristics of combining SPT, APT, and sIgE in
serial or parallel..(Table 36) The combined use of APT and SPT and sIgE (in serial) was
compared with individual tests and other combinations of tests in a study of 98 children
admitted consecutively to a Berlin pediatric hospital pneumonology ward with atopic dermatitis
and suspected allergy to cow’s milk, hen’s egg, wheat, or soy. All children received DBPCFC
147
NPV
NPV
Soy:
Sp PPV NPV
1.00
0.62
PPV
Wheat:
Sp PPV NPV
≥17.5 0.40
0.69
Sp
Egg:
Sp PPV NPV
0.41 0.87 0.86 0.43
Se
Se
CM:
CM:
Se
0.63
Egg-Late reactions
Egg-Late
437 children
referred to
specialist for
diagnosis of
suspected allergy
to CM, egg,
wheat, soy (3
mos-14 yrs),
confirmed with
DBPCFC
0.75
Egg-Early reactions
Egg-Early
Mehl, 2005149
0.96
NPV
based on previous history and all received SPT, APT, and sIgE.171 Combining the SPT, APT, and
sIgE did not improve the PPV or NPV over that of the individual tests (this study satisfied 9 of
the 12 QUADAS domains assessed).
In a second study, the performance of APT was compared with that of APT+SPT+sIgE (in
parallel) in 34 children with suspected milk allergy (5 mos-16 years).199 Positive reactions on
any of three tests improved the sensitivity and PPV of cow’s milk allergy diagnosis among
children younger than 3 years (0.80 and 0.73 for APT alone vs. 0.92 and 0.85 for all three tests,
respectively); however, specificity and NPV did not improve (this study satisfied 7 of the 12
QUADAS domains assessed).
A third study compared the performance of the APT+SPT+cow’s milk sIgE (in serial) with that
of the individual tests and the combination of APT+SPT.173 The combination of the three tests
had greater sensitivity and NPV than any of the tests alone but was no better than the APT+SPT
on any performance parameter (this study satisfied 10 of the 12 QUADAS domains assessed).
The performance of the APT+SPT+sIgE (in serial) was compared with those of each test alone
as well as with the combination of APT+SPT and APT+sIgE to assess the value of adding the
APT to determination of early-phase, presumably IgE-mediated reactions.149 Their population
comprised 437 children (3 mos-14 years) in a large German medical center who had received a
DBPCFC. The use of all three tests improved the sensitivity and NPV of the cow’s milk
assessment over that of the other combinations of tests and had a better NPV than the individual
tests alone. The specificity and PPV were also improved over that of sIgE or SPT or APT alone
for cow’s milk, egg, wheat, and soy (this study satisfied 9 of the 12 QUADAS domains
assessed).
Finally, a study that enrolled all children (3-48 months) referred to an Italian pediatric
gastroenterology center for evaluation of suspected food hypersensitivity compared the
combination of SPT and APT and sIgE in parallel to that of the individual tests for diagnosing
allergy to cow’s milk and hen’s egg.175 The study found that accepting a positive APT or a
positive SPT or a positive sIgE as indication of an allergic reaction maximized the performance
characteristics of the test for allergy to cow’s milk (sensitivity for cow’s milk 0.0.90; specificity
0.52; PPV 0.72; NPV 0.80) (this study satisfied 11 of the 12 QUADAS domains assessed).
Skin Prick Test and Antigen-specific IgE and Immediate Skin Application
Food Test
One study compared response to a combination of SPT, sIgE and I-SAFT with that of the
individual tests in diagnosing peanut allergy.178 The study was conducted among 84 children
who were consecutively recruited from children attending a Sydney pediatric hospital allergy
clinic based on positive skin prick test for peanut allergy using a commercial extract and a wheal
size cutoff of 3mm larger than the saline control. All participants without a history of having
ingested peanut in the preceding 3 months were given an open in-hospital challenge. The
combination of tests did not increase the sensitivity or specificity over those of any of the
individual tests (this study satisfied 9 of the 12 QUADAS domains assessed).
148
Table 36: Combination of SPT and APT and Antigen-specific IgE compared with Individual Tests
Study
Roehr, 2001171
Population
98 children (2 months-11
years) consecutively admitted
to a Berlin university hospital
pneumonology ward with
atopic dermatitis
SPT
Results
Se
Sp
PPV
NPV
0.78
0.69
0.81
0.64
Se
Sp
PPV
NPV
0.89
0.57
0.81
0.73
Se
Sp
Cudowska,
2005199
PPV
NPV
Se
Sp
PPV
NPV
0.47
0.96
0.95
0.51
0.84
0.38
0.70
0.59
Sp
PPV
NPV
0.57
0.93
0.94
0.52
0.90
Sp
PPV
NPV
0.50
0.90
0.86
0.50
0.95
PPV
NPV
Se
Sp
PPV
NPV
0.60
0.89
0.94
0.94
0.89
Wheat
Sp
0.53
0.60
34 children (5 mos-16 yrs)
20< 3yrs
14≥3 yrs
w/suspected milk allergy
Se
Sp
PPV
NPV
0.96
0.36
0.75
0.83
Se
0.75
Sp
PPV
0.67
37 children referred for suspected
CMA
Cutoff point≥3mm
Se Sp PPV NPV
437 children referred to specialist
for diagnosis of suspected allergy
to CM, egg, wheat, soy (3 mos-14
yrs), confirmed with DBPCFC
CM:
Se Sp
PPV NPV
0.85 0.70 0.73 0.83
Egg:
Se Sp
PPV NPV
0.81
1.00
1.00
0.67
Se
Sp
PPV
NPV
0.94
0.75
0.94
0.75
Se
Sp
PPV
NPV
1.00
1.00
1.00
0.52
0.23
0.92
Sp
PPV
NPV
Se
Sp
PPV
NPV
0.57
0.91
0.86
0.91
0.86
Wheat
0.47
0.57
Age<3 years
Se Sp PPV NPV
Age<3 years
Se Sp PPV NPV
0.80 0.79 0.73 0.22
0.92 0.71 0.85 0.17
Age ≥3 years
Se Sp PPV NPV
Age ≥3 years
Se Sp PPV NPV
Se
Sp PPV NPV
0.91 0.50 0.75 0.76
0.91 0.50 0.75 0.65
Mehl, 2006149
NPV
1.00
0.80 0.89 0.80 0.11
Keskin,
2005173
PPV
NPV
Wheat
Se
Sp
Soy
Soy
Se
Se
Hen’s Egg
Hen’s Egg
Se
0.75
Wheat
0.67
Sp
NPV
PPV
Milk
Se
Soy
Soy
SPT+APT+sIgE
Results
Cutoff point≥:0.35
Milk
Hen’s Egg
Hen’s Egg
Se
sIgE
Results
Milk
Milk
0.50
APT
Results
CM:
Se
Sp PPV NPV
0.31 0.95 0.86 0.60
Egg:
Se
149
Sp PPV NPV
0.80 0.89 0.80 0.11
Cutoff point≥0.7kU/L
Se Sp PPV NPV
Criterion: >1 positive
Se Sp PPV NPV
0.74 0.79 0.85 0.65
1.00 0.50 0.76 1.00
CM:
Se
Sp PPV NPV
0.87 0.49 0.62 0.79
Egg:
Se
Sp PPV NPV
CM:
Se
Sp PPV NPV
0.82 0.95 0.91 0.90
Egg:
Se
Sp PPV NPV
0.93 0.54 0.79 0.81
Wheat:
Se Sp
PPV NPV
0.75 0.64 0.49 0.85
Soy:
Se Sp
PPV NPV
0.29 0.85 0.33 0.82
Canani, 2007
175
All children 3-48 months
referred to Pediatric
gastroenterology center in
Naples for suspected FArelated symptoms
Reference Test:
OFC with fresh CM, HE, and
wheat powder based on
reactions to SPT, APT, and
sIgE: 89 challenges performed
in 60 patients
CM: 31/55 positive (10 early
reax, 21 late reax)
HE: 19/28 positive
(5 early reax, 14 late reax)
SPT with fresh foods
Positive reaction ≥3mm with no
reaction to control
Cow’s milk:
Se
Sp
PPV NPV
0.41 0.87 0.86 0.43
0.96 0.48 0.79 0.85
0.92 0.82 0.92 0.82
Wheat:
Se Sp PPV NPV
Wheat:
Se Sp PPV NPV
Wheat:
Se Sp PPV NPV
0.27 0.89 0.58 0.69
0.82 0.34 0.41 0.77
0.60 0.85 0.60 0.85
Soy:
Se
0.23 0.86 0.30 0.82
APT with fresh vs.
commercial food
extracts
APT with fresh food
Cow’s milk:
Se
0.45 0.70 0.67 0.51
Hen’s Egg:
Se
Sp
PPV NPV
Sp PPV NPV
Sp
PPV NPV
0.65 0.96 0.95 0.67
Hen’s Egg:
Se
0.58 0.67 0.79 0.43
Sp
Soy:
Se
Sp PPV NPV
0.65 0.50 0.22 0.86
sIgE
Cow’s milk:
Se
Sp
PPV NPV
0.23 0.74 0.54 0.42
Hen’s Egg:
Se
Sp
PPV NPV
0.32 0.67 0.67 0.32
Soy:
Se
Sp PPV NPV
0.20 0.93 0.33 0.87
APT using fresh food or SPT or sIgE
Cow’s milk:
Se
Sp
PPV NPV
0.90 0.52 0.72 0.80
Hen’s Egg:
Se
Sp
PPV NPV
0.95 0.44 0.78 0.80
PPV NPV
0.84 1.00 1.00 0.75
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA cow’s milk allergy; DBPCFC double blind placebocontrolled food challenge; FC food challenge; FEIA fluorescent enzyme immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive
predictive value; RAST radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
150
Antigen-specific IgE Plus Lymphocyte Stimulation with Beta Lactoglobulin
One study assessed the performance of combining cow’s milk sIgE with a relatively uncommon
in vitro test that assesses the induction of lymphocyte proliferation with beta-lactoglobulin
(BLG).183 Cow’s milk allergy was assessed in 34 children, 19 of whom had a positive DBPCFC.
By itself, the BLG test showed a sensitivity of 0.40 and a specificity of 0.83. Combining the two
tests had a sensitivity of 0.88 and a specificity of 0.67 (this study satisfied 8 of the 12 QUADAS
domains assessed)
Summary
Of the ten studies that tried to improve diagnostic specificity or sensitivity by combining two or
more tests, seven paired the APT with SPT, sIgE, or both, in an attempt to capture both
immediate and delayed responses to antigen, whereas two combined SPT with sIgE to try to
improve sensitivity, and one combined sIgE assessment with BLG-induced proliferation. Pairing
the APT with SPT, sIgE, or both improved sensitivity and specificity over the use of individual
tests in most studies; however, the small number of studies that calculated the proportion of
patients for whom two or more tests could obviate the need for DBPCFC found these proportions
to be quite small. Of the three studies that paired SPT with sIgE in an attempt to improve
identification of IgE-mediated allergy, one found improved performance with the two tests, and
the other two found no difference. These studies satisfied 7 to 10 out of 12 QUADAS domains.
The quality of evidence is judged to be very low, meaning any estimate of effect is uncertain.
Diagnosis of Specific non-IgE Mediated Conditions
Diagnosis of Cow’s Milk and Other Protein-Induced Enteropathy
Several studies that attempted to establish a method to differentially diagnose IgE- and non-IgEmediated cow’s milk allergy (using a combination of APT and SPT or sIgE) and that met the
inclusion criteria were described above. A small number of studies specifically focused on the
diagnosis of (non-IgE-mediated) Cow’s milk-induced or protein-induced enteropathy but none
met the inclusion criteria. These studies are described here.
A study of 142 consecutive infants admitted to a Korean hospital with gastrointestinal symptoms
following cow’s milk ingestion were subjected to milk elimination and open challenge as well as
assessments of growth, serum albumin, acidosis, and peripheral leukocytosis.200 Among 16
patients diagnosed with cow’s milk protein-induced enterocolitis based on challenge,
hypoalbuminemia and failure to thrive were found to be independent predictors of the diagnosis.
A retrospective record review of ten Thai children with cow’s milk sensitive enteropathy found
that cow’s milk sIgE and total serum IgE levels were predictive of the course of the allergy
(likelihood of recovery).201
The utility of the lymphocyte proliferation (LP) assay was tested in a group of US children (9
with milk-induced enterocolitis syndrome (ME), 27 with IgE-mediated milk allergy (diagnosed
with history, food challenge, and SPT), and 21 controls.202 Among children with ME, in vitro LP
151
was higher than controls in terms of total radioactivity incorporated but not in terms of the
stimulation index (the ratio of incorporation by stimulated cells to incorporation by unstimulated
cells). Median LP for children with IgE-mediated allergy was higher than that of control children
but the ranges overlapped greatly. And probably most indicative of the lack of utility of this
assay was the finding that LP was elevated in response to soy exposure in a subgroup of milkallergic patients who had no response to soy on food challenge.
Finally, 20 US infants with proctocolitis attributed to cow’s milk, soy milk, or breast milk (by
clinical history) underwent colonic mucosal biopsy at three different anatomical sites.203
Nineteen of the 20 infants had at least one abnormal biopsy, characterized by eosinophilic
infiltration. The authors concluded that multisite colonic mucosal biopsy is useful for
confirmation of this disorder.
Diagnosis of Eosinophilic Esophagitis
The diagnosis of eosinophilic esophagitis is defined as esophageal biopsy with the finding of
greater than 20 eosinophils per high power field; the gold standard for establishing food allergy
as the causal mechanism is resolution of esophageal eosinophilia and symptoms following
elimination of the food from diet followed by recurrent esophageal eosinophilia with food
challenge.
Three articles addressing the diagnosis of food allergy-induced eosinophilic esophagitis were
discovered in our literature search: these studies were all produced by the same group and based
on the same patient population.33, 204, 205 Because all three papers reported results from the same
patient population, only the results of the final publication from this series are reported here.205
In this paper, the authors report the effectiveness of using skin prick and patch tests to identify
causative foods in patients with eosinophilic esophagitis. Results are reported for a subset of
patients with EE (n=316) at Children's Hospital Philadelphia in whom single causative foods
were identified (note that patients had to choose to have a subsequent esophageal biopsy). Skin
prick tests were performed using a commercial extract (Allergy Labs of Ohio) with a wheal of
3mm greater than the negative control being considered positive. Patch tests were performed
using a mix of dry foods and isotonic saline with the patches removed at 48 hours and the results
read at 72 hours. The diagnosis of food allergy as the cause of EE was made by normalization of
esophageal biopsy (0 eosinophils/HPF) after elimination of that food for 1-2 months, with
esophageal eonsinophilia (>20 eos/HPF) recurring on challenge with that food. The authors do
not report the number of subjects who test positive for APT and SPT for each food, but do report
the number of individuals whose diagnosis was confirmed with elimination and challenge (this
study satisfied 5 of the 12 QUADAS domains assessed). The results are reported in Table 37.
152
Table 37: Sensitivity and Specificity of SPT and APT in EE
SPT
APT
Food*
SPT+APT
Se
Sp
PPV
NPV
Se
Sp
PPV
NPV
Se
Sp
PPV
NPV
Milk (n = 46)
0.42
0.98
0.96
0.58
0.44
0.90
0.83
0.59
0.64
0.82
0.92
0.41
Egg (n = 39)
0.65
0.90
0.85
0.75
0.62
0.91
0.78
0.83
0.87
0.86
0.85
0.88
Soy (n = 28)
0.38
0.90
0.70
0.69
0.67
0.87
0.67
0.87
0.88
0.84
0.74
0.93
Wheat (n = 26)
0.19
0.97
0.78
0.65
0.72
0.86
0.74
0.84
0.81
0.87
0.77
0.90
Corn (n = 26)
0.14
0.95
0.57
0.71
0.89
0.78
0.66
0.94
0.87
0.77
0.63
0.93
Beef (n=23)
0.30
0.97
0.82
0.75
0.65
0.98
0.94
0.87
0.82
0.94
0.85
0.93
Chicken (n=15)
0.26
0.93
0.50
0.83
0.80
0.92
0.67
0.96
0.94
0.89
0.63
0.99
Rice (n=14)
0.13
0.98
0.50
0.86
0.87
0.88
0.59
0.97
1.00
0.89
0.61
1.00
Potato (n=11)
0.25
0.98
0.60
0.90
0.64
0.92
0.54
0.95
0.85
0.91
0.61
0.97
Peanut (n=10)
0.78
0.98
0.78
0.98
0.60
0.99
0.75
0.98
1.00
0.95
0.71
1.00
Oat (n=9)
0.10
0.98
0.33
0.90
0.90
0.87
0.47
0.99
1.00
0.89
0.50
1.00
Barley (n=9)
0.27
0.95
0.43
0.91
0.90
0.99
0.90
0.99
1.00
0.95
0.73
1.00
0.67
0.97
0.57
0.98
Apple (n=?)
Table Notes: AD atopic dermatitis; ALA α-lactalbumin; APT atopy patch test; BLG β-lactoglobulin; CM cow’s milk; CMA
cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; FC food challenge; FEIA fluorescent enzyme
immunoassay; HE hen’s egg; NPV negative predictive value; OFC open food challenge; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick test
* number in parentheses is the number of subjects in 316 cohort in which the given food was diagnosed as the
causative agent.
153
Diagnosis of Heiner's Syndrome (Pulmonary Hemosiderosis)
No studies addressing the diagnosis of Heiner's Syndrome met our inclusion criteria. One study
that did not meet the exclusion criteria examined the utility of the LP assay (using peripheral
monocytes) among 22 Japanese patients with non-IgE-mediated food allergies, including one
patient with buckwheat flour-sensitive pulmonary hemosiderosis; 18 patients with IgE-mediated
allergies; and 15 controls.206 Whereas LP for patients with IgE-mediated allergies did not differ
from that of controls, response to suspect foods correlated with oral food challenge results
among patients with non-IgE-mediated allergies.
Diagnostic Tools Used by Different Groups of Clinicians
Only a small number of studies have addressed the differences between allergists and nonallergists in the types of diagnostic tests used or the implications of any differences. Two studies
conducted surveys of physician knowledge and practices. A third study addressed a tangential
issue by comparing diagnoses made by allergists using DBPCFC with those of primary care
physicians using sIgE tests. None of these studies satisfied the inclusion criteria for this review.
Krugman (2006) reported on the results of a survey mailed to a random sample of 1,130 US
pediatricians (drawn from the membership roster of the American Academy of Pediatrics) that
used clinical cases to assess knowledge of food-induced anaphylaxis diagnosis and management
(treatment, counseling, and prevention) among primary care physicians. The response rate was
approximately 40 percent (419/1,130). Of the respondents (most of whom were in private
practice), 86 percent said they cared for children with food allergies; 66 percent said they felt
comfortable managing food allergy patients. Some 69 percent reported having received CME
credit in the prior 3 years for food allergy-related training. For a clear-cut case of food-induced
anaphylaxis, 30 percent of responding pediatricians missed the diagnosis (suggesting it could be
oral allergy syndrome), which resulted in their not administering epinephrine or prescribing self
(parent)-injectible epinephrine. Pediatricians who managed children with food allergy had
greater knowledge about food allergy management than those who did not; recent participation
in CME was not a predictor of greater knowledge when the researchers controlled for caring for
food allergy patients.207
The AAAAI Adverse Reactions to Food Committee conducted a survey among 3,000 allergists
and 4,000 non-allergists to assess differences in diagnosis and management between the two
groups. This survey was prompted by reports of large discrepancies between patient/parental
perceptions of allergy prevalence and the results of comprehensive diagnostic workups. The
response rate was 19.5 percent for allergists and 1.9 percent for non-allergists, thus few statistical
analyses were conducted. Non-allergists and allergists differed greatly in their use of the various
allergy tests. No statistical differences were found between allergists and non-allergists in the use
of medical history, food diaries, or elimination diets. However, allergists were significantly more
likely than non-allergists to use percutaneous skin testing (SPT and APT), sIgE, and food
challenge. Allergists were significantly less likely to report using intradermal tests, sIgG4, and
sublingual tests than non-allergists (tests that have shown poor PPV compared with DBPCFC).
Regarding food challenge, non-allergists were also more likely than allergists to regard open or
154
single-blinded food challenge as inadequate in infants and children under 6 years. The two
groups also differed in their ranking of the most common food allergens. E.g., for infants and
children under 20, non-allergists failed to consider soy as a common allergen; among adults,
non-allergists considered wheat to be the third most common allergen, whereas wheat was not
among the top five considered by allergists. Sucrose was viewed as a cause of food allergy by
35.1 percent of non-allergists vs. 5.2 percent of allergists.208
Summary
A small number of studies have examined differences in the use of diagnostic tests between
allergists and non-allergists. The findings of one survey suggest that PCPs who do not care for
many patients with allergies lack knowledge about appropriate diagnostic criteria. Another
survey suggests that allergists differ considerably from non-allergists in their choice of
diagnostic tests as well as the foods they consider to be of greatest concern, with allergists
relying more on DBPCFC, sIgE, and SPT/APT tests. Additional studies in more diverse
metropolitan areas are clearly needed on differences in the types of allergy tests conducted
among various health care settings and the value of commercial tests in the absence of
confirmation by FC.
Discussion/Limitations
Although the DBPCFC is widely used as the gold standard for food allergy testing, the literature
reveals same problems with the use of the DBPCFC as a gold standard (since some individuals
who have a positive challenge are able to tolerate the food under different conditions, and vice
versa). Related to this issue is the observation that in a number of studies that reported using
DBPCFC as the gold standard, DBPCFC was not always administered to all participants, and
instead, history was sometimes substituted (with no attempt to compare individual SPT or sIgE
results with that of DBPCFC or history). (See below for additional discussion of concerns about
DBPCFC)
A number of studies that employed SPT or sIgE failed to define the cutoff points for a positive
test, and comparisons among studies often showed different cutoff points being used. Although
several studies attempted to assess the effect of age or other factors on cutoff points (sensitivity
and specificity of the test at various cutoff points), these findings were inconsistent.
Although a number of studies attempted to assess the incremental value of performing multiple
tests, results were inconclusive.
The inclusion/exclusion criteria for study participation were not always clearly defined and
differed among otherwise similar studies. For example, some studies included only patients with
a history of atopic dermatitis or a personal or family history of other allergies.
Several studies assessed the effect of the form of test food used (e.g., raw vs. cooked; boiled vs.
roasted) on the results of food challenges, SPTs, and APTs. Although these studies did not draw
firm conclusions, the literature appears to support a difference in response to various forms of
155
particular foods. However, not all studies reported the form of the food used (or the amount), and
those that did varied widely.
The Practice Parameter on allergy diagnosis states that actual wheal size (in response to SPT)
and sIgE levels have been correlated with increasing likelihood of clinical reaction (but not with
clinical manifestations of the allergy).162 Such a correlation is critical if the simple-to-perform
SPT and sIgE are to be considered valid and reliable substitutes for food challenge tests.
However, these points were not supported or refuted in any of the original studies reviewed. A
2002 review addressed the question of whether SPT wheal sizes or sIgE levels predict clinical
reactivity (positive DBPCFC). Early tests with large sample sizes showed good correlation
between sIgE levels and clinical reactivity as well as skin test results. False positives in young
children were found to predict subsequent sensitization (i.e., sIgE appearance preceded
symptoms).209 However, the 2009 Work Group Report on oral food challenge testing concludes
that sIgE levels and wheal sizes do not predict severity of clinical reactions and that guidelines
for deciding whether to perform or defer an oral food challenge based on SPT wheal diameter or
sIgE levels are constantly evolving based on new evidence.159 Another 2009 review on this topic
also asserted that determining whether and when to administer DBPCFC in adults is contentious
and that the use of sIgE or SPT wheal size cutoffs to determine whether or not to administer
DBPCFC is of dubious value, because the cutoffs that predict positive DBPCFC results differ by
age, population, preparation of food used, and for SPT, the methods and reading times as well.
Most cutoff levels have been determined in populations of children, making their value for adults
even more questionable.210
Finally, the diagnostic tests reviewed in this section are those for which we were able to identify
studies that assessed their validity against a gold standard (usually the DBPCFC). We are aware
that other tests have been used in or proposed for the diagnosis of food allergy, including
tryptase assays, chymase assays, component resolution sIgE assays with purified antigens or
specific epitopes, provocation-neutralization tests, applied kinesiology, hair analysis, and
cytotoxic food testing; however, no literature was identified on the validation of any of these
tests for food allergy.
156
Section IV. Management, Treatment and Prevention of Food
Allergy
Overview
In the sections that follow we present the evidence on strategies for the prevention, treatment,
and management of food allergies. The key questions are organized principally by intervention
type (e.g., dietary avoidance, immunotherapy). We first present the results for the key questions,
then present the evidence according to common foods evaluated (e.g., cow’s milk, peanut), and
finally present the evidence for common clinical allergy syndromes (e.g., oral allergy syndrome,
eosinophilic esophagitis).
For those key questions not well addressed by systematic reviews or RCTs, we found eleven
observational studies: None included a comparison and eight had sample sizes over 100 (range of
the sample sizes: 102-567). Two studies (Hoffmann et al211 and Narisety et al.212) with fewer
than 100 participants were included, given the paucity of studies and the concern for safety of
immunotherapy. The study by Henriksen et al.213 reported nutrient intake among 34 children on
cows’ milk restricted diets. The study quality of ten of these was poor. Only one study214 was
considered to be of fair quality, given its large sample size (567 participants) and its complete
reporting of dropouts.
Prevention
In general, the RCTs of food allergy prevention enrolled pregnant women with a history of
allergic disease and/or their newborns, randomized them to receive special diets/formula or
placebo (to be given with or without breast milk), and followed the children to compare the
cumulative incidence of allergic disease in the intervention and placebo groups. We identified
seven systematic reviews (Table 39) and 46 randomized controlled trials that evaluated methods
to prevent food allergies (Table 40-Table 42). Twenty-one of the included RCTs were evaluated
in one or more of these systematic reviews and were not analyzed further.215-235 Two studies236,
237
reporting information on identical populations were excluded because they did not report data
comparing the intervention and control groups. We also excluded an RCT that evaluated the use
of cetirizine for the prevention of food allergies238 and the publications by Chandra et al. given
the published reports that seriously question the validity of his data.239, 240
157
Figure 7: Distribution of Prevention RCTs by Country
Finland
Germany
Multicenter
Sweden
Norway
Denmark
Korea
Italy
UK
Poland
Thailand
0
1
2
3
4
Of the 19 RCTs of allergy prevention strategies that were included, 17 were performed in Europe
(Figure 7) and randomized a total of 11,759 patients, (sample sizes ranged from 62 to 4753). Six
studies evaluated strategies for the prevention of milk allergies either alone or in combination
with other food allergies; 10 evaluated allergies to more than one food. The average follow up
period was 3 years (range: 1-3 years).
158
Figure 8: Distribution of Prevention RCTs by Intervention
The included RCTs evaluated five allergy prevention strategies: seven evaluated breastfeeding
either alone or in combination with other interventions, six studied special diets for infants, two
studied special diets for pregnant mothers, four evaluated probiotics, and one studied C-section
delivery (Figure 8).
Quality information for each of the included prevention trials is presented in Appendix F.
Management/Treatment
We identified three systematic reviews (Table 43: Food allergy treatment systematic reviews and
meta-analyses) and 28 randomized controlled trials (Table 44-Table 46) that evaluated methods
to manage or treat food allergies. Five RCTs241-245 were included in one or more systematic
reviews and were not analyzed further.
Figure 9: Distribution of Management/Treatment RCTs by Country
159
The 23 RCTs that were included were performed around the world, including five trials in the
US (Figure 9). The RCTs of management and treatment were considerably smaller in total than
the prevention trials: they included 1,371 participants (sample size ranged from 10 to 200
participants). The most commonly evaluated foods in the management/treatment RCTs were
milk (11 RCTs), egg (7 RCTs), and nuts (6 RCTs)—most studies evaluated more than one type
of food allergy. The duration of the management/treatment RCTs was far shorter than for the
prevention trials: follow up ranged from 7 days to 3 years but 19 studies were six months or less.
Figure 10: Distribution of Management/Treatment RCTs by Intervention
The included RCTs evaluated four main types of treatment/management strategies:
pharmacological management, allergen-specific immunotherapy, specific immunotherapy with
cross-reactive allergies, and allergen avoidance (Figure 10).
Quality information for each of the included management/treatment trials is presented in
Appendix F.
Key Question H. What methods are currently used to manage patients
diagnosed with IgE-mediated food allergy?
i. Dietary avoidance (including cross-reacting allergens and issues
of breast feeding and delay of solids) in the context of preventing
food allergy.
i. a. What are the effects of early versus delayed introduction of certain foods
into an infant’s diet?
Background
Several guidelines recommend delaying the introduction of solid foods to infants for four or six
months after birth in an effort to prevent atopic disease.246-249 However, there is not a clear
consensus regarding the risks and benefits of delaying introduction of solid foods in infants.
160
Results
We identified one systematic review on this topic.250 However, 12 of the 13 publications
included in the review were observational studies, a study design that we excluded from our
review on this key question. Therefore, we did not consider this systematic review any further.
We identified two controlled trials that evaluated the effect of breastfeeding in combination with
delayed introduction of solid foods in infants at high risk for all allergies (Table 40-Table 42).
Halmerbauer et al.251 conducted an RCT on environmental procedures to reduce house dustmites as well as an educational intervention to delay introduction of solid foods. They found a
significantly reduced risk of parent-reported food intolerance (vomiting, prolonged crying,
diarrhea, and swollen lips after eating) in the intervention group. However, the study findings
should be interpreted with caution because the study was only of fair quality and the intervention
included both breastfeeding and education regarding the delayed introduction of foods; therefore
it is difficult to evaluate the independent effects of individual components of the intervention.
Kajosaari and colleagues reported results from a comparative study that evaluated the effect of
exclusive breastfeeding and delayed introduction of solid foods until six months.252 They
conducted an extended analysis and found a possible protective effect of prolonged
breastfeeding; they reported a higher incidence of atopy in the control group that did not reach
conventional levels of statistical significance (p=0.15), but no differences in rates of asthma,
atopic eczema, or fresh fruit allergy. This study was rated as poor quality because it was not
randomized, and no information was provided on the comparability of the two groups.
Summary
The quality of evidence for this key question is low given that only two controlled trials of
relatively low quality address this question. While both of the included studies found some
association between delayed solids and decreased incidence of atopic symptoms, their findings
should be interpreted with caution given the multimodal nature of one study and the poor quality
of the other . In summary, we found insufficient evidence to support the association between
delayed introduction of solid foods in infants and the incidence of atopic disease.
i. b. What is the effect of maternal diets during pregnancy and lactation on the
development of, and clinical course of, food allergy?
Background
Several authors have observed that maternal dietary antigens can pass into breast milk and have
hypothesized a protective effect of a diet in which certain allergens are reduced or avoided
during pregnancy and lactation by women at high risk of having infants who will go on to
develop atopic disease.
Results
One systematic review and one non-randomized comparative study evaluated the effect of
maternal diet during pregnancy and lactation on the development of food allergy. Kramer et al.
conducted a systematic review (search conducted as of March 2006) that evaluated the effect of
maternal dietary avoidance on either treating or preventing atopic disease in children (Table
161
39).253 The literature search and screening process was comprehensive and followed the methods
used by the Cochrane Collaboration. Articles were selected if they were controlled trials
comparing dietary avoidance or reduction of potential allergens to usual diet by pregnant women
at high risk of delivering infants with atopic disease; articles where both the mothers and infants’
diets (other than breast milk) were manipulated were excluded. The review scored highly on the
AMSTAR criteria for evaluating systematic reviews. Their analysis pooled data from two trials
with a total of 334 pregnant women; however, they acknowledged that the two trials were of
unequal methodologic quality. The authors found no significant difference in the incidence of
atopic eczema (relative risk 1.01; 95% confidence interval CI 0.57-1.79), asthma (RR 2.22; 95%
CI 0.39-12.67), positive skin prick tests to egg (RR 0.95; 95% CI 0.52-1.74) or milk (RR 0.86;
95% CI 0.16-4.59) during the first 18 months of life in infants whose mothers avoided dietary
antigens during pregnancy. There was insufficient evidence to determine the effect on urticaria,
allergic rhinitis, conjunctivitis, or both since these outcomes were reported by only one trial. One
included trial evaluated the avoidance of dietary antigens during lactation on the incidence of
atopic eczema and found no significant difference in the incidence of atopic eczema between the
two groups (RR 0.73; 95% CI 0.32-1.64). Overall, the review concluded that a maternal allergen
avoidance diet was “unlikely to reduce substantially” the risk of having a child with atopic
disease but that such a diet may have “adverse effects on maternal or fetal nutritional status;”
however, more data on these adverse effects were needed.
Two publications254, 255 reporting on one non-randomized comparative study, evaluated the effect
of restricting maternal diet during lactation for the first three months after birth, on the incidence
of food allergies (Table 40-Table 42). Hattevig et al.254 reported study results at 18 months and
Sigurs et al.255 reported results at four years of age. The authors found significantly reduced
cumulative incidence and prevalence of atopic dermatitis at four years in children in the
intervention group compared to the control group. The authors also observed this reduced
incidence at three and six months of age, but not at nine, 12, and 18 months. They found no
significant differences in the cumulative incidence and prevalence of respiratory allergic
diseases, in adverse reactions to egg or cow’s milk, or in positive skin prick tests or positive
serum specific IgE tests at any ages. This study was rated as poor quality; however, the authors
report that the two groups were comparable and matched through recruitment.
Summary
We found conflicting evidence on maternal diet during pregnancy and/or lactation and its effect
on atopic disease among children at high risk for atopic disease. While the systematic review
reported no evidence to support a protective effect of maternal diet, the comparative study found
significantly reduced incidence of atopic dermatitis in children whose mothers had a restricted
diet during lactation; however, this study was of poor quality. Given these findings, we conclude
that there is insufficient evidence to determine the effect of restricting maternal diet in reducing
the risk of atopic disease in infants.
i. c. What is the effect of breastfeeding infants on the development of, and clinical course of,
food allergy?
162
Background
The protective role of breastfeeding in preventing atopic disease has been uncertain, with some
studies reporting favorable outcomes associated with breastfeeding256, 257 and others reporting no
effects.258, 259 The effectiveness of combining exclusive breastfeeding with other interventions to
prevent atopic disease is also unclear.
Results
We found seven studies that evaluated the effect of breastfeeding in combination with either
restricted maternal or infant diet, use of hydrolyzed formulas, or delayed introduction of solid
foods (Table 40-Table 42).252, 260-264 These studies are reviewed in the relevant key questions for
those topics. One study was an RCT from Spain that only reported SPT and sIgE sensitization
outcomes for children but not the development of food allergies and therefore was excluded. 264
In addition, we identified three analyses of data from the same study population that randomized
participants to either exclusive breastfeeding or partial or complete cow milk formula and
compared their incidence of atopic dermatitis (Table 40-Table 42).265 Schoetzau et al. reported
results on a sub-group of infants who were part of the German Nutritional Intervention Study
(GINI) cohort study and found a significantly lower risk of atopic dermatitis at one year of age in
infants who were exclusively breastfed compared to infants who were not (9.5 percent versus
14.8 percent, respectively, p=0.015). Their logistic regression model found that the risk of atopic
dermatitis was reduced by nearly 50 percent in the exclusively breastfed group, after adjusting
for atopic risk factors and other confounders such as parent education, gender, pet keeping, and
maternal smoking (adjusted OR 0.47, 95% CI 0.3-0.74).265 They also conducted analyses to
determine the effect of delayed introduction of solid foods between the two groups but did not
find a significant effect modification of either age at first introduction (Wald-Chi square p=0.58)
or diversity of foods (p=0.89). The analysis conducted in this paper differed from that by Filipiak
et al.260 using the infant population from the GINI study. Schoetzau et al. compared differences
based on exclusive breastfeeding or not in only intervention group infants of the GINI study
whereas the Filipiak study compared breastfeeding, use of hydrolysed formulas, and delayed
introduction of solid foods in intervention group infants to a separate control group of infants
whose mothers did not receive these recommendations. They concluded that there was no
evidence to support a protective effect of delayed introduction of solids for eczema.
Laubereau, et al 266 also reported on the GINI-birth cohort study and found exclusive breastfeeding was not associated with higher risk for atopic dermatitis either in the entire cohort (OR,
0.95; 95% CI, 0.79-1.14) or if stratified by family history of atopic dermatitis. In the intervention
subgroup, but not in the non-intervention subgroup, exclusive breast-feeding showed a
significant protective effect on atopic dermatitis if compared with conventional cow’s milk
formula (OR, 0.64; 95% CI, 0.45-0.90).
Summary
The quality of evidence for this key question is low given that we found only one fair quality
non-randomized comparative study addressing this question and conflicting evidence from that
study.
163
i. d. What are the effects of special diets in infants and young children (e.g.,
formula, hydrolyzed formula) on the development of, and clinical course of,
food allergy?
Background
Food allergies in infants and children may be associated with cow milk proteins, and various
hydrolyzed or soy-based formulas have been used to treat infants with food intolerance or
allergies. However, it is unclear if these formulas can be used to prevent food allergies in infants
without established food allergies.
Results
We identified two systematic reviews that evaluated the effects of hydrolyzed infant formulas267,
268
and one of soy formula269 on the development of food allergies in children (Table 39). The
literature search and screening process was comprehensive for all three reviews and followed the
methods used by the Cochrane Collaboration for two reviews. Articles were selected if they were
controlled trials comparing dietary avoidance or reduction of potential allergens to usual diet by
pregnant women at high risk of delivering infants with atopic disease; articles where both the
mothers and infants’ diets (other than breast milk) were manipulated were excluded. Two
reviews scored highly on the AMSTAR criteria for evaluating systematic reviews (9 criteria
met); the third scored lower (5 criteria met).267
Soy Formulas vs Hydrolyzed Formulas vs Cow’s Milk
Osborn and Sinn269 conducted a review to determine the effect of feeding infants adapted soy
formula compared to human milk, hydrolysed protein formulas, or cow milk formula. Their
search (conducted as of March 2006) resulted in the inclusion of three studies that compared soy
formula to cow milk formula. They reported no significant differences in incidence of childhood
allergies, infant or childhood asthma, infant or childhood eczema, or infant or childhood rhinitis.
The authors concluded that there was no evidence to suggest that the use of soy formula instead
of cow milk formula prevented allergies in infants at high risk for food allergies, either in later
infancy or childhood.
Hydrolyzed Formulas vs Cow’s Milk Formula or Breastfeeding
Osborn and Sinn also conducted a Cochrane review comparing the effect of hydrolyzed formulas
to cow milk formula or human milk in preventing food allergy.268 We note that several studies on
hydrolyzed formulas failed to specify the exact type/composition/brand name of the formulas
provided. Also, the terms “partially” and “extensively” hydrolyzed are not well defined in this
literature. They included four trials comparing short term hydrolyzed formula feeding to human
milk or cow’s milk formula and found no significant differences in infant or childhood cow’s
milk allergy between the groups. When assessing prolonged feeding with hydrolyzed formula
compared to cow milk formula in infants at high risk, their meta-analysis of seven studies found
a significant decrease in infant allergies (RR 0.79 95% CI 0.66-0.94), but no difference in the
incidence of childhood allergy (two studies, RR: 0.85, 95% CI 0.68-1.04); they also found no
significant differences in infant or childhood eczema or infant or childhood asthma, rhinitis and
food allergy. Their subgroup analysis restricted to studies using partially hydrolyzed formulas
had similar findings. There was no significant difference in outcomes when comparing
164
extensively hydrolyzed formulas with cow milk formula; however, when compared with partially
hydrolyzed formulas, infants fed extensively hydrolyzed formulas had a significant decrease in
food allergy overall (two studies, RR 0.43; 95% CI 0.19-0.99), but not in any specific food
allergy. Their meta-analysis of three studies comparing extensively hydrolyzed casein formula
with cow milk formula found a significant decrease in incidence of infant eczema (RR 0.71; 95%
CI 0.51-0.97). The authors concluded in their review that there was limited evidence that
prolonged feeding with hydrolyzed formulas in high risk infants reduced infant and childhood
allergy and infant cow’s milk allergy when compared with cow milk formula; however, they
reported concerns about the methodology of the included studies as well as inconsistencies in the
findings.
In their review, Hays and Wood267 included controlled trials to assess the effect of hydrolyzed
formulas in preventing allergies when compared with breastfeeding, cow’s milk formula, or soy
formula and the difference between extensively (eHF) and partially (pHF) hydrolyzed formulas.
The authors included nine trials on eHFs (all were casein hydrolysate formulas) and 11 studies
on pHFs (10 whey formulas and one casein formula). Due to the heterogeneity of trial methods,
the authors did not pool the data but presented a narrative synthesis and a table with each
included trial. They concluded that for both eHFs and pHFs, “the data support a protective
effect…but the research falls short of meeting the American Academy of Pediatrics criteria for
evidence of allergy prevention.”
A related trial is the GINI study,270, 271 which randomized 2,252 infants less than 2 weeks old
who had at least one parent or sibling with a history of allergic disease, and without any history
of formula supplementation to receive one of three hydrolyzed formulas or to cow’s milk
formula. Children were followed to six years. Children fed with partially hydrolyzed whey
formula (pHF-W) and extensively hydrolyzed casein formula (eHF-C) were less likely to have
“any allergy diagnosis from a physician” compared with children fed cow’s milk formula (47.1
percent, 46.1 percent, vs 56 percent respectively). However, there was no difference between
extensively hydrolyzed whey formula (eHF-W) and cow’s milk formula.
An RCT by Odelram et al.272 examined whey hydrosylate and cow milk formula compared to
strict breastfeeding in the prevention of atopic disease of infants. Inclusion criteria were at least
two atopic family members or one atopic parent and total cord blood IgE >0.5 kU/I. Exclusion
criteria were gestational age below 37 weeks, complicated delivery, neonatal illness, severe birth
defects, and documented or expected noncompliance with diet prescription. Presence of atopic
disease was 10/25 in the infants fed extensively hydrolyzed formula, 15/32 in the infants fed cow
milk formula, and 3/13 in those who were breastfed. No statistical difference in the presence of
atopic disease was found. There was no statistically significant difference in positive SPT or in
serum IgE at 18 months.
Von Berg et al.270, 271 evaluated the long-term allergy-preventive effect of three hydrolyzed infant
formulas compared with cow’s milk formula. Between 1995 and 1998, 2,252 newborns with
atopic heredity were randomly assigned at birth to receive one of four blinded formulas: partially
or extensively hydrolyzed whey formula, extensively hydrolyzed casein formula, or cow’s milk
formula as milk substitute for the first four months when breast feeding was insufficient. At
three years of follow-up, there was no statistically significant effect on the incidence of asthma.
165
In an intention to treat analysis of 2,252 children at six years of follow-up, it was found that only
the extensively-hydrolyzed whey formula was associated with an increased RR of asthma of 2.16
(CI 1.02-4.58). This was not found in the per protocol analysis.
A trial by Arslanoglu et al.273 randomized 259 infants with a family history of atopy to receive
either a hypoallergenic formula supplemented with a mixture of 90 percent short-chain
galactooligosaccharides and 10 percent long-chain fructooligosaccharides (IMMUNOFORTIS)
intended to mimic human milk oligosaccharides or to the same formula without this
supplementation (Table 40-Table 42). The cumulative incidences of atopic dermatitis, recurrent
wheezing, and allergic urticaria were lower in the treatment group than the control group (13.6
vs 27.9 percent, 7.6 vs 20.6 percent, 1.5 vs 10.3 percent respectively, p<0.05).
Szajewska et al.274 studied the prevention of allergic disease in preterm infants by comparing
extensively and partially hydrolyzed preterm formulas with standard preterm formula. This
study did not show any difference in the incidence of allergic diseases in preterm infants.
Han et al.263 studied the effects of partially hydrolyzed formula on development of atopic
dermatitis in infants at high risk. The infants of parents with allergy symptoms and serum total
IgE over 200 kU/L were divided into three groups: partially hydrolyzed formula, standard
formula, and breast milk. In addition, the infants received no allergenic food for 6 months, and
breastfeeding mothers avoided egg ingestion. The cumulative incidence and prevalence of atopic
dermatitis at the age of 6 months were significantly less in the partially hydrolyzed formula
group than in the SF group (47% vs. 78%, p<0.05; 20% vs. 59%, p<0.05). There was no
statistically significant difference in comparison with the breastfed group.
Summary
The quality of evidence for the key question on special diets in infants and young children is
moderate to high. The quality of evidence on use of soy formulas is moderate given that this was
addressed by a high quality review that included only three small RCTs; the evidence suggests
that there is little difference between soy formula and cow's milk formula for the prevention of
allergies in high risk infants. The quality of evidence on use of hydrolyzed formulas is high
given that two systematic reviews and four other RCTs address this question; there is some
evidence that hydrolyzed formulas (particularly extensively and partially hydrolyzed formulas)
may reduce infant and childhood allergy, asthma, and cow's milk allergy syndrome in high risk
infants when compared with cow milk formula.
i.e. What are the recommendations by professional organizations regarding
the avoidance of food and non-food allergens by people with food allergy?
Table 38 presents the recommendations found in our search of the websites of professional
organizations.
.
166
Table 38: Recommendations on Food Avoidance by Professional Societies
Food Allergy Expert Panel
Guidance Organizations
Recommendations
Allergy and Asthma
Network Mothers of
Asthmatics
http://www.aanma.org/
п‚·
п‚·
п‚·
American Academy of
Pediatrics
http://www.aap.org/
п‚·
п‚·
п‚·
п‚·
No formal recommendations. Advice on FAQ page sums up to: Avoid your food
triggers, read labels, and check with your doctor/pharmacist.
http://www.aanma.org/faqs/
Children with life-threatening food allergies should always have two doses of
auto-injectable epinephrine available to treat anaphylaxis – especially if they also
have asthma. Advice based on a in the Journal of Allergy and Clinical
Immunology. http://www.aanma.org/2009/05/keep-two-doses-of-epi/
Article offering basic advice (carry Epipen, alert school, etc.) for allergic
children/parents in schools. http://www.aanma.org/2009/01/food-allergies-atschool/
FAQ directed at parents gives information on distinguishing food allergy from
food intolerance and other conditions that can be confused with food allergy.
http://www.aap.org/publiced/BR_FoodAllergy.htm
AAP also produces (for sale) books and pamphlets to educate parents.
No specific recommendations on their Web site, however, these were found on
Guideline.gov: Effects of early nutritional interventions on the development of
atopic disease in infants and children: the role of maternal dietary restriction,
breastfeeding, timing of introduction of complementary foods, and hydrolyzed
formulas. American Academy of Pediatrics - Medical Specialty Society. 2008
Jan.
Guidelines for the administration of medication in school. American Academy of
Pediatrics – Medical Specialty Society. 2003 Sep. (These cover all kinds of
medications, such as insulin, and are not specific to allergy meds.)
American Academy of
Allergy Asthma and
Immunology
http://www.aaaai.org/
A brochure for parents, updated in 2009, includes these specific guidelines:
п‚· Try to wait until babies are 6 months old before you give them solid foods.
п‚· Wait until they are 1 year old before giving them milk and other dairy (like
cheese and yogurt).
п‚· Toddlers should not eat eggs until they are 2 years old.
п‚· Children should not eat peanuts, nuts or fish until they are 3 years old.
п‚· Talk to your doctor about a plan for introducing these foods.
http://www.aaaai.org/patients/resources/easy_reader/food.pdf
Other Web sites/Advice of
Note
п‚·
п‚·
п‚·
п‚·
Allergic Child.com recommends parents “err on the side of caution” and use
EpiPens, even if the source of a reaction has not been determined.
http://www.allergicchild.com/epipen_ana_medicalert.htm
Food Allergy.org has a Food Allergy Action for teachers of allergic children.
There is still no federal regulation requiring all public schools to allow students
to carry their own auto-injectables (as opposed to leaving them with school
nurses). This is a great concern to parents of children in “zero tolerance” school
districts. The Action Plan is downloadable at:
http://www.foodallergy.org/downloads/FAAP.pdf
“Common Beliefs About Peanut Allergy: Fact or Fiction?” written for FAAN by
Michael C. Young, M.D., Assistant Clinical Professor of Pediatrics, Harvard
Medical School for FAAN. Young’s article underscores the need to distinguish
between anaphylactic shock caused by contact and shock caused by conditioned
fear.
http://www.allergysafecommunities.ca/assets/common_beliefs_faan_2003.pdf
167
Additional Information Relevant to Key Question H.i.: Systematic
review of the association of caesarean delivery and allergic diseases.
Background
Some authors have raised a suspicion of an association between the mode of delivery (vaginal vs.
cesarean/c-section) and allergic diseases on the basis that babies born by c-section have different
gut flora than babies born by vaginal delivery. Specifically, it has been hypothesized that this
difference in gut flora may lead to prolonged immunologic immaturity in babies born by csection that may increase the risk of allergic disease later in life.
Results
We identified two systematic reviews275, 276 and a prospective controlled trial of 609 patients277
that evaluated the risk of allergic diseases after c-section (Table 39 and Table 40). All studies in
the review by Koplin et al.276 were listed in the review by Bager et al.275 The Bager et al
review275included six articles that specifically evaluated the association of food allergies/atopy
and c-section, three of which found no statistically significant association and three of which
found a significant association; although all six studies had a positive odds ratios.278-283 Overall,
the review found an increased incidence of food allergies/food atopy among children delivered
by c-section compared with those delivered vaginally, with a random effects odd ratio of 1.45
(95% CI 1.12-1.86, heterogeneity statistics: Q=8.99, p 0.11). However, the authors note that this
result may be subject to significant publication bias. Additionally, the metrics of food allergy
varied among the six included studies (e.g., IgE to food allergen, parent report of food allergy),
and the ages of the children varied from 0 to 17 years. Kvenshagen et al.277enrolled 609 children
at birth and followed them for two years. Food allergy was diagnosed in 36.2% (62/171) of
children delivered by c-section and in 39.8% (136/341) of children delivered vaginally. There
was no statistical difference in food allergies between the two modes of delivery.
Summary
There may be an association between c-section and the development of allergic disease later in
life; however, the total body of evidence on this issue is mixed and has significant methodologic
concerns, necessitating further investigation; the grade of evidence for this conclusion is
therefore low.
Additional Information Relevant to Key Question H.i.: Studies on the use of
probiotics for the prevention of food allergies.
Background
Probiotics are live microbial food ingredients. Some authors suggest that probiotic bacteria, like
other gut microflora, may affect neonatal mucosal barrier function and the digestion of protein
antigens and oligosaccharides present in breast milk and formula and in doing so, prevent the
development of food allergies later in life.
168
Results
Five high quality RCTs of similar design284-288 reported the use of probiotics prenatally and in
the neonatal period for the prevention of food allergies in children considered high risk for
developing them (Table 40-Table 42). Four of these studies were done in Finland and one in
Sweden.
Two studies284, 285 performed by the same investigators at the University of Turku, Finland
evaluated the role of probiotics in combination with breastfeeding as a means of preventing
atopy in children. In their 2002 publication,285 the Turku group evaluated whether the probiotic
Lactobacillus rhamnosus given to 64 pregnant women starting four weeks before delivery and
continued with breastfeeding for three months postpartum decreased the risk of atopy among
their children at two years. They found that only four of the 27 children of the women who
received probiotics developed chronic relapsing atopic eczema compared with 14 of the 30
whose mothers received placebo (RR 0.32, 95% CI 0.12-0.85, p=0.0098).285 In their 2008
publication,284 the Turku group randomized 72 pregnant women to receive the probiotics L.
rhamnosus and Bifidobacterum lactis and 68 women to receive placebo from the first trimester
of pregnancy to the end of exclusive breastfeeding. There was no difference in positive reactions
to SPT at one year between the children of women who received probiotics (29 percent) and
those who did not (31 percent; OR: 0.92, 95% CI 0.45-1.90, p=0.825).
Two studies286, 287 were performed by the same investigators in Helsinki and Tampere, Finland.
In a similar design to the work by the Turku group, these investigators recruited pregnant women
who were randomized to receive four probiotics twice daily beginning two to four weeks
prenatally (L. rhamnosus GG, L. rhamnosus LC705, B. breve, and Proprionibacterium
freudenreichii). Newborns in the treatment arm continued these probiotics for six months. At age
five years, there were no significant differences in the primary end points of allergic and IgEassociated allergic disease or frequencies of eczema, asthma, allergic rhinitis, or atopic
sensitization in the probiotic and placebo arms. In post-hoc secondary analyses, the authors
reported a significant decrease in IgE-associated allergic diseases, particularly eczema, and less
IgE sensitization in the probiotics group of children born by c-section delivery than among the
placebo group. However, there were no such differences between treatment groups among
children born by vaginal delivery.286
Abrahamsson et al.288 provided the probiotic L. reuteri to pregnant women in Sweden starting
four weeks prenatally and continued by the infants for 12 months (mothers were encouraged to
breast feed, and at weaning, infants were offered a hypoallergic formula). At 24 months, the
cumulative incidence of eczema was not different between the treatment (36 percent) and
placebo groups (34 percent), and there was also no difference in the cumulative incidence of
wheeze. However, IgE-mediated eczema was lower in the probiotics group (8 percent versus 20
percent; p=0.02) as was the circulating IgE to egg white—although not to other food allergens.
Summary
The quality of evidence for this key question is moderate. There are five high-quality RCTs that
address this question but there is some heterogeneity in the results. The use of probiotics in the
prenatal and early neonatal period may be associated with mild reductions in the cumulative
incidence of allergic skin disease in children. However, these results are interpreted with caution
169
since the trials with the most significant results used probiotics in conjunction with breastfeeding
and/or hypoallergenic formula. Therefore, the independent effects of probiotics cannot be
established in these trials.
170
Table 39: Food allergy prevention systematic reviews and meta-analyses
Author/
Study Question
Databases
Intervention
Year
searched/
Years
Kramer, To evaluate the effect of
Cochrane
Mothers prescribed a
an antigen avoidance diet
2009253
Pregnancy and
diet to either exclude
during pregnancy and/or
Childbirth Group or reduce potentially
lactation on the prevention Trial register;
allergenic foods: cow
of atopic disease in
Up to March
milk, egg, peanuts,
children
2006
fish, chocolate during
pregnancy or
lactation
Inclusion/
Exclusion
RCTs or quasiRCTs
comparing diets
of different
levels of antigen
avoidance
Total
Outcomes
Publications
reported
Included
4
Occurrence/sever
ity of atopic
disease in child;
nutritional status
of mother and
fetus; other
pregnancy
outcomes; cord
blood IgE levels
Osborn,
2009269
To assess the effect of soy
formula compared to cow
milk formula, hydrolyzed
protein formula or human
milk in preventing food
allergy in infants who do
not have clinical evidence
of food allergy
Medline (1966March 2006;
EMBASE (1980March 2006);
CINAHL (1982March 2006);
Cochrane Central
(up to March
2006)
Use of an adapted soy
formula
RCTs or quasiRCTs with >
80% follow up;
cross-over trials
excluded
3
All allergies;
asthma; atopic
dermatitis;
allergic rhinitis;
food allergy; food
intolerance
Osborn,
2009268
To assess the effect of
hydrolyzed protein
formulas compared to
human milk or adapted
cow milk in preventing
food allergies in infants
who do no have clinical
evidence of food allergies
Medline (1966March 2006;
EMBASE (1980March 2006);
CINAHL (1982March 2006);
Cochrane Central
(up to March
2006)
Use of any
hydrolyzed infant
formulas
RCTs or quasiRCTs with >
80% follow up
4
All allergies;
asthma; atopic
dermatitis;
allergic rhinitis;
food allergy; food
intolerance;
infant growth
parameters; cost;
infant feed
refusal
171
AMSTAR
Criteria
01. Can’t Answer
02. Yes
03. Yes
04. Yes
05. Yes
06. Yes
07. Yes
08. Yes
09. Yes
10. No
11. Yes
01. Can’t Answer
02. Yes
03. Yes
04. Yes
05. Yes
06. Yes
07. Yes
08. Yes
09. Yes
10. No
11. Yes
01. Can’t Answer
02. Yes
03. Yes
04. Yes
05. Yes
06. Yes
07. Yes
08. Yes
09. Yes
10. No
11. Yes
Table 39: Food allergy prevention systematic reviews and meta-analyses (Continued)
Study
Study Question
Databases
Intervention
Inclusion
searched/
Exclusion
Years
To assess the effect of
Hays,
Medline (1985Infants received
Prospective
hydrolyzed infant formulas 2005)
2005267
extensively
controlled trials
in preventing food
hydrolyzed or
allergies
partially hydrolyzed
formulas
Bager,
2008275
To evaluate whether
caesarean delivery is
associated with an
increased risk of atopy and
allergy disease
MEDLINE
(1966-2007)
Caesarean delivery
(c-section)
172
Studies of csection that
presented
information on
at least one of 6
allergic
conditions
including food
allergy/food
atopy.
Total
Outcomes
Publications
reported
Included
18
Atopic dermatitis;
urticaria; asthma;
angioedema; GI
disease; allergic
rhinitis; cow’s
milk allergy;
conjunctivitis
26 total but
only 6
reported on
food
allergy/food
atopy
Food
allergy/atopy,
inhalant atopy,
eczema/atopic
dermatitis,
allergic rhinitis,
asthma,
hospitalization
for asthma.
AMSTAR
Criteria
01. Can’t Answer
02. Can’t Answer
03. No
04. Yes
05. No
06. Yes
07. Yes
08. Yes
09. NA
10. No
11. Yes
01. Can’t Answer
02. Can’t Answer
03. No
04. No
05. Yes
06. Yes
07. No
08. No
09. Yes
10. Yes
11. Yes
Table 39: Food allergy prevention systematic reviews and meta-analyses (Continued)
Study
Study Question
Databases
Intervention
Inclusion
searched/
Exclusion
Years
To determine whether
Koplin,
MEDLINE and
Caesarean delivery
Studies with
there is sufficient evidence PubMed (prior to (c-section)
2008276
mode of delivery
to support an association
July 1997)
and either IgEbetween delivery by
mediated
cesarean section and the
sensitization to
development of food
food allergies or
allergens and IgE
confirmed food
mediated food allergy
allergy
Maas,
2009289
To compare the
effectiveness of mono- and
multifaceted allergen
reduction interventions in
the primary prevention of
asthma and asthma
symptoms in children
judged to be at high risk of
developing asthma
Cochrane
Airways Trials
Register up to
December 2008
Reduced exposure to
allergens, either multi
(inhalants and food)
or mono (inhalants or
food)
RCTs of
allergen
exposure for the
primary
prevention of
asthma in
children with
follow up from
birth or
pregnancy to a
minimum of 2
years
Total
Outcomes
Publications
reported
Included
4
Number positive
for food allergy
4
Physician
diagnosed asthma
in children <5
years and asthma
as defined by
respiratory
symptoms and
lung function in
children > 5 years
AMSTAR
Criteria
01. Can’t Answer
02. Can’t Answer
03. No
04. No
05. Yes
06. Yes
07. No
08. No
09. Yes
10. No
11. Yes
01. Can’t Answer
02. Yes
03. Yes
04. Yes
05. Yes
06. Yes
07. Yes
08. Yes
09. Yes
10. No
11. Yes
Table Notes: RCTs randomized controlled trials; GI gastrointestinal; sIgE antigen-specific immunoglobulin
AMSTAR criteria: 01. Was an a priori study design provided? 02. Was there duplicate study selection and data extraction? 03. Was a comprehensive literature search
performed? 04. Was the status of publication (gray literature) used as an inclusion criterion? 05. Was a listed of studies (included/excluded) provided? 06. Were the characteristics
of the included studies provided? 07. Was the scientific quality of the included studies assessed and documented? 08. Was the scientific quality of the included studies used
appropriately in formulating conclusions? 09. Were the methods used to combine the findings of studies appropriate? 10. Was the likelihood of publication bias assessed? 11.
Was the conflict of interest stated?
173
Table 40: Food allergy prevention controlled trials: study information
Study
Country
Purpose
Food
Breastfeeding and delayed introduction of solid foods
Halmerbauer, Austria;
To determine if reduction in house-dust mites and prolonged
Germany; breastfeeding and delayed introduction of solids reduce rates of
2002251
UK
sensitization and atopic diseases.
Finland
To determine the benefit of exclusive breastfeeding and delayed
Kajosaari,
introduction of solid foods in children at risk for atopy
1994252
Maternal diets
Hattevig,
Sweden
To determine effect of maternal avoidance of eggs, cow's milk, and
1989254 and
fish during lactation and delayed introduction of solids to infants on
Sigurs,
allergies in children
1992255
Breastfeeding (with other interventions)
Germany
To assess association between solid food introduction and eczema
Filipiak,
occurrence
2007260
Italy
To evaluate the effect of breastfeeding vs soy formula vs soy with
Bardare,
dietary restrictions on the incidence of atopic disease in infants at risk
1993261
of allergy
UK
To determine effect of breast feeding (with mothers placed on a low
Arshad,
allergen diet) or hydrolzed formula and house dust mite exposure
2007262
prevention on the development of atopic dermatitis, asthma, and atopy
Germany
To evaluate the effect of exclusive breast-feeding and early solid food
Schoetzau,
avoidance on atopic dermatitis
2009265
Germany
To investigate if exclusive breast-feeding for 4 months is associated
Laubereau,
with atopic dermatitis during the first 3 years of life.
2004,266
Special diets for infants and young children
Von Berg,
Germany
To assess the effect of hydrolyzed formulas in preventing allergy
2008,270
development (GINI trial)
2007271
Denmark
To examine whey hydrosylate compared with cow milk based formula
Odelram,
on atopic disease
1996272
174
Condition of interest
Study
quality
Milk, Egg
Food intolerance
Fair
NS
Atopic eczema; asthma; food
allergy
Poor
Multiple
Eczema, asthma, bronchial
obstruction, rhinoconjunctivitis
Poor
Multiple
Eczema
Poor
Multiple
Atopic eczema; allergic asthma;
allergic rhinitis
Poor
Multiple
Asthma, AD, food allergy
Fair
Multiple
Atopic dermatitis
Fair
Multiple
Atopic dermatitis
Fair
Milk
Multiple
Milk
Atopic diseases (including
uticaria, atopic dermatitis, and
cow’s milk allergy)
Good
Fair
Table 40: Food allergy prevention controlled trials: study information (Continued)
Poland
To evaluate extensively and partially hydrolised preterm formulas in
Szajewska,
the prevention of allergic disease in preterm infants
2004274
Milk
Han, 2003263
Korea
Arslanoglu,
2008273
Multiple
European
countries
Probiotics
Rautava,
2002285
Huurre,
2008284
Kuitunen,
2009286
Kukkonen,
2007287
Abrahamsso,
2007288
Kvenshagen,
2009277
Finland
Finland
To assess the effects of partially hydrolyzed formula on the prevention
of atopic dermatitis in high risk infants
To determine the effect of prebiotic oligosaccharides in formula-fed
infants on the incidence of allergies and infections
To determine the effect of probiotic supplementation in pregnant and
lactating women on reducing the risk of allergies in their infants
To evaluate the effect of probiotics for allergy prevention in infants.
Finland
To assess probiotic supplementation in pregnant women and infants in
reducing the risk of allergies in children
Sweden
To assess the effect of L reuteri in infancy as a method of prevention
of IgE associated eczema at year 2 of life
To investigate whether children delivered by cesarean section were
more prone to develop food allergy
Norway
Good
Milk
Atopic diseases (atopic
dermatitis, gastrointestinal
symptoms, wheezing, and
cow’s milk allergy)
Atopic dermatitis
Milk
Allergies, infections
Good
Milk,
other
Milk,
other
Multiple
Allergy, not specified
Good
Allergy, not specified
Good
Multiple
Good
Multiple
Eczema, atopic dermatitis,
Asthma
Multiple
Good
Multiple
Table Notes: AD atopic dermatitis; GINI German Infant Nutritional Intervention; sIgE antigen-specific immunoglobulin
175
Poor
Poor
Table 41: Food allergy prevention controlled trials: patient characteristics
Study
Intervention Group Selection Criteria
Inclusion/
IgE
exclusion criteria
Breastfeeding and delayed introduction of solid foods
Inclusion: infants with allergic disease in one or
Halmerbauer,
No
both parents which was confirmed by allergy
2002251
testing. Exclusion: birth weight less than 2500
grams; admission to NICU for more than 7 days
Inclusion: infants of atopic parents
No
Kajosaari,
1994252
No
No
Same as
intervention
group
NR
NR
No
No
Same as
intervention
group
NR
NR
Maternal diets
Hattevig254 and
Sigurs255
cord
blood
IgE =
0.9
ku/L
No
No
Same as
intervention
group
NR
NR
No
No
No
Infants
without
family
history of
allergy or
those whose
parents did
not
participate in
the
intervention
group
cord
blood
IgE
levels
>= 1
IU/mL
No
No
Same as
intervention
group
Males: 1006
Males: 1441
(51.9%); no
(51.2%); Parental
significant
education: Low
difference between (<10 years): 366
groups for gender;
(13%); Middle
Parental education: (10-12 years): 893
Low (<10 years):
(31.7%); High
140 (7.2%); Middle (>12 years): 1555
(10-12 years): 534
(30.7%)
(27.5%); High (>12
years): 1265 (65.2);
p<0.001 for
difference between
groups for
education
Control group had more infants with
"anamnestic risk" (p>0.05); intervention
group had more infants with high cordblood IgE (p<0.001)
Inclusion: children included if they had double
heredity (both parents, one parent and one sibling,
or two siblings) or if they had single heredity and
cord blood IgE level >= 0.9 kU/L; nonsmoking
families with no indoor pets.
Breastfeeding (with other interventions)
Filipiak, 2007260
Inclusion: Infants with family history of allergy
Bardare, 1993261
Inclusion: newborns with family risk of atopy;
family risk defined as history of atopy in either
parent or siblings who had been clinically
diagnosed with allergy (respiratory, atopic
eczema, urticaria, GI complaints qualified as
allergies); cord blood IgE levels >= 1 IU/mL
Skin
Test
176
Clinical
reaction
Control
Selection
Criteria
Subject Demographics
Intervention
Control
Table 41: Food allergy prevention controlled trials: patient characteristics (Continued)
Study
Intervention Group Selection Criteria
Inclusion/
IgE
Skin
Clinical
exclusion criteria
Test
reaction
Arshad, 2007262
Inclusion: infants at high risk for atopic disease
No
No
No
plus cord blood serum IgE > 0.5 kilo units/L;
high risk defined as two or more members of
immediate family with allergic disease (asthma,
AD or allergic rhinitis) or either parent or sibling
with allergic disease;
Control
Selection
Criteria
Same as
intervention
group
Schoetzau,
2002265
Inclusion: infants with family history of atopy
No
No
No
Same as
intervention
group
Laubereau, 2004
Inclusion: infants with family history of atopy
No
No
No
Infants
without
family
history of
allergy or
those whose
parents did
not
participate
in the
intervention
group
266
177
Subject Demographics
Intervention
Control
Mean age, y (SD):
Mean age, y (SD):
8.5 (0.2); Males: 28
8.5 (0.3); Males:
(48%); Sibling
33 (53%);
allergy and maternal
asthma more
prevalent in
intervention group
Similar distribution of gender, number of
family members with AD, cord blood IgE
levels, number of siblings. Intervention
group had higher atopic risk level, higher
level of parent school education, less
maternal smoking after pregnancy; lower
prevalence of pets at home.
Intervention
Intervention nonexclusive
exclusive
breastfeeding
breastfeeding
males=441 (49%);
males=376 (55%);
Non-intervention
Non-intervention
exlcusive
non-exclusive
breastfeeding
breastfeeding
males=557 (49.%)
males=609 (51%)
Table 41: Food allergy prevention controlled trials: patient characteristics (Continued)
Special diets for infants and young children
Inclusion: infants with at least 1 parent or sibling
Von Berg,
No
No
No
with a history of allergic disease, less than 2
2008271
weeks old, and without any history of formula
supplementation
Odelram, 1996272 Inclusion: at least 2 atopic family members or
Yes
No
No
one atopic parent, total cord blood IgE was >0.5
kU/I.
Exclusion: gestational age below 37 weeks,
complicated delivery, neonatal illness, severe
birth defects, documented or expected
noncompliance with diet prescriptions
Inclusion: birth weight < 2500 grams but
Szajewska,
No
No
No
appropriate for gestational age, had not received a
2004274
non-study formula before randomization and had
at least one first degree relative with allergic
disease
Same as
intervention
group
NR
NR
Same as
intervention
group but
breastfed >
9 months
Group 1 (EHF): 19
males; 13 females.
Group 2 (CMF): 23
males; 16 females
Exclusively fed
breast milk for > 9
months: 6 males;
14 females
Same as
intervention
group
EHF preterm: 14
male; 12 female,
GA: 31.2 +/-3; PHF
preterm: 14 male; 18
female; GA: 31.2 +/2.3; fortified breast
milk: 15 male; 17
female; GA: 31.1 +/1.9
Partially hydrolyzed
formula: 30% male
Standard
formula:19% male
Standard preterm
formula: 17 male;
15 female; GA:
31.2 +/- 2.9
Han, 2003 263
Infants of parents with allergy symptoms and
serum total IgE over 200 kU/L. Excluded if birth
defects, severe chronic diseases, or gestational
age less than 36 weeks.
Yes
No
No
Same as
intervention
group
Arslanoglu,
2008273
Inclusion: term infants with a parental history of
atopy; birth weight appropriate for gestational
age, and start of formula feeding within the first 2
weeks of life.
No
No
No
Same as
intervention
group
Biparental atopy:
23.5%
Biparental atopy:
25.8%
Inclusion: pregnant women from atopic families;
included breast-feeding women and the maternal
use of probiotics until age 3 months
No
No
No
Same as
intervention
group
maternal atopic
disease 60%
maternal atopic
disease 75%
Probiotics
Rautava, 2002285
178
Breastfeeding:
47% male
Table 41: Food allergy prevention controlled trials: patient characteristics (Continued)
Inclusion: enrolled in the nutrition modulation by No
Huurre, 2008284
No
No
dietary counseling for allergic families; no
chronic or metabolic disease in the mother before
or during early pregnancy, and completed followup and SPT of the infant at age 1 year.
Inclusion: pregnant mothers carrying children at
Kuitunen,
NS
NS
NS
increased risk for allergy defined as at least on
2009287
parent having physician-diagnosed allergic
disease.
Exclusion: Infants born before 37 weeks, with
major malformations, and B-twins
Families with allergic disease (1 or more family
Abrahamsson,
NS
NS
NS
members with eczema, asthma, gastrointestinal
2007288
allergy, allergic urticaria, or allergic
rhinoconjunctivitis) were recruited at antenatal
clinics; diagnosis made by family history.
Same as
intervention
Maternal atopic
disease 81%
Maternal atopic
disease 78%
Same as
intervention
males 50%; maternal
allergy: 80%
males 45%;
maternal allergy:
81%
Same as
intervention
100% infants; 56%
boys; Family history
of 54% eczema; 47%
asthma; 91% food
allergy
100% infants;48%
boys; Family
history of 58%
eczema; 47%
asthma; 90% food
allergy
Same as
intervention
48% premature; 52%
full-term
25% premature;
75% full-term
Cesarean section delivery
Kvenshagen,
2009277
One hundred and ninety-three premature infants
born consecutively at the maternity clinic of
Ostfold Hospital Trust and the two following
children born at term
No
No
No
Table Notes: AD atopic dermatitis; CMF cow milk formula; EHF=extensively hydrolysed formula; GA gestational age; GI gastrointestinal; NICU neonatal intensive care unit;
PHF=partially hydrolysed formula; SD standard deviation; sIgE antigen-specific immunoglobulin; SPT skin prick test
179
Table 42: Food allergy prevention controlled trials: intervention characteristics and outcomes reported
Author
Timing
Intervention Description
Sample Size
Info
Experimental
Control
Experimental Control
Breastfeeding and delayed introduction of solid foods
Exclusive breastfeeding for as long as
Halmerbauer,
Same
12 months
349
347
possible and at least until 3 months of
2002251
recommendations
age; Introduction of solids and soy milk
made as those to
delayed until 6 months; hypoallergenic
intervention group; no
formula used if supplementation
protective mattress
required prior to 6 months (except for
cover provided
UK infants); Cow milk, egg and fish
after 12 months; peanut or tree nuts
after 3 years; Environmental measures
for anti-dust-mite procedures; all beds
in child's room had special dust-mite
protection covers
Exclusive breastfeeding until 6 months
Kajosaari,
Exclusive
5 years
51
62
of age; no introduction of solid foods
1994252
breastfeeding until 3
until 6 months of age
months of age at
which time solid
feeding was started
Maternal diets
Hattevig,
Lactating mothers diet up to 3 months
Mothers: no restriction Infant
65
50
1989254 and
post-partum to be free from eggs, cow
on diet. Infants: same
seen at
Sigurs, 1992255
milk and fish product. After 3 months
as intervention group
neonatolo
all returned to normal diet. Infants: cow
gy and at
milk after 6 months and fish after 9
3, 6, 9, 12,
months; during first 6 months
18
breastfeeding or hydrolyzed casein
months;
formula
again at 4
years
Breastfeeding (with other interventions)
Filipiak, 2007260 Mothers encouraged to breastfeed for at Did not receive any
4 years
1939
2814
least 4 months; if this was not possible
dietary
then they were to use one of four
recommendations
hydrolyzed formulas; delayed
introduction of solids until 4 months and
potentially allergenic food to be delayed
until 1st year
180
Outcomes reported
Food allergy; parent report of
food intolerance; positive SPT or
IgE for egg and milk
Atopy; atopic eczema; asthma;
fresh fruit allergy
Cumulative incidence and
cumulative prevalence at age 4 of
eczema, asthma, bronchial
obstruction, rhinoconjunctivitis
Doctor-diagnosed eczema;
symptomatic eczema
Table 42: Food allergy prevention controlled trials: intervention characteristics and outcomes reported (Continued)
Author
Timing Info
Intervention Description
Sample Size
Experimental
Control
Experimental Control
Infants: soy formula supplementation if
Bardare,
No diet prescribed;
Examined at
158
218
required; gluten after 8th month; cow
1993261
parents informed of
3, 6, 9, 12,
milk and dairy products after 10th
infant's atopy risk
18 and 24
month; lamb, turkey rabbit, pear,
months; data
pineapple allowed before 1 year;
reported at
avoidance of tobacco smoke and animal
12 months
dander recommended; Mother during
breastfeeding: no more than 200 dL of
milk and only one egg per week;
completely avoid tomato, fish, shellfish,
nuts and foods mother was allergic to;
Arshad, 2007262 Infants: Elimination of dairy products,
Infants followed
Assessments
58
62
eggs, wheat, nuts, fish and soy until 12
standard
made at 1, 2,
months of age. Extensively hydrolyzed
recommendations at that 4 and 8
formula supplementation if breasttime
years of age;
feeding discontinued before 9 months;
data
reduction in exposure to house dust mite
reported at 8
allergens. Mothers: elimination of same
years
foods as infants except wheat, during
lactation
Infants were exclusively breastfed for at Partially or exclusively
Schoetzau,
1 year of
865
256
least 4 months
received cow milk
2002265
age
formula
181
Outcomes reported
Atopic symptoms; IgE levels
based on symptoms; atopic
eczema
Clinical asthma diagnosed at
least once during the first 8
years
AD incidence; sensitization to
egg and milk
Table 42: Food allergy prevention controlled trials: intervention characteristics and outcomes reported (Continued)
Mothers encouraged to breastfeed for at Did not receive any
Laubereau,
3 years
I--900
I—684
least 4 months; if this was not possible
2004 266
dietary
NI--1131
NI-then they were to use one of four
recommendations
1188
hydrolyzed formulas; delayed
introduction of solids until 4 months and
potentially allergenic food to be delayed
until 1st year
Special diets for infants and young children
Received one of three hydrolyzed
Von Berg,
Cow milk formula
6 years
pHFW--557;
556
formulas: partially hydrolyzed whey
20082702007271
eHFW--559;
formula (pHF-W); extensively
eHFC--580
hydrolyzed casein formula eHF-W;
extensively hydrolyzed casein formula
(eHF-C)
EHF was a whey hydrosylate. Lactating Continued breast milk
Odelram,
18 months
Group 1
20
mothers and infants were on elimination for >9 months.
1996272
(EHF): 32.
diets for cow milk, egg, and fish
Lactating mothers and
Group 2
infants were on
(CMF): 39
elimination diets for
cow milk, egg, and fish
Preterm infants were assigned an
Szajewska,
Infants received a
Evaluated
EHF--20,
26
extensively hydrolyzed formula or a
2004274
standard formula for 4-5 4-5 months
PHF--22,
partially hydrolyzed formula or fortified months
after
fortified
breast milk (with extensively
intervention breast milk
hydrolyzed mixture) for 4-5 months
and then
(BMF)
again at 12
months
182
Atopic dermatitis
Physician's diagnosis of: any
allergy; atopic eczema; food
intolerance; urticaria; hay
fever; asthma
Presence of atopic disease;
positive skin prick test; serum
IgE at 18 months > or = to the
median
Any allergic disease; atopic
dermatitis; gastrointestinal
symptoms; wheezing; elevated
total IgE; elevated IgE specific
to cow milk
Table 42: Food allergy prevention controlled trials: intervention characteristics and outcomes reported (Continued)
All encouraged to be fed with breast
Han, 2003 263
When the parents did
Evaluated
PHF—15
22
milk. During the nursing period,
not want to feed their
every 2
SF—32
lactating mothers eliminated all sources
babies with breast milk
months for 6
of egg from their diet.
or breast milk was not
months
available, partially
hydrolyzed formula was
recommended as
substitution. Standard
formula was given in
cases when the parents
did not want partially
hydrolyzed formula.
Formula supplemented with a mixture
Arslanoglu,
Same hypoallergenic
2 years
66
68
of 90% short-chain
2008273
formula as experimental
galactooligosaccharies and 10% longgroup without the
chain fructooligosaccharies
oligosaccharide
(IMMUNOFORTIS) intended to mimic
supplementation
human milk oligosaccharides
Probiotics
Rautava,
2002285
Starting 4 weeks before term and
continuing for 3 months post partum
(with breastfeeding), L rhamnosus
probiotics given to mother and then to
neonate
Placebo
2 years
183
30
32
Incidence, prevalence, and
severity of atopic dermatitis
Growth (height/wt);
cumulative incidences of
atopic dermatitis, recurrent
wheezing, and allergic
urticaria; physician diagnosed
infections, fever episodes
witnessed by the parent.
Chronic relapsing atopic
eczema;, GI symptoms; cow’s
milk allergy; SPT; serum IgE;
specific IgE
Table 42: Food allergy prevention controlled trials: intervention characteristics and outcomes reported (Continued)
Huurre, 2008284 Dietary counseling, breastfeeding, L
Placebo
1 year
72
68
rhamnosus and B lactis from first
trimester of pregnancy to the end of
exclusive breastfeeding.
Kuitunen,
2009286 and
Kukkonen,
2007287
Abrahamsson,
2007288
Starting at week 35 gestation, mothers
took 1 capsule of Lactobacillus,
Bifidobacterium and propionibacterium
species bid. The newborn infants
received 1 opened capsule of the same
mixed with 20 drops of sugar containing
galacto-oligosaccharides once daily for
the first 6months of life.
Mothers started taking L reuteri4 weeks
before term and continued daily after
delivery. After birth, baby continued
same preparation for 12 months.
Cesarean section Delivery
Cesarean section delivery
Kvenshagen,
2008290
Atopic sensitization of
children measured by SPT to
numerous allergens; atopic
eczema; cytokine
concentrations in breast milk.
Cumulative incidence of any
allergic disease (food allergy,
eczema, asthma, allergic
rhinitis) and IgE associated
atopic disease. Secondary
outcome measure: eczema and
IgE sensitization.
Identical appearing
capsules of cellulose
2 years and
5 years
506
512
Mothers started taking
placebo 4 weeks before
term and continued
daily after delivery.
After birth, baby
continued same
preparation for 12
months.
2 years
95
93
Cumulative incidence of
eczema; IgE mediated eczema;
SORAD scores among those
with eczema; incidence of
wheezing; cumulative
incidence of SPT; circulating
IgE to egg white; infections
(otitis media); use of
antibiotics; gastrointestinal
symptoms; body weight
Vaginal delivery
2 years
195
414
Food allergy diagnosed by
clinical history, SPT, or
elevated IgE and open
elimination diet for children
<12 months and DBPCFC test
for children >12 months
Table Notes: AD atopic dermatitis; CMF=cow milk formula; DBPCFC double blind placebo-controlled food challenge; eHF-W: eHF–C Extensively hydrolyzed casein formula;
Extensively hydrolyzed whey formula; sIgE antigen-specific immunoglobulin; HF Hydrolysed formula; PHF=partially hydrolysed formula;; SCORAD scoring atopic dermatitis;
SPT skin prick test
184
ii. What methods are currently used in the management of existing
food allergy?
ii. a. What are the data on the effects of allergen avoidance based on both the
primary literature and the recommendations of key organizations? This
question should include the effect on nutritional status.
Background
The first therapeutic approach to food allergy is often to eliminate the allergenic food from the
diet. However, it may be very difficult to avoid some foods completely, and the avoidance of
foods such as milk and eggs may cause nutritional problems in children.
Results
One non-randomized comparative study291 examined the effect of allergen avoidance through
elimination diets on patients with food allergies (Table 44-Table 46). Agata et al291 studied the
effect of an elimination diet for milk or egg allergies on atopic dermatitis. Twenty-seven patients
sensitive to egg and 16 patients sensitive to milk who underwent an elimination diet for at least
three months were compared with six patients sensitive to egg and five patients sensitive to milk
who did not eliminate the allergic food from their diet. The results showed that in those with egg
allergy, 100 percent showed improvement in their atopic dermatitis with an elimination diet
(compared with 0/6 not on an elimination diet). In those with a milk allergy, 15/16 showed
improvement in their atopic dermatitis with elimination diet (compared with 0/5 not on an
elimination diet). They concluded that an elimination diet is a good treatment for food allergy
and that specific IgE antibodies to food antigens were useful as indexes of the effect of
elimination diets in patients with positive RAST.
One population-based cohort of children with cow’s milk allergy reported on the nutrient intake
of cows’ milk-restricted diets213 (Table 51). The Oslo Birth cohort followed children born in
Olso until age 2. Children with diagnosed egg and milk allergy were divided into four groups:
milk-free diet (totally free of any cow milk protein n=10), hypoallergenic formula diet (formula
used in varying amounts n=6), milk-reduced diet that included some dairy but no cow milk
(n=8), and milk diet (children allergic to egg but not to milk n=10). Parents recorded dietary
intake for 4 days. Compared to the children on the milk diet, children on the milk-free diet had
significantly decreased intake of energy (p<0.001), protein (p<0.001), fat (p<0.001), riboflavin
(p<0.001), niacin (p<0.01), calcium (p<0.001), and potassium (p<0.01). There were no
statistically significant differences between the children on the hypoallergenic formula diet
compared to those on the milk diet for energy, protein, or fat but there were statistically
significant decreases in riboflavin (p<0.01), calcium (p<0.001), and potassium (p<0.05). The
formula-fed group had increased intake of Vitamin E (p<0.05) and iron (p<0.05). Children on
the milk-reduced diet had decreased consumption only of riboflavin (p<0.001) and calcium
(p<0.001) compared with children on the milk diet.
185
Summary
Allergen avoidance is a common treatment strategy for food allergy and may work. However,
this intervention has not been adequately studied, and the quality of evidence for this key
question is low, given that only one non-randomized comparative study of poor quality addresses
this question. Confounding this key question is that allergen avoidance diets are commonly used
as a diagnostic test in addition to a treatment strategy. If a patient is placed on an allergen
avoidance diet and continues to have symptoms, it is not clear if the allergen avoidance diet is
ineffective or if the patient did not in fact, have an allergy to that particular food. Complete
absence of cow milk protein may result in decreased energy, protein, and fat consumption while
formula and milk-restricted diets may lead to micronutrient deficiencies. The quality of evidence
for this key question is low, given that only one small observational study addressed this topic
ii. b. What are the data on the benefits and adverse effects of immunotherapy
with foods (e.g., parenteral, oral, sublingual) to treat food allergy?
Background
Immunotherapy broadly encompasses those interventions that alter the immune system to treat
food allergy. To clarify terminology, the term “immunotherapy” in the context of allergic
conditions traditionally refers to an allergen-specific therapeutic approach by which the immune
response to allergen exposure is altered using protocols designed to gradually administer over
time increasing doses of native or modified forms of the causative allergen. More recently, the
term “immunotherapy” has been used to describe a number of biologic agents that alter the
immune response in an allergen nonspecific manner (i.e. omalizumab). The discussion below
focuses on allergen-specific immunotherapy for the treatment of food allergy.
Allergen-specific immunotherapy protocols vary with regard to dosing, schedule, and route of
administration. Historically, oral, sublingual, and subcutaneous routes of allergen administration
have most frequently been investigated. To further distinguish terminology, allergen-specific
immunotherapy protocols may potentially result in “desensitization” or “tolerance” to the
specific allergen. Desensitization refers to a temporary clinical state in which allergen exposure
fails to cause allergic symptomatology in the allergic individual. However, this state of clinical
non-reactivity must be maintained by continuous recurrent administration of the allergen. In the
absence of repeat allergen dosing, the state of clinical reactivity with allergen exposure returns
and the individual is at risk for recurrent allergic reactions. In contrast, immunotherapy
protocols inducing specific allergen tolerance result in long-term or permanent immunological
changes with the outcome of clinical nonreactivity to allergen exposure even after long periods
of abstinence. Immune tolerance putatively results in measurable changes in the immunological
response to allergen including decreased allergen-specific IgE and IL-4 production, and
increased allergen-specific IgG and IL-10 production. Additionally, we identify studies below
which distinguish between use of the native food allergen for immunotherapy (allergen-specific
immunotherapy) and use of allergens that cross react with food allergens (specificimmunotherapy with cross-reactive allergens).
186
Allergen-specific immunotherapy
Six RCT studies used desensitization protocols with the allergic food to induce tolerance292 293297
(Table 44-Table 46). Three observational studies with fewer than 100 patients were also
included, given the paucity of data on harms for this treatment. Hoffman et al211 specifically
reported on the safety of oral immunotherapy in 28 patients. Narisety et al212 reported safety
results for 12 participants in the original Skripak RCT that were subsequently continued on openlabel maintenance for three months after completion of the trial292 (Table 51). Zapatero et al
reported on 18 patients undergoing oral desensitization for cow’s milk allergy. 298
Staden et al. assigned children with a food allergy to either milk or hen’s egg confirmed by a
DBPCFC to oral immunotherapy or an elimination diet. They found that desensitization at a
median of 21 months was achieved more often in the group that received oral immunotherapy
(16/25) than in the group that adhered to an elimination diet (7/20) p=0.05. Only 9/25 children
that were tested after two months of an elimination diet demonstrated tolerance.293 Morisset et
al.294 performed a randomized study to examine an oral desensitization protocol in children with
IgE-mediated milk or egg allergies. Diagnosis of food allergy was established by SPT and/or
specific IgE, and allergy confirmed by positive oral food challenge or complete recovery from
symptoms after 3 weeks of avoiding the suspected food allergen. When the oral desensitized
group was compared to the continued avoidance group for milk allergy, a significant
improvement in single (S)BPCFC was found (3/27 versus 12/30; p<0.025) as well as a decrease
in the size of the prick test wheal (p<0.002). Comparing the oral desensitized group to the
continued avoidance group for egg allergy, a significant improvement in SBPCFC was again
found (15/49 vs 17/35; p<0.10) as well as a decrease in the size of the prick test wheal (p<0.05).
In addition, there was a statistically significant decrease in egg-specific IgE (p<0.01). Skripak et
al292 studied milk oral immunotherapy in treating cow’s milk allergy in patients aged 6-21
diagnosed with SPT or specific IgE and a food challenge. Once the immunotherapy dose of
15mL of milk was reached, patients were then treated for 13 weeks. They found that the milk
dose threshold was higher in the group receiving oral immunotherapy (p=0.002) and that the cow
milk-specific IgG levels were reportedly higher (p=0.002) (data not shown). There was no
statistically significant change in cow-milk-specific IgE. Long-term tolerance was not assessed.
Nelson et al.295 studied the effect of injections of subcutaneous peanut extract on patients with
anaphylaxis to peanuts treated with weekly injections of peanut extract for one year. They
reported a decreased peanut sensitivity at one month (p=0.0002) but no effect on SPT or peanutspecific IgE as compared to patients with peanut allergy who did not receive subcutaneous
injections. Enrique et al.299 studied the effect of sublingual hazelnut extract on patients with a
hazelnut food allergy diagnosed by positive DBPCFC. They observed that the mean hazelnut
quantity that provoked symptoms increased in the group receiving hazelnut extract but not in the
placebo group (p=0.02). Furthermore, there was an increase in hazelnut-specific IgG4 (p<0.05)
but no difference in the hazelnut-specific IgE between the groups. Patriarca et al.296 evaluated
oral desensitization protocols in patients with a wide variety of allergies, including milk, hen’s
egg, wheat, bean, and cod diagnosed by a clinical history and allergenic workup. They found that
36/48 people assigned to the desensitization arm had a negative DBPCFC, compared with none
of the control patients. Long-term tolerance was not addressed in any of these studies.
187
Safety data for allergen-specific immunotherapy was reported in only four of the six studies
(Table 47). The observational study by Hofmann et al211 specifically reported on the safety of
peanut oral immunotherapy in 28 children with peanut allergy (Table 51). They divided the
study into three separate phases (initial escalation day, buildup phase, and home dosing phase)
(Table 47). They concluded that subjects were more likely to have significant allergic symptoms
during the initial escalation day when they were in a closely monitored setting than during other
phases of the study. Narisety et al212 reported safety data on 12 children that had completed the
Skripak trial for milk oral immunotherapy and were able to tolerate >2540 mg (about 2.5 ounces)
of milk. These patients were followed for an additional 3 months (Skripak trial followed for 3
months) (Table 47). Zapatero reported some safety information for 18 patients undergoing oral
desensitization with cow’s milk allergy; 2/18 required epinephrine during the desensitization
protocol.298
Specific immunotherapy with cross-reactive allergens
We found four RCTs that used immunotherapy with cross-reactive allergens to treat food
allergies (Table 44-Table 46).300-303 Apple allergy was examined in three studies300-302 and
hazelnut allergy in one.301 One study was not directed at specific food allergies but evaluated the
oral allergy syndrome in the setting of natural rubber latex allergy.303 Three studies examined the
effect of tree pollen extract immunotherapy on the oral allergy syndrome.
Hansen et al. noted that clinical manifestations of allergenic cross-reactions between pollen and
plant foods are frequent in birch pollen allergic patients and evaluated the effect of birch pollen
extract immunotherapy in patients with apple allergy diagnosed by clinical history, SPT<
specific IgE, and positive conjunctival provocation test.300 There was no statistically significant
change in oral allergy syndrome response to an open apple food challenge after treatment with
placebo, sublingual, or subcutaneous birch pollen extracts. There was a statistically significant
decrease in apple-specific IgE in patients treated with subcutaneous birch pollen extract (from
5.9 kU/L to 1.8 kU/L, p=0.009). No statistically significant change was reported in those patients
receiving sublingual birch pollen extract (pre=0.8 kU/L; post=1.4 kU/L) or placebo (pre=2.6
kU/L; post=2.1 kU/L).
Bucher et al. also examined the effect of subcutaneous immunotherapy with tree pollen extract
on patients’ oral allergy syndrome to apple and hazelnuts.301 Patients with birch-pollen allergy,
oral allergy syndrome, and positive SPT to apple or hazelnut were selected for study.
Improvement of oral allergy syndrome was statistically significant (p<0.05) with 10/15 patients
receiving subcutaneous immunotherapy showing improvement and only 2/12 control patients
showing improvement. Serum-specific IgE to apple was also measured. In the immunotherapy
group, the baseline value was 39.1 kU/L, which rose after a year of treatment to 42.8 kU/L. In
the control group, the baseline value was 29.2, rising to 36.2 after a year of placebo. This
difference was not statistically significant. This group also reported that IgG4 r Bet v1 (human
IgG4 antibody that is specific for the major birch pollen antigen) was statistically significant
(p<0.001) in the group treated with immunotherapy, but no values were given.
Asero at el. evaluated birch pollen-allergic patients with a clear history of apple-induced oral
allergy syndrome who received injection immunotherapy with birch pollen extract.302 This
188
treatment was found to reduce clinical apple sensitivity (p<0.001) but not apple-specific IgE.
Bernardini et al. explored the safety and efficacy of sublingual immunotherapy with a latex
extract in patients with clinical history of latex food allergies.303 They found no significant
difference in SPT for food allergies after treatment.
Safety was reported for only one of four studies that examined specific immunotherapy with
cross-reactive allergens (Table 47). In this study, no signs of local or gastrointestinal symptoms
were reported.
Summary
The quality of evidence for this key question—does immunotherapy improve clinical
symptoms—is high, given six RCTs regarding allergen-specific immunotherapy and four RCTs
regarding specific-immunotherapy with cross reactive allergens. Allergen-specific
immunotherapy and specific-immunotherapy with cross-reactive allergens are effective in
desensitization and improve clinical symptoms of food allergy. Long-term tolerance has been
inadequately studied. The safety of such treatment was reported in only four of six studies on
allergen-specific immunotherapy and without doing a search specific for harms, it is difficult to
draw conclusions on the safety of such an approach.
ii. c. How effective are current standards for food labeling for prevention of
food allergic reactions?
In 2004, the federal government passed the Food Allergen Labeling and Consumer Protection
Act, which mandated that processed foods that might contain any one of a number of common
food allergens (e.g., milk, eggs, wheat, peanuts, tree nuts) were required to carry information on
their labels identifying these foods. Although we identified 8 studies related to this question, no
study explicitly assessed the effectiveness of food labeling, that is attempted to infer a cause-andeffect relationship between a change in frequency of severe symptoms from accidental exposure
(e.g., peanut) as a consequence of implementation of food labeling. The identified studies
mostly assessed knowledge and preferences for food labeling. Three studies were from the
US,304-306 two studies from the United Kingdom,307, 308 one study (in abstract form only) from
Australia,309 one from Brazil and Spain,310 and one study compared consumer preferences across
cultures.311 Unfortunately, even the US studies did not collect data after the most recent change
in US labeling laws, so even the US studies are of limited relevance. The two most relevant
studies are now described.
The first study asked 91 parents of children attending the pediatric allergy clinic at Mt. Sinai
Medical Center in New York to review 23 food labels and to name the food allergens to which
their child was allergic that were presented in the particular product.312 Forty-two percent of
parents indicated their child had experienced anaphylaxis. Of 60 parents of milk allergic
patients, four (seven percent) were able to correctly identify all 14 labels that indicated some
form of milk was contained in the product. Six of 27 parents of soy-allergic children (22
percent) correctly identified soy protein in all seven products that contained soy, and peanut was
189
correctly identified by 44 of 82 (54 percent) parents in all five products containing peanut.
Identification was much better for products containing wheat and egg.
The second relevant study assessed 489 respondents (84 percent response rate) from attendees at
the Food Allergy and Anaphylaxis Network (FAAN) Conference, of whom 96 percent were
white.305 The self-identified allergic foods were peanut (81 percent), tree nut (53 percent), milk
(51 percent), egg (51 percent), soy (17 percent0, wheat (16 percent), shellfish (17 percent), and
fin fish (12 percent). Ingredient labels were “always” or “frequently” read before purchasing a
product by 99 percent of consumers doing the shopping and by 94 percent of people doing the
cooking for food allergic patients. Adverse reactions were attributed to misunderstanding of the
food label in 16 percent of cases and to ingredients not declared on the label in 22 percent of
cases.
Similar problems in identification were reported in a study of parents of children with cow milk
allergy in Brazil and Spain,310 and difficulties interpreting labels and general dissatisfaction with
current labels were noted in studies from the US,306 the United Kingdom,307 and the Netherlands
and Greece.311 One Australian study, available only as an abstract, reported that new standards
had led to food labels that were an improvement over old food labels, but that a lack of
understanding still persisted.309 In a UK study of government advice on avoidance of peanut
consumption during pregnancy and breastfeeding in women with a family history of atopy, only
65 percent of mothers successfully complied.308
ii. d. What are the allergenic cross-reactivities (with other foods or non-food
allergens) of foods (i.e., other legumes in peanut allergic patients, tree nuts in
peanut allergic patients, etc)? What are the clinical consequences?
Only one included RCT addressed this type of cross reactivity. As described in the answer to the
key question regarding the use of special diets in infants for the prevention of food allergy, the
RCT by Klemola et al.313 evaluated the incidence of adverse reactions or allergies to soy
formulas in infants with cow’s milk allergy syndrome during the first two years of life. Parents’
suspicions of adverse reactions to formula was significantly higher among children who had
received soy formula but still statistically significantly greater in the soy formula group (28%,
95% CI 18-39 percent) than children who had received extensively hydrolyzed formula (11
percent, 95% CI 5-19 percent). However, the cumulative incidence of adverse reactions
confirmed by DBPCFC was low for both the soy formula (8 infants, 10 percent, 95% CI 4.4-18.8
percent) and for the extensively hydrolyzed formula (two infants, 2.2 percent; 95% CI 0.3-7.8
percent; RR=4.50, p=0.03). Adverse reactions to soy were suspected in 12 of 46 infants with
IgE-associated cow’s milk allergy and in 13 of 34 infants with non-IgE associated cow’s milk
allergy (p=0.25). Adverse reactions to soy were confirmed by DBPCFC in five of 46 (11
percent) infants with IgE associated cow’s milk allergy and in three of 34 (9 percent) infants with
non-IgE associated cow’s milk allergy (p=0.76). We conclude that there is insufficient evidence
to evaluate the allergenic cross-reactivities of foods.
190
ii. e. What are the effects of food allergen avoidance, and other food allergy
management strategies, on co-morbid conditions such as, but not limited to,
atopic dermatitis, asthma, and eosinophilic gastrointestinal disorders?
Background
It is unclear which specific strategies (e.g. allergen avoidance, elimination diet, pharmacological
management) are effective in the treatment and management of specific clinical conditions
associated with food allergies.
Results
We identified two systematic reviews that evaluated the effect of dietary exclusion for treating
atopic eczema. Two publications were on the same systematic review56, 314 (Table 43). All
reviews had a comprehensive literature search and screening process and followed the methods
used by the Cochrane Collaboration. They all scored highly on the AMSTAR criteria. Kramer et
al. assessed as part of their review on allergy prevention, whether maternal dietary antigen
avoidance during lactation by mothers of infants with eczema could reduce eczema severity. The
review found one small trial (n=17) that met inclusion criteria for this part of the review, which
found no significant reduction in eczema area score (mean difference -0.8; 95% CI -4.43 - 2.83)
or eczema activity score (mean difference -1.4; 95% CI -7.18 to 4.38) between infants whose
mothers avoided dietary antigens and those whose mothers followed a usual diet.253
Bath-Hextall et al. evaluated the effect of dietary exclusion by patients for treating established
atopic eczema and reported these findings in two pulications.56, 314 Their search of the published
literature (conducted as of March 2006) resulted in the inclusion of nine low-quality RCTs, of
which they considered only two sufficiently similar to combine. Six of the RCTs examined milk
and egg exclusion, one was a study of a diet including only a few foods, and two evaluated
elemental diets. The authors found no evidence to support the use of these dietary exclusion
strategies for treating atopic eczema in an unselected population; this finding was possibly due to
patients not being allergic to the substances being eliminated or to the small study sizes and poor
reporting. However, they suggested that there might be some benefit of an egg-free diet in
infants with positive egg sIgE results (results from one study).
Summary
The quality of evidence for the effect of food allergen avoidance in treating atopic dermatitis is
high given that we found two high-quality systematic reviews addressing this topic. Both
reported no evidence supporting the use of allergen avoidance in treating atopic dermatitis. We
did not find any studies specifically addressing food allergen avoidance in other co-morbid
conditions.
191
Additional Information Relevant to Key Question H ii. Pharmacological
management of food allergies
Background
Often, the first therapeutic approach to food allergy is to eliminate the food from the diet, but
avoidance of foods such as milk and eggs can cause nutritional problems in children. Drug
therapy is often employed as an alternate mechanism to manage food allergies, especially when
diet compliance is extremely difficult. Commonly, drugs that alter the immune response to these
allergens are utilized.
Results
We identified six RCTs that evaluated drugs to treat food allergy315-320 and one study that used
probiotics to treat rectal bleeding caused by food allergy (Table 44-Table 47).321
Bindslev-Jensen et al.315 examined the effect of astemizole on oral allergy syndrome induced by
consumption of hazelnuts in patients with positive SPT to birch pollen. They included patients
with a case history of immediate local symptoms (itching and swelling of mouth/throat) and
excluded any patients with a severe reaction after intake of hazelnuts. All patients were given
two open oral provocations of five hazelnuts (at least two days apart) to obtain a baseline value.
Then the treatment group ingested aztemizole (10 mg each morning for 14 days) and the control
group ingested placebo for 14 days, both followed by two open oral provocations for final
values. Symptom severity to the oral provocation test was graded on a scale where 0=no
reaction and 5= severe itching and swelling of mouth and throat. The baseline values
were obtained from combining the two initial oral provocation tests and the final values were
obtained from combining the two final oral provocation tests. For the treatment group, the
baseline assessment was 6.33 and the final assessment was 3.67; for the placebo group, the
baseline was 5.89 and the final was 5.47. Symptom severity to the oral provocation test was
statistically significantly lower in the group that got aztemizole than in the placebo group
(p=0.004).
Burks and Sampson318 studied cromolyn in children with atopic dermatitis and documented food
hypersensitivity to egg. All included patients had atopic dermatitis as defined by Hanifin and
Rajka, all had positive SPT, all were on a strict egg-avoidance diet for one year, antihistamines
were stopped one week before trial, and beta-agonists were stopped 12 hours before trial.
Patients were treated for a week with either cromolyn or placebo and then were
evaluated. Patients then had a washout period of three to five weeks and were crossed over to
the other arm (cromolyn or placebo) for a week and again evaluated. Evaluations included
symptoms and responses to DBPCFC. Symptom cards were assessed on a scale of 0-3 for rash
distribution, pruritis, uticaria, sneezing/itching, congestion, rhinorrhea, wheezing, nausea/pain,
and vomiting/diarrhea. This crossover study showed that after one week of treatment with either
cromolyn or placebo, there was no statistically significant difference in the symptom score for
atopic dermatitis or in the response to a DBPCFC.
192
Schaefer et al.319 compared oral prednisone to topical fluticasone in the treatment of eosinophilic
esophagitis. Food allergy was found in only 63 percent of the patients treated with prednisone
and 52.5 percent of the patients treated with fluticasone. One group received 1 mg/kg of
prednisone twice daily for 12 weeks and the other group received fluticasone by MDI two puffs
four times daily for 12 weeks. They found a statistically significant difference in histological
response favoring the prednisone over the fluticasone group between weeks 0 and 4 (p=0.0440)
and a histological improvement of distal esophageal biopsies in both groups compared to
baseline (p<0.0001).
Szajewska et al.321 determined that using probiotics to treat breast-fed infants with rectal
bleeding did not show a statistically significant effect on reducing the number of days of rectal
bleeding.
Leung et al.316 evaluated the effect of anti-IgE therapy in patients with peanut allergy. They
determined that a 450-mg dose of TNX-901, a humanized IgG1 monoclonal antibody, increased
the threshold of sensitivity to peanut on oral food challenge from a level equal to one peanut to
almost nine peanuts. Cavagni et al.317 evaluated the effects of adding thymomodulin to
elimination diets in treating atopic dermatitis induced by food allergy. They noted a more
favorable course of the skin lesions in the patients treated with thymomodulin after two weeks of
food challenge. They also noted a statistically significant decrease in total and sIgE serum levels
in the group receiving thymomodulin.
Businco et al.320 evaluated 31 children aged 6 months-10 years old with atopic dermatitis
exacerbated by foods in a crossover study to evaluate the effects of sodium cromoglycate and an
elimination diet on the severity of eczema. They concluded that eczema (measured both by the
clinician and the parents) was statistically improved when the patients were receiving sodium
cromoglycate.
Summary
Given the heterogeneity of the pharmacologic interventions and allergic conditions evaluated, we
conclude that there is insufficient evidence to evaluate the extent to which pharmacologic
therapy is useful in treating food allergies.
Additional Information Relevant to Key Question H ii. Other strategies
for the management of food allergies
Results
We found five RCTs that evaluated other types of management strategies for food allergies not
addressed in the other key questions (Table 44-Table 46).322-326
Hill et al.322 evaluated the effect of a low-allergen maternal diet on colic among breastfed infants.
They found a statistically significant improvement of colic in the low allergen group with
adjusted RR of 37 percent (CI 18-56 percent).
193
Amadi et al.323 examined the role of an amino acid-based elemental feeding regimen in treating
children with persistent diarrhea and malnutrition and found that the median gain in weight-forage z score favored the amino acid-based elemental feed (p=0.002).
Cantani et al.324 studied a home-made meat-based formula for feeding atopic babies. They
reported significant improvement in SCORAD scores in the group treated with the meat-based
formula.
Salpietro et al.325 performed a RCT to evaluate the safety and efficacy of almond milk in infants
with cow’s milk allergy. They reported reductions in a variety of symptoms (e.g., vomiting,
diarrhea, wheezing, eczema) and weight gain among all infants taken off cow’s milk but no
difference among those given almond milk compared to soy-based formula or hydrolyzed
formula.
Viljanen et al.326 studied probiotics in the treatment of infants with atopic eczema/dermatitis and
suspected of cow’s milk allergy. In addition to skin treatment and elimination of cow’s milk
from the infants’ and breast-feeding mothers’ diets, 252 infants were randomized to capsules
containing lactobacillus alone, a mixture of probiotics including lactobacillus, or placebo for four
weeks. There was no statistically significant change in the SCORAD scores.
Summary
Given the heterogeneity of these studies, there is insufficient data as to whether these strategies
for treating and managing food allergy are effective.
Additional Information: Reported Variation in Management Style
A retrospective cohort study examining the management of food related acute reactions in 21
emergency rooms in the US and Canada reported great variability in treatment across
participating sites.15 Researchers reviewed a random sample of 678 food allergy patient charts.
Regarding severity, only 18% arrived by ambulance, although 55% were considered "severe." Of
the patients with "severe" reactions, only 24% received epinephrine. Of the total patients, 72%
received antihistamines, 48% received systemic corticosteroids, 16% received epinephrine, and
33% received respiratory treatments such as inhaled albuterol. Upon discharge, 16% were
prescribed self-injectable epinephrine. The authors also note that “emergency department
discharge plans varied widely across participating sites.”
Key Question H ii. f. What are the effects of co-morbid conditions on
the clinical course of, and management of, food allergy?
We did not find studies specifically focused on the effect of co-morbid conditions on the course
or management of food allergy. Studies of the opposite question – the effect that food allergy
management has on the co-morbid condition – are reviewed in the sections appropriate to that
food or the condition.
194
Table 43: Food allergy treatment systematic reviews and meta-analyses
Author/ Study Question
Databases searched/
Intervention
Year
Years
Inclusion
Exclusion
Kramer
2009253
To evaluate the
effect of an
antigen
avoidance diet
during lactation
for treating
eczema
Cochrane Pregnancy and
Childbirth Group Trial register;
Up to March 2006
Mothers prescribed
a diet to either
exclude or reduce
potentially
allergenic foods:
cow milk, egg,
peanuts, fish,
chocolate during
lactation
RCTs or
quasi-RCTs
comparing
diets of
different levels
of antigen
avoidance
BathHextall
2009314
To evaluate the
effect of dietary
exclusion for
treating
established
atopic eczema
Cochrane Skin Group
Specialized Register (to Mar
2006); Medline; EMBASE
(2003-Mar 2006); LILACS (to
Mar 2006); PsycINFO (1806Mar 2006); AMED (1985-Mar
2006); ISI Web of Science (Mar
2006); CENTRAL (Mar 2006);
www.controlledtrials.com;
www.clinicaltrials.gov;
www.nottingham.ac.uk/ongoing
skintrials (Mar 2006)
Egg and milk
exclusion; few
foods diet;
elemental diet
RCTs of
exclusion
diets; double
blind placebo
controlled
food
challenges
conducted in
isolation
excluded
195
Total
Outcomes Reported
Publications
Included
1
Eczema severity
9
Short term: change in
parent-rated eczema
symptoms (e.g. itching);
Long term: degree of
control (e.g. reduction in
number of flares or
reduced need for other
treatment);
Global severity; QOL;
palatability of diet; adverse
events (e.g. long term
consequences on growth)
AMSTAR
Criteria
01. Can’t
Answer
02. Yes
03. Yes
04. Yes
05. Yes
06. Yes
07. Yes
08. Yes
09. Yes
10. No
11. Yes
01. Can’t
Answer
02. Yes
03. Yes
04. Yes
05. Yes
06. Yes
07. Yes
08. Yes
09. Yes
10. No
11. Yes
Table 43: Food allergy treatment systematic reviews and meta-analyses (Continued)
Author/ Study Question
Databases searched/
Intervention
Inclusion
Year
Years
Exclusion
Kukuruz
ovic
2009327
To evaluate
medical
management
strategies for
EE
Cochrane upper GI and
pancreatic diseases group
register (to 2006); CENTRAL
(to 2006); Medline (1966 to Feb
2006); EMBASE (1980 to Feb
2006).
Total
Outcomes Reported
Publications
Included
1 abstract Symptom improvement;
from an
potential benefits; potential
unfinished harms
RCT
Medical (e.g.
RCTs or
metered dose
quasi-RCTs
steroid, oral
comparing
steroids, sodium
different
chromoglycate,
interventions
leukotriene
with placebo
receptor
or each other
antagonists) or
dietary (e.g.
elemental milk
formula)
intervention
Table Notes: EE eosinophilic esophagitis; GI gastrointestinal; QOL quality of life; RCT’s randomized controlled trials
AMSTAR
Criteria
01. Can’t
Answer
02. Yes
03. Yes
04. Yes
05. Yes
06. Yes
07. Yes
08. Yes
09. NA
10. No
11. Yes
AMSTAR criteria: 01. Was an a priori study design provided? 02. Was there duplicate study selection and data extraction? 03. Was a comprehensive literature search performed?
04. Was the status of publication (gray literature) used as an inclusion criterion? 05. Was a listed of studies (included/excluded) provided? 06. Were the characteristics of the
included studies provided? 07. Was the scientific quality of the included studies assessed and documented? 08. Was the scientific quality of the included studies used
appropriately in formulating conclusions? 09. Were the methods used to combine the findings of studies appropriate? 10. Was the likelihood of publication bias assessed? 11.
Was the conflict of interest stated?
196
Table 44: Food allergy treatment/management controlled trials: study information
Author
Country
Purpose
Allergen avoidance
Agata, 1993291 Japan
To determine effect of elimination diets in patients with atopic
dermatitis and allergies to egg or milk
Allergen-specific immunotherapy
Germany
To evaluate the effect of oral tolerance induction or elimination diet
Staden,
for managing cow milk or egg allergy in children
2007293
France
To examine an oral desensitization protocol to allergenic foods in
Morisset,
IgE-dependent milk or egg allergies in children
2007294
Food
Condition of interest
Study
quality
Milk, egg
Atopic dermatitis
Poor
Milk, egg
Allergy, not specified
Good
Milk, egg
Fair
Good
Skripak,
2007292
Nelson,
1997295
Enrique,
2005299
US
To evaluate milk oral immunotherapy for cow's milk allergy
Milk
Atopic dermatitis,
uticaria, angioedema,
asthma, GI symptoms
Multiple
US
To determine the effect of immunotherapy in patients with
anaphylaxis to peanuts
To evaluate the efficacy and tolerance of sublingual immunotherapy
with a hazelnut extract in patients with a hazelnut allergy
Peanut, tree nut
Anaphylaxis
Poor
Hazelnut
Good
Patriarca,
2007296
Italy
Oral allergy syndrome,
anaphylaxis, uticariaangioedema
Multiple
Apples
Oral allergy syndrome
Good
Peanut, tree nut, apple
Oral allergy syndrome
Poor
Apples
Oral allergy syndrome
Poor
Latex, fruits
Oral allergy syndrome
Fair
Hazelnut
Oral allergy syndrome
Fair
Spain
To evaluate specific oral desensitization in children with food
allergies
Specific immunotherapy with cross-reactive allergens
Denmark
To examine the effects of sublingual and subcutaneous
Hansen,
administration of birch pollen extract in patients with apple allergy.
2004300
SwitzerTo evaluate the effect of subcutaneous immunotherapy on the oral
Bucher,
land
allergy syndrome to apple and hazelnut
2004301
Asero, 1998302 Italy
To evaluate the clinical and immunological effects of birch pollen
specific immunotherapy on oral allergy syndrome induced by apples
Italy
To evaluate the safety and efficacy of SLIT with natural rubber
Bernadini,
latex (NRL) extract in children with NRL allergy
2006303
Pharmacological management
BindslevDenmark
To evaluate the effect of treatment with astemizole on symptoms
Jensen,
elicited by the ingestion of hazelnuts in birch pollen-allergic
1991315
patients
197
Milk, whole egg, egg
albumin, wheat, cod,
apple, beans
Poor
Table 44: Food allergy treatment/management controlled trials: study information (Continued)
Author
Burks, 1988318
Country
US
Purpose
Food
To evaluate oral cromolyn in children with atopic dermatitis and
documented food hypersensitivity
To compare oral prednisone and topical fluticasone in treating EE in
children**
To determine the effect of lactobacillus in infants with rectal bleeding
US
Schaeffer,
2008319
Poland
Szajewska,
2007321
US
To determine the effect of anti-IgE therapy in patients with peanut
Leung,
allergy
2003316
Italy
To evaluate if addition of an immunomodulating agent to an
Cavagni,
elimination diet improves food allergy in children
1989317
Italy
To evaluate oral sodium cromoglycate in children with atopic
Businco,
dermatitis
1986320
Other management strategies for food allergies
Hill, 2005322
Australia
To evaluate the effect of a hypoallergenic maternal diet on persistent
crying among breastfed infants presenting with colic
Amadi,
2002323
Zambia
To compare outcomes with either standard diet for diarrhea and
malnutrition or an amino acid-based elemental feed
Cantani,
2006324
Salpietro,
2005325
Viljanen,
2005326
Italy
To evaluate the effectiveness of a home-made meat-based formula for
feeding atopic babies
To test the safety and efficacy almond-based formula, soy formula, or
hydrolyzed formula for infants with cow’s milk allergy
To investigate whether probiotic bacteria have any beneficial effect on
atopic eczema/dermatitis in infants with cow’s milk allergy
Italy
Finland
Condition of interest
Egg
Atopic dermatitis
Not specified
EE
Milk
Peanut
Cow’s milk allergy
syndrome
Anaphylaxis
Egg, milk, pea, fish
Atopic dermatitis
Fair
Milk, egg, fish,
wheat
Atopic dermatitis
Fair
Milk, egg, peanut,
tree nut, wheat,
soy, fish
Milk
Gastrointestinal hypersensitivity
Fair
Cow’s milk allergy
syndrome, Gastrointestinal hypersensitivity
Atopic dermatitis
Fair
Milk
Milk
Milk
Cow’s milk allergy
syndrome
Atopic
eczema/dermatitis
syndrome
Table Notes: EE= eosinophilic esophagitis; GI gastrointestinal; NRL natural rubber latex; sIgE antigen-specific immunoglobulin; SLIT sublingual immunotherapy
** Food allergy was only found only in 63% of the patients treated with prednisone and 52.5% of the patients treated with fluticasone
198
Study
quality
Fair
Fair
Good
Good
Poor
Fair
Good
Table 45: Food allergy treatment/management controlled trials: patient characteristics
Author
Intervention Group Selection Criteria
Control
Selection
Inclusion/exclusion criteria
IgE
Skin
Clinical
Criteria
Test
reaction
Allergen avoidance
Inclusion: clinical history of atopic
Yes
No
Yes
Same as
Agata,
dermatitis and milk/egg allergy
intervention
1993291
group
Allergen-specific immunotherapy
Inclusion: IgE-mediated food allergy to
Staden,
either cow milk or hen egg as confirmed
2007293
by DBPCFC Exclusions: severe atopic
dermatitis with SCORAD >75
Inclusion: Children with cow’s milk
Morisset,
allergy or egg allergy as established on
2007294
the basis of 1. skin prick test OR specific
IgE AND 2. confirmed by either positive
oral/labial food challenge OR complete
recovery from symptoms after 3 weeks of
food avoidance. Although, 15 cases of
milk allergy were non-IgE mediated with
negative skin/RAST but positive food
challenge and/or recovery. These subjects
were then seen 6 months to 1 year after
continuous avoidance and were selected if
they demonstrated non-reactivity to milk
or egg (skin prick test, specific IgE, and
placebo-controlled food challenge)
Inclusion: children aged 6-21 from
Skripak,
pediatric allergy clinics with positive SPT
2007292
to milk extract, milk IgE >0.35 kU/Lwith
a positive milk challenge result to 2.5 g or
less of milk protein. Exclusion: history of
anaphylaxis requiring hospitalization,
history of intubation related to asthma, or
a current diagnosis of severe, persistent
asthma.
Subject Demographics
Intervention
Control
27 sensitive to egg, (age
range: 4 months to 12
years); 16 sensitive to milk
(age range 3 months to 12
years)
6 sensitive to egg (age
range: 1-10 years); 5
sensitive to milk (age
range 8 months to 10
years)
Yes
No
No
Same as
intervention
group
NR
NR
Yes
Yes
Yes
Same as
intervention
group
Milk: mean age 2.4 years
(sd 1.2);
Egg: mean age 3.5 years (sd
1.7)
Milk: mean age 2
years (sd 0.8)
Egg: mean age 3.6
years (sd 1.7)
Yes
Yes
Yes
Same as
intervention
group
Males: 8/13 (62%); mean
age=9.3 years (SD=3.3)
Males: 4/7 (57%);
mean age= 10.2
(SD=3.3)
199
Table 45: Food allergy treatment/management controlled trials: patient characteristics (Continued)
Author
Control Selection
Intervention Group Selection Criteria
Criteria
Inclusion/exclusion criteria
IgE
Skin Test
Clinical
reaction
Adults with a history of immediate
Nelson,
No
No
Yes
Same as
hypersensitivity reactions to
1997295
intervention group
peanuts
but patients selfselected to be
controls
Enrique,
2005299
Patriarca,
2007296
Potential patients were preselected
on a clear history of hazelnut food
allergy and positive skin prick test.
Inclusion: positive DBPCFC with
hazelnuts. Exclusion: pregnancy,
uncontrolled asthma, systemic
corticosteroids, B-blockers,
antihistamines, antidepressants,
systemic disease/inflammation not
compatible with the treatment
Consecutive children affected by
food allergy (defined by clinical
history, skin prick tests, serum total
and specific IgE, and DBPCFC)
Subject demographics
Intervention
Control
4 males; 2 females; age
range: 18-56 years; all
had cutaneous and
pulmonary symptoms to
peanuts and one had
hypotension
4 males; 2 females; age
range: 33-46 years; 1
reported cutaneous and GI
symptoms, 4 reported
cutaneous and lower
respiratory symptoms, 1
reported uticaria/
throat swelling/
hypotension
7 (63%) males; 4 (37%)
females; age: 29.6 years
(19-42)
No
Yes
Yes
Same as
intervention group
3 (25%) males; 9 (75%)
females; age: 29.2 years
(19-53)
Yes
Yes,
wheal <3
mm was
negative
Yes
Patients that were
offered
desensitization
treatment but
whose parents
refused because of
work problems
24 males; 18 females;
age: 3-16. 14/42 (7 boys
and 7 girls) also had
atopic dermatitis
6 males; 4 females; age:
5-13
Positive
for birch
pollen
No
NR
NR
NR
Specific immunotherapy with cross-reactive allergens
Inclusion: Rhino-conjunctivitis
Hansen,
Positive
during birch pollen season, combined for
2004300
with birch pollen specific IgE, birch birch
pollen positive SPT, and a positive
pollen
conjunctival provocation test to birch
pollen using standardized extracts
200
Table 45: Food allergy treatment/management controlled trials: patient characteristics (Continued)
Author
Bucher,
2004301
Asero,
1998302
Intervention Group Selection Criteria
Inclusion/exclusion criteria
IgE
Skin Test
Inclusion: oral allergy syndrome
induced by apple or hazelnut with a
positive SPT to birch pollen AND
hazelnut or apple
Inclusion: clear history of oral
allergy syndrome
Inclusion: age above 4 years and
below 16 with a clinical history of
uticaria, rhino-conjunctivitis,
and/or asthma due to natural rubber
latex (NRL). Exclusion:
anaphylactic shock,
immunosuppressive treatment,
severe immunological diseases, and
dermatographism
Pharmacological management
BindslevPatients with birch pollen allergy.
Jensen,
Inclusion: case history of
1991315
immediate local symptoms (itching
and swelling of mouth/throat)
Exclusion: anamnestic severe
reaction after intake of hazelnuts
Bernadini,
2006303
No
Yes
Clinical
reaction
No
No
No
Yes
No
No
Yes, for
latex
allergy
NR
All had
positive
skin prick
test to
birch
pollen,
but only
15 had a
positive
SPT to
hazelnut
Yes
201
Subject demographics
Intervention
Control
Control Selection
Criteria
Same as
intervention group
4 males; 11 females;
mean age: 30 years
(range 17-48)
5 males; 7 females; mean
age: 34 years (range 2048)
Group 1: had
birch-pollen
allergies with
typical OAS after
ingestion of apples
and were not
submitted to
immunotherapy.
Group 2:
submitted to
immuno-therapy
Same as
intervention group
18 males; 31 females;
mean age: 34.4 years
NR
8 males; 4 females; mean
age 10.3 year (5-14)
Placebo group: 4 males; 4
females; mean age 11.0
(5-14); Control group: 2
males; 4 females; mean
age: 10.7 (4-15)
Same as
intervention group
NR
NR
Table 45: Food allergy treatment/management controlled trials: patient characteristics (Continued)
Author
Burks,
1988318
Schaeffer,
2008319
Szajewska,
2007321
Leung,
2003316
Intervention Group Selection Criteria
Inclusion/exclusion criteria
IgE
Skin Test
Inclusion: atopic dermatitis as
defined by Hanifin and Rajka, all
had positive SPT, all were on a
strict egg-avoidance diet for 1 year,
antihistamines were stopped 1
week before trial and beta-agonists
were stopped 12 hours before trial,
Exclusion: renal, hepatic, or
cardiovascular disease, known
tolerance to cromolyn, female
patients of child-bearing potential,
or a history of life-threatening
anaphylactic reaction to egg
Inclusion: patients between 1 and
18 years of age diagnosed with EE
as defined as esophageal mucosal
biopsy specimen showing >/= 15
eos/hpf
Exclusion: co-existing esophageal
conditions (stricture, Barrett's,
caustic injury), H. pylori infection,
IBD, inability to tolerate
corticosteroids
Inclusion: rectal bleeding
diagnosed as the presence of bloodstreaked normal-to-soft stools,
exclusive breast feeding, age < 6
months. Exclusion: infectious
origin of rectal bleeding
(pathogenic bacteria/C. diff),
necrotizing enterocolitis, and
coagulopathies
Inclusion: Serum total IgE between
30 and 1000 IU/mL, good health,
body weight within 20% of ideal,
Clinical
reaction
Control Selection
Criteria
Subject demographics
Intervention
Control
NR
Yes
NR
Same as
intervention: cross
over trial
4 males; 4 females;
mean age 7.6 years +/3.2
NR
NR
NR
NR
Same as
intervention
Prednisone group: 31
males; 9 females; mean
age 7.0 years (1.1-15.8);
positive food allergy in
25/40
Fluticasone group: 28
males; 12 females; mean
age 7.2 years (1.1-16.1);
positive food allergy in
17/40
No
No
Yes
Same as
intervention group
4 males; 10 females;
age: 3.1 months +/- 1.4
7 males; 8 females; age:
4.1 months +/- 1.3
Yes
Yes
No
Same as
intervention group
150 mg group: 11 males;
8 females; mean age:
34.9 years (13-49); mean
10 males; 13 females;
mean age 34.4 years (1459); mean total serum IgE
202
Table 45: Food allergy treatment/management controlled trials: patient characteristics (Continued)
Author
Intervention Group Selection Criteria
Inclusion/exclusion criteria
IgE
Skin Test
Clinical
reaction
Control Selection
Criteria
positive SPT to peanut and
negative SPT to tuna oil, no prior
exposure to monoclonal AB,
Exclusion: pregnancy, uncontrolled
asthma
Cavagni,
1989317
Children with a food allergy
manifesting as atopic dermatitis
No
Businco,
1986320
Children < 12 years old with severe
eczema requiring continuous
therapy but no steroids and
exacerbation of symptoms from
food allergy
Yes
Yes-used
to determine
which
foods to
evaluate
Yes
No
Same as
intervention group
Yes
Same as
intervention group
203
Subject demographics
Intervention
Control
total serum IgE 349.8
IU/mL (101-902 IU/mL)
serum peanut-specific
IgE 21.7 IU/mL (0.34100 IU/mL); 300 mg
group: 12 males; 7
females; mean age: 28.3
years (13-52); mean total
serum IgE 205.1 IU/mL
(11-496 IU/mL), serum
peanut-specific IgE 24.3
IU/mL (0.34-100
IU/mL); 450 mg group:
12 males; 9 females;
mean age: 31.6 years
(13-53); mean total
serum IgE 286.7 IU/mL
(33-1017 IU/mL) serum
peanut-specific IgE 32.9
IU/mL (0.69-100 IU/mL)
Mean age: 73.7 (51.7)
months
14 males; 17 females;
age range: 6months-10
years
251.3 IU/mL (36-955
IU/mL) serum peanutspecific IgE 24.0 IU/mL
(0.34-100 IU/mL)
Mean age: 46.4 (17.1)
months
14 males; 17 females; age
range: 6 months-10 years
Table 45: Food allergy treatment/management controlled trials: patient characteristics (Continued)
Author
Intervention Group Selection Criteria
Inclusion/exclusion criteria
IgE
Skin Test
Other management strategies for food allergies
Hill, 2005322
Inclusion: exclusively breast fed
infants <6 weeks of age with colic,
term infants (>37 weeks), normal
singleton pregnancy, uneventful
perinatal history, no perinatal
morbidity other than distress.
Exclusion: mothers on strict vegan
diets
No specific food allergies were
Amadi,
diagnosed, but the thought was that
2002323
underlying cow’s milk allergy
might be exacerbating the problem.
Exclusion criteria: measles, chicken
pox, neurologic disorders, and
those that were exclusively breastfed
Inclusion: children with severe
Cantani,
atopic dermatitis and suspected
2006324
cow’s milk allergy on the basis of
personal history and positive SPT
to cow milk and egg
Clinical
reaction
Subject demographics
Intervention
Control
Control Selection
Criteria
No
No
Colic in
babies
Same as
intervention group
For those that completed
the study: 28 male
infants and 19 female
infants
For those that completed
the study: 26 male infants
and 17 female infants
No
No
No
Same as
intervention group
49 males; 51 females,
age: 17 months range
(14-20)
45 males; 55 females; age:
18 months range (13-22)
No
Yes
Yes
Same as
intervention
NR
NR
204
Table 45: Food allergy treatment/management controlled trials: patient characteristics (Continued)
Author
Salpietro,
2005325
Viljanen,
2005326
Intervention Group Selection Criteria
Inclusion/exclusion criteria
IgE
Skin Test
Infants aged 5 to 9 months with
histories and symptoms suggestive
of food allergy. Diagnosis of CMA
was confirmed by personal and
family history, physical exam,
improvement on milk free diet and
symptom relapse by milk
challenge, SPT, and RAST.
Excluded low birth weight <3kg,
intrauterine growth retardation,
congenital anomalies, and
significant perinatal medical
complication. Also excluded
subjects with +RAST to
aeroallergens.
Inclusion: infants under 12 months
upon entering the study, symptoms
suggestive of cow’s milk allergy,
obligatory atopic eczema/dermatitis
Exclusion: No probiotic
preparations used longer than 1
week and within 6 weeks of
entering the study
Yes
Yes
Clinical
reaction
Yes
Yes
Yes
Yes
Control Selection
Criteria
Subject demographics
Intervention
Control
Age and sex
matched healthy
formula fed
infants seen in the
same hospital over
the same period as
the intervention
group
7.04 months old; 5/26
had history of atopy
7.08 months old; 0/13 had
history of atopy
Same as
intervention
Lactobacillus alone mean
age: 5.9 months;
exclusive breast-feeding
for 2.1 months
Lactobacillus and
mixture mean age: 5.8
months; exlcusive breastfeeding 2.0 months
Mean age 6.1 months;
exclusive breast-feeding
2.3 months
Table Notes: CMA cow’s milk allergy; DBPCFC double blind placebo-controlled food challenge; GI gastrointestinal; NRL natural rubber latex; OAS
oral allergy syndrome; RAST radioallergosorbent test; SCORAD scoring atopic dermatitis; SD standard deviation; sIgE antigen-specific
immunoglobulin; SPT skin prick test
205
Table 46: Food allergy treatment/management controlled trials: intervention characteristics and outcomes reported
Author
Timing
Intervention Description
Sample Size
Info
Experimental
Control
Experimental Control
Allergen avoidance
Agata, 1993291
Elimination diet of allergic food: egg or
No elimination diet
>= 3
43
11
milk
months
Allergen-specific immunotherapy
Staden, 2007293 Assigned to specific oral tolerance
induction with both an induction and
maintenance phase. Patients then
underwent an elimination diet for 2
months prior to follow-up food challenge
Oral desensitization with whole
Morisset,
pasteurized milk for those with cow’s
2007294
milk allergy, in weekly increasing doses.
Oral desensitization with hard-boiled
eggs for those with egg allergy, in weekly
increasing doses
Skripak, 2007292 Immunotherapy dose schedule that was
initiated in the clinic and then patient
continued with maximum tolerated dose
at home for 7-14 days. The patient
returned to the clinic to get a dose
increase. Once a dose of 500 mg (=15mL
of milk) was achieved, patient continued
on that dose for 13 weeks.
Nelson, 1997295 Injections of peanut extract--a
maintenance level of tolerance was first
achieved by a rush protocol, then
maintained with weekly injections for at
least a year. Maximum projected dose of
0.5 mL of 1:100 wt/vol peanut extract
Biologically standardized hazelnut extract
Enrique,
given in increasing concentrations for 5
2005299
days.
Outcomes reported
Improvement of atopic
dermatitis; specific IgE
antibodies; proliferative
responses of PBMCs
Elimination diet
median
follow-up:
21 months
(18-24)
25
20
Tolerance as defined by either
complete or partial allergen
specific IgE
Continued avoidance of
either milk or egg
6 months
Milk: 28
Egg: 51
Milk: 32
Egg: 39
Single blind placebo controlled
food challenge; skin prick test
wheals; IgE level
Placebo instead of
immunotherapy dose
23 weeks
with an
initial test
and then a
repeat at
week 23
13
7
Milk threshold; median end-point
titration SPT milk-specific IgE;
milk IgG levels; reactions to
doses
No treatment
6 weeks
and 1 year
6
6
Threshold to oral peanut
challenge; cutaneous reactivity to
peanut challenge; peanut-specific
IgE and IgG
Saline solution in vials
with exactly the same
appearance, color, and
taste but without
allergens
12 weeks
12
11
Quantity of hazelnut provoking
objective symptoms; hazelnut
specific IgE; hazelnut specific
IgG4; IL-10
206
Table 46: Food allergy treatment/management controlled trials: intervention characteristics and outcomes reported (Continued)
Author
Timing info
Outcomes reported
Intervention description
Sample size
Experimental
Control
Experimental
Control
Desensitization per a protocol to the Continued elimination diet 18 months
Patriarca,
42
10
Successful tolerance as
food(s) to which each person was
2007296
to allergic food(s)
determined by DBPCFC,
allergic--increasing in dose every 3
IgE, IgG.
days. If an adverse reaction was
noted, H-2 blocker or cromolyn was
given 20 minutes before the
desensitization. Patients were then
asked to eat the allergenic food at
least 2x week
Specific immunotherapy with cross-reactive allergens
Hansen, 2004300 Sublingual or subcutaneous birch
Placebo
2 years
Sublingual= 14
Oral food challenge to
pollen extract
12;
apple; symptom scores to
subcutaneou
apple in the oral food
s=16
challenge; specific IgE to
apple
Bucher, 2004301 Subcutaneous immunotherapy with
Did not receive tree extract 1 year
15
12
Improvement of oral
tree pollen extract
immunotherapy
allergy syndrome;
subjective symptoms
after oral provocation
tests; serum IgE to
apple; serum IgG4 to
rBet v 1.
Asero, 1998302
Injection of specific immunotherapy Group 1: no
12, 24 or 36 at 12 months Group 1: at
Symptom of oral allergy
for both induction and maintenance
immunotherapy Group 2:
months
n=12, at 24
12 months
syndrome
phases; group divided to receive
underwent immunotherapy
months
n=7, at 24
treatment for either 12, 24, or 36
similar to the intervention
n=21, at 36
months n=
months
group
months
5, at 36
n=13
months,
n=11.
Group 2: at
12 months
n= 8, at 24
months n=4,
at 36 months
n=3
207
Table 46: Food allergy treatment/management controlled trials: intervention characteristics and outcomes reported (Continued)
Author
Bernadini,
2006303
Intervention description
Experimental
Control
Given a natural rubber latex extract
Placebo group: placebo;
for sublingual administration with a control group: nothing
build up phase and maintenance
phase for 12 months
Pharmacologic management
Patients given two open oral
Bindslevprovocations of five hazelnuts (at
Jensen, 1991315
least 2 days apart). Then the
treatment group ingested aztemizole
10 mg each morning for 14 days
followed by 2 open oral
provocations
Placebo
Timing info
1 year
14 days
208
Sample size
Experimental
Control
12
Placebo: 8;
control: 6
15
15
Outcomes reported
Conventional skin prick
tests with a NRL extract,
prick-by-prick with
NRL-containing gloves
and serum NRL-specific
IgE in order to check for
variations in the IgE
responses to the allergen;
skin prick tests with
inhalant and with food
allergens which are
known to be associated
with sensitization and
allergy to NRL; prickby-prick tests with
vegetables, which
display a clinical and/or
immunological crossreactive behavior with
NRL allergens; changes
in severity of oral
allergic symptoms
Symptom severity to oral
provocation test
Table 46: Food allergy treatment/management controlled trials: intervention characteristics and outcomes reported (Continued)
Author
Burks, 1988318
Intervention description
Experimental
Control
Patients were treated for a week
Placebo (cross-over trial)
with cromolyn or placebo and then
evaluated. They then had a washout
period of 3-5 weeks. The patients
then crossed over to the other arm
for a week and were again
evaluated.
Schaefer,
2008319
Oral prednisone (1 mg/kg) bid
Fluticasone by MDI 2
puffs 4x daily
Szajewska,
2007321
Mothers eliminated cow milk from
their diet and infants received
lactobacillus fhamnosus GG
3 groups receiving different doses of
TNX-901 (150 mg, 300 mg, 450
mg), a humanized IgG1monoclonal
antibody against IgE
Mothers eliminated cow
milk from their diet and
infants received placebo
Placebo
Leung, 2003316
209
Timing info
1 week
Esophageal
histology
evaluated at
baseline and
after 4
weeks of
therapy.
Clinical
assessment
made at
weeks 0, 4,
12, 18, and
24. Patients
received
therapy for
12 weeks
and then
were
followed up
for 12 weeks
Treatment
period: 4
weeks
6-8 weeks
Sample size
Experimental
Control
10
NR
Outcomes reported
Symptom cards assessed
on a scale of 0-3 for rash
distribution, pruritis,
uticaria,
sneezing/itching,
congestion, rhinorrhea,
wheezing, nausea/pain,
and vomiting/diarrhea;
response to DBPCFC
Primary endpoint:
histological response by
an improvement in
biopsy grade after 4
weeks of corticosteroid
therapy. Secondary
endpoint: defined as
clinical response to
corticosteroids based on
the presence or absence
of the presenting
symptom.
40
40
11
15
Days of rectal bleeding
150 mg--19;
300 mg--19;
450 mg--21
23
Threshold of sensitivity
to peanut on oral food
challenge
Table 46: Food allergy treatment/management controlled trials: intervention characteristics and outcomes reported (Continued)
Author
Cavagni,
1989317
Intervention description
Experimental
Control
Food to which a positive prick test
Same as experimental
was found was excluded from the
group but received placebo
diet for 90 days. During this period, rather than thymomodulin
treatment group received 120
mg/day of thymomodulin as syrup
Cross-over trial in which children
underwent a washout elimination
diet followed by on-going
elimination diet with either placebo
or sodium cromoglycate. Subjects
then crossed into the other arm
(placebo vs sodium cromoglycate
Other management strategies for food allergies
Hill, 2005322
Maternal diet that was low allergen,
excluding dairy products, soy,
wheat, eggs, peanuts, tree nuts, and
fish
Businco,
1986320
Same as experimental
description
Regular diet including 7
day supply of cow and
soy powder, 1 serving of
peanuts, 1 serving of
wheat, and 1 chocolate
muesli bar/day
Amadi, 2002323
Malnourished children to receive 4
weeks of standard skimmed
milk/soy diet
Malnourished children to
receive Neocate for 4
weeks
Cantani, 2006324
Elimination diet for 4-6 weeks,
followed by 2 months of Rezza's
diet
Continued the usual
elimination diets for
suspected cow’s milk
210
Timing info
90 days of
elimination
diet and then
2 weeks
after the
challenge
Sample size
Experimental
Control
10
9
Outcomes reported
Dermatologic condition
based on "The Italian
Group of Pediatric
Immunology"; WBC;
differential leukocyte
count; T-cell subsets;
total IgE; specific IgE;
favourable change in
skin lesions after 2
weeks of oral challenge
in the thymomodulin
group
Changes in severity of
eczema
Total of 20
weeks, 10
weeks for
each aarm
31
31
Diet was
followed for
7 days and
then the
infants
underwent a
48 hours
cry/fuss chart
Patients
treated for 4
weeks and
then
outcomes
measured
4-6 weeks
47
43
Improvement of >25% of
cry/fuss for a duration
>360 min per 48 hours
comparing days 1 and 2
with days 8 and 9 (after
completion of the diet)
100
100
Weight gain;
hemoglobin; serum
albumin; diarrhea,
activity; developmental
milestones
25
26
SCORAD; weight; open
challenge test
Table 46: Food allergy treatment/management controlled trials: intervention characteristics and outcomes reported (Continued)
Author
Salpietro,
2005325
Viljanen,
2005326
Intervention description
Experimental
Control
allergy
Group A received almond milk;
"Formula fed" not other
Group B received soy based
wise specified
formula; Group c received protein
based formula
Elimination diet and skin treatment
with 4 weeks of lactobacillus or a
mixture of lactobacillus and other
probiotics
Elimination diet and skin
treatment with 4 weeks of
placebo
Timing info
6 months
4 weeks
Sample size
Experimental
Control
Almond
milk: 26;
Soy
formula: 13
Protein
formula: 13
Lactobacillu
s alone:44
Mixture: 44
Outcomes reported
13
Weight; length; head
circumference; serum
levels of soluble CD30
(cytokine associated with
atopy)
32
SCORAD
Table Notes: DBPCFC double blind placebo-controlled food challenge; GG NRL natural rubber latex; IgG Immunoglobulin G; OAS oral allergy syndrome; SCORAD scoring
atopic dermatitis; SD standard deviation; sIgE antigen-specific immunoglobulin; PBMCs Peripheral Blood Mononuclear Cells; SPT skin prick test; WBC white blood cells
211
Table 47: Safety data for allergen specific immunotherapy
Symptom/Treatment
Study
Number/total doses
(%)* or number/patient
(%)** in
immunotherapy group
Total Reactions
Local Symptoms
Gastrointestinal
Skin (eczema and
uticaria)
Angioedema
Cardiovascular (not
P value
Skripak, 2008292
1107/2437 (45.4)*
Staden, 2007293
25/25 (100)**
6/20 (30.0)**
NR
Hofmann, 2009211
initial escalation day
Hofmann, 2009211
buildup phase
Hofmann, 2009211 home
dosing phase
Skripak, 2008292
93% (77%-99%)***
No control
NR
46% (37%-56%)***
No control
NR
3.5% (2.3%-5.1%)***
No control
NR
870/2437 (35.7)*
0.006
419/2465 (17)*
109/1466 (7.6)*
0/12 (0)**
458/2437 (18.7)*
90/2465 (3.7)*
15/25 (60.0)**
7/76 (9.2)**
4/12 (33.3)**
0/12 (0)**
68% (48%-84%)***
104/1193
(8.7)*
No control
NR
0/8 (0)**
16/1193 (1.3)*
No control
3/30 (10.0)**
8/65 (12.3)
NR
0/8 (0)**
No control
NR
NR
NS
0.02
NR
NR
NR
NR
NS
NR
5.5% (3.2%-9.2%)***
No control
NR
0.9% (0.6%-1.4%)***
No control
NR
198/2437 (8.1)*
28/171 (2.3)*
0.3
Staden, 2007293
Narisety, 2009212
Morisset, 2007294
Skripak, 2008292
2/25 (9.0)**
21/2465 (0.9)*
2/76 (2.6)**
22/2437 (0.9)*
0/20 (0)**
No control
3/65 (4.6)
1/1193 (0.1)*
NR
NR
NR
0.1
Narisety, 2009212
Staden, 2007293
Morisset, 2007294
Enrique, 2005299
Hofmann, 2009211
initial escalation day
Hofmann, 2009211
buildup phase
Hofmann, 2009211 home
dosing phase
20/2465 (0.8)*
24/25 (96.0)**
3/76 (3.9)**
1/12 (8.3)**
61% (41%-79%)***
No control
5/20 (25.0)**
6/65 (9.2)**
1/11 (9.1)**
No control
NR
NR
NR
NR
NR
24% (17%-32%)***
No control
NR
1.1% (0.7%-1.8%)***
No control
NR
Staden, 2007293
Morisset, 2007294
Staden, 2007293
4/25 (16.0)**
3/76 (3.9)**
0/25 (0)**
0/20 (0)**
4/65 (6.2)**
1/25 (4%)
NR
NR
NR
Narisety, 2009212
Enrique, 2005299
Bernardini, 2006303
Skripak, 2008292
Narisety, 2009212
Staden, 2007293
294
Lower respiratory
(asthma NOT
rhinoconjunctivitis)
Number/total
doses (%)* or
number/patient
(%)** in
control group
134/1193
(11.2)*
Enrique, 2005299
Bernardini, 2006}303
Hofmann, 2009211
initial escalation day
Hofmann, 2009211
buildup phase
Hofmann, 2009211 home
dosing phase
Skripak, 2008292
212
0.02
further defined)
Multiple systems (not
further defined)
Diphenhydramine used
to treat reaction
Albuterol used to treat
reaction
Epinephrine used to
treat reaction
Skripak, 2008292
29/2437 (1.2)*
0/1193 (0)*
0.01
Enrique, 2005299
Skripak, 2008292
3/1466 (0.2)*
249/2437 (10.2)*
NR
14/1193 (1.1)*
NR
0.3
Narisety, 2009212
Hofmann, 2009211
initial escalation day
Hofmann, 2009211
buildup doses
Hofmann, 2009211 home
doses
Skripak, 2008292
93/2465 (3.8)*
20/28 (71)**
No control
No control
NR
NR
5/301 (1.7)*
No control
NR
65/10184 (0.6)*
No control
NR
21/2437 (0.9)*
2/1193 (0.2)*
0.2
Narisety, 2009212
Hofmann, 2009211
initial escalation day
Hofmann, 2009211
buildup doses
Hofmann, 2009211 home
doses
Skripak, 2008292
12/2465 (0.5)*
3/28 (11)**
No control
No control
NR
NR
2/301 (0.7)*
No control
NR
24/10184 (0.2)*
No control
NR
4/2437 (0.2)*
0/1193 (0)*
0.1
Narisety, 2009212
Hofmann, 2009211
initial escalation day
Hofmann, 2009211
buildup doses
Hofmann, 2009211 home
doses
Zapatero, 2008 298
4/2437 (0.2)*
6/2465 (0.2)*
0/1193 (0)*
No control
0.1
NR
4/28 (14)**
No control
NR
0/301 (0)*
No control
NR
2/18 (11)**
No control
NR
*Some studies reported per dose, some reported per patient, and some had mixed depending on the symptom (per dose or per
patient).
213
Key Question I. What methods are currently used to manage patients
diagnosed with non-IgE-mediated reactions to food, and how do they
differ from methods used to manage patients diagnosed with IgEmediated food allergy?
The literature can not readily be divided on the basis of IgE-mediated and non-IgE mediated
reactions. In the relevant tables, we describe IgE-mediated reactions reported by the included
prevention (Table 40) and management/treatment trials (Table 44). We also describe the use of
Ig-E testing as inclusion criteria and the effects of interventions on both allergen specific and
total IgE (e.g., see description of the RCT by Klemola et al.313 on the use of soy milk formula in
children with cow’s milk allergy syndrome (Table 50).
Key Question J. What are the appropriate methods of diagnosis and
treatment of acute and life-threatening, IgE-mediated food allergic
reactions?
Background
Anaphylaxis is an acute multi-system and severe type-I allergic hypersensitivity reaction. After
an initial exposure to a substance, the person's immune system becomes sensitized to that
allergen. On a subsequent exposure, an allergic reaction occurs. This reaction is sudden, severe,
and involves the whole body.
Results
No studies specifically described the diagnosis of these serious reactions to food. Also, we
found no RCTs involving anaphylaxis, but we did identify three cohort studies .(Table 48-Table
50).328-331
Jarvinen et al.328 distributed questionnaires to families of children with food allergies to help
determine the rate, circumstances, and risk factors for repeated doses of epinephrine in the
treatment of food-induced anaphylaxis (Table 48-Table 50). The population they targeted was
from a hospital-based pediatric allergy clinic and a private practice-based pediatric food allergy
referral clinic at Mount Sinai Hospital, New York. Of 542 distributed questionnaires, 512 (94
percent) were returned, and 413 were included (exclusions were for incomplete data, no
documented food allergy, or age >18). They found that peanut, tree nut, and cow’s milk allergy
were responsible for more than 75 percent of the reactions requiring epinephrine. They also
found that patients requiring multiple doses of epinephrine more often had asthma (p=0.027) and
that 19 percent of food-induced anaphylactic reactions were treated with more than one dose of
epinephrine.
de Silva et al.329 performed a retrospective case study to describe the demographic
characteristics, clinical features, causative agents, settings, and administered therapy in children
presenting with anaphylaxis to an Emergency Department in Royal Children's Hospital,
Melbourne (Table 48-Table 50). In 117 patients, the median age of presentation was 2.4 years,
and food (85 percent) was the most common trigger and respiratory symptoms were the most
common clinical presentation (97 percent). Peanut (18 percent) and cashew nut (13 percent) were
214
the most common causes of anaphylaxis. Adrenaline (subcutaneous, intravenous, and
intramuscular) was used in 94/123 cases (76 percent) with the median time to administration of
40 minutes (range 23-78). Steroids were used in 95/123 cases (77 percent) with the median time
to administration of 80 minutes (range 66-138) and antihistaimes were used in 73/123 cases (59
percent) with the median time to administration of 90 minutes (range 42-132). The admission
rate was 83 percent (102/12) and the median length of stay after admission was 17 hours (range
12-22).
Pouessel et al.330 performed a prospective study to assess which food allergies children who used
an Anapen (an injectable epinephrine) suffered from. They sent questionnaires to families with
food-allergic children (Table 48-Table 50). The questionnaires were sent to patients previously
prescribed the Anapen device between June 2000 and March 2003. These children were cared
for by pediatricians or allergists working in (and referring patients to) five children’s hospitals.
The response rate was 73 percent. Of the 111 included children, the main food allergens were
peanuts (n=89), egg (n=39), and cow’s milk (n=10).
Summary
There are few data on effective strategies for the prevention or management of life-threatening
food allergies. In three published studies, anaphylaxis reaction to food allergy is seen most
frequently in patients with a peanut allergy—however the literature is insufficient to reach
conclusions regarding methods to prevent or treat this reaction.
215
Table 48: Cohort studies on anaphylaxis: study information
Author
Country
Purpose
Food
de Silva,
2008329
Australia
To describe demographic characteristics, clinical features,
causative agents, settings and administered therapy in
children presenting with anaphylaxis.
Egg, cow milk, peanut,
nut, fruit, vegetable, soy,
rice, wheat
Pousse, 2006330
France
Peanut, egg, cow milk,
nut, corn mustard, fish
Jarvinen,
2008328
US
To determine the use of Anapen prescribed for food-allergic
children; to assess parental knowledge regarding Anapen; to
evaluate the arrangements for emergency kits and
personalized care projects in everyday life.
To determine the rate, circumstances, and risk factors for
repeated doses of epinephrine in the treatment of foodinduced anaphylaxis in children.
Table 49: Cohort studies on anaphylaxis: patient characteristics
Author
Intervention Group Selection Criteria
Inclusion/exclusion criteria
IgE
de Silva, 2008329
Pousse, 2006330
Jarvinen, 2008328
Clinical history of anaphylaxis or generalized allergic
reaction
Families of children that had previously used the
ANAPEN (injection epi)
Parents/caregivers of consecutive patients presenting
for evaluation for food allergy to the pediatric allergy
clinic and to private practice-based pediatric food
allergy referral clinic at Mount Sinai Hospital, NY
Peanut, tree nut, hen’s
egg, cow milk, soybean,
wheat, shellfish, fish
No
Skin
Test
No
Clinical
reaction
Yes
No
No
Yes
No
No
Yes
Intervention
Demographics
Median age: 2.4
years
Median age: 6.5
years
Male: 63%;
median age: 4.5
years (0.5-17.5)
Table 50: Cohort studies on anaphylaxis: intervention characteristics and outcomes reported
Author
Intervention description
Timing Sample
Outcomes reported
info
size
Chart review to see the
de Silva,
Conducte
117 1 death; home most common setting (48%); food (85%)
clinical course of patients
most common trigger; peanut (18%) and cashew nut
2008329
d from 1
admitted to a children's ER
(13%) most common cause of anaphylaxis; median time
June 1998
with anaphylaxis
from exposure to anaphylaxis for all agents was 10 min;
to 30 June
median time from onset to therapy was 40 min;
2003
respiratory features principal presenting symptoms
(97%); 17% had experienced anaphylaxis previously.
Questionnaire sent to
Pousse,
June
111 Main food allergens were peanuts (n=89), egg (n=39)
families with children with
2006330
and cow’s milk (n=10).
2000history of anaphylaxis who
March
had previously used anapen 2003
Anonymous questionnaires
Jarvinen,
Between
413 Peanut, tree nut and cow’s milk allergy responsible for
were distributed to families
>75% of the reactions requiring epinephrine; patients
2008328
September
requiring multiple doses of epinephrine often had asthma
of children with food
2006 and
(p=0.027); 19% of food-induced anaphylactic reactions
allergies during allergy
February
were treated with >1 dose of epinephrine; soybean
outpatient visits to a food
2007.
allergy accounted for 107/413 (26%) of reactions and
allergy referral center.
peanut allergy 290/413 (70%) of anaphylactic reactions.
216
Evidence for the Prevention, Treatment, or Management of Specific
Food Allergies
Most of the included studies evaluated multiple foods and included patients who were allergic to
several foods. The most common foods evaluated in the included trials were peanuts and tree
nuts, cow’s milk, hen’s egg, and apple (Figure 11). The tables for this section only provide data
not already previously presented in the other evidence tables (Table 51-Table 53).
Prevention, Treatment, Management of Cow’s Milk Allergy
Background
Cow milk protein allergy is the most common food allergy in children—some reports estimate
that cow’s milk allergy or intolerance occur in two percent to seven percent of children aged 3 or
younger.325 While many infants outgrow this allergy, people of all ages with gastrointestinal tract
disease may have difficulty digesting these proteins and may absorb them as antigens.
Results
We identified 16 studies reported in 18 articles that focused on cow’s milk allergy.260, 265, 272, 293,
294, 296, 313, 325, 326, 332-340
Those studies not previously presented in an evidence table are described
in Table 51-Table 53. We note that there is considerable overlap between this section and the
results presented for Key Questions H.i.c. and H.i.d (on breastfeeding and special diets in infants
and children). We have organized this section according to the types of interventions but present
study results according to the key outcomes reported.
Early exposure to cow’s milk
Several authors have addressed the issue of whether exposure to cow’s milk in infancy result in
increased or decreased allergic disease later in life. The BOKAAL study group of Utrecht, The
Netherlands332, 334 randomized 1,533 newborns to either a brief exposure to cow’s milk protein or
placebo in the first few days of life and compared their subsequent rates of atopic disease up to
five years later. Symptom outcome: They found no difference in atopic disease or wheezing in
children exposed to cow’s milk protein early in life. Lab outcome: There was no difference in
specific IgE outcomes between the groups.
In contrast, Lindfors et al.339 randomized 207 term but low weight infants to receive cow’s milk
formula in the first few days of life before initiation of full breastfeeding or breast milk only and
followed them for four to six years to evaluate the rate of allergic symptoms in childhood. They
reported that 9/95 (9.5%) children who had received cow’s milk and 9/88 (10.2%) children who
had been exclusively breast fed had evidence of obvious allergic disease at age 4-6 years (and
16/95 (16.8%) vs 18/88 (20.5%) had suspected allergic disease). Symptom outcome: They
conclude that there may be a protective effect of the introduction of cow’s milk prior to breast
feeding, although the differences seen were not statistically significant.
Given the conflicting evidence and the fact that neither study controlled for exposure to cow’s
milk proteins later in life or exposure to other allergens, we conclude that benefits and harms of
early neonatal exposure to cow’s milk remains uncertain.
217
Breastfeeding vs. cow’s milk formula
Two analyses of data from the same study population randomized participants to either exclusive
breastfeeding or partial or complete cow milk formula and compared their incidence of atopic
dermatitis.265 Schoetzau et al. reported results on a sub-group of infants who were part of the
GINI cohort study and found a significantly lower risk of atopic dermatitis at one year of age in
infants who were exclusively breastfed compared to infants who were not (9.5% versus 14.8%,
respectively, p=0.015). Symptoms outcome: Their logistic regression model found that the risk
of AD was reduced by nearly 50% in the exclusively breastfed group, after adjusting for atopic
risk factors and other confounders such as parent education, gender, pet keeping and maternal
smoking (adjusted OR 0.47, 95% CI 0.3-0.74).265 They also conducted analysis to determine the
effect of delayed introduction of solid foods between the two groups but did not find a significant
effect modification of either age at first introduction (Wald-Chi square p=0.58) or diversity of
foods (p=0.89). The analysis conducted in this paper differed from that by Filipiak et al.260 who
conducted a similar analysis using the infant population from the GINI study. Schoetzau et al.
compared differences based on exclusive breastfeeding or not in only intervention group infants
of the GINI study whereas the Filipiak study compared breastfeeding, use of hydrolysed
formulas, and delayed introduction of solid foods in intervention group infants to a separate
control group of infants that did not receive these recommendations. Symptom outcome: They
concluded that there was no evidence to support a protective effect of delayed introduction of
solids for eczema.
Odelram272 compared whey hydrosylate and cow’s milk formula to strict breastfeeding in the
prevention of atopic disease of infants. Inclusion criteria were at least two atopic family
members or one atopic parent and total cord blood IgE >0.5 kU/I. Exclusion criteria were
gestational age below 37 weeks, complicated delivery, neonatal illness, severe birth defects, or
documented or expected noncompliance with diet prescription. Symptom outcome: Presence of
atopic disease was 10/25 in the infants fed extensively hydrolyzed formula, 15/32 in the infants
fed cow milk formula, and 3/13 in those who were breastfed. No statistical difference in the
presence of atopic disease was found. Lab outcome: There was no significant difference in
positive SPT or in sIgE at 18 months.
Cow’s milk vs. substitute milks
Several studies evaluated replacing cow’s milk with other milks. For example, Vita et al.338
assessed the tolerability and clinical effect of ass's milk compared with goat's milk in children
with atopic dermatitis from cow’s milk allergy. Symptom Outcome: Ass milk significantly
improved both the SCORAD index and the visual analog scale (p<0.03) where goat milk had no
effect. Iacono et al.335 compared cow milk and soy milk in children with chronic constipation.
Symptom outcome: Soy milk significantly increased the number of bowel movements
(p<0.001). Salpietro et al.325 performed a RCT to evaluate the safety and efficacy of almond
milk in infants with cow’s milk allergy. Symptom outcome: They reported reductions in a
variety of symptoms (e.g., vomiting, diarrhea, wheezing, eczema) among children taken off
cow’s milk but no difference in those given almond milk compared to soy-based formula or
hydrolyzed formula. Nutritional outcome: They reported a reduction in weight gain among all
infants taken off cow’s milk but no difference among those given almond milk compared to soybased formula or hydrolyzed formula.
218
Reactions to various formulas
The RCT by Klemola et al.313 evaluated the incidence of adverse reactions or allergies to soy
formulas in infants with cow’s milk allergy syndrome during the first two years of life. Symptom
outcome: Parents’ suspicions of adverse reactions to formula was significantly higher among
children who had received soy formula (28 percent, 95% CI 18-39 percent) than children who
had received extensively hydrolyzed formula (11 percent, 95% CI 5-19 percent). The cumulative
incident of adverse reactions confirmed by DBPCFC was lower for both the soy formula (8
infants: 10 percent, 95% CI 4.4-18.8 percent) and for the extensively hydrolyzed formula (2
infants: 2.2 percent; 95% CI 0.3-7.8 percent); but still statistically significantly greater in the soy
formula group (relative risk =4.50, p =0.03). Adverse reactions to soy were suspected in 12 of 46
infants with IgE associated cow’s milk allergy and in 13 of 34 infants with non-IgE associated
cow’s milk allergy (p=0.25). Food challenge outcome: Adverse reactions to soy were confirmed
by DBPCFC in five of 46 (11 percent) infants with IgE associated cow’s milk allergy and in
three of 34 (nine percent) infants with non-IgE associated cow’s milk allergy (p=0.76).
Niggemann et al.336 compared the tolerance and growth of infants with cow’s milk allergy who
were fed a new extensively hydrolyzed formula containing lactose with those who were fed an
amino acid formula. Nutritional outcome: They found no difference in tolerance or growth
parameters. Garzi et al.337 studied extensively hydrolyzed cow milk formula in children with
gastroesophageal reflux. Symptom outcome: Given the low number of patients with documented
cow’s milk allergy, they were not able to statistically evaluate the gastric emptying time or
gastroesophagel reflux symptoms. Savino et al.340 evaluated the growth of infants with atopic
dermatitis and cow’s milk allergy fed a rice-hydrolysate formula compared with a soy or
extensively hydrolyzed casein formula. Nutritional outcome: No significant differences in the zscore weight for age were found.
Jirapinyo et al333 prospectively randomized 38 infants and children (aged 2-24 months) with a
diagnosis of cow’s milk allergy to 14 days of either soy formula or a formula made of chicken
meat. Symptom outcome: They found that 12 of the 18 children who received the soy formula
were intolerant to it compared to four of the 20 children who received the chicken-meat based
formula (p=0.009) (although it is not clear if the assessment of “tolerance to the formula” was
made by an investigator blinded to the treatment assignment).
Allergen-specific Immunotherapy
Several studies evaluated oral immunotherapy for cow’s milk. Morisset et al.294 performed a
randomized study to examine an oral immunotherapy protocol in children with IgE-dependent
milk or egg allergies. Lab outcome: When the oral desensitized group was compared to the
continued avoidance group for milk allergy, a significant decrease in the size of the prick test
wheal (p<0.002) was seen . Food challenge outcome: When the oral desensitized group was
compared to the continued avoidance group for milk allergy, a significant improvement in
SBPCFC was noted (3/27 vs 12/30 p<0.025). Patriarca et al.296 also evaluated oral
immunotherapy protocols. Food challenge outcome: They found that 12/18 patients that
underwent immunotherapy had a negative DBPCFC while 0/10 of the control patients had a
negative DBPCFC.
219
Probiotics
Viljanen et al.326 studied probiotics in the treatment of infants with atopic eczema/dermatitis and
suspected of cow’s milk allergy. In addition to skin treatment and elimination of cow’s milk
from the infants’ and breast-feeding mothers’ diets, 252 infants were randomized to capsules
containing lactobacillus alone, a mixture of probiotics including lactobacillus, or placebo for four
weeks. There was no statistically significant change in the SCORAD scores.
Summary
The quality of evidence regarding the management of cow’s milk allergy is moderate given the
amount of inconsistency across the studies; numerous RCTs report heterogeneous but generally
favorable results for immunotherapy.
Prevention, Treatment, Management of Hen’s Egg Allergy
Background
Eggs are one of the most common allergy-causing foods. Although egg allergy can affect adults,
it's more common in children. This allergy can be a challenge, as eggs and egg products are
common food ingredients.
Results
We found nine RCTs and one observational study that specifically evaluated egg allergies either
alone or in combination with other food allergies.
Delayed introduction of food
Halmerbauer et al.251 conducted an RCT on environmental procedures to reduce house dustmites as well as an educational intervention to delay introduction of solid foods. They found a
significantly reduced risk of parent reported food intolerance (vomiting, prolonged crying,
diarrhea, or swollen lips after eating) in the intervention group. However, the study findings
should be interpreted with caution with respect to the effect of delayed introduction of solids; the
study was of fair quality and the multimodal nature of the intervention makes it difficult to
evaluate the effect of any single component of the intervention.
Elimination diets
Agata et al.291 studied the effect of an elimination diet for egg allergies on atopic dermatitis in a
non-randomized comparative study. Twenty-seven patients sensitive to egg that underwent an
elimination diet for at least three months were compared with six patients sensitive to egg that
did not eliminate the allergic food from their diet. The results showed that in those with egg
allergy, 27/27 had improvement in their atopic dermatitis with an elimination diet (compared
with 0/6 not on an elimination diet). They concluded that an elimination diet is a good treatment
for food allergy and that specific IgE antibodies to food antigens were useful as indexes of the
effect of elimination diets in patients with positive RAST.
Cavagni et al.317 evaluated the effects of adding thymomodulin to elimination diets in treating
atopic dermatitis induced by food allergy. They noted a more favorable course of the skin
220
lesions in the patients treated with thymomodulin after two weeks of food challenge. They also
noted a statistically significant decrease in total and specific IgE serum levels in the group
receiving thymomodulin.
The fair quality RCT by Arshad et al.262 reported study results at eight years and found a
“sustained preventive effect of egg allergen avoidance in infancy.” The non-randomized
comparative study by Hermann et al.341 found no significant difference in either atopic dermatitis
or sensitization to egg or cow milk between the intervention and control groups at 12 months.
Pharmacology
Burks and Sampson318 studied cromolyn in children with atopic dermatitis and documented food
hypersensitivity. This crossover study showed that after one week of treatment with either
cromolyn or placebo, there was no statistically significant difference in the symptom score for
atopic dermatitis or in the response to a DBPCFC.
Maternal diets
Hill et al.322 evaluated the effect of a low-allergen maternal diet on colic among breastfed infants.
They found a statistically significant improvement of colic in the low allergen group with
adjusted RR of 37 percent (CI 18-56 percent).
Allergen-specific immunotherapy
Morisset et al.294 performed a randomized study to examine an oral desensitization protocol in
children with IgE-dependent egg allergies. When the oral desensitized group was compared to
the continued avoidance group for egg allergy, a significant improvement in SBPCFC (15/49 vs
17/35; p<0.1), and a statistically significant decrease in egg-sIgE, as well as a decrease in the
size of the SPT wheal (p<0.005) were noted. Similarly, Patriarca et al.296 evaluated oral
desensitization protocols and found that 12/17 patients who underwent desensitization had a
negative DBPCFC (compared with 0/10 of the control patients).
Staden et el.293 assigned children with a food allergy to either milk or hen’s egg to oral
immunotherapy or an elimination diet. They found that tolerance was achieved more often in the
group that received oral tolerance induction (16/25) than in the group that adhered to an
elimination diet (7/20) p=0.05.
Summary
A variety of strategies have been used to prevent and treat egg allergies in children. Although
the heterogeneity of the studies on this topic preclude definitive conclusion, delayed introduction
of foods, hypoallergenic maternal diets, and elimination diets are worthy of additional study as
promising methods for the reduction of egg allergies in children.
Prevention, Treatment, Management of Peanut and Hazelnut Allergy
Background
Nut allergies are common and often appear in the first years of life. An allergic reaction to
peanuts can range from a minor irritation to a life-threatening reaction called anaphylaxis. Even
221
people who have had only had a mild reaction in the past are thought to be at risk of a more
serious future reaction.
Results
We identified two controlled trials295, 316 and three cohort studies214, 342 that examined the
treatment and management of peanut allergy.328 Leung et al.316 evaluated the effect of anti-IgE
therapy in patients with peanut allergy. They found that a 450 mg dose of TNX-901, a
humanized IgG1 monoclonal antibody, increased the threshold of sensitivity to peanut on oral
food challenge from a level equal to one peanut to almost nine peanuts.
Nelson et al.295 studied the effect of injections of subcutaneous peanut extract on patients with
peanut allergy (Table 44-Table 46). They enrolled 12 patients, six of whom agreed to be treated
with injections of peanut extract and six of whom served as a control. They reported a decreased
peanut sensitivity at one month (p=0.0002) but no effect on SPT or peanut-sIgE as compared to
patients with peanut allergy who did not receive subcutaneous injections.
Ewan and Clark214 followed 567 patients with peanut allergy, unselected consecutive referrals to
a regional specialist allergy clinic (Table 51-Table 53). After giving them verbal and written
advice on nut avoidance as well as on self-recognition of reactions, they found that 88 (15
percent) of 567 patients had a follow-up reaction of reduced severity and only three (0.5 percent)
of 567 patients, had a severe follow-up reaction, compared with 12 percent initially. They
concluded that self-treatment combined with advice for nut avoidance was effective.
Jarvinen et al.328 distributed questionnaires to families of children with food allergies to help
determine the rate, circumstances, and risk factors for repeated doses of epinephrine in the
treatment of food-induced anaphylaxis (Table 48-Table 50). The population they targeted was
from a hospital-based pediatric allergy clinic and a private practice-based pediatric food allergy
referral clinic at Mount Sinai Hospital, New York. Of 542 distributed questionnaires, 512 (94
percent) were returned, and 413 were included in the study (exclusions were for incomplete data,
no documented food allergy, or age >18). They found that peanut allergy accounted for 290/413
(70 percent) of anaphylactic food reactions.
Jones et al342 evaluated the clinical efficacy and immunological changes associated with oral
immunotherapy in patients with peanut allergy. They found that of 29 subjects who completed
the protocol, 27 ingested 3.9 g peanut protein during food challenge. Further, most symptoms
noted during immunotherapy resolved spontaneously or with antihistamines.
Because nut allergies can be so severe and because we found little evidence from RCTs or large
cohort studies about these allergies, we sought additional studies on this topic. We found one
small cohort study on hazelnuts. Hansen et al343 report a case series of 17 patients with food
challenge-confirmed allergy to hazelnuts. Roasting the hazelnuts at 140 degrees centigrade for
40 minutes resulted in only five of these 17 patients having a reaction on DBPCFC. Despite this
significant reduction, about 30 percent of patients remained sensitive even to roasted hazelnuts,
so the authors concluded that roasting hazelnuts cannot be considered "safe" for hazelnut-allergic
patients.
222
Summary
The quality of evidence is moderate in support of immunotherapy in the treatment and
management of peanut allergy, and advice on nut avoidance accompanied by instructions for
self-administered medication should be utilized.
Prevention, Treatment, Management of Fin Fish Allergy
Background
Pollock, salmon, cod, tuna, snapper, and tilapia are among the fish that commonly trigger fish
allergies. Fin fish allergies are similar to shellfish allergies in that they are more likely than many
food allergies to start during adulthood and less likely than other allergies to be outgrown. While
it is easier to avoid fish than it is to avoid many other allergens, fish allergies are often quite
severe in their symptoms.
Results
We found four RCTs studies of the prevention and treatment of fish allergies—all were of
elimination diets (Table 44-Table 46).
The fair quality RCT by Arshad et al.262 reported study results at eight years and found a
“sustained preventive effect of allergen avoidance in infancy.”
Cavagni et al317 evaluated the effects of adding thymomodulin to elimination diets in treating
atopic dermatitis induced by food allergy. They noted a more favorable course of the skin
lesions in the patients treated with thymomodulin after two weeks of food challenge. They also
noted a statistically significant decrease in total and sIgE serum levels in the group receiving
thymomodulin.
Hill et al.322 evaluated the effect of a low-allergen maternal diet on colic among breastfed infants.
They found a statistically significant improvement of colic in the low allergen group with
adjusted RR of 37 percent (CI 18-56 percent).
Patriarca et al296 evaluated oral desensitization protocols and found that 9/9 patients completing
the oral desensitization had a negative DBPCFC (compared with 0/10 control patients).
Summary
No studies were found that evaluated fish allergy alone; instead, studies included a small sample
of patients with fish allergy among a larger sample of patients with other allergies. While
definitive conclusions are hard to reach, allergen avoidance holds promise in the prevention,
treatment and management of fish allergy.
223
Prevention, Treatment, Management of Apple Allergy
Background
The prevalence of apple allergy is most frequently associated with birch pollinosis in Northern
Europe and North America. It is estimated that 40 to 90 percent of birch pollen allergic patients
are sensitized to apples. Apple is one of the major foods involved in Oral Allergy Syndrome,
which presents IgE-mediated symptoms that occur mainly at the mucosa of lips, tongue and
throat after ingestion of apples and other fruits. Oral allergy syndrome is not a major clinical
problem.
Results
We found four RCTs296, 300-302 that specifically evaluated apple allergies either alone or in
combination with other food allergies.
Hansen et al.300 noted that clinical manifestations of allergenic cross-reactions between pollen
and plant foods are frequent in birch pollen allergic patients and evaluated the effect of birch
pollen extract immunotherapy in patients with apple allergy. There was no statistically
significant change in oral allergy syndrome responses to an open apple food challenge after
treatment with placebo, sublingual, or subcutaneous birch pollen extracts. However; there was a
statistically significant decrease in apple sIgE in patients treated with subcutaneous birch pollen
extract from 5.9 kU/L to 1.8 kU/L (p=0.009). No statistically significant change was reported in
those patients receiving sublingual birch pollen extract or placebo.
Bucher et al.301 also examined the effect of subcutaneous immunotherapy with tree pollen extract
on patients’ oral allergy syndrome to apple and hazelnuts. Improvement of oral allergy
syndrome was statistically significant (p<0.05) with 10/15 patients receiving subcutaneous
immunotherapy showing improvement (compared with only 2/12 control patients). sIgE to apple
was also measured and the difference was found to be non-significant. However, it was reported
that IgG4 r Bet v1 was significantly different (p<0.001) in the group treated with
immunotherapy, but no values were given in the publication.
Asero et al.302 evaluated birch pollen-sensitive patients with apple-induced oral allergy syndrome
who received injection immunotherapy with birch pollen extract. This treatment was found to
reduce clinical apple sensitivity (p<0.001) but not apple sIgE.
Patriarca et al.296 evaluated oral desensitization protocols and found that 1/1 patients completing
the oral desensitization had a negative DBPCFC (compared with 0/10 control patients).
Summary
The quality of evidence for apple allergy is moderate and indicates that immunotherapy with tree
pollen appears to be effective in treating the apple-induced oral allergy syndrome. Oral
224
desensitization may also help in the management of apple allergy, although further exploration of
this treatment modality is warranted.
Prevention, Treatment, Management of Soybean Allergy
Background
Soybean allergy is of concern because soy protein is prevalent in the diets of millions of people
worldwide.
Results
We identified one cohort study that examined soybean allergies.328 Jarvinen et al.328 distributed
questionnaires to families of children with food allergies to help determine the rate,
circumstances, and risk factors for repeated doses of epinephrine in the treatment of foodinduced anaphylaxis. They found that soybean allergy accounted for 107/413 (26 percent) of
anaphylactic food reactions.
Summary
There are insufficient data to reach conclusions for the management of soybean allergies.
225
Table 51: Treatment/management - specific food allergy studies: study information
Author
Country
Purpose
Peanut/Hazelnut Allergy
Ewan, 2001214
UK
Jones, 2009342
United
States
Hansen, 2003343
Switzerlan
d Denmark
US
Hofmann et al.,
2009211
Cow’s milk allergy
Jong, 2002332
Netherlands
Lindfors, 1992339
Iacono, 1998335
Klemola, 2002313
Italy
Finland
Niggemann,
2008336
Germany
Jirapinyo, 2007333
Thailand
Garzi, 2002337
Italy
Vita, 2007338
Italy
Savino, 2005340
Italy
Narisety, 2009212
US
Henriksen, 2000213
Norway
Zapatero, 2008 298
Spain
Study
design
Condition of interest
To determine effect of a management plan for peanut and nut allergy
To investigate the clinical efficacy and immunologic changes associated with oral
immunotherapy in patients with peanut allergy.
To evaluate the reduction in allergenicity by roasting hazelnuts
Cohort
Cohort
Multiple
Multiple
Cohort
Multiple
To examine safety during the initial escalation day, buildup phase, and home dosing
phase in subjects enrolled in a peanut oral immunotherapy study
Cohort
Multiple
To determine effect of brief exposure to cow's milk in the neonatal period on later
development of atopic disease.
To evaluate the longer term (age 4-6yrs) incidence of allergic symptoms in children
given cow's milk neonatally
To compare cow's milk and soy milk in children with chronic constipation
To evaluate incidence of allergy or other adverse reactions to soy formula and to
hydrolyzed formula in patients with cow's milk allergy
To compare tolerance and growth of infants with CMPA who were fed a new
extensively hydrolyzed formula containing lactose with those who were fed an
amino acid formula
To compare the ability of children with cow’s milk allergy to tolerate chicken-based
formula and soy formula
To examine effects of a hydrolyzed cow milk formula on GERD and gastric
emptying time
To assess tolerability and clinical effect of ass's milk compared with goat's milk to
manage atopic dermatitis and cow's milk allergy in children
To evaluate growth of infants with AD and CMA fed a rice-hydrolysate formula
compared with a soy or extensively hydrolysed casein formula
To assess the efficacy and safety of open-label maintenance after milk oral
immunotherapy in children with cow’s milk allergy
To examine nutrient intake in children with cow’s milk allergy on diets with
variable amounts of cow milk protein.
To assess cow’s milk desensitization protocol
RCT
Allergy, not specified
RCT
Not specified
RCT
RCT
Chronic constipation
Cow’s milk allergy syndrome
RCT
Cow’s milk allergy syndrome,
Rhinitis, rhino-conjunctivitis,
conjunctivitis
Cutaneous, respiratory, gastrointestinal
symptoms (not otherwise specified)
Cow’s milk allergy syndrome
RCT
CT
RCT
CT
Cow’s milk allergy syndrome; atopic
dermatitis
Atopic dermatitis
Cohort
Multiple
Cohort
Cow’s milk allergy
Cohort
Cow’s milk allergy
** Only 3/10 infants with GERD were diagnosed with cow’s milk allergy.
Table Notes: AD atopic dermatitis; CMA=cow’s milk allergy; CMF cow milk formula; CMPA cow’s milk protein allergy; CT controlled trial (not randomized); EHF
extensively hydrolysed formula; GERD Gastroesophageal reflux disease
226
Table 52: Treatment/management - specific food allergy studies: patient characteristics
Author
Intervention Group Selection Criteria
Inclusion/exclusion criteria
IgE
Skin
Clini
Test
cal
rxn
Peanut
Allergy
Inclusion: patients with peanut and nut allergy
No
Yes
Yes
Ewan,
2001214
Inclusion: Age 1-16 years with a clinical history of
Jones,
Yes
Yes
Yes
reaction to peanut within 60
2009342
minutes of ingestion, a positive peanut skin prick test
and a peanut CAP. Exlusion: history of severe, lifethreatening anaphylaxis (with hypotension) to peanut,
severe or poorly controlled asthma, or a medical
condition
preventing undergoing a food challenge
Inclusion: Food allergy to hazelnuts
No
No
Yes
Hansen,
Exclusion: Anaphylaxis due to hazelnuts
2003343
Inclusion: Age 1-16 years with peanut allergy.
Hofmann et
Yes
Yes
Yes
Exclusion: Severe anaphylaxis, inability to cooperate
al., 2009211
with challenge procedures or follow-up
Cow’s milk
allergy
Inclusion: pregnant women recruited from midwives
Jong,
No
No
No
practices who intended to breastfeed for at least 6
2002332
weeks who spoke Dutch, birth weight >2749g,
gestational age over 36wks, newborn not treated with
oxygen for longer than 30 minutes after birth, newborn
not needing ICU services/parenteral feeding/or IV
antibiotics; newborn did not have any disorder that
required substitution or supplementation.
Term but low birth weight infants (-1 to -2 SD)
No
No
No
Lindfors,
1992339
227
Control
Selection
Criteria
NA
NA
NA
Subject Demographics
Intervention
Control
Median age: 7.5
years
Median age: 57.5
months, 64% male
NA
NA
Median age: 24.5
years, 65% female
Mean age 4.8 years
(1.1-9.4)
NA
Same as
intervention
group
high family risk of
atopy: 58%
high family risk of
atopy: 57%
Same as
intervention
group
age 4.8 years
age 4.7 years
NA
NA
Table 52: Treatment/management - specific food allergy studies: patient characteristics (Continued)
Author
Savino,
2005340
Iacono,
1998335
Klemola,
2002313
Niggemann,
2008336
Intervention Group Selection Criteria
Inclusion/exclusion criteria
IgE
Skin
Test
Inclusion: born at term with a birthweight between
2500 and 4000 grams, Apgar >7 at 5 minutes, no
clinical evidence of acute or chronic diseases that
affect growth, atopic dermatitis, absence of GI
symptoms of food allergy, cow’s milk allergy
Inclusion: chronic constipation (1 bowel movement
every 3-15 days).
Exclusion: anatomical reasons for constipation (i.e.
Hirschsprung, spinal disease), constipation due to
another disorder (i.e. hypothyroidism/
psychomotor-retardation), prior surgery, use of
medications that cause constipation (i.e.
chlorpromazine), and referral for reasons other than
constipation
Infants with IgE or non-IgE cow's milk allergy as
diagnosed by double blind placebo controlled food
challenge or a history of anaphylaxis with cow's milk
and presence of IgE specific antibodies
No
Yes
Clini
cal
rxn
Yes
NR
NR
NR
Yes
Yes
Inclusion: healthy infants who had previously been
diagnosed with CMPA; birth at term (37-42 weeks),
birth weight between 2500 and 4000 grams, maximum
intake of breast milk 2x/day
Exclusion: malformations, congenital cardiovascular,
kidney, liver, CNS, or metabolic diseases, serious GI
tract disease, or lactose intolerance
No
No
228
Control
Selection
Criteria
Subject Demographics
Intervention
Control
Same as
intervention
group but
without cow’s
milk allergy
Same as
intervention
group: crossover study
age: 3.27 months
+/- 0.32
age: 4.03 months
29 males; 36
females; mean age
34.6 months (range
11-71 months)
NR: cross-over
study
Yes
Same as
intervention
group
Yes
Same as
intervention
group
Age: 7.1 years;
Immediate/
delayed CMA:
41/39; atopic
eczema: 52%; GI
symptoms: 19%;
IgE antibodies+ to
CM: 37%; SPT+
with CM: 38%
13 males; 19
females;
age: 250 days (75)
Age: 6.9 years;
Immediate/
delayed CMA:
59/319; atopic
eczema: 64%; GI
symptoms: 28%;
IgE antibodies+ to
CM: 64%; SPT+
with CM: 34%
12 males; 18
females;
age: 236 days (91)
Table 52: Treatment/management - specific food allergy studies: patient characteristics (Continued)
Author
Intervention Group Selection Criteria
Inclusion/exclusion criteria
IgE
Jirapinyo,
2007333
Inclusion: infants aged 2-24 months with diagnosis of
cow’s milk allergy based on disappearance of
symptoms with elimination of cow’s milk and
reappearance on reintroduction of it. Excluded: infants
with systemic diseases or severe malnutrition
No
No
Clini
cal
rxn
Yes
Garzi,
2002337
Inclusion: exclusively fed with cow milk derived
formula and had clinical symptoms of GERD with
symptom score >7
Yes
Yes
No
Vita,
2007338
Inclusion: age between 6 months and 3 years, clinical
history or cow’s milk allergy, positive prick test to cow
milk, positive DBPCFC to cow milk, active atopic
dermatitis with SCORAD Index >20 Exclusion:
Previously been fed with either ass milk or goat milk
Participants that could tolerate >2540 mg in their postmilk oral immunotherapy challenge upon conclusion of
the Skripak RCT
Children with parentally perceived reactions to milk or
egg at the age of 2 years
Children aged 4 or older with confirmed allergy to
cow’s milk
No
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Narisety et
al., 2009212
Henriksen et
al., 2000213
Zapatero,
2008 298
Skin
Test
Control
Selection
Criteria
Same as
intervention
group
Subject Demographics
Intervention
Control
Parental allergy:
12/18; 17% with
respiratory sx; 44%
with cutaneous sx;
39% with GI sx;
22% with
eosinophilia; 22%
with specific IgE
elevation
average age: 4.9
months (range 2-6)
Parental allergy:
13/20; 5% with
respiratory sx; 55%
with cutaneous sx;
40% with GI sx;
15% with
eosinophilia; 5%
with specific IgE
elevation
average age: 4.7
months (range 4-6
months)
First received ass
milk: 8 males; 6
females; mean age:
2.7 years (0.8-3.8),
First received goat
milk: 6 males; 8
females; mean age:
2.5 (0.6-3.7)
NA
Age range 6-16
years
NA
Yes
NA
NA
Yes
NA
Mean age: 2.5
years
Mean age 5.05
years
Exclusively fed
with cow milk
derived formula
without GERD
and not taking
any medications
Same as
intervention
group
NA
Table Notes: CM cow’s milk; CMA cow’s milk allergy; CMF cow milk formula; CMPA cow milk protein allergy; CNS central nervous system; GERD GI gastrointestinal;
DBPCFC double blind placebo controlled food challenge; EHF extensively hydrolysed formula; GERD Gastroesophageal reflux disease ICU intensive care unit; RCT randomized
controlled trial; SCORAD scoring atopic dermatitis; SD standard deviation; sIgE antigen-specific immunoglobulin; SPT skin prick test;
229
Table 53: Treatment/management - specific food allergy studies: intervention characteristics and outcomes reported
Author
Timing Info
Intervention Description
Sample Size
Experimental
Control
Experimental Control
Peanut allergy
Ewan, 2001214
Advice on avoidance and
Not applicable
1 year
567
NA
medications to use in case of an
accidental ingestion of peanuts;
medications also provided.
Jones, 2009342
Oral immunotherapy protocol
Not applicable
18 months
29
NA
including initial day escalation,
buildup, and
maintenance phases, and then
oral food challenge
Hansen, 2003343
Patients ingested raw and
Not applicable
Immediate after 17
NA
roasted hazelnuts
intervention
Hofmann et al.,
2009211
Oral immunotherapy protocol
with the goal to achieve
ingestion of a daily maintenance
dose of 300 mg of peanut
protein
Cow’s milk allergy
Jong, 2002332
Supplementation with whey
protein dominant cows' milk
formula given at least 3 times
during first 3 days after
randomization. Then, women
breast feed for 6 months
thereafter. No instructions
given with respect to avoidance
of cow's milk proteins after this
first 3 day period.
Not applicable
24 months
28
NA
Placebo formula free of
cows' milk protein given
during first 3 days after
randomization.
5 years
758
775
230
Outcomes reported
Follow-up reaction
Skin prick tests, peanutspecific IgE and IgG, IL-10,
IL-5, interferon-gamma, TNFalpha
DBPCFC, Clinical symptoms
of OAS, SPT, Heart rate,
specific IgE
Symptoms (upper respiratory
tract, skin, abdominal, chest)
or treatment
(diphenhydramine, albuterol,
or epinephrine) after treatment
with oral immunotherapy
Presence of atopic eczema,
rhinoconjunctivitis, wheezing,
and other clinical signs of
allergy; specific IgE by RAST
against cows' milk, hen's egg,
house dust mite, cat dander
and dog dander, grass pollen,
tree pollen, and moulds.
Table 53: Treatment/management - specific food allergy studies: intervention characteristics and outcomes reported (Continued)
Author
Lindfors, 1992339
Iacono, 1998335
Intervention Description
Experimental
Control
Cow milk formula from the first Breast milk only
day of life until normal
breastfeeding started
Timing Info
4-6 years
Sample Size
Experimental Control
109
98
Klemola, 2002313
Patients given soy milk or cow
milk for 2 weeks and then had
chronic constipation assessed.
This was followed by a 1 week
washout period and then 2
weeks with the opposite food,
either cow or soy
Soy formula
Niggemann,
2008336
New extensively hydrolyzed
formula
Jirapinyo, 2007333
Formula made from chicken
meat
Soy formula
Infants
evaluated at 30,
60, 90, and 180
days
14 days
Garzi, 2002337
Infants with GERD fed an
extensively hydrolyzed
hypoallergenic formula
Crossover trial; subjects
received either goat milk or ass
milk for 6 months, were
evaluated and then received the
other type of milk for 3 months.
Treatment group was first
assigned ass milk.
Continued to feed on
cow milk formula
1 week after
formula
10**
10
Cross-over trial
Evaluated 6
months after
first treatment
and then again 3
months after
next treatment
14
14
Vita, 2007338
Cow milk
2 weeks
65
Not
reported
Extensively hydrolyzed
formula
Amino acid formula
2 year
80
90
34
32
20
18
231
Outcomes reported
Clinical allergy as defined by
pediatrician examination; SPT
IgE for antibodies against
airway allergens and a custom
pediatric food allergen mix for
egg, milk, wheat, peanut and
soy bean.
Median number of bowel
movements before and after
treatment
Parents suspicion of adverse
reactions to formula
Z-scores for length, head
circumference, and weight;
SCORAD scores; IgE titers
Intolerance to formula, any
cutaneous, respiratory, or GI
symptoms (not otherwise
specified)
Gastric emptying time;
symptom scale of GERD
SCORAD to assess atopic
dermatitis; VAS
Table 53: Treatment/management - specific food allergy studies: intervention characteristics and outcomes reported (Continued)
Author
Savino, 2005340
Narisety et al.,
2009212
Henriksen et al.,
2000213
Zapatero, 2008 298
Intervention Description
Experimental
Control
Either rice based hydrosylate
Free diet
formula (RHF), soy-based
formula (SF), or extensively
hydrolyzed casein formula
(eHCF)
Gradual home dose escalations
of milk of no more than 50%
increments every 2 weeks
Divided into 4 groups: milkfree, formula, milk-reduced, and
milk
Desensitization protocol to
cow’s milk
Timing Info
Every 3 months
in the 1st year
of life and then
at 6 month
intervals in 2nd
year of life
Median=17
weeks (range
13-75 weeks)
4 day
Not applicable
Not applicable
Not applicabale
Median=14
weeks (range 932 weeks)
Sample Size
Experimental Control
RHF--15;
30
SF--17;
eHCF--26
Outcomes reported
Z-score of weight
15
NA
Adverse reactions, milk
threshold, SPT, IgE, IgG
34
NA
Dietary recall recorded by
parents
18
NA
Tolerance to cow’s milk
** Only 3/10 infants with GERD were diagnosed with cow’s milk allergy.
Table Notes: EHF=extensively hydrolyzed formula; CMF=cow milk formula; NA=not applicable; GERD=gastroesophageal reflux disease; GI gastrointestinal; HCF hydrolysed
casein formula; IgG immunoglobulin G; RAST=radioallergosorbent test; RHF rice-based hydrolysate formula; SCORAD=scoring atopic dermatitis; SF soy-based formula; sIgE
antigen-specific immunoglobulin; SPT skin prick test
232
Figure 11: Treatment/management - summary of Evidence by Food Type
Specific Food
Peanut/
Hazelnut
Prevention
Strategies
Cow’s Milk
Hen’s Egg
Delayed introduction of foods
пЃ¬ 251
Maternal diets
пЃ¬ 322
Fish
Apple
Breast feeding
пЃ¬335
пЃ¬313
333
пЃ¬
пѓ…338
пѓ…325
Special diets for infants and
young children
в—‹332 в—‹336
в—‹337в—‹340
в—‹339
Probiotics
пЃ¬291
пЃ¬317
Elimination diet
Treatment
Management
Strategies
Immunotherapy
Allergen avoidance
пѓ…295
в—‹C342
пЃ¬294
пЃ¬296
пЃ¬C214
пЃ¬262
в—‹C343
в—‹341
пЃ¬
316
пѓ…300пѓ…301
пѓ…302
пЃ¬296
в—‹318
Pharmacology
Probiotics
пЃ¬294
пЃ¬296
пЃ¬262пЃ¬317
пЃ¬322пЃ¬296
в—‹326
пЃ¬ Statistically significant improvement
в—‹ No statistically significant improvement
пѓ… Some statistically significant improvement in some outcomes but not in all outcomes measured. C=Cohort study. Other studies are controlled trials.
233
Evidence for the Prevention, Treatment, or Management of Specific
Clinical Conditions Associated with Food Allergies
Most of the included studies evaluated multiple clinical conditions associated with food allergies.
The most common food allergy-related conditions studied were asthma, oral allergy syndrome,
AD, EE, and dermatitis herpetiformis (Figure 11). The tables for this section only provide data
not already previously presented in the other evidence tables.
Prevention, Treatment, Management of Asthma
Background
Crossectional studies of adults with asthma report that in excess of 20 percent have
allergic/asthmatic symptoms to at least one food.101 Moreover, these patients are more likely
than the non-food allergic asthma patients to have increased health care utilization (e.g.,
hospitalizations and emergency department visits for asthma).
Results
Eight studies evaluated strategies for the prevention, treatment, and/or management of asthma in
the setting of food allergy.226, 252, 255, 269-271, 288, 289
Mass et al289 performed a review of mono or multifaceted inhalant and/or food allergen reduction
interventions for preventing asthma in children at high risk of developing asthma. The literature
search and screening process was comprehensive and followed the methods used by the
Cochrane Collaboration. The search was conducted in December, 2008 and included 9
randomized controlled trials of allergen exposure reduction for the primary prevention of asthma
in children with follow up to a minimum of two years of age in 3,271 children. The review
scored highly on the AMSTAR criteria for evaluating systematic reviews (9 criteria met). They
reported that the reduction of exposure to multiple allergens (inhalant and food), resulted in
fewer cases of physician diagnosed asthma for children < 5 years of age; OR 0.72; 95% CI 0.540.96 and fewer cases of asthma as defined by respiratory symptoms and lung function for
children > 5 years if age OR 0.52; 95% CI 0.32-0.85. However, there was no statistical
difference in cases of physician diagnosed asthma from the reduction of exposure to
monofaceted allergens (inhalant or food); OR 1.12; 95% CI 0.76-1.64 for < 5 years of age and
OR 0.83; 95% CI 0.59-1.16 for > 5 years of age.
Von Berg270, 271 performed a study to investigate the long-term allergy-preventive effect of three
hydrolyzed infant formulas compared with cow’s milk formula. Between 1995 and 1998, 2,252
newborns with atopic heredity were randomly assigned at birth to receive one of four blinded
formulas: partially or extensively hydrolyzed whey formula, extensively hydrolyzed casein
formula, or CMF as milk substitute for the first four months when breast feeding was
insufficient. At three years of follow-up, there was no statistically significant effect on the
incidence of asthma. In an intention to treat analysis of 2,252 children at six years of follow-up,
it was found that only the extensively-hydrolyzed whey formula had an increased RR of asthma
of 2.16 (95%CI, 1.02, 4.58). This was not found in the per protocol analysis.
In a meta-analysis, by Osborn and Sinn,269 three studies exploring the effect of soy formula vs.
cow milk formula in the prevention of asthma were synthesized (Miskelly 1988, Johnstone 1966,
234
and Kjellman 1979). A weighted least squares regression for soymilk found a non-significant
RR of 0.71 (95%CI, 0.26,1.92). Burr et al226 studied 453 children with a family history of
allergic disease. Withholding cow milk and replacing it with soymilk during the first three
months of life did not significantly decrease the incidence of wheezing at a follow-up of seven
years of age. Children who had ever been breastfed had a lower incidence of wheeze than
children who had not (59 percent vs. 74 percent).
Kajosaari252 performed a five-year prospective study to determine the benefits of exclusive
breastfeeding for six months combined with delayed introduction of solid foods in children at
high risk for atopic disease. In an examination at 5 years of age, 8 percent of infants who were
exclusively breastfed until 6 months of age had asthma while 15 percent of those who started
solid foods at three months of age had asthma, a non-significant difference.
Abrahamsson et al288 studied the prevention of eczema and sensitization using oral
supplementation of probiotics in infants with a family history of allergic disease. After
treatment, the cumulative incidence of asthma was not significantly different between the
placebo group (10 percent) and the group receiving probiotics (7 percent).
Sigurs et al255 studied the effect of maternal avoidance of egg, cow milk, and fish during the first
three months of lactation on allergic manifestations in children at 4 years of age. There was no
effect on the cumulative incidence of asthma in children with mothers on a restricted diet (11
percent) and those with mothers on a non-restricted diet (12 percent).
Summary
The quality of evidence for interventions aimed at preventing, treating, or managing asthma is
highly heterogeneous in that there is not a preponderance of literature for any particular type of
intervention. Avoidance of food allergens in combination with avoidance of inhalant allergens
does appear to prevent asthma, but solely avoiding food allergens does not.
Prevention, Treatment, Management of Oral Allergy Syndrome
Background
In adults, up to 60 percent of all food allergic reactions are due to cross-reactions between foods
and inhaled allergens. OAS is a type of food allergy typified by a cluster of allergic reactions in
the mouth in response to eating certain fruits and nuts that typically develops in adults who suffer
from hay fever. OAS sufferers may have any of a number of allergic reactions that usually occur
very rapidly, within minutes of eating a trigger food. The most common reaction is an itching or
burning sensation in the lips and mouth.
235
Results
Four RCT studies evaluated the prevention, treatment, or management of OAS.300-302, 315 Three
of these studies examined immunotherapy as a treatment for the oral allergy syndrome,300-302 and
one studied the effect of drug therapy with an H2-blocker315 In addition, one study344 was an
open observational study that examined the effect of pollen-specific sublingual immunotherapy
on OAS triggered by several foods.
Hansen et al.300 noted that clinical manifestations of allergenic cross-reactions between pollen
and plant foods are frequent in birch pollen allergic patients and evaluated the effect of birch
pollen extract immunotherapy in patients with apple allergy. Symptom Outcome: There was no
statistically significant change in oral allergy syndrome to an open apple food challenge after
treatment with placebo, or sublingual or subcutaneous birch pollen extracts. Lab Outcome:
There was a statistically significant decrease in apple sIgE in patients treated with subcutaneous
birch pollen extract from 5.9 kU/L to 1.8 kU/L (p=0.009). No statistically significant change
was reported in those patients receiving sublingual birch pollen extract or placebo.
Bucher et al.301 also examined the effect of subcutaneous immunotherapy with tree pollen extract
on patients’ OAS-related responses to apple and hazelnuts. Symptom Outcome: Improvement
of OAS was statistically significant (p<0.05) with 10/15 patients receiving subcutaneous
immunotherapy showing improvement (compared with only 2/12 controls). Lab Outcome:
changes in sIgE to apple were also measured and found to be non-significant. However, it was
reported that changes in IgG4 r Bet v1 were statistically significant p<0.001 in the group treated
with immunotherapy, but no values were given.
Asero at el.302 evaluated birch pollen-sensitive patients with apple-induced OAS who received
injection immunotherapy with birch pollen extract. Symptom Outcome: This treatment was
found to reduce clinical apple sensitivity (p<0.001). Lab Outcome: No reduction in apple sIgE
was noted.
Bindslev et al.315 examined the effect of astemizole (an H2-blocker) on oral allergy syndrome
induced by consumption of hazelnuts in patients with positive SPT to birch pollen. Symptom
Outcome: Symptom severity to the oral provocation test was significantly lower in the group
that got aztemizole than the placebo group (p=0.004).
The open observational study by Bergmann et al.344 studied pollen-specific sublingual
immunotherapy in treating the OAS. Symptom Outcome: The investigators rated OAS severity
at baseline as at least moderate in 94.9 percent of patients compared with 36.9 percent after 12
months of treatment with pollen-specific sublingual immunotherapy. After 12 months, OAS was
rated as much- or very much improved in 72.9 percent of patients.
Summary
The quality of evidence here is high. Immunotherapy is effective in improving some outcomes
for patients with OAS. IgG4 levels appear to increase with treatment while allergen-sIgE levels
may or may not decrease with immunotherapy.
236
Prevention, Treatment, Management of Atopic Dermatitis
Background
Atopic dermatitis, a type of eczema, is an inflammatory, chronically relapsing, non-contagious,
and pruritic skin disease often triggered by irritants such as food and environmental allergens.
Results
Two reviews and six RCTs evaluated atopic dermatitis prevention, management, or treatment.
We identified two reviews that evaluated the effect of dietary exclusion for treating atopic
eczema253, 314 and one controlled trial not included in the review.291 Probiotics for the treatment
of atopic eczema/dermatitis was reported in one study326.One study reported the effect of sodium
cromoglycate and an elimination diet on the severity of eczema320. We also identified one study
that reported the effect of adding thymomodulin to an elimination diet in the treatment of food
allergen-induced atopic dermatitis.317 Two studies evaluated formulas in infants with atopic
dermatitis.324, 340 One evaluated a home-made meat based formula for feeding atopic babies.324
and the other compared a rice-hydrolysate formula with soy or extensively hydrolyzed casein
formula.340 The effect of cromolyn in children with atopic dermatitis and food sensitivity was
also explored.318
Both reviews had a comprehensive literature search and screening process and followed the
methods used by the Cochrane Collaboration. They both scored highly on the AMSTAR criteria.
As part of their review on allergy prevention, Kramer et al. whether maternal dietary antigen
avoidance during lactation by mothers of infants with eczema could reduce eczema severity.253
The review found one small trial (n=17) that met their inclusion criteria for this part of the
review, which found no significant reduction in eczema area score (mean difference -0.8; 95%
CI -4.43 to 2.83) or eczema activity score (mean difference -1.4; 95% CI -7.18 to 4.38) between
infants whose mothers avoided dietary antigens and those whose mothers followed a usual
diet.253
Bath-Hextall et al. evaluated the effect of patient dietary exclusion for treating established atopic
eczema.314 Their search of the published literature (conducted as of March 2006) resulted in the
inclusion of nine low-quality RCTs of which they considered only two sufficiently similar to
combine. Six of the RCTs examined milk and egg exclusion, one was a study of a diet limited to
only a few foods, and two evaluated elemental diets. The authors found no evidence to support
the use of these dietary exclusion strategies for treating atopic eczema in an unselected
population, possibly due to patients not being allergic to the substances being eliminated or
because of small study sizes and poor reporting. However, the authors suggested that there might
be some benefit of an egg-free diet in infants with positive egg sIgE results (results from one
study).
Agata et al.291 studied the effect of an elimination diet for milk or egg allergies on atopic
dermatitis in a non-randomized comparative study. Twenty-seven patients sensitive to egg and
16 patients sensitive to milk underwent an elimination diet for at least three months. They were
237
compared with six patients sensitive to egg and five patients sensitive to milk who did not
eliminate the allergen from their diets. The results showed that in those with egg allergy, 27/27
showed improvement in their atopic dermatitis with an elimination diet (compared with 0/6 not
on an elimination diet). In those with a milk allergy, 15/16 showed improvement in their atopic
dermatitis with elimination diet (compared with 0/5 not on an elimination diet). They concluded
that an elimination diet is a good treatment for food allergy and that sIgE antibodies to food
antigens were useful as indexes of the effect of elimination diets in patients with positive RAST.
Cavagni et al.317 evaluated the effects of adding thymomodulin to elimination diets in treating
atopic dermatitis induced by food allergy. They noted a more favorable course of the skin
lesions in the patients treated with thymomodulin after two weeks of food challenge. They also
noted a statistically significant decrease in total and sIgE serum levels in the group receiving
thymomodulin.
Cantani324 studied the effect of a home-made meat-based formula for feeding atopic babies. They
reported significant improvement in SCORAD scores in the group treated with the meat-based
formula.
Savino et al.340 evaluated the growth of infants with atopic dermatitis and cow’s milk allergy fed
a rice-hydrolysate formula compared with a soy or extensively hydrolyzed casein formula. No
significant differences in the z-score weight for age were found.
Burks and Sampson318 studied cromolyn in children with atopic dermatitis and documented food
hypersensitivity. This crossover study showed that after one week of treatment with either
cromolyn or placebo, there was no statistically significant difference in the symptom score for
atopic dermatitis.
Vita et al.338 assessed the tolerability and clinical effect of ass's milk compared with goat's milk
in children with atopic dermatitis from cow’s milk allergy. Ass milk significantly improved both
the SCORAD index and the visual analog scale (p<0.03) whereas goat milk had no effect.
Businco et al.320 evaluated 31 children aged 6 months-10 years old with atopic dermatitis
exacerbated by foods in a crossover study to evaluate the effects of sodium cromoglycate and an
elimination diet on the severity of eczema. They concluded that eczema (measured both by the
clinician and the parents was statistically improved when the patients were receiving sodium
cromoglycate.
Maternal/neonatal interventions
One RCT262 and two non-randomized comparative studies261, 341 evaluated the effect of restricted
maternal diet during pregnancy or lactation, supplementation with either soy or hydrolyzed
formulas and delayed introduction of solids to infants, on the incidence of atopic disease in
children.
238
Two of the studies261, 262 found a protective effect of the intervention on atopic disease, while the
third341 found no significant difference in either atopic dermatitis or sensitization to egg or cow
milk between the intervention and control groups at 12 months. The fair quality RCT by Arshad
et al.262 reported study results at eight years and found a “sustained preventive effect of allergen
avoidance in infancy” (Table 38-Table 41)
Filipiak et al. reported their results based on an expanded analysis of the GINI (German Infant
Nutritional Intervention Program) cohort study. They examined the effect of a multimodal
intervention (exclusive breastfeeding or supplementation with one of four hydrolyzed formulas
and delayed introduction of solid foods) on the occurrence of eczema during the first four years
of life.260 They compared infants at high risk of developing atopic disease whose mothers were
given recommendations to delay solid food introduction to infants without a family history of
allergy or those infants whose parents refused to participate in the intervention. They found
significantly higher rates of doctor-diagnosed eczema in the intervention group (29 percent)
compared to the control group (20 percent) (p<0.001), but found no association between eczema
and feeding practices (time of introduction or diversity of foods introduced); this study was rated
as poor quality.
Summary
The quality of evidence here is moderate. Maternal avoidance diets appear to have no effect on
infant atopic dermatitis while elimination diets of persons suffering from atopic dermatitis and
food allergy may improve atopic dermatitis.
Prevention, Treatment, Management of Eosinophilic Esophagitis
Background. Eosinophilic esophagitis (EE) is characterized by infiltration of the esophagus
with eosinophils without infiltration in other parts of the gastrointestinal tract. The symptoms of
EE are similar to gastroesophageal reflux disease (GERD) but patients with EE are unresponsive
to standard GERD treatment and have normal pH probe results.
Results. We identified one systematic review,327 two RCTs,319, 345 and two cohort studies204, 346
that evaluated dietary or medical interventions for treating EE.
Kukuruzov et al.327 conducted a comprehensive literature search and screening process and
followed the methods used by the Cochrane Collaboration; the review scored highly on the
AMSTAR criteria. Their search found an abstract of preliminary results from one unfinished
RCT comparing topical (swallowed metered dose) fluticasone with oral prednisone in children.
In the 50 children enrolled to date the results indicated no difference between the two treatments.
The authors also identified another ongoing RCT comparing swallowed fluticasone with placebo
among 3- to 21-year-olds; no results are available on this RCT as yet.
Schaefer et al.319 compared oral prednisone to topical fluticasone in the treatment of EE. They
found a statistically significant difference in histologic response favoring the prednisone over the
fluticasone group between weeks 0 and 4 (p=0.0440).
239
Konikoff et al.345 randomly assigned 36 patients to receive 880ug of swallowing of inhaled
fluticasone or placebo. They found that disease remission, defined as a peak eosinophil count п‚Ј1
eosinophils per high-powered field (eo/HPF), favored the fluticasone group with a p=0.47.
Spergel et al.204 performed a cohort study to evaluate the effect of an elimination diet in treating
EE. They found a decrease in the number of eo/HPF in 112/146 patients.
Liacouras et al.346 reported a retrospective study of 381 children with EE. They found that
clinical symptoms improved in 27 of 29 patients treated with oral methylprednisolone for four
weeks and the number of eo/HPF decreased from 33.5 (9.5) to 0.9 (0.6). In patients treated with
inhaled fluticasone, 14/17 showed clinical improvement and the eo/HPF decreased from 27.7
(5.0) to 11.2 (2.7). All of these findings reversed within 4-6 months upon removal of the
medication. In 14 patients treated with cromolyn there was no improvement in clinical
symptoms or reduction in eosinophils. Elimination diet was found to be helpful in reducing
clinical symptoms in 75/132 patients, and 160/164 patients who underwent complete dietary
elimination with an amino-acid based formula showed clinical improvement.
Summary
The quality of evidence here is moderate and supports the use of oral corticosteroids and
elimination diets to treat eosinophilic esophagitis.
240
Table 54: Specific clinical conditions associated with food allergies: design and patient characteristics
Author
Country Purpose
Study design Food of
Intervention Group Selection Criteria
interest
Inclusion/
IgE Skin Clinical
exclusion criteria
Test reaction
Oral allergy syndrome (OAS)
Germany To examine the effect Prospective apple,
Bergmann,
Patients had pollenNo
No
Yes
of pollen-specific
hazelnut,
2008344
induced allergic
cohort
carrot
sublingual
rhinoconjunctivitis and
immunotherapy on
concomitant OAS and did
OAS
not have known
contraindications to
specific immunotherapy.
Eosinophilic esophagitis (EE)
Diagnosis of EE with one
Spergel, 2005204
US
To determine if an
Prospective milk, egg,
No
Yes
Yes
or more of the following:
elimination diet is
soy, peanut,
cohort
chicken,
vomiting, regurgitation,
useful in treating EE
wheat, peas,
abdominal pain, or
beef, corn,
dysphagia unresponsive to
potatoes, rice 2 months of PPI and EGD
bx with > 15 eosinophils
per hpf
All patients diagnosed
US
To describe EE in
Retrospective milk, egg,
Liacouras,
No
Yes
Yes
with eosinophilic
children
case series
wheat, soy,
2005346
corn, beef,
esophagitis from Jan 1
chicken,
1994-Jan 1 2004 at the
potatoes,
Children's hospital in
oats,
Philadelphia
peanuts,
turkey,
barley, rice,
pork, green
beans,
apples,
pineapple
Dermatitis herpetiformis (DH)
Gariouch, 1994347 UK
To describe 25 years
Gluten
Patients seen in
Cohort
No
No
Yes
of experience in
dermatology clinic with
patients on a glutendermatitis herpetiformis.
free diet to treat DH
Intervention
Demographics
Median age
34.5 years (664); 33.3 %
male and
66.7% female.
mean age 6.5
+/- 4.5 years
251 males;
mean age 9.1
years +/- 3.1
128 males; 84
females;
average age 42
(9-83)
Table Notes: DH dermatitis herpetiformis; EGD Esophagogastroduodenoscopy; EE eosinophilic esophagitis; OAS oral allergy syndrome; PPI protein pump inhibitors
241
Table 55: Specific clinical conditions associated with food allergies: intervention characteristics and outcomes reported
Author
Timing Sample Size
Intervention Description
Info
Experimental
Control
Experimental Control
Oral allergy syndrome (OAS)
An open observational study examined the
Bergmann,
NA
12
102
NA
effect of pollen specific sublingual
2008344
months
immunotherapy on OAS triggered by
several foods
Eosinophilic esophagitis (EE)
Spergel, 2005204
People were asked to follow an elimination
diet for 6 weeks and then underwent a
repeat EGD to determine if their EE had
improved or worsened
Multiple: medications; elimination diet
Liacouras,
2005346
Dermatitis herpetiformis (DH)
Gariouch, 1994347 Gluten-free diet
Outcomes reported
At baseline, investigators rated
OAS severity as at least
moderate in 94.9% of patients
compared with 36.9% after 12
months of treatment. After 12
months, OAS was rated as
much or very much improved
in 72.9% of patients
Not applicable
6 weeks
146
Not
applicable
Resolution of EE
Not applicable
6
months
381
Not
applicable
Clinical symptoms; number of
eosinophils per high-powered
field
Not applicable
19671992
212
Not
applicable
Control of rash; reduction in
medication dose
Table Notes: DH dermatitis herpetiformis; EGD Esophagogastroduodenoscopy; EE eosinophilic esophagitis; OAS oral allergy syndrome; PPI protein pump inhibitors
242
Figure 12: Summary of Evidence by Specific Clinical Condition
Asthma
Specific Clinical Condition
Oral Allergy
Atopic
Eosinophilic
Syndrome
Dermatitis
Esophagitis
Dermatitis
Herpetiformis
Delayed introduction of foods
пЃ¬262
пЃ¬C261
в—‹C341
в—‹255
Maternal diets
Prevention Strategies
Breast feeding
Special diets for infants and
young children
Probiotics
Allergen Avoidance
в—‹252
в—‹R269
в—‹270
в—‹226
в—‹
в—‹340
в—‹324
в—‹340
пЃ¬324
пЃ¬338
пѓ…260
288
пѓ…289
в—‹R314
в—‹R*253
пЃ¬291
в—‹317
Elimination diet
Treatment
Management
Strategies
пЃ¬C346
пЃ¬C204
пѓ…300
пѓ…301
пѓ…302
пѓ…299
в—‹303
пЃ¬C344
Immunotherapy
Desensitization
Allergen avoidance
пЃ¬315
Pharmacology
243
в—‹318
пЃ¬320
в—‹R327
пЃ¬319
пЃ¬C346
пЃ¬C347
Probiotics
в—‹326
пЃ¬ Statistically significant improvement пѓ… Some statistically significant improvement in some outcomes but not in all outcomes measured.
в—‹ No statistically significant improvement
C=Cohort study; R=Systematic review; Other studies are controlled trials. *This review253included only one RCT
that evaluated elimination diet.
244
Conclusions
A principal conclusion of this review is that the quality of evidence is poor for most
aspects of food allergy. After screening more than 11,000 titles from which we identified
and read in more detail nearly 1,000 published papers, we found very few areas where we
could draw anything more than tentative conclusions. Central to the problem of
synthesizing the literature on food allergy is the lack of an agreed-upon criteria for
diagnosis. This lack of a standardized, operational criteria means that results of
incidence, prevalence, and natural history cannot be compared across studies, that there is
no single “gold standard” to use for assessing the sensitivity, specificity, and other
properties of diagnostic tests, and that studies of treatments may not be comparable due
to differing methods used to identify patients with food allergy for inclusion in the study.
The lack of standardized criteria for what constitutes a diagnosis of food allergy is a
major limitation to further understanding of this.
With that limitation in mind, there are a few consistent findings that we can point to.
First, while the prevalence of food allergies varies from study to study and depends
greatly on the criteria used for diagnosis, in general it is not much more than 10%, and
may be much lower. For specific foods, allergy to cow’s milk is generally greater than
allergies to other foods, at least in children, but the prevalence of cow’s milk allergy
declines in adults, while the prevalence of allergies to other foods generally remains more
constant. Allergies to other foods are common in patients with one identified food
allergy, and other conditions such as asthma and atopic dermatitis are extremely common
in individuals identified as food-allergic. Cow’s milk allergy clearly lessens in
prevalence over time. While there are documented cases of some patients “outgrowing”
their allergy, in general this does not happen for nuts, peanuts, and shellfish; although
reactions to any particular exposure can be variable. The natural history of other food
allergies has not been studied in US populations.
Second, with regard to diagnosis, the double-blind placebo-controlled food challenge
remains the gold standard, although concerns exist regarding its practicality, validity, and
safety. As a result, simpler, less intensive tests are often used. The skin prick test is one
such method. Studies assessing its utility are plagued by lack of standardization of how
to administer the test and what constitutes a positive test. Compared to a food challenge,
sensitivities of 60%-95% and specificities of 40%-95% are commonly reported, and
depend on food type and wheal size, among other things. Blood tests for antigen-specific
IgE are also commonly used, and also suffer from differing thresholds being used to
classify a test as “positive”, along with differences in the type of test and type of food.
Compared to a food challenge, sensitivities of 44%-57% are reported, with specificities
of 95% to 100%. Atopy patch testing is commonly used to assess delayed immunologic
response, but also suffers from lack of standardization. A number of other tests have
been proposed as useful for diagnosing food allergies, but few have been subjected to
rigorous assessment. Combinations of tests may offer some benefits, but the incremental
value, and optimal sequencing, of series of tests remains uncertain. Our meta-analysis of
those conditions (cow’s milk, egg, wheat) and those tests (SPT, sIgE, APT) where data
245
were efficient to support construction of Receiver Operator Characteristic curves did not
find evidence that any one test was more accurate than any other tests either, within foods
or across foods.
Third, with regard to treatment, special diets in infancy seem to help reduce the
occurrence of childhood atopic diseases in high-risk babies, some forms of
immunotherapy with or without desensitization improve some symptoms of food allergy,
and allergen avoidance is a commonly recommended management strategy for specific
food allergies but has been relatively little studied, in part perhaps because of uncertainty
regarding how to assess a “failed” trial of allergen avoidance (was the diet a failure or is
the patient not allergic to the food that was avoided?)
Fourth, the most common treatment for food allergies—allergen avoidance—was
evaluated in only one small non-randomized comparative study which suggested that it
may be an effective means of reducing allergy symptoms. A key gap in the food allergy
literature is a detailed evaluation of how to assess a “failed” trial of allergen avoidance.
Some forms of allergen specific immunotherapy improve some symptoms of food
allergy. The potential for anaphylaxis and other significant side effects, coupled with the
fact that only four of the six studies of this treatment strategy specifically reported side
effects, suggests that future studies of immunotherapy should systematically assess and
report on common and serious side effects.
The importance of guidelines for the diagnosis and management of food allergy are made
clear by two studies we identified as part of this literature review. In the first, caregivers
of children attending the University of Maryland Allergy practice were invited to
complete a survey that included the Food Allergy Impact Scale.348 Of 101 caregivers
approached, 87 (86 percent) agreed to participate. More than 60 percent of respondents
stated that the presence of food allergy affected meal preparation, more than half stated
that it affected family social activities, and one quarter stated they never allowed a child
to go to camp or a sleepover because of food allergy. With these kinds of effects on their
lives of children and their families, the need for accurate diagnosis is clear.
The second article reported on the treatment of food allergy patients at 21 emergency
departments in 5 US states and 4 Canadian provinces.15 In this study, 678 records were
reviewed from among 5296 charts identified as having a physician-diagnosed foodrelated acute allergic reaction. In 51 percent of cases the reaction was considered severe.
Thirty three percent of patients had a documented respiratory rate. Four patients (0.5
percent) had a peak flow recorded. About three quarters of patients received an
antihistamine, and almost half received systemic steroids, while only 16 percent received
epinephrine. These data indicate that current care is probably not adequate for acute
allergic reactions. Similar data are not available describing the details of chronic
management, but it can be expected to also vary. Effective practice guidelines will be a
first step at improving care for food allergies.
246
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Appendix A: Search Strategies
FOOD ALLERGIES – SEARCH METHODOLOGIES
SEARCH #1a (Diagnosis/Testing):
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2008 (December)
LIMITERS:
Human
SEARCH STRATEGY:
food hypersensitivity/diagnosis
OR
food hypersensitivity AND (Diagnostic Techniques and Procedures[majr] OR Diagnostic
Equipment[majr])
OR
food hypersensitivity AND (test[tiab] OR testing[tiab] OR tests[tiab])
OR
(food*[tiab] AND allerg*[tiab]) AND (diagnosis OR diagnose OR diagnosing OR diagnostic* OR
test[tiab] OR testing[tiab] OR tests[tiab])
NOT
case report*
NUMBER OF ITEMS RETRIEVED: 4654
================================================================
SEARCH #1b (Diagnosis/Testing - Revision)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March 3)
LIMITERS:
Human
SEARCH STRATEGY:
food hypersensitivit* OR food allerg*
AND
predictive value of tests OR skin tests OR patch tests OR immunologic tests OR
radioallergosorbent tests OR in vitro tests OR immunoassay OR basophil histamine release
assay OR food challenge* OR diagnosis[ti] OR diagnoses[ti] OR diagnostic[ti] OR diagnosing
NUMBER OF ITEMS RETRIEVED: 3131
================================================================
277
SEARCH #1c (Diagnosis/Testing)
DATABASE:
Cochrane Database of Systematic Reviews
SEARCH STRATEGY:
(food hypersensitivity or (food* and (allergy or allergies or allergic or allergen*))).mp. [mp=title,
abstract, full text, keywords, caption text]
AND
(diagnosis or diagnoses or diagnose or diagnostic* or diagnosing or test or tests or testing).mp.
NUMBER OF ITEMS RETRIEVED: 82
================================================================
SEARCH #1d (Treatment)
DATABASE:
Cochrane Database of Systematic Reviews
SEARCH STRATEGY:
(food hypersensitivity or (food* and (allergy or allergies or allergic or allergen*))).mp. [mp=title,
abstract, full text, keywords, caption text]
AND
(treatment or treat or treating or treated or therapy or therapies or therapeutic or manage or
management or managing).mp
NOT
Results of Search 1c
NUMBER OF ITEMS RETRIEVED: 7
================================================================
SEARCH #1e (Diagnosis/Testing)
DATABASE:
Cochrane Database of Abstracts of Reviews of Effects (DARE)
SEARCH STRATEGY:
(food hypersensitivity or (food* and (allergy or allergies or allergic or allergen*))).mp. [mp=title,
abstract, full text, keywords, caption text]
AND
(diagnosis or diagnoses or diagnose or diagnostic* or diagnosing or test or tests or testing).mp.
NUMBER OF ITEMS RETRIEVED: 2
================================================================
SEARCH #1f (Treatment)
DATABASE:
Cochrane Database of Abstracts of Reviews of Effects (DARE)
SEARCH STRATEGY:
278
(food hypersensitivity or (food* and (allergy or allergies or allergic or allergen*))).mp. [mp=title,
abstract, full text, keywords, caption text]
AND
(treatment or treat or treating or treated or therapy or therapies or therapeutic or manage or
management or managing).mp
NOT
Results of Search 1e
NUMBER OF ITEMS RETRIEVED: 4
================================================================
SEARCH #1g (Diagnosis/Testing)
DATABASE:
Cochrane Central Register of Controlled Trials
SEARCH STRATEGY:
(food hypersensitivity or (food* and (allergy or allergies or allergic or allergen*))).mp. [mp=title,
original title, abstract, mesh headings, heading words, keyword]
AND
(diagnosis or diagnoses or diagnose or diagnostic* or diagnosing or test or tests or testing).mp.
NUMBER OF ITEMS RETRIEVED: 372 (Sample of 200 reviewed)
================================================================
SEARCH #1h (Treatment)
DATABASE:
Cochrane Central Register of Controlled Trials
SEARCH STRATEGY:
(food hypersensitivity or (food* and (allergy or allergies or allergic or allergen*))).mp. [mp=title,
original title, abstract, mesh headings, heading words, keyword]
AND
(treatment or treat or treating or treated or therapy or therapies or therapeutic or manage or
management or managing).mp
NOT
Results of Search 1g
NUMBER OF ITEMS RETRIEVED: 101
================================================================
SEARCH #2 (Acute Allergic Reaction - Treatment)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (January)
LIMITERS:
Human
SEARCH STRATEGY:
acute AND (allergy OR allergies OR allergic) AND (react OR reaction*)
279
AND
treat OR treated OR treatment* OR therapy OR therapies
NOT
drug allerg* OR drug reaction* OR drug hypersensitiv* OR reaction to drug*
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 1030
================================================================
SEARCH #3 (Anaphylaxis)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND allergy OR allergies OR allergic OR
hypersensitiv*)
AND
anaphylaxis OR anaphylactic
AND
treat OR treated OR treatment* OR therapy OR therapies
NOT
drug allerg* OR drug reaction* OR drug hypersensitiv* OR reaction to drug*
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 558
================================================================
SEARCH #4a (Specific Conditions - Angioedema)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
angioedema*
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 238
================================================================
280
SEARCH #4b (Specific Conditions - Asthma)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
asthma*
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 2291
================================================================
SEARCH #4c (Specific Conditions – Celiac Disease) Omitted at request of the NIAID
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
celiac disease OR celiac[tiab]
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 211
================================================================
SEARCH #4d (Specific Conditions – Colitis)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
food hypersensitivit* OR food allerg*
AND
colitis
NUMBER OF ITEMS RETRIEVED: 106
================================================================
SEARCH #4e (Specific Conditions – Cow Milk-Induced Colitis or Blood in Stool)
DATABASE & TIME PERIOD COVERED:
281
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
cow* AND milk
AND
colitis OR (blood AND stool*) OR proctocolitis OR (rectal AND bleed*)
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 83
================================================================
SEARCH #4f (Specific Conditions – Dermatitis, Atopic & Contact)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
dermatitis
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 1919
================================================================
SEARCH #4g (Specific Conditions – Dermatitis Herpetiformis) Omitted at request of the
NIAID
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
dermatitis herpetiformis
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NOT
Results of Search 4f
282
NUMBER OF ITEMS RETRIEVED: 507
================================================================
SEARCH #4h (Specific Conditions – Eosinophilic Esophagitis)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
eosinophilic esophagitis
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 326
================================================================
SEARCH #4i (Specific Conditions – Eosinophilic Gastroenteritis)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
eosinophilic gastroenteritis
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NOT
Results of Search 4h
NUMBER OF ITEMS RETRIEVED: 200
================================================================
SEARCH #4j (Specific Conditions – Exercise-Induced)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
food hypersensitivit* OR food allerg*
AND
exercise OR exercise-induced OR physical activity
283
NUMBER OF ITEMS RETRIEVED: 196
================================================================
SEARCH #4k (Specific Conditions – Flushing)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
food hypersensitivit* OR food allerg*
AND
flushing
NUMBER OF ITEMS RETRIEVED: 27
================================================================
SEARCH #4l (Specific Conditions – Food-Induced Proctocolitis Syndrome)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
(food induced OR food-induced) AND proctocolitis AND syndrome*
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 2
================================================================
SEARCH #4m (Specific Conditions – Food Protein-Induced Enterocolitis Syndrome)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food AND (protein OR proteins) AND enterocolitis AND syndrome*
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 28
================================================================
SEARCH #4n (Specific Conditions – Gastrointestinal Hypersensitivity)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
284
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
gastrointestinal hypersensitiv* OR vomiting OR colic OR diarrhea
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 475
================================================================
SEARCH #4o (Specific Conditions – Heiner’s Syndrome)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
heiner* OR pulmonary hemisiderosis
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 6
================================================================
SEARCH #4p (Specific Conditions – Inflammatory Bowel Disease)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
inflammatory bowel diseases[mh] OR inflammatory bowel disease*[tiab]
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 170
================================================================
SEARCH #4q (Specific Conditions – Laryngeal Edema)
DATABASE & TIME PERIOD COVERED:
285
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
laryngeal edema
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 27
================================================================
SEARCH #4r (Specific Conditions – Milk Protein Allergy of Infancy)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
milk AND (protein OR proteins) AND infan*
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 1059
================================================================
SEARCH #4s (Specific Conditions – Oral Allergy Syndrome)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
food hypersensitivit* OR food allerg*
AND
oral allergy syndrome*
NUMBER OF ITEMS RETRIEVED: 219
================================================================
SEARCH #4t (Specific Conditions – Rhinitis)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
286
food hypersensitivit* OR food allerg*
AND
rhinitis
NUMBER OF ITEMS RETRIEVED: 641
================================================================
SEARCH #4u (Specific Conditions – Rhinoconjunctivitis)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
food hypersensitivit* OR food allerg*
AND
rhinoconjunctivitis OR conjunctivitis
NUMBER OF ITEMS RETRIEVED: 186
================================================================
SEARCH #4v (Specific Conditions – Urticaria)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (March)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
urticaria OR hives
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 687
================================================================
SEARCH #5 (Epinephrine)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009 (February)
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
epinephrine
NOT
case report* OR case reports[pt]
NOT
animal NOT human
287
NUMBER OF ITEMS RETRIEVED: 244
================================================================
SEARCH #6
DATABASE & TIME PERIOD COVERED:
World Allergy Organization Journal – 1988-2009 (February)
SEARCH STRATEGY:
food
NUMBER OF ITEMS RETRIEVED: 163
================================================================
SEARCH #7 (Cow’s Milk Allergy - Revision)
DATABASE & TIME PERIOD COVERED:
PUBMED – 1988-2009/7/20
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
cow* AND milk
NOT
case report* OR case reports[pt]
NOT
animal NOT human
NUMBER OF ITEMS RETRIEVED: 1264
================================================================
SEARCH #8a (Food Allergy/Food Hypersensitivity - Revision)
DATABASE & TIME PERIOD COVERED:
PUBMED – 2008/11-2009/8/24
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
NOT
animal* NOT (human OR humans)
NUMBER OF ITEMS RETRIEVED: 777
================================================================
SEARCH #8b (Food Allergy/Food Hypersensitivity - Revision)
DATABASE & TIME PERIOD COVERED:
PubMed 1988-2009/9/2
288
SEARCH STRATEGY:
food hypersensitivity[mh]
NOT
food hypersensitivit*
NOT
animal* NOT (human OR humans)
NUMBER OF ITEMS RETRIEVED: 1427
NUMBER OF ITEMS AFTER REMOVING DUPLICATES FROM PREVIOUS SEARCHES: 409
================================================================
SEARCH #8c (Food Allergy/Food Hypersensitivity - Revision)
DATABASE & TIME PERIOD COVERED:
Cochrane Database of Systematic Reviews – 2008-2009
SEARCH STRATEGY:
(food hypersensitivity or (food* and (allergy or allergies or allergic or allergen*))).mp.
NUMBER OF ITEMS RETRIEVED: 54
================================================================
SEARCH #8d (Food Allergy/Food Hypersensitivity - Revision)
DATABASE & TIME PERIOD COVERED:
Cochrane Controlled Trials Register (CCTR) – 2008-2009
SEARCH STRATEGY:
(food hypersensitivity or (food* and (allergy or allergies or allergic or allergen*))).mp.
NUMBER OF ITEMS RETRIEVED: 23
================================================================
SEARCH #8e (Food Allergy/Food Hypersensitivity - Revision)
DATABASE & TIME PERIOD COVERED:
Cochrane Database of Abstracts of Reviews of Effects (DARE) – All years
SEARCH STRATEGY:
(food hypersensitivity or (food* and (allergy or allergies or allergic or allergen*))).mp.
NUMBER OF ITEMS RETRIEVED: 11
================================================================
SEARCH #9 (Author L. Schwartz articles on Tryptase)
DATABASE & TIME PERIOD COVERED:
PubMed – All years
SEARCH STRATEGY:
289
schwartz l*
AND
tryptase* OR trypsin* OR beta-tryptase*
NUMBER OF ITEMS RETRIEVED: 164
================================================================
SEARCH #10a (Atopic Dermatitis and Food Avoidance)
DATABASE & TIME PERIOD COVERED:
PubMed 1988-2009/9/2
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
atopic dermatitis
AND
avoid* OR exclusion OR exclude*
AND
(randomized controlled trial* OR rct* OR random allocation OR randomi*[tiab]) OR Limits:
Randomized Controlled Trial
NUMBER OF ITEMS RETRIEVED: 32
================================================================
SEARCH #10b (Atopic Dermatitis and Food Avoidance)
DATABASE & TIME PERIOD COVERED:
Cochrane Database of Systematic Reviews, DARE, Controlled Trials Register – All years
SEARCH STRATEGY:
atopic dermatitis and (food or foods)).mp.
AND
(avoid* or exclusion* or exclude*).mp.
NUMBER OF ITEMS RETRIEVED: 38
================================================================
SEARCH #11a (Anaphylaxis – Systematic Reviews)
DATABASE & TIME PERIOD COVERED:
PubMed – 1966-2009
SEARCH STRATEGY:
anaphyla*
AND
systematic[sb]
290
NUMBER OF ITEMS RETRIEVED: 183
================================================================
SEARCH #11b (Anaphylaxis – Systematic Reviews)
DATABASE & TIME PERIOD COVERED:
Cochrane Database of Systematic Reviews – 1988-2009
SEARCH STRATEGY:
(anaphylaxis or anaphylactic).af.
NUMBER OF ITEMS RETRIEVED: 48
NUMBER OF ITEMS RELEVANT TO TOPIC: 4
================================================================
SEARCH #11c (Anaphylaxis – Systematic Reviews)
DATABASE & TIME PERIOD COVERED:
Cochrane DARE – 1988-2009
SEARCH STRATEGY:
(anaphylaxis or anaphylactic).af.
NUMBER OF ITEMS RETRIEVED: 14
NUMBER OF ITEMS RELEVANT TO TOPIC: 2
================================================================
SEARCH #12a (Influenza Vaccine and Egg Allergy)
DATABASE & TIME PERIOD COVERED:
PubMed – 1966-2009
SEARCH STRATEGY:
food hypersensitivity OR ((food OR foods) AND (allergy OR allergies OR allergic OR
hypersensitiv*))
AND
influenza vaccine OR ((vaccine* OR vaccination) AND (flu OR influenza))
AND
egg OR eggs
NOT
animal* NOT (human OR humans)
NUMBER OF ITEMS RETRIEVED: 31
================================================================
SEARCH #12b (Influenza Vaccine and Egg Allergy)
DATABASE & TIME PERIOD COVERED:
Cochrane Database of Systematic Reviews – All years
SEARCH STRATEGY:
(egg or eggs).af.
291
AND
(allerg* or hypersensitiv*).af.
AND
(vaccin* or immuniz* or immunis*).af.
AND
(flu or influenza).af.
NUMBER OF ITEMS RETRIEVED: 3
================================================================
SEARCH #12c (Influenza Vaccine and Egg Allergy)
DATABASE & TIME PERIOD COVERED:
Cochrane Controlled Trials Register – All years
SEARCH STRATEGY:
(egg or eggs).af.
AND
(allerg* or hypersensitiv*).af.
AND
(vaccin* or immuniz* or immunis*).af.
AND
(flu or influenza).af.
NUMBER OF ITEMS RETRIEVED: 3
================================================================
292
Appendix B: Screening Form
293
294
Appendix C: Study Design Definitions
Review/meta-analysis
Review: A review article that summarizes a number of different studies and may draw
conclusions about a particular intervention. The methods used to identify, select and
appraise the studies are not systematic or necessarily reproducible. (Any review article
that is not clearly a systematic review or a meta-analysis is a "review.") The summary in
a review is generally narrative.
Systematic review: A review of a clearly formulated question that uses systematic and
explicit methods to identify, select and critically appraise relevant research, and to collect
and analyze data from the studies that are included in the review. Statistical methods are
NOT used to analyze and summarize the results of the included studies.
Meta-analysis: A systematic review that uses statistical methods to integrate the results
of the individual studies. A meta-analysis contains at least one pooled analysis.
Controlled trials
Randomized clinical trial: includes a trial in which the participants (or other units) were
definitely assigned prospectively to one or two (or more) alternative forms of health care
[interventions] using a process of random allocation.i
Trial with open-label extension: Randomized clinical trial or controlled clinical trial
with an open-label extension.
Controlled clinical trial: includes a trial in which participants (or other units) were: a)
definitely assigned prospectively to one or two (or more) alternative forms of health care
[interventions] using a quasi-random allocation method or; b) possibly assigned
prospectively to one or two (or more) alternative forms of health care using a process of
random or quasi-random allocation.
Cohort / case series
Cohort: two or more groups assembled on a specific characteristic or characteristics are
subjected to an exposure, and followed.
In a retrospective cohort study, all the events - exposure, latent period, and subsequent
development of disease, have already occurred in the past. The investigators collect the
data now and establish the risk of developing a disease if exposed to a particular risk
factor. In contrast, a prospective cohort study is conducted by starting with two groups
at the current point, and following up in future for occurrence of disease, if any.
Prospective cohorts should be summarized with the relative risk; retrospective cohorts
should be summarized with the odds ratio.
295
Case series: a group or series of case reports involving patients who were given similar
treatment. Reports of case series usually contain detailed information about the individual
patients, including demographic information and information on diagnosis, treatment,
response to treatment, and follow-up after treatment.
Case-control
A retrospective design in which cases are matched to controls and then exposure is
compared.
Case study
A case study is a medical case report describing the course of an illness or a response to
treatment in a single patient. Published case reports can be the first indication of a new
benefit of a treatment in an unexpected population group or a may act as the first warning
of a new unexpected adverse event.
Mixed
Any combination of the above.
Unsure / None of the above
Includes any study design not listed above, such as editorials, letters, general clinical
review articles, etc.
i
Adapted from Cochrane Effective Practice and Organization of Care Review Group, The Data Collection
Checklist, Inclusion Criteria.
296
Appendix D: Criteria for Assessing the Quality of Studies
of Diagnostic Accuracy
Lijmer Criteria for Scoring Study Quality
Study Characteristic
Spectrum
Verification
Interpretation of test results
Patient selection
Data collection
Details test
Details reference test
Details population
Score
Clinical population
Case-control
Complete
Different reference tests
Partial
Blinded
Not blinded
Consecutive
Nonconsecutive
Prospective
Unknown
Retrospective
Sufficient
Insufficient
Sufficient
Insufficient
Sufficient
Insufficient
Reference: Lijmer JG, Mol BW, Heisterkamp S, Bonsel GJ, Prins MH, van der Meulen
JHP, Bossuyt PMM. Empirical evidence of design-related bias in studies of diagnostic
tests. JAMA Vol. 282, No. 11, Pp. 1061-1066, 1999)
297
QUADAS Tool for Assessing Study Quality (Each item is assessed as yes (1), no (2), or unclear (3) For the present study, domains
12 and 13 were not assessed
298
Reference: Whiting P, Rutjes AWS, Reitsma JB, Bossuyt PMM, Kleijnen J. The development of QUADAS: a tool for the quality assessmentof studies of
diagnostic accuracy included in systematic reviews. BMC Medical Research Methodology Vol. 3, Pp. 25-38, 2003.
299
STARD checklist for reporting of studies of diagnostic accuracy
Section and Topic
TITLE/ABSTRACT/
KEYWORDS
INTRODUCTION
METHODS
Participants
Item
#
1
2
3
4
5
6
Test methods
7
8
9
10
11
Statistical methods
12
13
RESULTS
Participants
14
15
16
Test results
17
On page #
Identify the article as a study of diagnostic accuracy (recommend MeSH
heading 'sensitivity and specificity').
State the research questions or study aims, such as estimating diagnostic
accuracy or comparing accuracy between tests or across participant
groups.
The study population: The inclusion and exclusion criteria, setting and
locations where data were collected.
Participant recruitment: Was recruitment based on presenting symptoms,
results from previous tests, or the fact that the participants had received the
index tests or the reference standard?
Participant sampling: Was the study population a consecutive series of
participants defined by the selection criteria in item 3 and 4? If not,
specify how participants were further selected.
Data collection: Was data collection planned before the index test and
reference standard were performed (prospective study) or after
(retrospective study)?
The reference standard and its rationale.
Technical specifications of material and methods involved including how
and when measurements were taken, and/or cite references for index tests
and reference standard.
Definition of and rationale for the units, cut-offs and/or categories of the
results of the index tests and the reference standard.
The number, training and expertise of the persons executing and reading
the index tests and the reference standard.
Whether or not the readers of the index tests and reference standard were
blind (masked) to the results of the other test and describe any other
clinical information available to the readers.
Methods for calculating or comparing measures of diagnostic accuracy,
and the statistical methods used to quantify uncertainty (e.g. 95%
confidence intervals).
Methods for calculating test reproducibility, if done.
When study was performed, including beginning and end dates of
recruitment.
Clinical and demographic characteristics of the study population (at least
information on age, gender, spectrum of presenting symptoms).
The number of participants satisfying the criteria for inclusion who did or
did not undergo the index tests and/or the reference standard; describe why
participants failed to undergo either test (a flow diagram is strongly
recommended).
Time-interval between the index tests and the reference standard, and any
treatment administered in between.
300
18
19
20
Estimates
21
22
23
DISCUSSION
24
25
Distribution of severity of disease (define criteria) in those with the target
condition; other diagnoses in participants without the target condition.
A cross tabulation of the results of the index tests (including indeterminate
and missing results) by the results of the reference standard; for
continuous results, the distribution of the test results by the results of the
reference standard.
Any adverse events from performing the index tests or the reference
standard.
Estimates of diagnostic accuracy and measures of statistical uncertainty
(e.g. 95% confidence intervals).
How indeterminate results, missing data and outliers of the index tests
were handled.
Estimates of variability of diagnostic accuracy between subgroups of
participants, readers or centers, if done.
Estimates of test reproducibility, if done.
Discuss the clinical applicability of the study findings.
Reference: http://www.stard-statement.org/
301
Appendix E. Excluded Studies: Incidence/Prevalence,
Natural History
Population-based/systematic sample
1.
Assa'ad AH, Putnam PE, Collins MH, Akers RM, Jameson SC, Kirby CL, et al.
Pediatric patients with eosinophilic esophagitis: an 8-year follow-up. 2007;119(3):731-8.
2.
Bhombal S, Bothwell MR, Bauer SM. Prevalence of elevated total IgE and food
allergies in a consecutive series of ENT pediatric patients. 2006;134(4):578-80.
3.
Bock SA, Atkins FM. The natural history of peanut allergy. J Allergy Clin
Immunol. 1989;83(5):900-4.
4.
Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic
reactions to foods. J Allergy Clin Immunol. 2001;107(1):191-3.
5.
Burks AW, Mallory SB, Williams LW, Shirrell MA. Atopic dermatitis: clinical
relevance of food hypersensitivity reactions. 1988;113(3):447-51.
6.
Burks AW, Williams LW, Mallory SB, Shirrell MA, Williams C. Peanut protein
as a major cause of adverse food reactions in patients with atopic dermatitis.
1989;10(4):265-9.
7.
Chehade M, Magid MS, Mofidi S, Nowak-Wegrzyn A, Sampson HA, Sicherer
SH. Allergic eosinophilic gastroenteritis with protein-losing enteropathy: intestinal
pathology, clinical course, and long-term follow-up. 2006;42(5):516-21.
8.
Dauer EH, Freese DK, El-Youssef M, Thompson DM. Clinical characteristics of
eosinophilic esophagitis in children. Ann Otol Rhinol Laryngol. 2005;114(11):827-33.
9.
Dixon HS. Dysphonia and delayed food allergy: a provocation/neutralization
study with strobovideolaryngoscopy. 1999;121(4):418-29.
10.
Eigenmann PA, Pastore FD, Zamora SA. An Internet-based survey of
anaphylactic reactions to foods. Allergy. 2001;56(6):540-3.
11.
Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA.
Prevalence of IgE-mediated food allergy among children with atopic dermatitis.
Pediatrics. 1998;101(3):E8.
12.
Eigenmann PA, Zamora SA. An internet-based survey on the circumstances of
food-induced reactions following the diagnosis of IgE-mediated food allergy. Allergy.
2002;57(5):449-53.
302
13.
Fleischer DM, Conover-Walker MK, Christie L, Burks AW, Wood RA. Peanut
allergy: recurrence and its management. J Allergy Clin Immunol. 2004;114(5):1195-201.
14.
Fleischer DMC-W, M. K. Matsui, E. C. Wood, R. A. The natural history of tree
nut allergy. J Allergy Clin Immunol. 2005 Nov;116(5):1087-93.
15.
Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, et al.
Eosinophilic esophagitis in children and adults: a systematic review and consensus
recommendations for diagnosis and treatment. 2007;133(4):1342-63.
16.
Green TD, LaBelle VS, Steele PH, Kim EH, Lee LA, Mankad VS, et al. Clinical
characteristics of peanut-allergic children: recent changes. Pediatrics. 2007;120(6):130410.
17.
Greenhawt MJS, A. M. Baptist, A. P. Food allergy and food allergy attitudes
among college students. J Allergy Clin Immunol. 2009 Aug;124(2):323-7.
18.
James JM, Bernhisel-Broadbent J, Sampson HA. Respiratory reactions provoked
by double-blind food challenges in children. Am J Respir Crit Care Med.
1994;149(1):59-64.
19.
Jiang T, Jeter JM, Nelson SE, Ziegler EE. Intestinal blood loss during cow milk
feeding in older infants: quantitative measurements. 2000;154(7):673-8.
20.
Keet CAM, E. C. Dhillon, G. Lenehan, P. Paterakis, M. Wood, R. A. The natural
history of wheat allergy. Ann Allergy Asthma Immunol. 2009 May;102(5):410-5.
21.
Kelso JM. Resolution of peanut allergy. 2000;106(4):777.
22.
Kim KT, Hussain H. Prevalence of food allergy in 137 latex-allergic patients.
Allergy Asthma Proc. 1999;20(2):95-7.
23.
Machida HM, Catto Smith AG, Gall DG, Trevenen C, Scott RB. Allergic colitis
in infancy: clinical and pathologic aspects. 1994;19(1):22-6.
24.
Penfield JDL, D. M. Goldblum, J. R. Lopez, R. Falk, G. W. The Role of Allergy
Evaluation in Adults With Eosinophilic Esophagitis. J Clin Gastroenterol. 2009 Jun 25.
25.
Perry TT, Matsui EC, Conover-Walker MK, Wood RA. Risk of oral food
challenges. J Allergy Clin Immunol. 2004;114(5):1164-8.
26.
Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, Sodergren E, et al. The
prevalence of food allergy: a meta-analysis. 2007;120(3):638-46.
27.
Roy-Ghanta S, Larosa DF, Katzka DA. Atopic characteristics of adult patients
with eosinophilic esophagitis. 2008;6(5):531-5.
303
28.
Sampson HA, Scanlon SM. Natural history of food hypersensitivity in children
with atopic dermatitis. 1989;115(1):23-7.
29.
Sampson HA MC. Food hypersensitivity and atopic dermatitis: evaluation of 113
patients. The Journal of pediatrics. 1985;107(5):669-75.
30.
Savage JHL, S. L. Brereton, N. H. Wood, R. A. The natural history of peanut
allergy: Extending our knowledge beyond childhood. J Allergy Clin Immunol. 2007
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333
Appendix F: Food allergy treatment/management controlled trials: study quality
characteristics
Author
Randomized
No
Yes
Randomization
approp.
NA
Yes
Treatment
allocation
concealed
NA
Yes
Agata, 1993291
Hansen,
2004300
Bucher,
2004301
Asero, 1998302
Leung, 2003316
Cavagni,
1989317
Staden,
2007293
Bernardini,
2006303
Morisset,
2007294
Skripak,
2007292
Nelson,
1997295
Enrique,
2005299
Patriarca,
2007296
BindsleyJensen,
1991315
Burks, 1988318
Schaefer,
NS
NA
NS
Yes
Yes
Double
blind
Outcome
assessor
blinded
NS
Yes
Care
provider
blinded
NS
NS
Patients
blinded
Co-interventions
No
Yes
Blinding
approp.
NA
Yes
No
Yes
No
No
NA
NS
NS
NS
Yes
NS
NS
Yes
Yes
NS
Yes
Yes
NS
Yes
Yes
NS
Yes
NS
Yes
NS
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
NS
No
NS
NS
Dropout
<50%
NA
Yes
Yes
Yes
Poor
Good
No
NS
NA
Yes
Poor
NS
Yes
NS
NS
Yes
Yes
NS
NS
NS
NA
Yes
Yes
NA
Yes
NA
Poor
Good
Fair
Yes
NS
Yes
NS
Yes
Yes
Good
Yes
Yes
NS
Yes
NS
NA
NA
Fair
No
NA
NS
NS
No
NS
Yes
Yes
Fair
Yes
Yes
Yes
Yes
NS
Yes
NS
Yes
Yes
Good
NA
No
No
NA
No
NS
No
NS
NA
No
Poor
Yes
Yes
Yes
Yes
Yes
NS
NS
Yes
NS
Yes
Yes
Good
No
NA
No
No
NA
NS
NS
No
NS
Yes
No
Poor
Yes
NS
Yes
Yes
Yes
Yes
NS
Yes
NS
NS
NS
Fair
NS
Yes
NS
Yes
Yes
No
Yes
No
Yes
No
NS
No
NS
NS
Yes
No
NS
NS
Yes
Yes
No
Yes
Fair
Fair
334
ITT
Overall
quality
2008319
Jirapinyo,
2007333
Szajewska,
2007321
Hill, 2005322
Amadi,
2002323
Cantani,
2006324
Salpietro,
2005325
Jong, 2002332
Yes
NS
NS
NS
NS
NS
NS
NS
NS
Yes
Yes
Fair
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Good
Yes
Yes
Yes
Yes
No
No
No
No
NA
No
Yes
NS
Yes
NS
No
NS
NS
NS
Yes
Yes
No
No
Fair
Fair
No
NA
No
No
No
No
NS
No
NS
NA
NS
Poor
Yes
NS
Yes
NS
NS
NS
NS
Yes
NS
Yes
Yes
Fair
Yes
Yes
Yes
Yes
Yes
NS
NS
Yes
Yes
Yes
Good
Yes
NS
NS
NS
NS
Lindfors,
1992339
Yes
Yes
Yes
Yes
Yes
Iacono,
1998335
Yes
Yes
Yes
NS
NS
Klemola,
2002313
Yes
Yes
Yes
Yes
Yes
Niggemann,
2008336
Garzi, 2002337 No
NA
NS
NS
NS
Vita, 2007338
Yes
Yes
No
No
Yes
Note: NS=Not stated; NA=not applicable; ITT=intention to treat analysis
Yes
NS
NS
Yes
Yes
At 2
years
but not
5
years
Yes
Fair
Yes
NS
Yes
NS
Yes
Yes
Good
NS
NS
Yes
Yes
NS
Yes
Fair
Yes
NS
Yes
Yes
Yes
No
Fair
NS
Yes
NS
Yes
NS
No
NS
NS
NS
Yes
Yes
No
Poor
Fair
335
Appendix G: Abbreviations used in this report
Abbreviation
AAAAI
AAP
ACAAI
AD
AGA
ALA
AMSTAR
APT
BLG
CD
CLA receptor
CLEIA
CM
CMA
CMPA
CME
CMF
CMPI
CMPIE
ConA
COU
DARE
DBPCFC
DH
ECAAI
EE/EG
EGID
eHF
ELISA
EmA
Eos/HPF
EPC
FAAN
FC
FDEIA
FEIA
FHx
GA
GFD
GERD
GI
GINI
HE
HCF
Term
American Academy of Allergy Asthma and Immunology
American Academy of Pediatrics
American College of Allergy, Asthma & Immunology
Atopic dermatitis
Alpha gliadin antibody
Alpha lactalbumin
Assessment of multiple systematic reviews
Atopy patch test
beta-lactoglobulin
Celiac disease
Cutaneous lymphocyte-associated antigens receptor
Chemiluminescent enzyme immunoassay
Cow’s milk
Cow’s milk allergy
Cow’s milk protein allergy
Continuing medical education
Cow milk formula
Cow’s milk protein intolerance
Cow’s milk protein induced enteropathy
Concanavalin A
Chronic ordinary urticaria
Cochrane Database of Abstracts of Reviews of Effects
Double blind placebo controlled food challenge
Dermatitis herpetiformis
European Academy of Allergy and Clinical Immunology)
Eosinophilic esophagitis/gastroenteritis
Eosinophil-associated gastrointestinal disorders
Extensively hydrolyzed formulas
Enzyme-linked immunosorbent assay
Endomysial antibody
Eosinophils per high-powered field
Evidence-based Practice Center
Food Allergy and Anaphylaxis Network
Food challenge
Food-associated, exercise-induced syndromes
Fluorescent enzyme immunoassay
Family History
Gastrointestinal age
Gluten free diet
Gastroesophageal reflux disease
Gastrointestinal
German infant nutritional intervention
Hen’s egg
Hydrolysed casein formula
336
Abbreviation
HF
HLA
IgA/E/G
IL
L/M
LP
ME
NASPGHN
NHANES
NIAID
NIH
NRL
NPV
OAS
OFC
OVA
OVM
OVT
PAR
PBMC
PHA
pHF
PPV
QOL
QUADAS
RAST
RCT
RHF
ROC
ROU
SAR
SCORAD
SD
Se
SES
SF
sIgE
SLIT
Sp
SPT
STARD
TEP
Th2
TN
Term
Hydrolyzed formula
Human Leukocyte antigen
Immunoglobin class A/E/G
Interleukin
Lactulose/Mannitol
Lymphocyte proliferation
Milk-induced enterocolitis syndrome
North American Society for Pediatric Gastroenterology, Hepatology
and Nutrition
National Health and Nutrition Examination Survey
National Institutes of Allergy and Infectious Disease
National Institute of Health
Natural rubber latex
Negative predictive value
Oral allergy syndrome
Open food challenge
Ovalbumin
Ovomucoid
Ovotransferrin
Perennial allergic rhinoconjunctivitis
Peripheral blood mononuclear cells
Phytohemagglutinin
Partially hydrolyzed formulas
Positive predictive value
Quality of life
Quality Assessment of Studies of Diagnostic Accuracy
Radioallergosorbic test
Randomized controlled trial
Rice-based hydrolysate formula
Receiver-operating characteristics
Recurrent oral ulceration
Seasonal allergic rhinoconjunctivitis
Scoring atopic dermatitis
Standard deviation
Sensitivity
Socioeconomic Status
Soy-based Formula
Antigen-specific Immunoglobulin
Sublingual immunotherapy
Specificity
Skin prick test
Standards for the Reporting of Diagnostic Accuracy
Technical Expert Panel
T-helper type 2 cell
Tree nut
337
Abbreviation
TNF
tTG
Term
Tumor necrosis factor
Tissue transglutaminase
338
Appendix H: Evidence Tables-Diagnosis Studies
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
Bernardi,
2008195
19
different
foods
Multiple
gastrointesti
nal
symptoms
and
headache
68 consecutive
patients seen at a
university hospital
allergy clinic for
symptoms, after
ruling out lactose
intolerance, celiac
disease, pathological
GI disease, and
psychological
disorders
History suggestive of
food intolerance and
elimination diet
Serum IgG4
Cow’s milk:
CM ≥2.8 U/L
Bischoff,
1996156
Unclear
Gastrointesti
nal disease
Calvani
2007174
Milk
CMA
375 randomly
selected patients in
GI clinic (Germany)
with Crohns,
ulcerative colitis, or
other GI conditions
who fit clinical
criteria of intestinal
food allergy (3 of the
following 6 (clinical
history): Hx of foodrelated GI symptoms,
increased total sIgE,
food sIgE,
eosinophilia,
improvement w/
cromoglycate,
clinical atopy; and 1
of the following 2:
+response to
provocation or +
response to
elimination)
104 children
consecutively
Se
0.83
Test 2
Sp
PP
V*
NP
V*
Test 3
Comments,
Conclusions, (values for
QUADAS domains)*
Negative predictive value
for sIgG4 may allow it to
be used to rule out food
allergy
(1,1,3,1,1,1,1,1,1,1,3,1)
0.92 0.35 0.99
Hen’s Egg:
≥2.0 U/L
Se
0.73
Clinical history and +
elimination response
Food challenge (70
open and 34
339
Sp
PP
V*
NP
V*
0.83 0.25 0.99
*Estimated
Prevalence 5%
Endoscopic
allergen
provocation:
13 patients
underwent a total
of 34 tests.
Sensitivity: 59%
Specificity: 97%
SPT with:
- lactalbumin
Conclusion not related to
Dx test but to possibility
that food allergy may be
cause of some % of GI
disease
(2,2,3,1,2,2,1,1,3,1,3,3)
Author,
Yr
Canani,
2007175
Food(s)
CM, HE,
wheat
Condition
Suspected
food-related
GI
symptoms
Population
Reference
test
Test 1
referred to an Italian
pediatric allergy
clinic for evaluation
of suspected CMA
DBPCFC)
- casein
- beta-lactoglobulin
- fresh milk
All children 3-48
months referred to
Pediatric
gastroenterology
center in Naples for
suspected FA-related
symptoms
OFC with fresh CM,
HE, and wheat
powder based on
reactions to SPT,
APT, and sIgE: 89
challenges performed
in 60 patients
CM: 31/55 positive
(10 early reax, 21 late
reax)
HE: 19/28 positive
(5 early reax, 14 late
reax)
28/104 tests were
positive
Test 2
Test 3
Comments,
Conclusions, (values for
QUADAS domains)*
sIgE
Cow’s milk:
APT with fresh
vs. commercial
food extracts
NP
VAPT with fresh
0.42
food
Cow’s milk:
APT commercial assay
(freeze-dried)
Cow’s milk:
NP Se
V
Hen’s Egg:
with positive tests
defined as mean
wheal diameters
3mm ≥ the negative
control.
SPT with fresh
foods
Positive reaction
≥3mm with no
reaction to control
Cow’s milk:
Se
0.45
Sp
PP
V
NP
V
0.70 0.67 0.51
Hen’s Egg:
Se
0.58
Sp
PP
V
Se
0.23
Sp
PP
V
0.74 0.54
Hen’s Egg:
Se
0.32
Sp
PP
V
0.65
0.67 0.67 0.32
Sp
PP
V
NP
V
0.67 0.79 0.43
Se
0.84
Sp
PP
V
0.87
1.00 1.00 0.75
Sp
PP
V
NP
V
0.65 0.77 0.79
Hen’s Egg:
Se
0.95
Sp
PP
V
NP
V
0.67 0.86 0.86
APT using fresh
food or SPT or
sIgE
Cow’s milk:
Se
0.90
Sp
PP
V
NP
V
0.52 0.72 0.80
Hen’s Egg:
Se
340
Se
0.05
NP
V
APT using fresh
food or SPT
Cow’s milk:
Se
0.06
0.96 0.95 0.67
Hen’s Egg:
NP
V
Se
Sp
PP
V
NP
V
Sp
PP
V
NP
V
0.96 0.67 0.43
Sp
PP
V
NP
V
1.00 1.00 0.33
Occlusion time 48 hours;
Results read at 72 hours;
Positive test defined as a
minimum of erythema
and slight infiltration
Fresh foods provided
more sensitive APT than
extracts; “combination” of
test results (APT + SPT
and/or sIgE) also
increased sensitivity
(1,1,1,1,1,1,1,1,1,1,1,2)
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
Test 2
Test 3
0.95
CelikBilgili,
2005185
CM, egg,
wheat, soy
AD(88%)
501 children (1 mo16.1 yr)
Food challenge:
DBPCFC if > 1 yr
Clark,
2007154
Egg
Egg allergy
24 children in the UK
(2.6-14 yoa) with
suspected egg allergy
(parent report or
Objective symptoms
of DBPCFC
341
sIgE CAP system
Milk:
Sensitivity 0.83
Specificity 0.53
PPV 0.63
NPV 0.76
Efficiency 0.68
Predictive decision
points:
90%: 88.8 kU/L
Egg:
Sensitivity 0.97
Specificity 0.51
PPV 0.80
NPV 0.89
Efficiency 0.81
Predictive decision
points:
90%: 6.3 kU/L
95%: 12.6
99%: 59.2
Wheat:
Sensitivity: 0.79
Specificity 0.38
PPV 0.41
NPV 0.77
Efficiency 0.53
Soy:
Sensitivity: 0.69
Specificity 0.50
PPV 0.22
NPV 0.88
Efficiency 0.53
Facial
thermography in
DBPCFC:
Sensitivity: 0.92
Comments,
Conclusions, (values for
QUADAS domains)*
0.44 0.78 0.80
In general sIgE for CM
and egg correlated w/
food challenge.
Meaningful predictive
decision point values for
egg could potentially
prevent the need for
challenge.
Subgrouping children at
<, >1 year: predictive
probability values for
hen’s egg differed by age
group
(1,1,1,1,1,1,1,3,1,1,1,3)
(3,3,1,1,1,1,2,1,1,3,1,3)
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
positive SPT)
challenged with
cooked (CE) or
uncooked egg (UE)
Cobbaert,
2005191
Cudowska
, 2005199
De
Boissieu,
2003184
Egg
white,
milk,
codfish,
wheat,
peanut,
soy
Milk
Milk
AEDS
CMA
118 pts >=15 yrs
Clinical HX+SPT?
34 children (5 mos16 yrs)
A: 20< 3yrs
B: 14≥3 yrs
Food challenge:
A: 65%+
B: 35.7%+
35 patients, 2-57
months, referred for
diagnosis of nonspecific persistent
digestive symptoms.
Food challenge (open
with f/u DBPCFC if
open challenge
equivocal)
24 allergic, 11 not
allergic
342
Test 2
Test 3
Comments,
Conclusions, (values for
QUADAS domains)*
Immulite
2000
AlaTOP
Pharmacia??
Referred to as 3rd
generation sIgE test
systems
(1,3,1,1,1,3,1,1,1,1,1,3)
APT (delayed)
A.
Sensitivity 0.80
Specificity 0.79
PPV 0.73
NPV 0.22
+LR 2.67
-LR 0.29
B.
Sensitivity 0.80
Specificity0.89
PPV0.80
NPV 0.11
+LR 7.2
-LR 0.23
SPT+sIgE
(immediate)
A.
Sensitivity 1
Specificity
0.94
PPV 0.75
NPV0
+LR 17.0
-LR 0
SPT+sIgE+APT
APT superior to
SPT+sIGE for diagnosing
delayed CMA.
APT + SPT enhances
identification of CMA.
Age doesn’t seem to
affect APT outcome.
(1,1,1,1,1,1,1,1,1,1,3,3)
APT
positive in 19/24
with CMA,
positive in 1/11
w/o CMA
sIgE
positive in
3/24 with
CMA (0.6В KUI/L,В 0.36В KUI/L,В andВ 0.49В KUI/L),
positive in
0/11 w/o
Specificity: 1 based
on comparison to
objective
symptoms of
DBPCFC
13+DBPCFC
11-DBPCFC
sIgE using DPC
ImmuliteВ® 2000
A.
Sensitivity 0.92
Specificity 0.71
PPV 0.85
NPV0.17
+LR 3.23
-LR 0.11
B.
Sensitivity 0.80
Specificity 0.89
PPV 0.80
NPV0.11
+LR 7.2
-LR 0.23
History: (number
positive in CMA
and non CMA
groups)
GERD 15/24,
4/11; colic
11/24, 4/11;
diarrhea 13/24,
6/11;
constipation
Also reports no positive
sIgE tests in 6 CMA and 6
nonCMA patients.
(2,2,1,3,1,1,1,1,1,1,3,1)
Author,
Yr
Dieguez,
2008177
Fiocchi,
2004188
GarciaAra,
2001167
Food(s)
Egg
Milk,
alpha
lactalbumi
n, casein,
egg white,
egg yolk,
peanut,
wheat,
codfish,
soy,
tomato
Milk
Condition
Egg allergy
Population
104 milk allergic
children with no prior
egg exposure.
Reference
test
Test 1
Food challenge
SPT Egg white
Cutoff 3mm
Sensitivity0.95
Specificity0.40
PPV0.59
NPV0.89
+LR1.58
-LR0.14
Test 2
Test 3
CMAВ 3/24, 1/11; FTT
3/24, 1/11
SPT OVM
Cutoff 3mm
Sensitivity0.67
Specificity0.85
PPV0.83
NPV0.71
+LR4.53
-LR0.39
SPT Egg
white
Cutoff 6mm
Sensitivity0.
81
Specificity0.
73
PPV0.73
NPV0.81
+LR2.95
-LR0.26
Allergen
Area
under
ROC
Opt.
Decis
ion
Point
Egg white
Yolk
Ova
OVM
OVT
Lysozyme
0.83
0.73
0.55
0.82
0.55
0.60
6mm
3mm
3mm
5mm
Comments,
Conclusions, (values for
QUADAS domains)*
SPT OVM
Cutoff 6mm
Sensitivity0.58
Specificity0.97
PPV0.95
NPV0.69
+LR20.42
-LR0.43
(1,1,1,1,1,1,1,1,1,1,3,1)
Wheezing,
excema
147 children (0.1-4
yoa)
Food challenge, SPT,
History
61 received Dx of
IgE-mediated allergy
78 received Dx of
non-IgE mediated
8 were considered
inconclusive (Exact
criteria somewhat
unclear)
sIgE Phadiatop
Infant
Results not
reported by food
Sensitivity: 0.92
Specificity: 0.82
PPV: 80
NPV: 93
Pharmacia
CAP
Results not
reported
Phadioatop Infant found
to be useful for
diagnosing IgE-mediated
food allergy in children.
(1,3,3,1,3,3,1,3,2,3,3,3)
CMA
170 infants (aged 112 months)
consecutively seen at
a Madrid children’s
hospital allergy
Open controlled
challenge tests
performed in 161
infants; remaining 9
had history of severe
SPT
Skin prick test with
alpha-lactalbumin
(ALA), betalactoglobulin
sIgE
CAP FEIA
using milk,
ALA, BLG,
and casein;
(1,1,1,1,2,2,1,1,1,1,2,3)
343
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
Test 2
service for suspected
cow milk allergy
allergic reaction to
cow’s milk protein
and evidence of milk
sIgE
(BLG), whole
milk, and casein;
positive test
defined as a net
wheel diameter
3mm>negative
control (see Table
19)
SPT+sIgE
positive in 37/68
with CMA,
negative in 61/67
w/o CMA
positive test
defined as
sIgE≥0.35
(see Table
24)
14/16
vomiting+
5/16+
Peripheral
absolute
neutrophil
count
12/16+
Fecal white
blood cells
0/16+ Creactive
protein
(>1mg/dL)
Hill,
1988198
Milk
CMA
135 children referred
to specialist with
CMA (5 mos-13 yrs)
Food challenge:
intolerance escluded
by duodenal biopsy:
68 positive and 67
negative challenges
Hwang,
2008155
Milk
Cow milk
proteininduced
enterocolitis
>1 of vomiting,
lethargy, diarrhea,
GJA for leuks,
peripheral blood
leukocyte count and
ANC, CRP, stool
smear test for occult
blood or leuks
following food
challenge test
Gastric Juice
Analysis
(leukocyte ct.)
15/16 positive
Cf. 14/16 positive
for vomiting
Iacono
2006146
Milk
CMPI
16 Korean patients
(14-44 days)
admitted to hospital
with suspected
CMPIE: (vomiting,
diarrhea, failure to
thrive, lethargy).
Infants switched to
protein hydrolysate
formula and/or breast
milk, other factors
ruled out (e.g.,
infection), and weight
stabilized prior to
challenge
796 children (aged 1
month to 10 years)
consecutively
referred to the
gastroenterology
clinic at an Italian
hospital with
suspected CMPI
Elimination and
DBPCFC
Umbilical
erythema:
Of 384 diagnosed
with CMPI, 36
children had
umbilical
erythema:
sensitivity=0.09.
There were no
cases of children
with umbilical
erythema and
344
Test 3
Comments,
Conclusions, (values for
QUADAS domains)*
Children divided into <5
and 5 and over.
Predictive value of RAST
alone not reported
(1,1,1,1,1,1,1,1,1,1,1,3)
GJA was positive in 15 of
16 patients with CMPIE
(though the definitive
diagnosis appeared to
have used GJA).
(3,1,1,1,1,1,2,1,1,3,3,1)
(1,1,1,1,1,1,1,1,3,1,1,3)
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
Isolauri,
1996148
Milk
CMA
183 patients (2-36
months) referred to
specialist for
evaluation of AD
Food challenge (open
and DBPCFC)
Jarvinen,
2003196
Cereals
Milk
AD
(SCORAD)
90 children (2.5-36
months) w/CMA
(both IgE- and nonIgE-mediated)
controlled via
elimination but w/
residual symptoms
that did not respond
to elimination of
eggs, nuts, fruits,
chocolate, fish
Elimination and
Open Challenge w/
oats, wheat, rye,
barley:
+challenge 73%
(17% immediate,
83% delayed)
(Elimination led to
improvement in AD)
(Blinding?)
345
without CMPI:
specificity=1.0
SPT sensitivity
0.48, specificity
0.86
SPT cereal (wheat)
Sensitivity:
0.23(0.17)
Specificity:
1.0 (1.0)
PPV: 1.0 (1.0)
NPV: 0.32 (0.36)
Test 2
Test 3
Comments,
Conclusions, (values for
QUADAS domains)*
APT:
sensitivity
0.61,
specificity
0.81
SPT+APT:
parallel:
specificity 0.86,
sensitivity 0.72
serial:
specificity 0.24
sensitivity 0.94
SPT+APT
Sensitivity:
0.73 (0.77)
Specificity:
0.83 (0.17)
PPV: 0.92 (0.85)
NPV: 0.53 (0.59)
(3,1,1,1,1,1,1,1,1,1,3,1)
APT cereal
(wheat)
Sensitivity:
0.67 (0.7)
Specificity:
0.79 (0.71)
PPV: 0.9
(0.84)
NPV: 0.46
(0.53)
Sensitivity
decreased
with age;
specificity
increased
with age
APT as sensitive as SPT
for immed
hypersensitivity but far
more efficient for
detecting delayed.
APT aids in Dx cereal
allergy, esp. w/SPT, but
challenge still needed to
confirm Dx
(3,1,1,1,1,1,1,1,1,1,3,3)
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
Test 2
Test 3
Keskin,
2005173
Milk
CMA
37 children referred
to specialist for
suspected CMA.
DBPCFC
SPT
Cutoff point≥3mm
Sensitivity 0.91
Specificity 0.50
PPV 0.75
NPV 0.65
APT
sIgE
Cutoff
point≥0.7kU/L
Sensitivity 0.74
Specificity 0.79
PPV 0.85
NPV 0.65
Lee,
2009193
Egg, milk,
peanut,
shrimp
Unspecified
283 Korean patients
with suspected
allergy from 1-75
years old
SPT
sIgE Immulite
2000
Lilja,
1995190
CM, egg,
fish,
hazelnut,
soy,
peanut,
wheat
Atopy (AD
or asthma)
193 children w/ FHx
of atopy (4.7-5.9 yrs)
followed from birth
Summarized SPT and
clinical hx at 5 yoa:
20 children w/+SPT
to food (94%
specificity cf. clinical
signs/symptoms); 36
children w/+SPT to
food or aeroallergen;
68 children
w/+clinical
signs/symptoms
Maloney,
2008189
Peanut,
tree nuts,
seeds
Suspected
allergy to
peanuts, tree
nuts, seeds:
AD, asthma
All individuals
referred to pediatric
allergy clinic in
Boulder CO for
suspected allergy to
peanut, tree nut,
seeds; 324 patients
(2.4 months – 40.2
years)
Clinical history,
questionnaire, and/or
SPT or sIgE
72% had convincing
history of peanut
allergy
Phadiatop
paediatric (PP)
(food+inhalant
allergens):
44 children (23%)
w/+test
Sensitivity,
specificity, and
efficacy lower than
for P
where
efficacy=#true
positives + #true
negatives)/total n
ImunoCAP sIgE
Peanut Cutoff: ≥13
kU/L
Se
0.60
Sp
PP
V
NP
V
0.96 0.99 0.35
Walnut Cutoff:
≥18.5 kU/L
Se
0.17
346
Sp
PP
V
NP
V
0.98 0.99 0.56
Sensitivity
0.91
Specificity
0.50
PPV 0.75
NPV 0.76
sIgE FEIA
UniCAP
Phadiatop
(P) (inhalant
allergens
only) cf.
+SPT:
Sensitivity:0
.86
Specificity:0
.94
Efficacy:
92%
P+Mixed Food
RAST (PMF) cf.
+SPT:
Sensitivity:0.89
Specificity:0.83
Efficacy:0.84
Comments,
Conclusions, (values for
QUADAS domains)*
SPT+APT+sIgE
Criterion: >1 positive
Sensitivity 1
Specificity 0.50
PPV 0.76
NPV 1
(1,1,1,1,2,1,1,1,1,1,1,3)
% agreement between
tests: egg 94.6; milk 88.9;
peanut 75.0; shrimp 56.3.
(did not report
specificity/sensitivity for
food allergens)
(3,1,2,1,1,1,1,1,1,1,1,3)
In preschool children,
identification of source of
atopic allergy depends
highly on test chosen. P
appears preferable to PP
or PMF, esp. where birch
pollen is common
allergen
(3,3,3,1,1,1,1,1,1,1,1,3)
Only peanut and walnut
had sIgE levels that
reached 95% predictive
probability
(3,1,3,1,1,1,2,1,2,3,3,2)
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
Test 2
Test 3
Mehl,
2006149
Milk, egg,
wheat, soy
various
437 children referred
to specialist
(Germany) for
diagnosis of
suspected food
allergy (3 mos-14
yrs).
Food challenge
SPT
CM:
Sensitivity 0.85
Specificity0.70
PPV 0.73
NPV 0.83
Efficiency 0.78
APT
CM:
Sensitivity
0.31
Specificity
0.95
PPV 0.86
NPV 0.60
Efficiency
0.63
SPT+APT
CM:
Sensitivity 0.69
Specificity 0.97
PPV 0.92
NPV 0.86
Efficiency 0.87
Comments,
Conclusions, (values for
QUADAS domains)*
sIgE
CM:
Sensitivity 0.87
Specificity 0.49
PPV 0.62;
NPV 0.79
Efficiency 0.68
Egg:
Sensitivity 0.85
Specificity 0.89
PPV 0.92
NPV 0.80
Efficiency: 0.87
Egg:
Sensitivity 96
Specificity 48
PPV 79
NPV85
Efficiency 80
Wheat:
Sensitivity 0.43
Specificity 0.90
PPV 0.50
NPV 0.86
Efficiency 0.80
Wheat:
Sensitivity 0.82
Specificity 0.34
PPV 0.41
NPV0.77
Efficiency 0.51
Soy:
Sensitivity 0.14
Specificity 0.96
PPV: 0.43
NPV: 0.82
Efficiency: 0.79
Soy:
Sensitivity 0.65
Specificity 0.50
PPV
0.22
NPV 0.86
Efficiency 0.52
Egg:
Sensitivity 0.93
Specificity 0.54
PPV: 0.79
NPV 0.81
Efficiency: 0.79
Wheat:
Sensitivity 0.75
Specificity 0.64
PPV 0.49
NPV 0.85
Efficiency 0.68
Soy:
Sensitivity 0.29
Specificity 0.85
PPV: 0.33
NPV: 0.82
Efficiency: 0.73
Monti,
Egg
AD
107 children (1-19
Oral challenge
SPT w/albumin
347
Egg:
Sensitivity
0.41
Specificity
0.87
PPV 0.86
NPV 0.43
Efficiency:
0.56
Wheat:
Sensitivity
0.27
Specificity
0.89
PPV 0.58
NPV 0.69
Efficiency
0.67
Soy:
Sensitivity
0.23
Specificity
0.86
PPV: 0.30
NPV: 0.82
Efficiency:
0.74
Specific
(1,3,1,1,1,1,1,1,1,1,2,3)
(3,3,1,1,1,1,1,1,2,1,3,1)
Author,
Yr
Food(s)
Condition
2002176
Population
Reference
test
mos)
Test 1
Test 2
and yolk ≥5mm:
Specificity: 1
IgEs
Albumin>99
KU/L
Yolk ≥17.5
KU/L
Specificity:
1
AntigenSpecific
IgE:
Correlated
with +SPT
to
correspondi
ng spice
extracts
Ninimaki,
1995182
Spices,
fruits,
vegetables
AD,
respiratory
symptoms
49 patients (1-51 yrs)
with strongly +
(≥5mm wheal) SPT
results to ≥1 native
spice
Repeat SPT w/native
spices and extracts:
46/49 +SPT
Total IgE:
No correlation w/
SPT
Osterballe
, 2004169
CM and
HE
Report of
food
hypersensiti
vity by
questionnair
e
495 children 3 years
of age with and
without AD (Danish
birth cohort)
OFC to assess both
early and late
reactions:
3/8 positive for CM
8/14 positive for HE
SPT
Cutoff: ≥3mm
Cow’s milk:
2/8 positive
Se
0.66
Sp
PP
V
NP
V
0.80 0.66 0.80
Hen’s Egg:
9/14 positive
Se
0.88
Sp
PP
V
NP
V
0.83 0.88 0.83
APT
Scoring after
72 hours;
positive test
ranged from
erythema
and slight
infiltration
to papules
and vesicles
Cow’s milk:
0/8 positive
Se
0.0
Sp
1.00
Test 3
Comments,
Conclusions, (values for
QUADAS domains)*
Clinical
signs/symptoms
of ingesting or
handling spices:
No correlation
w/ SPT or
specific IgE;
only a minority
seem to produce
clinical
symptoms
sIgE (Magic
Lite)
Cutoff: 1.43
sU/ml
Cow’s milk:
5/8 positive
(3,2,3,1,1,1,1,1,1,1,3,3)
Se
0.66
Sp
PP
V
0.40 0.40 0.66
Hen’s Egg:
7/14 positive
Se
PP
V
NP
V 0.63
0.0
0.62
Sp
PP
V
0.63
Prahl,
1988166
Milk
CMA
26 children (aged 163 months)
consecutively
Open food challenge
348
Skin prick test with
raw cow’s milk,
positive test
Sp
PP
V
Se
0.66
PP
V
NP
V
0.80 0.66 0.80
Hen’s Egg:
7/13 positive
Se
NP
V
Sp
0.71
Sp
PP
V
NP
V
0.80 0.71 0.80
0.66 0.71 0.57
(1,2,1,3,2,1,1,1,1,1,2,1)
Hen’s Egg:
6/13 positive
Se
NP
V
Basophil Histamine
Release (n=305)
Cutoff: ≥10ng/ml
Cow’s milk:
3/8 positive
NP
V
0.80 0.83 0.57
sIgE
(RAST)
with raw
Basophil
histamine
release test
(1,3,1,1,1,1,1,1,1,3,3,3)
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
referred to a Danish
university hospital
allergy clinic for
suspected cow milk
allergy
Rance,
2002165
Peanut
RancГ©,
2004170
Cow’s
milk,
fresh egg,
peanut,
wheat
powder,
soymilkm
ustard
powder
AD
Test 2
defined as wheal
diameter ≥
histamine
(positive) control
S S P N
e p P P
V V
0 0 0 0
.
.
.
.
8 6 8 5
0 6 9 0
363 children referred
for suspected peanut
allergy
DBPCFC:
177 +
186 --
SPT:
NPV for raw
extract =1
SPT>3mm:
specificity 74%
SPT≥16mm:
PPV=1
48 children, 3-29
months,
consecutively
recruited to a French
pediatric hospital
allergy clinic
OFC (based on
results of APT, SPT,
or sIgE) or sIgE
APT
Occlusion times:
1st row: 24 hr; 2nd
row: 48 hr.
Cow’s milk:
Se
Sp
PP
V
NP
V
0.18
1.00 1.00 0.63
0.89
0.96 0.94 0.92
Se
349
Sp
PP
V
cow’s milk
Se Sp
Se Sp P N NPV
P P
0.7 0.6
V V
5 6
0.7 0.6 0. 0. 0.50.
5 6 88 5 44
sIgE
(CAP)
Median
kUA/L
+ reax: 10
(0-100)
- reax: 0 (056)
kUA/L≥57:
PPV=1
SPT
Fresh foods
Cutoff:
≥3mm
greater than
negative
control and
at least 50%
greater than
positive
control
Cow’s milk:
Se
Hen’s Egg:
NP
V
0.15
0.83 0.86 0.12
0.97
0.71 0.95 0.83
Test 3
0.59
Sp
PP
V
PP
V
Comments,
Conclusions, (values for
QUADAS domains)*
NPV
0.8 0.44
8
sIgE+SPT
Predictive values
of nearly 1 for
the following
cutoffs:
+ Dx: SPT≥16
and sIgE≥57
-Dx: SP<3 and
sIgE<57
Performance
characteristics of raw
extracts were superior to
commercial. DBPCFC
can be avoided if SPT<3
and sIgE<57 (neg Dx) or
if SPT≥3 and sIgE≥57
(pos Dx)
(3,3,1,1,1,1,1,1,1,1,1,1)
sIgE
Pharmacia
Upjohn CAP
FEIA
Cutoff:
≥0.35kU/L
Sensitivity, PPV, and
NPV were all better for
the 48-hour occlusion
time
(1,1,1,1,1,1,1,1,1,1,2,2)
Cow’s milk:
Se
NP
V 0.31
Sp
PP
V
NP
V
0.66 0.83 0.15
0.50 0.91 0.56
Hen’s Egg:
Hen’s Egg:
Se
Sp
PP
V
NP
V
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
Test 2
Wheat:
Se
Sp
Se
PP
V
NP
V
0.25
1.00 1.00 0.94
0.83
0.94 0.71 0.97
Peanut:
Se
Sp
0.93
NP
V
0.13
0.97 0.67 0.72
0.71
0.82 0.66 0.85
0.75
0.70
Cow’s
milk (CM)
and hen’s
egg (HE)
Multiple
allergic
symptoms
151 children
consecutively
referred to a
university hospital
pediatric allergy
clinic in Bologna
FC (blinding not
specified)
27 positive for CM
40 positive for HE
SPT
Cutoff: wheal
diameter≥3mm
Cow’s milk: 17/22
positive
Se
0.77
Sp
PP
V
NP
V
0.88 0.63 0.94
Hen’s Egg:
31/34 positive
Se
0.91
Sp
PP
V
Se
0.77 0.65 0.95
0.94
350
Se
Sp
PP
V
0.75 0.96 0.21
NP0.40
V
Sp
PP
V
NP
V
0.50 0.66 0.25
0.50 0.75 0.50
Peanut:
Se
Sp
PP
V
NP0.53
V
Sp
PP
V
NP
V
0.66 0.89 0.21
0.50 0.60 0.55
Sp
PP
V
sIgE ADVIA
Centaur
cutoff>0.35kU/L
Cow’s milk:
Se
NP0.82
V
Sp
PP
V
NP
V
0.74 0.45 0.94
Hen’s Egg
0.70 0.44 0.97
Hen’s Egg
Se
NP0.65
V
Comments,
Conclusions, (values for
QUADAS domains)*
0.50 0.97 0.66
Wheat:
sIgE
Pharmacia
UniCAP
cutoff>0.35k
U/L
Cow’s milk
0.91
NP
V
PP
V
Peanut:
Se
Ricci,
2003168
Sp
Wheat:
Se
PP
V
Test 3
Sp
PP
V
Se
NP0.88
V
0.64 0.55 0.96
Sp
PP
V
NP
V
0.52 0.46 0.90
UniCAP system is
slightly more sensitive
than Centaur (and more
sensitive than SPT) for
both allergens
(1,1,1,1,1,1,1,1,1,3,1,2)
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
Test 2
Rodriguez
, 2000180
Melon
(and
avocado,
banana,
kiwi,
chestnut)
Oral allergy
syndrome,
anaphylaxis
53 consecutive adult
patients (15-69 years)
referred to a
university hospital
allergy clinic in
Madrid complaining
of reaction to melon
OFC followed by
DBPCFC unless
history of
anaphylactic reaction
to food (2 pts)
59 OFC and 25
DBPCFC performed
in remaining 51 pts:
25 OFC positive
17/25 DBPCFC
positive
So 19/53 positive
SPT
Cutoff: wheal
diameter≥3mm
using fresh foods
sIgE
Pharmacia
ImmunoCA
P
cutoff>0.35k
U/L
71 DBPCFC with
cow milk based on
history
SPT
Skin prick test with
fresh milk; positive
test defined as a net
wheel diameter ≥
3mm with no
reaction to negative
control; 43/98
positive reactions
(see Tables 19-23)
Roehr,
2001171
Milk, egg,
wheat, soy
Food allergy
in children
with AD
98 children (2
months-11 years)
consecutively
admitted to a Berlin
university hospital
pneumonology ward
with atopic dermatitis
45/71 diagnosed with
milk allergy
351
Se
0.79
Sp
PP
V
NP
V
Test 3
Comments,
Conclusions, (values for
QUADAS domains)*
SPT and sIgE not
considered useful for
diagnosis of melon
allergy
(1,1,1,3,1,1,1,3,1,1,3,1)
0.38 0.42 0.77
Se
Sp
0.53
PP
V
NP
V
0.62 0.44 0.70
APT
One drop of
fresh cow’s
milk placed
on filter
paper and
applied to
patients’
backs using
12mm
aluminum
cups;
occlusion
time, 48
hours, read
20 minutes
after
removal of
the cup, and
then again at
72 hours;
erythema
with
infiltration
constituted
positive
sIgE
Pharmacia CAP
Additional comparisons
included the following:
combinations of
SPT+APT, sIgE+APT,
SPT+sIgE, and
SPT+APT+sIgE
Early vs. late reaction
sIgE, SPT, APT,
sIgE+APT (see Tables
33-36)
(1,3,1,1,1,1,1,1,1,1,3,2)
Author,
Yr
Rottem,
2008187
Food(s)
Cow’s
milk
Condition
Cow’s milk
allergy
Population
All individuals seen
between 1994 and
2006 for suspected
milk allergy (1800
infants and children
0-18 years of age)
Reference
test
Test 1
Food challenge or
suggestive history
and sIgE
Immulite sIgE to
whole milk and
component Cutoff
≥1 kU/L
135 children
considered
positive; 56
children had
persistent allergy
past 3 years of age
Test 2
reaction
(see Tables
29-32)
Immulite
sIgE: Cutoff
≥3 kU/L at
п‚Ј1 year of
age as
prediction of
persistent
milk allergy
at age 3:
Se
Sp
0.68
Saarinen,
2001172
Sampson,
2001186
Milk
Egg, milk,
peanut,
soy,
wheat,
fish
CMA
Misc. atopy
239 infants (6-7
months) from a
prospective Finnish
birth cohort study on
the effect of infant
formulae on
development of
cow’s milk allergy
with symptoms that
disappeared on
withdrawal of milk
239 open challenges
100 consecutive
children (0.4-14.3
yrs)
Hx or DBPCFC:
118/239 positive
Egg: n=75
Milk: 62
Peanut: 68
Fish: 8
Soybean: 25
Wheat: 23
352
SPT
Skin prick test with
Cow’s milk
formula, whole
milk, or protein
fractions; a positive
test was defined as
a wheal diameter of
≥3 (see Table 19)
Test 3
PP
V
Comments,
Conclusions, (values for
QUADAS domains)*
CM sIgE ≥3 kU/L at 1
year of age was
considered predictive of
persistent CM allergy at 3
years of age
(1,1,1,2,1,1,1,1,2,1,2,2)
NP
V
0.70 0.83 0.
APT
CM formula
powder,
bovine
serum
albumin,
crystallized
bovine
BLG, and
bovine
casein (see
Table 29)
sIgE
CAP RAST (see
Table 24)
90% predictive decision points for food-sIgE levels
Decision Point(kUA/L) Sens Spec Effic. PPV
NPV
7
61
95
68 98 38
15
57
94
69 95 53
14
57
100 84 100 36
3
30
26
Additional test: Serum
Eosinophil Cationic
Protein
15.0, 20.0, and 24.7
micrograms(пЃ­g )/L.
Cutoff ≥15.9g/L:
sensitivity: 0.27
specificity: 0.74;
PPV 0.67;
NPV 0.34;
Cutoff value 24.7пЃ­g/L:
Sensitivity: 0.13
Specificity: 0.98;
PPV 0.93;
NPV 0.37)
(1,1,1,1,1,1,1,1,1,1,2,1)
Food-specific IgE useful
for Dx allergy to egg,
milk, peanut, fish; better
for egg and milk
(1,1,1,1,1,3,1,1,1,1,2,3)
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
Test 2
Test 3
Tainio,
1990183
Milk
CMA
(cutaneous,
respiratory,
and/or GI
symptoms)
34 patients w/
suspected CMA (351 mos) (19
confirmed with
challenge: 14
immediate and 5
delayed)
Elimination and
challenge
1. Total IgE:
Sensitivity:11/19
Specificity: 11/15
2. CM-specific IgE
(RAST)
Sensitivity: 0.63
Specificity: 0.8
Combinations of
tests:
CM-specific IgE
+ BLGmediated
lymphocyte
proliferation
(LP):
Sensitivity: 0.88
Specificity: 0.67
Wainstein,
2007178
Peanut
Peanut
allergy
84 children
consecutively
recruited in a Sydney
pediatric hospital
allergy clinic with
positive SPT (defined
as a wheal 3x3mm>
control)
DBPCFC or
documented recent
reaction to peanut
SPT
SPT performed
with commercial
whole peanut
extract; geometric
mean of wheal
calculated
3. Serum
IgG
4. Serum
IgM
5-6.
Complement
fractions 3
and 4
7. CMspecific IgG
8. CMspecific IgM
9. CMspecific IgA
10-12.
Lymphocyte
stimulation
with PHA,
ConA, BLG
sIgE
Pharmacia
CAP FEIA
Cutoff:
0.37kU/L
Sensitivity:
0.98,
Specificity:0
.33,
PPV: 0.70
NPV: 0.92
51/84 peanut allergic
by FC
Cutoff: ≥8mm
Sensitivity: 0.75,
Specificity: 0.67,
PPV: 0.78
NPV: 0.63
Cutoff: ≥15mm
Sensitivity: 0.0.06,
Specificity: 1.00,
PPV: 1.00
NPV: 0.40
353
Cutoff:
10.0kU/L
Sensitivity:
0.54,
Specificity:1
.00,
PPV: 1.00
NPV: 0.58
Immediate Skin
Application
Food Test
1 gram
commercial
peanut butter on
a cardboard
square applied
directly to the
skin; response
read after 15
minutes. Positive
score consisted
of the
appearance of
any wheal in the
area
Sensitivity: 0.06,
Specificity: 1.00,
PPV: 1.00
NPV: 0.40
Comments,
Conclusions, (values for
QUADAS domains)*
No one test alone had the
sensitivity or specificity
to predict challenge
outcomes. The
combination of CMspecific IgE and BLGmediated LP was the best
(1,3,1,1,1,1,1,1,1,3,3,3)
Combination of three tests
also assessed; neither the
individual tests nor the
combination had
sensitivity or specificity
adequate to replace FC
(1,1,1,1,2,1,1,1,1,1,3,3)
Author,
Yr
Food(s)
Condition
Population
Reference
test
Test 1
Wananuk
ul, 2005181
CM,HE,
wheat,
shrimp
Urticaria
100 consecutive
patients with urticaria
who presented at a
university hospital
pediatric dermatology
clinic in Bangkok
over 2 years
50 consecutive
patients at an allergy
clinic, 3-18 years
DBPCFC or OFC in
22 patients, recent
history of
anaphylactic reaction
to foods in 5 patients
SPT
Cutoff: not
reported
All foods together
Wang,
2008192
Milk, Egg,
Peanut
Not
specified
Se
0.83
ImmunoCAP (sIgE)
Test 2
Sp
PP
V
Test 3
Comments,
Conclusions, (values for
QUADAS domains)*
(1,1,1,3,2,1,1,3,1,1,2,1)
NP
V
0.38 0.28 0.89
Turbo-MP (sIgE):
concordance with
ImmunoCAP: milk
46%, egg 42%,
peanut 56%
Immulite
2000 (sIgE):
concordance
with
ImmunoCA
P: milk
52%, egg
64%, peanut
60%
(1,3,3,1,1,1,1,3,3,1,1,3)
Table Notes: AD Atopic dermatitis; AGA anti-gliadin antibodies; ALA О±-lactalbumin; APT atopic patch test; BLG beta lactoglobulin; CD Celiac Disease; cf compared with; CM
cow’s milk; CMA cow’s milk allergy; ConA Concanavalin A; DBPCFC double blind placebo-controlled food challenge; DH dermatitis herpetiformis; EMA Endomysial
antibodies; FC food challenge; FEIA fluorescent enzyme immunoassay FHx family history; GFD gluten-free diet; HE hen’s egg; HLA Human Leukocyte antigen; L/M
Lactulose/Mannitol; NPV Negative predictive value; OFC open food challenge; OVM ovomucoid; PHA Phytohemagglutinin; PPV positive predictive value; RAST
radioallergosorbent test; Se sensitivity; sIgE antigen-specific immunoglobulin E; Se sensitivity; sIgE antigen-specific immunoglobulin E; Sp Specificity; SPT skin prick
test; SPT skin prick test; tTg tissue transglutaminase; *QUADAS domains are shown in Appendix D; for the present study, domains 12 and 13 were not assessed; the grades are
yes(1), no (2), and unclear (3).
354
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9.
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355
13.
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15.
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16.
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17.
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21.
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23.
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Ram FS, Ducharme FM, Scarlett J. Cow's milk protein avoidance and development of
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19.
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397
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3.
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Chehade M, Magid MS, Mofidi S, Nowak-Wegrzyn A, Sampson HA, Sicherer SH.
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24.
Hansen KS, Ballmer-Weber BK, Luttkopf D, Skov PS, Wuthrich B, Bindslev-Jensen C,
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26.
Hill DJ, Cameron DJ, Francis DE, Gonzalez-Andaya AM, Hosking CS. Challenge
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27.
Hofmann AMS, A. M. Jones, S. M. Palmer, K. P. Lokhnygina, Y. Steele, P. H.
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