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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

WR-757-1

August 2010

Prepared for the National Institute of Allergy and Infectious Diseases

WORK ING P A P E R

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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 1776 Main Street 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.

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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 NON-IGE-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 IGE-MEDIATED FOOD ALLERGY?.................................................................................................................... 160 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? ................................................................ 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

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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

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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

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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).

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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

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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 IgE-mediated 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.

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:

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) Contact dermatitis Eczema, atopic dermatitis Generalized flushing Oral Allergy Syndrome Rhinitis, rhinoconjunctivitis conjunctivitis Urticaria Angioedema

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Key Questions B & C: What are the incidence/prevalence of IgE-mediated food allergy (B) and immunologic but non-IgE-mediated 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 self-report 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.

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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 community-based 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-IgE-mediated 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 IgE-mediated 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.

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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 IgE-mediated (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.

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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 double-blind- 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.

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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.

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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

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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:

Try to wait until babies are 6 months old before you give them solid foods. Wait until they are 1 year old before giving them milk and other dairy (like cheese

and yogurt). Toddlers should not eat eggs until they are 2 years old. Children should not eat peanuts, nuts or fish until they are 3 years old. 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.

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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 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. 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 cross- reactive 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 allergen-specific 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.

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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.

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Key Question J. What are the appropriate methods of diagnosis and treatment of acute and life-threatening, IgE-mediated food allergic reactions? There were no specific trials evaluating methods for the diagnosis of acute or life-threatening 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

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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.

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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

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guideline development process. This report will serve as the basis for the further development of guidelines according to the NIAID’s processes..

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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 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. 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?

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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 co-morbid 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-IgE-mediated adverse reactions to food? The following should be addressed:

i. Describe the symptoms and natural history of immunologic but non-IgE-

mediated 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

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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-IgE-mediated 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 IgE-mediated 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?

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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 non-

IgE-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 food-induced 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:

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a. epinephrine and route b. antihistamines and route c. corticosteroids and route d. 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 high-impact 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

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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:. 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

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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 pre-determined 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-IgE-mediated 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?

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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:

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.

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Table 1: Organization of report

KEY QUESTION

REPORT SECTION

Preliminary Material

Introduction

Methods

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

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

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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:

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.

Specific definitions were used for both exclusion criteria and categorization.

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

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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:

Article Type Included: Original data or systematic reviews. Excluded: Background/contextual reviews; non-systematic

reviews, commentary or other types of articles. 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 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:

Incidence/prevalence/natural history studies From where were the patients identified? How were the patients selected? In which country was the study performed/did patients reside? How was food allergy assessed?

Diagnosis studies How were the patients identified? What diagnostic tests were performed? What reference tests were performed? Were data reported on sensitivity or specificity or positive/negative

predictive value or false positive/false negative rate? Treatment/management/prevention studies

Who was the target of the intervention? What were the specific interventions? 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.

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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 meta-analyses, which we assessed using the AMSTAR criteria:3

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

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?

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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

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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:

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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:

Serious (-1) or very serious (-2) limitation to study quality

Important inconsistency (-1)

Some (-1) or major (-2) uncertainty about directness

Imprecise or sparse data (-1)

High probability of reporting bias (-1)

Increase grade if:

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)

Very strong evidence of association-significant relative risk of > 5 (< 0.2) based on direct evidence with no major threats to validity (+2)

Evidence of a dose response gradient (+1)

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.

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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.

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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

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Figure 2: Conceptual model of Key Questions

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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 Proportion of Reviews including

characteristic (N=71) Immune response 62 (87.3%) Reproducibility 22 (31.0%) Particular food 32 (45.1%) Separate from food intolerance, pharmacologic, or toxin- mediated reactions

35 (49.3%)

IgE-mediated reactions 56 (78.9%) Non-IgE-mediated immunologic mechanisms 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.

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Table 4: Web sites with food allergy definitions

Definition – Key Characteristic Proportion of sites/definition including characteristic (N=19)

Immune response 18 (94.7%) Reproducibility 1 (5.3%) Particular given food 9 (47.4%) Separate from food intolerance —pharmacologic or toxin- mediated reactions

6 (31.6%)

IgE-mediated reactions 8 (42.1%) Non-IgE-mediated immunologic mechanisms 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 Proportion of reviews including this condition as “food allergy”(N=71)

Angioedema 31 (43.7%) Asthma 28 (39.4%) Atopic dermatitis 21 (29.6%) Colitis 0 Food related eosinophilic esophagitis 2 (2.8%) Food related exercise induced 15 (21.1%) Gastrointestinal hypersensitivity 22 (31.0%) Generalized flushing 5 (7.0%) Laryngeal edema 3 (4.2%) Oral allergy syndrome 35 (49.3%) Rhinitis 20 (28.2%) Rhinoconjunctivitis 14 (19.7%) Urticaria 38 (53.5%)

* Note: Not all reviews specified a list of conditions

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Table 6: Terms associated with Non-IgE-mediated conditions


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


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 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.

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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 self-administered 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 food-induced 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: Abdominal pain or cramping Abnormal (high-pitched) breathing sounds Anxiety Confusion

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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: 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

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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 Avocadoes Cantaloupes Chocolate Dairy Products Lima Beans Monosodium glutamate Soy Sauce` Spinach Tomatoes 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): 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

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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 IgE-mediated. 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

http://www.worldallergy.org/public/allergic_diseases_center/foodallergy

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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 cell-mediated 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 non-IgE 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 amino-acid 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) 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

43

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,

44

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

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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

46

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 food-allergic 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

47

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: 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

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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 rhino-conjunctivitis (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

49

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

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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.

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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.

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Key Question B/C: What are the incidence/prevalence of IgE-mediated food allergy and immunologic but non-IgE-mediated adverse reactions to food?

i. Incidence and prevalence in the adult and pediatric populations ii. Incidence and prevalence for specific foods iii. 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

53

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.

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Table 8: Systematic Reviews and Meta-Analyses of the Prevalence of Food Allergies Author/ Year

Study Question

Food Allergies Included

Databases Searched/ Years

Excludes Total Publications Included

AMSTAR Criteria

Prevalence of food allergy Findings

Ove

rall

Pea

nut

Mil

k

Egg

Fis

h

She

llfi

sh

Self Report of Symptoms

Children 12% Adults 13%

All Ages 0.75% 3.5%* 1% 0.6% 1.1% Symptoms and Skin Prick Test or Serum IgE

All Ages 3% 0.75% 0.6% 0.9% 0.2% 0.6% Double-Blind Placebo-Controlled Food Challenge

Rona, 20071

To assess the prevalence of food allergy

Cow’s Milk Hen’s Egg Peanut Fish Shellfish

Medline, EMBASE Cochrane 1990-2005

Prevalence of food allergy in asthma, eczema, or allergic rhinitis; estimates from selected populations not representative of a community

51 01. Can’t Answer 02. Yes 03. Yes 04. Yes 05. Yes 06. Yes 07. No 08. No 09. Yes 10. No 11. Yes

All Ages 3% N.E. 0.9% 0.3% 0.3% N.E.

Fru

its

Veg

etab

les/

Leg

umes

Tre

e N

uts

Whe

at

Soy

Symptoms 0.02- 8.5%

0.01- 13.7%

0- 4.1%

0.2- 1.3%

0- 0.6%

Skin Prick Test 0.02- 4.2%

0.01-2.7%

0.04- 4.5%

0.2- 1.2%

0.03- 0.2%

Challenge Test 0.1- 4.3%

0.1- 0.3%

0.1- 4.3%

0- 0.5%

0- 0.7%

Meta-Analysis Adults

1.22% (Symptoms)

0.1% (Symptoms)

N.E.

0.4% (symptoms) 2% (sensitization)

N.E.

Zuidmeer, 200870

To assess the prevalence of allergy to plant foods

Fruits Vegetables/ legumes Tree nuts (not peanuts) Wheat Soy

Medline, EMBASE Cochrane 1990-2005

Prevalence of food allergy in asthma, eczema, or allergic rhinitis; estimates from selected populations not representative of a community

33 01. Can’t Answer 02. Yes 03. Yes 04. Yes 05. Yes 06. Yes 07. No 08. No 09. Yes 10. No 11. Yes

Children 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

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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:

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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)

≥65 y 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)

Age not known 485 3 0.6 (0.1-1.8) 3 0.6 (0.1-1.8)

Overall 13493 166 1.2 (1.0-1.4) 32 0.2 (0.2-0.3) 52 0.4 (0.3-0.5) 57 0.4 (0.3-0.5) 25 0.2 (0.1-0.3)

Table adapted from Sicherer, 200372

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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.

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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

Age 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 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)

Sex/age

Male (<18 y) 1526 26 1.70 (1.05-2.35) 4 0.26 (0.01-0.52) 15 0.98 (0.49-1.48) 5 0.33 (0.04-0.61) 2 0.13 (0.0-0.31) Female (<18 y) 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)


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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 Shellfish Both fish and shellfish Any seafood

Age

Total Sample Population, n = 14,498 n % (95% CI) n % (95% CI) n % (95% CI) n % (95% CI)

White 11176 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)

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 5.4 (3.3-8.2)

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) 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) Female (>18 y) 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)


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.

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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?”

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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 Eggs Peanut Tree nut Shellfish Fish Fruits Zuidmeer, 200870 Symptoms

Skin Prick IgE Challenge Test

0-4.1% 0.01-4.5% - 0.1-4.3%

0.02-8.5% 0.02-4.2% - 0.1-4.3%

Rona, 20071 Symptoms Skin Prick IgE Challenge Test

3% 0.60% - 0.90%

1% 0.90% - 0.30%

0.60% 0.75% - 0.90%

1.20% 0.60% - NE

0.60% 0.20% - 0.30%

Sicherer, 200473 Symptoms Skin Prick IgE Challenge Test

2% 0.40%

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Sicherer, 200372 Symptoms Skin Prick IgE Challenge Test

0.40% 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,

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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

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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.

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Table 13: US Studies of the Incidence of Anaphylaxis due to Food

Author/Year Study 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

August-September 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 person-years

44 percent of cases in children/teenagers

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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 community-based 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).

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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

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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

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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

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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

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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.

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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

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-life-threatening = 73%

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

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

8 patients selected due to low peanut-specific IgE had negative food challenges at a median age = 6 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 food-specific IgE or food challenge

140 2000-2006 Male = 66% Median age at first visit =28 months

Accidental exposure to peanuts after diagnosis = 39% Developed tolerance = 3%

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

No patient developed tolerance

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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

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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

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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

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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.

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Table 15: US Studies of the Natural History of Eosinophilic Esophagitis

Author/Year Population Criteria for Diagnosis Sample Size

Years of Study

Population Characteristics

Foods with positive skin prick test or

atopy patch test Natural History

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: 65% Age at diagnosis: Mean = 10.5 yearsMode = 12 year

SPT or RAST performed in 47 patients. 60% of patients had food allergies. Most common were milk, peanuts, & soy beans.

Of 96 patients treated with swallowed fluticasone, follow up data available for only 26. 17 of these had “complete response.”

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 yearsMode = 1 year

Egg = 39%Peanut = 39%Soy = 34%Beans = 29%Cow Milk = 29%Pea = 29%Mustard = 26%

Resolved = 8/57 Resolved with Relapse = 30/57 Persisted = 19/57

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 yearsMode = 0-3 years

Milk = 17%Egg = 11%Wheat = 10%Soy = 8%Corn = 8%Peanut = 5%

Resolved = 11/562 Partial Resolution = 33/562 Progression to eosinophilia in colon or stomach = 0

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Table 16: Studies of Allergies to Specific Foods, Non US/Canada

Food Country Reference Asparagus Spain 117 Buckwheat China 118 Celery France 119 Cow Milk Australia 120 Cow Milk Italy 121

Cow Milk, Egg & Atopic Dermatitis Europe 55 Egg Turkey 122 Egg Norway 123 Kiwi Spain 124 Legume Spain 125 Melon Spain 126 Mustard France 127 Mustard Spain 128 Mustard France 129 Peanut Australia 130 Peanut UK & Israel 131 Peanut UK 99 Sesame Israel 132 Sesame Israel 133 Sesame France 134 Sesame Israel 135 Snail Spain 136 Soy Bean Europe 137 Zucchini Switzerland 138

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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 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.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

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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 Negative

Positive True Positives (TP) False Positives (FP) (Type I error)

PPV TP/(TP+FP)

Study Test Negative False Negatives (FN)

(Type II error) True Negatives (TN) 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,

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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

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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

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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 Neocate® 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 124,000g/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

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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, placebo-controlled 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, -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 Reference Test Test and Results 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)

DBPCFC Open food challenge: 54% positive tests for both open and DBPC challenges (99+), 49 immediate and 50 delayed

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)

Objective symptoms of DBPCFC

Facial Thermography at 10-min. intervals: Sensitivity: 0.92 Specificity: 1 based on comparison to objective symptoms of DBPCFC

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


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)

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

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%

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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 (-lactalbumin[ALA], -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.

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Table 19: Summary of Cow's Milk Allergy Studies with Skin Prick Tests

Study Population Reference Test Assay Results

Prahl, 1988166

26 children (aged 1-63 months) consecutively referred to a Danish university hospital allergy clinic for suspected cow milk allergy

Open food challenge Skin prick test with raw cow’s milk, positive test defined as wheal diameter ≥ histamine (positive) control

Se Sp PPV NPV

0.8 0.66 0.89 0.50

Garcia-Ara, 2000167

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

Skin prick test with alpha-lactalbumin (ALA), beta-lactoglobulin (BLG), whole milk, and casein; positive test defined as a net wheel diameter 3mm>negative control

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

Roehr, 2001171*

98 children (2 months-11 years)

consecutively admitted to a Berlin university hospital

pneumonology ward with atopic

dermatitis

71 DBPCFC with cow milk based on history 45/71 diagnosed with

milk allergy

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

Se Sp PPV NPV

0.78 0.69 0.81 0.64

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

Skin prick test with Cow’s milk formula, whole milk, or protein fractions; a positive test was defined as a wheal diameter of ≥3

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

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

SPT with foods, preparation not specified Cutoff: wheal diameter≥3mm

Cow’s milk: 17/22 positive Se Sp PP

V NPV

0.77 0.88

0.63

0.94

97


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

OFC to assess both early and late reactions: 3/8 positive for CM

Skin prick test performed with fresh CM Cutoff: ≥3mm

2/8 positive Se Sp PPV NPV

0.66 0.80 0.66 0.80

Rancé, 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 CM Cutoff: ≥3mm larger than negative control and ≥50% larger than positive control

Se Sp PPV

NPV

0.59 0.50

0.91

0.56

Mehl, 2006149*

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. 168/437 diagnosed with cow’s milk allergy by DBPCFC

Skin prick test with fresh food samples, definition of positive tests not reported.

Se Sp PPV NPV

0.85 0.7 0.73 0.83

Decision Points

PPV wheal n

0.95 9.2 mm 19/437

0.99 14.5 mm 2/437

Canani, 2007175

All children 3-48 months referred to Pediatric gastroenterology center in Naples for suspected FA-related 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)

SPT with fresh CM Positive reaction: ≥3mm with no reaction to control

Se Sp PP

V NPV

0.45 0.70

0.67

0.51

98


Isolauri, 1996148

183 Finnish children (ages 2-36 months) with AD and suspected CMA

Patients randomized to DBPCFC (n=118) and open FC (n=65) 99/183 confirmed with CMA by oral challenge.

Commercial cow milk allergen (ALK) and milk powder. Reactions read at 15 minutes with wheals greater than half the histamine reactions size were considered positive.

DBPCFC (Open)

SPT positive % n=64 (35)

negative % n=54 (30)

positive 48 (47) 14 (17)

negative 52 (53) 86 (83)

FC Se Sp

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 1.5-84 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. 23/37 had positive challenges or history of anaphylactic reaction

Skin prick test with commercial allergen (ALK) wheal greater than or equal to 3mm larger than negative control was considered positive

positive SPT

early late

neg

positive 19 2 7

negative 0 2 7

Reaction Se Sp PPV NPV

All 91 50 75 78

Early 100 50 73 100

Late 50 50 22 78

Calvani, 2007174

104 children consecutively referred to an Italian pediatric allergy clinic for evaluation of suspected CMA

Food challenge (70 open and 34 DBPCFC) 28/104 tests were positive

SPT with: - lactalbumin - casein - beta-lactoglobulin - fresh milk with positive tests defined as mean wheal diameters 3mm ≥ the negative control.

Test Se Sp PPV NPV

lactalbumin 75 80 58 90

casein 61 96 85 87

beta-lactoglobulin

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

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Table 20: Summary of Hen's Egg Allergy Studies with Skin Prick Tests


Roehr, 2001171

98 children (2 months-11 years) consecutively admitted to a Berlin university hospital pneumonology ward with atopic dermatitis

DBPCFC on 42 children based on history 28/42 diagnosed with egg allergy

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

Se Sp PPV NPV

0.89 0.57 0.81 0.73

Ricci, 2003168


FC (blinding not specified) 40 positive for HE

SPT with foods, preparation not specified Cutoff: wheal diameter≥3mm


0.91 0.77 065 0.95

Osterballe, 2004169


OFC to assess both early and late reactions: 8/14 positive for HE

Skin prick test performed with fresh HE Cutoff: ≥3mm


0.88 0.83 0.88 0.83

Rancé, 2004170



Skin prick test performed with fresh whole HE Cutoff: ≥3mm larger than negative control and ≥50% larger than positive control

Se Sp PPV NPV

0.93 0.50 0.97 0.66

Canani, 2007175


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

Se Sp PPV NPV

0.58 0.67 0.79 0.43

100


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. 193/437 diagnosed with egg allergy


Se Sp PPV NPV Eff

0.93 0.54 0.79 0.81 0.79

PPV wheal n

0.95 9.0 mm 68/437

0.99 11.9 mm 31/437

Monti, 2002176

107 children (age 1-19 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) 72/107 children had positive food challenges.

SPTs were performed with commercial extracts of albumin and yolk; they reported the absolute measure of the wheal diameter.

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

SPT w/Albumin

Wheal Se Sp PPV NPV

≥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

Diéguez, 2008177

104 patients (ages 12-15 months) with IgE mediated CMA (by history and SPT/sIgE) with no prior egg exposure consecutively seen in the allergy clinic of a Spanish hospital

Open oral challenge with egg components. 38/104 were egg allergic by oral challenge.

SPTs with egg white, yolk, ovalbumin (OVA), ovomucoid (OVM), ovotransferrin (OVT), and lysozyme commercial extracts (Bial-Aristegui laboratories). Wheal of 3 mm or larger was regarded as positive.

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

Egg white

3 mm 0.95 0.4 0.59 0.89

6 mm 0.81 0.73 0.73 0.81

OVM

3 mm 0.67 0.85 0.83 0.71

5 mm 0.58 0.97 0.95 0.69 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

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Table 21: Summary of Peanut Allergy Assessments with Skin Prick Tests


Wainstein, 2007178

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 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

Wheal (mm)

Se Sp PPV NPV

≥ 8 0.75 0.67 0.78 0.63

(95% CI) 0.62-.86

0.48-.82

≥ 15 0.06 1.00 1.00 0.40

(95% CI) 0.01-.16

0.89-1.00

Rancé, 2004170



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

Se Sp PPV NPV

0.70 0.50 0.60 0.55

Rancé, 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. 177/393 peanut allergic by FC

SPT performed with commercial extract (Allerbio) and fresh peanut mix with wheals 3 mm greater than negative control defined as positive tests.

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 antigen-specific immunoglobulin E; Sp specificity; SPT skin prick test

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Table 22: Summary of Soy Allergy Assessments with Skin Prick Tests


Roehr, 2001171


DBPCFC on 25 children for soy based on history 4/25 diagnosed with soy allergy

Skin prick test with soy milk; positive test defined as a net wheel diameter ≥ 3mm with no reaction to negative control; 4/98 positive reactions to soy milk

Se Sp PPV NPV

0.50 0.90 0.50 0.90

Mehl, 2006149


DBPCFC (except patients under 1 year of age with clear history of immediate reactions) guided by SPT, sIgE, and clinical history. 37/437 diagnosed with wheat allergy


Se Sp PPV NPV

0.29 0.85 0.33 0.82

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

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Table 23: Summary of Wheat Allergy assessments with Skin Prick Tests


Roehr, 2001171


DBPCFC on 35 children for wheat based on history 18/35 diagnosed with wheat allergy

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

Se Sp PPV NPV

0.67 0.53 0.60 0.60

Rancé, 2004170



Skin prick test performed with wheat powder dissolved in water Cutoff: ≥3mm larger than negative control and ≥50% larger than positive control

Se Sp PPV NPV

0.75 0.50 0.75 0.50

Mehl, 2006149


DBPCFC (except patients under 1 year of age with clear history of immediate reactions) guided by SPT, sIgE, and clinical history. 159/437 diagnosed with wheat allergy.


Se Sp PPV NPV

0.75 0.64 0.49 0.85

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 IgE-mediated 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

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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., UniCAP®), and the third generation is referred to as the chemiluminescent enzyme immunoassay (CLEIA) (e.g., Immulite 2000®). 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).

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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 (-lactalbumin[ALA], -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).

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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 early-onset, 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).

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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-IgE-mediated mechanisms.

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Table 24: sIgE Measures of Cow’s Milk Allergy Using Food Challenge as Reference Study Population (age range) Reference Test Assay System Results Prahl, 1988 166 26 children (aged 1-63 months)

consecutively referred to a Danish university hospital allergy clinic for suspected cow milk allergy

Open food challenge 20/26 positive

RAST with commercial raw cow’s milk extract

Se Sp PPV NPV

0.8 0.66 0.89 0.50

(sIgE positive in 16/18 with CMA and 2/18 without CMA)

Tainio, 1990183 34 children w/ suspected CMA (3-

51 mos) Open challenge 19/34 positive (14 immediate and 5 delayed

RAST Se Sp

0.63 0.8

Roehr, 2001171* 98 children (2 months-11 years) consecutively admitted to a Berlin university hospital pneumonology ward with atopic dermatitis

71 DBPCFC with cow milk based on history 45/71 diagnosed with milk allergy

CAP Se Sp PPV NPV

0.84 0.38 0.70 0.59

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


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

≥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

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Study Population (age range) Reference Test Assay System Results DeBoisseau, 2003184

35 children (2-57 months) referred for diagnosis of non-specific persistent digestive symptoms.

Food challenge (open unless results equivocal) 24/35 positive

CAP-RAST sIgE positive in 3/24 with CMA, positive in 0/11 w/o CMA

Se Sp

0.89 1.00

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

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



Magic Lite sIgE Cutoff: 1.43 sU/ml

Se Sp PPV NPV

0.66 0.40 0.40 0.66

Canani, 2007175 All children 3-48 months referred to Pediatric gastroenterology center in Naples for suspected FA-related 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)

Pharmacia CAP RAST Positive test ≥0.35kU/L

Se Sp PPV NPV

0.23 0.74 0.54 0.42

Rottem, 2008187 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)

Food challenge or suggestive history

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

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

Rancé, 2004 170 48 children, 3-29 months, consecutively recruited to a French pediatric hospital allergy clinic with AD


Pharmacia Upjohn CAP FEIA Cutoff: ≥0.35 kU/L

Se Sp PPV NPV

0.31 0.66 0.83 0.15

Mehl, 2006149* 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

RAST Se Sp PPV NPV

0.87 0.49 0.62 0.79

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Study Population (age range) Reference Test Assay System Results Celik-Bilgili, 2005185

501 children (1 mo-16.1 yr) Food challenge in children >1 year of age

CAP-RAST

Se Sp PPV NPV

0.83 0.53 0.63 0.76

Predictive decision points: 90%: 88.8 kU/L

Keskin, 2005173 37 children referred for suspected CMA


ImmunoCAP FEIA

Cutoff point≥0.7kU/L Se Sp PPV NPV

0.74 0.79 0.85 0.65

Sampson, 2001186

100 consecutive children (0.4-14.3 yrs)

Food challenge or strong history 62/100 positive, 1/3 based on food challenge

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

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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

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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.

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Table 25: sIgE Measures of Hen’s Egg Allergy Using Food Challenge as Reference ID/Author, Yr.

Population (age range) Reference Test

Assay System Results

Sampson, 2001186

75 consecutive children (0.4-14.3 yrs)

Food challenge or strong history

Pharmacia CAP FEIA

Decision Point (kUA/L) 7

Se Sp PPV NPV

0.61 0.95 0.98 0.38

Roehr, 2001171


DBPCFC

Pharmacia CAP FEIA

Decision Point (kUA/L) 0.35

Se Sp PPV NPV

0.96 0.36 0.75 0.83

Monti, 2002176

107 children (1-19 mos) Open egg challenge, monitoring for early and late reactions (up to 8 days)

RAST Albumin>99kU/L Yolk ≥17.5 kU/L Specificity: 1

Celik-Bilgili, 2005185

501 children (1 mo-16.1 yr)

Food challenge in children >1 year of age

CAP system

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

Ricci, 2003168


FC (blinding not specified) 40 positive for HE

Pharmacia UniCAP vs. ADVIA Centaur cutoff>0.35kU/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

Magic Lite sIgE Cutoff: 1.43 sU/ml

Se Sp PPV NPV

0.63 0.66 0.71 0.57

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ID/Author, Yr.


Assay System Results

birth cohort) whose parents responded to a questionnaire about food hypersensitivity

and late reactions: 8/14 positive for HE

Canani, 2007175


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)

Pharmacia CAP RAST Positive test ≥0.35kU/L

Se Sp PPV NPV

0.32 0.67 0.67 0.32

Rancé, 2004 170



Pharmacia Upjohn CAP FEIA Cutoff: ≥0.35 kU/L

Se Sp PPV NPV

0.65 0.75 0.96 0.21

Mehl, 2006149

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.

RAST 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

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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).

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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, Yr.


Assay System

Results

Sampson, 2001186

68 consecutive children 93 mos-14 yrs)


Pharmacia CAP FEIA

Decision Point (kUA/L) 14

Se Sp PPV NPV

0.57 1.00 1.00 0.36 Rancé, 2002165

363 children, 177 with positive challenge, 186 with negative challenge

DBPCFC preceded by elimination diet. Patients monitored for reactions for 4 hours following test. 177/363 peanut allergic by FC

Pharmacia CAP FEIA

Decision Point (kU kUA/L) 15

Se Sp PPV NPV

0.44 0.95 ND ND

Maloney, 2008189

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

ImunoCAP sIgE

Decision Point: ≥13 kU/L Se Sp PPV NPV

0.60 0.96 0.99 0.35

Rancé, 2004170

48 children, 3-29 months, consecutively recruited to a French pediatric hospital allergy clinic


Pharmacia Upjohn CAP FEIA

Decision Point: ≥0.35kU/L Se Sp PPV NPV

0.53 0.66 0.89 0.21 Wainstein, 2007178



Pharmacia CAP FEIA

Se Sp PPV NPV

0.37 0.98 0.33 0.70 0.92

CI 0.9-1.0

0.18-.52

10 0.54 1.00 1.00 0.58

CI 0.39-0.67

0.89-1.00

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

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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

System Results

Sampson, 2001186

100 children (3 mos-14 yrs): 21 with positive food challenge and 4 with strong history

Pharmacia CAP FEIA

95% Decision Point (kUA/L): 65

Se Sp PPV NPV

0.24 0.99 0.86 0.78


Se Sp PPV NPV

0.44 0.94 0.73 0.82 Roehr, 2001171 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

Pharmacia CAP FEIA

Cutoff: 0.35 kUA/L

Se Sp PPV NPV

0.75 0.52 0.23 0.92


501 children (1 mo-16.1 yrs), 189 administered food challenge,

Pharmacia CAP FEIA

Cutoff: 0.35 kUA/L

118

of which 38 were positive Se Sp PPV NPV

0.69 0.50 0.22 0.88 Mehl, 2006149 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


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).

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Table 28: sIgE Measures of Wheat Allergy Using Food Challenge as Reference ID/Author, Yr.


Assay System

Results

Sampson, 2001186

100 children (3 mos-14 yrs), 17 with positive food challenge and 6 with strong history


Pharmacia CAP FEIA


Se Sp PPV NPV

0.13 1.00 1.00 0.76


Se Sp PPV NPV

0.61 0.92 0.74 0.87 Roehr, 2001171

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

DBPCFC Pharmacia CAP FEIA

Se Sp PPV NPV

0.67 0.47 0.57 0.57

Rancé, 2004170



Pharmacia Upjohn CAP FEIA

Se Sp PPV NPV

0.40 0.50 0.66 0.25


501 children (1 mo-16.1 yrs), 178 administered wheat challenge, of which 62 were positive

Food challenge in children >1 year of age

Pharmacia CAP FEIA

Cutoff: 0.35 kUA/L

Se Sp PPV NPV

0.79 0.38 0.41 0.77 Mehl, 2006149 423 children (3 mos-14 yrs),

159 administered wheat challenge; 57 positive

DBPCFC (except patients under 1 year of age with clear history of immediate reactions) guided by SPT, sIgE, and clinical history.

Pharmacia CAP FEIA

Se Sp PPV NPV

0.82 0.34 0.41 0.77


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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 Pediatric® (PP) test (a test designed primarily for children under 7) and the RAST mixed food panel, and 18 had a positive Phadiatop® test (a test designed primarily for children over 7). Among the 17 clinically atopic children with positive SPT, all had a positive Phadiatop® 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

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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 UniCAP® 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 allergy-positive (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

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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).

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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 ≥15.9g/L, t he sensitivity was 0.27 (specificity 0.74; PPV 0.67; NPV 0.34)); at a cutoff value of 24.7g/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

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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

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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).

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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).

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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

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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

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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.

130

Table 29: APT studies of cow's milk

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

71 DBPCFC with cow milk based on history

45/71 diagnosed with milk allergy

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

Se Sp PPV NPV

0.47 0.96 0.95 0.51

Saarinen, 2001 172

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

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.

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

Isolauri, 1996148

183 Finnish children (ages 2-36 months) with AD and suspected CMA

Patients randomized to DBPCFC (n=118) and open FC (n=65) 99/183 confirmed with CMA by oral challenge.

humidified powdered skim cow milk applied to patient's backs with aluminum cups, occlusion time of 48 hours, results read at 15 minutes after cup removal and again at 72 hours

DBPCFC (Open)

APT Positive %n = 64 (35)

Negative %n = 54 (30)

Positive 61 (59) 19 (17)

Negative 39 (41) 81 (83)

FC Se Sp

Blind 61 81

Open 59 83

Osterballe, 2004169



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 PPV NPV

0.0 1.00 0.0 0.62

131


Rancé, 2004 170



APT scoring compared after 24- and 48-hour occlusion times; positive test required a minimum of erythema and slight infiltration

Se Sp PPV NPV

24 hr 0.18 1.00 1.00 0.63

48 hr 0.89 0.96 0.94 0.92

Canani, 2007 175


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

Se Sp PPV NPV

Fresh

0.65 0.96 0.95 0.67

Extract

0.06 0.96 0.67 0.43

Mehl, 2006149

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. 168/437 diagnosed with cow’s milk allergy by DBPCFC

One drop fresh CM 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 (72 hours after application).


Overall 31 95 86 60

Immediate 27

Late 45

Combined 36

AD+ 32 93

AD- 30 100

sensitivity of APT increased with age, and was 100% for children 3-6 years of age.

Keskin, 2005173

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.


cow's milk powder mixed with saline, applied with aluminum cups to packs. Children examined after 30 minutes for immediate reactions. Cups removed after 48 hours and read 72 hours after application.

positive SPT

early late

neg

positive 13 3 2

negative 5 1 12


All 73 86 89 67

Immediate 72 86 87 71

Late 75 86 60 92


132

Table 30: APT studies of hen’s egg


Roehr, 2001171


DBPCFC in 42 children 28/42 positive

One drop of fresh whisked egg white and yolk 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 . 17/98 positive

Se Sp PPV NPV

0.57 0.93 0.94 0.52

Osterballe, 2004169


OFC to assess both early and late reactions: 8/14 positive for HE

APT scored after 72 hours; positive test ranged from erythema and slight infiltration to papules and vesicles Hen’s egg: 6/13 positive

Se Sp PPV NPV

0.63 0.80 0.83 0.57

Rancé, 2004 170




Se Sp PPV NPV

24 hr 0.15 0.83 0.86 0.12

48 hr 0.97 0.71 0.95 0.83

Canani, 2007 175


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

Se Sp PPV NPV

Fresh 0.84 1.00 1.00 0.75

Extract 0.05 1.00 1.00 0.33

Mehl, 2006149


DBPCFC (except patients under 1 year of age with clear history of immediate reactions) guided by SPT, sIgE, and clinical history. 193/437 diagnosed with egg allergy

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.


Overall 41 87 86 43

Immediate 45

Late 17

Combined 36

AD+ 40 91

AD- 60 85

there was no effect of age on sensitivity.


133

Table 31: APT studies of soy


Roehr, 2001171


DBPCFC in 25 children 4/25 positive

One drop of soy 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 . 6/98 positive

Se Sp PPV NPV

0.75 0.86 0.50 0.95

Mehl, 2006149


DBPCFC (except patients under 1 year of age with clear history of immediate reactions) guided by SPT, sIgE, and clinical history. 37/437 diagnosed with wheat allergy

One drop soy milk 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.


Overall 23 86 30 82

AD+ 25 88

AD- 0 86

No difference seen in the sensitivity of the test by reaction timing sensitivity of APT increased with age, and was 100% for children older than 6 years of age.


134

Table 32: APT studies of wheat/cereal


Roehr, 2001171


DBPCFC performed with wheat powder on 35 children 18/35 positive

One drop of wheat powder dissolved in water 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 . 17/98 positive

Se Sp PPV NPV

0.89 0.94 0.94 0.89

Rancé, 2004 170




Se Sp PPV NPV

24 hr 0.25 1.00 1.00 0.94

48 hr 0.83 0.94 0.71 0.97

Mehl, 2006149


DBPCFC (except patients under 1 year of age with clear history of immediate reactions) guided by SPT, sIgE, and clinical history. 159/437 diagnosed with wheat allergy.

One drop wheat powder (Kröner) dissolved in water, 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.


Overall 27 89 58 69

Immediate 22

Late 29

Combined 50

sensitivity of APT increased with age, and was 100% for children older than 6 years of age.

Jarvinen, 2003196

90 children (2.5-36 months) w/CMA (both IgE- and non-IgE-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. 30/44 OFCs were positive for wheat 66/90 OFCs were positive for all cereals (wheat, rye, barley, oats)

wheat flour mixed with isotonic saline was applied to the back with aluminum cups. Cups were removed after 48 hours and reactions read 72 hours after the cups were applied. Presence of edema or eczema was considered a positive reaction.

Food Se Sp PPV NPV

Wheat 70 71 84 53

All Cereals 67 79 90 46


135

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).

136

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.

137

Figure 4: ROC curve for SPT. sIgE, APT for Cow’s Milk

.2.4

.6.8

1S

ens

itivi

ty

0 .2 .4 .6 .8 11 - Specificity

APT APT studiessIgE sIgE studiesSPT SPT studies

138

Figure 5: ROC curve for SPT and sIgE for Hen's egg

0.2

.4.6

.81

Se

nsiti

vity

0 .2 .4 .6 .8 11 - Specificity

sIgE sIgE studiesSPT SPT studies

139

Figure 6: Figures 6a, 6b, and 6c

140

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.

141

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).

142

Table 33: Combination of SPT and APT compared with Individual Tests Study Population SPT

Results APT Results

SPT+/or APT Results

Isolauri, 1995148

Se Sp

0.48 0.86

Se Sp

0.61 0.81

Either test +:

Se Sp

0.72 0.86

Both tests +:

Se Sp

0.92 0.24

Roehr, 2001171


Cutoff Milk

Se Sp PPV NPV

0.78 0.69 0.81 0.64

Hen’s Egg Se Sp PPV NPV

0.89 0.57 0.81 0.73

Soy Se Sp PPV NPV

0.50 0.90 0.50 0.90

Wheat Se Sp PPV NPV

0.67 0.53 0.60 0.60

Milk Se Sp PPV NPV

0.47 0.96 0.95 0.51


0.57 0.93 0.94 0.52

Soy Se Sp PPV NPV

0.75 0.86 0.50 0.95

Wheat Se Sp PPV NPV

0.89 0.94 0.94 0.89

Milk Se Sp PPV NPV

0.74 1.00 1.00 0.74


0.84 0.89 0.94 0.73

Soy Se Sp PPV NPV

0.67 1.00 1.00 0.94

Wheat Se Sp PPV NPV

0.86 0.90 0.92 0.82

Keskin, 2005173

37 children referred for suspected CMA

Cutoff point≥3mm Se Sp PPV NPV

0.91 0.50 0.75 0.65

Se Sp PPV NPV

0.91 0.50 0.75 0.76

Cutoff:>1+

Se Sp PPV NPV

1.00 0.50 0.76 1.00

Jarvinen, 2003196

90 children (2.5-36 months) w/CMA (both IgE- and non-IgE-mediated) controlled via elimination but w/ residual symptoms that did not respond to elimination of eggs, nuts, fruits, chocolate, fish. DBPCFC was reference.

SPT cereal Se Sp PPV NPV

0.23 1.0 1.0 0.32

Wheat:

Se Sp PPV NPV

0.17 1.0 1.0 0.36

APT cereal Se Sp PPV NPV

0.67 0.79 0.9 0.46

Wheat:

Se Sp PPV NPV

0.7 0.71 0.84 0.53

Sensitivity decreased with age; specificity increased with age

SPT+APT Cereal:

Se Sp PPV NPV

0.73 0.83 0.92 0.53

Wheat:

Se Sp PPV NPV

0.77 0.17 0.85 0.59

Mehl, 2006149 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

0.93 0.54 0.79 0.81

Wheat:

Se Sp PPV NPV

0.75 0.64 0.49 0.85

Soy:

CM: Se Sp PPV NPV

0.31 0.95 0.86 0.60

Egg:

Se Sp PPV NPV

0.41 0.87 0.86 0.43

Wheat:

Se Sp PPV NPV

0.27 0.89 0.58 0.69

CM: Se Sp PPV NPV

0.69 0.97 0.92 0.86

Egg:

Se Sp PPV NPV

0.85 0.89 0.92 0.80

Wheat:

Se Sp PPV NPV

0.43 0.90 0.50 0.86

143

Se Sp PPV NPV

0.29 0.85 0.33 0.82

Soy: Se Sp PPV NPV

0.23 0.86 0.30 0.82

Soy: Se Sp PPV NPV

0.14 0.96 0.43 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 PPV NPV

0.58 0.67 0.79 0.43

APT with fresh food Cow’s milk:

Se Sp PPV NPV

0.65 0.96 0.95 0.67


0.84 1.00 1.00 0.75

APT or SPT Cow’s milk:

Se Sp PPV NPV

0.87 0.65 0.77 0.79


0.95 0.67 0.86 0.86


144

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).

145

Table 34: Combination of SPT and sIgE compared with Individual Tests Study Population SPT

Results sIgE

Results SPT+sIgE

Results Hill, 1988198

135 children referred to specialist with CMA (5 mos-13 yrs); ½ CMA+ by food challenge

SPT≥4=positive PPV: 1 NPV: 0.65

RAST Predictive value not reported

Se Sp PPV NPV

0.54 0.91 0.86 0.66

Roehr, 2001171 98 children (2 months-11 years) consecutively admitted to a Berlin university hospital pneumonology ward with atopic dermatitis

Cutoff≥3mm (no reaction to control) Milk

Se Sp PPV NPV

0.78 0.69 0.81 0.64


0.89 0.57 0.81 0.73

Soy Se Sp PPV NPV

0.50 0.90 0.50 0.90

Wheat Se Sp PPV NPV

0.67 0.53 0.60 0.60

Cutoff: ≥0.35 kU/L Milk

Se Sp PPV NPV

0.84 0.38 0.70 0.59


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 0.47 0.57 0.57

Milk

Se Sp PPV NPV

0.85 0.56 0.83 0.30


0.96 0.43 0.86 0.75

Soy Se Sp PPV NPV

1.00 0.91 0.50 1.00

Wheat Se Sp PPV NPV

0.71 0.50 0.63 0.60 Rance, 2002165

363 children referred for suspected peanut allergy

NPV for raw extract =1 SPT>3mm: specificity 74% PPV=1 for SPT≥16mm:

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


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.

146

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).

147

Table 35: Combination of APT and Antigen-specific IgE Compared with Individual Tests Study Population APT

Results sIgE

Results APT+sIgE

Results Roehr, 2001171 98 children (2

months-11 years) consecutively admitted to a Berlin university hospital pneumonology ward with atopic dermatitis

Milk-Early reactions Se Sp PPV NPV

0.26 0.96 0.88 0.56

Milk-Late reactions

Se Sp PPV NPV

0.78 0.96 0.93 0.86

Egg-Early

Se Sp PPV NPV

0.44 0.93 0.89 0.57

Egg-Late

Se Sp PPV NPV

0.80 0.93 0.89 0.87


≥0.35 0.85 0.38 0.59 0.71

≥17.5 0.22 0.96 0.86 0.54

Milk-Late reactions

Se Sp PPV NPV

≥0.35 0.83 0.38 0.48 0.77

≥17.5 0.17 0.96 0.75 0.63

Egg-Early reactions

Se Sp PPV NPV

≥0.35 0.94 0.36 0.65 0.83

≥17.5 0.28 1.00 1.00 0.52

Egg-Late reactions

Se Sp PPV NPV

≥0.35 1.00 0.38 0.53 1.00

≥17.5 0.20 1.00 1.00 0.64


≥0.35 0.64 1.00 1.00 0.69

≥17.5 0.06 1.00 1.00 0.62

Milk-Late reactions

Se Sp PPV NPV

≥0.35 0.92 1.00 1.00 0.90

≥17.5 0.40 1.00 1.00 0.89

Egg-Early reactions

Se Sp PPV NPV

≥0.35 0.94 0.83 0.94 0.83

≥17.5 0.35 1.00 1.00 0.54

Egg-Late reactions

Se Sp PPV NPV

≥0.35 1.00 0.83 0.89 1.00

≥17.5 0.50 1.00 1.00 0.87 Mehl, 2005149 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

0.31 0.95 0.86 0.60

Egg:

Se Sp PPV NPV

0.41 0.87 0.86 0.43

Wheat:

Se Sp PPV NPV

0.27 0.89 0.58 0.69

Soy:

Se Sp PPV NPV

0.23 0.86 0.30 0.82

CM: Se Sp PPV NPV

0.87 0.49 0.62 0.79

Egg:

Se Sp PPV NPV

0.96 0.48 0.79 0.85

Wheat:

Se Sp PPV NPV

0.82 0.34 0.41 0.77

Soy:

Se Sp PPV NPV

0.65 0.50 0.22 0.86

CM: Se Sp PPV NPV

0.74 0.94 0.90 0.83

Egg:

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:

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

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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).

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Table 36: Combination of SPT and APT and Antigen-specific IgE compared with Individual Tests Study Population SPT

Results APT

Results sIgE

Results SPT+APT+sIgE

Results

Roehr, 2001171 98 children (2 months-11 years) consecutively admitted to a Berlin university hospital pneumonology ward with atopic dermatitis

Milk

Se Sp PPV NPV

0.78 0.69 0.81 0.64


0.89 0.57 0.81 0.73

Soy Se Sp PPV NPV

0.50 0.90 0.50 0.90

Wheat Se Sp PPV NPV

0.67 0.53 0.60 0.60

Milk

Se Sp PPV NPV

0.47 0.96 0.95 0.51


0.57 0.93 0.94 0.52

Soy Se Sp PPV NPV

0.75 0.86 0.50 0.95

Wheat Se Sp PPV NPV

0.89 0.94 0.94 0.89

Cutoff point≥:0.35 Milk

Se Sp PPV NPV

0.84 0.38 0.70 0.59


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 0.47 0.57 0.57

Milk

Se Sp PPV NPV

0.81 1.00 1.00 0.67


0.94 0.75 0.94 0.75

Soy Se Sp PPV NPV

1.00 1.00 1.00 1.00

Wheat Se Sp PPV NPV

0.91 0.86 0.91 0.86

Cudowska, 2005199

34 children (5 mos-16 yrs) 20< 3yrs 14≥3 yrs w/suspected milk allergy

Age<3 years

Se Sp PPV NPV

0.80 0.79 0.73 0.22

Age ≥3 years

Se Sp PPV NPV

0.80 0.89 0.80 0.11

Age<3 years

Se Sp PPV NPV

0.92 0.71 0.85 0.17

Age ≥3 years

Se Sp PPV NPV

0.80 0.89 0.80 0.11 Keskin, 2005173

37 children referred for suspected CMA

Cutoff point≥3mm

Se Sp PPV NPV

0.91 0.50 0.75 0.65

Se Sp PPV NPV

0.91 0.50 0.75 0.76

Cutoff point≥0.7kU/L

Se Sp PPV NPV

0.74 0.79 0.85 0.65

Criterion: >1 positive

Se Sp PPV NPV

1.00 0.50 0.76 1.00

Mehl, 2006149

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

CM:

Se Sp PPV NPV

0.31 0.95 0.86 0.60

Egg:

Se Sp PPV NPV

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

150

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

0.41 0.87 0.86 0.43

Wheat:

Se Sp PPV NPV

0.27 0.89 0.58 0.69

Soy:

Se Sp PPV NPV

0.23 0.86 0.30 0.82

0.96 0.48 0.79 0.85

Wheat:

Se Sp PPV NPV

0.82 0.34 0.41 0.77

Soy:

Se Sp PPV NPV

0.65 0.50 0.22 0.86

0.92 0.82 0.92 0.82

Wheat:

Se Sp PPV NPV

0.60 0.85 0.60 0.85

Soy:

Se Sp PPV NPV

0.20 0.93 0.33 0.87 Canani, 2007 175

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)


Se Sp PPV NPV

0.45 0.70 0.67 0.51


0.58 0.67 0.79 0.43

APT with fresh vs. commercial food extracts APT with fresh food Cow’s milk:

Se Sp PPV NPV

0.65 0.96 0.95 0.67


0.84 1.00 1.00 0.75

sIgE Cow’s milk:

Se Sp PPV NPV

0.23 0.74 0.54 0.42


0.32 0.67 0.67 0.32

APT using fresh food or SPT or sIgE Cow’s milk:

Se Sp PPV NPV

0.90 0.52 0.72 0.80


0.95 0.44 0.78 0.80


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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-IgE-mediated 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

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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 milk-allergic 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.

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Table 37: Sensitivity and Specificity of SPT and APT in EE

SPT APT SPT+APT

Food* 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

Apple (n=?) 0.67 0.97 0.57 0.98 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.

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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 non-allergists 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

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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

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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.

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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

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Figure 7: Distribution of Prevention RCTs by Country

0 1 2 3 4

Thailand

Poland

UK

Italy

Korea

Denmark

Norway

Sweden

Multicenter

Germany

Finland

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).

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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

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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.

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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 dust-mites 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

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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?

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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 breast-feeding 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.

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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

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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.

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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. .

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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/

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-at-school/

American Academy of Pediatrics http://www.aap.org/

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: Try to wait until babies are 6 months old before you give them solid foods. Wait until they are 1 year old before giving them milk and other dairy (like

cheese and yogurt). Toddlers should not eat eggs until they are 2 years old. Children should not eat peanuts, nuts or fish until they are 3 years old. 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

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

http://www.aanma.org/

http://www.aanma.org/faqs/

http://www.aanma.org/2009/05/keep-two-doses-of-epi/

http://www.aanma.org/2009/01/food-allergies-at-school/

http://www.aanma.org/2009/01/food-allergies-at-school/

http://www.aap.org/

http://www.aap.org/publiced/BR_FoodAllergy.htm

http://www.aaaai.org/

http://www.aaaai.org/patients/resources/easy_reader/food.pdf

http://www.allergicchild.com/epipen_ana_medicalert.htm

http://www.foodallergy.org/downloads/FAAP.pdf

http://www.allergysafecommunities.ca/assets/common_beliefs_faan_2003.pdf

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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 c-section 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.

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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 IgE-associated 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

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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.

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Table 39: Food allergy prevention systematic reviews and meta-analyses Author/

Year Study Question Databases

searched/ Years

Intervention Inclusion/ Exclusion

Total Publications

Included

Outcomes reported

AMSTAR Criteria

Kramer, 2009253

To evaluate the effect of an antigen avoidance diet during pregnancy and/or lactation on the prevention of atopic disease in children

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 pregnancy or lactation

RCTs or quasi-RCTs comparing diets of different levels of antigen avoidance

4 Occurrence/severity of atopic disease in child; nutritional status of mother and fetus; other pregnancy outcomes; cord blood IgE levels

01. Can’t Answer 02. Yes 03. Yes 04. Yes 05. Yes 06. Yes 07. Yes 08. Yes 09. Yes 10. No 11. Yes

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 (1966-March 2006; EMBASE (1980-March 2006); CINAHL (1982-March 2006); Cochrane Central (up to March 2006)

Use of an adapted soy formula

RCTs or quasi-RCTs 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 (1966-March 2006; EMBASE (1980-March 2006); CINAHL (1982-March 2006); Cochrane Central (up to March 2006)

Use of any hydrolyzed infant formulas

RCTs or quasi-RCTs with > 80% follow up

4 All allergies; asthma; atopic dermatitis; allergic rhinitis; food allergy; food intolerance; infant growth parameters; cost; infant feed refusal


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Table 39: Food allergy prevention systematic reviews and meta-analyses (Continued) Study Study Question Databases

searched/ Years

Intervention Inclusion Exclusion

Total Publications

Included

Outcomes reported

AMSTAR Criteria

Hays, 2005267

To assess the effect of hydrolyzed infant formulas in preventing food allergies

Medline (1985-2005)

Infants received extensively hydrolyzed or partially hydrolyzed formulas

Prospective controlled trials

18 Atopic dermatitis; urticaria; asthma; angioedema; GI disease; allergic rhinitis; cow’s milk allergy; conjunctivitis

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

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)

Studies of c-section that presented information on at least one of 6 allergic conditions including food allergy/food atopy.

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.

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

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Table 39: Food allergy prevention systematic reviews and meta-analyses (Continued) Study Study Question Databases

searched/ Years

Intervention Inclusion Exclusion

Total Publications

Included

Outcomes reported

AMSTAR Criteria

Koplin, 2008276

To determine whether there is sufficient evidence to support an association between delivery by cesarean section and the development of food allergens and IgE mediated food allergy

MEDLINE and PubMed (prior to July 1997)

Caesarean delivery (c-section)

Studies with mode of delivery and either IgE-mediated sensitization to food allergies or confirmed food allergy

4 Number positive for food allergy

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

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

4 Physician diagnosed asthma in children <5 years and asthma as defined by respiratory symptoms and lung function in children > 5 years


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?

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Table 40: Food allergy prevention controlled trials: study information Study Country Purpose Food Condition of interest Study

quality Breastfeeding and delayed introduction of solid foods Halmerbauer, 2002251

Austria; Germany; UK

To determine if reduction in house-dust mites and prolonged breastfeeding and delayed introduction of solids reduce rates of sensitization and atopic diseases.

Milk, Egg Food intolerance Fair

Kajosaari, 1994252

Finland To determine the benefit of exclusive breastfeeding and delayed introduction of solid foods in children at risk for atopy

NS Atopic eczema; asthma; food allergy

Poor

Maternal diets Hattevig, 1989254 and Sigurs, 1992255

Sweden To determine effect of maternal avoidance of eggs, cow's milk, and fish during lactation and delayed introduction of solids to infants on allergies in children

Multiple Eczema, asthma, bronchial obstruction, rhinoconjunctivitis

Poor

Breastfeeding (with other interventions) Filipiak, 2007260

Germany To assess association between solid food introduction and eczema occurrence

Multiple Eczema Poor

Bardare, 1993261

Italy To evaluate the effect of breastfeeding vs soy formula vs soy with dietary restrictions on the incidence of atopic disease in infants at risk of allergy

Multiple Atopic eczema; allergic asthma; allergic rhinitis

Poor

Arshad, 2007262

UK To determine effect of breast feeding (with mothers placed on a low allergen diet) or hydrolzed formula and house dust mite exposure prevention on the development of atopic dermatitis, asthma, and atopy

Multiple Asthma, AD, food allergy Fair

Schoetzau, 2009265

Germany To evaluate the effect of exclusive breast-feeding and early solid food avoidance on atopic dermatitis

Multiple Atopic dermatitis Fair

Laubereau, 2004,266

Germany To investigate if exclusive breast-feeding for 4 months is associated with atopic dermatitis during the first 3 years of life.

Multiple Atopic dermatitis Fair

Special diets for infants and young children Von Berg, 2008,270 2007271

Germany To assess the effect of hydrolyzed formulas in preventing allergy development (GINI trial)

Milk Multiple Good

Odelram, 1996272

Denmark To examine whey hydrosylate compared with cow milk based formula on atopic disease

Milk Atopic diseases (including uticaria, atopic dermatitis, and cow’s milk allergy)

Fair

175

Table 40: Food allergy prevention controlled trials: study information (Continued) Szajewska, 2004274

Poland To evaluate extensively and partially hydrolised preterm formulas in the prevention of allergic disease in preterm infants

Milk Atopic diseases (atopic dermatitis, gastrointestinal symptoms, wheezing, and cow’s milk allergy)

Good

Han, 2003263 Korea To assess the effects of partially hydrolyzed formula on the prevention of atopic dermatitis in high risk infants

Milk Atopic dermatitis Poor

Arslanoglu, 2008273

Multiple European countries

To determine the effect of prebiotic oligosaccharides in formula-fed infants on the incidence of allergies and infections

Milk Allergies, infections Good

Probiotics Rautava, 2002285

Finland To determine the effect of probiotic supplementation in pregnant and lactating women on reducing the risk of allergies in their infants

Milk, other

Allergy, not specified Good

Huurre, 2008284

Finland To evaluate the effect of probiotics for allergy prevention in infants. Milk, other

Allergy, not specified Good

Kuitunen, 2009286 Kukkonen, 2007287

Finland To assess probiotic supplementation in pregnant women and infants in reducing the risk of allergies in children

Multiple Multiple Good

Abrahamsso, 2007288

Sweden To assess the effect of L reuteri in infancy as a method of prevention of IgE associated eczema at year 2 of life

Multiple Eczema, atopic dermatitis, Asthma

Good

Kvenshagen, 2009277

Norway To investigate whether children delivered by cesarean section were more prone to develop food allergy

Multiple Multiple Poor

Table Notes: AD atopic dermatitis; GINI German Infant Nutritional Intervention; sIgE antigen-specific immunoglobulin

176

Table 41: Food allergy prevention controlled trials: patient characteristics Intervention Group Selection Criteria Subject Demographics Study

Inclusion/ exclusion criteria

IgE Skin Test

Clinical reaction

Control Selection Criteria

Intervention Control

Breastfeeding and delayed introduction of solid foods Halmerbauer, 2002251

Inclusion: infants with allergic disease in one or both parents which was confirmed by allergy testing. Exclusion: birth weight less than 2500 grams; admission to NICU for more than 7 days

No No No Same as intervention group

NR NR

Kajosaari, 1994252

Inclusion: infants of atopic parents No No No Same as intervention group

NR NR

Maternal diets Hattevig254 and Sigurs255

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.

cord blood IgE = 0.9 ku/L

No No Same as intervention group

NR NR

Breastfeeding (with other interventions) Filipiak, 2007260 Inclusion: Infants with family history of allergy No No No Infants

without family history of allergy or those whose parents did not participate in the intervention group

Males: 1006 (51.9%); no significant difference between groups for gender; Parental education: Low (<10 years): 140 (7.2%); Middle (10-12 years): 534 (27.5%); High (>12 years): 1265 (65.2); p<0.001 for difference between groups for education

Males: 1441 (51.2%); Parental education: Low (<10 years): 366 (13%); Middle (10-12 years): 893 (31.7%); High (>12 years): 1555 (30.7%)

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

cord blood IgE levels >= 1 IU/mL

No No Same as intervention group

Control group had more infants with "anamnestic risk" (p>0.05); intervention group had more infants with high cord-blood IgE (p<0.001)

177

Table 41: Food allergy prevention controlled trials: patient characteristics (Continued) Intervention Group Selection Criteria Subject Demographics Study Inclusion/

exclusion criteria IgE Skin

Test Clinical reaction



Arshad, 2007262 Inclusion: infants at high risk for atopic disease 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;


Mean age, y (SD): 8.5 (0.2); Males: 28 (48%); Sibling allergy and maternal asthma more prevalent in intervention group

Mean age, y (SD): 8.5 (0.3); Males: 33 (53%);

Schoetzau, 2002265

Inclusion: infants with family history of atopy No No No Same as 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.

Laubereau, 2004 266

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

Intervention exclusive breastfeeding males=441 (49%); Non-intervention exlcusive breastfeeding males=557 (49.%)

Intervention non-exclusive breastfeeding males=376 (55%); Non-intervention non-exclusive breastfeeding males=609 (51%)

178

Table 41: Food allergy prevention controlled trials: patient characteristics (Continued) Special diets for infants and young children Von Berg, 2008271

Inclusion: infants with at least 1 parent or sibling with a history of allergic disease, less than 2 weeks old, and without any history of formula supplementation


NR NR

Odelram, 1996272 Inclusion: at least 2 atopic family members or 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

Yes No No 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

Szajewska, 2004274

Inclusion: birth weight < 2500 grams but appropriate for gestational age, had not received a non-study formula before randomization and had at least one first degree relative with allergic disease


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

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

Partially hydrolyzed formula: 30% male Standard formula:19% male

Breastfeeding: 47% male

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.


Biparental atopy: 23.5%

Biparental atopy: 25.8%

Probiotics Rautava, 2002285 Inclusion: pregnant women from atopic families;

included breast-feeding women and the maternal use of probiotics until age 3 months


maternal atopic disease 60%

maternal atopic disease 75%

179

Table 41: Food allergy prevention controlled trials: patient characteristics (Continued) Huurre, 2008284 Inclusion: enrolled in the nutrition modulation by

dietary counseling for allergic families; no chronic or metabolic disease in the mother before or during early pregnancy, and completed follow-up and SPT of the infant at age 1 year.

No No No Same as intervention

Maternal atopic disease 81%

Maternal atopic disease 78%

Kuitunen, 2009287

Inclusion: pregnant mothers carrying children at increased risk for allergy defined as at least on parent having physician-diagnosed allergic disease. Exclusion: Infants born before 37 weeks, with major malformations, and B-twins

NS NS NS Same as intervention

males 50%; maternal allergy: 80%

males 45%; maternal allergy: 81%

Abrahamsson, 2007288

Families with allergic disease (1 or more family members with eczema, asthma, gastrointestinal allergy, allergic urticaria, or allergic rhinoconjunctivitis) were recruited at antenatal clinics; diagnosis made by family history.

NS NS NS 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

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 Same as intervention

48% premature; 52% full-term

25% premature; 75% full-term

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

180

Table 42: Food allergy prevention controlled trials: intervention characteristics and outcomes reported Intervention Description Sample Size Author

Experimental Control Timing

Info Experimental Control Outcomes reported

Breastfeeding and delayed introduction of solid foods Halmerbauer, 2002251

Exclusive breastfeeding for as long as possible and at least until 3 months of age; Introduction of solids and soy milk delayed until 6 months; hypoallergenic formula used if supplementation required prior to 6 months (except for 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

Same recommendations made as those to intervention group; no protective mattress cover provided

12 months 349 347 Food allergy; parent report of food intolerance; positive SPT or IgE for egg and milk

Kajosaari, 1994252

Exclusive breastfeeding until 6 months of age; no introduction of solid foods until 6 months of age

Exclusive breastfeeding until 3 months of age at which time solid feeding was started

5 years 51 62 Atopy; atopic eczema; asthma; fresh fruit allergy

Maternal diets Hattevig, 1989254 and Sigurs, 1992255

Lactating mothers diet up to 3 months post-partum to be free from eggs, cow milk and fish product. After 3 months all returned to normal diet. Infants: cow milk after 6 months and fish after 9 months; during first 6 months breastfeeding or hydrolyzed casein formula

Mothers: no restriction on diet. Infants: same as intervention group

Infant seen at neonatology and at 3, 6, 9, 12, 18 months; again at 4 years

65 50 Cumulative incidence and cumulative prevalence at age 4 of eczema, asthma, bronchial obstruction, rhinoconjunctivitis

Breastfeeding (with other interventions) Filipiak, 2007260 Mothers encouraged to breastfeed for at

least 4 months; if this was not possible then they were to use one of four hydrolyzed formulas; delayed introduction of solids until 4 months and potentially allergenic food to be delayed until 1st year

Did not receive any dietary recommendations

4 years 1939 2814 Doctor-diagnosed eczema; symptomatic eczema

181

Table 42: Food allergy prevention controlled trials: intervention characteristics and outcomes reported (Continued) Intervention Description Sample Size Author

Experimental Control Timing Info

Experimental Control Outcomes reported

Bardare, 1993261

Infants: soy formula supplementation if required; gluten after 8th month; cow milk and dairy products after 10th month; lamb, turkey rabbit, pear, pineapple allowed before 1 year; avoidance of tobacco smoke and animal 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;

No diet prescribed; parents informed of infant's atopy risk

Examined at 3, 6, 9, 12, 18 and 24 months; data reported at 12 months

158 218 Atopic symptoms; IgE levels based on symptoms; atopic eczema

Arshad, 2007262 Infants: Elimination of dairy products, eggs, wheat, nuts, fish and soy until 12 months of age. Extensively hydrolyzed formula supplementation if breast-feeding discontinued before 9 months; reduction in exposure to house dust mite allergens. Mothers: elimination of same foods as infants except wheat, during lactation

Infants followed standard recommendations at that time

Assessments made at 1, 2, 4 and 8 years of age; data reported at 8 years

58 62 Clinical asthma diagnosed at least once during the first 8 years

Schoetzau, 2002265

Infants were exclusively breastfed for at least 4 months

Partially or exclusively received cow milk formula

1 year of age

865 256 AD incidence; sensitization to egg and milk

182

Table 42: Food allergy prevention controlled trials: intervention characteristics and outcomes reported (Continued) Laubereau, 2004 266

Mothers encouraged to breastfeed for at least 4 months; if this was not possible then they were to use one of four hydrolyzed formulas; delayed introduction of solids until 4 months and potentially allergenic food to be delayed until 1st year

Did not receive any dietary recommendations

3 years I--900 NI--1131

I—684 NI--1188

Atopic dermatitis

Special diets for infants and young children Von Berg, 20082702007271

Received one of three hydrolyzed formulas: partially hydrolyzed whey formula (pHF-W); extensively hydrolyzed casein formula eHF-W; extensively hydrolyzed casein formula (eHF-C)

Cow milk formula 6 years pHFW--557; eHFW--559; eHFC--580

556 Physician's diagnosis of: any allergy; atopic eczema; food intolerance; urticaria; hay fever; asthma

Odelram, 1996272

EHF was a whey hydrosylate. Lactating mothers and infants were on elimination diets for cow milk, egg, and fish

Continued breast milk for >9 months. Lactating mothers and infants were on elimination diets for cow milk, egg, and fish

18 months Group 1 (EHF): 32. Group 2 (CMF): 39

20 Presence of atopic disease; positive skin prick test; serum IgE at 18 months > or = to the median

Szajewska, 2004274

Preterm infants were assigned an extensively hydrolyzed formula or a partially hydrolyzed formula or fortified breast milk (with extensively hydrolyzed mixture) for 4-5 months

Infants received a standard formula for 4-5 months

Evaluated 4-5 months after intervention and then again at 12 months

EHF--20, PHF--22, fortified breast milk (BMF)

26 Any allergic disease; atopic dermatitis; gastrointestinal symptoms; wheezing; elevated total IgE; elevated IgE specific to cow milk

183

Table 42: Food allergy prevention controlled trials: intervention characteristics and outcomes reported (Continued) Han, 2003 263 All encouraged to be fed with breast

milk. During the nursing period, lactating mothers eliminated all sources of egg from their diet.

When the parents did not want to feed their babies with breast milk or breast milk was not available, partially hydrolyzed formula was recommended as substitution. Standard formula was given in cases when the parents did not want partially hydrolyzed formula.

Evaluated every 2 months for 6 months

PHF—15 SF—32

22 Incidence, prevalence, and severity of atopic dermatitis

Arslanoglu, 2008273

Formula supplemented with a mixture of 90% short-chain galactooligosaccharies and 10% long-chain fructooligosaccharies (IMMUNOFORTIS) intended to mimic human milk oligosaccharides

Same hypoallergenic formula as experimental group without the oligosaccharide supplementation

2 years 66 68 Growth (height/wt); cumulative incidences of atopic dermatitis, recurrent wheezing, and allergic urticaria; physician diagnosed infections, fever episodes witnessed by the parent.

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 30 32 Chronic relapsing atopic eczema;, GI symptoms; cow’s milk allergy; SPT; serum IgE; specific IgE

184

Table 42: Food allergy prevention controlled trials: intervention characteristics and outcomes reported (Continued) Huurre, 2008284 Dietary counseling, breastfeeding, L

rhamnosus and B lactis from first trimester of pregnancy to the end of exclusive breastfeeding.

Placebo 1 year 72 68 Atopic sensitization of children measured by SPT to numerous allergens; atopic eczema; cytokine concentrations in breast milk.

Kuitunen, 2009286 and Kukkonen, 2007287

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.

Identical appearing capsules of cellulose

2 years and 5 years

506 512 Cumulative incidence of any allergic disease (food allergy, eczema, asthma, allergic rhinitis) and IgE associated atopic disease. Secondary outcome measure: eczema and IgE sensitization.

Abrahamsson, 2007288

Mothers started taking L reuteri4 weeks before term and continued daily after delivery. After birth, baby continued same preparation for 12 months.

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

Cesarean section Delivery Kvenshagen, 2008290

Cesarean section delivery 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

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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.

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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 (specific-immunotherapy with cross-reactive allergens).

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Allergen-specific immunotherapy

Six RCT studies used desensitization protocols with the allergic food to induce tolerance292 293-

297 (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 open-label 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 peanut-specific 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.

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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

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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-and-effect 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

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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.

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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.

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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.

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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).

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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-for-age 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.

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Table 43: Food allergy treatment systematic reviews and meta-analyses Author/

Year Study Question Databases searched/

Years Intervention Inclusion

Exclusion Total

Publications Included

Outcomes Reported AMSTAR Criteria

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

1 Eczema severity 01. Can’t Answer 02. Yes 03. Yes 04. Yes 05. Yes 06. Yes 07. Yes 08. Yes 09. Yes 10. No 11. Yes

Bath-Hextall 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 (1806-Mar 2006); AMED (1985-Mar 2006); ISI Web of Science (Mar 2006); CENTRAL (Mar 2006); www.controlledtrials.com; www.clinicaltrials.gov; www.nottingham.ac.uk/ongoingskintrials (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

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)


http://www.controlledtrials.com

http://www.clinicaltrials.gov

http://www.nottingham.ac.uk/ongoingskintrials/

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Table 43: Food allergy treatment systematic reviews and meta-analyses (Continued) Author/

Year Study Question Databases searched/

Years Intervention Inclusion

Exclusion Total

Publications Included

Outcomes Reported AMSTAR Criteria

Kukuruzovic 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).

Medical (e.g. metered dose steroid, oral steroids, sodium chromoglycate, leukotriene receptor antagonists) or dietary (e.g. elemental milk formula) intervention

RCTs or quasi-RCTs comparing different interventions with placebo or each other

1 abstract from an

unfinished RCT

Symptom improvement; potential benefits; potential harms

01. Can’t Answer 02. Yes 03. Yes 04. Yes 05. Yes 06. Yes 07. Yes 08. Yes 09. NA 10. No 11. Yes

Table Notes: EE eosinophilic esophagitis; GI gastrointestinal; QOL quality of life; RCT’s randomized controlled trials 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?

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Table 44: Food allergy treatment/management controlled trials: study information Author Country Purpose Food Condition of interest Study

quality Allergen avoidance Agata, 1993291 Japan To determine effect of elimination diets in patients with atopic

dermatitis and allergies to egg or milk Milk, egg Atopic dermatitis Poor

Allergen-specific immunotherapy Staden, 2007293

Germany To evaluate the effect of oral tolerance induction or elimination diet for managing cow milk or egg allergy in children

Milk, egg Allergy, not specified Good

Morisset, 2007294

France To examine an oral desensitization protocol to allergenic foods in IgE-dependent milk or egg allergies in children

Milk, egg Atopic dermatitis, uticaria, angioedema, asthma, GI symptoms

Fair

Skripak, 2007292

US To evaluate milk oral immunotherapy for cow's milk allergy Milk Multiple Good

Nelson, 1997295

US To determine the effect of immunotherapy in patients with anaphylaxis to peanuts

Peanut, tree nut Anaphylaxis Poor

Enrique, 2005299

Spain To evaluate the efficacy and tolerance of sublingual immunotherapy with a hazelnut extract in patients with a hazelnut allergy

Hazelnut Oral allergy syndrome, anaphylaxis, uticaria-angioedema

Good

Patriarca, 2007296

Italy To evaluate specific oral desensitization in children with food allergies

Milk, whole egg, egg albumin, wheat, cod, apple, beans

Multiple Poor

Specific immunotherapy with cross-reactive allergens Hansen, 2004300

Denmark To examine the effects of sublingual and subcutaneous administration of birch pollen extract in patients with apple allergy.

Apples Oral allergy syndrome Good

Bucher, 2004301

Switzer-land

To evaluate the effect of subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut

Peanut, tree nut, apple Oral allergy syndrome Poor

Asero, 1998302 Italy To evaluate the clinical and immunological effects of birch pollen specific immunotherapy on oral allergy syndrome induced by apples

Apples Oral allergy syndrome Poor

Bernadini, 2006303

Italy To evaluate the safety and efficacy of SLIT with natural rubber latex (NRL) extract in children with NRL allergy

Latex, fruits Oral allergy syndrome Fair

Pharmacological management Bindslev-Jensen, 1991315

Denmark To evaluate the effect of treatment with astemizole on symptoms elicited by the ingestion of hazelnuts in birch pollen-allergic patients

Hazelnut Oral allergy syndrome Fair

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Table 44: Food allergy treatment/management controlled trials: study information (Continued)

Author Country Purpose Food Condition of interest Study quality

Burks, 1988318 US To evaluate oral cromolyn in children with atopic dermatitis and documented food hypersensitivity

Egg Atopic dermatitis Fair

Schaeffer, 2008319

US To compare oral prednisone and topical fluticasone in treating EE in children**

Not specified EE Fair

Szajewska, 2007321

Poland To determine the effect of lactobacillus in infants with rectal bleeding Milk Cow’s milk allergy syndrome

Good

Leung, 2003316

US To determine the effect of anti-IgE therapy in patients with peanut allergy

Peanut Anaphylaxis Good

Cavagni, 1989317

Italy To evaluate if addition of an immunomodulating agent to an elimination diet improves food allergy in children

Egg, milk, pea, fish Atopic dermatitis Fair

Businco, 1986320

Italy To evaluate oral sodium cromoglycate in children with atopic dermatitis

Milk, egg, fish, wheat

Atopic dermatitis Fair

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 Milk, egg, peanut, tree nut, wheat, soy, fish

Gastrointestinal hyper-sensitivity

Fair

Amadi, 2002323

Zambia To compare outcomes with either standard diet for diarrhea and malnutrition or an amino acid-based elemental feed

Milk Cow’s milk allergy syndrome, Gastro-intestinal hyper-sensitivity

Fair

Cantani, 2006324

Italy To evaluate the effectiveness of a home-made meat-based formula for feeding atopic babies

Milk Atopic dermatitis Poor

Salpietro, 2005325

Italy To test the safety and efficacy almond-based formula, soy formula, or hydrolyzed formula for infants with cow’s milk allergy

Milk Cow’s milk allergy syndrome

Fair

Viljanen, 2005326

Finland To investigate whether probiotic bacteria have any beneficial effect on atopic eczema/dermatitis in infants with cow’s milk allergy

Milk Atopic eczema/dermatitis syndrome

Good

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

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Table 45: Food allergy treatment/management controlled trials: patient characteristics Intervention Group Selection Criteria Subject Demographics Author

Inclusion/exclusion criteria IgE Skin Test

Clinical reaction



Allergen avoidance Agata, 1993291

Inclusion: clinical history of atopic dermatitis and milk/egg allergy

Yes No Yes Same as intervention group

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)

Allergen-specific immunotherapy Staden, 2007293

Inclusion: IgE-mediated food allergy to either cow milk or hen egg as confirmed by DBPCFC Exclusions: severe atopic dermatitis with SCORAD >75

Yes No No Same as intervention group

NR NR

Morisset, 2007294

Inclusion: Children with cow’s milk allergy or egg allergy as established on 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)

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)

Skripak, 2007292

Inclusion: children aged 6-21 from pediatric allergy clinics with positive SPT 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.


Males: 8/13 (62%); mean age=9.3 years (SD=3.3)

Males: 4/7 (57%); mean age= 10.2 (SD=3.3)

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Table 45: Food allergy treatment/management controlled trials: patient characteristics (Continued) Intervention Group Selection Criteria Subject demographics Author

Inclusion/exclusion criteria IgE Skin Test Clinical reaction

Control Selection Criteria Intervention Control

Nelson, 1997295

Adults with a history of immediate hypersensitivity reactions to peanuts

No No Yes Same as intervention group but patients self-selected to be controls

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

Enrique, 2005299

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

No Yes Yes Same as intervention group

3 (25%) males; 9 (75%) females; age: 29.2 years (19-53)

7 (63%) males; 4 (37%) females; age: 29.6 years (19-42)

Patriarca, 2007296

Consecutive children affected by food allergy (defined by clinical history, skin prick tests, serum total and specific IgE, and DBPCFC)

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

Specific immunotherapy with cross-reactive allergens Hansen, 2004300

Inclusion: Rhino-conjunctivitis during birch pollen season, combined with birch pollen specific IgE, birch pollen positive SPT, and a positive conjunctival provocation test to birch pollen using standardized extracts

Positive for birch pollen

Positive for birch pollen

No NR NR NR

201

Intervention Group Selection Criteria Subject demographics Author Inclusion/exclusion criteria IgE Skin Test Clinical

reaction


Bucher, 2004301

Inclusion: oral allergy syndrome induced by apple or hazelnut with a positive SPT to birch pollen AND hazelnut or apple

No Yes No Same as intervention group

4 males; 11 females; mean age: 30 years (range 17-48)

5 males; 7 females; mean age: 34 years (range 20-48)

Asero, 1998302

Inclusion: clear history of oral allergy syndrome

No No Yes 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

18 males; 31 females; mean age: 34.4 years

NR

Bernadini, 2006303

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

No No Yes, for latex allergy

Same as intervention group

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)

Pharmacological management Bindslev-Jensen, 1991315

Patients with birch pollen allergy. Inclusion: case history of immediate local symptoms (itching and swelling of mouth/throat) Exclusion: anamnestic severe reaction after intake of hazelnuts

NR All had positive skin prick test to birch pollen, but only 15 had a positive SPT to hazelnut

Yes Same as intervention group

NR NR

Table 45: Food allergy treatment/management controlled trials: patient characteristics (Continued)

202


reaction


Burks, 1988318

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

NR Yes NR Same as intervention: cross over trial

4 males; 4 females; mean age 7.6 years +/- 3.2

NR

Schaeffer, 2008319

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

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

Szajewska, 2007321

Inclusion: rectal bleeding diagnosed as the presence of blood-streaked normal-to-soft stools, exclusive breast feeding, age < 6 months. Exclusion: infectious origin of rectal bleeding (pathogenic bacteria/C. diff), necrotizing enterocolitis, and coagulopathies

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

Leung, 2003316

Inclusion: Serum total IgE between 30 and 1000 IU/mL, good health, body weight within 20% of ideal,

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 (14-59); mean total serum IgE


203


reaction


positive SPT to peanut and negative SPT to tuna oil, no prior exposure to monoclonal AB, Exclusion: pregnancy, uncontrolled asthma

total serum IgE 349.8 IU/mL (101-902 IU/mL) serum peanut-specific IgE 21.7 IU/mL (0.34-100 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)

251.3 IU/mL (36-955 IU/mL) serum peanut-specific IgE 24.0 IU/mL (0.34-100 IU/mL)

Cavagni, 1989317

Children with a food allergy manifesting as atopic dermatitis

No Yes-used to deter-mine which foods to evaluate

No Same as intervention group

Mean age: 73.7 (51.7) months

Mean age: 46.4 (17.1) months

Businco, 1986320

Children < 12 years old with severe eczema requiring continuous therapy but no steroids and exacerbation of symptoms from food allergy


14 males; 17 females; age range: 6months-10 years

14 males; 17 females; age range: 6 months-10 years


204


reaction


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 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

Amadi, 2002323

No specific food allergies were diagnosed, but the thought was that underlying cow’s milk allergy might be exacerbating the problem. Exclusion criteria: measles, chicken pox, neurologic disorders, and those that were exclusively breast-fed


49 males; 51 females, age: 17 months range (14-20)

45 males; 55 females; age: 18 months range (13-22)

Cantani, 2006324

Inclusion: children with severe atopic dermatitis and suspected cow’s milk allergy on the basis of personal history and positive SPT to cow milk and egg

No Yes Yes Same as intervention

NR NR


205


reaction


Salpietro, 2005325

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.

Yes Yes Yes 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

Viljanen, 2005326

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 Yes 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 breast-feeding 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

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Table 46: Food allergy treatment/management controlled trials: intervention characteristics and outcomes reported Intervention Description Sample Size Author

Experimental Control Timing

Info Experimental Control Outcomes reported

Allergen avoidance Agata, 1993291 Elimination diet of allergic food: egg or

milk No elimination diet >= 3

months 43 11 Improvement of atopic

dermatitis; specific IgE antibodies; proliferative responses of PBMCs

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

Elimination diet median follow-up: 21 months (18-24)

25 20 Tolerance as defined by either complete or partial allergen specific IgE

Morisset, 2007294

Oral desensitization with whole pasteurized milk for those with cow’s milk allergy, in weekly increasing doses. Oral desensitization with hard-boiled eggs for those with egg allergy, in weekly increasing doses

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

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.

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

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

No treatment 6 weeks and 1 year

6 6 Threshold to oral peanut challenge; cutaneous reactivity to peanut challenge; peanut-specific IgE and IgG

Enrique, 2005299

Biologically standardized hazelnut extract given in increasing concentrations for 5 days.

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

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Table 46: Food allergy treatment/management controlled trials: intervention characteristics and outcomes reported (Continued) Intervention description Sample size Author

Experimental Control Timing info

Experimental Control Outcomes reported

Patriarca, 2007296

Desensitization per a protocol to the food(s) to which each person was allergic--increasing in dose every 3 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

Continued elimination diet to allergic food(s)

18 months 42 10 Successful tolerance as determined by DBPCFC, IgE, IgG.

Specific immunotherapy with cross-reactive allergens Hansen, 2004300 Sublingual or subcutaneous birch

pollen extract Placebo 2 years Sublingual=

12; subcutaneous=16

14 Oral food challenge to apple; symptom scores to apple in the oral food challenge; specific IgE to apple

Bucher, 2004301 Subcutaneous immunotherapy with tree pollen extract

Did not receive tree extract immunotherapy

1 year 15 12 Improvement of oral allergy syndrome; subjective symptoms after oral provocation tests; serum IgE to apple; serum IgG4 to rBet v 1.

Asero, 1998302 Injection of specific immunotherapy for both induction and maintenance phases; group divided to receive treatment for either 12, 24, or 36 months

Group 1: no immunotherapy Group 2: underwent immunotherapy similar to the intervention group

12, 24 or 36 months

at 12 months n=12, at 24 months n=21, at 36 months n=13

Group 1: at 12 months n=7, at 24 months n= 5, at 36 months, n=11. Group 2: at 12 months n= 8, at 24 months n=4, at 36 months n=3

Symptom of oral allergy syndrome

208

Intervention description Sample size Author Experimental Control

Timing info Experimental Control

Outcomes reported

Bernadini, 2006303

Given a natural rubber latex extract for sublingual administration with a build up phase and maintenance phase for 12 months

Placebo group: placebo; control group: nothing

1 year 12 Placebo: 8; control: 6

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; prick-by-prick tests with vegetables, which display a clinical and/or immunological cross-reactive behavior with NRL allergens; changes in severity of oral allergic symptoms

Pharmacologic management Bindslev-Jensen, 1991315

Patients given two open oral provocations of five hazelnuts (at least 2 days apart). Then the treatment group ingested aztemizole 10 mg each morning for 14 days followed by 2 open oral provocations

Placebo 14 days 15 15 Symptom severity to oral provocation test

Table 46: Food allergy treatment/management controlled trials: intervention characteristics and outcomes reported (Continued)

209



Outcomes reported

Burks, 1988318 Patients were treated for a week 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.

Placebo (cross-over trial) 1 week 10 NR 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

Schaefer, 2008319

Oral prednisone (1 mg/kg) bid Fluticasone by MDI 2 puffs 4x daily

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

40 40 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.

Szajewska, 2007321

Mothers eliminated cow milk from their diet and infants received lactobacillus fhamnosus GG

Mothers eliminated cow milk from their diet and infants received placebo

Treatment period: 4 weeks

11 15 Days of rectal bleeding

Leung, 2003316 3 groups receiving different doses of TNX-901 (150 mg, 300 mg, 450 mg), a humanized IgG1monoclonal antibody against IgE

Placebo 6-8 weeks 150 mg--19; 300 mg--19; 450 mg--21

23 Threshold of sensitivity to peanut on oral food challenge


210



Outcomes reported

Cavagni, 1989317

Food to which a positive prick test was found was excluded from the diet for 90 days. During this period, treatment group received 120 mg/day of thymomodulin as syrup

Same as experimental group but received placebo rather than thymomodulin

90 days of elimination diet and then 2 weeks after the challenge

10 9 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

Businco, 1986320

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

Same as experimental description

Total of 20 weeks, 10 weeks for each aarm

31 31 Changes in severity of eczema

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

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

Diet was followed for 7 days and then the infants underwent a 48 hours cry/fuss chart

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)

Amadi, 2002323 Malnourished children to receive 4 weeks of standard skimmed milk/soy diet

Malnourished children to receive Neocate for 4 weeks

Patients treated for 4 weeks and then outcomes measured

100 100 Weight gain; hemoglobin; serum albumin; diarrhea, activity; developmental milestones

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

4-6 weeks 25 26 SCORAD; weight; open challenge test


211



Outcomes reported

allergy Salpietro, 2005325

Group A received almond milk; Group B received soy based formula; Group c received protein based formula

"Formula fed" not other wise specified

6 months Almond milk: 26; Soy formula: 13 Protein formula: 13

13 Weight; length; head circumference; serum levels of soluble CD30 (cytokine associated with atopy)

Viljanen, 2005326

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

4 weeks Lactobacillus alone:44

Mixture: 44

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


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Table 47: Safety data for allergen specific immunotherapy Symptom/Treatment Study Number/total doses

(%)* or number/patient (%)** in immunotherapy group

Number/total doses (%)* or number/patient (%)** in control group

P value

Total Reactions Skripak, 2008292 1107/2437 (45.4)* 134/1193 (11.2)*

0.02

Staden, 2007293

25/25 (100)** 6/20 (30.0)** NR

Hofmann, 2009211 initial escalation day

93% (77%-99%)*** No control NR

Hofmann, 2009211 buildup phase

46% (37%-56%)*** No control NR

Hofmann, 2009211 home dosing phase

3.5% (2.3%-5.1%)*** No control NR

Local Symptoms Skripak, 2008292 870/2437 (35.7)* 104/1193 (8.7)*

0.006

Narisety, 2009212 419/2465 (17)* No control NR Enrique, 2005299 109/1466 (7.6)* NR NR Bernardini, 2006303 0/12 (0)** 0/8 (0)** NS Gastrointestinal Skripak, 2008292 458/2437 (18.7)* 16/1193 (1.3)* 0.02 Narisety, 2009212 90/2465 (3.7)* No control NR Staden, 2007293 15/25 (60.0)** 3/30 (10.0)** NR 294 7/76 (9.2)** 8/65 (12.3) NR Enrique, 2005299 4/12 (33.3)** NR NR Bernardini, 2006}303 0/12 (0)** 0/8 (0)** NS Hofmann, 2009211

initial escalation day 68% (48%-84%)*** No control NR


5.5% (3.2%-9.2%)*** No control NR


0.9% (0.6%-1.4%)*** No control NR

Lower respiratory (asthma NOT rhinoconjunctivitis)

Skripak, 2008292 198/2437 (8.1)* 28/171 (2.3)* 0.3

Staden, 2007293 2/25 (9.0)** 0/20 (0)** NR Narisety, 2009212 21/2465 (0.9)* No control NR Morisset, 2007294 2/76 (2.6)** 3/65 (4.6) NR Skin (eczema and uticaria)

Skripak, 2008292 22/2437 (0.9)* 1/1193 (0.1)* 0.1

Narisety, 2009212 20/2465 (0.8)* No control NR Staden, 2007293 24/25 (96.0)** 5/20 (25.0)** NR Morisset, 2007294 3/76 (3.9)** 6/65 (9.2)** NR Enrique, 2005299 1/12 (8.3)** 1/11 (9.1)** NR Hofmann, 2009211

initial escalation day 61% (41%-79%)*** No control NR


24% (17%-32%)*** No control NR


1.1% (0.7%-1.8%)*** No control NR

Angioedema Staden, 2007293 4/25 (16.0)** 0/20 (0)** NR Morisset, 2007294 3/76 (3.9)** 4/65 (6.2)** NR Cardiovascular (not Staden, 2007293 0/25 (0)** 1/25 (4%) NR

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further defined) Multiple systems (not further defined)

Skripak, 2008292 29/2437 (1.2)* 0/1193 (0)* 0.01

Enrique, 2005299 3/1466 (0.2)* NR NR Diphenhydramine used to treat reaction

Skripak, 2008292

249/2437 (10.2)* 14/1193 (1.1)* 0.3

Narisety, 2009212 93/2465 (3.8)* No control NR Hofmann, 2009211

initial escalation day 20/28 (71)** No control NR

Hofmann, 2009211 buildup doses

5/301 (1.7)* No control NR

Hofmann, 2009211 home doses

65/10184 (0.6)* No control NR

Albuterol used to treat reaction

Skripak, 2008292 21/2437 (0.9)* 2/1193 (0.2)* 0.2

Narisety, 2009212 12/2465 (0.5)* No control NR Hofmann, 2009211

initial escalation day 3/28 (11)** No control NR


2/301 (0.7)* No control NR


24/10184 (0.2)* No control NR

Epinephrine used to treat reaction

Skripak, 2008292 4/2437 (0.2)* 0/1193 (0)* 0.1

Narisety, 2009212 4/2437 (0.2)* 0/1193 (0)* 0.1 Hofmann, 2009211

initial escalation day 6/2465 (0.2)* No control NR


4/28 (14)** No control NR


0/301 (0)* No control NR

Zapatero, 2008 298 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).

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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 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

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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.

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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 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.

Peanut, egg, cow milk, nut, corn mustard, fish

Jarvinen, 2008328

US To determine the rate, circumstances, and risk factors for repeated doses of epinephrine in the treatment of food-induced anaphylaxis in children.

Peanut, tree nut, hen’s egg, cow milk, soybean, wheat, shellfish, fish

Table 49: Cohort studies on anaphylaxis: patient characteristics

Table 50: Cohort studies on anaphylaxis: intervention characteristics and outcomes reported

Author Intervention description Timing info

Sample size

Outcomes reported

de Silva, 2008329

Chart review to see the clinical course of patients admitted to a children's ER with anaphylaxis

Conducted from 1 June 1998 to 30 June 2003

117 1 death; home most common setting (48%); food (85%) most common trigger; peanut (18%) and cashew nut (13%) most common cause of anaphylaxis; median time from exposure to anaphylaxis for all agents was 10 min; median time from onset to therapy was 40 min; respiratory features principal presenting symptoms (97%); 17% had experienced anaphylaxis previously.

Pousse, 2006330

Questionnaire sent to families with children with history of anaphylaxis who had previously used anapen

June 2000-March 2003

111 Main food allergens were peanuts (n=89), egg (n=39) and cow’s milk (n=10).

Jarvinen, 2008328

Anonymous questionnaires were distributed to families of children with food allergies during allergy outpatient visits to a food allergy referral center.

Between September 2006 and February 2007.

413 Peanut, tree nut and cow’s milk allergy responsible for >75% of the reactions requiring epinephrine; patients requiring multiple doses of epinephrine often had asthma (p=0.027); 19% of food-induced anaphylactic reactions were treated with >1 dose of epinephrine; soybean allergy accounted for 107/413 (26%) of reactions and peanut allergy 290/413 (70%) of anaphylactic reactions.

Intervention Group Selection Criteria Author Inclusion/exclusion criteria IgE Skin

Test Clinical reaction

Intervention Demographics

de Silva, 2008329 Clinical history of anaphylaxis or generalized allergic reaction

No No Yes Median age: 2.4 years

Pousse, 2006330 Families of children that had previously used the ANAPEN (injection epi)

No No Yes Median age: 6.5 years

Jarvinen, 2008328 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

No No Yes Male: 63%; median age: 4.5 years (0.5-17.5)

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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.

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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 soy-based formula or hydrolyzed formula.

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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 z-score 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.

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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 dust-mites 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

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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

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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.

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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.

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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

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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 food-induced 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.

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Table 51: Treatment/management - specific food allergy studies: study information

Author Country Purpose Study design

Condition of interest

Peanut/Hazelnut Allergy Ewan, 2001214 UK To determine effect of a management plan for peanut and nut allergy Cohort Multiple Jones, 2009342 United

States To investigate the clinical efficacy and immunologic changes associated with oral immunotherapy in patients with peanut allergy.

Cohort Multiple

Hansen, 2003343 Switzerland Denmark

To evaluate the reduction in allergenicity by roasting hazelnuts Cohort Multiple

Hofmann et al., 2009211

US 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

Cow’s milk allergy Jong, 2002332 Nether-

lands To determine effect of brief exposure to cow's milk in the neonatal period on later development of atopic disease.

RCT Allergy, not specified

Lindfors, 1992339 To evaluate the longer term (age 4-6yrs) incidence of allergic symptoms in children given cow's milk neonatally

RCT Not specified

Iacono, 1998335 Italy To compare cow's milk and soy milk in children with chronic constipation RCT Chronic constipation Klemola, 2002313 Finland To evaluate incidence of allergy or other adverse reactions to soy formula and to

hydrolyzed formula in patients with cow's milk allergy RCT Cow’s milk allergy syndrome

Niggemann, 2008336

Germany 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

RCT Cow’s milk allergy syndrome, Rhinitis, rhino-conjunctivitis, conjunctivitis

Jirapinyo, 2007333 Thailand To compare the ability of children with cow’s milk allergy to tolerate chicken-based formula and soy formula

RCT Cutaneous, respiratory, gastrointestinal symptoms (not otherwise specified)

Garzi, 2002337 Italy To examine effects of a hydrolyzed cow milk formula on GERD and gastric emptying time

CT Cow’s milk allergy syndrome

Vita, 2007338 Italy 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

RCT Cow’s milk allergy syndrome; atopic dermatitis

Savino, 2005340 Italy To evaluate growth of infants with AD and CMA fed a rice-hydrolysate formula compared with a soy or extensively hydrolysed casein formula

CT Atopic dermatitis

Narisety, 2009212 US To assess the efficacy and safety of open-label maintenance after milk oral immunotherapy in children with cow’s milk allergy

Cohort Multiple

Henriksen, 2000213 Norway To examine nutrient intake in children with cow’s milk allergy on diets with variable amounts of cow milk protein.

Cohort Cow’s milk allergy

Zapatero, 2008 298 Spain To assess cow’s milk desensitization protocol 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

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Table 52: Treatment/management - specific food allergy studies: patient characteristics

Intervention Group Selection Criteria Subject Demographics Author Inclusion/exclusion criteria IgE Skin

Test Clinical rxn



Peanut Allergy

Ewan, 2001214

Inclusion: patients with peanut and nut allergy No Yes Yes NA Median age: 7.5 years

NA

Jones, 2009342

Inclusion: Age 1-16 years with a clinical history of reaction to peanut within 60 minutes of ingestion, a positive peanut skin prick test and a peanut CAP. Exlusion: history of severe, life-threatening anaphylaxis (with hypotension) to peanut, severe or poorly controlled asthma, or a medical condition preventing undergoing a food challenge

Yes Yes Yes NA Median age: 57.5 months, 64% male

NA

Hansen, 2003343

Inclusion: Food allergy to hazelnuts Exclusion: Anaphylaxis due to hazelnuts

No No Yes NA Median age: 24.5 years, 65% female

NA


Inclusion: Age 1-16 years with peanut allergy. Exclusion: Severe anaphylaxis, inability to cooperate with challenge procedures or follow-up

Yes Yes Yes NA Mean age 4.8 years (1.1-9.4)

NA


Jong, 2002332

Inclusion: pregnant women recruited from midwives practices who intended to breastfeed for at least 6 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.


high family risk of atopy: 58%

high family risk of atopy: 57%

Lindfors, 1992339

Term but low birth weight infants (-1 to -2 SD) No No No Same as intervention group

age 4.8 years age 4.7 years

228


Test Clinical rxn



Savino, 2005340

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

No Yes Yes Same as intervention group but without cow’s milk allergy

age: 3.27 months +/- 0.32

age: 4.03 months

Iacono, 1998335

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

NR NR NR Same as intervention group: cross-over study

29 males; 36 females; mean age 34.6 months (range 11-71 months)

NR: cross-over study

Klemola, 2002313

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


Age: 7.1 years; Immediate/ delayed CMA: 41/39; atopic eczema: 52%; GI symptoms: 19%; IgE antibodies+ to CM: 37%; SPT+ with CM: 38%

Age: 6.9 years; Immediate/ delayed CMA: 59/319; atopic eczema: 64%; GI symptoms: 28%; IgE antibodies+ to CM: 64%; SPT+ with CM: 34%

Niggemann, 2008336

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


13 males; 19 females; age: 250 days (75)

12 males; 18 females; age: 236 days (91)

Table 52: Treatment/management - specific food allergy studies: patient characteristics (Continued)

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Test Clinical rxn



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


Parental allergy: 12/18; 17% with respiratory sx; 44% with cutaneous sx; 39% with GI sx; 22% with eosinophilia; 22% with specific IgE elevation

Parental allergy: 13/20; 5% with respiratory sx; 55% with cutaneous sx; 40% with GI sx; 15% with eosinophilia; 5% with specific IgE elevation

Garzi, 2002337

Inclusion: exclusively fed with cow milk derived formula and had clinical symptoms of GERD with symptom score >7

Yes Yes No Exclusively fed with cow milk derived formula without GERD and not taking any medications

average age: 4.9 months (range 2-6)

average age: 4.7 months (range 4-6 months)

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

No Yes Yes Same as intervention group

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)

Narisety et al., 2009212

Participants that could tolerate >2540 mg in their post-milk oral immunotherapy challenge upon conclusion of the Skripak RCT

Yes Yes Yes NA Age range 6-16 years

NA

Henriksen et al., 2000213

Children with parentally perceived reactions to milk or egg at the age of 2 years

No Yes Yes NA Mean age: 2.5 years

NA

Zapatero, 2008 298

Children aged 4 or older with confirmed allergy to cow’s milk

Yes Yes Yes NA Mean age 5.05 years

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;

Table 52: Treatment/management - specific food allergy studies: patient characteristics (Continued)

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Table 53: Treatment/management - specific food allergy studies: intervention characteristics and outcomes reported

Intervention Description Sample Size Outcomes reported Author Experimental Control

Timing Info Experimental Control

Peanut allergy Ewan, 2001214 Advice on avoidance and

medications to use in case of an accidental ingestion of peanuts; medications also provided.

Not applicable 1 year 567 NA Follow-up reaction

Jones, 2009342 Oral immunotherapy protocol including initial day escalation, buildup, and maintenance phases, and then oral food challenge

Not applicable 18 months 29 NA Skin prick tests, peanut-specific IgE and IgG, IL-10, IL-5, interferon-gamma, TNF-alpha

Hansen, 2003343 Patients ingested raw and roasted hazelnuts

Not applicable Immediate after intervention

17 NA DBPCFC, Clinical symptoms of OAS, SPT, Heart rate, specific IgE


Oral immunotherapy protocol with the goal to achieve ingestion of a daily maintenance dose of 300 mg of peanut protein

Not applicable 24 months 28 NA Symptoms (upper respiratory tract, skin, abdominal, chest) or treatment (diphenhydramine, albuterol, or epinephrine) after treatment with oral immunotherapy

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.

Placebo formula free of cows' milk protein given during first 3 days after randomization.

5 years 758 775 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.

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Lindfors, 1992339 Cow milk formula from the first day of life until normal breastfeeding started

Breast milk only 4-6 years 109 98 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.

Iacono, 1998335 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

Cow milk 2 weeks 65 Not reported

Median number of bowel movements before and after treatment

Klemola, 2002313 Soy formula Extensively hydrolyzed formula

2 year 80 90 Parents suspicion of adverse reactions to formula

Niggemann, 2008336

New extensively hydrolyzed formula

Amino acid formula Infants evaluated at 30, 60, 90, and 180 days

34 32 Z-scores for length, head circumference, and weight; SCORAD scores; IgE titers

Jirapinyo, 2007333 Formula made from chicken meat

Soy formula 14 days 20 18 Intolerance to formula, any cutaneous, respiratory, or GI symptoms (not otherwise specified)

Garzi, 2002337 Infants with GERD fed an extensively hydrolyzed hypoallergenic formula

Continued to feed on cow milk formula

1 week after formula

10** 10 Gastric emptying time; symptom scale of GERD

Vita, 2007338 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.

Cross-over trial Evaluated 6 months after first treatment and then again 3 months after next treatment

14 14 SCORAD to assess atopic dermatitis; VAS

Table 53: Treatment/management - specific food allergy studies: intervention characteristics and outcomes reported (Continued)

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Savino, 2005340 Either rice based hydrosylate formula (RHF), soy-based formula (SF), or extensively hydrolyzed casein formula (eHCF)

Free diet Every 3 months in the 1st year of life and then at 6 month intervals in 2nd year of life

RHF--15; SF--17; eHCF--26

30 Z-score of weight

Narisety et al., 2009212

Gradual home dose escalations of milk of no more than 50% increments every 2 weeks

Not applicable Median=17 weeks (range 13-75 weeks)

15 NA Adverse reactions, milk threshold, SPT, IgE, IgG

Henriksen et al., 2000213

Divided into 4 groups: milk-free, formula, milk-reduced, and milk

Not applicable 4 day 34 NA Dietary recall recorded by parents

Zapatero, 2008 298 Desensitization protocol to cow’s milk

Not applicabale Median=14 weeks (range 9-32 weeks)

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

Table 53: Treatment/management - specific food allergy studies: intervention characteristics and outcomes reported (Continued)

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Figure 11: Treatment/management - summary of Evidence by Food Type Specific Food

Peanut/ Hazelnut

Cow’s Milk Hen’s Egg Fish Apple

Delayed introduction of foods

251

Maternal diets

322

Prevention Strategies

Breast feeding

Special diets for infants and young children

335 313 333 338 325

○332 ○336

○337○340

○339

Probiotics

Elimination diet 291 317

262317 322296

Immunotherapy295

○C342 294 296

294 296

300301 302 296

Allergen avoidanceC214

○C343

262

○341

Treatment Management

Strategies

Pharmacology316

○318

Probiotics ○326

Statistically significant improvement ○ No statistically significant improvement Some statistically significant improvement in some outcomes but not in all outcomes measured. C=Cohort study. Other studies are controlled trials.

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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 0.54-0.96 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,

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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.

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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.

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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

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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.

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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).

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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 1 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.

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Table 54: Specific clinical conditions associated with food allergies: design and patient characteristics Intervention Group Selection Criteria Author Country Purpose Study design Food of

interest Inclusion/ exclusion criteria

IgE Skin Test

Clinical reaction

Intervention Demographics

Oral allergy syndrome (OAS) Bergmann, 2008344

Germany To examine the effect of pollen-specific sublingual immunotherapy on OAS

Prospective cohort

apple, hazelnut, carrot

Patients had pollen-induced allergic rhinoconjunctivitis and concomitant OAS and did not have known contraindications to specific immunotherapy.

No No Yes Median age 34.5 years (6-64); 33.3 % male and 66.7% female.

Eosinophilic esophagitis (EE) Spergel, 2005204 US To determine if an

elimination diet is useful in treating EE

Prospective cohort

milk, egg, soy, peanut, chicken, wheat, peas, beef, corn, potatoes, rice

Diagnosis of EE with one or more of the following: vomiting, regurgitation, abdominal pain, or dysphagia unresponsive to 2 months of PPI and EGD bx with > 15 eosinophils per hpf

No Yes Yes mean age 6.5 +/- 4.5 years

Liacouras, 2005346

US To describe EE in children

Retrospective case series

milk, egg, wheat, soy, corn, beef, chicken, potatoes, oats, peanuts, turkey, barley, rice, pork, green beans, apples, pineapple

All patients diagnosed with eosinophilic esophagitis from Jan 1 1994-Jan 1 2004 at the Children's hospital in Philadelphia

No Yes Yes 251 males; mean age 9.1 years +/- 3.1

Dermatitis herpetiformis (DH) Gariouch, 1994347 UK To describe 25 years

of experience in patients on a gluten-free diet to treat DH

Cohort Gluten Patients seen in dermatology clinic with dermatitis herpetiformis.

No No Yes 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

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Table 55: Specific clinical conditions associated with food allergies: intervention characteristics and outcomes reported

Intervention Description Sample Size Author Experimental Control


Outcomes reported

Oral allergy syndrome (OAS) Bergmann, 2008344

An open observational study examined the effect of pollen specific sublingual immunotherapy on OAS triggered by several foods

NA 12 months

102 NA 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

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

Not applicable 6 weeks 146 Not applicable

Resolution of EE

Liacouras, 2005346

Multiple: medications; elimination diet Not applicable 6 months

381 Not applicable

Clinical symptoms; number of eosinophils per high-powered field

Dermatitis herpetiformis (DH) Gariouch, 1994347 Gluten-free diet Not applicable 1967-

1992

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

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Figure 12: Summary of Evidence by Specific Clinical Condition Specific Clinical Condition Asthma Oral Allergy

Syndrome Atopic

Dermatitis Eosinophilic Esophagitis

Dermatitis Herpetiformis

Delayed introduction of foods

Maternal diets

○255

262 C261 ○C341

Prevention Strategies Breast feeding

○252

Special diets for infants and young children

○R269 ○270 ○226

○340 ○324

○340 324

338 260

Probiotics ○288

Allergen Avoidance

289

Elimination diet

○R314 ○R*253 291 ○317

C346 C204

C347

Immunotherapy

300 301 302 299 ○303 C344

Desensitization

Allergen avoidance

Treatment Management

Strategies

Pharmacology

315

○318 320

○R327 319 C346

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Probiotics ○326

Statistically significant improvement Some statistically significant improvement in some outcomes but not in all outcomes measured.

○ No statistically significant improvement C=Cohort study; R=Systematic review; Other studies are controlled trials. *This review253included only one RCT that evaluated elimination diet.

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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

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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 food-related 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.

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Reference List

1. Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, Sodergren E, et al. The prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol. 2007;120(3):638-46. 2. American Gastroenterological Association medical position statement: guidelines for the evaluation of food allergies. Gastroenterology. 2001 March;120(4):1023-5. 3. Shea BJG, J. M. Wells, G. A. Boers, M. Andersson, N. Hamel, C. Porter, A. C. Tugwell, P. Moher, D. Bouter, L. M. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 2007;7:10. 4. Lijmer JGM, B. W. Heisterkamp, S. Bonsel, G. J. Prins, M. H. van der Meulen, J. H. Bossuyt, P. M. Empirical evidence of design-related bias in studies of diagnostic tests. JAMA. 1999;282(11):1061-6. 5. STARD. [cited]; Available from: http://www.stard-statement.org/. 6. Whiting PR, A. W. Reitsma, J. B. Bossuyt, P. M. Kleijnen, J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003;3:25. 7. Jadad ARM, R. A. Carroll, D. Jenkinson, C. Reynolds, D. J. Gavaghan, D. J. McQuay, H. J. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12. 8. Moher DP, B. Jones, A. Cook, D. J. Jadad, A. R. Moher, M. Tugwell, P. Klassen, T. P. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998;352(9128):609-13. 9. Atkins DB, D. Briss, P. A. Eccles, M. Falck-Ytter, Y. Flottorp, S. Guyatt, G. H. Harbour, R. T. Haugh, M. C. Henry, D. Hill, S. Jaeschke, R. Leng, G. Liberati, A. Magrini, N. Mason, J. Middleton, P. Mrukowicz, J. O'Connell, D. Oxman, A. D. Phillips, B. Schunemann, H. J. Edejer, T. T. Varonen, H. Vist, G. E. Williams, J. W., Jr. Zaza, S. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490. 10. Shunemann AO, A. Brozek, J. et al. GRADE:grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336:1106-10.

http://www.stard-statement.org/

248

11. Metcalfe DS, H. Simon, R. Food Allergy: Adverse Reactions to Foods and Food Additives, 4th Edition. Wiley-Blackwell; 2008. 12. Keet CA, Wood RA. Food allergy and anaphylaxis. Immunol Allergy Clin North Am. 2007;27(2):193-212, vi. 13. Yunginger JWS, D. L. Jones, R. T. Helm, R. M. Fatal anaphylactic reactions induced by peanuts. Allergy Proc. 1989;10(4):249-53. 14. Sampson HA. Update on food allergy. J Allergy Clin Immunol. 2004;113(5):805-19; quiz 20. 15. Clark S, Bock SA, Gaeta TJ, Brenner BE, Cydulka RK, Camargo CA. Multicenter study of emergency department visits for food allergies. J Allergy Clin Immunol. 2004;113(2):347-52. 16. Wang J, Sampson HA. Food anaphylaxis. Clin Exp Allergy. 2007;37(5):651-60. 17. Young M. Common Beliefs About Peanut Allergy: Fact or Fiction? ; [cited]; Available from: http://www.allergysafecommunities.ca/assets/common_beliefs_faan_2003.pdf. 18. Simonte SJ, Ma S, Mofidi S, Sicherer SH. Relevance of casual contact with peanut butter in children with peanut allergy. J Allergy Clin Immunol. 2003;112(1):180-2. 19. Beaudouin ER, J. M. Morisset, M. Codreanu, F. Kanny, G. Moneret-Vautrin, D. A. Food-dependent exercise-induced anaphylaxis--update and current data. Eur Ann Allergy Clin Immunol. 2006;38(2):45-51. 20. Atkins D. Food allergy: diagnosis and management. Prim Care. 2008;35(1):119-40, vii. 21. Sampson HA. 9. Food allergy. J Allergy Clin Immunol. 2003;111(2 Suppl):S540-7. 22. Burks AW. Peanut allergy. Lancet. 2008;371(9623):1538-46. 23. Crespo JF, James JM, Rodriguez J. Diagnosis and therapy of food allergy. Mol Nutr Food Res. 2004;48(5):347-55. 24. Moneret-Vautrin DA, Morisset M. Adult food allergy. Curr Allergy Asthma Rep. 2005;5(1):80-5. 25. O'Hollaren M. Orego Dyspnea Due to Vocal Cord Dysfuntion: Dyspnea and the Larynx.

http://www.allergysafecommunities.ca/assets/common_beliefs_faan_2003.pdf

249

26. Jones SMB, A. W. The Spectrum of Allergic Reactions to Foods. In: Metcalfe DS, H. Simon, R., editor. Food Allergy: Adverse Reactions to Foods and Food Additives. 4th ed: Wiley-Blackwell; 2008. p. 101-9. 27. Sicherer SH. Clinical aspects of gastrointestinal food allergy in childhood. Pediatrics. 2003;111(6 Pt 3):1609-16. 28. Adkinson NF, W. B, B. B, S. H, E. SF, R. L. Middleton's Allergy: Principles and Practice, 7th Edition. Mosby; 2008. 29. Rowe A. Chronic Ulcerative ColitisAllergy in Its Etiology. Annals of Internal Medicine. 1942;17(1):83-100. 30. Franciosi JPM, J. E. Liacouras, C. A. Eosinophilic Esophagitis, Gastroenteritis, and Colitis. In: Metcalfe DS, H. Simon, R., editor. Food Allergy: Adverse Reactions to Foods and Food Additives. 4th ed: Wiley-Blackwell; 2008. p. 182-94. 31. Chehade MS, H. A. The role of lymphocytes in eosinophilic gastrointestinal disorders. Immunol Allergy Clin North Am. 2009;29(1):149-58, xii. 32. Ferguson DDF-O, A. E. Eosinophilic esophagitis: an update. Dis Esophagus. 2007;20(1):2-8. 33. Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol. 2002;109(2):363-8. 34. DeBrosse CWR, M. E. Allergy and eosinophil-associated gastrointestinal disorders (EGID). Curr Opin Immunol. 2008;20(6):703-8. 35. Leinbach GER, C. E. Eosinophilic gastroenteritis: a simple reaction to food allergens? Gastroenterology. 1970;59(6):874-89. 36. Gonsalves N. Food allergies and eosinophilic gastrointestinal illness. Gastroenterol Clin North Am. 2007;36(1):75-91, vi. 37. Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). J Allergy Clin Immunol. 2004;113(1):11-28; quiz 9. 38. Bonis PA. Putting the puzzle together: epidemiological and clinical clues in the etiology of eosinophilic esophagitis. Immunol Allergy Clin North Am. 2009;29(1):41-52, viii.

250

39. Kelly KJL, A. J. Rowe, P. C. Yardley, J. H. Perman, J. A. Sampson, H. A. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology. 1995;109(5):1503-12. 40. Markowitz JES, J. M. Ruchelli, E. Liacouras, C. A. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol. 2003;98(4):777-82. 41. Pasha SFS, V. K. Crowell, M. D. Current concepts and treatment options in eosinophilic esophagitis. Curr Opin Investig Drugs. 2006;7(11):992-6. 42. Sicherer SH. Food allergy. 2002;360(9334):701-10. 43. Heine RG, Elsayed S, Hosking CS, Hill DJ. Cow's milk allergy in infancy. Curr Opin Allergy Clin Immunol. 2002;2(3):217-25. 44. Arvola T, Ruuska T, Keranen J, Hyoty H, Salminen S, Isolauri E. Rectal bleeding in infancy: clinical, allergological, and microbiological examination. Pediatrics. 2006;117(4):e760-8. 45. Paajanen L, Korpela R, Tuure T, Honkanen J, Jarvela I, Ilonen J, et al. Cow milk is not responsible for most gastrointestinal immune-like syndromes--evidence from a population-based study. Am J Clin Nutr. 2005;82(6):1327-35. 46. Motala C. Food Allergy. World Allergy Organization; [cited]; Available from: http://www.worldallergy.org/public/allergic_diseases_center/foodallergy/. 47. Moissidis IC, D. Vichyanond, P. Bahna, S. L. Milk-induced pulmonary disease in infants (Heiner syndrome). Pediatr Allergy Immunol. 2005;16(6):545-52. 48. Fasano MB. Dermatologic food allergy. Pediatr Ann. 2006;35(10):727-31. 49. Skypala IV, C., editor. Food Hypersensitivity: Diagnosing and Managing Food Allergies and Intolerance: Wiley-Blackwell Publishing; 2009. 50. Calvert MLR, I. Samaratunga, H. Mango dermatitis: allergic contact dermatitis to Mangifera indica. Australas J Dermatol. 1996 Feb;37(1):59-60. 51. Amadoa A, Jacob S. Contact Dermatitis to Foods. Actas Dermosifiliogr. 2007;98:452-8. 52. Warshaw EM, Botto NC, Zug KA, Belsito DV, Maibach HI, Sasseville D, et al. Contact dermatitis associated with food: retrospective cross-sectional analysis of North American Contact Dermatitis Group data, 2001-2004. Dermatitis. 2008;19(5):252-60.

http://www.worldallergy.org/public/allergic_diseases_center/foodallergy/

251

53. Incorvaia CF, F. Verna, N. D'Alo, S. Motolese, A. Pucci, S. Allergy and the skin. Clin Exp Immunol. 2008;153 Suppl 1:27-9. 54. Wuthrich B. Food-induced cutaneous adverse reactions. Allergy. 1998;53(46 Suppl):131-5. 55. Wolkerstorfer A, Wahn U, Kjellman NI, Diepgen TL, De Longueville M, Oranje AP. Natural course of sensitization to cow's milk and hen's egg in childhood atopic dermatitis: ETAC study group. 2002;32(1):70-3. 56. Bath-Hextall FD, F. M. Williams, H. C. Dietary exclusions for improving established atopic eczema in adults and children: systematic review. Allergy. 2009 Feb;64(2):258-64. 57. Schafer T. The impact of allergy on atopic eczema from data from epidemiological studies. Curr Opin Allergy Clin Immunol. 2008;8(5):418-22. 58. Burks W. Skin manifestations of food allergy. Pediatrics. 2003;111(6 Pt 3):1617-24. 59. Muller BA. Urticaria and angioedema: a practical approach. Am Fam Physician. 2004;69(5):1123-8. 60. Grattan CEH, F. Guidelines for evaluation and management of urticaria in adults and children. Br J Dermatol. 2007;157(6):1116-23. 61. Raap U, Schaefer T, Kapp A, Wedi B. Exotic food allergy: anaphylactic reaction to lychee. J Investig Allergol Clin Immunol. 2007;17(3):199-201. 62. Charlesworth EN. Urticaria and angioedema: a clinical spectrum. Ann Allergy Asthma Immunol. 1996;76(6):484-95; quiz 95-9. 63. European Medicines A. "Guidelines on the Clinical Development of Medicinal Products for the Treatment of Allergic Rhino-Conjunctivitis. 64. Malik V, Ghosh S, Woolford TJ. Rhinitis due to food allergies: fact or fiction? J Laryngol Otol. 2007;121(6):526-9. 65. Eigenmann PAJ, J. M. The Respiratory Tract and Food Hypersensitivity. Food Allergy. 2008:149-50. 66. Woods RK, Stoney RM, Raven J, Walters EH, Abramson M, Thien FC. Reported adverse food reactions overestimate true food allergy in the community. Eur J Clin Nutr. 2002;56(1):31-6.

252

67. Eggesbo M, Botten G, Halvorsen R, Magnus P. The prevalence of CMA/CMPI in young children: the validity of parentally perceived reactions in a population-based study. Allergy. 2001;56(5):393-402. 68. Bengtsson U, Nilsson-Balknas U, Hanson LA, Ahlstedt S. Double blind, placebo controlled food reactions do not correlate to IgE allergy in the diagnosis of staple food related gastrointestinal symptoms. 1996;39(1):130-5. 69. Whitlock EP, Lin JS, Chou R, Shekelle P, Robinson KA. Using existing systematic reviews in complex systematic reviews. Ann Intern Med. 2008;148(10):776-82. 70. Zuidmeer L, Goldhahn K, Rona RJ, Gislason D, Madsen C, Summers C, et al. The prevalence of plant food allergies: a systematic review. 2008;121(5):1210-8 e4. 71. Sicherer SH, Munoz-Furlong A, Burks AW, Sampson HA. Prevalence of peanut and tree nut allergy in the US determined by a random digit dial telephone survey. J Allergy Clin Immunol. 1999;103(4):559-62. 72. Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol. 2003;112(6):1203-7. 73. Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of seafood allergy in the United States determined by a random telephone survey. J Allergy Clin Immunol. 2004;114(1):159-65. 74. Luccioli SR, M. Labiner-Wolfe, J. Fein, S. B. Maternally reported food allergies and other food-related health problems in infants: characteristics and associated factors. Pediatrics. 2008 Oct;122 Suppl 2:S105-12. 75. Branum AML, S. L. Food allergy among U.S. children: trends in prevalence and hospitalizations. NCHS Data Brief. 2008 Oct(10):1-8. 76. Branum AML, S.L. Food Allergy Among Children in the United States. Pediatrics. 2009;124(6). 77. Yocum MW, Butterfield JH, Klein JS, Volcheck GW, Schroeder DR, Silverstein MD. Epidemiology of anaphylaxis in Olmsted County: A population-based study. J Allergy Clin Immunol. 1999;104(2 Pt 1):452-6. 78. Bohlke K, Davis RL, DeStefano F, Marcy SM, Braun MM, Thompson RS. Epidemiology of anaphylaxis among children and adolescents enrolled in a health maintenance organization. J Allergy Clin Immunol. 2004;113(3):536-42.

253

79. Mulla ZD, Simon MR. Hospitalizations for anaphylaxis in Florida: epidemiologic analysis of a population-based dataset. Int Arch Allergy Immunol. 2007;144(2):128-36. 80. Lin RY, Anderson AS, Shah SN, Nurruzzaman F. Increasing anaphylaxis hospitalizations in the first 2 decades of life: New York State, 1990 -2006. Ann Allergy Asthma Immunol. 2008;101(4):387-93. 81. Decker WW, Campbell RL, Manivannan V, Luke A, St Sauver JL, Weaver A, et al. The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project. J Allergy Clin Immunol. 2008;122(6):1161-5. 82. Ross MPF, M. Street, D. Klontz, K. Schroeder, T. Luccioli, S. Analysis of food-allergic and anaphylactic events in the National Electronic Injury Surveillance System. J Allergy Clin Immunol. 2008 Jan;121(1):166-71. 83. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med. 1992;327(6):380-4. 84. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol. 2001;107(1):191-3. 85. Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2007;120(5):1172-7. 86. Shek LP, Soderstrom L, Ahlstedt S, Beyer K, Sampson HA. Determination of food specific IgE levels over time can predict the development of tolerance in cow's milk and hen's egg allergy. J Allergy Clin Immunol. 2004;114(2):387-91. 87. 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. 88. Savage JHM, E. C. Skripak, J. M. Wood, R. A. The natural history of egg allergy. J Allergy Clin Immunol. 2007 Dec;120(6):1413-7. 89. 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. 90. Bock SA, Atkins FM. The natural history of peanut allergy. J Allergy Clin Immunol. 1989;83(5):900-4. 91. 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):1304-10.

254

92. Vander Leek TK, Liu AH, Stefanski K, Blacker B, Bock SA. The natural history of peanut allergy in young children and its association with serum peanut-specific IgE. J Pediatr. 2000;137(6):749-55. 93. Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA, Burks W, Wood RA. The natural history of peanut allergy. J Allergy Clin Immunol. 2001;107(2):367-74. 94. 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. 95. Kelso JM. Resolution of peanut allergy. J Allergy Clin Immunol. 2000;106(4):777. 96. Grundy JM, S. Bateman, B. Dean, T. Arshad, S. H. Rising prevalence of allergy to peanut in children: Data from 2 sequential cohorts. J Allergy Clin Immunol. 2002 Nov;110(5):784-9. 97. Kagan RSJ, L. Dufresne, C. Gray-Donald, K. Turnbull, E. Pierre, Y. S. Clarke, A. E. Prevalence of peanut allergy in primary-school children in Montreal, Canada. J Allergy Clin Immunol. 2003 Dec;112(6):1223-8. 98. Ben-Shoshan MK, R. S. Alizadehfar, R. Joseph, L. Turnbull, E. St Pierre, Y. Clarke, A. E. Is the prevalence of peanut allergy increasing? A 5-year follow-up study in children in Montreal. J Allergy Clin Immunol. 2009 Apr;123(4):783-8. 99. Lack G, Fox D, Northstone K, Golding J. Factors associated with the development of peanut allergy in childhood. N Engl J Med. 2003;348(11):977-85. 100. Fox ATS, P. du Toit, G. Syed, H. Lack, G. Household peanut consumption as a risk factor for the development of peanut allergy. J Allergy Clin Immunol. 2009 Feb;123(2):417-23. 101. Berns SH, Halm EA, Sampson HA, Sicherer SH, Busse PJ, Wisnivesky JP. Food allergy as a risk factor for asthma morbidity in adults. J Asthma. 2007;44(5):377-81. 102. Wang J, Visness CM, Sampson HA. Food allergen sensitization in inner-city children with asthma. J Allergy Clin Immunol. 2005;115(5):1076-80. 103. Vogel NM, Katz HT, Lopez R, Lang DM. Food allergy is associated with potentially fatal childhood asthma. J Asthma. 2008;45(10):862-6. 104. Emery NL, Vollmer WM, Buist AS, Osborne ML. Self-reported food reactions and their associations with asthma. West J Nurs Res. 1996;18(6):643-54.

255

105. Schroeder AK, R. Pongracic, J. A. Sullivan, C. L. Caruso, D. M. Costello, J. Meyer, K. E. Vucic, Y. Gupta, R. Kim, J. S. Fuleihan, R. Wang, X. Food allergy is associated with an increased risk of asthma. Clin Exp Allergy. 2009 Feb;39(2):261-70. 106. James JME, P. A. Eggleston, P. A. Sampson, H. A. Airway reactivity changes in asthmatic patients undergoing blinded food challenges. Am J Respir Crit Care Med. 1996 Feb;153(2):597-603. 107. Sampson HA MC. Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. The Journal of pediatrics. 1985;107(5):669-75. 108. Sampson HA, Scanlon SM. Natural history of food hypersensitivity in children with atopic dermatitis. J Pediatr. 1989;115(1):23-7. 109. 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. 110. Quaranta JH, Rohr AS, Rachelefsky GS, Siegel SC, Katz RM, Spector SL, et al. The natural history and response to therapy of chronic urticaria and angioedema. Ann Allergy. 1989;62(5):421-4. 111. 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. 112. 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. 113. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R, et al. 14 years of eosinophilic esophagitis: clinical features and prognosis. 2009;48(1):30-6. 114. Veerappan GRP, J. L. Duncan, T. J. Baker, T. P. Maydonovitch, C. Lake, J. M. Wong, R. K. Osgard, E. M. Prevalence of eosinophilic esophagitis in an adult population undergoing upper endoscopy: a prospective study. Clin Gastroenterol Hepatol. 2009 Apr;7(4):420-6, 6 e1-2. 115. 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. 116. Shadick NA, Liang MH, Partridge AJ, Bingham C, Wright E, Fossel AH, et al. The natural history of exercise-induced anaphylaxis: survey results from a 10-year follow-up study. J Allergy Clin Immunol. 1999;104(1):123-7.

256

117. Tabar AI, Alvarez-Puebla MJ, Gomez B, Sanchez-Monge R, Garcia BE, Echechipia S, et al. Diversity of asparagus allergy: clinical and immunological features. 2004;34(1):131-6. 118. Wieslander G, Norback D, Wang Z, Zhang Z, Mi Y, Lin R. Buckwheat allergy and reports on asthma and atopic disorders in Taiyuan City, Northern China. 2000;18(3):147-52. 119. Pauli G, Bessot JC, Braun PA, Dietemann-Molard A, Kopferschmitt-Kubler MC, Thierry R. Celery allergy: clinical and biological study of 20 cases. Ann Allergy. 1988;60(3):243-6. 120. Hill DJ, Firer MA, Ball G, Hosking CS. Natural history of cows' milk allergy in children: immunological outcome over 2 years. Clin Exp Allergy. 1993;23(2):124-31. 121. Cantani A, Micera M. Natural history of cow's milk allergy. An eight-year follow-up study in 115 atopic children. Eur Rev Med Pharmacol Sci. 2004;8(4):153-64. 122. Kucukosmanoglu E, Yazi D, Yesil O, Akkoc T, Gezer M, Bakirci N, et al. Prevalence of egg sensitization in Turkish infants based on skin prick test. Allergol Immunopathol (Madr). 2008;36(3):141-4. 123. Eggesbo M, Botten G, Halvorsen R, Magnus P. The prevalence of allergy to egg: a population-based study in young children. 2001;56(5):403-11. 124. Aleman A, Sastre J, Quirce S, de las Heras M, Carnes J, Fernandez-Caldas E, et al. Allergy to kiwi: a double-blind, placebo-controlled food challenge study in patients from a birch-free area. J Allergy Clin Immunol. 2004;113(3):543-50. 125. Martinez San Ireneo M, Ibanez MD, Sanchez JJ, Carnes J, Fernandez-Caldas E. Clinical features of legume allergy in children from a Mediterranean area. 2008;101(2):179-84. 126. Figueredo E, Cuesta-Herranz J, De-Miguel J, Lazaro M, Sastre J, Quirce S, et al. Clinical characteristics of melon (Cucumis melo) allergy. Ann Allergy Asthma Immunol. 2003;91(3):303-8. 127. Rance F, Dutau G, Abbal M. Mustard allergy in children. Allergy. 2000;55(5):496-500. 128. Figueroa J, Blanco C, Dumpierrez AG, Almeida L, Ortega N, Castillo R, et al. Mustard allergy confirmed by double-blind placebo-controlled food challenges: clinical features and cross-reactivity with mugwort pollen and plant-derived foods. Allergy. 2005;60(1):48-55.

257

129. Morisset M, Moneret-Vautrin DA, Maadi F, Fremont S, Guenard L, Croizier A, et al. Prospective study of mustard allergy: first study with double-blind placebo-controlled food challenge trials (24 cases). Allergy. 2003;58(4):295-9. 130. Ho MH, Wong WH, Heine RG, Hosking CS, Hill DJ, Allen KJ. Early clinical predictors of remission of peanut allergy in children. J Allergy Clin Immunol. 2008;121(3):731-6. 131. Du Toit G, Katz Y, Sasieni P, Mesher D, Maleki SJ, Fisher HR, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008;122(5):984-91. 132. Chiang WC, Kidon MI, Liew WK, Goh A, Tang JP, Chay OM. The changing face of food hypersensitivity in an Asian community. Clin Exp Allergy. 2007;37(7):1055-61. 133. Dalal I, Binson I, Levine A, Somekh E, Ballin A, Reifen R. The pattern of sesame sensitivity among infants and children. Pediatr Allergy Immunol. 2003;14(4):312-6. 134. Agne PS, Bidat E, Rance F, Paty E. Sesame seed allergy in children. Eur Ann Allergy Clin Immunol. 2004;36(8):300-5. 135. Dalal I, Binson I, Reifen R, Amitai Z, Shohat T, Rahmani S, et al. Food allergy is a matter of geography after all: sesame as a major cause of severe IgE-mediated food allergic reactions among infants and young children in Israel. 2002;57(4):362-5. 136. de la Cuesta CG, Garcia BE, Cordoba H, Dieguez I, Oehling A. Food allergy to Helix terrestre (snail). Allergol Immunopathol (Madr). 1989;17(6):337-9. 137. Ballmer-Weber BK, Holzhauser T, Scibilia J, Mittag D, Zisa G, Ortolani C, et al. Clinical characteristics of soybean allergy in Europe: a double-blind, placebo-controlled food challenge study. J Allergy Clin Immunol. 2007;119(6):1489-96. 138. Reindl J, Anliker MD, Karamloo F, Vieths S, Wuthrich B. Allergy caused by ingestion of zucchini (Cucurbita pepo): characterization of allergens and cross-reactivity to pollen and other foods. J Allergy Clin Immunol. 2000;106(2):379-85. 139. Almqvist C, Pershagen G, Wickman M. Low socioeconomic status as a risk factor for asthma, rhinitis and sensitization at 4 years in a birth cohort. Clin Exp Allergy. 2005;35(5):612-8. 140. Tsai HJK, R. Pongracic, J. Liu, X. Story, R. Yu, Y. Caruso, D. Costello, J. Schroeder, A. Fang, Y. Demirtas, H. Meyer, K. E. O'Gorman, M. R. Wang, X. Familial aggregation of food allergy and sensitization to food allergens: a family-based study. Clin Exp Allergy. 2009 Jan;39(1):101-9.

258

141. Kusunoki TO, I. Yoshioka, T. Saito, M. Nishikomori, R. Heike, T. Sugai, M. Shimizu, A. Nakahata, T. SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis. J Allergy Clin Immunol. 2005 Mar;115(3):636-8. 142. Torgerson TRL, A. Moes, N. Anover, S. Mateo, V. Rieux-Laucat, F. Hermine, O. Vijay, S. Gambineri, E. Cerf-Bensussan, N. Fischer, A. Ochs, H. D. Goulet, O. Ruemmele, F. M. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology. 2007 May;132(5):1705-17. 143. Hitomi YE, M. Tomikawa, M. Imai, T. Komata, T. Hirota, T. Harada, M. Sakashita, M. Suzuki, Y. Shimojo, N. Kohno, Y. Fujita, K. Miyatake, A. Doi, S. Enomoto, T. Taniguchi, M. Higashi, N. Nakamura, Y. Tamari, M. Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma. J Allergy Clin Immunol. 2009 Oct;124(4):779-85 e6. 144. Beck LAB, M. Hata, T. Schneider, L. C. Hanifin, J. Gallo, R. Paller, A. S. Lieff, S. Reese, J. Zaccaro, D. Milgrom, H. Barnes, K. C. Leung, D. Y. Phenotype of atopic dermatitis subjects with a history of eczema herpeticum. J Allergy Clin Immunol. 2009 Aug;124(2):260-9, 9 e1-7. 145. van den Oord RAS, A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ. 2009;339:b2433. 146. Iacono G, Di Prima L, D'Amico D, Scalici C, Geraci G, Carroccio A. The "red umbilicus": a diagnostic sign of cow's milk protein intolerance. J Pediatr Gastroenterol Nutr. 2006;42(5):531-4. 147. Chapman J. Food Allergy: A practice parameter. Annals of Allergy, Asthma and Immunology. 2006;96:1-68. 148. Isolauri E, Turjanmaa K. Combined skin prick and patch testing enhances identification of food allergy in infants with atopic dermatitis. J Allergy Clin Immunol. 1996;97(1 Pt 1):9-15. 149. Mehl A, Rolinck-Werninghaus C, Staden U, Verstege A, Wahn U, Beyer K, et al. The atopy patch test in the diagnostic workup of suspected food-related symptoms in children. J Allergy Clin Immunol. 2006;118(4):923-9. 150. Vlieg-Boerstra BJ, van der Heide S, Bijleveld CM, Kukler J, Duiverman EJ, Dubois AE. Placebo reactions in double-blind, placebo-controlled food challenges in children. Allergy. 2007;62(8):905-12.

259

151. Venter C, Pereira B, Voigt K, Grundy J, Clayton CB, Gant C, et al. Comparison of open and double-blind placebo-controlled food challenges in diagnosis of food hypersensitivity amongst children. J Hum Nutr Diet. 2007;20(6):565-79. 152. Rincon de Arellano IRV-C, S. Sinaniotis, A. C. Fernandez-Rivas, M. False positive placebo reaction in a double-blind placebo-controlled food challenge. J Investig Allergol Clin Immunol. 2009;19(3):241-2. 153. Caffarelli C, Petroccione T. False-negative food challenges in children with suspected food allergy. Lancet. 2001;358(9296):1871-2. 154. Clark AT, Mangat JS, Tay SS, King Y, Monk CJ, White PA, et al. Facial thermography is a sensitive and specific method for assessing food challenge outcome. Allergy. 2007;62(7):744-9. 155. Hwang JB, Song JY, Kang YN, Kim SP, Suh SI, Kam S, et al. The significance of gastric juice analysis for a positive challenge by a standard oral challenge test in typical cow's milk protein-induced enterocolitis. J Korean Med Sci. 2008;23(2):251-5. 156. Bischoff SC, Herrmann A, Manns MP. Prevalence of adverse reactions to food in patients with gastrointestinal disease. Allergy. 1996;51(11):811-8. 157. Niggemann B, Beyer K. Pitfalls in double-blind, placebo-controlled oral food challenges. Allergy. 2007;62(7):729-32. 158. Gellerstedt M, Magnusson J, Grajo U, Ahlstedt S, Bengtsson U. Interpretation of subjective symptoms in double-blind placebo-controlled food challenges - interobserver reliability. Allergy. 2004;59(3):354-6. 159. Nowak-Wegrzyn AAa, A. H. Bahna, S. L. Bock, S. A. Sicherer, S. H. Teuber, S. S. Work Group report: oral food challenge testing. J Allergy Clin Immunol. 2009 Jun;123(6 Suppl):S365-83. 160. 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. 161. Perry TT, Matsui EC, Conover-Walker MK, Wood RA. Risk of oral food challenges. J Allergy Clin Immunol. 2004;114(5):1164-8. 162. Bernstein IL, Li JT, Bernstein DI, Hamilton R, Spector SL, Tan R, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol. 2008;100(3 Suppl 3):S1-148. 163. European Academy of AC, Immunology. Allergen standardization and skin tests. European Journal of Allergy and Clinical Immunology. 1993;48:48-82.

260

164. Liccardi G, D'Amato G, Canonica GW, Salzillo A, Piccolo A, Passalacqua G. Systemic reactions from skin testing: literature review. J Investig Allergol Clin Immunol. 2006;16(2):75-8. 165. Rance F, Abbal M, Lauwers-Cances V. Improved screening for peanut allergy by the combined use of skin prick tests and specific IgE assays. J Allergy Clin Immunol. 2002;109(6):1027-33. 166. Prahl P, Krasilnikof F, Stahl Skov P, Norn S. Basophil histamine release in children with adverse reactions to cow milk. Comparison with RAST and skin prick test. Allergy. 1988;43(6):442-8. 167. Garcia-Ara C, Boyano-Martinez T, Diaz-Pena JM, Martin-Munoz F, Reche-Frutos M, Martin-Esteban M. Specific IgE levels in the diagnosis of immediate hypersensitivity to cows' milk protein in the infant. J Allergy Clin Immunol. 2001;107(1):185-90. 168. Ricci G, Capelli M, Miniero R, Menna G, Zannarini L, Dillon P, et al. A comparison of different allergometric tests, skin prick test, Pharmacia UniCAP and ADVIA Centaur, for diagnosis of allergic diseases in children. Allergy. 2003;58(1):38-45. 169. Osterballe M, Andersen KE, Bindslev-Jensen C. The diagnostic accuracy of the atopy patch test in diagnosing hypersensitivity to cow's milk and hen's egg in unselected children with and without atopic dermatitis. J Am Acad Dermatol. 2004;51(4):556-62. 170. Rance F. What is the optimal occlusion time for the atopy patch test in the diagnosis of food allergies in children with atopic dermatitis? Pediatr Allergy Immunol. 2004;15(1):93-6. 171. Roehr CC, Reibel S, Ziegert M, Sommerfeld C, Wahn U, Niggemann B. Atopy patch tests, together with determination of specific IgE levels, reduce the need for oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2001;107(3):548-53. 172. Saarinen KM, Suomalainen H, Savilahti E. Diagnostic value of skin-prick and patch tests and serum eosinophil cationic protein and cow's milk-specific IgE in infants with cow's milk allergy. Clin Exp Allergy. 2001;31(3):423-9. 173. Keskin O, Tuncer A, Adalioglu G, Sekerel BE, Sackesen C, Kalayci O. Evaluation of the utility of atopy patch testing, skin prick testing, and total and specific IgE assays in the diagnosis of cow's milk allergy. Ann Allergy Asthma Immunol. 2005;94(5):553-60.

261

174. Calvani M, Alessandri C, Frediani T, Lucarelli S, Miceli Sopo S, Panetta V, et al. Correlation between skin prick test using commercial extract of cow's milk protein and fresh milk and food challenges. Pediatr Allergy Immunol. 2007;18(7):583-8. 175. Canani RB, Ruotolo S, Auricchio L, Caldore M, Porcaro F, Manguso F, et al. Diagnostic accuracy of the atopy patch test in children with food allergy-related gastrointestinal symptoms. Allergy. 2007;62(7):738-43. 176. Monti G, Muratore MC, Peltran A, Bonfante G, Silvestro L, Oggero R, et al. High incidence of adverse reactions to egg challenge on first known exposure in young atopic dermatitis children: predictive value of skin prick test and radioallergosorbent test to egg proteins. Clin Exp Allergy. 2002;32(10):1515-9. 177. Dieguez MC, Cerecedo I, Muriel A, Zamora J, Sanchez-Cano M, De la Hoz B. Skin prick test predictive value on the outcome of a first known egg exposure in milk-allergic children. Pediatr Allergy Immunol. 2008;19(4):319-24. 178. Wainstein BKY, A. Jelley, D. Ziegler, M. Ziegler, J. B. Combining skin prick, immediate skin application and specific-IgE testing in the diagnosis of peanut allergy in children. Pediatr Allergy Immunol. 2007 May;18(3):231-9. 179. Mortz CG, Andersen KE, Bindslev-Jensen C. The prevalence of peanut sensitization and the association to pollen sensitization in a cohort of unselected adolescents--The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis (TOACS). Pediatr Allergy Immunol. 2005;16(6):501-6. 180. Rodriguez J, Crespo JF, Burks W, Rivas-Plata C, Fernandez-Anaya S, Vives R, et al. Randomized, double-blind, crossover challenge study in 53 subjects reporting adverse reactions to melon (Cucumis melo). J Allergy Clin Immunol. 2000;106(5):968-72. 181. Wananukul S, Chatchatee P, Chatproedprai S. Food induced urticaria in children. Asian Pac J Allergy Immunol. 2005;23(4):175-9. 182. Niinimaki A, Hannuksela M, Makinen-Kiljunen S. Skin prick tests and in vitro immunoassays with native spices and spice extracts. Ann Allergy Asthma Immunol. 1995;75(3):280-6. 183. Tainio VM, Savilahti E. Value of immunologic tests in cow milk allergy. Allergy. 1990;45(3):189-96. 184. De Boissieu D, Waguet JC, Dupont C. The atopy patch tests for detection of cow's milk allergy with digestive symptoms. J Pediatr. 2003;142(2):203-5. 185. Celik-Bilgili S, Mehl A, Verstege A, Staden U, Nocon M, Beyer K, et al. The predictive value of specific immunoglobulin E levels in serum for the outcome of oral food challenges. Clin Exp Allergy. 2005;35(3):268-73.

262

186. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol. 2001;107(5):891-6. 187. Rottem M, Shostak D, Foldi S. The predictive value of specific immunoglobulin E on the outcome of milk allergy. Isr Med Assoc J. 2008;10(12):862-4. 188. Fiocchi A, Besana R, Ryden AC, Terracciano L, Andreotti M, Arrigoni S, et al. Differential diagnosis of IgE-mediated allergy in young children with wheezing or eczema symptoms using a single blood test. Ann Allergy Asthma Immunol. 2004;93(4):328-33. 189. Maloney JM, Rudengren M, Ahlstedt S, Bock SA, Sampson HA. The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy. J Allergy Clin Immunol. 2008;122(1):145-51. 190. Lilja G, Kusoffsky E, Johansson SG, Oman H. Screening of atopic allergy in 5-year-old children--a comparison of the diagnostic properties of Phadiatop Paediatric and Phadiatop. Allergy. 1995;50(4):316-21. 191. Cobbaert CM, Jonker GJ. Allergy testing on the IMMULITE 2000 Random-Access immunoanalyzer - a clinical evaluation study. Clin Chem Lab Med. 2005;43(7):772-81. 192. Wang J, Godbold JH, Sampson HA. Correlation of serum allergy (IgE) tests performed by different assay systems. J Allergy Clin Immunol. 2008;121(5):1219-24. 193. Lee YW, Sohn JH, Lee JH, Hong CS, Park JW. Allergen-specific IgE measurement with the IMMULITE 2000 system: intermethod comparison of detection performance for allergen-specific IgE antibodies from Korean allergic patients. Clin Chim Acta. 2009;401(1-2):25-32. 194. Wood RA, Segall N, Ahlstedt S, Williams PB. Accuracy of IgE antibody laboratory results. Ann Allergy Asthma Immunol. 2007;99(1):34-41. 195. Bernardi D, Borghesan F, Faggian D, Bianchi FC, Favero E, Billeri L, et al. Time to reconsider the clinical value of immunoglobulin G4 to foods? Clin Chem Lab Med. 2008;46(5):687-90. 196. Jarvinen KM, Turpeinen M, Suomalainen H. Concurrent cereal allergy in children with cow's milk allergy manifested with atopic dermatitis. Clin Exp Allergy. 2003;33(8):1060-6. 197. Ronchetti R, Jesenak M, Barberi S, Ronchetti F, Rennerova Z, Trubacova D, et al. Reproducibility of atopy patch tests with food and inhalant allergens. J Biol Regul Homeost Agents. 2008;22(1):27-33.

263

198. Hill DJ, Duke AM, Hosking CS, Hudson IL. Clinical manifestations of cows' milk allergy in childhood. II. The diagnostic value of skin tests and RAST. Clin Allergy. 1988;18(5):481-90. 199. Cudowska B, Kaczmarski M. Atopy patch test in the diagnosis of food allergy in children with atopic eczema dermatitis syndrome. Rocz Akad Med Bialymst. 2005;50:261-7. 200. Hwang JB, Lee SH, Kang YN, Kim SP, Suh SI, Kam S. Indexes of suspicion of typical cow's milk protein-induced enterocolitis. J Korean Med Sci. 2007;22(6):993-7. 201. Yimyaem P, Chongsrisawat V, Vivatvakin B, Wisedopas N. Gastrointestinal manifestations of cow's milk protein allergy during the first year of life. J Med Assoc Thai. 2003;86(2):116-23. 202. Hoffman KM, Ho DG, Sampson HA. Evaluation of the usefulness of lymphocyte proliferation assays in the diagnosis of allergy to cow's milk. J Allergy Clin Immunol. 1997;99(3):360-6. 203. Odze RD, Bines J, Leichtner AM, Goldman H, Antonioli DA. Allergic proctocolitis in infants: a prospective clinicopathologic biopsy study. 1993;24(6):668-74. 204. Spergel JM, Andrews T, Brown-Whitehorn TF, Beausoleil JL, Liacouras CA. Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests. Ann Allergy Asthma Immunol. 2005;95(4):336-43. 205. Spergel JM, Brown-Whitehorn T, Beausoleil JL, Shuker M, Liacouras CA. Predictive values for skin prick test and atopy patch test for eosinophilic esophagitis. J Allergy Clin Immunol. 2007;119(2):509-11. 206. Kondo N, Fukutomi O, Agata H, Yokoyama Y. Proliferative responses of lymphocytes to food antigens are useful for detection of allergens in nonimmediate types of food allergy. J Investig Allergol Clin Immunol. 1997;7(2):122-6. 207. Krugman SD, Chiaramonte DR, Matsui EC. Diagnosis and management of food-induced anaphylaxis: a national survey of pediatricians. Pediatrics. 2006;118(3):e554-60. 208. Wilson BG, Cruz NV, Fiocchi A, Bahna SL. Survey of physicians' approach to food allergy, Part 2: Allergens, diagnosis, treatment, and prevention. Ann Allergy Asthma Immunol. 2008;100(3):250-5. 209. Ahlstedt S, Holmquist I, Kober A, Perborn H. Accuracy of specific IgE antibody assays for diagnosis of cow's milk allergy. Ann Allergy Asthma Immunol. 2002;89(6 Suppl 1):21-5.

264

210. Asero RF-R, M. Knulst, A. C. Bruijnzeel-Koomen, C. A. Double-blind, placebo-controlled food challenge in adults in everyday clinical practice: a reappraisal of their limitations and real indications. Curr Opin Allergy Clin Immunol. 2009 Aug;9(4):379-85. 211. Hofmann AMS, A. M. Jones, S. M. Palmer, K. P. Lokhnygina, Y. Steele, P. H. Kamilaris, J. Burks, A. W. Safety of a peanut oral immunotherapy protocol in children with peanut allergy. J Allergy Clin Immunol. 2009 Aug;124(2):286-91, 91 e1-6. 212. Narisety SDS, J. M. Steele, P. Hamilton, R. G. Matsui, E. C. Burks, A. W. Wood, R. A. Open-label maintenance after milk oral immunotherapy for IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2009 Sep;124(3):610-2. 213. Henriksen C, Eggesbo M, Halvorsen R, Botten G. Nutrient intake among two-year-old children on cows' milk-restricted diets. Acta Paediatr. 2000;89(3):272-8. 214. Ewan PW, Clark AT. Long-term prospective observational study of patients with peanut and nut allergy after participation in a management plan. Lancet. 2001;357(9250):111-5. 215. Halken S, Host A, Hansen LG, Osterballe O. Preventive effect of feeding high-risk infants a casein hydrolysate formula or an ultrafiltrated whey hydrolysate formula. A prospective, randomized, comparative clinical study. Pediatr Allergy Immunol. 1993;4(4):173-81. 216. Chandra RK, Puri S, Hamed A. Influence of maternal diet during lactation and use of formula feeds on development of atopic eczema in high risk infants. 1989;299(6693):228-30. 217. Juvonen P, Mansson M, Andersson C, Jakobsson I. Allergy development and macromolecular absorption in infants with different feeding regimens during the first three days of life. A three-year prospective follow-up. Acta Paediatr. 1996;85(9):1047-52. 218. Saarinen KM, Juntunen-Backman K, Jarvenpaa AL, Klemetti P, Kuitunen P, Lope L, et al. Breast-feeding and the development of cows' milk protein allergy. Adv Exp Med Biol. 2000;478:121-30. 219. Willems R, Duchateau J, Magrez P, Denis R, Casimir G. Influence of hypoallergenic milk formula on the incidence of early allergic manifestations in infants predisposed to atopic diseases. Ann Allergy. 1993;71(2):147-50. 220. Vandenplas Y, Hauser B, Van den Borre C, Clybouw C, Mahler T, Hachimi-Idrissi S, et al. The long-term effect of a partial whey hydrolysate formula on the prophylaxis of atopic disease. Eur J Pediatr. 1995;154(6):488-94.

265

221. Nentwich I, Michkova E, Nevoral J, Urbanek R, Szepfalusi Z. Cow's milk-specific cellular and humoral immune responses and atopy skin symptoms in infants from atopic families fed a partially (pHF) or extensively (eHF) hydrolyzed infant formula. 2001;56(12):1144-56. 222. Lilja G, Dannaeus A, Foucard T, Graff-Lonnevig V, Johansson SG, Oman H. Effects of maternal diet during late pregnancy and lactation on the development of IgE and egg- and milk-specific IgE and IgG antibodies in infants. 1991;21(2):195-202. 223. Lovegrove JA, Hampton SM, Morgan JB. The immunological and long-term atopic outcome of infants born to women following a milk-free diet during late pregnancy and lactation: a pilot study. Br J Nutr. 1994;71(2):223-38. 224. Lilja G, Dannaeus A, Foucard T, Graff-Lonnevig V, Johansson SG, Oman H. Effects of maternal diet during late pregnancy and lactation on the development of atopic diseases in infants up to 18 months of age--in-vivo results. Clin Exp Allergy. 1989;19(4):473-9. 225. Falth-Magnusson K, Kjellman NI. Allergy prevention by maternal elimination diet during late pregnancy--a 5-year follow-up of a randomized study. J Allergy Clin Immunol. 1992;89(3):709-13. 226. Burr ML, Limb ES, Maguire MJ, Amarah L, Eldridge BA, Layzell JC, et al. Infant feeding, wheezing, and allergy: a prospective study. Arch Dis Child. 1993;68(6):724-8. 227. von Berg A, Koletzko S, Grubl A, Filipiak-Pittroff B, Wichmann HE, Bauer CP, et al. The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial. J Allergy Clin Immunol. 2003;111(3):533-40. 228. Halken S, Hansen KS, Jacobsen HP, Estmann A, Faelling AE, Hansen LG, et al. Comparison of a partially hydrolyzed infant formula with two extensively hydrolyzed formulas for allergy prevention: a prospective, randomized study. 2000;11(3):149-61. 229. Saarinen KM, Juntunen-Backman K, Jarvenpaa AL, Kuitunen P, Lope L, Renlund M, et al. Supplementary feeding in maternity hospitals and the risk of cow's milk allergy: A prospective study of 6209 infants. J Allergy Clin Immunol. 1999;104(2 Pt 1):457-61. 230. Vandenplas Y, Hauser B, Van den Borre C, Sacre L, Dab I. Effect of a whey hydrolysate prophylaxis of atopic disease. Ann Allergy. 1992;68(5):419-24. 231. Zeiger RS, Heller S, Mellon MH, Forsythe AB, O'Connor RD, Hamburger RN, et al. Effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: a randomized study. J Allergy Clin Immunol. 1989;84(1):72-89.

266

232. Marini A, Agosti M, Motta G, Mosca F. Effects of a dietary and environmental prevention programme on the incidence of allergic symptoms in high atopic risk infants: three years' follow-up. Acta Paediatr Suppl. 1996;414:1-21. 233. Chandra RKP, S. Suraiya, C. Cheema, P. S. Influence of maternal food antigen avoidance during pregnancy and lactation on incidence of atopic eczema in infants. Clin Allergy. 1986 Nov;16(6):563-9. 234. Cant AJB, J. A. Marsden, R. A. Hewitt, D. Effect of maternal dietary exclusion on breast fed infants with eczema: two controlled studies. Br Med J (Clin Res Ed). 1986 Jul 26;293(6541):231-3. 235. Saarinen KM, Savilahti E. Infant feeding patterns affect the subsequent immunological features in cow's milk allergy. Clin Exp Allergy. 2000;30(3):400-6. 236. Poysa L, Remes K, Korppi M, Launiala K. Compliance with a dietary manipulation programme in families with infants prone to atopy. 1988;77(4):563-8. 237. Poysa L, Korppi M, Remes K, Juntunen-Backman K. Atopy in childhood and diet in infancy. A nine-year follow-up study. I. Clinical manifestations. Allergy Proc. 1991;12(2):107-11. 238. Simons FE. Prevention of acute urticaria in young children with atopic dermatitis. J Allergy Clin Immunol. 2001;107(4):703-6. 239. Chandra RK, Hamed A. Cumulative incidence of atopic disorders in high risk infants fed whey hydrolysate, soy, and conventional cow milk formulas. Ann Allergy. 1991;67(2 Pt 1):129-32. 240. Chandra RK, Singh G, Shridhara B. Effect of feeding whey hydrolysate, soy and conventional cow milk formulas on incidence of atopic disease in high risk infants. Ann Allergy. 1989;63(2):102-6. 241. Leung TF, Ma KC, Cheung LT, Lam CW, Wong E, Wan H, et al. A randomized, single-blind and crossover study of an amino acid-based milk formula in treating young children with atopic dermatitis. 2004;15(6):558-61. 242. Lever R, MacDonald C, Waugh P, Aitchison T. Randomised controlled trial of advice on an egg exclusion diet in young children with atopic eczema and sensitivity to eggs. 1998;9(1):13-9. 243. Niggemann B, Binder C, Dupont C, Hadji S, Arvola T, Isolauri E. Prospective, controlled, multi-center study on the effect of an amino-acid-based formula in infants with cow's milk allergy/intolerance and atopic dermatitis. 2001;12(2):78-82.

267

244. Mabin DC, Sykes AE, David TJ. Controlled trial of a few foods diet in severe atopic dermatitis. 1995;73(3):202-7. 245. Isolauri E, Sutas Y, Makinen-Kiljunen S, Oja SS, Isosomppi R, Turjanmaa K. Efficacy and safety of hydrolyzed cow milk and amino acid-derived formulas in infants with cow milk allergy. 1995;127(4):550-7. 246. Host A, Koletzko B, Dreborg S, Muraro A, Wahn U, Aggett P, et al. Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child. 1999;81(1):80-4. 247. Muraro A, Dreborg S, Halken S, Host A, Niggemann B, Aalberse R, et al. Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol. 2004;15(4):291-307. 248. AAP. Committee on Nutrition: Pediatric nutrion handbook. 5th ed. Elk Grove, Ill. 249. WHO, editor. Fifty-fourth World Health Assembly: Infant and Young Child Nutrition; 2004. 250. Tarini BA, Carroll AE, Sox CM, Christakis DA. Systematic review of the relationship between early introduction of solid foods to infants and the development of allergic disease. Arch Pediatr Adolesc Med. 2006;160(5):502-7. 251. Halmerbauer G, Gartner C, Schier M, Arshad H, Dean T, Koller DY, et al. Study on the prevention of allergy in Children in Europe (SPACE): allergic sensitization in children at 1 year of age in a controlled trial of allergen avoidance from birth. Pediatr Allergy Immunol. 2002;13 Suppl 15:47-54. 252. Kajosaari M. Atopy prevention in childhood: the role of diet. Prospective 5-year follow-up of high-risk infants with six months exclusive breastfeeding and solid food elimination. Pediatr Allergy Immunol. 1994;5(6 Suppl):26-8. 253. Kramer MS, Kakuma R. Maternal dietary antigen avoidance during pregnancy or lactation, or both, for preventing or treating atopic disease in the child. Cochrane Database Syst Rev. 2006;3:CD000133. 254. Hattevig G, Kjellman B, Sigurs N, Bjorksten B, Kjellman NI. Effect of maternal avoidance of eggs, cow's milk and fish during lactation upon allergic manifestations in infants. Clin Exp Allergy. 1989;19(1):27-32.

268

255. Sigurs N, Hattevig G, Kjellman B. Maternal avoidance of eggs, cow's milk, and fish during lactation: effect on allergic manifestations, skin-prick tests, and specific IgE antibodies in children at age 4 years. Pediatrics. 1992;89(4 Pt 2):735-9. 256. Hide DWG, B. M. Clinical manifestations of allergy related to breast and cows' milk feeding. Arch Dis Child. 1981;56(3):172-5. 257. Grulee CG. The influence of breast and artificial feeding on infantile eczema. J Pediatr. 1936;9:223-5. 258. Kramer MSM, B. Do breast-feeding and delayed introduction of solid foods protect against subsequent atopic eczema? J Pediatr. 1981;98(4):546-50. 259. Van Asperen PP, Kemp AS, Mellis CM. Relationship of diet in the development of atopy in infancy. Clin Allergy. 1984;14(6):525-32. 260. Filipiak B, Zutavern A, Koletzko S, von Berg A, Brockow I, Grubl A, et al. Solid food introduction in relation to eczema: results from a four-year prospective birth cohort study. J Pediatr. 2007;151(4):352-8. 261. Bardare M, Vaccari A, Allievi E, Brunelli L, Coco F, de Gaspari GC, et al. Influence of dietary manipulation on incidence of atopic disease in infants at risk. Ann Allergy. 1993;71(4):366-71. 262. Arshad SH, Bateman B, Sadeghnejad A, Gant C, Matthews SM. Prevention of allergic disease during childhood by allergen avoidance: the Isle of Wight prevention study. J Allergy Clin Immunol. 2007;119(2):307-13. 263. Han YS, Park HY, Ahn KM, Lee JS, Choi HM, Lee SI. Short-term effect of partially hydrolyzed formula on the prevention of development of atopic dermatitis in infants at high risk. J Korean Med Sci. 2003;18(4):547-51. 264. Perdomo-Ponce D, Benarroch L, Gonzalez-Cerrutti R, Barroso R, Carneiro F, Meijomil P. [Family education, a model for allergy prevention]. Invest Clin. 1996;37(4):221-45. 265. Schoetzau A, Filipiak-Pittroff B, Franke K, Koletzko S, Von Berg A, Gruebl A, et al. Effect of exclusive breast-feeding and early solid food avoidance on the incidence of atopic dermatitis in high-risk infants at 1 year of age. Pediatr Allergy Immunol. 2002;13(4):234-42. 266. Laubereau B, Brockow I, Zirngibl A, Koletzko S, Gruebl A, von Berg A, et al. Effect of breast-feeding on the development of atopic dermatitis during the first 3 years of life--results from the GINI-birth cohort study. J Pediatr. 2004;144(5):602-7.

269

267. Hays T, Wood RA. A systematic review of the role of hydrolyzed infant formulas in allergy prevention. Arch Pediatr Adolesc Med. 2005;159(9):810-6. 268. Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev. 2006(4):CD003664. 269. Osborn DA, Sinn J. Soy formula for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev. 2006(4):CD003741. 270. von Berg A, Filipiak-Pittroff B, Kramer U, Link E, Bollrath C, Brockow I, et al. Preventive effect of hydrolyzed infant formulas persists until age 6 years: long-term results from the German Infant Nutritional Intervention Study (GINI). J Allergy Clin Immunol. 2008;121(6):1442-7. 271. von Berg A, Koletzko S, Filipiak-Pittroff B, Laubereau B, Grubl A, Wichmann HE, et al. Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: three-year results of the German Infant Nutritional Intervention Study. J Allergy Clin Immunol. 2007;119(3):718-25. 272. Odelram H, Vanto T, Jacobsen L, Kjellman NI. Whey hydrolysate compared with cow's milk-based formula for weaning at about 6 months of age in high allergy-risk infants: effects on atopic disease and sensitization. Allergy. 1996;51(3):192-5. 273. Arslanoglu S, Moro GE, Schmitt J, Tandoi L, Rizzardi S, Boehm G. Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. J Nutr. 2008;138(6):1091-5. 274. Szajewska H, Mrukowicz JZ, Stoinska B, Prochowska A. Extensively and partially hydrolysed preterm formulas in the prevention of allergic diseases in preterm infants: a randomized, double-blind trial. Acta Paediatr. 2004;93(9):1159-65. 275. Bager P, Wohlfahrt J, Westergaard T. Caesarean delivery and risk of atopy and allergic disease: meta-analyses. Clin Exp Allergy. 2008;38(4):634-42. 276. Koplin JA, K. Gurrin, L. Osborne, N. Tang, M. L. Dharmage, S. Is caesarean delivery associated with sensitization to food allergens and IgE-mediated food allergy: a systematic review. Pediatr Allergy Immunol. 2008 Dec;19(8):682-7. 277. Kvenshagen BH, R. Jacobsen, M. Is there an increased frequency of food allergy in children delivered by caesarean section compared to those delivered vaginally? Acta Paediatr. 2009 Feb;98(2):324-7. 278. Liem JJ, Kozyrskyj AL, Huq SI, Becker AB. The risk of developing food allergy in premature or low-birth-weight children. J Allergy Clin Immunol. 2007;119(5):1203-9.

270

279. Salam MT, Margolis HG, McConnell R, McGregor JA, Avol EL, Gilliland FD. Mode of delivery is associated with asthma and allergy occurrences in children. Ann Epidemiol. 2006;16(5):341-6. 280. Renz-Polster H, David MR, Buist AS, Vollmer WM, O'Connor EA, Frazier EA, et al. Caesarean section delivery and the risk of allergic disorders in childhood. Clin Exp Allergy. 2005;35(11):1466-72. 281. Negele K, Heinrich J, Borte M, von Berg A, Schaaf B, Lehmann I, et al. Mode of delivery and development of atopic disease during the first 2 years of life. Pediatr Allergy Immunol. 2004;15(1):48-54. 282. Laubereau B, Filipiak-Pittroff B, von Berg A, Grubl A, Reinhardt D, Wichmann HE, et al. Caesarean section and gastrointestinal symptoms, atopic dermatitis, and sensitisation during the first year of life. Arch Dis Child. 2004;89(11):993-7. 283. Eggesbo M, Botten G, Stigum H, Nafstad P, Magnus P. Is delivery by cesarean section a risk factor for food allergy? J Allergy Clin Immunol. 2003;112(2):420-6. 284. Huurre A, Laitinen K, Rautava S, Korkeamaki M, Isolauri E. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: a double-blind placebo-controlled study. Clin Exp Allergy. 2008;38(8):1342-8. 285. Rautava S, Kalliomaki M, Isolauri E. Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant. J Allergy Clin Immunol. 2002;109(1):119-21. 286. Kuitunen M, Kukkonen K, Juntunen-Backman K, Korpela R, Poussa T, Tuure T, et al. Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort. J Allergy Clin Immunol. 2009;123(2):335-41. 287. Kukkonen K, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, et al. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2007;119(1):192-8. 288. Abrahamsson TR, Jakobsson T, Bottcher MF, Fredrikson M, Jenmalm MC, Bjorksten B, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119(5):1174-80. 289. Maas TK, Janneke Sheikh, Aziz Knottnerus, J. Andre Wesseling, Geertjan Dompeling, Edward Muris, Jean WM van Schayck, Constant Paul. Mono and multifaceted inhalant and/or food allergen reduction interventions for preventing asthma in children at high risk of developing asthma [Systematic Review]. Cochrane Database of Systematic Reviews. 2009(3).

271

290. Gupte ARD, P. V. Eosinophilic esophagitis. World J Gastroenterol. 2009 Jan 7;15(1):17-24. 291. Agata H, Kondo N, Fukutomi O, Shinoda S, Orii T. Effect of elimination diets on food-specific IgE antibodies and lymphocyte proliferative responses to food antigens in atopic dermatitis patients exhibiting sensitivity to food allergens. J Allergy Clin Immunol. 1993;91(2):668-79. 292. Skripak JM, Nash SD, Rowley H, Brereton NH, Oh S, Hamilton RG, et al. A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy. J Allergy Clin Immunol. 2008;122(6):1154-60. 293. Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K. Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy. 2007;62(11):1261-9. 294. Morisset M, Moneret-Vautrin DA, Guenard L, Cuny JM, Frentz P, Hatahet R, et al. Oral desensitization in children with milk and egg allergies obtains recovery in a significant proportion of cases. A randomized study in 60 children with cow's milk allergy and 90 children with egg allergy. Eur Ann Allergy Clin Immunol. 2007;39(1):12-9. 295. Nelson HS, Lahr J, Rule R, Bock A, Leung D. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol. 1997;99(6 Pt 1):744-51. 296. Patriarca G, Nucera E, Pollastrini E, Roncallo C, De Pasquale T, Lombardo C, et al. Oral specific desensitization in food-allergic children. Dig Dis Sci. 2007;52(7):1662-72. 297. Ebo DG, Hagendorens MM, Bridts CH, Schuerwegh AJ, De Clerck LS, Stevens WJ. Flow cytometric analysis of in vitro activated basophils, specific IgE and skin tests in the diagnosis of pollen-associated food allergy. Cytometry B Clin Cytom. 2005;64(1):28-33. 298. Zapatero L, Alonso E, Fuentes V, Martinez MI. Oral desensitization in children with cow's milk allergy. J Investig Allergol Clin Immunol. 2008;18(5):389-96. 299. Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella R, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol. 2005;116(5):1073-9. 300. Hansen KS, Khinchi MS, Skov PS, Bindslev-Jensen C, Poulsen LK, Malling HJ. Food allergy to apple and specific immunotherapy with birch pollen. Mol Nutr Food Res. 2004;48(6):441-8.

272

301. Bucher X, Pichler WJ, Dahinden CA, Helbling A. Effect of tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut. Allergy. 2004;59(12):1272-6. 302. Asero R. Effects of birch pollen-specific immunotherapy on apple allergy in birch pollen-hypersensitive patients. Clin Exp Allergy. 1998;28(11):1368-73. 303. Bernardini R, Campodonico P, Burastero S, Azzari C, Novembre E, Pucci N, et al. Sublingual immunotherapy with a latex extract in paediatric patients: a double-blind, placebo-controlled study. Curr Med Res Opin. 2006;22(8):1515-22. 304. Joshi PM, S. Sicherer, S. H. Interpretation of commercial food ingredient labels by parents of food-allergic children. J Allergy Clin Immunol. 2002;109(6):1019-21. 305. Simons EW, C. C. Furlong, T. J. Sicherer, S. H. Impact of ingredient labeling practices on food allergic consumers. Ann Allergy Asthma Immunol. 2005;95(5):426-8. 306. Vierk KAK, K. M. Fein, S. B. Street, D. A. Prevalence of self-reported food allergy in American adults and use of food labels. J Allergy Clin Immunol. 2007;119(6):1504-10. 307. Noimark LG, J. Warner, J. O. Parents' attitudes when purchasing products for children with nut allergy: A UK perspective. Pediatr Allergy Immunol. 2009. 308. Dean T, Venter C, Pereira B, Grundy J, Clayton CB, Higgins B. Government advice on peanut avoidance during pregnancy--is it followed correctly and what is the impact on sensitization? J Hum Nutr Diet. 2007;20(2):95-9. 309. Henderson JM, N. J. Cooper, J. The impact of FSANZ labelling changes on knowledge of nutrition and allergens by consumer's, health professional's and allergen sufferers. Asia Pac J Clin Nutr. 2003;12 Suppl:S16. 310. Weber TKSP, G. Sdepanian, V. L. Neto, U. F. de Morais, M. B. The performance of parents of children receiving cow's milk free diets at identification of commercial food products with and without cow's milk. J Pediatr (Rio J). 2007;83(5):459-64. 311. Cornelisse-Vermaat JRV, J. Yiakoumaki, V. Theodoridis, G. Frewer, L. J. Food-allergic consumers' labelling preferences: a cross-cultural comparison. Eur J Public Health. 2008;18(2):115-20. 312. Haboubi NYT, S. Jones, S. Coeliac disease and oats: a systematic review. Postgrad Med J. 2006;82(972):672-8. 313. Klemola T, Vanto T, Juntunen-Backman K, Kalimo K, Korpela R, Varjonen E. Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cow's

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milk allergy: a prospective, randomized study with a follow-up to the age of 2 years. J Pediatr. 2002;140(2):219-24. 314. Bath-Hextall F, Delamere FM, Williams HC. Dietary exclusions for established atopic eczema. Cochrane Database Syst Rev. 2008(1):CD005203. 315. Bindslev-Jensen C, Vibits A, Stahl Skov P, Weeke B. Oral allergy syndrome: the effect of astemizole. Allergy. 1991;46(8):610-3. 316. Leung DY, Sampson HA, Yunginger JW, Burks AW, Jr., Schneider LC, Wortel CH, et al. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med. 2003;348(11):986-93. 317. Cavagni G, Piscopo E, Rigoli E, Iuliano P, Bertolini P, Cazzola P. "Food allergy in children: an attempt to improve the effects of the elimination diet with an immunomodulating agent (thymomodulin). A double-blind clinical trial". Immunopharmacol Immunotoxicol. 1989;11(1):131-42. 318. Burks AW, Sampson HA. Double-blind placebo-controlled trial of oral cromolyn in children with atopic dermatitis and documented food hypersensitivity. J Allergy Clin Immunol. 1988;81(2):417-23. 319. Schaefer ET, Fitzgerald JF, Molleston JP, Croffie JM, Pfefferkorn MD, Corkins MR, et al. Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children. Clin Gastroenterol Hepatol. 2008;6(2):165-73. 320. Businco L BN, Nini G, Businco E, Cantani A, De Angelis M. Double-blind crossover trial with oral sodium cromoglycate in children with atopic dermatitis due to food allergy. Annals of allergy. 1986;57(6):433-8. 321. Szajewska H, Gawronska A, Wos H, Banaszkiewicz A, Grzybowska-Chlebowczyk U. Lack of effect of Lactobacillus GG in breast-fed infants with rectal bleeding: a pilot double-blind randomized controlled trial. J Pediatr Gastroenterol Nutr. 2007;45(2):247-51. 322. Hill DJ, Roy N, Heine RG, Hosking CS, Francis DE, Brown J, et al. Effect of a low-allergen maternal diet on colic among breastfed infants: a randomized, controlled trial. Pediatrics. 2005;116(5):e709-15. 323. Amadi B. Role of food antigen elimination in treating children with persistent diarrhea and malnutrition in Zambia. J Pediatr Gastroenterol Nutr. 2002;34 Suppl 1:S54-6. 324. Cantani A. A home-made meat-based formula for feeding atopic babies: a study in 51 children. Eur Rev Med Pharmacol Sci. 2006;10(2):61-8.

274

325. Salpietro CD, Gangemi S, Briuglia S, Meo A, Merlino MV, Muscolino G, et al. The almond milk: a new approach to the management of cow-milk allergy/intolerance in infants. Minerva Pediatr. 2005;57(4):173-80. 326. Viljanen M SE, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, Tuure T, Kuitunen M. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy. 2005;60(4):494-500. 327. Kukuruzovic RH, Elliott EE, O'Loughlin EV, Markowitz JE. Non-surgical interventions for eosinophilic oesophagitis. 2004(3):CD004065. 328. Jarvinen KM, Sicherer SH, Sampson HA, Nowak-Wegrzyn A. Use of multiple doses of epinephrine in food-induced anaphylaxis in children. J Allergy Clin Immunol. 2008;122(1):133-8. 329. de Silva IL, Mehr SS, Tey D, Tang ML. Paediatric anaphylaxis: a 5 year retrospective review. Allergy. 2008;63(8):1071-6. 330. Pouessel G, Deschildre A, Castelain C, Sardet A, Sagot-Bevenot S, de Sauve-Boeuf A, et al. Parental knowledge and use of epinephrine auto-injector for children with food allergy. Pediatr Allergy Immunol. 2006;17(3):221-6. 331. Warrier PC, T. B. Omalizumab in idiopathic anaphylaxis. Ann Allergy Asthma Immunol. 2009 Mar;102(3):257-8. 332. de Jong MH, Scharp-Van Der Linden VT, Aalberse R, Heymans HS, Brunekreef B. The effect of brief neonatal exposure to cows' milk on atopic symptoms up to age 5. Arch Dis Child. 2002;86(5):365-9. 333. Jirapinyo P, Densupsoontorn N, Wongarn R, Thamonsiri N. Comparisons of a chicken-based formula with soy-based formula in infants with cow milk allergy. Asia Pac J Clin Nutr. 2007;16(4):711-5. 334. de Jong MH, Scharp-van der Linden VT, Aalberse RC, Oosting J, Tijssen JG, de Groot CJ. Randomised controlled trial of brief neonatal exposure to cows' milk on the development of atopy. Arch Dis Child. 1998;79(2):126-30. 335. Iacono G, Cavataio F, Montalto G, Florena A, Tumminello M, Soresi M, et al. Intolerance of cow's milk and chronic constipation in children. N Engl J Med. 1998;339(16):1100-4. 336. Niggemann B, von Berg A, Bollrath C, Berdel D, Schauer U, Rieger C, et al. Safety and efficacy of a new extensively hydrolyzed formula for infants with cow's milk protein allergy. Pediatr Allergy Immunol. 2008;19(4):348-54.

275

337. Garzi A, Messina M, Frati F, Carfagna L, Zagordo L, Belcastro M, et al. An extensively hydrolysed cow's milk formula improves clinical symptoms of gastroesophageal reflux and reduces the gastric emptying time in infants. Allergol Immunopathol (Madr). 2002;30(1):36-41. 338. Vita D, Passalacqua G, Di Pasquale G, Caminiti L, Crisafulli G, Rulli I, et al. Ass's milk in children with atopic dermatitis and cow's milk allergy: crossover comparison with goat's milk. Pediatr Allergy Immunol. 2007;18(7):594-8. 339. Lindfors AT, Danielsson L, Enocksson E, Johansson SG, Westin S. Allergic symptoms up to 4-6 years of age in children given cow milk neonatally. A prospective study. Allergy. 1992;47(3):207-11. 340. Savino F, Castagno E, Monti G, Serraino P, Peltran A, Oggero R, et al. Z-score of weight for age of infants with atopic dermatitis and cow's milk allergy fed with a rice-hydrolysate formula during the first two years of life. Acta Paediatr Suppl. 2005;94(449):115-9. 341. Herrmann ME, Dannemann A, Gruters A, Radisch B, Dudenhausen JW, Bergmann R, et al. Prospective study of the atopy preventive effect of maternal avoidance of milk and eggs during pregnancy and lactation. 1996;155(9):770-4. 342. Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009. 343. Hansen KS, Ballmer-Weber BK, Luttkopf D, Skov PS, Wuthrich B, Bindslev-Jensen C, et al. Roasted hazelnuts--allergenic activity evaluated by double-blind, placebo-controlled food challenge. Allergy. 2003;58(2):132-8. 344. Bergmann KC, Wolf H, Schnitker J. Effect of pollen-specific sublingual immunotherapy on oral allergy syndrome: An observational study. World Allergy Organization Journal. 2008;1(5):79-84. 345. Konikoff MR, Noel RJ, Blanchard C, Kirby C, Jameson SC, Buckmeier BK, et al. A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology. 2006;131(5):1381-91. 346. Liacouras CA, Spergel JM, Ruchelli E, Verma R, Mascarenhas M, Semeao E, et al. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol. 2005;3(12):1198-206. 347. Garioch JJ, Lewis HM, Sargent SA, Leonard JN, Fry L. 25 years' experience of a gluten-free diet in the treatment of dermatitis herpetiformis. 1994;131(4):541-5.

276

348. Bollinger ME, Dahlquist LM, Mudd K, Sonntag C, Dillinger L, McKenna K. The impact of food allergy on the daily activities of children and their families. Ann Allergy Asthma Immunol. 2006;96(3):415-21.

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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 ================================================================

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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:

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(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*)

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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 ================================================================

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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:

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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

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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

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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)

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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:

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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:

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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

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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

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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:

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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]

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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.

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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 ================================================================

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Appendix B: Screening Form

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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.

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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. iAdapted from Cochrane Effective Practice and Organization of Care Review Group, The Data Collection Checklist, Inclusion Criteria.

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Appendix D: Criteria for Assessing the Quality of Studies of Diagnostic Accuracy

Lijmer Criteria for Scoring Study Quality Study Characteristic Score

Clinical population Spectrum Case-control Complete Different reference tests

Verification

Partial Blinded Interpretation of test results Not blinded Consecutive Patient selection Nonconsecutive Prospective Unknown

Data collection

Retrospective Sufficient Details test Insufficient Sufficient Details reference test Insufficient Sufficient Details population 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)

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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

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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.

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STARD checklist for reporting of studies of diagnostic accuracy Section and Topic Item

# On page #

TITLE/ABSTRACT/ KEYWORDS

1 Identify the article as a study of diagnostic accuracy (recommend MeSH heading 'sensitivity and specificity').

INTRODUCTION 2 State the research questions or study aims, such as estimating diagnostic accuracy or comparing accuracy between tests or across participant groups.

METHODS Participants 3 The study population: The inclusion and exclusion criteria, setting and

locations where data were collected. 4 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?

5 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.

6 Data collection: Was data collection planned before the index test and reference standard were performed (prospective study) or after (retrospective study)?

Test methods 7 The reference standard and its rationale. 8 Technical specifications of material and methods involved including how

and when measurements were taken, and/or cite references for index tests and reference standard.

9 Definition of and rationale for the units, cut-offs and/or categories of the results of the index tests and the reference standard.

10 The number, training and expertise of the persons executing and reading the index tests and the reference standard.

11 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.

Statistical methods 12 Methods for calculating or comparing measures of diagnostic accuracy, and the statistical methods used to quantify uncertainty (e.g. 95% confidence intervals).

13 Methods for calculating test reproducibility, if done. RESULTS

Participants 14 When study was performed, including beginning and end dates of recruitment.

15 Clinical and demographic characteristics of the study population (at least information on age, gender, spectrum of presenting symptoms).

16 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).

Test results 17 Time-interval between the index tests and the reference standard, and any treatment administered in between.

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18 Distribution of severity of disease (define criteria) in those with the target condition; other diagnoses in participants without the target condition.

19 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.

20 Any adverse events from performing the index tests or the reference standard.

Estimates 21 Estimates of diagnostic accuracy and measures of statistical uncertainty (e.g. 95% confidence intervals).

22 How indeterminate results, missing data and outliers of the index tests were handled.

23 Estimates of variability of diagnostic accuracy between subgroups of participants, readers or centers, if done.

24 Estimates of test reproducibility, if done. DISCUSSION 25 Discuss the clinical applicability of the study findings.

Reference: http://www.stard-statement.org/

http://www.stard-statement.org/

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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.

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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):1304-10. 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.

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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 Sep;120(3):717-9. 31. Savage JHM, E. C. Skripak, J. M. Wood, R. A. The natural history of egg allergy. J Allergy Clin Immunol. 2007 Dec;120(6):1413-7. 32. Shah UK, Jacobs IN. Pediatric angioedema: ten years' experience. Arch Otolaryngol Head Neck Surg. 1999;125(7):791-5. 33. Shek LP, Soderstrom L, Ahlstedt S, Beyer K, Sampson HA. Determination of food specific IgE levels over time can predict the development of tolerance in cow's milk and hen's egg allergy. J Allergy Clin Immunol. 2004;114(2):387-91. 34. Sicherer SH, Eigenmann PA, Sampson HA. Clinical features of food protein-induced enterocolitis syndrome. J Pediatr. 1998;133(2):214-9. 35. Sicherer SH, Furlong TJ, Munoz-Furlong A, Burks AW, Sampson HA. A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants. J Allergy Clin Immunol. 2001;108(1):128-32. 36. Simonte SJ, Ma S, Mofidi S, Sicherer SH. Relevance of casual contact with peanut butter in children with peanut allergy. J Allergy Clin Immunol. 2003;112(1):180-2. 37. Simpson AB, Glutting J, Yousef E. Food allergy and asthma morbidity in children. Pediatr Pulmonol. 2007;42(6):489-95. 38. Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2007;120(5):1172-7. 39. Spergel JM, Beausoleil JL, Fiedler JM, Ginsberg J, Wagner K, Pawlowski NA. Correlation of initial food reactions to observed reactions on challenges. 2004;92(2):217-24. 40. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R, et al. 14 years of eosinophilic esophagitis: clinical features and prognosis. 2009;48(1):30-6.

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41. Thompson MM, Tofte SJ, Simpson EL, Hanifin JM. Patterns of care and referral in children with atopic dermatitis and concern for food allergy. Dermatol Ther. 2006;19(2):91-6. 42. Vander Leek TK, Liu AH, Stefanski K, Blacker B, Bock SA. The natural history of peanut allergy in young children and its association with serum peanut-specific IgE. 2000;137(6):749-55. 43. Vogel NM, Katz HT, Lopez R, Lang DM. Food allergy is associated with potentially fatal childhood asthma. J Asthma. 2008;45(10):862-6. 44. Zeiger RS, Sampson HA, Bock SA, Burks AW, Jr., Harden K, Noone S, et al. Soy allergy in infants and children with IgE-associated cow's milk allergy. 1999;134(5):614-22.

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Not US/Canada UK/Ireland/Australia/New Zealand 1. Allen CWK, A. S. Campbell, D. E. Dietary advice, dietary adherence and the acquisition of tolerance in egg-allergic children: a 5-yr follow-up. Pediatr Allergy Immunol. 2009 May;20(3):213-8. 2. Arshad SH, Hide DW. Effect of environmental factors on the development of allergic disorders in infancy. J Allergy Clin Immunol. 1992;90(2):235-41. 3. Arshad SH, Tariq SM, Matthews S, Hakim E. Sensitization to common allergens and its association with allergic disorders at age 4 years: a whole population birth cohort study. Pediatrics. 2001;108(2):E33. 4. Bentley SJ, Pearson DJ, Rix KJ. Food hypersensitivity in irritable bowel syndrome. Lancet. 1983;2(8345):295-7. 5. Braganza SC, Acworth JP, McKinnon DR, Peake JE, Brown AF. Paediatric emergency department anaphylaxis: different patterns from adults. Arch Dis Child. 2006;91(2):159-63. 6. Carroccio A, Cavataio F, Montalto G, D'Amico D, Alabrese L, Iacono G. Intolerance to hydrolysed cow's milk proteins in infants: clinical characteristics and dietary treatment. Clin Exp Allergy. 2000;30(11):1597-603. 7. Clark AT, Anagnostou K, Ewan PW. Cashew nut causes more severe reactions than peanut: case-matched comparison in 141 children. Allergy. 2007;62(8):913-6. 8. Clark ATE, P. W. The development and progression of allergy to multiple nuts at different ages. Pediatr Allergy Immunol. 2005 Sep;16(6):507-11. 9. Davoren M, Peake J. Cashew nut allergy is associated with a high risk of anaphylaxis. 2005;90(10):1084-5. 10. de Benedictis FM, Franceschini F, Hill D, Naspitz C, Simons FE, Wahn U, et al. The allergic sensitization in infants with atopic eczema from different countries. Allergy. 2009;64(2):295-303. 11. de Silva IL, Mehr SS, Tey D, Tang ML. Paediatric anaphylaxis: a 5 year retrospective review. Allergy. 2008;63(8):1071-6. 12. Dean T, Venter C, Pereira B, Arshad SH, Grundy J, Clayton CB, et al. Patterns of sensitization to food and aeroallergens in the first 3 years of life. J Allergy Clin Immunol. 2007;120(5):1166-71.

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13. Dias RP, Summerfield A, Khakoo GA. Food hypersensitivity among Caucasian and non-Caucasian children. 2008;19(1):86-9. 14. Du Toit G, Katz Y, Sasieni P, Mesher D, Maleki SJ, Fisher HR, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008;122(5):984-91. 15. Ewan PW. Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations. BMJ. 1996;312(7038):1074-8. 16. Firer MA, Hosking CS, Hill DJ. Possible role for rotavirus in the development of cows' milk enteropathy in infants. Clin Allergy. 1988;18(1):53-61. 17. Fox ATS, P. du Toit, G. Syed, H. Lack, G. Household peanut consumption as a risk factor for the development of peanut allergy. J Allergy Clin Immunol. 2009 Feb;123(2):417-23. 18. Grundy J, Matthews S, Bateman B, Dean T, Arshad SH. Rising prevalence of allergy to peanut in children: Data from 2 sequential cohorts. J Allergy Clin Immunol. 2002;110(5):784-9. 19. Gupta R, Sheikh A, Strachan DP, Anderson HR. Burden of allergic disease in the UK: secondary analyses of national databases. Clin Exp Allergy. 2004;34(4):520-6. 20. Hardman CM, Garioch JJ, Leonard JN, Thomas HJ, Walker MM, Lortan JE, et al. Absence of toxicity of oats in patients with dermatitis herpetiformis. 1997;337(26):1884-7. 21. Hill DJ, Firer MA, Ball G, Hosking CS. Natural history of cows' milk allergy in children: immunological outcome over 2 years. Clin Exp Allergy. 1993;23(2):124-31. 22. Hill DJ, Heine RG, Hosking CS, Brown J, Thiele L, Allen KJ, et al. IgE food sensitization in infants with eczema attending a dermatology department. 2007;151(4):359-63. 23. Hill DJ, Hosking CS. Food allergy and atopic dermatitis in infancy: an epidemiologic study. 2004;15(5):421-7. 24. Hill DJ, Hosking CS, de Benedictis FM, Oranje AP, Diepgen TL, Bauchau V. Confirmation of the association between high levels of immunoglobulin E food sensitization and eczema in infancy: an international study. 2008;38(1):161-8. 25. Hill SM, Milla PJ. Colitis caused by food allergy in infants. Arch Dis Child. 1990;65(1):132-3. 26. Ho MH, Wong WH, Heine RG, Hosking CS, Hill DJ, Allen KJ. Early clinical

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predictors of remission of peanut allergy in children. J Allergy Clin Immunol. 2008;121(3):731-6. 27. Hourihane J, Kilburn S, et al. An evaluation of the sensitivity of subjects with peanut allergy to very low doses of peanut protein: a randomized, double-blind, placebo-controlled food challenge study. J Allergy Clin Immunol. 1997;100(5):596-600. 28. Hourihane JO, Roberts SA, Warner JO. Resolution of peanut allergy: case-control study. BMJ. 1998;316(7140):1271-5. 29. Hourihane JOA, R. Briggs, R. Gudgeon, L. A. Grimshaw, K. E. DunnGalvin, A. Roberts, S. R. The impact of government advice to pregnant mothers regarding peanut avoidance on the prevalence of peanut allergy in United Kingdom children at school entry. J Allergy Clin Immunol. 2007 May;119(5):1197-202. 30. Kemeny DM, Price JF, Richardson V, Richards D, Lessof MH. The IgE and IgG subclass antibody response to foods in babies during the first year of life and their relationship to feeding regimen and the development of food allergy. 1991;87(5):920-9. 31. Kljakovic MG, P. Hawkins, C. Attewell, R. G. Ciszek, K. Kratochvil, G. Moreira, A. Ponsonby, A. L. The parent-reported prevalence and management of peanut and nut allergy in school children in the Australian Capital Territory. J Paediatr Child Health. 2009 Mar;45(3):98-103. 32. Lack G, Fox D, Northstone K, Golding J. Factors associated with the development of peanut allergy in childhood. 2003;348(11):977-85. 33. Macdougall CF, Cant AJ, Colver AF. How dangerous is food allergy in childhood? The incidence of severe and fatal allergic reactions across the UK and Ireland. Arch Dis Child. 2002;86(4):236-9. 34. Marinho S, Simpson A, Soderstrom L, Woodcock A, Ahlstedt S, Custovic A. Quantification of atopy and the probability of rhinitis in preschool children: a population-based birth cohort study. Allergy. 2007;62(12):1379-86. 35. McGowan M, Gibney MJ. Calcium intakes in individuals on diets for the management of cows' milk allergy: a case control study. 1993;47(9):609-16. 36. Mehr S, Kakakios A, Frith K, Kemp AS. Food protein-induced enterocolitis syndrome: 16-year experience. Pediatrics. 2009;123(3):e459-64. 37. Mehr SS, Kakakios AM, Kemp AS. Rice: a common and severe cause of food protein-induced enterocolitis syndrome. Arch Dis Child. 2009;94(3):220-3. 38. Mullins RJ. Anaphylaxis: risk factors for recurrence. Clin Exp Allergy. 2003;33(8):1033-40.

309

39. Ooi CY, Day AS, Jackson R, Bohane TD, Tobias V, Lemberg DA. Eosinophilic esophagitis in children with celiac disease. 2008;23(7 Pt 1):1144-8. 40. Peng MM, Jick H. A population-based study of the incidence, cause, and severity of anaphylaxis in the United Kingdom. 2004;164(3):317-9. 41. Pereira B, Venter C, Grundy J, Clayton CB, Arshad SH, Dean T. Prevalence of sensitization to food allergens, reported adverse reaction to foods, food avoidance, and food hypersensitivity among teenagers. 2005;116(4):884-92. 42. Poulos LM, Waters AM, Correll PK, Loblay RH, Marks GB. Trends in hospitalizations for anaphylaxis, angioedema, and urticaria in Australia, 1993-1994 to 2004-2005. J Allergy Clin Immunol. 2007;120(4):878-84. 43. Rennick GJ, Moore E, Orchard DC. Skin prick testing to food allergens in breast-fed young infants with moderate to severe atopic dermatitis. 2006;47(1):41-5. 44. Roberts G, Golder N, Lack G. Bronchial challenges with aerosolized food in asthmatic, food-allergic children. 2002;57(8):713-7. 45. Roberts G, Patel N, Levi-Schaffer F, Habibi P, Lack G. Food allergy as a risk factor for life-threatening asthma in childhood: a case-controlled study. J Allergy Clin Immunol. 2003;112(1):168-74. 46. Roberts GP, C. Northstone, K. Strachan, D. Lack, G. Henderson, J. Golding, J. Relationship between aeroallergen and food allergen sensitization in childhood. Clin Exp Allergy. 2005 Jul;35(7):933-40. 47. Senna G, Mistrello G, Roncarolo D, Crivellaro M, Bonadonna P, Schiappoli M, et al. Exercise-induced anaphylaxis to grape. 2001;56(12):1235-6. 48. Sugnanam KK, Collins JT, Smith PK, Connor F, Lewindon P, Cleghorn G, et al. Dichotomy of food and inhalant allergen sensitization in eosinophilic esophagitis. Allergy. 2007;62(11):1257-60. 49. Summers CW, Pumphrey RS, Woods CN, McDowell G, Pemberton PW, Arkwright PD. Factors predicting anaphylaxis to peanuts and tree nuts in patients referred to a specialist center. J Allergy Clin Immunol. 2008;121(3):632-8.e2. 50. Tariq SM, Matthews SM, Hakim EA, Arshad SH. Egg allergy in infancy predicts respiratory allergic disease by 4 years of age. 2000;11(3):162-7. 51. van Asperen PP, Kemp AS. The natural history of IgE sensitisation and atopic disease in early childhood. Acta Paediatr Scand. 1989;78(2):239-45.

310

52. Venter C, Pereira B, Grundy J, Clayton CB, Arshad SH, Dean T. Prevalence of sensitization reported and objectively assessed food hypersensitivity amongst six-year-old children: a population-based study. 2006;17(5):356-63. 53. Venter C, Pereira B, Grundy J, Clayton CB, Roberts G, Higgins B, et al. Incidence of parentally reported and clinically diagnosed food hypersensitivity in the first year of life. 2006;117(5):1118-24. 54. Venter C, Pereira B, Voigt K, Grundy J, Clayton CB, Higgins B, et al. Prevalence and cumulative incidence of food hypersensitivity in the first 3 years of life. Allergy. 2008;63(3):354-9. 55. Watura JC. Nut allergy in schoolchildren: a survey of schools in the Severn NHS Trust. 2002;86(4):240-4. 56. Woods RK, Stoney RM, Raven J, Walters EH, Abramson M, Thien FC. Reported adverse food reactions overestimate true food allergy in the community. Eur J Clin Nutr. 2002;56(1):31-6. 57. Woods RK, Thien F, Raven J, Walters EH, Abramson M. Prevalence of food allergies in young adults and their relationship to asthma, nasal allergies, and eczema. Ann Allergy Asthma Immunol. 2002;88(2):183-9. 58. Young E, Stoneham MD, Petruckevitch A, Barton J, Rona R. A population study of food intolerance. 1994;343(8906):1127-30. Scandinavia/Europe 1. Agne PS, Bidat E, Rance F, Paty E. Sesame seed allergy in children. Eur Ann Allergy Clin Immunol. 2004;36(8):300-5. 2. Aleman A, Sastre J, Quirce S, de las Heras M, Carnes J, Fernandez-Caldas E, et al. Allergy to kiwi: a double-blind, placebo-controlled food challenge study in patients from a birch-free area. J Allergy Clin Immunol. 2004;113(3):543-50. 3. Almqvist C, Pershagen G, Wickman M. Low socioeconomic status as a risk factor for asthma, rhinitis and sensitization at 4 years in a birth cohort. Clin Exp Allergy. 2005;35(5):612-8. 4. Alvarado MI, Perez M. Study of food allergy in the Spanish population. Allergol Immunopathol (Madr). 2006;34(5):185-93. 5. Andre F, Andre C, Cavagna S. Oral food challenge increases in vitro IL-4 production by peripheral blood mononuclear cells in allergic patients. 1998;18(6):369-75.

311

6. Anveden-Hertzberg L, Finkel Y, Sandstedt B, Karpe B. Proctocolitis in exclusively breast-fed infants. 1996;155(6):464-7. 7. Armisen Pedrejon A, Sancho Madrid B, Almaraz Garzon E, Prieto Bozano G, Polanco Allue I. [Colitis induced by a food allergen. A report of 20 cases]. An Esp Pediatr. 1996;44(1):21-4. 8. Arvola T, Ruuska T, Keranen J, Hyoty H, Salminen S, Isolauri E. Rectal bleeding in infancy: clinical, allergological, and microbiological examination. Pediatrics. 2006;117(4):e760-8. 9. Asero R. Detection and clinical characterization of patients with oral allergy syndrome caused by stable allergens in Rosaceae and nuts. 1999;83(5):377-83. 10. Asero R, Monsalve R, Barber D. Profilin sensitization detected in the office by skin prick test: a study of prevalence and clinical relevance of profilin as a plant food allergen. Clin Exp Allergy. 2008;38(6):1033-7. 11. Baehler P, Chad Z, Gurbindo C, Bonin AP, Bouthillier L, Seidman EG. Distinct patterns of cow's milk allergy in infancy defined by prolonged, two-stage double-blind, placebo-controlled food challenges. Clin Exp Allergy. 1996;26(3):254-61. 12. Bakos N, Scholl I, Szalai K, Kundi M, Untersmayr E, Jensen-Jarolim E. Risk assessment in elderly for sensitization to food and respiratory allergens. 2006;107(1):15-21. 13. Ballmer-Weber BK, Holzhauser T, Scibilia J, Mittag D, Zisa G, Ortolani C, et al. Clinical characteristics of soybean allergy in Europe: a double-blind, placebo-controlled food challenge study. J Allergy Clin Immunol. 2007;119(6):1489-96. 14. Bardella MT, Fredella C, Saladino V, Trovato C, Cesana BM, Quatrini M, et al. Gluten intolerance: gender- and age-related differences in symptoms. 2005;40(1):15-9. 15. Bengtsson U, Nilsson-Balknas U, Hanson LA, Ahlstedt S. Double blind, placebo controlled food reactions do not correlate to IgE allergy in the diagnosis of staple food related gastrointestinal symptoms. 1996;39(1):130-5. 16. Bergmann RL, Edenharter G, Bergmann KE, Guggenmoos-Holzmann I, Forster J, Bauer CP, et al. Predictability of early atopy by cord blood-IgE and parental history. Clin Exp Allergy. 1997;27(7):752-60. 17. Bischoff SC, Herrmann A, Manns MP. Prevalence of adverse reactions to food in patients with gastrointestinal disease. 1996;51(11):811-8. 18. Bjornsson E, Janson C, Plaschke P, Norrman E, Sjoberg O. Prevalence of sensitization to food allergens in adult Swedes. 1996;77(4):327-32.

312

19. Blanco C, Carrillo T, Castillo R, Quiralte J, Cuevas M. Avocado hypersensitivity. Allergy. 1994;49(6):454-9. 20. Boyano-Martinez T, Garcia-Ara C, Diaz-Pena JM, Martin-Esteban M. Prediction of tolerance on the basis of quantification of egg white-specific IgE antibodies in children with egg allergy. 2002;110(2):304-9. 21. Breuer K, Heratizadeh A, Wulf A, Baumann U, Constien A, Tetau D, et al. Late eczematous reactions to food in children with atopic dermatitis. 2004;34(5):817-24. 22. Brockow IZ, A. Hoffmann, U. Grubl, A. von Berg, A. Koletzko, S. Filipiak, B. Bauer, C. P. Wichmann, H. E. Reinhardt, D. Berdel, D. Kramer, U. Heinrich, J. Early allergic sensitizations and their relevance to atopic diseases in children aged 6 years: results of the GINI study. J Investig Allergol Clin Immunol. 2009;19(3):180-7. 23. Bruni FM, Piacentini GL, Peroni DG, Bodini A, Fasoli E, Boner AL. Cow's milk allergic children can present sensitisation to probiotics. 2009;98(2):321-3. 24. Bruno G, Giampietro PG, Del Guercio MJ, Gallia P, Giovannini L, Lovati C, et al. Soy allergy is not common in atopic children: a multicenter study. Pediatr Allergy Immunol. 1997;8(4):190-3. 25. Caffarelli C, Cavagni G, Giordano S, Stapane I, Rossi C. Relationship between oral challenges with previously uningested egg and egg-specific IgE antibodies and skin prick tests in infants with food allergy. 1995;95(6):1215-20. 26. Cantani A, Micera M. Natural history of cow's milk allergy. An eight-year follow-up study in 115 atopic children. 2004;8(4):153-64. 27. Castillo R, Delgado J, Quiralte J, Blanco C, Carrillo T. Food hypersensitivity among adult patients: epidemiological and clinical aspects. Allergol Immunopathol (Madr). 1996;24(3):93-7. 28. Cianferoni A, Novembre E, Mugnaini L, Lombardi E, Bernardini R, Pucci N, et al. Clinical features of acute anaphylaxis in patients admitted to a university hospital: an 11-year retrospective review (1985-1996). Ann Allergy Asthma Immunol. 2001;87(1):27-32. 29. Ciprandi G, Canonica GW. Incidence of digestive diseases in patients with adverse reactions to foods. Ann Allergy. 1988;61(5):334-6. 30. Collin P, Reunala T, Rasmussen M, Kyronpalo S, Pehkonen E, Laippala P, et al. High incidence and prevalence of adult coeliac disease. Augmented diagnostic approach. 1997;32(11):1129-33.

313

31. Colver AF, Nevantaus H, Macdougall CF, Cant AJ. Severe food-allergic reactions in children across the UK and Ireland, 1998-2000. Acta Paediatr. 2005;94(6):689-95. 32. Corrado G, Luzzi I, Lucarelli S, Frediani T, Pacchiarotti C, Cavaliere M, et al. Positive association between Helicobacter pylori infection and food allergy in children. 1998;33(11):1135-9. 33. Crespo JF, Pascual C, Burks AW, Helm RM, Esteban MM. Frequency of food allergy in a pediatric population from Spain. 1995;6(1):39-43. 34. Crespo JF, Pascual C, Dominguez C, Ojeda I, Munoz FM, Esteban MM. Allergic reactions associated with airborne fish particles in IgE-mediated fish hypersensitive patients. Allergy. 1995;50(3):257-61. 35. Crespo JF, Rodriguez J, James JM, Daroca P, Reano M, Vives R. Reactivity to potential cross-reactive foods in fruit-allergic patients: implications for prescribing food avoidance. 2002;57(10):946-9. 36. Cuesta-Herranz J, Lazaro M, de las Heras M, Lluch M, Figueredo E, Umpierrez A, et al. Peach allergy pattern: experience in 70 patients. Allergy. 1998;53(1):78-82. 37. Czarnecka-Operacz M, Jenerowicz D, Silny W. Oral allergy syndrome in patients with airborne pollen allergy treated with specific immunotherapy. Acta Dermatovenerol Croat. 2008;16(1):19-24. 38. de Benedictis FM, Franceschini F, Hill D, Naspitz C, Simons FE, Wahn U, et al. The allergic sensitization in infants with atopic eczema from different countries. Allergy. 2009;64(2):295-303. 39. de Boissieu D, Dupont C. Time course of allergy to extensively hydrolyzed cow's milk proteins in infants. J Pediatr. 2000;136(1):119-20. 40. de la Cuesta CG, Garcia BE, Cordoba H, Dieguez I, Oehling A. Food allergy to Helix terrestre (snail). Allergol Immunopathol (Madr). 1989;17(6):337-9. 41. de Martino M, Donzelli GP, Galli L, Scarano E, de Marco A, Rapisardi G, et al. Food allergy in preterm infants fed human milk. Biol Neonate. 1989;56(6):301-5. 42. de Martino M, Novembre E, Galli L, de Marco A, Botarelli P, Marano E, et al. Allergy to different fish species in cod-allergic children: in vivo and in vitro studies. J Allergy Clin Immunol. 1990;86(6 Pt 1):909-14. 43. de Martino M, Peruzzi M, de Luca M, Amato AG, Galli L, Lega L, et al. Fish allergy in children. Ann Allergy. 1993;71(2):159-65. 44. De Swert LF, Cadot P, Ceuppens JL. Allergy to cooked white potatoes in infants

314

and young children: A cause of severe, chronic allergic disease. 2002;110(3):524-35. 45. Dominguez C, Ojeda I, Crespo JF, Pascual C, Ojeda A, Martin-Esteban M. Allergic reactions following skin contact with fish. Allergy Asthma Proc. 1996;17(2):83-7. 46. Drisko J, Bischoff B, Hall M, McCallum R. Treating irritable bowel syndrome with a food elimination diet followed by food challenge and probiotics. J Am Coll Nutr. 2006;25(6):514-22. 47. Duchen K, Einarsson R, Grodzinsky E, Hattevig G, Bjorksten B. Development of IgG1 and IgG4 antibodies against beta-lactoglobulin and ovalbumin in healthy and atopic children. 1997;78(4):363-8. 48. Eggesbo M, Botten G, Halvorsen R, Magnus P. The prevalence of allergy to egg: a population-based study in young children. 2001;56(5):403-11. 49. Eggesbo M, Botten G, Halvorsen R, Magnus P. The prevalence of CMA/CMPI in young children: the validity of parentally perceived reactions in a population-based study. Allergy. 2001;56(5):393-402. 50. Ehlers I, Niggemann B, Binder C, Zuberbier T. Role of nonallergic hypersensitivity reactions in children with chronic urticaria. Allergy. 1998;53(11):1074-7. 51. Eigenmann PA, Calza AM. Diagnosis of IgE-mediated food allergy among Swiss children with atopic dermatitis. Pediatr Allergy Immunol. 2000;11(2):95-100. 52. Eller E, Kjaer HF, Host A, Andersen KE, Bindslev-Jensen C. Food allergy and food sensitization in early childhood: results from the DARC cohort. 2009. 53. Eriksson NE, Moller C, Werner S, Magnusson J, Bengtsson U, Zolubas M. Self-reported food hypersensitivity in Sweden, Denmark, Estonia, Lithuania, and Russia. J Investig Allergol Clin Immunol. 2004;14(1):70-9. 54. Figueredo E, Cuesta-Herranz J, De-Miguel J, Lazaro M, Sastre J, Quirce S, et al. Clinical characteristics of melon (Cucumis melo) allergy. Ann Allergy Asthma Immunol. 2003;91(3):303-8. 55. Figueroa J, Blanco C, Dumpierrez AG, Almeida L, Ortega N, Castillo R, et al. Mustard allergy confirmed by double-blind placebo-controlled food challenges: clinical features and cross-reactivity with mugwort pollen and plant-derived foods. Allergy. 2005;60(1):48-55. 56. Fiocchi A, Restani P, Bernardini R, Lucarelli S, Lombardi G, Magazzu G, et al. A hydrolysed rice-based formula is tolerated by children with cow's milk allergy: a multi-

315

centre study. Clin Exp Allergy. 2006;36(3):311-6. 57. Fiocchi A, Terracciano L, Bouygue GR, Veglia F, Sarratud T, Martelli A, et al. Incremental prognostic factors associated with cow's milk allergy outcomes in infant and child referrals: the Milan Cow's Milk Allergy Cohort study. Ann Allergy Asthma Immunol. 2008;101(2):166-73. 58. Flinterman AEK, A. C. Meijer, Y. Bruijnzeel-Koomen, C. A. Pasmans, S. G. Acute allergic reactions in children with AEDS after prolonged cow's milk elimination diets. Allergy. 2006 Mar;61(3):370-4. 59. Fuglsang G, Madsen C, Saval P, Osterballe O. Prevalence of intolerance to food additives among Danish school children. Pediatr Allergy Immunol. 1993;4(3):123-9. 60. Garcia Ara MC, Boyano Martinez MT, Diaz Pena JM, Martin Munoz F, Pascual Marcos C, Garcia Sanchez G, et al. [Incidence of allergy to cow's milk protein in the first year of life and its effect on consumption of hydrolyzed formulae]. An Pediatr (Barc). 2003;58(2):100-5. 61. Garcia C, El-Qutob D, Martorell A, Febrer I, Rodriguez M, Cerda JC, et al. Sensitization in early age to food allergens in children with atopic dermatitis. 2007;35(1):15-20. 62. Germano P, Pezzini A, Boccagni P, Zanoni G, Tridente G. Specific humoral response to cows' milk proteins and ovalbumin in children with atopic dermatitis. 1993;23(4):206-11. 63. Ghisolfi J, Olives JP, Le Tallec C, Cohen J, Ser N. [Milk feeding of infants and cow's milk protein hypersensitivity]. 1995;2(6):526-31. 64. Guillet G, Guillet MH. Natural history of sensitizations in atopic dermatitis. A 3-year follow-up in 250 children: food allergy and high risk of respiratory symptoms. 1992;128(2):187-92. 65. Guillet MH, Guillet G. [Allergologic survey in 251 patients with moderate or severe dermatitis. Incidence and value of the detection of contact eczema, food allergy or sensitization to air-borne allergens]. 1996;123(3):157-64. 66. Gustafsson D, Lowhagen T, Andersson K. Risk of developing atopic disease after early feeding with cows' milk based formula. Arch Dis Child. 1992;67(8):1008-10. 67. Gustafsson D, Sjoberg O, Foucard T. Development of allergies and asthma in infants and young children with atopic dermatitis--a prospective follow-up to 7 years of age. 2000;55(3):240-5. 68. Gustafsson D, Sjoberg O, Foucard T. Sensitization to food and airborne allergens

316

in children with atopic dermatitis followed up to 7 years of age. Pediatr Allergy Immunol. 2003;14(6):448-52. 69. Hidvegi E, Cserhati E, Kereki E, Savilahti E, Arato A. Serum immunoglobulin E, IgA, and IgG antibodies to different cow's milk proteins in children with cow's milk allergy: association with prognosis and clinical manifestations. Pediatr Allergy Immunol. 2002;13(4):255-61. 70. Hill DJ, Hosking CS, de Benedictis FM, Oranje AP, Diepgen TL, Bauchau V. Confirmation of the association between high levels of immunoglobulin E food sensitization and eczema in infancy: an international study. 2008;38(1):161-8. 71. Host A, Halken S, Jacobsen HP, Christensen AE, Herskind AM, Plesner K. Clinical course of cow's milk protein allergy/intolerance and atopic diseases in childhood. Pediatr Allergy Immunol. 2002;13 Suppl 15:23-8. 72. Host A, Husby S, Osterballe O. A prospective study of cow's milk allergy in exclusively breast-fed infants. Incidence, pathogenetic role of early inadvertent exposure to cow's milk formula, and characterization of bovine milk protein in human milk. Acta Paediatr Scand. 1988;77(5):663-70. 73. Iacono G, Carroccio A, Cavataio F, Montalto G, Cantarero MD, Notarbartolo A. Chronic constipation as a symptom of cow milk allergy. 1995;126(1):34-9. 74. Iacono G, Cavataio F, Montalto G, Soresi M, Notarbartolo A, Carroccio A. Persistent cow's milk protein intolerance in infants: the changing faces of the same disease. Clin Exp Allergy. 1998;28(7):817-23. 75. Isolauri E, Virtanen E, Jalonen T, Arvilommi H. Local immune response measured in blood lymphocytes reflects the clinical reactivity of children with cow's milk allergy. Pediatr Res. 1990;28(6):582-6. 76. Jarisch R, Beringer K, Hemmer W. Role of food allergy and food intolerance in recurrent urticaria. Curr Probl Dermatol. 1999;28:64-73. 77. Jarvinen KM, Aro A, Juntunen-Backman K, Suomalainen H. Large number of CD19+/CD23+ B cells and small number of CD8+ T cells as early markers for cow's milk allergy (CMA). 1998;9(3):139-42. 78. Jarvinen KM, Laine ST, Jarvenpaa AL, Suomalainen HK. Does low IgA in human milk predispose the infant to development of cow's milk allergy? Pediatr Res. 2000;48(4):457-62. 79. Jarvinen KM, Turpeinen M, Suomalainen H. Concurrent cereal allergy in children with cow's milk allergy manifested with atopic dermatitis. 2003;33(8):1060-6.

317

80. Jesenak M, Rennerova Z, Babusikova E, Havlicekova Z, Jakusova L, Villa MP, et al. Food allergens and respiratory symptoms. 2008;59 Suppl 6:311-20. 81. Juvonen P, Mansson M, Andersson C, Jakobsson I. Allergy development and macromolecular absorption in infants with different feeding regimens during the first three days of life. A three-year prospective follow-up. Acta Paediatr. 1996;85(9):1047-52. 82. Kaczmarski M, Kurzatkowska B. The contribution of some constitutional factors to the development of cow's milk and gluten intolerance in children. 1988;33-34:167-76. 83. Kaczmarski M, Kurzatkowska B. The contribution of some environmental factors to the development of cow's milk and gluten intolerance in children. Rocz Akad Med Bialymst. 1988;33-34:151-65. 84. Kaeser P, Revelly ML, Frei PC. Prevalence of IgE antibodies specific for food allergens in patients with chronic urticaria of unexplained etiology. Allergy. 1994;49(8):626-9. 85. Kanny G, Moneret-Vautrin DA, Flabbee J, Beaudouin E, Morisset M, Thevenin F. Population study of food allergy in France. J Allergy Clin Immunol. 2001;108(1):133-40. 86. Kapel N, Matarazzo P, Haouchine D, Abiola N, Guerin S, Magne D, et al. Fecal tumor necrosis factor alpha, eosinophil cationic protein and IgE levels in infants with cow's milk allergy and gastrointestinal manifestations. 1999;37(1):29-32. 87. Kaukinen K, Turjanmaa K, Maki M, Partanen J, Venalainen R, Reunala T, et al. Intolerance to cereals is not specific for coeliac disease. 2000;35(9):942-6. 88. Kihlstrom A, Lilja G, Pershagen G, Hedlin G. Exposure to high doses of birch pollen during pregnancy, and risk of sensitization and atopic disease in the child. Allergy. 2003;58(9):871-7. 89. Kokkonen J, Haapalahti M, Laurila K, Karttunen TJ, Maki M. Cow's milk protein-sensitive enteropathy at school age. 2001;139(6):797-803. 90. Kulig M, Bergmann R, Tacke U, Wahn U, Guggenmoos-Holzmann I. Long-lasting sensitization to food during the first two years precedes allergic airway disease. The MAS Study Group, Germany. Pediatr Allergy Immunol. 1998;9(2):61-7. 91. Kull I, Wickman M, Lilja G, Nordvall SL, Pershagen G. Breast feeding and allergic diseases in infants-a prospective birth cohort study. Arch Dis Child. 2002;87(6):478-81. 92. Kummeling I, Thijs C, Huber M, van de Vijver LP, Snijders BE, Penders J, et al.

318

Consumption of organic foods and risk of atopic disease during the first 2 years of life in the Netherlands. Br J Nutr. 2008;99(3):598-605. 93. Kvenshagen B, Halvorsen R, Jacobsen M. Adverse reactions to milk in infants. Acta Paediatr. 2008;97(2):196-200. 94. Laubereau B, Filipiak-Pittroff B, von Berg A, Grubl A, Reinhardt D, Wichmann HE, et al. Caesarean section and gastrointestinal symptoms, atopic dermatitis, and sensitisation during the first year of life. Arch Dis Child. 2004;89(11):993-7. 95. Le TM, Lindner TM, Pasmans SG, Guikers CL, van Hoffen E, Bruijnzeel-Koomen CA, et al. Reported food allergy to peanut, tree nuts and fruit: comparison of clinical manifestations, prescription of medication and impact on daily life. Allergy. 2008;63(7):910-6. 96. Legrain V, Taieb A, Maleville J. [Epidemiology of urticaria in infants]. Allerg Immunol (Paris). 1993;25(8):324-6. 97. Lindfors A, Enocksson E. Development of atopic disease after early administration of cow milk formula. Allergy. 1988;43(1):11-6. 98. Malanin G, Kalimo K. The results of skin testing with food additives and the effect of an elimination diet in chronic and recurrent urticaria and recurrent angioedema. Clin Exp Allergy. 1989;19(5):539-43. 99. Malinowska E, Kaczmarski M, Wasilewska J. Total IgE levels and skin test results in children under three years of age with food hypersensitivity. 2002;8(4):CR280-7. 100. Marklund B, Ahlstedt S, Nordstrom G. Health-related quality of life among adolescents with allergy-like conditions - with emphasis on food hypersensitivity. Health Qual Life Outcomes. 2004;2:65. 101. Marklund B, Ahlstedt S, Nordstrom G. Health-related quality of life in food hypersensitive schoolchildren and their families: parents' perceptions. Health Qual Life Outcomes. 2006;4:48. 102. Martinez San Ireneo M, Ibanez MD, Sanchez JJ, Carnes J, Fernandez-Caldas E. Clinical features of legume allergy in children from a Mediterranean area. 2008;101(2):179-84. 103. Martorell A, Garcia Ara MC, Plaza AM, Bone J, Nevot S, Echeverria L, et al. The predictive value of specific immunoglobulin E levels in serum for the outcome of the development of tolerance in cow's milk allergy. Allergol Immunopathol (Madr). 2008;36(6):325-30.

319

104. Martorell A, Plaza AM, Bone J, Nevot S, Garcia Ara MC, Echeverria L, et al. Cow's milk protein allergy. A multi-centre study: clinical and epidemiological aspects. Allergol Immunopathol (Madr). 2006;34(2):46-53. 105. Matricardi PM, Bockelbrink A, Beyer K, Keil T, Niggemann B, Gruber C, et al. Primary versus secondary immunoglobulin E sensitization to soy and wheat in the Multi-Centre Allergy Study cohort. Clin Exp Allergy. 2008;38(3):493-500. 106. Mattila L, Kilpelainen M, Terho EO, Koskenvuo M, Helenius H, Kalimo K. Food hypersensitivity among Finnish university students: association with atopic diseases. Clin Exp Allergy. 2003;33(5):600-6. 107. Mehl A, Wahn U, Niggemann B. Anaphylactic reactions in children--a questionnaire-based survey in Germany. Allergy. 2005;60(11):1440-5. 108. Moneret-Vautrin DA, Rance F, Kanny G, Olsewski A, Gueant JL, Dutau G, et al. Food allergy to peanuts in France--evaluation of 142 observations. Clin Exp Allergy. 1998;28(9):1113-9. 109. Morisset M, Moneret-Vautrin DA, Kanny G, Guenard L, Beaudouin E, Flabbee J, et al. Thresholds of clinical reactivity to milk, egg, peanut and sesame in immunoglobulin E-dependent allergies: evaluation by double-blind or single-blind placebo-controlled oral challenges. Clin Exp Allergy. 2003;33(8):1046-51. 110. Morisset M, Moneret-Vautrin DA, Maadi F, Fremont S, Guenard L, Croizier A, et al. Prospective study of mustard allergy: first study with double-blind placebo-controlled food challenge trials (24 cases). Allergy. 2003;58(4):295-9. 111. Mortureux P, Leaute-Labreze C, Legrain-Lifermann V, Lamireau T, Sarlangue J, Taieb A. Acute urticaria in infancy and early childhood: a prospective study. Arch Dermatol. 1998;134(3):319-23. 112. Mortz CG, Andersen KE, Bindslev-Jensen C. The prevalence of peanut sensitization and the association to pollen sensitization in a cohort of unselected adolescents--The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis (TOACS). Pediatr Allergy Immunol. 2005;16(6):501-6. 113. Muhlemann RJ, Wuthrich B. [Food allergies 1983-1987]. Schweiz Med Wochenschr. 1991;121(46):1696-700. 114. Nettis E, Colanardi MC, Ferrannini A, Tursi A. Suspected tartrazine-induced acute urticaria/angioedema is only rarely reproducible by oral rechallenge. Clin Exp Allergy. 2003;33(12):1725-9. 115. Nettis E, Colanardi MC, Ferrannini A, Tursi A. Sodium benzoate-induced repeated episodes of acute urticaria/angio-oedema: randomized controlled trial. Br J

320

Dermatol. 2004;151(4):898-902. 116. Nickel R, Kulig M, Forster J, Bergmann R, Bauer CP, Lau S, et al. Sensitization to hen's egg at the age of twelve months is predictive for allergic sensitization to common indoor and outdoor allergens at the age of three years. J Allergy Clin Immunol. 1997;99(5):613-7. 117. Norgaard A, Bindslev-Jensen C. Egg and milk allergy in adults. Diagnosis and characterization. 1992;47(5):503-9. 118. Novembre E, Cianferoni A, Bernardini R, Mugnaini L, Caffarelli C, Cavagni G, et al. Anaphylaxis in children: clinical and allergologic features. Pediatrics. 1998;101(4):E8. 119. Oehling A, Fernandez M, Cordoba H, Sanz ML. Skin manifestations and immunological parameters in childhood food allergy. J Investig Allergol Clin Immunol. 1997;7(3):155-9. 120. Oehling A, Garcia B, Santos F, Cordoba H, Dieguez I, Fernandez M, et al. Food allergy as a cause of rhinitis and/or asthma. J Investig Allergol Clin Immunol. 1992;2(2):78-83. 121. Oldak E. The incidence and clinical manifestation of food allergy in unselected Polish infants: follow-up from birth to one year of age. 1997;42(1):196-204. 122. Ostblom E, Lilja G, Pershagen G, van Hage M, Wickman M. Phenotypes of food hypersensitivity and development of allergic diseases during the first 8 years of life. Clin Exp Allergy. 2008;38(8):1325-32. 123. Ostblom E, Wickman M, van Hage M, Lilja G. Reported symptoms of food hypersensitivity and sensitization to common foods in 4-year-old children. Acta Paediatr. 2008;97(1):85-90. 124. Osterballe M, Hansen TK, Mortz CG, Host A, Bindslev-Jensen C. The prevalence of food hypersensitivity in an unselected population of children and adults. 2005;16(7):567-73. 125. Osterballe M, Mortz CG, Hansen TK, Andersen KE, Bindslev-Jensen C. The Prevalence of food hypersensitivity in young adults. Pediatr Allergy Immunol. 2009. 126. Paajanen L, Korpela R, Tuure T, Honkanen J, Jarvela I, Ilonen J, et al. Cow milk is not responsible for most gastrointestinal immune-like syndromes--evidence from a population-based study. Am J Clin Nutr. 2005;82(6):1327-35. 127. Paranos S, Nikolic G. Antibodies to cow's milk proteins in chronic urticaria. Allergy. 1996;51(4):273-5.

321

128. Pastar Z, Lipozencic J. Adverse reactions to food and clinical expressions of food allergy. Skinmed. 2006;5(3):119-25; quiz 26-7. 129. Pastorello EA, Stocchi L, Pravettoni V, Bigi A, Schilke ML, Incorvaia C, et al. Role of the elimination diet in adults with food allergy. J Allergy Clin Immunol. 1989;84(4 Pt 1):475-83. 130. Patrizi A, Guerrini V, Ricci G, Neri I, Specchia F, Masi M. The natural history of sensitizations to food and aeroallergens in atopic dermatitis: a 4-year follow-Up. 2000;17(4):261-5. 131. Pauli G, Bessot JC, Braun PA, Dietemann-Molard A, Kopferschmitt-Kubler MC, Thierry R. Celery allergy: clinical and biological study of 20 cases. Ann Allergy. 1988;60(3):243-6. 132. Penard-Morand C, Raherison C, Kopferschmitt C, Caillaud D, Lavaud F, Charpin D, et al. Prevalence of food allergy and its relationship to asthma and allergic rhinitis in schoolchildren. Allergy. 2005;60(9):1165-71. 133. Peroni DG, Piacentini GL, Alfonsi L, Zerman L, Di Blasi P, Visona G, et al. Rhinitis in pre-school children: prevalence, association with allergic diseases and risk factors. Clin Exp Allergy. 2003;33(10):1349-54. 134. Peroni DG, Piacentini GL, Bodini A, Rigotti E, Pigozzi R, Boner AL. Prevalence and risk factors for atopic dermatitis in preschool children. Br J Dermatol. 2008;158(3):539-43. 135. Pesonen M, Kallio MJ, Ranki A, Siimes MA. Prolonged exclusive breastfeeding is associated with increased atopic dermatitis: a prospective follow-up study of unselected healthy newborns from birth to age 20 years. 2006;36(8):1011-8. 136. Plaza-Martin AM, Jimenez-Feijoo R, Andaluz C, Giner-Munoz MT, Martin-Mateos MA, Piquer-Gibert M, et al. Polysensitization to aeroallergens and food in eosinophilic esophagitis in a pediatric population. 2007;35(1):35-7. 137. Poikonen S, Puumalainen TJ, Kautiainen H, Burri P, Palosuo T, Reunala T, et al. Turnip rape and oilseed rape are new potential food allergens in children with atopic dermatitis. Allergy. 2006;61(1):124-7. 138. Poikonen S, Puumalainen TJ, Kautiainen H, Palosuo T, Reunala T, Turjanmaa K. Sensitization to turnip rape and oilseed rape in children with atopic dermatitis: a case-control study. Pediatr Allergy Immunol. 2008;19(5):408-11. 139. Poikonen S, Rance F, Puumalainen TJ, Le Manach G, Reunala T, Turjanmaa K. Sensitization and allergy to turnip rape: a comparison between the Finnish and French

322

children with atopic dermatitis. Acta Paediatr. 2009;98(2):310-5. 140. Pumberger W, Pomberger G, Geissler W. Proctocolitis in breast fed infants: a contribution to differential diagnosis of haematochezia in early childhood. 2001;77(906):252-4. 141. Pumphrey RS. Fatal anaphylaxis in the UK, 1992-2001. Novartis Found Symp. 2004;257:116-28; discussion 28-32, 57-60, 276-85. 142. Pyrhonen K, Nayha S, Kaila M, Hiltunen L, Laara E. Occurrence of parent-reported food hypersensitivities and food allergies among children aged 1-4 yr. Pediatr Allergy Immunol. 2009;20(4):328-38. 143. Rance F, Dutau G, Abbal M. Mustard allergy in children. Allergy. 2000;55(5):496-500. 144. Rance F, Grandmottet X, Grandjean H. Prevalence and main characteristics of schoolchildren diagnosed with food allergies in France. Clin Exp Allergy. 2005;35(2):167-72. 145. Rance F, Kanny G, Dutau G, Moneret-Vautrin DA. Food hypersensitivity in children: clinical aspects and distribution of allergens. Pediatr Allergy Immunol. 1999;10(1):33-8. 146. Rautava S, Isolauri E. Cow's milk allergy in infants with atopic eczema is associated with aberrant production of interleukin-4 during oral cow's milk challenge. 2004;39(5):529-35. 147. Reindl J, Anliker MD, Karamloo F, Vieths S, Wuthrich B. Allergy caused by ingestion of zucchini (Cucurbita pepo): characterization of allergens and cross-reactivity to pollen and other foods. J Allergy Clin Immunol. 2000;106(2):379-85. 148. Rhodes HL, Sporik R, Thomas P, Holgate ST, Cogswell JJ. Early life risk factors for adult asthma: a birth cohort study of subjects at risk. J Allergy Clin Immunol. 2001;108(5):720-5. 149. Romano A, Di Fonso M, Giuffreda F, Papa G, Artesani MC, Viola M, et al. Food-dependent exercise-induced anaphylaxis: clinical and laboratory findings in 54 subjects. Int Arch Allergy Immunol. 2001;125(3):264-72. 150. Romano A, Di Fonso M, Giuffreda F, Quaratino D, Papa G, Palmieri V, et al. Diagnostic work-up for food-dependent, exercise-induced anaphylaxis. 1995;50(10):817-24. 151. Ronchetti R, Jesenak M, Trubacova D, Pohanka V, Villa MP. Epidemiology of atopy patch tests with food and inhalant allergens in an unselected population of children.

323

2008;19(7):599-604. 152. Saarinen KM, Juntunen-Backman K, Jarvenpaa AL, Klemetti P, Kuitunen P, Lope L, et al. Breast-feeding and the development of cows' milk protein allergy. Adv Exp Med Biol. 2000;478:121-30. 153. Saarinen KM, Pelkonen AS, Makela MJ, Savilahti E. Clinical course and prognosis of cow's milk allergy are dependent on milk-specific IgE status. J Allergy Clin Immunol. 2005;116(4):869-75. 154. Sabbah A. [Food allergy in childhood asthma]. Allerg Immunol (Paris). 1990;22(8):325-31. 155. Sabbah A, Drouet M, Heulin MG, Marsollier I, Trouillard V. [Role of food allergy in atopic dermatitis]. 1989;21(6):232-6. 156. Sabbah A, Drouet M, Millet B, Biset T. [Perennial rhinitis from food allergy]. Allerg Immunol (Paris). 1990;22(2):51-5. 157. Sandin A, Annus T, Bjorksten B, Nilsson L, Riikjarv MA, van Hage-Hamsten M, et al. Prevalence of self-reported food allergy and IgE antibodies to food allergens in Swedish and Estonian schoolchildren. 2005;59(3):399-403. 158. Savilahti E, Tuomikoski-Jaakkola P, Jarvenpaa AL, Virtanen M. Early feeding of preterm infants and allergic symptoms during childhood. 1993;82(4):340-4. 159. Schade RP, Van Ieperen-Van Dijk AG, Van Reijsen FC, Versluis C, Kimpen JL, Knol EF, et al. Differences in antigen-specific T-cell responses between infants with atopic dermatitis with and without cow's milk allergy: relevance of TH2 cytokines. 2000;106(6):1155-62. 160. Schafer T, Bohler E, Ruhdorfer S, Weigl L, Wessner D, Heinrich J, et al. Epidemiology of food allergy/food intolerance in adults: associations with other manifestations of atopy. 2001;56(12):1172-9. 161. Schneider S, Mohnen S, Schiltenwolf M. ["Are rich people healthier?"--Representative epidemiological data on socioeconomic group-specific disease prevalences among adults in Germany]. Dtsch Med Wochenschr. 2006;131(37):1998-2003. 162. Schrander JJ, van den Bogart JP, Forget PP, Schrander-Stumpel CT, Kuijten RH, Kester AD. Cow's milk protein intolerance in infants under 1 year of age: a prospective epidemiological study. Eur J Pediatr. 1993;152(8):640-4. 163. Schulmeister U, Swoboda I, Quirce S, de la Hoz B, Ollert M, Pauli G, et al. Sensitization to human milk. 2008;38(1):60-8.

324

164. Semeniuk J, Kaczmarski M. Gastroesophageal reflux in children and adolescents. clinical aspects with special respect to food hypersensitivity. Adv Med Sci. 2006;51:327-35. 165. Sinagra JL, Bordignon V, Ferraro C, Cristaudo A, Di Rocco M, Amorosi B, et al. Unnecessary milk elimination diets in children with atopic dermatitis. Pediatr Dermatol. 2007;24(1):1-6. 166. Snijders BE, Thijs C, van Ree R, van den Brandt PA. Age at first introduction of cow milk products and other food products in relation to infant atopic manifestations in the first 2 years of life: the KOALA Birth Cohort Study. Pediatrics. 2008;122(1):e115-22. 167. Sorea S, Dabadie A, Bridoux-Henno L, Balancon-Morival M, Jouan H, Le Gall E. [Hemorrhagic colitis in exclusively breast-fed infants]. 2003;10(9):772-5. 168. Stewart AG, Ewan PW. The incidence, aetiology and management of anaphylaxis presenting to an accident and emergency department. QJM. 1996;89(11):859-64. 169. Straumann A, Spichtin HP, Grize L, Bucher KA, Beglinger C, Simon HU. Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. 2003;125(6):1660-9. 170. Sutas Y, Hurme M, Isolauri E. Oral cow milk challenge abolishes antigen-specific interferon-gamma production in the peripheral blood of children with atopic dermatitis and cow milk allergy. 1997;27(3):277-83. 171. Tabar AI, Alvarez-Puebla MJ, Gomez B, Sanchez-Monge R, Garcia BE, Echechipia S, et al. Diversity of asparagus allergy: clinical and immunological features. 2004;34(1):131-6. 172. Tariq SM, Stevens M, Matthews S, Ridout S, Twiselton R, Hide DW. Cohort study of peanut and tree nut sensitisation by age of 4 years. BMJ. 1996;313(7056):514-7. 173. Thaminy A, Lamblin C, Perez T, Bergoin C, Tonnel AB, Wallaert B. Increased frequency of asymptomatic bronchial hyperresponsiveness in nonasthmatic patients with food allergy. Eur Respir J. 2000;16(6):1091-4. 174. Tikkanen S, Kokkonen J, Juntti H, Niinimaki A. Status of children with cow's milk allergy in infancy by 10 years of age. Acta Paediatr. 2000;89(10):1174-80. 175. Vanto T, Helppila S, Juntunen-Backman K, Kalimo K, Klemola T, Korpela R, et al. Prediction of the development of tolerance to milk in children with cow's milk hypersensitivity. J Pediatr. 2004;144(2):218-22. 176. Virtanen SMK, M. Pekkanen, J. Kenward, M. G. Uusitalo, U. Pietinen, P.

325

Kronberg-Kippila, C. Hakulinen, T. Simell, O. Ilonen, J. Veijola, R. Knip, M. Early introduction of oats associated with decreased risk of persistent asthma and early introduction of fish with decreased risk of allergic rhinitis. Br J Nutr. 2009 Aug 13:1-8. 177. von Hertzen L, Makela MJ, Petays T, Jousilahti P, Kosunen TU, Laatikainen T, et al. Growing disparities in atopy between the Finns and the Russians: a comparison of 2 generations. 2006;117(1):151-7. 178. Waser M, Michels KB, Bieli C, Floistrup H, Pershagen G, von Mutius E, et al. Inverse association of farm milk consumption with asthma and allergy in rural and suburban populations across Europe. Clin Exp Allergy. 2007;37(5):661-70. 179. Wickman M, Lilja G, Soderstrom L, van Hage-Hamsten M, Ahlstedt S. Quantitative analysis of IgE antibodies to food and inhalant allergens in 4-year-old children reflects their likelihood of allergic disease. Allergy. 2005;60(5):650-7. 180. Willers SM, Wijga AH, Brunekreef B, Kerkhof M, Gerritsen J, Hoekstra MO, et al. Maternal food consumption during pregnancy and the longitudinal development of childhood asthma. Am J Respir Crit Care Med. 2008;178(2):124-31. 181. Wolkerstorfer AW, U. Kjellman, N. I. Diepgen, T. L. De Longueville, M. Oranje, A. P. Natural course of sensitization to cow's milk and hen's egg in childhood atopic dermatitis: ETAC study group. Clin Exp Allergy. 2002 Jan;32(1):70-3. 182. Woods RK, Abramson M, Bailey M, Walters EH. International prevalences of reported food allergies and intolerances. Comparisons arising from the European Community Respiratory Health Survey (ECRHS) 1991-1994. 2001;55(4):298-304. 183. Worm M, Forschner K, Lee HH, Roehr CC, Edenharter G, Niggemann B, et al. Frequency of atopic dermatitis and relevance of food allergy in adults in Germany. Acta Derm Venereol. 2006;86(2):119-22. 184. Zuberbier T, Edenharter G, Worm M, Ehlers I, Reimann S, Hantke T, et al. Prevalence of adverse reactions to food in Germany - a population study. 2004;59(3):338-45. 185. Zutavern A, Brockow I, Schaaf B, Bolte G, von Berg A, Diez U, et al. Timing of solid food introduction in relation to atopic dermatitis and atopic sensitization: results from a prospective birth cohort study. Pediatrics. 2006;117(2):401-11. Japan/China/Taiwan/Korea/Singapore 1. Ahn KM, Han YS, Nam SY, Park HY, Shin MY, Lee SI. Prevalence of soy protein hypersensitivity in cow's milk protein-sensitive children in Korea. J Korean Med Sci. 2003;18(4):473-7.

326

2. Chiang WC, Kidon MI, Liew WK, Goh A, Tang JP, Chay OM. The changing face of food hypersensitivity in an Asian community. Clin Exp Allergy. 2007;37(7):1055-61. 3. Fukutomi O, Kondo N, Agata H, Shinoda S, Kuwabara N, Shinbara M, et al. Timing of onset of allergic symptoms as a response to a double-blind, placebo-controlled food challenge in patients with food allergy combined with a radioallergosorbent test and the evaluation of proliferative lymphocyte responses. 1994;104(4):352-7. 4. Hikino S, Nakayama H, Yamamoto J, Kinukawa N, Sakamoto M, Hara T. Food allergy and atopic dermatitis in low birthweight infants during early childhood. 2001;90(8):850-5. 5. Hon KL, Leung TF, Kam WY, Lam MC, Fok TF, Ng PC. Dietary restriction and supplementation in children with atopic eczema. 2006;31(2):187-91. 6. Hon KL, Leung TF, Lam MC, Wong KY, Chow CM, Ko WS, et al. Eczema exacerbation and food atopy beyond infancy: how should we advise Chinese parents about dietary history, eczema severity, and skin prick testing? 2007;24(2):223-30. 7. Hong SP, Park HS, Lee MK, Hong CS. Oral provocation tests with aspirin and food additives in asthmatic patients. Yonsei Med J. 1989;30(4):339-45. 8. Hur GY, Koh DH, Kim HA, Park HJ, Ye YM, Kim KS, et al. Prevalence of work-related symptoms and serum-specific antibodies to wheat flour in exposed workers in the bakery industry. Respir Med. 2008;102(4):548-55. 9. Irei AV, Sato Y, Lin TL, Wang MF, Chan YC, Hung NT, et al. Overweight is associated with allergy in school children of Taiwan and Vietnam but not Japan. J Med Invest. 2005;52(1-2):33-40. 10. Kumagai H, Masuda T, Maisawa S, Chida S. Apoptotic epithelial cells in biopsy specimens from infants with streaked rectal bleeding. 2001;32(4):428-33. 11. Kusunoki TO, I. Yoshioka, T. Saito, M. Nishikomori, R. Heike, T. Sugai, M. Shimizu, A. Nakahata, T. SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis. J Allergy Clin Immunol. 2005 Mar;115(3):636-8. 12. Lee JH, Lin YT, Chiang BL. The role of food allergens in childhood asthma. Asian Pac J Allergy Immunol. 2003;21(3):131-8. 13. Lee SI, Shin MH, Lee HB, Lee JS, Son BK, Koh YY, et al. Prevalences of symptoms of asthma and other allergic diseases in korean children: a nationwide questionnaire survey. J Korean Med Sci. 2001;16(2):155-64.

327

14. Leung TF, Lam CW, Chan IH, Li AM, Tang NL. Sensitization to common food allergens is a risk factor for asthma in young Chinese children in Hong Kong. J Asthma. 2002;39(6):523-9. 15. Shinoda S, Agata H, Fukutomi O, Kondo N. Combinations of IgE values and lymphocyte proliferative responses for consideration of the clinical course of infantile hen's-egg-sensitive atopic dermatitis. 1997;112(2):163-8. 16. Tanaka S. An epidemiological survey on food-dependent exercise-induced anaphylaxis in kindergartners, schoolchildren and junior high school students. Asia Pac J Public Health. 1994;7(1):26-30. 17. Thong BY, Cheng YK, Leong KP, Tang CY, Chng HH. Immediate food hypersensitivity among adults attending a clinical immunology/allergy centre in Singapore. Singapore Med J. 2007;48(3):236-40. 18. Tsai HJ, Tsai AC. The association of diet with respiratory symptoms and asthma in schoolchildren in Taipei, Taiwan. J Asthma. 2007;44(8):599-603. 19. Wieslander G, Norback D, Wang Z, Zhang Z, Mi Y, Lin R. Buckwheat allergy and reports on asthma and atopic disorders in Taiyuan City, Northern China. 2000;18(3):147-52. 20. Wu AY, Williams GA. Clinical characteristics and pattern of skin test reactivities in shellfish allergy patients in Hong Kong. 2004;25(4):237-42. Mediterranean 1. Cow's milk allergy in the first year of life. An Italian Collaborative Study. Acta Paediatr Scand Suppl. 1988;348:1-14. 2. Aaronov D, Tasher D, Levine A, Somekh E, Serour F, Dalal I. Natural history of food allergy in infants and children in Israel. Ann Allergy Asthma Immunol. 2008;101(6):637-40. 3. Aba-Alkhail BA, El-Gamal FM. Prevalence of food allergy in asthmatic patients. Saudi Med J. 2000;21(1):81-7. 4. Asero R, Antonicelli L, Arena A, Bommarito L, Caruso B, Crivellaro M, et al. EpidemAAITO: Features of food allergy in Italian adults attending allergy clinics: a multi-centre study. Clin Exp Allergy. 2009. 5. Bakirtas A, Turktas I, Dalgic B. Cow milk allergy presenting as colitis. 2003;162(9):653; author reply 4.

328

6. Carroccio A, Iacono G, Di Prima L, Ravelli A, Pirrone G, Cefalu AB, et al. Food hypersensitivity as a cause of rectal bleeding in adults. 2009;7(1):120-2. 7. Cataldo F, Accomando S, Fragapane ML, Montaperto D. Are food intolerances and allergies increasing in immigrant children coming from developing countries ? 2006;17(5):364-9. 8. Celik G, Mungan D, Bavbek S, Sin B, Ediger D, Demirel Y, et al. The prevalence of allergic diseases and atopy in Ankara, Turkey: a two-step population-based epidemiological study. J Asthma. 1999;36(3):281-90. 9. Dalal I, Binson I, Levine A, Somekh E, Ballin A, Reifen R. The pattern of sesame sensitivity among infants and children. Pediatr Allergy Immunol. 2003;14(4):312-6. 10. Dalal I, Binson I, Reifen R, Amitai Z, Shohat T, Rahmani S, et al. Food allergy is a matter of geography after all: sesame as a major cause of severe IgE-mediated food allergic reactions among infants and young children in Israel. 2002;57(4):362-5. 11. Dantonio C, Galimberti M, Barbone B, Calamari M, Airoldi G, Campanini M, et al. Suspected acute allergic reactions: analysis of admissions to the Emergency Department of the AOU Maggiore della Carita Hospital in Novara from 2003 to 2007. Eur Ann Allergy Clin Immunol. 2008;40(4):122-9. 12. de Seta L, Siani P, Santoro C, Cimaduomo L, Coletta S. [The natural history of allergy to eggs in atopic dermatitis]. Pediatr Med Chir. 1994;16(5):485-7. 13. Emin O, Nermin G, Ulker O, Gokcay G. Skin sensitization to common allergens in Turkish wheezy children less than 3 years of age. Asian Pac J Allergy Immunol. 2004;22(2-3):97-101. 14. Foroutan MN, A. Molaei, M. Mirbagheri, S. A. Irvani, S. Sadeghi, A. Derakhshan, F. Tavassoli, S. Besharat, S. Zali, M. Eosinophilic Esophagitis in Patients with Refractory Gastroesophageal Reflux Disease. Dig Dis Sci. 2009 Feb 25. 15. Gelincik A, Buyukozturk S, Gul H, Isik E, Issever H, Ozseker F, et al. Confirmed prevalence of food allergy and non-allergic food hypersensitivity in a Mediterranean population. Clin Exp Allergy. 2008;38(8):1333-41. 16. Iacono G, Carroccio A, Cavataio F, Montalto G, Kazmierska I, Lorello D, et al. Gastroesophageal reflux and cow's milk allergy in infants: a prospective study. J Allergy Clin Immunol. 1996;97(3):822-7. 17. Iacono G, Cavataio F, Montalto G, Florena A, Tumminello M, Soresi M, et al. Intolerance of cow's milk and chronic constipation in children. N Engl J Med. 1998;339(16):1100-4.

329

18. Kivity S, Fireman E, Sade K. Bronchial hyperactivity, sputum analysis and skin prick test to inhalant allergens in patients with symptomatic food hypersensitivity. 2005;7(12):781-4. 19. Kucukosmanoglu E, Yazi D, Yesil O, Akkoc T, Gezer M, Bakirci N, et al. Prevalence of egg sensitization in Turkish infants based on skin prick test. Allergol Immunopathol (Madr). 2008;36(3):141-4. 20. Kucukosmanoglu E, Yazi D, Yesil O, Akkoc T, Gezer M, Ozdemir C, et al. Prevalence of immediate hypersensitivity reactions to cow's milk in infants based on skin prick test and questionnaire. Allergol Immunopathol (Madr). 2008;36(5):254-8. 21. Lunardi C, Favari F, Venturini G, Zagni P, Nicolis F, Pacor ML. [Prevalence of food allergy in patients with urticaria-angioedema syndrome]. G Ital Dermatol Venereol. 1990;125(7-8):319-22. 22. Mazon A, Solera E, Alentado N, Oliver F, Pamies R, Caballero L, et al. Frequent IgE sensitization to latex, cow's milk, and egg in children with short bowel syndrome. Pediatr Allergy Immunol. 2008;19(2):180-3. 23. Nermes M, Karvonen H, Sarkkinen E, Isolauri E. Safety of barley starch syrup in patients with allergy to cereals. Br J Nutr. 2009;101(2):165-8. 24. Ottolenghi A, De Chiara A, Arrigoni S, Terracciano L, De Amici M. [Diagnosis of food allergy caused by fruit and vegetables in children with atopic dermatitis]. 1995;17(6):525-30. 25. Priftis KN, Mermiri D, Papadopoulou A, Papadopoulos M, Fretzayas A, Lagona E. Asthma symptoms and bronchial reactivity in school children sensitized to food allergens in infancy. 2008;45(7):590-5. 26. Raimondi F, Indrio F, Crivaro V, Araimo G, Capasso L, Paludetto R. Neonatal hyperbilirubinemia increases intestinal protein permeability and the prevalence of cow's milk protein intolerance. 2008;97(6):751-3. 27. Ravelli A, Villanacci V, Chiappa S, Bolognini S, Manenti S, Fuoti M. Dietary protein-induced proctocolitis in childhood. 2008;103(10):2605-12. 28. Uz E, Turkay C, Aytac S, Bavbek N. Risk factors for irritable bowel syndrome in Turkish population: role of food allergy. J Clin Gastroenterol. 2007;41(4):380-3. 29. Volonakis M, Katsarou-Katsari A, Stratigos J. Etiologic factors in childhood chronic urticaria. Ann Allergy. 1992;69(1):61-5. 30. Yariktas M, Doner F, Dogru H, Demirci M. Asymptomatic food hypersensitivity prevalence in patients with eczematous external otitis. 2004;25(1):1-4.

330

31. Zapatero Remon L, Alonso Lebrero E, Martin Fernandez E, Martinez Molero MI. Food-protein-induced enterocolitis syndrome caused by fish. Allergol Immunopathol (Madr). 2005;33(6):312-6. Argentina 1. Bezrodnik L, Raccio AC, Canil LM et al. Hypogammaglobulinaemia secondary to cow-milk allergy in children under 2 years of age. 2007; 122(1):140-6. Bangladesh 1. Kabir I, Speelman P, Islam A. Systemic allergic reaction and diarrhoea after pineapple ingestion. Trop Geogr Med 1993; 45(2):77-9. Brazil 1. Daher S, Tahan S, Sole D et al. Cow's milk protein intolerance and chronic constipation in children. 2001; 12(6):339-42. 2. Diaz NJ, Patricio FS, Fagundes-Neto U. [Allergic colitis: clinical and morphological aspects in infants with rectal bleeding]. 2002; 39(4):260-7. Chile 1. Cruchet S, Faundez R, Laguna C, Araya M. [Challenge testes for diagnosis and follow-up of children with food allergy]. Rev Med Chil 2003; 131(3):275-82. 2. Rossel M, Ceresa S, Las Heras J, Araya M. [Eosinophilic colitis caused by allergy to cow's milk protein]. Rev Med Chil 2000; 128(2):167-75. Hongkong 1. Leung TF, Yung E, Wong YS, Lam CW, Wong GW. Parent-reported adverse food reactions in Hong Kong Chinese pre-schoolers: epidemiology, clinical spectrum and risk factors. Pediatr Allergy Immunol 2008. India 1. Shaikh WA, Shaikh SW. Allergies in India: an analysis of 3389 patients attending an allergy clinic in Mumbai, India. J Indian Med Assoc 2008; 106(4):220, 222, 224 passim. 2. Misra A, Prasad R, Das M, Dwivedi PD. Prevalence of legume sensitization in patients with naso-bronchial allergy. Immunopharmacol Immunotoxicol 2008; 30(3):529-42. 3. Mandal J, Das M, et. al. Immediate hypersensitivity to common food allergens: An investigation on food sensitization in respiratory allergic patients of Calcutta, India . 2. 2009:9-12.

331

4. Poddar U, Shukla P, Yachha SK, Aggarwal R, Krishnani N. Role of IgG anti-beta-lactoglobulin antibody in the diagnosis of cow's milk protein intolerance in India. 2008; 27(5):190-4. International 1. Bager P, Wohlfahrt J, Westergaard T. Caesarean delivery and risk of atopy and allergic disease: meta-analyses. Clin Exp Allergy 2008; 38(4):634-42. Iran 1. Pourpak Z, Mesdaghi M, Mansouri M, Kazemnejad A, Toosi SB, Farhoudi A. Which cereal is a suitable substitute for wheat in children with wheat allergy? 2005; 16(3):262-6. Israel 1. Cohen A, Goldberg M, Levy B, Leshno M, Katz Y. Sesame food allergy and sensitization in children: the natural history and long-term follow-up. Pediatr Allergy Immunol 2007; 18(3):217-23. 2. Kivity S, Dunner K, Marian Y. The pattern of food hypersensitivity in patients with onset after 10 years of age. Clin Exp Allergy 1994; 24(1):19-22. Malaysia 1. Gendeh BS, Murad S, Razi AM, Abdullah N, Mohamed AS, Kadir KA. Skin prick test reactivity to foods in adult Malaysians with rhinitis. Otolaryngol Head Neck Surg 2000; 122(5):758-62. Mexico 1. Estrada-Reyes E, Pardo-Castaneda MG, Toledo-Bahena ME, Lerma-Ortiz ML, del Rio-Navarro B, Nava-Ocampo AA. A case-control study of food hyper-sensitivity, timing of weaning and family history of allergies in young children with atopic dermatitis. Allergol Immunopathol (Madr) 2007; 35(3):101-4. Netherlands 1. Hospers IC, de Vries-Vrolijk K, Brand PL. [Double-blind, placebo-controlled cow's milk challenge in children with alleged cow's milk allergies, performed in a general hospital: diagnosis rejected in two-thirds of the children]. Ned Tijdschr Geneeskd 2006; 150(23):1292-7. Phillipines 1. Hill DJ, Cameron DJ, Francis DE, Gonzalez-Andaya AM, Hosking CS. Challenge confirmation of late-onset reactions to extensively hydrolyzed formulas in infants with multiple food protein intolerance. J Allergy Clin Immunol 1995; 96(3):386-94.

332

Russia 1. von Hertzen L, Makela MJ, Petays T et al. Growing disparities in atopy between the Finns and the Russians: a comparison of 2 generations. 2006; 117(1):151-7. South Africa 1. de Benedictis FM, Franceschini F, Hill D et al. The allergic sensitization in infants with atopic eczema from different countries. Allergy 2009; 64(2):295-303. 2. Steinman HA, Potter PC. The precipitation of symptoms by common foods in children with atopic dermatitis. 1994; 15(4):203-10. Thailand 1. Aanpreung P, Atisook K. Hematemesis in infants induced by cow milk allergy. Asian Pac J Allergy Immunol 2003; 21(4):211-6. 2. Harikul S, Haruehasavasin Y, Varavithya W, Chaicumpa W. Cow milk protein allergy during the first year of life: a 12 year experience at the children's hospital, Bangkok. Asian Pac J Allergy Immunol 1995; 13(2):107-11. 3. Kulthanan K, Jiamton S, Rutnin NO, Insawang M, Pinkaew S. Prevalence and relevance of the positivity of skin prick testing in patients with chronic urticaria. J Dermatol 2008; 35(6):330-5. 4. Kulthanan K, Jiamton S, Boochangkool K, Jongjarearnprasert K. Angioedema: clinical and etiological aspects. Clin Dev Immunol 2007; 2007:26438. Poachanukoon O, Paopairochanakorn C. Incidence of anaphylaxis in the emergency department: a 1-year study in a university hospital. Asian Pac J Allergy Immunol 2006; 24(2-3):111-6. 5. Poachanukoon O, Paopairochanakorn C. Incidence of anaphylaxis in the emergency department: a 1-year study in a university hospital. Asian Pac J Allergy Immunol. 2006;24(2-3):111-6. 6. Santadusit S, Atthapaisalsarudee S, Vichyanond P . Prevalence of adverse food reactions and food allergy among Thai children. J Med Assoc Thai 2005; 88 Suppl 8:S27-32. Unclear 1. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008;122(5):984-991 2. Langan SM, Williams HC. What causes worsening of eczema? A systematic review. 2006; 155(3):504-14.

333

3. Pourpak Z, Farhoudi A, Mahmoudi M, et al. The role of cow milk allergy in increasing the severity of atopic dermatitis. Immunol Invest. 2004;33(1):69-79. 4. Wolkerstorfer A, Wahn U, Kjellman NI, Diepgen TL, De Longueville M, Oranje AP. Natural course of sensitization to cow's milk and hen's egg in childhood atopic dermatitis: ETAC study group. 2002; 32(1):70-3.’ Vietnam 1. Irei AV, Takahashi K, Le DS et al. Obesity is associated with increased risk of allergy in Vietnamese adolescents. Eur J Clin Nutr 2005; 59(4):571-7. 2. Irei AV, Sato Y, Lin TL et al. Overweight is associated with allergy in school children of Taiwan and Vietnam but not Japan. J Med Invest 2005; 52(1-2):33-40.

334

Appendix F: Food allergy treatment/management controlled trials: study quality characteristics Author Randomized Random-

ization approp.

Treatment allocation concealed

Double blind

Blind- ing

approp.

Outcome assessor blinded

Care provider blinded

Patients blinded

Co-inter-ventions

Drop-out

<50%

ITT Overall quality

Agata, 1993291 No NA NA No NA NS NS No NS NA Yes Poor Hansen, 2004300

Yes Yes Yes Yes Yes Yes NS Yes NS Yes Yes Good

Bucher, 2004301

NS NA No No NA NS NS No NS NA Yes Poor

Asero, 1998302 NS NS NS NS NS NS NS NS NS NA NA Poor Leung, 2003316 Yes Yes Yes Yes Yes Yes Yes Yes NS Yes Yes Good Cavagni, 1989317

Yes NS Yes Yes Yes NS NS Yes NS Yes NA Fair

Staden, 2007293

Yes NS Yes Yes Yes Yes NS Yes NS Yes Yes Good

Bernardini, 2006303

Yes Yes Yes Yes Yes Yes NS Yes NS NA NA Fair

Morisset, 2007294

Yes Yes Yes No NA NS NS No NS Yes Yes Fair

Skripak, 2007292

Yes NS Yes Yes Yes Yes NS Yes NS Yes Yes Good

Nelson, 1997295

No NA No No NA No NS No NS NA No Poor

Enrique, 2005299

Yes Yes Yes Yes Yes NS NS Yes NS Yes Yes Good

Patriarca, 2007296

No NA No No NA NS NS No NS Yes No Poor

Bindsley-Jensen, 1991315

Yes NS Yes Yes Yes Yes NS Yes NS NS NS Fair

Burks, 1988318 NS NS Yes Yes Yes NS NS Yes NS Yes No Fair Schaefer, Yes Yes No No No No NS No NS Yes Yes Fair

335

2008319 Jirapinyo, 2007333

Yes NS NS NS NS NS NS NS NS Yes Yes Fair

Szajewska, 2007321

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Good

Hill, 2005322 Yes Yes No No NA Yes Yes No NS Yes No Fair Amadi, 2002323

Yes Yes No No No NS NS NS NS Yes No Fair

Cantani, 2006324

No NA No No No No NS No NS NA NS Poor

Salpietro, 2005325

Yes NS Yes NS NS NS NS Yes NS Yes Yes Fair

Jong, 2002332 Yes Yes Yes Yes Yes NS NS Yes Yes Yes At 2 years but not 5 years

Good

Lindfors, 1992339

Yes NS NS NS NS Yes NS NS Yes Yes Yes Fair

Iacono, 1998335

Yes Yes Yes Yes Yes Yes NS Yes NS Yes Yes Good

Klemola, 2002313

Yes Yes Yes NS NS NS NS Yes Yes NS Yes Fair

Niggemann, 2008336

Yes Yes Yes Yes Yes Yes NS Yes Yes Yes No Fair

Garzi, 2002337 No NA NS NS NS NS NS NS NS NS Yes Poor Vita, 2007338 Yes Yes No No Yes Yes Yes No NS Yes No Fair Note: NS=Not stated; NA=not applicable; ITT=intention to treat analysis

336

Appendix G: Abbreviations used in this report Abbreviation Term AAAAI American Academy of Allergy Asthma and Immunology AAP American Academy of Pediatrics ACAAI American College of Allergy, Asthma & Immunology AD Atopic dermatitis AGA Alpha gliadin antibody ALA AMSTAR

Alpha lactalbumin Assessment of multiple systematic reviews

APT Atopy patch test BLG beta-lactoglobulin CD Celiac disease CLA receptor Cutaneous lymphocyte-associated antigens receptor CLEIA Chemiluminescent enzyme immunoassay CM Cow’s milk CMA CMPA

Cow’s milk allergy Cow’s milk protein allergy

CME CMF

Continuing medical education Cow milk formula

CMPI Cow’s milk protein intolerance CMPIE ConA

Cow’s milk protein induced enteropathy Concanavalin A

COU Chronic ordinary urticaria DARE Cochrane Database of Abstracts of Reviews of Effects DBPCFC Double blind placebo controlled food challenge DH Dermatitis herpetiformis ECAAI European Academy of Allergy and Clinical Immunology) EE/EG Eosinophilic esophagitis/gastroenteritis EGID Eosinophil-associated gastrointestinal disorders eHF Extensively hydrolyzed formulas ELISA Enzyme-linked immunosorbent assay EmA Endomysial antibody Eos/HPF Eosinophils per high-powered field EPC Evidence-based Practice Center FAAN Food Allergy and Anaphylaxis Network FC Food challenge FDEIA Food-associated, exercise-induced syndromes FEIA FHx GA

Fluorescent enzyme immunoassay Family History Gastrointestinal age

GFD GERD

Gluten free diet Gastroesophageal reflux disease

GI GINI

Gastrointestinal German infant nutritional intervention

HE HCF

Hen’s egg Hydrolysed casein formula

337

Abbreviation Term HF HLA

Hydrolyzed formula Human Leukocyte antigen

IgA/E/G Immunoglobin class A/E/G IL L/M

Interleukin Lactulose/Mannitol

LP Lymphocyte proliferation ME Milk-induced enterocolitis syndrome NASPGHN North American Society for Pediatric Gastroenterology, Hepatology

and Nutrition NHANES National Health and Nutrition Examination Survey NIAID National Institutes of Allergy and Infectious Disease NIH NRL

National Institute of Health Natural rubber latex

NPV Negative predictive value OAS OFC OVA OVM OVT

Oral allergy syndrome Open food challenge Ovalbumin Ovomucoid Ovotransferrin

PAR PBMC PHA

Perennial allergic rhinoconjunctivitis Peripheral blood mononuclear cells Phytohemagglutinin

pHF Partially hydrolyzed formulas PPV QOL

Positive predictive value Quality of life

QUADAS Quality Assessment of Studies of Diagnostic Accuracy RAST Radioallergosorbic test RCT RHF

Randomized controlled trial Rice-based hydrolysate formula

ROC Receiver-operating characteristics ROU Recurrent oral ulceration SAR SCORAD

Seasonal allergic rhinoconjunctivitis Scoring atopic dermatitis

SD Se SES SF

Standard deviation Sensitivity Socioeconomic Status Soy-based Formula

sIgE SLIT Sp

Antigen-specific Immunoglobulin Sublingual immunotherapy Specificity

SPT Skin prick test STARD Standards for the Reporting of Diagnostic Accuracy TEP Technical Expert Panel Th2 T-helper type 2 cell TN Tree nut

338

Abbreviation Term TNF Tumor necrosis factor tTG

Tissue transglutaminase

339

Appendix H: Evidence Tables-Diagnosis Studies Author, Yr

Food(s) Condition Population Reference test

Test 1 Test 2 Test 3 Comments, Conclusions, (values for QUADAS domains)*

Bernardi, 2008195

19 different foods

Multiple gastrointestinal 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

Se Sp PPV*

NPV*

0.83 0.92 0.35 0.99

Hen’s Egg: ≥2.0 U/L

Se Sp PPV*

NPV*

0.73 0.83 0.25 0.99

*Estimated Prevalence 5%

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)

Bischoff, 1996156

Unclear Gastrointestinal disease

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 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

Endoscopic allergen provocation: 13 patients underwent a total of 34 tests. Sensitivity: 59% Specificity: 97%

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)

Calvani 2007174

Milk CMA 104 children consecutively

Food challenge (70 open and 34

SPT with: - lactalbumin

340

Author, Yr



referred to an Italian pediatric allergy clinic for evaluation of suspected CMA

DBPCFC) 28/104 tests were positive

- casein - beta-lactoglobulin - fresh milk with positive tests defined as mean wheal diameters 3mm ≥ the negative control.

Canani, 2007175

CM, HE, wheat

Suspected food-related GI 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)


Se Sp PPV

NPV

0.45 0.70 0.67 0.51

Hen’s Egg: Se Sp PP

V NPV

0.58 0.67 0.79 0.43

sIgE Cow’s milk:

Se Sp PPV

NPV

0.23 0.74 0.54 0.42


V NPV

0.32 0.67 0.67 0.32

APT with fresh vs. commercial food extracts APT with fresh food Cow’s milk:

Se Sp PPV

NPV

0.65 0.96 0.95 0.67


V NPV

0.84 1.00 1.00 0.75

APT using fresh food or SPT Cow’s milk:

Se Sp PPV

NPV

0.87 0.65 0.77 0.79


V NPV

0.95 0.67 0.86 0.86

APT using fresh food or SPT or sIgE Cow’s milk:

Se Sp PPV

NPV

0.90 0.52 0.72 0.80


V NPV

APT commercial assay (freeze-dried) Cow’s milk:

Se Sp PPV

NPV

0.06 0.96 0.67 0.43


V NPV

0.05 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)

341

Author, Yr



0.95 0.44 0.78 0.80


CM, egg, wheat, soy

AD(88%) 501 children (1 mo-16.1 yr)

Food challenge: DBPCFC if > 1 yr

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

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)

Clark, 2007154

Egg Egg allergy 24 children in the UK (2.6-14 yoa) with suspected egg allergy (parent report or


Facial thermography in DBPCFC: Sensitivity: 0.92

(3,3,1,1,1,1,2,1,1,3,1,3)

342

Author, Yr



positive SPT) challenged with cooked (CE) or uncooked egg (UE)

Specificity: 1 based on comparison to objective symptoms of DBPCFC 13+DBPCFC 11-DBPCFC

Cobbaert, 2005191

Egg white, milk, codfish, wheat, peanut, soy

118 pts >=15 yrs Clinical HX+SPT? sIgE using DPC Immulite® 2000

Immulite 2000 AlaTOP

Pharmacia?? Referred to as 3rd generation sIgE test systems (1,3,1,1,1,3,1,1,1,1,1,3)

Cudowska, 2005199

Milk AEDS 34 children (5 mos-16 yrs) A: 20< 3yrs B: 14≥3 yrs

Food challenge: A: 65%+ B: 35.7%+

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 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

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)

De Boissieu, 2003184

Milk CMA 35 patients, 2-57 months, referred for diagnosis of non-specific persistent digestive symptoms.

Food challenge (open with f/u DBPCFC if open challenge equivocal) 24 allergic, 11 not allergic

APT positive in 19/24 with CMA, positive in 1/11 w/o CMA

sIgE positive in 3/24 with CMA (0.6 KUI/L, 0.36 KUI/L, and 0.49 KUI/L), positive in 0/11 w/o

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)

343

Author, Yr



CMA 3/24, 1/11; FTT 3/24, 1/11

Dieguez, 2008177

Egg Egg allergy 104 milk allergic children with no prior egg exposure.

Food challenge SPT Egg white Cutoff 3mm Sensitivity0.95 Specificity0.40 PPV0.59 NPV0.89 +LR1.58 -LR0.14

SPT Egg white Cutoff 6mm Sensitivity0.81 Specificity0.73 PPV0.73 NPV0.81 +LR2.95 -LR0.26

SPT OVM Cutoff 3mm Sensitivity0.67 Specificity0.85 PPV0.83 NPV0.71 +LR4.53 -LR0.39

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)

Allergen Area under ROC

Opt. Decision Point

Egg white 0.83 6mm Yolk 0.73 3mm Ova 0.55 3mm OVM 0.82 5mm OVT 0.55 Lysozyme 0.60

Fiocchi, 2004188

Milk, alpha lactalbumin, casein, egg white, egg yolk, peanut, wheat, codfish, soy, tomato

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)

Garcia-Ara, 2001167

Milk CMA 170 infants (aged 1-12 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), beta-lactoglobulin

sIgE CAP FEIA using milk, ALA, BLG, and casein;

(1,1,1,1,2,2,1,1,1,1,2,3)

344

Author, Yr



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)

positive test defined as sIgE≥0.35 (see Table 24)

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

SPT+sIgE positive in 37/68 with CMA, negative in 61/67 w/o CMA

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)

Hwang, 2008155

Milk Cow milk protein-induced enterocolitis

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

>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

14/16 vomiting+ 5/16+ Peripheral absolute neutrophil count 12/16+ Fecal white blood cells 0/16+ C-reactive protein (>1mg/dL)

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)

Iacono 2006146

Milk CMPI 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

(1,1,1,1,1,1,1,1,3,1,1,3)

345

Author, Yr



without CMPI: specificity=1.0

Isolauri, 1996148

Milk CMA 183 patients (2-36 months) referred to specialist for evaluation of AD

Food challenge (open and DBPCFC)

SPT sensitivity 0.48, specificity 0.86

APT: sensitivity 0.61, specificity 0.81

SPT+APT: parallel: specificity 0.86, sensitivity 0.72 serial: specificity 0.24 sensitivity 0.94

(3,1,1,1,1,1,1,1,1,1,3,1)

Jarvinen, 2003196

Cereals Milk

AD (SCORAD)

90 children (2.5-36 months) w/CMA (both IgE- and non-IgE-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?)

SPT cereal (wheat) Sensitivity: 0.23(0.17) Specificity: 1.0 (1.0) PPV: 1.0 (1.0) NPV: 0.32 (0.36)

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

SPT+APT Sensitivity: 0.73 (0.77) Specificity: 0.83 (0.17) PPV: 0.92 (0.85) NPV: 0.53 (0.59)

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)

346

Author, Yr



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 Sensitivity 0.91 Specificity 0.50 PPV 0.75 NPV 0.76

sIgE Cutoff point≥0.7kU/L Sensitivity 0.74 Specificity 0.79 PPV 0.85 NPV 0.65

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)

Lee, 2009193

Egg, milk, peanut, shrimp

Unspecified 283 Korean patients with suspected allergy from 1-75 years old

SPT sIgE Immulite 2000

sIgE FEIA UniCAP

% 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)

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

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

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

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)

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

ImunoCAP sIgE Peanut Cutoff: ≥13 kU/L

Se Sp PPV

NPV

0.60 0.96 0.99 0.35

Walnut Cutoff: ≥18.5 kU/L

Se Sp PPV

NPV

0.17 0.98 0.99 0.56

Only peanut and walnut had sIgE levels that reached 95% predictive probability (3,1,3,1,1,1,2,1,2,3,3,2)

347

Author, Yr



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 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

APT CM: Sensitivity 0.31 Specificity 0.95 PPV 0.86 NPV 0.60 Efficiency 0.63 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

SPT+APT CM: Sensitivity 0.69 Specificity 0.97 PPV 0.92 NPV 0.86 Efficiency 0.87 Egg: Sensitivity 0.85 Specificity 0.89 PPV 0.92 NPV 0.80 Efficiency: 0.87 Wheat: Sensitivity 0.43 Specificity 0.90 PPV 0.50 NPV 0.86 Efficiency 0.80 Soy: Sensitivity 0.14 Specificity 0.96 PPV: 0.43 NPV: 0.82 Efficiency: 0.79

sIgE CM: Sensitivity 0.87 Specificity 0.49 PPV 0.62; NPV 0.79 Efficiency 0.68 Egg: Sensitivity 96 Specificity 48 PPV 79 NPV85 Efficiency 80 Wheat: Sensitivity 0.82 Specificity 0.34 PPV 0.41 NPV0.77 Efficiency 0.51 Soy: Sensitivity 0.65 Specificity 0.50 PPV 0.22 NPV 0.86 Efficiency 0.52 (1,3,1,1,1,1,1,1,1,1,2,3)

Monti, Egg AD 107 children (1-19 Oral challenge SPT w/albumin Specific (3,3,1,1,1,1,1,1,2,1,3,1)

348

Author, Yr



2002176 mos) and yolk ≥5mm: Specificity: 1

IgEs Albumin>99KU/L Yolk ≥17.5 KU/L Specificity: 1

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

Antigen-Specific IgE: Correlated with +SPT to corresponding spice extracts

Clinical signs/symptoms of ingesting or handling spices: No correlation w/ SPT or specific IgE; only a minority seem to produce clinical symptoms

(3,2,3,1,1,1,1,1,1,1,3,3)

Osterballe, 2004169

CM and HE

Report of food hypersensitivity by questionnaire

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 Sp PPV

NPV

0.66 0.80 0.66 0.80

Hen’s Egg: 9/14 positive

Se Sp PPV

NPV

0.88 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 Sp PPV

NPV

0.0 1.00 0.0 0.62


Se Sp PPV

NPV

0.63 0.80 0.83 0.57

sIgE (Magic Lite) Cutoff: 1.43 sU/ml Cow’s milk: 5/8 positive

Se Sp PPV

NPV

0.66 0.40 0.40 0.66


Se Sp PPV

NPV

0.63 0.66 0.71 0.57

Basophil Histamine Release (n=305) Cutoff: ≥10ng/ml Cow’s milk: 3/8 positive

Se Sp PPV

NPV

0.66 0.80 0.66 0.80


Se Sp PPV

NPV

0.71 0.80 0.71 0.80

(1,2,1,3,2,1,1,1,1,1,2,1)

Prahl, 1988166

Milk CMA 26 children (aged 1-63 months) consecutively

Open food challenge Skin prick test with raw cow’s milk, positive test

sIgE (RAST) with raw

Basophil histamine

release test

(1,3,1,1,1,1,1,1,1,3,3,3)

349

Author, Yr



referred to a Danish university hospital allergy clinic for suspected cow milk allergy

defined as wheal diameter ≥ histamine (positive) control

Se

Sp

PPV

NPV

0.80

0.66

0.89

0.50

cow’s milk

Se Sp PPV

NPV

NPV

0.75

0.66

0.88

0.5

0.50.44

Se Sp PPV

NPV

0.75

0.66

0.88

0.44

Rance, 2002165

Peanut 363 children referred for suspected peanut allergy

DBPCFC: 177 + 186 --

SPT: NPV for raw extract =1 SPT>3mm: specificity 74% SPT≥16mm: PPV=1

sIgE (CAP) Median kUA/L + reax: 10 (0-100) - reax: 0 (0-56) kUA/L≥57: PPV=1

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)

Rancé, 2004170

Cow’s milk, fresh egg, peanut, wheat powder, soymilkmustard powder

AD 48 children, 3-29 months, consecutively recruited to a French pediatric hospital allergy clinic


APT Occlusion times: 1st row: 24 hr; 2nd row: 48 hr. Cow’s milk:

Se Sp PPV

NPV

0.18 1.00 1.00 0.63

0.89 0.96 0.94 0.92


V NPV

0.15 0.83 0.86 0.12

0.97 0.71 0.95 0.83

SPT Fresh foods Cutoff: ≥3mm greater than negative control and at least 50% greater than positive control Cow’s milk:

Se Sp PPV

NPV

0.59 0.50 0.91 0.56

Hen’s Egg:

sIgE Pharmacia Upjohn CAP FEIA Cutoff: ≥0.35kU/L Cow’s milk:

Se Sp PPV

NPV

0.31 0.66 0.83 0.15

Hen’s Egg:

Se Sp PPV

NPV

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)

350

Author, Yr



Wheat: Se Sp PP

V NPV

0.25 1.00 1.00 0.94

0.83 0.94 0.71 0.97

Peanut: Se Sp PP

V NPV

0.13 0.97 0.67 0.72

0.71 0.82 0.66 0.85

Se Sp PPV

NPV

0.93 0.50 0.97 0.66

Wheat:

Se Sp PPV

NPV

0.75 0.50 0.75 0.50

Peanut:

Se Sp PPV

NPV

0.70 0.50 0.60 0.55

0.65 0.75 0.96 0.21

Wheat:

Se Sp PPV

NPV

0.40 0.50 0.66 0.25

Peanut:

Se Sp PPV

NPV

0.53 0.66 0.89 0.21

Ricci, 2003168

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 Sp PPV

NPV

0.77 0.88 0.63 0.94


Se Sp PPV

NPV

0.91 0.77 0.65 0.95

sIgE Pharmacia UniCAP cutoff>0.35kU/L Cow’s milk

Se Sp PPV

NPV

0.91 0.70 0.44 0.97

Hen’s Egg

Se Sp PPV

NPV

0.94 0.64 0.55 0.96

sIgE ADVIA Centaur cutoff>0.35kU/L Cow’s milk:

Se Sp PPV

NPV

0.82 0.74 0.45 0.94

Hen’s Egg

Se Sp PPV

NPV

0.88 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)

351

Author, Yr



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

Se Sp PPV

NPV

0.79 0.38 0.42 0.77

sIgE Pharmacia ImmunoCAP cutoff>0.35kU/L

Se Sp PPV

NPV

0.53 0.62 0.44 0.70

SPT and sIgE not considered useful for diagnosis of melon allergy (1,1,1,3,1,1,1,3,1,1,3,1)

Roehr, 2001171

Milk, egg, wheat, soy

Food allergy in children with AD


71 DBPCFC with cow milk based on history 45/71 diagnosed with milk allergy

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)

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)

352

Author, Yr



reaction (see Tables 29-32)

Rottem, 2008187

Cow’s milk


All individuals seen between 1994 and 2006 for suspected milk allergy (1800 infants and children 0-18 years of age)

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

Immulite sIgE: 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 (1,1,1,2,1,1,1,1,2,1,2,2)

Saarinen, 2001172

Milk CMA 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


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)

APT

CM formula powder, bovine serum albumin, crystallized bovine BLG, and bovine casein (see Table 29)

sIgE CAP RAST (see Table 24)

Additional test: Serum Eosinophil Cationic Protein 15.0, 20.0, and 24.7 micrograms(g )/L. Cutoff ≥15.9g/L: sensitivity: 0.27 specificity: 0.74; PPV 0.67; NPV 0.34; Cutoff value 24.7g/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)

Sampson, 2001186

Egg, milk, peanut, soy, wheat, fish

Misc. atopy 100 consecutive children (0.4-14.3 yrs)

Hx or DBPCFC: Egg: n=75 Milk: 62 Peanut: 68 Fish: 8 Soybean: 25 Wheat: 23

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

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)

353

Author, Yr



Tainio, 1990183

Milk CMA (cutaneous, respiratory, and/or GI symptoms)

34 patients w/ suspected CMA (3-51 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

3. Serum IgG 4. Serum IgM 5-6. Complement fractions 3 and 4 7. CM-specific IgG 8. CM-specific IgM 9. CM-specific IgA 10-12. Lymphocyte stimulation with PHA, ConA, BLG

Combinations of tests: CM-specific IgE + BLG- mediated lymphocyte proliferation (LP): Sensitivity: 0.88 Specificity: 0.67

No one test alone had the sensitivity or specificity to predict challenge outcomes. The combination of CM-specific IgE and BLG-mediated LP was the best (1,3,1,1,1,1,1,1,1,3,3,3)

Wainstein,2007178

Peanut Peanut allergy



SPT SPT performed with commercial whole peanut extract; geometric mean of wheal calculated 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

sIgE Pharmacia CAP FEIA Cutoff: 0.37kU/L Sensitivity: 0.98, Specificity:0.33, PPV: 0.70 NPV: 0.92 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

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)

354

Author, Yr



Wananukul, 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

DBPCFC or OFC in 22 patients, recent history of anaphylactic reaction to foods in 5 patients

SPT Cutoff: not reported All foods together

Se Sp PPV

NPV

0.83 0.38 0.28 0.89

(1,1,1,3,2,1,1,3,1,1,2,1)

Wang, 2008192

Milk, Egg, Peanut

Not specified

50 consecutive patients at an allergy clinic, 3-18 years

ImmunoCAP (sIgE) Turbo-MP (sIgE): concordance with ImmunoCAP: milk 46%, egg 42%, peanut 56%

Immulite 2000 (sIgE): concordance with ImmunoCAP: 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 α-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).

355

Appendix I. Excluded Studies at screener level

Not a Food Allergy study

1. Abdullah AM. Aetiology of chronic diarrhoea in children: experience at King Khalid University Hospital, Riyadh, Saudi Arabia. 1994;14(2):111-7. 2. Arslan G, Kahrs GE, Lind R, Froyland L, Florvaag E, Berstad A. Patients with subjective food hypersensitivity: the value of analyzing intestinal permeability and inflammation markers in gut lavage fluid. 2004;70(1):26-35. 3. Arslan G, Odegaard S, Elsayed S, Florvaag E, Berstad A. Food allergy and intolerance: response to intestinal provocation monitored by endosonography. 2002;15(1-2):29-36. 4. Bachert C, van Cauwenberge P, Olbrecht J, van Schoor J. Prevalence, classification and perception of allergic and nonallergic rhinitis in Belgium. Allergy. 2006;61(6):693-8. 5. Banerji A, Long AA, Camargo CA, Jr. Diphenhydramine versus nonsedating antihistamines for acute allergic reactions: a literature review. 2007;28(4):418-26. 6. Barros R, Moreira A, Fonseca J, de Oliveira JF, Delgado L, Castel-Branco MG, et al. Adherence to the Mediterranean diet and fresh fruit intake are associated with improved asthma control. Allergy. 2008;63(7):917-23. 7. Bernhisel-Broadbent J, Strause D, Sampson HA. Fish hypersensitivity. II: Clinical relevance of altered fish allergenicity caused by various preparation methods. 1992;90(4 Pt 1):622-9. 8. Bernstein DI, Wanner M, Borish L, Liss GM. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J Allergy Clin Immunol. 2004;113(6):1129-36. 9. Bijlsma PB, Backhaus B, Weidenhiller M, Donhauser N, Hahn EG, Raithel M. Food allergy diagnosis by detection of antigen-induced electrophysiological changes and histamine release in human intestinal biopsies during mucosa-oxygenation. 2004;53 Suppl 1:S29-30. 10. Bloom DA, Buonomo C, Fishman SJ, Furuta G, Nurko S. Allergic colitis: a mimic of Hirschsprung disease. 1999;29(1):37-41. 11. Blyth TP, Sundrum R. Adrenaline autoinjectors and schoolchildren: a community based study. Arch Dis Child. 2002;86(1):26-7. 12. Bolhaar ST, Zuidmeer L, Ma Y, Ferreira F, Bruijnzeel-Koomen CA, Hoffmann-Sommergruber K, et al. A mutant of the major apple allergen, Mal d 1, demonstrating hypo-allergenicity in the target organ by double-blind placebo-controlled food challenge. 2005;35(12):1638-44.

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13. Boussault P, Leaute-Labreze C, Saubusse E, Maurice-Tison S, Perromat M, Roul S, et al. Oat sensitization in children with atopic dermatitis: prevalence, risks and associated factors. Allergy. 2007;62(11):1251-6. 14. Brown AF, McKinnon D, Chu K. Emergency department anaphylaxis: A review of 142 patients in a single year. 2001;108(5):861-6. 15. Burks AW, Christie L, Althage KA, Kesler JM, Allgood GS. Randomized, double-blind, placebo-controlled, food allergy challenge to olestra snacks. Regul Toxicol Pharmacol. 2001;34(2):178-81. 16. Caliskaner Z, Ozturk S, Turan M, Karaayvaz M. Skin test positivity to aeroallergens in the patients with chronic urticaria without allergic respiratory disease. J Investig Allergol Clin Immunol. 2004;14(1):50-4. 17. Chatzi L, Torrent M, Romieu I, Garcia-Esteban R, Ferrer C, Vioque J, et al. Mediterranean diet in pregnancy is protective for wheeze and atopy in childhood. Thorax. 2008;63(6):507-13. 18. Corbo GM, Forastiere F, De Sario M, Brunetti L, Bonci E, Bugiani M, et al. Wheeze and asthma in children: associations with body mass index, sports, television viewing, and diet. Epidemiology. 2008;19(5):747-55. 19. Darbari A, Kalloo AN, Cuffari C. Diagnostic yield, safety, and efficacy of push enteroscopy in pediatrics. 2006;64(2):224-8. 20. de Batlle J, Garcia-Aymerich J, Barraza-Villarreal A, Anto JM, Romieu I. Mediterranean diet is associated with reduced asthma and rhinitis in Mexican children. Allergy. 2008;63(10):1310-6. 21. Di Lorenzo G, Pacor ML, Mansueto P, Martinelli N, Esposito-Pellitteri M, Lo Bianco C, et al. Food-additive-induced urticaria: a survey of 838 patients with recurrent chronic idiopathic urticaria. Int Arch Allergy Immunol. 2005;138(3):235-42. 22. Dorner T, Muller KH, Schmidl H, Freidl W, Stronegger WJ, Lawrence K, et al. Subjective health and impaired quality of life due to allergies in a representative population survey. Wien Med Wochenschr. 2007;157(11-12):243-7. 23. Ebo DG, Hagendorens MM, Bridts CH, Schuerwegh AJ, De Clerck LS, Stevens WJ. Flow cytometric analysis of in vitro activated basophils, specific IgE and skin tests in the diagnosis of pollen-associated food allergy. 2005;64(1):28-33. 24. Forsyth JS, Ogston SA, Clark A, Florey CD, Howie PW. Relation between early introduction of solid food to infants and their weight and illnesses during the first two years of life. 1993;306(6892):1572-6.

357

25. Fox RA, Sabo BM, Williams TP, Joffres MR. Intradermal testing for food and chemical sensitivities: a double-blind controlled study. 1999;103(5 Pt 1):907-11. 26. Fuchs G, DeWier M, Hutchinson S, Sundeen M, Schwartz S, Suskind R. Gastrointestinal blood loss in older infants: impact of cow milk versus formula. 1993;16(1):4-9. 27. Fuglsang G MG, Halken S, Jorgensen S, Ostergaard PA, Osterballe O. Adverse reactions to food additives in children with atopic symptoms. Allergy. 1994;49(1):31-7. 28. Hausen BM, Andersen KE, Helander I, Gensch KH. Lettuce allergy: sensitizing potency of allergens. Contact Dermatitis. 1986;15(4):246-9. 29. Helbling A, Gayer F, Pichler WJ, Brander KA. Mushroom (Basidiomycete) allergy: diagnosis established by skin test and nasal challenge. J Allergy Clin Immunol. 1998;102(5):853-8. 30. Helou EF, Simonson J, Arora AS. 3-yr-follow-up of topical corticosteroid treatment for eosinophilic esophagitis in adults. 2008;103(9):2194-9. 31. Hijazi N, Abalkhail B, Seaton A. Diet and childhood asthma in a society in transition: a study in urban and rural Saudi Arabia. 2000;55(9):775-9. 32. Hourihane JO, Bedwani SJ, Dean TP, Warner JO. Randomised, double blind, crossover challenge study of allergenicity of peanut oils in subjects allergic to peanuts. 1997;314(7087):1084-8. 33. James JME, P. A. Eggleston, P. A. Sampson, H. A. Airway reactivity changes in asthmatic patients undergoing blinded food challenges. Am J Respir Crit Care Med. 1996 Feb;153(2):597-603. 34. Kapel RC, Miller JK, Torres C, Aksoy S, Lash R, Katzka DA. Eosinophilic esophagitis: a prevalent disease in the United States that affects all age groups. 2008;134(5):1316-21. 35. Kumar V, Zane H, Kaul N. Serologic markers of gluten-sensitive enteropathy in bullous diseases. 1992;128(11):1474-8. 36. Kummeling I, Stelma FF, Dagnelie PC, Snijders BE, Penders J, Huber M, et al. Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study. Pediatrics. 2007;119(1):e225-31. 37. Lee CM, Changchien CS, Chen PC, Lin DY, Sheen IS, Wang CS, et al. Eosinophilic gastroenteritis: 10 years experience. 1993;88(1):70-4. 38. Lewis HM, Renaula TL, Garioch JJ, Leonard JN, Fry JS, Collin P, et al. Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis.

358

1996;135(3):363-7. 39. Liccardi GS, A. Spadaro, G. Senna, G. Canonica, W. G. D'Amato, G. Passalacqua, G. Anaphylaxis caused by skin prick testing with aeroallergens: Case report and evaluation of the risk in Italian allergy services. J Allergy Clin Immunol. 2003 Jun;111(6):1410-2. 40. Lowe AJ, Hosking CS, Bennett CM, Carlin JB, Abramson MJ, Hill DJ, et al. Skin prick test can identify eczematous infants at risk of asthma and allergic rhinitis. 2007;37(11):1624-31. 41. Martelli A, Bouygue GR, Isoardi P, Marelli O, Sarratud T, Fiocchi A. Oral food challenges in children in Italy. 2005;60(7):907-11. 42. Miyake Y, Sasaki S, Arakawa M, Tanaka K, Murakami K, Ohya Y. Fatty acid intake and asthma symptoms in Japanese children: the Ryukyus Child Health Study. Clin Exp Allergy. 2008;38(10):1644-50. 43. Morales Suarez-Varela MM, Garcia-Marcos Alvarez L, Gonzalez Diaz C, Arnedo Pena A, Dominguez Aurrecoechea B, Busquets Monge RM, et al. [Prevalence of atopic eczema and nutritional factors in 6-7 year old children]. Aten Primaria. 2007;39(7):355-60. 44. Morris ER, West J, Morgan JB, Hampton SM. Enzyme-linked immunosorbent assays for gliadin and ovalbumin and their application in normal subjects. 1993;47(9):673-7. 45. Morton RE, Nysenbaum A, Price K. Iron status in the first year of life. 1988;7(5):707-12. 46. Muller S, Puhl S, Vieth M, Stolte M. Analysis of symptoms and endoscopic findings in 117 patients with histological diagnoses of eosinophilic esophagitis. 2007;39(4):339-44. 47. Okoko BJ, Burney PG, Newson RB, Potts JF, Shaheen SO. Childhood asthma and fruit consumption. Eur Respir J. 2007;29(6):1161-8. 48. Olsen SF, Osterdal ML, Salvig JD, Mortensen LM, Rytter D, Secher NJ, et al. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial. Am J Clin Nutr. 2008;88(1):167-75. 49. O'Mahony S, Vestey JP, Ferguson A. Similarities in intestinal humoral immunity in dermatitis herpetiformis without enteropathy and in coeliac disease. 1990;335(8704):1487-90. 50. Pacor ML, Di Lorenzo G, Corrocher R. Efficacy of leukotriene receptor antagonist in chronic urticaria. A double-blind, placebo-controlled comparison of treatment with montelukast and cetirizine in patients with chronic urticaria with intolerance to food additive and/or acetylsalicylic acid. Clin Exp Allergy. 2001;31(10):1607-14. 51. Paganelli RA, I. J. Sastre, J. Lange, C. E. Roovers, M. H. de Groot, H. Lindholm, N. B. Ewan, P. W. Specific IgE antibodies in the diagnosis of atopic disease. Clinical evaluation of a new in vitro test system, UniCAP, in six European allergy clinics. Allergy. 1998 Aug;53(8):763-

359

8. 52. Park HW, Park CH, Park SH, Park JY, Park HS, Yang HJ, et al. Dermatologic adverse reactions to 7 common food additives in patients with allergic diseases: a double-blind, placebo-controlled study. J Allergy Clin Immunol. 2008;121(4):1059-61. 53. Paronen J, Bjorksten B, Hattevig G, Akerblom HK, Vaarala O. Effect of maternal diet during lactation on development of bovine insulin-binding antibodies in children at risk for allergy. J Allergy Clin Immunol. 2000;106(2):302-6. 54. Pauli G, Oster JP, Deviller P, Heiss S, Bessot JC, Susani M, et al. Skin testing with recombinant allergens rBet v 1 and birch profilin, rBet v 2: diagnostic value for birch pollen and associated allergies. J Allergy Clin Immunol. 1996;97(5):1100-9. 55. Potter PC, Crombie I, Marian A, Kosheva O, Maqula B, Schinkel M. Latex allergy at Groote Schuur Hospital--prevalence, clinical features and outcome. S Afr Med J. 2001;91(9):760-5. 56. Quaranta JH, Rohr AS, Rachelefsky GS, Siegel SC, Katz RM, Spector SL, et al. The natural history and response to therapy of chronic urticaria and angioedema. Ann Allergy. 1989;62(5):421-4. 57. Raphael G, Raphael MH, Kaliner M. Gustatory rhinitis: a syndrome of food-induced rhinorrhea. J Allergy Clin Immunol. 1989;83(1):110-5. 58. Reha CM, Ebru A. Specific immunotherapy is effective in the prevention of new sensitivities. Allergol Immunopathol (Madr). 2007;35(2):44-51. 59. Renz-Polster H, David MR, Buist AS, Vollmer WM, O'Connor EA, Frazier EA, et al. Caesarean section delivery and the risk of allergic disorders in childhood. Clin Exp Allergy. 2005;35(11):1466-72. 60. Roduit C, Scholtens S, de Jongste JC, Wijga AH, Gerritsen J, Postma DS, et al. Asthma at 8 years of age in children born by caesarean section. Thorax. 2009;64(2):107-13. 61. Sackesen C, Sekerel BE, Orhan F, Kocabas CN, Tuncer A, Adalioglu G. The etiology of different forms of urticaria in childhood. Pediatr Dermatol. 2004;21(2):102-8. 62. Salvatori N, Reccardini F, Convento M, Purinan A, Colle R, De Carli S, et al. Asthma induced by inhalation of flour in adults with food allergy to wheat. Clin Exp Allergy. 2008;38(8):1349-56. 63. Sgouros SN, Bergele C, Mantides A. Schatzki's rings are not associated with eosinophilic esophagitis. 2006;63(3):535-6; author reply 6. 64. Shaheen SON, K. Newson, R. B. Emmett, P. M. Sherriff, A. Henderson, A. J. Dietary

360

patterns in pregnancy and respiratory and atopic outcomes in childhood. Thorax. 2009 May;64(5):411-7. 65. Sheikh A, ten Broek V, Brown SG, Simons FE. H1-antihistamines for the treatment of anaphylaxis with and without shock. 2007(1):CD006160. 66. Sheikh A, Ten Broek V, Brown SG, Simons FE. H1-antihistamines for the treatment of anaphylaxis: Cochrane systematic review. 2007;62(8):830-7. 67. Simpson CR, Newton J, Hippisley-Cox J, Sheikh A. Incidence and prevalence of multiple allergic disorders recorded in a national primary care database. J R Soc Med. 2008;101(11):558-63. 68. Soares RL, Figueiredo HN, Maneschy CP, Rocha VR, Santos JM. Correlation between symptoms of the irritable bowel syndrome and the response to the food extract skin prick test. 2004;37(5):659-62. 69. Spanier JA, Howden CW, Jones MP. A systematic review of alternative therapies in the irritable bowel syndrome. Arch Intern Med. 2003;163(3):265-74. 70. Steiss JO, Strohner P, Zimmer KP, Lindemann H. Reduction of the total IgE level by omalizumab in children and adolescents. J Asthma. 2008;45(3):233-6. 71. Takaoka M, Norback D. Diet among Japanese female university students and asthmatic symptoms, infections, pollen and furry pet allergy. Respir Med. 2008;102(7):1045-54. 72. Teuber SS, Vogt PJ. An unproven technique with potentially fatal outcome: provocation/neutralization in a patient with systemic mastocytosis. Ann Allergy Asthma Immunol. 1999;82(1):61-5. 73. Thong BY, Cheng YK, Leong KP, Tang CY, Chng HH. Anaphylaxis in adults referred to a clinical immunology/allergy centre in Singapore. Singapore Med J. 2005;46(10):529-34. 74. Turkeltaub PC, Gergen PJ. The risk of adverse reactions from percutaneous prick-puncture allergen skin testing, venipuncture, and body measurements: data from the second National Health and Nutrition Examination Survey 1976-80 (NHANES II). J Allergy Clin Immunol. 1989;84(6 Pt 1):886-90. 75. Turner S, Zhang G, Young S, Cox M, Goldblatt J, Landau L, et al. Associations between postnatal weight gain, change in postnatal pulmonary function, formula feeding and early asthma. Thorax. 2008;63(3):234-9. 76. van Kampen V, Rabstein S, Sander I, Merget R, Bruning T, Broding HC, et al. Prediction of challenge test results by flour-specific IgE and skin prick test in symptomatic bakers. Allergy. 2008;63(7):897-902.

361

77. van Odijk J, Hulthen L, Ahlstedt S, Borres MP. Introduction of food during the infant's first year: a study with emphasis on introduction of gluten and of egg, fish and peanut in allergy-risk families. Acta Paediatr. 2004;93(4):464-70. 78. Vance GH, Thornton CA, Bryant TN, Warner JA, Warner JO. Ovalbumin-specific immunoglobulin G and subclass responses through the first 5 years of life in relation to duration of egg sensitization and the development of asthma. 2004;34(10):1542-9. 79. Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol. 2006;97(1):39-43. 80. Weiland SK, von Mutius E, Hirsch T, Duhme H, Fritzsch C, Werner B, et al. Prevalence of respiratory and atopic disorders among children in the East and West of Germany five years after unification. 1999;14(4):862-70. 81. Wickman M. Experience with quantitative IgE antibody analysis in relation to allergic disease within the BAMSE birth cohort--towards an improved diagnostic process. 2004;59 Suppl 78:30-1. 82. Willers SM, Devereux G, Craig LC, McNeill G, Wijga AH, Abou El-Magd W, et al. Maternal food consumption during pregnancy and asthma, respiratory and atopic symptoms in 5-year-old children. Thorax. 2007;62(9):773-9. 83. Williams PBD, W. K. Koepke, J. W. Selner, J. C. Comparison of skin testing and three in vitro assays for specific IgE in the clinical evaluation of immediate hypersensitivity. Ann Allergy. 1992 Jan;68(1):35-45. 84. Yamada K, Urisu A, Morita Y, Kondo Y, Wada E, Komada H, et al. Immediate hypersensitive reactions to buckwheat ingestion and cross allergenicity between buckwheat and rice antigens in subjects with high levels of IgE antibodies to buckwheat. 1995;75(1):56-61. 85. Yang MS, Lee SH, Kim TW, Kwon JW, Lee SM, Kim SH, et al. Epidemiologic and clinical features of anaphylaxis in Korea. Ann Allergy Asthma Immunol. 2008;100(1):31-6. 86. Zaenglein AL, Hafer L, Helm KF. Diagnosis of dermatitis herpetiformis by an avidin-biotin-peroxidase method. 1995;131(5):571-3. 87. Zeiger RS HS. Development of nasal basophilic cells and nasal eosinophils from age 4 months through 4 years in children of atopic parents. The Journal of allergy and clinical immunology. 1993;91(3):723-34. .

362

Not original data or a systematic review

1. Aalberse RC, Stapel SO, van Ree R. Standardization of in vivo and in vitro diagnostic procedures in food allergy. Allergy. 1998;53(46 Suppl):62-4. 2. Ahlstedt S, Holmquist I, Kober A, Perborn H. Accuracy of specific IgE antibody assays for diagnosis of cow's milk allergy. Ann Allergy Asthma Immunol. 2002;89(6 Suppl 1):21-5. 3. Allen KJK, J. J. Gould, C. Osborne, N. J. Prevalence of self-reported allergies to food in Australia as assessed by Internet-based questionnaires. Med J Aust. 2009 Jan 5;190(1):46-7. 4. Anderson JM, K. Snell, R. Is 6 months still the best for exclusive breastfeeding and introduction of solids? A literature review with consideration to the risk of the development of allergies. Breastfeed Rev. 2009 Jul;17(2):23-31. 5. Andres C, Chen WC, Ollert M, Mempel M, Darsow U, Ring J. Anaphylactic Reaction to Camomile Tea. Allergol Int. 2008;58(1). 6. Arshad SH. Primary prevention of asthma and allergy. J Allergy Clin Immunol. 2005 Jul;116(1):3-14; quiz 5. 7. Asero RF-R, M. Knulst, A. C. Bruijnzeel-Koomen, C. A. Double-blind, placebo-controlled food challenge in adults in everyday clinical practice: a reappraisal of their limitations and real indications. Curr Opin Allergy Clin Immunol. 2009 Aug;9(4):379-85. 8. Assa'ad AH. Gastrointestinal food allergy and intolerance. Pediatr Ann. 2006;35(10):718-26. 9. Bahna SL. Oral desensitization with cow's milk in IgE-mediated cow's milk allergy. Contra! Monogr Allergy. 1996;32:233-5. 10. Bahna SL. Clinical expressions of food allergy. Ann Allergy Asthma Immunol. 2003;90(6 Suppl 3):41-4. 11. Bahna SL. Adverse food reactions by skin contact. Allergy. 2004 Aug;59 Suppl 78:66-70. 12. Bahna SL. Hypoallergenic formulas: optimal choices for treatment versus prevention. Ann Allergy Asthma Immunol. 2008 Nov;101(5):453-9; quiz 9-61, 81. 13. Bahna SL. Reflections on current food allergy controversies: specific IgE test application, patch testing, eosinophilic esophagitis, and probiotics. Allergy Asthma Proc. 2008;29(5):447-52. 14. Barbi E, Berti I, Longo G. Food allergy: from the of loss of tolerance induced by exclusion diets to specific oral tolerance induction. Recent Pat Inflamm Allergy Drug Discov. 2008;2(3):212-4.

363

15. Berni Canani R, Ruotolo S, Discepolo V, Troncone R. The diagnosis of food allergy in children. Curr Opin Pediatr. 2008;20(5):584-9. 16. Beyer K, Wahn U. Oral immunotherapy for food allergy in children. Curr Opin Allergy Clin Immunol. 2008;8(6):553-6. 17. Brancaccio RR, Alvarez MS. Contact allergy to food. Dermatol Ther. 2004;17(4):302-13. 18. Breuer K, Kapp A, Werfel T. [The impact of food allergy in patients with atopic dermatitis]. Hautarzt. 2003;54(2):121-9. 19. Brown HM. Would oral desensitization for peanut allergy be safer than avoidance? Ann Allergy Asthma Immunol. 2007 Feb;98(2):203. 20. Burks AW. Peanut allergy. Lancet. 2008;371(9623):1538-46. 21. Canonica GW, Passalacqua G. Is sublingual immunotherapy the final answer? Implications for the allergist. World Allergy Organization Journal. 2008;1(5):73. 22. Cantani A. Nutrition of allergic babies and children. Eur Rev Med Pharmacol Sci. 1999;3(5):233-4. 23. Chan EF, Mowad C. Contact dermatitis to foods and spices. Am J Contact Dermat. 1998;9(2):71-9. 24. Charlesworth EN. Urticaria and angioedema. Allergy Asthma Proc. 2002;23(5):341-5. 25. Ciaccio CE, Portnoy JM. Strategies for primary prevention of atopy in children. Curr Allergy Asthma Rep. 2008;8(6):493-9. 26. Clark PJ. Utility of eosinophilia as a diagnostic clue in lower abdominal pain in northern Australia: a retrospective case-control study. Intern Med J. 2008;38(4):278-80. 27. Cochrane SB, K. Clausen, M. Wjst, M. Hiller, R. Nicoletti, C. Szepfalusi, Z. Savelkoul, H. Breiteneder, H. Manios, Y. Crittenden, R. Burney, P. Factors influencing the incidence and prevalence of food allergy. Allergy. 2009 Aug 5. 28. Darsow U, Ring J. [Atopy patch testing with aeroallergens and food]. Hautarzt. 2005;56(12):1133-40. 29. de Boissieu D. [Do breast-feeding and "diet" milks have any preventive or curative effect in the management of atopic dermatitis in children?]. Ann Dermatol Venereol. 2005;132 Spec No 1:1S104-11. 30. de Seta L, Siani P, Cirillo G, Di Gruttola M, Cimaduomo L, Coletta S. [The prevention of

364

allergic diseases with a hypoallergenic formula: a follow-up at 24 months. The preliminary results]. Pediatr Med Chir. 1994;16(3):251-4. 31. de Weck AL, Sanz ML. Cellular allergen stimulation test (CAST) 2003, a review. J Investig Allergol Clin Immunol. 2004;14(4):253-73. 32. de Weck AL, Sanz ML, Gamboa PM, Aberer W, Bienvenu J, Blanca M, et al. Diagnostic tests based on human basophils: more potentials and perspectives than pitfalls. Int Arch Allergy Immunol. 2008;146(3):177-89. 33. Dreborg S. Histamine reactivity of the skin. Allergy. 2001;56(5):359-64. 34. Dupont C, de Boissieu D. [Treatment of severe cow's milk protein allergy using Neocate.]. Allerg Immunol (Paris). 2002;34(3):85-90. 35. Ferre-Ybarz LNF, S. Plaza-Martin, A. M. Eosinophilic oesophagitis: clinical manifestations and treatment options. The role of the allergologist. Allergol Immunopathol (Madr). 2008 Nov-Dec;36(6):358-65. 36. Fleischer DM. The natural history of peanut and tree nut allergy. Curr Allergy Asthma Rep. 2007 Jun;7(3):175-81. 37. Furuta GT, Straumann A. Review article: the pathogenesis and management of eosinophilic oesophagitis. Aliment Pharmacol Ther. 2006;24(2):173-82. 38. Gangur V, Kelly C, Navuluri L. Sesame allergy: a growing food allergy of global proportions? Ann Allergy Asthma Immunol. 2005;95(1):4-11; quiz -3, 44. 39. Gonsalves NK, P. J. Eosinophilic oesophagitis in adults. Neurogastroenterol Motil. 2009 Apr 13. 40. Gosbee LL. Nuts! I can't figure out how to use my life-saving epinephrine auto-injector! Jt Comm J Qual Saf. 2004;30(4):220-3. 41. Greer FR, Sicherer SH, Burks AW. 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. Pediatrics. 2008;121(1):183-91. 42. Gupte ARD, P. V. Eosinophilic esophagitis. World J Gastroenterol. 2009 Jan 7;15(1):17-24. 43. Hafeez ZH. The role of diet in allergic dermatoses. J Pak Med Assoc. 1998;48(2):45-7. 44. Hanifin JM, Cooper KD, Ho VC, Kang S, Krafchik BR, Margolis DJ, et al. Guidelines of care for atopic dermatitis, developed in accordance with the American Academy of Dermatology

365

(AAD)/American Academy of Dermatology Association "Administrative Regulations for Evidence-Based Clinical Practice Guidelines". J Am Acad Dermatol. 2004;50(3):391-404. 45. Hauk PJ. The role of food allergy in atopic dermatitis. Curr Allergy Asthma Rep. 2008;8(3):188-94. 46. Hausen BM, Hjorth N. Skin reactions to topical food exposure. Dermatologic Clinics. 1984;2(4):567-78. 47. Heine RG, Elsayed S, Hosking CS, Hill DJ. Cow's milk allergy in infancy. Curr Opin Allergy Clin Immunol. 2002;2(3):217-25. 48. Henz BM, Zuberbier T. Most chronic urticaria is food-dependent, and not idiopathic. Exp Dermatol. 1998;7(4):139-42. 49. Hill DJ, Ford RP, Shelton MJ, Hosking CS. A study of 100 infants and young children with cow's milk allergy. Clin Rev Allergy. 1984;2(2):125-42. 50. Hill DJ, Heine RG, Hosking CS. The diagnostic value of skin prick testing in children with food allergy. Pediatr Allergy Immunol. 2004;15(5):435-41. 51. Hill DJH, C. S. Some limitations of double-blind, placebo-controlled food challenges in young children. J Allergy Clin Immunol. 1991 Jan;87(1 Pt 1):136-7. 52. Host A. Frequency of cow's milk allergy in childhood. Ann Allergy Asthma Immunol. 2002;89(6 Suppl 1):33-7. 53. Host A, Halken S. Hypoallergenic formulas--when, to whom and how long: after more than 15 years we know the right indication! Allergy. 2004;59 Suppl 78:45-52. 54. Kagan RS. Food allergy: an overview. Environ Health Perspect. 2003;111(2):223-5. 55. Kalliomaki MA. Food allergy and irritable bowel syndrome. Curr Opin Gastroenterol. 2005;21(6):708-11. 56. Keil T. Epidemiology of food allergy: what's new? A critical appraisal of recent population-based studies. Curr Opin Allergy Clin Immunol. 2007;7(3):259-63. 57. Kemp AS. Egg allergy. Pediatr Allergy Immunol. 2007;18(8):696-702. 58. Kim JS. Food allergy: diagnosis, treatment, prognosis, and prevention. Pediatr Ann. 2008;37(8):546-51. 59. Kirchlechner V, Dehlink E, Szepfalusi Z. [Cow's milk allergy: guidelines for the diagnostic evaluation]. Klin Padiatr. 2007;219(4):201-5.

366

60. Knight AK, Bahna SL. Diagnosis of food allergy. Pediatr Ann. 2006;35(10):709-14. 61. Kramer MS. Maternal antigen avoidance during lactation for preventing atopic eczema in infants. Cochrane Database Syst Rev. 2000(2):CD000131. 62. Ladoyanni E, Cheung ST, North J, Tan CY. Pellagra occurring in a patient with atopic dermatitis and food allergy. J Eur Acad Dermatol Venereol. 2007;21(3):394-6. 63. Lau S, Nickel R, Niggemann B, Gruber C, Sommerfeld C, Illi S, et al. The development of childhood asthma: lessons from the German Multicentre Allergy Study (MAS). Paediatr Respir Rev. 2002;3(3):265-72. 64. Lee BW, Shek LP, Gerez IFA, Soh SE, Van Bever HP. Food allergy-lessons from Asia. World Allergy Organization Journal. 2008;1(8):134. 65. Leinhas JL MC, Sampson HA. Food allergy challenges: guidelines and implications. Journal of the American Dietetic Association. 1987;87(5):604-8. 66. Lidholm J, Ballmer-Weber BK, Mari A, Vieths S. Component-resolved diagnostics in food allergy. Curr Opin Allergy Clin Immunol. 2006;6(3):234-40. 67. Lisi AJ. Chiropractic management of cow's milk protein intolerance in infants with sleep dysfunction syndrome: a therapeutic trial. J Manipulative Physiol Ther. 2007;30(3):247. 68. Losanoff JE, Sauter ER. Eosinophilic gastroenteritis: review of the literature. Dig Dis Sci. 2003;48(11):2214; author reply 5. 69. Lucas A, Brooke OG, Morley R, Cole TJ, Bamford MF. Early diet of preterm infants and development of allergic or atopic disease: randomised prospective study. BMJ. 1990;300(6728):837-40. 70. Magazzu G, Scoglio R. Gastrointestinal manifestations of cow's milk allergy. Ann Allergy Asthma Immunol. 2002;89(6 Suppl 1):65-8. 71. Miceli Sopo S, Radzik D, Calvani M. The predictive value of specific immunoglobulin E levels for the first diagnosis of cow's milk allergy. A critical analysis of pediatric literature. Pediatr Allergy Immunol. 2007;18(7):575-82. 72. Mickleborough TD. A nutritional approach to managing exercise-induced asthma. Exerc Sport Sci Rev. 2008;36(3):135-44. 73. Miniello VL, Francavilla R, Brunetti L, Franco C, Lauria B, Lieggi MS, et al. [Primary allergy prevention: partially or extensively hydrolyzed infant formulas?]. Minerva Pediatr. 2008;60(6):1437-43. 74. Moawad FJV, G. R. Wong, R. K. Eosinophilic esophagitis. Dig Dis Sci. 2009

367

Sep;54(9):1818-28. 75. Moneret-Vautrin DA, Gay G. [The so-called "idiopathic" anaphylaxis: allergic and pseudo-allergic reactions]. Allerg Immunol (Paris). 1991;23(3):89-93. 76. Muller UR. [Severe allergic-immunologic reactions]. Praxis (Bern 1994). 1997;86(8):314-8. 77. Munoz-Furlong AW, C. C. Characteristics of food-allergic patients placing them at risk for a fatal anaphylactic episode. Curr Allergy Asthma Rep. 2009 Jan;9(1):57-63. 78. Muraro A, Dreborg S, Halken S, Host A, Niggemann B, Aalberse R, et al. Dietary prevention of allergic diseases in infants and small children. Part II. Evaluation of methods in allergy prevention studies and sensitization markers. Definitions and diagnostic criteria of allergic diseases. Pediatr Allergy Immunol. 2004;15(3):196-205. 79. Nowak-Wegrzyn AAa, A. H. Bahna, S. L. Bock, S. A. Sicherer, S. H. Teuber, S. S. Work Group report: oral food challenge testing. J Allergy Clin Immunol. 2009 Jun;123(6 Suppl):S365-83. 80. Oranje AP, Wolkerstorfer A, de Waard-van der Spek FB. Natural course of cow's milk allergy in childhood atopic eczema/dermatitis syndrome. Ann Allergy Asthma Immunol. 2002;89(6 Suppl 1):52-5. 81. Ortolani C, Pastorello E, Ispano M, Ansaloni R. Food allergy diagnosis protocol. Allerg Immunol (Paris). 1988;20(2):48-50. 82. Ozdemir O, Mete E, Catal F, Ozol D. Food intolerances and eosinophilic esophagitis in childhood. Dig Dis Sci. 2009;54(1):8-14. 83. Passalacqua G, Compalati E, Schiappoli M, Senna G. Complementary and alternative medicine for the treatment and diagnosis of asthma and allergic diseases. Monaldi Arch Chest Dis. 2005;63(1):47-54. 84. Peroni DG, Chatzimichail A, Boner AL. Food allergy: what can be done to prevent progression to asthma? Ann Allergy Asthma Immunol. 2002;89(6 Suppl 1):44-51. 85. Ring J. Allergen-specific immunotherapy in food allergy: There is hope. World Allergy Organization Journal. 2008;1(5):73. 86. Rippere V. Food allergy: how much in the mind? Lancet. 1983;2(8340):45. 87. Rosetta L, Baldi A. On the role of breastfeeding in health promotion and the prevention of allergic diseases. Adv Exp Med Biol. 2008;606:467-83. 88. Sampson HA. The role of food allergy and mediator release in atopic dermatitis. J

368

Allergy Clin Immunol. 1988;81:635-45. 89. Sampson HA. The immunopathogenic role of food hypersensitivity in atopic dermatitis. Acta Derm Venereol Suppl (Stockh). 1992;176:34-7. 90. Schafer T. The impact of allergy on atopic eczema from data from epidemiological studies. Curr Opin Allergy Clin Immunol. 2008;8(5):418-22. 91. Segal M, Stokes JR, Casale TB. Anti-Immunoglobulin E therapy. World Allergy Organization Journal. 2008;1(10):174-83. 92. Seidman EG, Singer S. Therapeutic modalities for cow's milk allergy. Ann Allergy Asthma Immunol. 2003;90(6 Suppl 3):104-11. 93. Sicherer SH. Determinants of systemic manifestations of food allergy. J Allergy Clin Immunol. 2000;106(5 Suppl):S251-7. 94. Sicherer SH. Advances in anaphylaxis and hypersensitivity reactions to foods, drugs, and insect venom. J Allergy Clin Immunol. 2003;111(3 Suppl):S829-34. 95. Sicherer SH. Food for thought on prevention and treatment of atopic disease through diet. J Pediatr. 2007;151(4):331-3. 96. Sicherer SH, Leung DY. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2008. J Allergy Clin Immunol. 2009;123(2):319-27. 97. Simon RA. Adverse reactions to food additives. Curr Allergy Asthma Rep. 2003;3(1):62-6. 98. Simons FE, Frew AJ, Ansotegui IJ, Bochner BS, Golden DB, Finkelman FD, et al. Risk assessment in anaphylaxis: current and future approaches. J Allergy Clin Immunol. 2007;120(1 Suppl):S2-24. 99. Simpson AC, A. Prevention of allergic sensitization by environmental control. Curr Allergy Asthma Rep. 2009 Sep;9(5):363-9. 100. Sladden MJ, Johnston GA. Complete resolution of dermatitis herpetiformis with the Atkins' diet. Br J Dermatol. 2006;154(3):565-6. 101. Spears GC, Miyazawa NK, Gleason MC, Gyorkos EA, Wilson CG, Murphy JR, et al., editors. Over-reliance on serum testing for IgE to foods results in inappropriate food elimination diets. Annual meeting of the NAAAI; 2009 March. 102. Spergel JM, Brown-Whitehorn T. The use of patch testing in the diagnosis of food allergy. Curr Allergy Asthma Rep. 2005;5(1):86-90.

369

103. Stone KD, Prussin C. Immunomodulatory therapy of eosinophil-associated gastrointestinal diseases. Clin Exp Allergy. 2008;38(12):1858-65. 104. Straumann A. Clinical evaluation of the adult who has eosinophilic esophagitis. Immunol Allergy Clin North Am. 2009;29(1):11-8, vii. 105. Tang MM, R. J. Is "nut-free" sunflower seed butter safe for children with peanut allergy? Comment. Med J Aust. 2008 Mar 3;188(5):316. 106. Torgerson TRL, A. Moes, N. Anover, S. Mateo, V. Rieux-Laucat, F. Hermine, O. Vijay, S. Gambineri, E. Cerf-Bensussan, N. Fischer, A. Ochs, H. D. Goulet, O. Ruemmele, F. M. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology. 2007 May;132(5):1705-17. 107. Tuokkola J, Kaila M, Pietinen P, Simell O, Knip M, Virtanen SM. Agreement between parental reports and patient records in food allergies among infants and young children in Finland. J Eval Clin Pract. 2008;14(6):984-9. 108. Turck D. Soy protein for infant feeding: what do we know? Curr Opin Clin Nutr Metab Care. 2007;10(3):360-5. 109. Veien NK. Ingested food in systemic allergic contact dermatitis. Clin Dermatol. 1997;15(4):547-55. 110. Wahn UvM, E. Childhood risk factors for atopy and the importance of early intervention. J Allergy Clin Immunol. 2001 Apr;107(4):567-74. 111. Weidenhiller M. [Food intolerance--etiology of functional disorders and therapeutic possibilities]. Med Monatsschr Pharm. 2006;29(9):320-6; quiz 7-8. 112. Wennergren G. What if it is the other way around? Early introduction of peanut and fish seems to be better than avoidance. Acta Paediatr. 2009 Jul;98(7):1085-7. 113. Werfel T. Skin manifestations in food allergy. Allergy. 2001;56 Suppl 67:98-101. 114. Werfel T, Breuer K. Role of food allergy in atopic dermatitis. Curr Opin Allergy Clin Immunol. 2004;4(5):379-85. 115. Whorwell P, Lea R. Dietary Treatment of the Irritable Bowel Syndrome. Curr Treat Options Gastroenterol. 2004;7(4):307-16. 116. Yoo J, Tcheurekdjian H, Lynch SV, Cabana M, Boushey HA. Microbial manipulation of immune function for asthma prevention: inferences from clinical trials. Proc Am Thorac Soc. 2007;4(3):277-82.

370

Not Incidence/Prevalence/Natural History, Diagnosis, Treatment/Management/Prevention, or Background

1. Bock SA, Atkins FM. Patterns of food hypersensitivity during sixteen years of double-blind, placebo-controlled food challenges. J Pediatr. 1990;117(4):561-7. 2. Bollinger ME, Dahlquist LM, Mudd K, Sonntag C, Dillinger L, McKenna K. The impact of food allergy on the daily activities of children and their families. Ann Allergy Asthma Immunol. 2006;96(3):415-21. 3. Boyano-Martinez T, Garcia-Ara C, Pedrosa M, Diaz-Pena JM, Quirce S. Accidental allergic reactions in children allergic to cow's milk proteins. J Allergy Clin Immunol. 2009;123(4):883-8. 4. Cantani A, Micera M. Can skin prick tests provoke severe allergic reactions? Eur Rev Med Pharmacol Sci. 2000;4(5-6):145-8. 5. Charlesworth EN, Kagey-Sobotka A, Norman PS, Lichtenstein LM, Sampson HA. Cutaneous late-phase response in food-allergic children and adolescents with atopic dermatitis. 1993;23(5):391-7. 6. Codreanu F, Moneret-Vautrin DA, Morisset M, Guenard L, Rance F, Kanny G, et al. The risk of systemic reactions to skin prick-tests using food allergens: CICBAA data and literature review. Eur Ann Allergy Clin Immunol. 2006;38(2):52-4. 7. Crespo JF, Pascual C, Ferrer A, Burks AW, Diaz Pena JM, Martin Esteban M. Egg white-specific IgE level as a tolerance marker in the follow up of egg allergy. 1994;15(2):73-6. 8. Cruz NV, Wilson BG, Fiocchi A, Bahna SL. Survey of physicians' approach to food allergy, Part 1: Prevalence and manifestations. Ann Allergy Asthma Immunol. 2007;99(4):325-33. 9. Davis RF, Mortimer NJ, Sladden MJ, Johnston GA. The use of dietary manipulation in patients referred to a contact dermatitis clinic. Br J Dermatol. 2008;158(3):639-40. 10. Dawson KP, Ford RP, Mogridge N. Childhood asthma: what do parents add or avoid in their children's diets? N Z Med J. 1990;103(890):239-40. 11. Dean T, Venter C, Pereira B, Grundy J, Clayton CB, Higgins B. Government advice on peanut avoidance during pregnancy--is it followed correctly and what is the impact on sensitization? J Hum Nutr Diet. 2007;20(2):95-9. 12. Devenney I, Falth-Magnusson K. Skin prick tests may give generalized allergic reactions in infants. Ann Allergy Asthma Immunol. 2000;85(6 Pt 1):457-60. 13. Enrique E MT, Pineda F, Palacios R, Bartra J, Tella R, Basagana M, Alonso R, Cistero-

371

Bahima A. Sublingual immunotherapy for hazelnut food allergy: a follow-up study. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2008;100(3):283-4. 14. Fergusson DM, Horwood LJ. Early solid food diet and eczema in childhood: a 10-year longitudinal study. 1994;5(6 Suppl):44-7. 15. Hol J, van Leer EH, Elink Schuurman BE, de Ruiter LF, Samsom JN, Hop W, et al. The acquisition of tolerance toward cow's milk through probiotic supplementation: a randomized, controlled trial. J Allergy Clin Immunol. 2008;121(6):1448-54. 16. Hwang JB, Sohn SM, Kim AS. Prospective follow up-oral food challenge in food protein-induced enterocolitis syndrome. Arch Dis Child. 2008. 17. Kaila M, Vanto T, Valovirta E, Koivikko A, Juntunen-Backman K. Diagnosis of food allergy in Finland: survey of pediatric practices. 2000;11(4):246-9. 18. Konturek PC, Rienecker H, Hahn EG, Raithel M. Helicobacter pylori as a protective factor against food allergy. Med Sci Monit. 2008;14(9):CR452-8. 19. Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics. 2000;106(4):762-6. 20. Leung PS, Lee YS, Tang CY, Kung WY, Chuang YH, Chiang BL, et al. Induction of shrimp tropomyosin-specific hypersensitivity in mice. 2008;147(4):305-14. 21. Montano Garcia ML, Orea M. [Frequency of urticaria and angioedema induced by food additives]. Rev Alerg Mex. 1989;36(1):15-8. 22. Noimark LG, J. Warner, J. O. Parents' attitudes when purchasing products for children with nut allergy: a UK perspective. Pediatr Allergy Immunol. 2009 Aug;20(5):500-4. 23. Ravelli AM, Tobanelli P, Volpi S, Ugazio AG. Vomiting and gastric motility in infants with cow's milk allergy. J Pediatr Gastroenterol Nutr. 2001;32(1):59-64. 24. Sabbah A, Drouet M, Lauret MG. [Western blotting or immunoblotting: application of the Alastat-Alablot to the study of cross reactions between cow's milk and goat's milk]. 1996;28(10):335-9. 25. Sasai K, Furukawa S, Sugawara T, Kaneko K, Baba M, Yabuta K. IgE levels in faecal extracts of patients with food allergy. Allergy. 1992;47(6):594-8. 26. Thompson MM, Hanifin JM. Effective therapy of childhood atopic dermatitis allays food allergy concerns. J Am Acad Dermatol. 2005;53(2 Suppl 2):S214-9. 27. Tripodi SB, A. D. Alessandri, C. Panetta, V. Restani, P. Matricardi, P. M. Predicting the

372

outcome of oral food challenges with hen's egg through skin test end-point titration. Clin Exp Allergy. 2009 Aug;39(8):1225-33. 28. van der Velde JLF-dB, B. M. Vlieg-Boerstra, B. J. Oude Elberink, J. N. Schouten, J. P. Dunngalvin, A. Hourihane, J. O. Duiverman, E. J. Dubois, A. E. Test-retest reliability of the Food Allergy Quality of Life Questionnaires (FAQLQ) for children, adolescents and adults. Qual Life Res. 2009 Mar;18(2):245-51. 29. van Odijk JA, S. Bengtsson, U. Borres, M. P. Hulthen, L. Double-blind placebo-controlled challenges for peanut allergy the efficiency of blinding procedures and the allergenic activity of peanut availability in the recipes. Allergy. 2005 May;60(5):602-5. 30. Veerappan GRP, J. L. Duncan, T. J. Baker, T. P. Maydonovitch, C. Lake, J. M. Wong, R. K. Osgard, E. M. Prevalence of eosinophilic esophagitis in an adult population undergoing upper endoscopy: a prospective study. Clin Gastroenterol Hepatol. 2009 Apr;7(4):420-6, 6 e1-2. 31. Wensing M, Penninks AH, Hefle SL, Akkerdaas JH, van Ree R, Koppelman SJ, et al. The range of minimum provoking doses in hazelnut-allergic patients as determined by double-blind, placebo-controlled food challenges. Clin Exp Allergy. 2002;32(12):1757-62. 32. Woods RK, Weiner J, Abramson M, Thien F, Walters EH. Patients' perceptions of food-induced asthma. Aust N Z J Med. 1996;26(4):504-12. 33. Zijlstra WTF, A. E. Soeters, L. Knulst, A. C. Sinnema, G. L'Hoir M, P. Pasmans, S. G. Parental anxiety before and after food challenges in children with suspected peanut and hazelnut allergy. Pediatr Allergy Immunol. 2009 Aug 17.

373

Duplicate Data

Sampson HA. Immediate hypersensitivity reactions to foods: blinded food challenges in children with atopic dermatitis. Ann Allergy. Sep 1986;57(3):209-212. Has duplicate data of the following article:

Sampson HA MC. Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. The Journal of pediatrics. 1985;107(5):669-675.

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Appendix J. Excluded Studies: Diagnosis

No sensitivity/specificity information

1. Agata H, Kondo N, Fukutomi O, Shinoda S, Nishida T, Orii T. Evaluation of lymphocyte proliferative responses to food antigens with regard to age and food-specific IgE antibodies in food-sensitive atopic dermatitis. J Investig Allergol Clin Immunol. 1993;3(4):174-7. 2. Aihara M, Miyazawa M, Osuna H, Tsubaki K, Ikebe T, Aihara Y, et al. Food-dependent exercise-induced anaphylaxis: influence of concurrent aspirin administration on skin testing and provocation. Br J Dermatol. 2002;146(3):466-72. 3. Albani S, Avanzini MA, Plebani A, Scotta MS, Perversi S, Licardi G, et al. Diagnostic value of a lymphocyte stimulation test in cow milk protein intolerance. Ann Allergy. 1989;63(6 Pt 1):489-92. 4. Armstrong D, Rylance G. Definitive diagnosis of nut allergy. Arch Dis Child. 1999;80(2):175-7. 5. Asero R, Jimeno L, Barber D. Component-resolved diagnosis of plant food allergy by SPT. Eur Ann Allergy Clin Immunol. 2008;40(4):115-21. 6. Asero R, Mistrello G, Roncarolo D, Casarini M, Falagiani P. Allergy to nonspecific lipid transfer proteins in Rosaceae: a comparative study of different in vivo diagnostic methods. Ann Allergy Asthma Immunol. 2001;87(1):68-71. 7. Ballmer-Weber BK, Weber JM, Vieths S, Wuthrich B. Predictive value of the sulfidoleukotriene release assay in oral allergy syndrome to celery, hazelnut, and carrot. J Investig Allergol Clin Immunol. 2008;18(2):93-9. 8. Bassotti G, Bertotto A, Spinozzi F. Heretical thoughts about food hypersensitivity: small bowel manometry as an objective way to document gut reactions. Eur J Clin Nutr. 1997;51(9):567-72. 9. Battais F, Richard C, Szustakowski G, Denery-Papini S, Moneret-Vautrin DA, Leduc V, et al. Wheat flour allergy: an entire diagnostic tool for complex allergy. Eur Ann Allergy Clin Immunol. 2006;38(2):59-61. 10. Beyer K, Niggemann B, Nasert S, Renz H, Wahn U. Severe allergic reactions to foods are predicted by increases of CD4+CD45RO+ T cells and loss of L-selectin expression. J Allergy Clin Immunol. 1997;99(4):522-9. 11. Beyer K, Renz H, Wahn U, Niggemann B. Changes in blood leukocyte distribution during double-blind, placebo-controlled food challenges in children with atopic dermatitis and suspected food allergy. Int Arch Allergy Immunol. 1998;116(2):110-5.

375

12. Bock S, Buckley J, Holst A. Proper use of skin tests with food extracts in diagnosis of food hypersensitivity. Clin Allergy. 1978;8:559-64. 13. Bodinier M, Brossard C, Triballeau S, Morisset M, Guerin-Marchand C, Pineau F, et al. Evaluation of an in vitro mast cell degranulation test in the context of food allergy to wheat. Int Arch Allergy Immunol. 2008;146(4):307-20. 14. Buczylko K, Obarzanowski T, Rosiak K, Staskiewicz G, Fiszer A, Chmielewski S, et al. Prevalence of food allergy and intolerance in children based on MAST CLA and ALCAT tests. Rocz Akad Med Bialymst. 1995;40(3):452-6. 15. Cantani A, Micera M. Epidemiology of atopy in 220 children. Diagnostic reliability of skin prick tests and total and specific IgE levels. Minerva Pediatr. 2003;55(2):129-37, 38-42. 16. Cantani A, Micera M. The prick by prick test is safe and reliable in 58 children with atopic dermatitis and food allergy. Eur Rev Med Pharmacol Sci. 2006;10(3):115-20. 17. Casanovas M, Bel I, Maranon F, Berrens L. Estimation of IgE antibodies to the common allergens by reverse enzyme immunoassay. Comparison with the radioallergosorbent test. J Investig Allergol Clin Immunol. 1991;1(4):247-52. 18. Contin-Bordes C, Petersen A, Chahine I, Boralevi F, Chahine H, Taieb A, et al. Comparison of ADVIA Centaur and Pharmacia UniCAP tests in the diagnosis of food allergy in children with atopic dermatitis. Pediatr Allergy Immunol. 2007;18(7):614-20. 19. de Boissieu D, Dupont C. Natural course of sensitization to hen's egg in children not previously exposed to egg ingestion. Eur Ann Allergy Clin Immunol. 2006;38(4):113-7. 20. de Boissieu D, Matarazzo P, Rocchiccioli F, Dupont C. Multiple food allergy: a possible diagnosis in breastfed infants. Acta Paediatr. 1997;86(10):1042-6. 21. De Luca L. [The food bronchial stimulation test (FBST) is a new method for the diagnosis of food allergens. Study of 86 children with food allergy with respiratory manifestations]. Pediatr Med Chir. 1988;10(1):103-10. 22. de Seta L, Siani P, Di Gruttola M, Santoro C, Baldassare C, Coletta S. [Correlation of prick tests, RAST and food challenge tests in atopic dermatitis]. Pediatr Med Chir. 1988;10(5):471-3. 23. Frisoni M, Volta U, Valentini RA, Treggiari EA, Corazza GR, Gasbarrini G. Antigliadin antibody levels in symptomless celiac disease. Dig Dis Sci. 1989;34(10):1639-40. 24. Gabriele C, Hol J, Kerkhof E, Elink Schuurman BE, Samsom JN, Hop W, et al. Fractional exhaled nitric oxide in infants during cow's milk food challenge. Pediatr Allergy Immunol. 2008;19(5):420-5.

376

25. Garcia-Ara MCB, M. T. Diaz-Pena, J. M. Quirce, S. Eliciting doses of positive challenge test in cow's milk allergy are related to cow's milk specific IgE levels. Allergol Immunopathol (Madr). 2008 Nov-Dec;36(6):315-9. 26. Guinnepain MT, Eloit C, Raffard M, Brunet-Moret MJ, Rassemont R, Laurent J. Exercise-induced anaphylaxis: useful screening of food sensitization. Ann Allergy Asthma Immunol. 1996;77(6):491-6. 27. Harsono A, Santosa G, Makmuri MS. The predictive value of Phadiatop Paediatric in the determination of atopy in allergic diseases in children. Paediatr Indones. 1991;31(9-10):281-8. 28. Hefle SL, Helm RM, Burks AW, Bush RK. Comparison of commercial peanut skin test extracts. J Allergy Clin Immunol. 1995;95(4):837-42. 29. Hill DJ, Firer MA, Ball G, Hosking CS. Recovery from milk allergy in early childhood: antibody studies. J Pediatr. 1989;114(5):761-6. 30. Ho MHH, R. G. Wong, W. Hill, D. J. Diagnostic accuracy of skin prick testing in children with tree nut allergy. J Allergy Clin Immunol. 2006 Jun;117(6):1506-8. 31. Hoffman KM, Ho DG, Sampson HA. Evaluation of the usefulness of lymphocyte proliferation assays in the diagnosis of allergy to cow's milk. J Allergy Clin Immunol. 1997;99(3):360-6. 32. Hourihane JO, Grimshaw KE, Lewis SA, Briggs RA, Trewin JB, King RM, et al. Does severity of low-dose, double-blind, placebo-controlled food challenges reflect severity of allergic reactions to peanut in the community? Clin Exp Allergy. 2005;35(9):1227-33. 33. Hwang JB, Lee SH, Kang YN, Kim SP, Suh SI, Kam S. Indexes of suspicion of typical cow's milk protein-induced enterocolitis. J Korean Med Sci. 2007;22(6):993-7. 34. 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. 35. Jenkins M, Vickers A. Unreliability of IgE/IgG4 antibody testing as a diagnostic tool in food intolerance. Clin Exp Allergy. 1998;28(12):1526-9. 36. Jensen LB, Andersen M, Skov PS, Poulsen LK, Bindslev-Jensen C. Risk assessment of clinical reactions to legumes in peanut-allergic children. World Allergy Organization Journal. 2008;1(10):162-7. 37. Jesenak M, Banovcin P, Rennerova Z, Havlicekova Z, Jakusova L, Ronchetti R. Side effects of food atopy patch tests. Clin Pediatr (Phila). 2008;47(6):602-3. 38. Jesenak M, Rennerova Z, Babusikova E, Havlicekova Z, Jakusova L, Villa MP, et al. Food allergens and respiratory symptoms. J Physiol Pharmacol. 2008;59 Suppl 6:311-20.

377

39. Kaiser C, Reibisch H, Folster-Holst R, Sick H. Cow's milk protein allergy--results of skin-prick test with purified milk proteins. Z Ernahrungswiss. 1990;29(2):122-8. 40. Kalach N, Soulaines P, Guerin S, de Boissieu D, Dupont C. Time course of total and food specific IgE antibodies (Rast Fx5) in the developing allergic child. Eur Ann Allergy Clin Immunol. 2005;37(7):257-61. 41. Kapel N, Matarazzo P, Haouchine D, Abiola N, Guerin S, Magne D, et al. Fecal tumor necrosis factor alpha, eosinophil cationic protein and IgE levels in infants with cow's milk allergy and gastrointestinal manifestations. Clin Chem Lab Med. 1999;37(1):29-32. 42. Keller KM, Burgin-Wolff A, Lippold R, Wirth S, Lentze MJ. The diagnostic significance of IgG cow's milk protein antibodies re-evaluated. Eur J Pediatr. 1996;155(4):331-7. 43. Kim TE, Park SW, Noh G, Lee S. Comparison of skin prick test results between crude allergen extracts from foods and commercial allergen extracts in atopic dermatitis by double-blind placebo-controlled food challenge for milk, egg, and soybean. Yonsei Med J. 2002;43(5):613-20. 44. Kontis KJ, Valcour A, Patel A, Chen A, Wang J, Chow J, et al. Correlation of the turbo-MP RIA with ImmunoCAP FEIA for determination of food allergen-specific immunoglobulin E. Ann Clin Lab Sci. 2006;36(1):79-87. 45. Krugman SD, Chiaramonte DR, Matsui EC. Diagnosis and management of food-induced anaphylaxis: a national survey of pediatricians. Pediatrics. 2006;118(3):e554-60. 46. Kumar R, Srivastava P, Kumari D, Fakhr H, Sridhara S, Arora N, et al. Rice (Oryza sativa) allergy in rhinitis and asthma patients: a clinico-immunological study. Immunobiology. 2007;212(2):141-7. 47. Lehman CW. The leukocytic food allergy test: a study of its reliability and reproducibility. Effect of diet and sublingual food drops on this test. Ann Allergy. 1980;45(3):150-8. 48. Liccardi G, D'Amato G, Canonica GW, Salzillo A, Piccolo A, Passalacqua G. Systemic reactions from skin testing: literature review. J Investig Allergol Clin Immunol. 2006;16(2):75-8. 49. Lin XP, Magnusson J, Ahlstedt S, Dahlman-Hoglund A, Hanson LL, Magnusson O, et al. Local allergic reaction in food-hypersensitive adults despite a lack of systemic food-specific IgE. J Allergy Clin Immunol. 2002;109(5):879-87. 50. Luttkopf D, Ballmer-Weber BK, Wuthrich B, Vieths S. Celery allergens in patients with positive double-blind placebo-controlled food challenge. J Allergy Clin Immunol. 2000;106(2):390-9.

378

51. Majamaa H, Aittoniemi J, Miettinen A. Increased concentration of fecal alpha1-antitrypsin is associated with cow's milk allergy in infants with atopic eczema. Clin Exp Allergy. 2001;31(4):590-2. 52. Majamaa H, Seppala U, Palosuo T, Turjanmaa K, Kalkkinen N, Reunala T. Positive skin and oral challenge responses to potato and occurrence of immunoglobulin E antibodies to patatin (Sol t 1) in infants with atopic dermatitis. Pediatr Allergy Immunol. 2001;12(5):283-8. 53. Mancini S, Fierimonte V, Iacovoni R, Spaini A, Viarani P, Pichi A. [Food allergy: comparison of diagnostic techniques]. Minerva Pediatr. 1995;47(5):159-63. 54. Marin A, Botey J, Eseverri JL. Inducement test in cow's milk allergy. Allerg Immunol (Paris). 1988;20(2):51, 3-4. 55. Medrala W, Wolanczyk-Medrala A, Malolepszy J, Patkowski J, Litwa M, Gietkiewicz K, et al. Comparative study between skin prick tests and TOP-CAST allergen leukocyte stimulation in diagnosis of allergic status. J Investig Allergol Clin Immunol. 1997;7(2):115-8. 56. Moneret-Vautrin DA, Halpern GM, Brignon JJ, Nicolas JP, Kanny G. Food specific IgE antibodies: a comparative study of AlaSTAT and Pharmacia RAST Phadebas CAP systems in 49 patients with food allergies. Ann Allergy. 1993;71(2):107-14. 57. Morgan JE, Daul CB, Lehrer SB. The relationships among shrimp-specific IgG subclass antibodies and immediate adverse reactions to shrimp challenge. J Allergy Clin Immunol. 1990;86(3 Pt 1):387-92. 58. Mortz CG, Andersen KE, Bindslev-Jensen C. The prevalence of peanut sensitization and the association to pollen sensitization in a cohort of unselected adolescents--The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis (TOACS). Pediatr Allergy Immunol. 2005;16(6):501-6. 59. Niggemann B, Celik-Bilgili S, Ziegert M, Reibel S, Sommerfeld C, Wahn U. Specific IgE levels do not indicate persistence or transience of food allergy in children with atopic dermatitis. J Investig Allergol Clin Immunol. 2004;14(2):98-103. 60. Niggemann B, Reibel S, Roehr CC, Felger D, Ziegert M, Sommerfeld C, et al. Predictors of positive food challenge outcome in non-IgE-mediated reactions to food in children with atopic dermatitis. J Allergy Clin Immunol. 2001;108(6):1053-8. 61. Niinimaki A, Bjorksten F, Puukka M, Tolonen K, Hannuksela M. Spice allergy: results of skin prick tests and RAST with spice extracts. Allergy. 1989;44(1):60-5. 62. Odze RD, Bines J, Leichtner AM, Goldman H, Antonioli DA. Allergic proctocolitis in infants: a prospective clinicopathologic biopsy study. Hum Pathol. 1993;24(6):668-74. 63. Oranje AP, Aarsen RS, Mulder PG, van Toorenenbergen AW, Liefaard G, Dieges PH.

379

Food immediate-contact hypersensitivity (FICH) and elimination diet in young children with atopic dermatitis. Preliminary results in 107 children. Acta Derm Venereol Suppl (Stockh). 1992;176:41-4. 64. Paajanen L, Tuure T, Poussa T, Korpela R. No difference in symptoms during challenges with homogenized and unhomogenized cow's milk in subjects with subjective hypersensitivity to homogenized milk. J Dairy Res. 2003;70(2):175-9. 65. Pearson DJ, Rix KJ, Bentley SJ. Food allergy: how much in the mind? A clinical and psychiatric study of suspected food hypersensitivity. Lancet. 1983;1(8336):1259-61. 66. Peeters KAK, S. J. van Hoffen, E. van der Tas, C. W. den Hartog Jager, C. F. Penninks, A. H. Hefle, S. L. Bruijnzeel-Koomen, C. A. Knol, E. F. Knulst, A. C. Does skin prick test reactivity to purified allergens correlate with clinical severity of peanut allergy? Clin Exp Allergy. 2007 Jan;37(1):108-15. 67. Perackis K, Staden U, Mehl A, Niggemann B. Skin prick test with hen's egg: whole egg or egg white? Allergy. 2004;59(11):1236-7. 68. Perry TT, Matsui EC, Conover-Walker MK, Wood RA. Risk of oral food challenges. J Allergy Clin Immunol. 2004;114(5):1164-8. 69. Perry TT, Matsui EC, Kay Conover-Walker M, Wood RA. The relationship of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol. 2004;114(1):144-9. 70. Peterson CG, Hansson T, Skott A, Bengtsson U, Ahlstedt S, Magnussons J. Detection of local mast-cell activity in patients with food hypersensitivity. J Investig Allergol Clin Immunol. 2007;17(5):314-20. 71. Raithel M, Weidenhiller M, Abel R, Baenkler HW, Hahn EG. Colorectal mucosal histamine release by mucosa oxygenation in comparison with other established clinical tests in patients with gastrointestinally mediated allergy. World J Gastroenterol. 2006;12(29):4699-705. 72. Raithel M, Weidenhiller M, Shaban M, Abel R, Tuchbreiter H, Backhaus B, et al. Diagnostic use of mucosa oxygenation and histamine release experiments in patients with gastrointestinally mediated allergy (GMA). Inflamm Res. 2003;52 Suppl 1:S13-4. 73. Rance F, Dutau G, Abbal M. Mustard allergy in children. Allergy. 2000;55(5):496-500. 74. Rasanen L, Lehto M, Turjanmaa K, Savolainen J, Reunala T. Allergy to ingested cereals in atopic children. Allergy. 1994;49(10):871-6. 75. Reekers R, Beyer K, Niggemann B, Wahn U, Freihorst J, Kapp A, et al. The role of circulating food antigen-specific lymphocytes in food allergic children with atopic dermatitis. Br J Dermatol. 1996;135(6):935-41.

380

76. Ridout SM, S. Gant, C. Twiselton, R. Dean, T. Arshad, S. H. The diagnosis of Brazil nut allergy using history, skin prick tests, serum-specific immunoglobulin E and food challenges. Clin Exp Allergy. 2006 Feb;36(2):226-32. 77. Rincon de Arellano IRV-C, S. Sinaniotis, A. C. Fernandez-Rivas, M. False positive placebo reaction in a double-blind placebo-controlled food challenge. J Investig Allergol Clin Immunol. 2009;19(3):241-2. 78. Romano A, Di Fonso M, Giuffreda F, Quaratino D, Papa G, Palmieri V, et al. Diagnostic work-up for food-dependent, exercise-induced anaphylaxis. Allergy. 1995;50(10):817-24. 79. Rowlands D, Tofte SJ, Hanifin JM. Does food allergy cause atopic dermatitis? Food challenge testing to dissociate eczematous from immediate reactions. Dermatol Ther. 2006;19(2):97-103. 80. Sainte-Laudy J, Dewilde FX, Brouillaud J. [Evaluation of the reproducibility of the MAST technique for pneumoallergens and food allergens. Biological study]. Allerg Immunol (Paris). 1996;28(10):340-2. 81. Sampson HA, Broadbent KR, Bernhisel-Broadbent J. Spontaneous release of histamine from basophils and histamine-releasing factor in patients with atopic dermatitis and food hypersensitivity. N Engl J Med. 1989;321(4):228-32. 82. Sant'Anna AM, Rolland S, Fournet JC, Yazbeck S, Drouin E. Eosinophilic esophagitis in children: symptoms, histology and pH probe results. J Pediatr Gastroenterol Nutr. 2004;39(4):373-7. 83. Schade RP, Meijer Y, Pasmans SG, Knulst AC, Kimpen JL, Bruijnzeel-Koomen CA. [Double blind placebo controlled cow's milk provocation for the diagnosis of cow's milk allergy in infants and children]. Ned Tijdschr Geneeskd. 2002;146(37):1739-42. 84. Schmitt WH, Jr., Leisman G. Correlation of applied kinesiology muscle testing findings with serum immunoglobulin levels for food allergies. Int J Neurosci. 1998;96(3-4):237-44. 85. Scibilia J, Pastorello EA, Zisa G, Ottolenghi A, Ballmer-Weber B, Pravettoni V, et al. Maize food allergy: a double-blind placebo-controlled study. Clin Exp Allergy. 2008;38(12):1943-9. 86. Scott H, Ek J, Havnen J, Michalsen H, Brunvand L, Howlid H, et al. Serum antibodies to dietary antigens: a prospective study of the diagnostic usefulness in celiac disease of children. J Pediatr Gastroenterol Nutr. 1990;11(2):215-20. 87. Sicherer SH, Morrow EH, Sampson HA. Dose-response in double-blind, placebo-controlled oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2000;105(3):582-6.

381

88. Sicherer SH, Sampson HA. Cow's milk protein-specific IgE concentrations in two age groups of milk-allergic children and in children achieving clinical tolerance. Clin Exp Allergy. 1999 Apr;29(4):507-12. 89. Sloper KS, Wadsworth J, Brostoff J. Children with atopic eczema. II: Immunological findings associated with dietary manipulations. Q J Med. 1991;80(292):695-705. 90. Sohn MH, Lee SY, Lee KE, Kim KE. Comparison of VIDAS Stallertest and Pharmacia CAP assays for detection of specific IgE antibodies in allergic children. Ann Clin Lab Sci. 2005;35(3):318-22. 91. Spergel JM, Andrews T, Brown-Whitehorn TF, Beausoleil JL, Liacouras CA. Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests. Ann Allergy Asthma Immunol. 2005;95(4):336-43. 92. Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol. 2002;109(2):363-8. 93. Stapel SO, Asero R, Ballmer-Weber BK, Knol EF, Strobel S, Vieths S, et al. Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report. Allergy. 2008;63(7):793-6. 94. Stricker WE, Anorve-Lopez E, Reed CE. Food skin testing in patients with idiopathic anaphylaxis. J Allergy Clin Immunol. 1986;77(3):516-9. 95. Sugai E, Smecuol E, Niveloni S, Vazquez H, Label M, Mazure R, et al. Celiac disease serology in dermatitis herpetiformis. Which is the best option for detecting gluten sensitivity? Acta Gastroenterol Latinoam. 2006;36(4):197-201. 96. Tay SS, Clark AT, Deighton J, King Y, Ewan PW. Patterns of immunoglobulin G responses to egg and peanut allergens are distinct: ovalbumin-specific immunoglobulin responses are ubiquitous, but peanut-specific immunoglobulin responses are up-regulated in peanut allergy. Clin Exp Allergy. 2007;37(10):1512-8. 97. Taylor CJ. Predictive value of intraepithelial lymphocyte counts in childhood coeliac disease. J Pediatr Gastroenterol Nutr. 1988;7(4):532-6. 98. Urisu A, Yamada K, Tokuda R, Ando H, Wada E, Kondo Y, et al. Clinical significance of IgE-binding activity to enzymatic digests of ovomucoid in the diagnosis and the prediction of the outgrowing of egg white hypersensitivity. Int Arch Allergy Immunol. 1999;120(3):192-8. 99. van Elburg RM, Kokke FT, Uil JJ, Mulder CJ, de Monchy JG, Heymans HS. [Measurement of selective intestinal permeability using a new, simple sugar absorption test]. Ned Tijdschr Geneeskd. 1993;137(41):2091-5.

382

100. Vanella L, de Gonzalez Lascano AM. CD4+, CD8+ cells, IgE and prick test in infants allergic to cow's milk. Allergol Immunopathol (Madr). 1988;16(5):327-31. 101. Varjonen E, Vainio E, Kalimo K, Juntunen-Backman K, Savolainen J. Skin-prick test and RAST responses to cereals in children with atopic dermatitis. Characterization of IgE-binding components in wheat and oats by an immunoblotting method. Clin Exp Allergy. 1995;25(11):1100-7. 102. Vlieg-Boerstra BJ, Duiverman EJ, van der Heide S, Bijleveld CM, Kukler J, Dubois AE. Should children with a history of anaphylaxis to foods undergo challenge testing? Clin Exp Allergy. 2008;38(12):1935-42. 103. Werfel T, Ahlers G, Schmidt P, Boeker M, Kapp A, Neumann C. Milk-responsive atopic dermatitis is associated with a casein-specific lymphocyte response in adolescent and adult patients. J Allergy Clin Immunol. 1997;99(1 Pt 1):124-33. 104. Wickman M, Ahlstedt S, Lilja G, van Hage Hamsten M. Quantification of IgE antibodies simplifies the classification of allergic diseases in 4-year-old children. A report from the prospective birth cohort study--BAMSE. Pediatr Allergy Immunol. 2003;14(6):441-7. 105. Woods RK, Stoney RM, Raven J, Walters EH, Abramson M, Thien FC. Reported adverse food reactions overestimate true food allergy in the community. Eur J Clin Nutr. 2002;56(1):31-6. 106. Xanthakos SA, Schwimmer JB, Melin-Aldana H, Rothenberg ME, Witte DP, Cohen MB. Prevalence and outcome of allergic colitis in healthy infants with rectal bleeding: a prospective cohort study. J Pediatr Gastroenterol Nutr. 2005;41(1):16-22. 107. Yamada K, Urisu A, Kakami M, Koyama H, Tokuda R, Wada E, et al. IgE-binding activity to enzyme-digested ovomucoid distinguishes between patients with contact urticaria to egg with and without overt symptoms on ingestion. Allergy. 2000;55(6):565-9. 108. Yazicioglu M, Baspinar I, Ones U, Pala O, Kiziler U. Egg and milk allergy in asthmatic children: assessment by immulite allergy food panel, skin prick tests and double-blind placebo-controlled food challenges. Allergol Immunopathol (Madr). 1999;27(6):287-93. 109. Yilmaz N, Bayraktaroglu Z, Ozaslan J. Efficiency of some in vitro allergy tests for evaluating atopy in children and adults. Clin Chem Lab Med. 1999;37(10):981-5. 110. Yimyaem P, Chongsrisawat V, Vivatvakin B, Wisedopas N. Gastrointestinal manifestations of cow's milk protein allergy during the first year of life. J Med Assoc Thai. 2003;86(2):116-23. 111. Zimmerman B, Forsyth S. Diagnosis of allergy in different age groups of children: use of mixed allergen RAST discs, Phadiatop and Paediatric Mix. Clin Allergy. 1988;18(6):581-7.

383

Poorly defined population Diagnosis

1. Agata H, Yomo A, Hanashiro Y, Muraki T, Kondo N, Orii T. Comparison of the MAST chemiluminescent assay system with RAST and skin tests in allergic children. Ann Allergy. 1993;70(2):153-7. 2. Akkerdaas JH, Wensing M, Knulst AC, Krebitz M, Breiteneder H, de Vries S, et al. How accurate and safe is the diagnosis of hazelnut allergy by means of commercial skin prick test reagents? Int Arch Allergy Immunol. 2003;132(2):132-40. 3. Anhoej C, Backer V, Nolte H. Diagnostic evaluation of grass- and birch-allergic patients with oral allergy syndrome. Allergy. 2001;56(6):548-52. 4. Arslan G, Gilja OH, Lind R, Florvaag E, Berstad A. Response to intestinal provocation monitored by transabdominal ultrasound in patients with food hypersensitivity. Scand J Gastroenterol. 2005;40(4):386-94. 5. Astier C, Morisset M, Roitel O, Codreanu F, Jacquenet S, Franck P, et al. Predictive value of skin prick tests using recombinant allergens for diagnosis of peanut allergy. J Allergy Clin Immunol. 2006;118(1):250-6. 6. Baker JC, Duncanson RC, Tunnicliffe WS, Ayres JG. Development of a standardized methodology for double-blind, placebo-controlled food challenge in patients with brittle asthma and perceived food intolerance. J Am Diet Assoc. 2000;100(11):1361-7. 7. Ballmer-Weber BK, Scheurer S, Fritsche P, Enrique E, Cistero-Bahima A, Haase T, et al. Component-resolved diagnosis with recombinant allergens in patients with cherry allergy. J Allergy Clin Immunol. 2002;110(1):167-73. 8. Ballmer-Weber BK, Vieths S, Luttkopf D, Heuschmann P, Wuthrich B. Celery allergy confirmed by double-blind, placebo-controlled food challenge: a clinical study in 32 subjects with a history of adverse reactions to celery root. J Allergy Clin Immunol. 2000;106(2):373-8. 9. Bischoff SC, Mayer J, Wedemeyer J, Meier PN, Zeck-Kapp G, Wedi B, et al. Colonoscopic allergen provocation (COLAP): a new diagnostic approach for gastrointestinal food allergy. Gut. 1997;40(6):745-53. 10. Bolhaar ST, van de Weg WE, van Ree R, Gonzalez-Mancebo E, Zuidmeer L, Bruijnzeel-Koomen CA, et al. In vivo assessment with prick-to-prick testing and double-blind, placebo-controlled food challenge of allergenicity of apple cultivars. J Allergy Clin Immunol. 2005;116(5):1080-6. 11. Bonamico M, Ballati G, Mariani P, Latini M, Triglione P, Rana I, et al. Screening for coeliac disease: the meaning of low titers of anti-gliadin antibodies (AGA) in non-coeliac children. Eur J Epidemiol. 1997;13(1):55-9.

384

12. Boyano MT, Garcia-Ara C, Diaz-Pena JM. Validity of specific IgE antibodies in children with egg allergy. Clin Exp Allergy. 2001;31(9):1464-9. 13. Burks AW, James JM, Hiegel A, Wilson G, Wheeler JG, Jones SM, et al. Atopic dermatitis and food hypersensitivity reactions. J Pediatr. 1998;132(1):132-6. 14. Caffarelli C, Cavagni G, Giordano S, Stapane I, Rossi C. Relationship between oral challenges with previously uningested egg and egg-specific IgE antibodies and skin prick tests in infants with food allergy. J Allergy Clin Immunol. 1995;95(6):1215-20. 15. Caffarelli C, Cavagni G, Romanini E, Caruana P, de Angelis G. Duodenal IgE-positive cells and elimination diet responsiveness in children with atopic dermatitis. Ann Allergy Asthma Immunol. 2001;86(6):665-70. 16. Caffarelli C, Petroccione T. False-negative food challenges in children with suspected food allergy. Lancet. 2001;358(9296):1871-2. 17. Carnes J, Ferrer A, Huertas AJ, Andreu C, Larramendi CH, Fernandez-Caldas E. The use of raw or boiled crustacean extracts for the diagnosis of seafood allergic individuals. Ann Allergy Asthma Immunol. 2007;98(4):349-54. 18. Clark AT, Ewan PW. Interpretation of tests for nut allergy in one thousand patients, in relation to allergy or tolerance. Clin Exp Allergy. 2003;33(8):1041-5. 19. Corey JP, Gungor A. In vitro testing for immunoglobulin E-mediated food allergies. Otolaryngol Head Neck Surg. 1996;115(4):312-8. 20. Costongs GM, Bas BM. The first fully automated allergy analyser UniCAP: comparison with IMMULITE for allergy panel testing. Eur J Clin Chem Clin Biochem. 1997;35(11):885-8. 21. Cudowska B, Kaczmarski M. Diagnostic value of birch recombinant allergens (rBet v 1, profilin rBet v 2) in children with pollen-related food allergy. Rocz Akad Med Bialymst. 2004;49:111-5. 22. Cudowska B, Kaczmarski M, Restani P. Lipid transfer protein in diagnosis of birch-apple syndrome in children. Immunobiology. 2008;213(2):89-96. 23. Darsow U, Laifaoui J, Kerschenlohr K, Wollenberg A, Przybilla B, Wuthrich B, et al. The prevalence of positive reactions in the atopy patch test with aeroallergens and food allergens in subjects with atopic eczema: a European multicenter study. Allergy. 2004;59(12):1318-25. 24. Daul CB, Morgan JE, Hughes J, Lehrer SB. Provocation-challenge studies in shrimp-sensitive individuals. J Allergy Clin Immunol. 1988;81(6):1180-6. 25. De Swert LF, Cadot P, Ceuppens JL. Diagnosis and natural course of allergy to cooked

385

potatoes in children. Allergy. 2007;62(7):750-7. 26. de Waard-van der Spek FB, Elst EF, Mulder PG, Munte K, Devillers AC, Oranje AP. Diagnostic tests in children with atopic dermatitis and food allergy. Allergy. 1998;53(11):1087-91. 27. Deluze C, Dunoyer-Geindre S, Girard JP. Comparative analysis of lyophilized fresh fruits and vegetables with commercial extracts for skin testing of patients with food allergy. J Investig Allergol Clin Immunol. 1991;1(1):53-7. 28. el Rafei A, Peters SM, Harris N, Bellanti JA. Diagnostic value of IgG4 measurements in patients with food allergy. Ann Allergy. 1989;62(2):94-9. 29. Erdmann SM, Sachs B, Schmidt A, Merk HF, Scheiner O, Moll-Slodowy S, et al. In vitro analysis of birch-pollen-associated food allergy by use of recombinant allergens in the basophil activation test. Int Arch Allergy Immunol. 2005;136(3):230-8. 30. Fiocchi A, Bouygue GR, Restani P, Bonvini G, Startari R, Terracciano L. Accuracy of skin prick tests in IgE-mediated adverse reactions to bovine proteins. Ann Allergy Asthma Immunol. 2002;89(6 Suppl 1):26-32. 31. Fogg MI, Brown-Whitehorn TA, Pawlowski NA, Spergel JM. Atopy patch test for the diagnosis of food protein-induced enterocolitis syndrome. Pediatr Allergy Immunol. 2006;17(5):351-5. 32. Freeman S, Rosen RH. Urticarial contact dermatitis in food handlers. Med J Aust. 1991;155(2):91-4. 33. Fremont S, Morisset M, Gerard P, Nicolas JP, Moneret-Vautrin DA. [Measurement of levels of specific IgE by the Efficient New Enzymatic Allergy (ENEA) System II (CIS bio)]. Allerg Immunol (Paris). 1999;31(8):278-84. 34. Hansen TK, Bindslev-Jensen C. Codfish allergy in adults. Identification and diagnosis. Allergy. 1992;47(6):610-7. 35. Hansen TK, Host A, Bindslev-Jensen C. An evaluation of the diagnostic value of different skin tests with egg in clinically egg-allergic children having atopic dermatitis. Pediatr Allergy Immunol. 2004;15(5):428-34. 36. Heine RG, Verstege A, Mehl A, Staden U, Rolinck-Werninghaus C, Niggemann B. Proposal for a standardized interpretation of the atopy patch test in children with atopic dermatitis and suspected food allergy. Pediatr Allergy Immunol. 2006;17(3):213-7. 37. Helbling A, Haydel R, Jr., McCants ML, Musmand JJ, El-Dahr J, Lehrer SB. Fish allergy: is cross-reactivity among fish species relevant? Double-blind placebo-controlled food challenge studies of fish allergic adults. Ann Allergy Asthma Immunol. 1999;83(6 Pt 1):517-23.

386

38. Hill DJ, Hosking CS, Reyes-Benito LV. Reducing the need for food allergen challenges in young children: a comparison of in vitro with in vivo tests. Clin Exp Allergy. 2001;31(7):1031-5. 39. Iikura Y, Akimoto K, Odajima Y, Akazawa A, Nagakura T. How to prevent allergic disease. I. Study of specific IgE, IgG, and IgG4 antibodies in serum of pregnant mothers, cord blood, and infants. Int Arch Allergy Appl Immunol. 1989;88(1-2):250-2. 40. Ispano M, Colafrancesco M, Ansaloni R, Vighi G, Ortolani C. Comparison of the results of skin prick tests, CAP system and ENEA system in the diagnosis of food allergy. Monogr Allergy. 1996;32:181-6. 41. Jewett DL, Fein G, Greenberg MH. A double-blind study of symptom provocation to determine food sensitivity. N Engl J Med. 1990;323(7):429-33. 42. Kalach N, Soulaines P, de Boissieu D, Dupont C. A pilot study of the usefulness and safety of a ready-to-use atopy patch test (Diallertest) versus a comparator (Finn Chamber) during cow's milk allergy in children. J Allergy Clin Immunol. 2005;116(6):1321-6. 43. Kleine-Tebbe J, Werfel S, Roedsgaard D, Nolte H, Skov PS, Wahn U, et al. Comparison of fiberglass-based histamine assay with a conventional automated fluorometric histamine assay, case history, skin prick test, and specific serum IgE in patients with milk and egg allergic reactions. Allergy. 1993;48(1):49-53. 44. Kondo N, Agata H, Fukutomi O, Motoyoshi F, Orii T. Lymphocyte responses to food antigens in patients with atopic dermatitis who are sensitive to foods. J Allergy Clin Immunol. 1990;86(2):253-60. 45. Kondo N, Fukutomi O, Agata H, Yokoyama Y. Proliferative responses of lymphocytes to food antigens are useful for detection of allergens in nonimmediate types of food allergy. J Investig Allergol Clin Immunol. 1997;7(2):122-6. 46. Korol D, Tobolczyk J, Hofman J. Differentiation of IgE-dependent and IgE-independent reactions in children with bronchial asthma on the basis of TOP CAST Paediatric Allergen Mix test. Adv Med Sci. 2006;51:232-6. 47. Lee S, Noh GW, Lee KY. Clinical application of histamine prick test for food challenge in atopic dermatitis. J Korean Med Sci. 2001;16(3):276-82. 48. Levy Y, Kornbroth B, Ofer I, Garty BZ, Danon YL. Food allergy in infants and children: clinical evaluation and management. Isr J Med Sci. 1994;30(12):873-9. 49. Lilja G, Oman H, Johansson SG. Development of atopic disease during childhood and its prediction by Phadiatop Paediatric. Clin Exp Allergy. 1996;26(9):1073-9.

387

50. Majamaa H, Moisio P, Holm K, Kautiainen H, Turjanmaa K. Cow's milk allergy: diagnostic accuracy of skin prick and patch tests and specific IgE. Allergy. 1999;54(4):346-51. 51. Majamaa H, Moisio P, Holm K, Turjanmaa K. Wheat allergy: diagnostic accuracy of skin prick and patch tests and specific IgE. Allergy. 1999;54(8):851-6. 52. Malet A, Sanosa J, Garcia-Calderon PA. Diagnosis of allergy to peach. A comparative study of "in vivo" and "in vitro" techniques. Allergol Immunopathol (Madr). 1988;16(3):181-4. 53. Martinez San Ireneo M, Ibanez Sandin MD, Fernandez-Caldas E, Maranon F, Munoz Martinez MC, Laso Borrego MT. The diagnostic value of crude or boiled extracts to identify tolerant versus nontolerant lentil-sensitive children. Ann Allergy Asthma Immunol. 2001;86(6):686-90. 54. Medina RR, Mora PM. [Evaluation of the RAST in the diagnosis of children with food allergy]. Rev Alerg Mex. 1996;43(1):9-12. 55. Moneret-Vautrin DA, Fremont S, Kanny G, Dejardin G, Hatahet R, Nicolas JP. The use of two multitests fx5 and fx10 in the diagnosis of food allergy in children: regarding 42 cases. Allerg Immunol (Paris). 1995;27(1):2-6. 56. Moneret-Vautrin DA, Gueant JL, Abdel-Ghani A, Maria Y, Nicolas JP. Comparative evaluation between two immunoenzymatic techniques (FAST and Phadezym) and the Phadebas RAST in food allergy. Allergy. 1990;45(2):104-8. 57. Niggemann B, Reibel S, Wahn U. The atopy patch test (APT)-- a useful tool for the diagnosis of food allergy in children with atopic dermatitis. Allergy. 2000;55(3):281-5. 58. Niggemann B, Ziegert M, Reibel S. Importance of chamber size for the outcome of atopy patch testing in children with atopic dermatitis and food allergy. J Allergy Clin Immunol. 2002;110(3):515-6. 59. Nolan RCR, P. Prescott, S. L. Mallon, D. F. Gong, G. Franzmann, A. M. Naidoo, R. Loh, R. K. Skin prick testing predicts peanut challenge outcome in previously allergic or sensitized children with low serum peanut-specific IgE antibody concentration. Pediatr Allergy Immunol. 2007 May;18(3):224-30. 60. Noma T, Yoshizawa I, Aoki K, Sugawara Y, Odajima H, Kabasawa Y, et al. Correlation between antigen-specific IL-2 response test and provocation test for egg allergy in atopic dermatitis. Clin Exp Allergy. 1998;28(9):1120-30. 61. Norgaard A, Bindslev-Jensen C. Egg and milk allergy in adults. Diagnosis and characterization. Allergy. 1992;47(5):503-9. 62. Norgaard A, Bindslev-Jensen C, Skov PS, Poulsen LK. Specific serum IgE in the diagnosis of egg and milk allergy in adults. Allergy. 1995;50(8):636-47.

388

63. Norgaard A, Skov PS, Bindslev-Jensen C. Egg and milk allergy in adults: comparison between fresh foods and commercial allergen extracts in skin prick test and histamine release from basophils. Clin Exp Allergy. 1992;22(10):940-7. 64. Ortolani C, Ballmer-Weber BK, Hansen KS, Ispano M, Wuthrich B, Bindslev-Jensen C, et al. Hazelnut allergy: a double-blind, placebo-controlled food challenge multicenter study. J Allergy Clin Immunol. 2000;105(3):577-81. 65. Ortolani C, Ispano M, Pastorello EA, Ansaloni R, Magri GC. Comparison of results of skin prick tests (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol. 1989;83(3):683-90. 66. Osterballe M, Bindslev-Jensen C. Threshold levels in food challenge and specific IgE in patients with egg allergy: is there a relationship? J Allergy Clin Immunol. 2003;112(1):196-201. 67. Osterballe M, Scheller R, Stahl Skov P, Andersen KE, Bindslev-Jensen C. Diagnostic value of scratch-chamber test, skin prick test, histamine release and specific IgE in birch-allergic patients with oral allergy syndrome to apple. Allergy. 2003;58(9):950-3. 68. Rance F, Juchet A, Bremont F, Dutau G. Correlations between skin prick tests using commercial extracts and fresh foods, specific IgE, and food challenges. Allergy. 1997;52(10):1031-5. 69. Rasanen L, Lehto M, Reunala T. Diagnostic value of skin and laboratory tests in cow's milk allergy/intolerance. Clin Exp Allergy. 1992;22(3):385-90. 70. Reuter A, Lidholm J, Andersson K, Ostling J, Lundberg M, Scheurer S, et al. A critical assessment of allergen component-based in vitro diagnosis in cherry allergy across Europe. Clin Exp Allergy. 2006;36(6):815-23. 71. Roger A, Pena M, Botey J, Eseverri JL, Marin A. The prick test and specific IgE (RAST and MAST-CLA) compared with the oral challenge test with milk, eggs and nuts. J Investig Allergol Clin Immunol. 1994;4(4):178-81. 72. Rokaite R, Labanauskas L, Vaideliene L. Role of the skin patch test in diagnosing food allergy in children with atopic dermatitis. Medicina (Kaunas). 2004;40(11):1081-7. 73. Sampson HA. Comparative study of commercial food antigen extracts for the diagnosis of food hypersensitivity. J Allergy Clin Immunol. 1988;82(5 Pt 1):718-26. 74. Sampson HA, Albergo R. Comparison of results of skin tests, RAST, and double-blind, placebo-controlled food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 1984;74(1):26-33. 75. Sampson HA, Ho DG. Relationship between food-specific IgE concentrations and the

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risk of positive food challenges in children and adolescents. J Allergy Clin Immunol. 1997;100(4):444-51. 76. Schwab D, Raithel M, Klein P, Winterkamp S, Weidenhiller M, Radespiel-Troeger M, et al. Immunoglobulin E and eosinophilic cationic protein in segmental lavage fluid of the small and large bowel identify patients with food allergy. Am J Gastroenterol. 2001;96(2):508-14. 77. Scibilia J, Pastorello EA, Zisa G, Ottolenghi A, Bindslev-Jensen C, Pravettoni V, et al. Wheat allergy: a double-blind, placebo-controlled study in adults. J Allergy Clin Immunol. 2006;117(2):433-9. 78. Seidenari S, Giusti F, Bertoni L, Mantovani L. Combined skin prick and patch testing enhances identification of peanut-allergic patients with atopic dermatitis. Allergy. 2003;58(6):495-9. 79. Sharnan J, Kumar L, Singh S. Comparison of results of skin prick tests, enzyme-linked immunosorbent assays and food challenges in children with respiratory allergy. J Trop Pediatr. 2001;47(6):367-8. 80. Skamstrup Hansen K, Vestergaard H, Stahl Skov P, Sondergaard Khinchi M, Vieths S, Poulsen LK, et al. Double-blind, placebo-controlled food challenge with apple. Allergy. 2001;56(2):109-17. 81. Sohn MH, Lee SY, Kim KE. Prediction of buckwheat allergy using specific IgE concentrations in children. Allergy. 2003;58(12):1308-10. 82. Spergel JM, Brown-Whitehorn T, Beausoleil JL, Shuker M, Liacouras CA. Predictive values for skin prick test and atopy patch test for eosinophilic esophagitis. J Allergy Clin Immunol. 2007;119(2):509-11. 83. Sporik R, Hill DJ, Hosking CS. Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children. Clin Exp Allergy. 2000;30(11):1540-6. 84. Stromberg L. Diagnostic accuracy of the atopy patch test and the skin-prick test for the diagnosis of food allergy in young children with atopic eczema/dermatitis syndrome. Acta Paediatr. 2002;91(10):1044-9. 85. Taylor CJ, Hendrickse RG, McGaw J, Macfarlane SB. Detection of cow's milk protein intolerance by an enzyme-linked immunosorbent assay. Acta Paediatr Scand. 1988;77(1):49-54. 86. Vassilopoulou E, Konstantinou G, Kassimos D, Douladiris N, Xepapadaki P, Manoussakis E, et al. Reintroduction of cow's milk in milk-allergic children: safety and risk factors. Int Arch Allergy Immunol. 2008;146(2):156-61. 87. Vatn MH, Grimstad IA, Thorsen L, Kittang E, Refnin I, Malt U, et al. Adverse reaction to food: assessment by double-blind placebo-controlled food challenge and clinical,

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psychosomatic and immunologic analysis. Digestion. 1995;56(5):421-8. 88. Venter C, Pereira B, Voigt K, Grundy J, Clayton CB, Gant C, et al. Comparison of open and double-blind placebo-controlled food challenges in diagnosis of food hypersensitivity amongst children. J Hum Nutr Diet. 2007;20(6):565-79. 89. Vicente-Serrano J, Caballero ML, Rodriguez-Perez R, Carretero P, Perez R, Blanco JG, et al. Sensitization to serum albumins in children allergic to cow's milk and epithelia. Pediatr Allergy Immunol. 2007;18(6):503-7. 90. Wang de Y, Gordon BR, Chan YH, Yeoh KH. Potential non-immunoglobulin E-mediated food allergies: comparison of open challenge and double-blind placebo-controlled food challenge. Otolaryngol Head Neck Surg. 2007;137(5):803-9.

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No Gold Standard

1. Adler BR, Assadullahi T, Warner JA, Warner JO. Evaluation of a multiple food specific IgE antibody test compared to parental perception, allergy skin tests and RAST. 1991;21(6):683-8. 2. Liu YH, Chou HH, Jan RL, Lin HJ, Liang CC, Wang JY, et al. Comparison of two specific allergen screening tests in different patient groups. 2006;47(3):116-22. 3. Plaza Martin AM, Martin Mateos MA, Giner Munoz MT, Sierra Martinez JI. Challenge testing in children with allergy to cow's milk proteins. Allergol Immunopathol (Madr). 2001;29(2):50-4. 4. Senna G, Bonadonna P, Schiappoli M, Leo G, Lombardi C, Passalacqua G. Pattern of use and diagnostic value of complementary/alternative tests for adverse reactions to food. 2005;60(9):1216-7.

392

Retrospective Data Collection Diagnosis

1. Breuer K, Heratizadeh A, Wulf A, Baumann U, Constien A, Tetau D, et al. Late eczematous reactions to food in children with atopic dermatitis. Clin Exp Allergy. 2004;34(5):817-24. 2. Eigenmann PA, Sampson HA. Interpreting skin prick tests in the evaluation of food allergy in children. Pediatr Allergy Immunol. 1998;9(4):186-91. 3. Kagan R, Hayami D, Joseph L, St Pierre Y, Clarke AE. The predictive value of a positive prick skin test to peanut in atopic, peanut-naive children. Ann Allergy Asthma Immunol. 2003;90(6):640-5. 4. Kalach N, Soulaines P, Imad AS, Salloum A, Guerin S, de Boissieu D, et al. Survey of prick test, total and specific age during food allergy in children. Eur Ann Allergy Clin Immunol. 2007;39(2):51-7. 5. Knight AK, Shreffler WG, Sampson HA, Sicherer SH, Noone S, Mofidi S, et al. Skin prick test to egg white provides additional diagnostic utility to serum egg white-specific IgE antibody concentration in children. J Allergy Clin Immunol. 2006;117(4):842-7. 6. Mankad VS, Williams LW, Lee LA, LaBelle GS, Anstrom KJ, Burks AW. Safety of open food challenges in the office setting. Ann Allergy Asthma Immunol. 2008;100(5):469-74. 7. Mehl A, Verstege A, Staden U, Kulig M, Nocon M, Beyer K, et al. Utility of the ratio of food-specific IgE/total IgE in predicting symptomatic food allergy in children. Allergy. 2005;60(8):1034-9. 8. Migliaccio P, Samueli S, Orsolini G, Baldini G, Paci A. [Correlations of the response to the prick test and blood levels of specific IgE in children]. Pediatr Med Chir. 1995;17(5):423-5. 9. Niggemann B, Sielaff B, Beyer K, Binder C, Wahn U. Outcome of double-blind, placebo-controlled food challenge tests in 107 children with atopic dermatitis. Clin Exp Allergy. 1999;29(1):91-6. 10. Ott H, Baron JM, Heise R, Ocklenburg C, Stanzel S, Merk HF, et al. Clinical usefulness of microarray-based IgE detection in children with suspected food allergy. Allergy. 2008;63(11):1521-8. 11. Plebani M, Borghesan F, Faggian D. Clinical efficiency of in vitro and in vivo tests for allergic diseases. Ann Allergy Asthma Immunol. 1995;74(1):23-8. 12. Pucar F, Kagan R, Lim H, Clarke AE. Peanut challenge: a retrospective study of 140 patients. Clin Exp Allergy. 2001;31(1):40-6.

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13. Roberts G, Lack G. Diagnosing peanut allergy with skin prick and specific IgE testing. J Allergy Clin Immunol. 2005;115(6):1291-6. 14. Ueno H, Yoshioka K, Matsumoto T. Usefulness of the skin index in predicting the outcome of oral challenges in children. J Investig Allergol Clin Immunol. 2007;17(4):207-10. 15. van Toorenenbergen AW, Oranje AP, Vermeulen AM, Aarsen RS. IgE antibody screening in children. Evaluation of the Phadiatop Paediatric. Allergy. 1991;46(3):180-5. 16. Verstege A, Mehl A, Rolinck-Werninghaus C, Staden U, Nocon M, Beyer K, et al. The predictive value of the skin prick test weal size for the outcome of oral food challenges. Clin Exp Allergy. 2005;35(9):1220-6.

394

Wrong Test-Diagnosis

1. Iacono G, Ravelli A, Di Prima L, Scalici C, Bolognini S, Chiappa S, et al. Colonic lymphoid nodular hyperplasia in children: relationship to food hypersensitivity. 2007;5(3):361-6. The above citation was a study of the use of colonoscopy with lymphoid nodular biopsy for diagnosis. This test was not within the scope of our report; therefore the study was excluded.

395

Celiac Disease

1. Kaukinen K, Turjanmaa K, Maki M, Partanen J, Venalainen R, Reunala T, et al. Intolerance to cereals is not specific for coeliac disease. 2000;35(9):942-6. 2. O'Farrelly C, O'Mahony C, Graeme-Cook F, Feighery C, McCartan BE, Weir DG. Gliadin antibodies identify gluten-sensitive oral ulceration in the absence of villous atrophy. 1991;20(10):476-8. 3. Valdimarsson T, Franzen L, Grodzinsky E, Skogh T, Strom M. Is small bowel biopsy necessary in adults with suspected celiac disease and IgA anti-endomysium antibodies? 100% positive predictive value for celiac disease in adults. 1996;41(1):83-7. 4. Vogelsang H, Genser D, Wyatt J, Lochs H, Ferenci P, Granditsch G, et al. Screening for celiac disease: a prospective study on the value of noninvasive tests. 1995;90(3):394-8.

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Appendix K. Excluded Studies: Treatment/Management/Prevention

Neither a Randomized Controlled Trial (RCT) nor Observational 1. Cow's milk allergy in the first year of life. An Italian Collaborative Study. Acta Paediatr Scand Suppl. 1988;348:1-14. 2. Alonso R, Enrique E, Pineda F, Basagana M, San Miguel-Moncin MM, Bartra J, et al. An observational study on outgrowing food allergy during non-birch pollen-specific, subcutaneous immunotherapy. Int Arch Allergy Immunol. 2007;143(3):185-9. 3. Dissemination CfRa. Systematic review concerning the age of introduction of complementary foods to the healthy full-term infant (Structured abstract). Database of Abstracts of Reviews of Effects. 2009(3). 4. Hays T, Wood RA. A systematic review of the role of hydrolyzed infant formulas in allergy prevention. Arch Pediatr Adolesc Med. 2005;159(9):810-6. 5. Hughes JL, Stewart M. Self-administration of epinephrine in children: a survey of current prescription practice and recommendations for improvement. Ulster Med J. 2003;72(2):80-5. 6. Koplin JA, K. Gurrin, L. Osborne, N. Tang, M. L. Dharmage, S. Is caesarean delivery associated with sensitization to food allergens and IgE-mediated food allergy: a systematic review. Pediatr Allergy Immunol. 2008 Dec;19(8):682-7. 7. Kramer MS. Maternal antigen avoidance during lactation for preventing atopic disease in infants of women at high risk. Cochrane Database Syst Rev. 2000(2):CD000132. 8. Ma S, Sicherer SH, Nowak-Wegrzyn A. A survey on the management of pollen-food allergy syndrome in allergy practices. J Allergy Clin Immunol. 2003;112(4):784-8. 9. Maas TK, Janneke Sheikh, Aziz Knottnerus, J. Andre Wesseling, Geertjan Dompeling, Edward Muris, Jean WM van Schayck, Constant Paul. Mono and multifaceted inhalant and/or food allergen reduction interventions for preventing asthma in children at high risk of developing asthma [Systematic Review]. Cochrane Database of Systematic Reviews. 2009(3). 10. Nowak-Wegrzyn A, Bloom KA, Sicherer SH, Shreffler WG, Noone S, Wanich N, et al. Tolerance to extensively heated milk in children with cow's milk allergy. 2008;122(2):342-7, 7 e1-2. 11. Nowak-Wegrzyn A, Conover-Walker MK, Wood RA. Food-allergic reactions in schools and preschools. Arch Pediatr Adolesc Med. 2001;155(7):790-5. 12. Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and

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food intolerance in infants. Cochrane Database Syst Rev. 2006(4):CD003664. 13. Osborn DA, Sinn J. Soy formula for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev. 2006(4):CD003741. 14. Pastorello EA, Stocchi L, Pravettoni V, Bigi A, Schilke ML, Incorvaia C, et al. Role of the elimination diet in adults with food allergy. J Allergy Clin Immunol. 1989;84(4 Pt 1):475-83. 15. Ram FS, Ducharme FM, Scarlett J. Cow's milk protein avoidance and development of childhood wheeze in children with a family history of atopy. Cochrane Database Syst Rev. 2002(3):CD003795. 16. TenBrook JA, Jr., Wolf MP, Hoffman SN, Rosenwasser LJ, Konstam MA, Salem DN, et al. Should beta-blockers be given to patients with heart disease and peanut-induced anaphylaxis? A decision analysis. J Allergy Clin Immunol. 2004;113(5):977-82. 17. van Odijk JK, I. Borres, M. P. Brandtzaeg, P. Edberg, U. Hanson, L. A. Host, A. Kuitunen, M. Olsen, S. F. Skerfving, S. Sundell, J. Wille, S. Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966-2001) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy. 2003 Sep;58(9):833-43. 18. Vierk KA, Koehler KM, Fein SB, Street DA. Prevalence of self-reported food allergy in American adults and use of food labels. J Allergy Clin Immunol. 2007;119(6):1504-10. 19. Weisselberg B, Dayal Y, Thompson JF, Doyle MS, Senior B, Grand RJ. A lamb-meat-based formula for infants allergic to casein hydrolysate formulas. Clin Pediatr (Phila). 1996;35(10):491-5. 20. Zeiger RS, Heller S, Mellon MH, Forsythe AB, O'Connor RD, Hamburger RN, et al. Effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: a randomized study. J Allergy Clin Immunol. 1989;84(1):72-89.

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Observational and sample < 100 -Treatment/Management/Prevention

1. Aceves SS, Bastian JF, Newbury RO, Dohil R. Oral viscous budesonide: a potential new therapy for eosinophilic esophagitis in children. 2007;102(10):2271-9; quiz 80. 2. Anveden-Hertzberg L, Finkel Y, Sandstedt B, Karpe B. Proctocolitis in exclusively breast-fed infants. 1996;155(6):464-7. 3. Asero R. Fennel, cucumber, and melon allergy successfully treated with pollen-specific injection immunotherapy. 2000;84(4):460-2. 4. 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. 5. Attwood SE, Lewis CJ, Bronder CS, Morris CD, Armstrong GR, Whittam J. Eosinophilic oesophagitis: a novel treatment using Montelukast. 2003;52(2):181-5. 6. Bishop JM, Hill DJ, Hosking CS. Natural history of cow milk allergy: clinical outcome. J Pediatr. 1990;116(6):862-7. 7. Buchanan AD, Green TD, Jones SM, Scurlock AM, Christie L, Althage KA, et al. Egg oral immunotherapy in nonanaphylactic children with egg allergy. 2007;119(1):199-205. 8. Burks AW, Jones SM. Egg oral immunotherapy in non-anaphylactic children with egg allergy: follow-up. J Allergy Clin Immunol. 2008 Jan;121(1):270-1. 9. Businco L, Cantani A, Longhi MA, Giampietro PG. Anaphylactic reactions to a cow's milk whey protein hydrolysate (Alfa-Re, Nestle) in infants with cow's milk allergy. 1989;62(4):333-5. 10. Carroccio A, Cavataio F, Montalto G, D'Amico D, Alabrese L, Iacono G. Intolerance to hydrolysed cow's milk proteins in infants: clinical characteristics and dietary treatment. Clin Exp Allergy. 2000;30(11):1597-603. 11. Carroccio A, Montalto G, Custro N, Notarbartolo A, Cavataio F, D'Amico D, et al. Evidence of very delayed clinical reactions to cow's milk in cow's milk-intolerant patients. 2000;55(6):574-9. 12. 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. 13. Chen MJ, Chu CH, Lin SC, Shih SC, Wang TE. Eosinophilic gastroenteritis: clinical experience with 15 patients. 2003;9(12):2813-6.

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14. Clarke PS. Titration of immunotherapy by periodical nasal allergic challenges in the treatment of allergic rhinitis. Med J Aust. 1992;157(1):11-3. 15. Cudowska B, Korol D, Kaczmarski M. Clinical trials of Astemizol in children with cow's milk hypersensitivity. Rocz Akad Med Bialymst. 1995;40(3):613-8. 16. Czarnecka-Operacz M, Jenerowicz D, Silny W. Oral allergy syndrome in patients with airborne pollen allergy treated with specific immunotherapy. Acta Dermatovenerol Croat. 2008;16(1):19-24. 17. David TJ. Anaphylactic shock during elimination diets for severe atopic eczema. Arch Dis Child. 1984;59(10):983-6. 18. de Boissieu D, Matarazzo P, Dupont C. Allergy to extensively hydrolyzed cow milk proteins in infants: identification and treatment with an amino acid-based formula. J Pediatr. 1997;131(5):744-7. 19. Devlin J, David TJ, Stanton RH. Six food diet for childhood atopic dermatitis. 1991;71(1):20-4. 20. Eggesbo M, Botten G, Stigum H, Samuelsen SO, Brunekreef B, Magnus P. Cesarean delivery and cow milk allergy/intolerance. Allergy. 2005;60(9):1172-3. 21. Foroughi S, Foster B, Kim N, Bernardino LB, Scott LM, Hamilton RG, et al. Anti-IgE treatment of eosinophil-associated gastrointestinal disorders. 2007;120(3):594-601. 22. Fox AT, Du Toit G, Lang A, Lack G. Food allergy as a risk factor for nutritional rickets. 2004;15(6):566-9. 23. Halken S, Host A, Hansen LG, Osterballe O. Safety of a new, ultrafiltrated whey hydrolysate formula in children with cow milk allergy: a clinical investigation. Pediatr Allergy Immunol. 1993;4(2):53-9. 24. Hansen KS, Ballmer-Weber BK, Luttkopf D, Skov PS, Wuthrich B, Bindslev-Jensen C, et al. Roasted hazelnuts--allergenic activity evaluated by double-blind, placebo-controlled food challenge. Allergy. 2003;58(2):132-8. 25. Henriksen C, Eggesbo M, Halvorsen R, Botten G. Nutrient intake among two-year-old children on cows' milk-restricted diets. Acta Paediatr. 2000;89(3):272-8. 26. Hill DJ, Cameron DJ, Francis DE, Gonzalez-Andaya AM, Hosking CS. Challenge confirmation of late-onset reactions to extensively hydrolyzed formulas in infants with multiple food protein intolerance. J Allergy Clin Immunol. 1995;96(3):386-94. 27. Hofmann AMS, A. M. Jones, S. M. Palmer, K. P. Lokhnygina, Y. Steele, P. H. Kamilaris, J. Burks, A. W. Safety of a peanut oral immunotherapy protocol in children with

400

peanut allergy. J Allergy Clin Immunol. 2009 Aug;124(2):286-91, 91 e1-6. 28. Iacono G, Carroccio A, Cavataio F, Montalto G, Cantarero MD, Notarbartolo A. Chronic constipation as a symptom of cow milk allergy. 1995;126(1):34-9. 29. Iwanczak F, Mozrzymas R, Heimrath Z, Koszewicz P. Clinical evaluation of food allergy and food intolerance dietary treatment in children. 1995;40(3):588-94. 30. Jamison JR, Davies NJ. Chiropractic management of cow's milk protein intolerance in infants with sleep dysfunction syndrome: a therapeutic trial. J Manipulative Physiol Ther. 2006;29(6):469-74. 31. Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009. 32. Kaczmarski M, Wasilewska J, Lasota M. Hypersensitivity to hydrolyzed cow's milk protein formula in infants and young children with atopic eczema/dermatitis syndrome with cow's milk protein allergy. 2005;50:274-8. 33. Kagalwalla AF, Sentongo TA, Ritz S, Hess T, Nelson SP, Emerick KM, et al. Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. 2006;4(9):1097-102. 34. Kamelmaz I, Elitsur Y. Cow's milk allergy in infants. 1999;95(5):265-7. 35. Kanny G, Moneret-Vautrin DA, Flabbee J, Hatahet R, Virion JM, Morisset M, et al. [Use of an amino-acid-based formula in the treatment of cow's milk protein allergy and multiple food allergy syndrome]. Allerg Immunol (Paris). 2002;34(3):82-4. 36. Kapoor S, Roberts G, Bynoe Y, Gaughan M, Habibi P, Lack G. Influence of a multidisciplinary paediatric allergy clinic on parental knowledge and rate of subsequent allergic reactions. Allergy. 2004;59(2):185-91. 37. Kaukinen K, Collin P, Holm K, Rantala I, Vuolteenaho N, Reunala T, et al. Wheat starch-containing gluten-free flour products in the treatment of coeliac disease and dermatitis herpetiformis. A long-term follow-up study. 1999;34(2):163-9. 38. Kinaciyan T, Jahn-Schmid B, Radakovics A, Zwolfer B, Schreiber C, Francis JN, et al. Successful sublingual immunotherapy with birch pollen has limited effects on concomitant food allergy to apple and the immune response to the Bet v 1 homolog Mal d 1. 2007;119(4):937-43. 39. Martino F, Bruno G, Aprigliano D, Agolini D, Guido F, Giardini O, et al. Effectiveness of a home-made meat based formula (the Rezza-Cardi diet) as a diagnostic tool in children with food-induced atopic dermatitis. 1998;9(4):192-6. 40. Meglio P, Bartone E, Plantamura M, Arabito E, Giampietro PG. A protocol for oral

401

desensitization in children with IgE-mediated cow's milk allergy. Allergy. 2004;59(9):980-7. 41. Meglio P, Giampietro PG, Gianni S, Galli E. Oral desensitization in children with immunoglobulin E-mediated cow's milk allergy--follow-up at 4 yr and 8 months. Pediatr Allergy Immunol. 2008;19(5):412-9. 42. Melamed I, Feanny SJ, Sherman PM, Roifman CM. Benefit of ketotifen in patients with eosinophilic gastroenteritis. 1991;90(3):310-4. 43. Monti G, Bertino E, Muratore MC, Coscia A, Cresi F, Silvestro L, et al. Efficacy of donkey's milk in treating highly problematic cow's milk allergic children: an in vivo and in vitro study. Pediatr Allergy Immunol. 2007;18(3):258-64. 44. Oren E, Banerji A, Clark S, Camargo CA, Jr. Food-induced anaphylaxis and repeated epinephrine treatments. Ann Allergy Asthma Immunol. 2007;99(5):429-32. 45. Patriarca G, Buonomo A, Roncallo C, Del Ninno M, Pollastrini E, Milani A, et al. Oral desensitisation in cow milk allergy: immunological findings. 2002;15(1):53-8. 46. Patriarca G, Pogna N, Cammarota G, Schiavino D, Lombardo C, Pollastrini E, et al. An attempt of specific desensitising treatment with gliadin in celiac disease. 2005;18(4):709-14. 47. Pelikan Z, Pelikan-Filipek M. Effects of oral cromolyn on the nasal response due to foods. Arch Otolaryngol Head Neck Surg. 1989;115(10):1238-43. 48. Pike MG, Carter CM, Boulton P, Turner MW, Soothill JF, Atherton DJ. Few food diets in the treatment of atopic eczema. 1989;64(12):1691-8. 49. Rance F, Brondeau V, Abbal M. Use of prick-tests in the screening of immediate allergy to protein: 16 cases. 2002;34(3):71-6. 50. Remedios M, Campbell C, Jones DM, Kerlin P. Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. 2006;63(1):3-12. 51. Rolinck-Werninghaus CS, U. Mehl, A. Hamelmann, E. Beyer, K. Niggemann, B. Specific oral tolerance induction with food in children: transient or persistent effect on food allergy? Allergy. 2005 Oct;60(10):1320-2. 52. Sampson HA, Bernhisel-Broadbent J, Yang E, Scanlon SM. Safety of casein hydrolysate formula in children with cow milk allergy. 1991;118(4 ( Pt 1)):520-5. 53. Sicherer SH, Noone SA, Koerner CB, Christie L, Burks AW, Sampson HA. Hypoallergenicity and efficacy of an amino acid-based formula in children with cow's milk and multiple food hypersensitivities. 2001;138(5):688-93.

402

54. Sierra Salinas C, Blasco Alonso J, Olivares Sanchez L, Barco Galvez A, del Rio Mapelli L. [Allergic colitis in exclusively breast-fed infants]. 2006;64(2):158-61. 55. Sloper KS, Wadsworth J, Brostoff J. Children with atopic eczema. I: Clinical response to food elimination and subsequent double-blind food challenge. 1991;80(292):677-93. 56. Sotto D, Tounian P, Baudon JJ, Pauliat S, Challier P, Fontaine JL, et al. [Allergy to cow's milk protein hydrolysates: apropos of 8 cases]. 1999;6(12):1279-85. 57. Teitelbaum JE, Fox VL, Twarog FJ, Nurko S, Antonioli D, Gleich G, et al. Eosinophilic esophagitis in children: immunopathological analysis and response to fluticasone propionate. 2002;122(5):1216-25. 58. Tesse R, Paglialunga C, Braccio S, Armenio L. Adequacy and tolerance to ass's milk in an Italian cohort of children with cow's milk allergy. Riv Ital Pediatr. 2009;35(1):19. 59. Vanderhoof JA, Murray ND, Kaufman SS, Mack DR, Antonson DL, Corkins MR, et al. Intolerance to protein hydrolysate infant formulas: an underrecognized cause of gastrointestinal symptoms in infants. 1997;131(5):741-4. 60. Varshney P, Jones SM, Pons L, Kulis M, Steele PH, Kemper AR, et al. Oral Immunotherapy (OIT) Induces Clinical Tolerance in Peanut-Allergic Children. Journal of Allergy and Clinical Immunology.123(2):S 174. 61. Vlieg-Boerstra BJ, Dubois AE, van der Heide S, Bijleveld CM, Wolt-Plompen SA, Oude Elberink JN, et al. Ready-to-use introduction schedules for first exposure to allergenic foods in children at home. 2008;63(7):903-9. 62. Vlieg-Boerstra BJ, van der Heide S, Bijleveld CM, Kukler J, Duiverman EJ, Wolt-Plompen SA, et al. Dietary assessment in children adhering to a food allergen avoidance diet for allergy prevention. 2006;60(12):1384-90. 63. Warrier PC, T. B. Omalizumab in idiopathic anaphylaxis. Ann Allergy Asthma Immunol. 2009 Mar;102(3):257-8. 64. Webber SA, Graham-Brown RA, Hutchinson PE, Burns DA. Dietary manipulation in childhood atopic dermatitis. 1989;121(1):91-8. 65. Zuberbier T, Chantraine-Hess S, Hartmann K, Czarnetzki BM. Pseudoallergen-free diet in the treatment of chronic urticaria. A prospective study. Acta Derm Venereol. 1995;75(6):484-7.

403

Observational and prevention article Treatment/Management/Prevention

1. Kull I, Wickman M, Lilja G, Nordvall SL, Pershagen G. Breast feeding and allergic diseases in infants-a prospective birth cohort study. Arch Dis Child. 2002;87(6):478-81. 2. Laitinen K, Kalliomaki M, Poussa T, Lagstrom H, Isolauri E. Evaluation of diet and growth in children with and without atopic eczema: follow-up study from birth to 4 years. 2005;94(4):565-74. 3. Stone KD, Prussin C. Immunomodulatory therapy of eosinophil-associated gastrointestinal diseases. Clin Exp Allergy. 2008;38(12):1858-65.

404

Celiac Disease- Treatment/Management/Prevention

1. Nino M, Ciacci C, Delfino M. A long-term gluten-free diet as an alternative treatment in severe forms of dermatitis herpetiformis. 2007;18(1):10-2.

405

Appendix L. Assessed for their definition of food allergy 1. Allen KJ, Hill DJ, Heine RG. 4. Food allergy in childhood. Med J Aust. 2006;185(7):394-

400. 2. Assa'ad AH. Gastrointestinal food allergy and intolerance. Pediatr Ann.

2006;35(10):718-726. 3. Atkins D. Food allergy: diagnosis and management. Prim Care. 2008;35(1):119-140, vii. 4. Bangash SA, Bahna SL. Pediatric food allergy update. Curr Allergy Asthma Rep.

2005;5(6):437-444. 5. Bischoff SC. Food allergies. Curr Gastroenterol Rep. 2006;8(5):374-382. 6. Bjorksten B. Genetic and environmental risk factors for the development of food allergy.

Curr Opin Allergy Clin Immunol. 2005;5(3):249-253. 7. Branco Ferreira M, Palma-Carlos A. Food anaphylaxis. Eur Ann Allergy Clin Immunol.

2005;37(10):387-391. 8. Brindslev-Jensen C. Adverse reactions to foods. Forum Nutr. 2003;56:154-155. 9. Burks AW. Peanut allergy. Lancet. 2008;371(9623):1538-1546. 10. Burks AW, Laubach S, Jones SM. Oral tolerance, food allergy, and immunotherapy:

implications for future treatment. J Allergy Clin Immunol. 2008;121(6):1344-1350. 11. Burks W. Current understanding of food allergy. Ann N Y Acad Sci. 2002;964:1-12. 12. Burks W, Ballmer-Weber BK. Food allergy. Mol Nutr Food Res. 2006;50(7):595-603. 13. Chandra RK. Food allergy. Indian J Pediatr. 2002;69(3):251-255. 14. Chandra RK. Food hypersensitivity and allergic diseases. Eur J Clin Nutr. 2002;56 Suppl

3:S54-56. 15. Chegini S, Metcalfe DD. Contemporary issues in food allergy: seafood toxin-induced

disease in the differential diagnosis of allergic reactions. Allergy Asthma Proc. 2005;26(3):183-190.

16. Chehade M. IgE and non-IgE-mediated food allergy: treatment in 2007. Curr Opin

Allergy Clin Immunol. 2007;7(3):264-268.

406

17. Colver A. Are the dangers of childhood food allergy exaggerated? BMJ. 2006;333(7566):494-496.

18. Crespo JF, James JM, Rodriguez J. Diagnosis and therapy of food allergy. Mol Nutr Food

Res. 2004;48(5):347-355. 19. Crespo JF, Rodriguez J. Food allergy in adulthood. Allergy. 2003;58(2):98-113. 20. David TJ. Adverse reactions and intolerance to foods. Br Med Bull. 2000;56(1):34-50. 21. Dear KL. Food intolerance and allergy in gastrointestinal disorders. Hosp Med.

2001;62(12):731-734. 22. El-Gamal YM, Hossny EM. Respiratory food allergy. Pediatr Ann. 2006;35(10):733-740. 23. Ewing WM, Allen PJ. The diagnosis and management of cow milk protein intolerance in

the primary care setting. Pediatr Nurs. 2005;31(6):486-493. 24. Fasano MB. Dermatologic food allergy. Pediatr Ann. 2006;35(10):727-731. 25. Ferreira CT, Seidman E. Food allergy: a practical update from the gastroenterological

viewpoint. J Pediatr (Rio J). 2007;83(1):7-20. 26. Fiocchi A, Assa'ad A, Bahna S. Food allergy and the introduction of solid foods to

infants: a consensus document. Adverse Reactions to Foods Committee, American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 2006;97(1):10-20; quiz 21, 77.

27. Fogg MI, Spergel JM. Management of food allergies. Expert Opin Pharmacother.

2003;4(7):1025-1037. 28. Gore C, Custovic A. Can we prevent allergy? Allergy. 2004;59(2):151-161. 29. Grimshaw KE. Dietary management of food allergy in children. Proc Nutr Soc.

2006;65(4):412-417. 30. Guarderas JC. Is it food allergy? Differentiating the causes of adverse reactions to food.

Postgrad Med. 2001;109(4):125-127, 131-124. 31. Hallett R, Teuber SS. Food allergies and sensitivities. Nutr Clin Care. 2004;7(3):122-

129. 32. Hays T, Wood RA. A systematic review of the role of hydrolyzed infant formulas in

allergy prevention. Arch Pediatr Adolesc Med. 2005;159(9):810-816.

407

33. Helm RM. Diet and the development of atopic disease. Curr Opin Allergy Clin Immunol. 2004;4(2):125-129.

34. Host A, Halken S. Primary prevention of food allergy in infants who are at risk. Curr

Opin Allergy Clin Immunol. 2005;5(3):255-259. 35. Host A, Halken S, Muraro A, et al. Dietary prevention of allergic diseases in infants and

small children. Pediatr Allergy Immunol. 2008;19(1):1-4. 36. James JM. Food allergy: opportunities and challenges in the clinical practice of allergy

and immunology. Clin Rev Allergy Immunol. 2004;27(2):105-114. 37. Jyonouchi H. Non-IgE mediated food allergy. Inflamm Allergy Drug Targets.

2008;7(3):173-180. 38. Kaza U, Knight AK, Bahna SL. Risk factors for the development of food allergy. Curr

Allergy Asthma Rep. 2007;7(3):182-186. 39. Keet CA, Wood RA. Food allergy and anaphylaxis. Immunol Allergy Clin North Am.

2007;27(2):193-212, vi. 40. Keil T. Epidemiology of food allergy: what's new? A critical appraisal of recent

population-based studies. Curr Opin Allergy Clin Immunol. 2007;7(3):259-263. 41. Khakoo A, Lack G. Preventing food allergy. Curr Allergy Asthma Rep. 2004;4(1):36-42. 42. Kim JS. Food allergy: diagnosis, treatment, prognosis, and prevention. Pediatr Ann.

2008;37(8):546-551. 43. Kimber I, Dearman RJ. Food allergy: what are the issues? Toxicol Lett. 2001;120(1-

3):165-170. 44. Knight AK, Bahna SL. Diagnosis of food allergy. Pediatr Ann. 2006;35(10):709-714. 45. Kumar R. Epidemiology and risk factors for the development of food allergy. Pediatr

Ann. 2008;37(8):552-558. 46. Kurowski K, Boxer RW. Food allergies: detection and management. Am Fam Physician.

2008;77(12):1678-1686. 47. Lee LA, Burks AW. Food allergies: prevalence, molecular characterization, and

treatment/prevention strategies. Annu Rev Nutr. 2006;26:539-565. 48. Leung AK. Food allergy: a clinical approach. Adv Pediatr. 1998;45:145-177.

408

49. Li XM, Sampson HA. Novel approaches to immunotherapy for food allergy. Clin Allergy Immunol. 2004;18:663-679.

50. Madsen C. Prevalence of food allergy: an overview. Proc Nutr Soc. 2005;64(4):413-417. 51. Mansueto P, Montalto G, Pacor ML, et al. Food allergy in gastroenterologic diseases:

Review of literature. World J Gastroenterol. 2006;12(48):7744-7752. 52. Mofidi S. Nutritional management of pediatric food hypersensitivity. Pediatrics.

2003;111(6 Pt 3):1645-1653. 53. Moneret-Vautrin DA, Morisset M. Adult food allergy. Curr Allergy Asthma Rep.

2005;5(1):80-85. 54. Moneret-Vautrin DA, Morisset M, Flabbee J, Beaudouin E, Kanny G. Epidemiology of

life-threatening and lethal anaphylaxis: a review. Allergy. 2005;60(4):443-451. 55. Montalto M, Santoro L, D'Onofrio F, et al. Adverse reactions to food: allergies and

intolerances. Dig Dis. 2008;26(2):96-103. 56. Muraro A, Dreborg S, Halken S, et al. Dietary prevention of allergic diseases in infants

and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol. 2004;15(4):291-307.

57. Murch SH. Clinical manifestations of food allergy: the old and the new. Eur J

Gastroenterol Hepatol. 2005;17(12):1287-1291. 58. Nieuwenhuizen NE, Lopata AL. Fighting food allergy: current approaches. Ann N Y Acad

Sci. 2005;1056:30-45. 59. Nowak-Wegrzyn A, Sampson HA. Adverse reactions to foods. Med Clin North Am.

2006;90(1):97-127. 60. O'Leary PF, Shanahan F. Food allergies. Curr Gastroenterol Rep. 2002;4(5):373-382. 61. Papageorgiou PS. Clinical aspects of food allergy. Biochem Soc Trans. 2002;30(Pt

6):901-906. 62. Pons L, Burks W. Novel treatments for food allergy. Expert Opin Investig Drugs.

2005;14(7):829-834. 63. Ramesh S. Food allergy overview in children. Clin Rev Allergy Immunol.

2008;34(2):217-230.

409

64. Rance F. Promising treatments in development for food allergies. Expert Opin Emerg Drugs. 2004;9(2):257-268.

65. Ree-Kim L, Lehrer SB. Seafood allergy. Curr Opin Allergy Clin Immunol.

2004;4(3):231-234. 66. Sabra A, Bellanti JA, Rais JM, Castro HJ, de Inocencio JM, Sabra S. IgE and non-IgE

food allergy. Ann Allergy Asthma Immunol. 2003;90(6 Suppl 3):71-76. 67. Sampson HA. 9. Food allergy. J Allergy Clin Immunol. 2003;111(2 Suppl):S540-547. 68. Sampson HA. Food-induced anaphylaxis. Novartis Found Symp. 2004;257:161-171;

discussion 171-166, 207-110, 276-185. 69. Sampson HA. Update on food allergy. J Allergy Clin Immunol. 2004;113(5):805-819;

quiz 820. 70. Schuller DE. Risk factors for food allergy. Curr Allergy Asthma Rep. 2004;4(6):433-438. 71. Scurlock AM, Lee LA, Burks AW. Food allergy in children. Immunol Allergy Clin North

Am. 2005;25(2):369-388, vii-viii. 72. Senna G, Passalacqua G, Lombardi C, Antonicelli L. Position paper: controversial and

unproven diagnostic procedures for food allergy. Eur Ann Allergy Clin Immunol. 2004;36(4):139-145.

73. Sicherer SH. Food allergy. Lancet. 2002;360(9334):701-710. 74. Sicherer SH, Sampson HA. Food Allergy: Recent Advances in Pathophysiology and

Treatment. Annu Rev Med. 2008. 75. Simon RA. Adverse reactions to food additives. Curr Allergy Asthma Rep. 2003;3(1):62-

66. 76. Soares RL, Figueiredo HN, Santos JM, Oliveira RF, Godoy RL, Mendonca FA.

Discrepancies between the responses to skin prick test to food and respiratory antigens in two subtypes of patients with irritable bowel syndrome. World J Gastroenterol. 2008;14(19):3044-3048.

77. Somers L. Food allergy: nutritional considerations for primary care providers. Pediatr

Ann. 2008;37(8):559-568. 78. Spergel JM, Brown-Whitehorn T. The use of patch testing in the diagnosis of food

allergy. Curr Allergy Asthma Rep. 2005;5(1):86-90.

410

79. Spergel JM, Fiedler J. Food allergy and additives: triggers in asthma. Immunol Allergy Clin North Am. 2005;25(1):149-167.

80. Spergel JM, Pawlowski NA. Food allergy. Mechanisms, diagnosis, and management in

children. Pediatr Clin North Am. 2002;49(1):73-96, vi. 81. Story RE. Manifestations of food allergy in infants and children. Pediatr Ann.

2008;37(8):530-535. 82. Turjanmaa K. The role of atopy patch tests in the diagnosis of allergy in atopic

dermatitis. Curr Opin Allergy Clin Immunol. 2005;5(5):425-428. 83. Vance G, Warner J. A GP guide to recognising food allergy, intolerance and aversion.

Practitioner. 2000;244(1609):352-359. 84. Walker-Smith J. An eye witness perspective of the changing patterns of food allergy. Eur

J Gastroenterol Hepatol. 2005;17(12):1313-1316. 85. Wood RA. The natural history of food allergy. Pediatrics. 2003;111(6 Pt 3):1631-1637.

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