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The predictive relationship of food-specific serum IgE concentrations to challenge outcomes for egg and milk varies by patient age
... The authors showed that the evaluation of food-specific IgE was useful for the diagnosis of symptomatic FA and for avoiding the need OFC in a considerable number of allergic children. For example, Komata et al. (7) found that specific IgE levels above 25.5 kUA/L for egg and 50.9 kUA/L for milk indicated a 95% risk of reaction to OFC. Specific IgE levels ≤2 kUA/L to milk, egg, or peanut (or ≤5 kUA/L to peanut without history of previous reaction) 41 were associated with 50% likelihood of negative OFC. Therefore, children with these specific IgE cutoffs were appropriate candidates for OFC to investigate the acquisition of tolerance (8). ...
... Sampson (6) and Komata (7) separately confirmed that quantification of food-specific IgE could avoid probably positive OFC tests thus reducing adverse reactions. At the same time, children with specific IgE ≤ 2 kUA/L to milk, egg, or peanut (or ≤5 kUA/L to peanut without history of previous reaction) were appropriate candidates for OFC to investigate the resolution of FA, because these specific IgE cut-offs were associated with 50% likelihood of negative OFC (7). As in the literature there are several reports about specific IgE role in assessment of acquisition of tolerance (6, 7), we hypothesized we could find a relationship also between total IgE values and acquired tolerance. ...
... We also found a substantial reduction of specific IgE values from diagnosis to the execution of OFC. It is well known that the greater the serum IgEs level, the greater the probability of allergic reactions (6,7). In 2018 in their systematic review Calvani et al. (30) suggested that raw egg allergy seems very likely if food-specific IgEis ≥ 1.7 kUA/L in children aged <2 years, while in children 2 years or older the suggested cut-off is ≥7.3 kUA/L (30). ...
Background
The gold standard to diagnose food allergy (FA) is a double-blind, placebo-controlled food challenge (OFC), even if it shows potential risk of severe allergic reactions for the patient and is time-consuming. Therefore, easier, and less invasive methods are needed to diagnose FA and predict the tolerance, changing the clinical practice.
Aim
The main aim of this study was to assess whether the total IgE values at the diagnosis of FA were associated with the duration of the tolerance acquisition and thus of the food elimination diet.
Methods
We retrospectively analyzed the medical records of 40 patients allergic to milk or egg who performed an OFC for the reintroduction of the causal food at the Pediatric Allergy and Respiratory Unit of the University of Chieti from January 2018 to December 2020.
Results
We found a positive association of total serum IgE with the elimination diet duration ( β = 0.152; CI, 95% 0.04–0.27) after adjusting for age, sex, and type of allergy (milk or egg). We also showed a significant correlation ( r = 0.41 and p -value = 0.007) between the total IgE values and the duration of the elimination diet and a significant correlation between the casein specific IgE values at diagnosis of FA and the severity of the clinical presentation ( r = 0.66; p -value 0.009).
Conclusion
Total serum IgE at baseline, along with the downward trend of food-specific IgE levels (to milk or egg), may be useful in the prognostication of natural tolerance acquisition.
... After taking up the allergen, they mature and migrate to regional lymph nodes, so that they can present these antigens to naive CD4+ T cells (Th0). Th0 cells will differentiate into Th2 cells, which begin to secrete IL-4, which is essential to induce the isotype switching from IgM to IgE class antibodies in B lymphocytes [11,12]. Once produced by plasma cells, IgE binds to FcεRI on the surface of blood basophils and tissue resident mast cells. ...
... Upon a repeated exposure to a bi-or multivalent allergen, cross-linking of FcεRI-bound IgE induces activation of those effector cells, and the immediate release of preformed mediators such as histamine and various proteases induces the immediate reaction, with symptoms as urticaria, flushing, angioedema, bronchospasm, and hypotension (early or immediate phase of type I hypersensitivity reaction) [3,11,12]. Moreover, effector cells start de novo synthesis of many inflammatory mediators such as certain Cys-LTs, PGs, and cytokines, which explain the "late phase" phenomena [3]. ...
... Moreover, effector cells start de novo synthesis of many inflammatory mediators such as certain Cys-LTs, PGs, and cytokines, which explain the "late phase" phenomena [3]. This late phase is followed by the release of many cytokines, as IL-1, IL-13, IL4, and IL-5, which induce activation of local cells and recruitment of other inflammatory cells (neutrophils, basophils, eosinophils, monocytes, and lymphocytes) to the site of inflammation [11,12]. ...
Purpose of review
The management of anaphylaxis, after a rapid clinical-based hypothesis and prompt treatment introduction, includes diagnosis confirmation. We reviewed main laboratory methods available for diagnosing anaphylaxis and its etiology. Then, we searched for new methods that can gain utility in the next few years.
Recent findings
Serum tryptase is still the most accurate and available method for diagnosis during the acute phase, although it is necessary to measure baseline levels after a period of time. However, measurement of other mediators, such as histamine and lipid metabolites, is available in many sites with good accuracy. For etiologic diagnosis, serum-specific IgE, component-resolved diagnosis (CRD), and basophil activation test (BAT) are available and sometimes helpful, and the new mast cell activation test (MAT) has been recently proposed to help confirming activation of those cells by a specific trigger.
Summary
In vitro tests can help clinicians to confirm anaphylaxis diagnosis and sometimes its etiology, but many triggers cannot be confirmed by laboratory methods. Then, allergist consultation after an anaphylactic reaction is mandatory to order the most appropriate tests and, if indicated, to perform in vivo tests.
... Casein is one of the major allergens that cause CMA. 5 Several studies have reported the importance of CM components in predicating CMA. 8,12,18 In the present study, the sIgE levels of casein are significantly elevated in patients who experienced GRADE II-IV anaphylaxis to CM. Of the four CM components tested, levels of casein-sIgE showed the strongest correlation with that of CM-sIgE. ...
... 12 Similarly, a Spanish study reported the cut-off point of 9 kUA/L corresponding to a 95% PPV. 8 The selection of clinical decision points in our study was predicated on the presence of anaphylaxis, besides, the included children were older, both of which contributed to the observed higher cut-off values. 8,18 Cow's milk components were also useful for predicting children's reactions to baked CM products and for monitoring the natural course of CMA. Casein has the strongest immunogenicity, and was noted to be heat stable for up to 60 min of heating to 95°C. ...
... 4 However, predictive values were different between studies, because these values depend on disease prevalence as well as patient age. 5 We have reported that a previous history of immediate reactions may change the predictive decision point (PPV) of positive buckwheat OFC. 6 Similarly, one Australian study of 1-year-old infants showed that a previous history of peanut reactions altered the 95% PPV of peanut sIgE for peanut allergy; however, no study has evaluated the influence of the presence of a previous history of immediate reactions on PPV of Ara h 2 sIgE and 5% PPV of peanut sIgE. ...
... It has been reported that infants are more likely to have lower 95% PPVs than children aged 2 or older. 5 Considering that age may influence PPVs, we developed fitted probability curves for patients <6 years and those 6 years or older. There was no obvious difference between these groups (Supplementary Figure S3). ...
... Careful protocols including a series of precise small increment in the challenging dose do not always warrant the safety. Probability curves predicting OFC results based on food-specific-IgE values are widely used to prevent serious allergic reactions [15,21]. However, the proposed probability for the risk of severe OFC reactions does not have sufficient reproducibility. ...
... Clinical variables were collected from the medical records of patients who underwent a unified protocol of OFC, including their age, sex, date, and severity of the first onset of milk allergy, duration of complete avoidance of milk, and consumed amount of milk until the first OFC, serum levels of milk-specific and total IgE antibodies, presence or absence of anaphylaxis episode, bronchial asthma, atopic dermatitis, and family history of bronchial asthma, atopic dermatitis, and food allergy, as reported previously [3,8,11,15,20,21,26]. A history of bronchial asthma was defined as having more than three episodes of wheezing illness according to the Japanese Pediatric Guidelines for the Treatment and Management of Asthma 2012 [10]. ...
Cow’s milk is one of the most common food allergens among children. Oral food challenge tests determine the threshold dose of allergens, but have not been standardized. To reduce the severe reactions, we developed a practical model of the test. We studied 111 high-risk patients who underwent a first milk oral food challenge on the risk-stratified dose between 2011 and 2017 for predicting the severe reaction risk. Severe reactions were defined as showing > 3 of Sampson’s classification grade. Twenty-eight patients (25%) showed severe reactions without death. Prior to oral food challenge, severe reaction patients experienced milk avoidance (71% vs. 45%, p = 0.02) or bronchial asthma (61% vs. 28%, p = 0.003) more frequently and showed higher milk-specific IgE levels (median 28.3 vs. 7.7 UA/mL, p < 0.0001) than non-severe reaction patients. Multivariate logistic regression analyses established a formula including severe reaction-associated factors; increased levels of milk-specific IgE (odds ratio 11.61, p = 0.001), milk avoidance (odds ratio 3.88, p = 0.02), and bronchial asthma (odds ratio 3.75, p = 0.02). This model had 86% sensitivity and 56% specificity (cut-off 0.25) for risk. Five patients with < 25% probability developed severe reactions, which started in > 3 grade dyspnea up to 20 mL of challenge.Conclusion: This model could effectively reduce the severe reaction development on the first milk oral food challenge test according to the individual needs.
What is Known:
•Higher levels of milk-specific IgE values, bronchial asthma, and complete milk avoidance are independent risk factors of severe reactions during the cow’s milk oral food challenge.
What is New:
•Statistical analyses of our milk oral food challenge records for 111 patients helped us develop a model formula predicting severe reactions at the first test with high specificity and sensitivity.•This simple risk-stratified protocol is useful for minimizing the adverse events in the first milk challenge.
... The utility of SPT and specific IgE testing may be hampered by the quality The interpretation of test results is specific to the food, the geographical location and the individual being tested. For instance, the diagnostic performance of tests is allergen-specific and, in the same Patient-specific factors need to be taken into account when determining the clinical relevance of an SPT or specific IgE result 33for example, in young children, lower levels of allergen-specific IgE can have higher probability of clinical allergy.34 There can also be TA B L E 7 Summary of diagnostic performance of various tests for specific foods based on the results of recent meta-analyses11 . ...
This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE‐mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy‐focused clinical history followed by tests to determine IgE sensitization, such as serum allergen‐specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen‐sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.
... As a part of the diagnosis of food allergies, immunological tests such as the antigen-specific IgE antibody test are usually performed. The presence of specific IgE antibodies indicates an underlying immunological mechanisms when symptoms are provoked in an OFC; moreover, higher IgE titers have been reported to be related to a higher probability of challenge-positive results (Komata et al. 2007). On the other hand, specific IgG4 antibodies compete with specific IgE antibodies to bind allergens, thereby interfering in specific IgE antibody-mediated activation of basophils ...
A single-arm study was conducted with 10 children aged 2–12 years with severe cow's milk allergy (CMA) requiring complete allergen elimination. Subjects were administered kestose, a prebiotic, at 1 or 2 g/day for 12 weeks. Results of a subsequent oral food challenge (OFC) showed a statistically significant increase in the total dose of cow's milk ingestion (1.6 ml vs. 2.7 ml, p = 0.041). However, the overall evaluation of the OFC results, TS/Pro (total score of Anaphylaxis Scoring Aichi (ASCA)/cumulative dose of protein), showed no statistically significant improvement, although the values were nominally improved in seven out of 10 subjects. The 16S rDNA analysis of fecal samples collected from the subjects revealed a statistically significant increase in the proportion of Faecalibacterium spp. (3.8 % vs. 6.8%, p = 0.013), a type of intestinal bacterium that has been reported to be associated with food allergy. However, no statistically significant correlation was found between Faecalibacterium spp. abundance and the results of the OFC.
... In our study, children aged 1-2 years had smaller optimal cutoff values and higher diagnostic efficacy compared with children aged 3-14 years, suggesting that younger children are more sensitive to smaller cutoff values. This finding is consistent with previous studies [44][45][46][47] . However, this difference still lacks statistical power because of the limited number of studies included and the relatively small advantage. ...
Background: The role of Component Resolved Diagnostics (CRD) in the diagnosis of cow’s milk allergy (CMA) remains highly controversial. In this systematic review, we aimed to evaluate the accuracy of CRD in diagnosing CMA in children. Methods: We searched four electronic databases (EMBASE, PubMed, the Cochrane Library, and Web of Science) from January 1, 2000, to March 27, 2023, for studies that utilized milk composition and oral food challenges (OFC) as a reference standard in patients with suspected milk allergy. The quality of the included studies was assessed using QUADAS-2. Due to the heterogeneity of the studies, a meta-analysis could not be performed, and a narrative synthesis of the findings was conducted. Results: Our analysis included 5 prospective studies, 2 retrospective studies, and 2 case-control studies, with a total of 958 children. The sensitivity of Bos d 4 ranged from 0.50 to 0.82, and specificity from 0.78 to 0.98. Bos d 5 sensitivity 0.24-1.0, and specificity 0.58-0.98. Bos d 6 sensitivity 0.09, and specificity 0.94. Bos d 8 sensitivity 0.34-0.90, specificity 0.79-0.98. CONCLUSION: The specific IgE (sIgE) of the Bos d 4, Bos d 6, and Bos d 8 components of milk is highly specific but not sensitive in diagnosing cow’s milk allergy in children. The use of CRD for the diagnosis of CMA in children may reduce the need for OFC.
... We included only values which have been previously validated thus this are not available for all foods. [18,[21][22][23]. ...
Background: The European Academy of Allergy and Clinical Immunology’s (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta-analyses to assess the accuracy of diagnostic tests for IgE-mediated food allergy. Methods : We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 October 2012 and 30 June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full-texts, and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta analyses were undertaken for food-test combination where 3 or more studies were available. Results : 149 studies comprising 24,489 patients met the inclusion criteria and were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% undertaken in Europe, ≥95% conducted in a specialized pediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% DBPCFC. Skin prick test (SPT) with fresh cow’s milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE to individual components had high specificity: Ara h 2 had 92%, Cor a 14 95%, Ana o 3 94%, casein 93%, ovomucoid 92/91% for the diagnosis of peanut, hazelnut, cashew, cow’s milk and raw/cooked egg allergies, respectively. BAT was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. Conclusions: SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies. PROSPERO registration: CRD42021259186 Funding: European Academy of Allergy (EAACI).
... However, in contrast to our study, a previous study has reported that younger children had a higher HE OFC positivity rate. 19 This difference may be attributable to a selection bias in our study, as patients with more accidental reactions may have received the initial OFC at a higher age. ...
Background
Children with hen's egg (HE) allergy and a positive initial oral food challenge (OFC) require rechallenge to assess for tolerance. However, the risk factors for a positive repeat OFC remain unclear.
Methods
We retrospectively analyzed data from 243 preschool children who failed an initial OFC with half a heated HE and repeated the same OFC after 6–24 months. Logistic regression models were used to determine risk factors for a positive repeat OFC, including factors that were ascertainable immediately after the initial OFC and at the repeat OFC as variables.
Results
The median age, egg white‐, and ovomucoid‐specific IgE (sIgE) were 3.5 years, 12.7, and 7.2 kUA/L, respectively. The median interval between OFCs was 12.4 months and repeat OFCs were positive in 132 (54%) patients. One multivariate analysis model indicated that risk factors for a positive repeat OFC included cumulative dose (adjusted odds ratio [aOR]:0.58), anaphylaxis (aOR: 3.09), total serum IgE (aOR: 0.41), ovomucoid‐sIgE (aOR: 3.21), and age (aOR: 1.68) at the initial OFC. Another model indicated that the risk factors were cumulative dose (aOR: 0.59) and anaphylaxis (aOR: 3.41) at initial OFC and total serum IgE (aOR: 0.36), ovomucoid‐sIgE (aOR: 4.93), and age (aOR: 1.30) at repeat OFC.
Conclusion
Low threshold dose and severe symptoms at initial OFC, and low total serum IgE, high ovomucoid‐sIgE and higher age at initial and repeat OFCs are risk factors for the persistence of HE allergy and they may be useful when deciding the rechallenge interval for heated HE in preschool children.
... However, in a large-scale study of children (n=467) who underwent OFCs, it was found that food-specific SPT wheal diameters of >8 mm (to cow's milk), >7 mm (to egg), and >8 mm (to peanut) were highly and correctly predictive of systemic responses (100% specificity) to each allergen (Sporik et al., 2000). The cut-offs may vary with the age of participants, the degree of cooking, and the type of allergens (commercial extract or raw food) (Komata et al., 2007;Nowak-Wegrzyn et al., 2008;Järvinen and Sicherer, 2012;Cuomo et al., 2017). Therefore, the relevance of such sensitivity to allergen extracts should be carefully interpreted in the light of the clinical history and situation, since many SPTs may yield false positives. ...
Food allergy (FA) is a global health problem that affects a large population, and thus effective treatment is highly desirable. Oral immunotherapy (OIT) has been showing reasonable efficacy and favorable safety in most FA subjects. Dependable biomarkers are needed for treatment assessment and outcome prediction during OIT. Several immunological indicators have been used as biomarkers in OIT, such as skin prick tests, basophil and mast cell reactivity, T cell and B cell responses, allergen-specific antibody levels, and cytokines. Other novel indicators also could be potential biomarkers. In this review, we discuss and assess the application of various immunological indicators as biomarkers for OIT.
... There are still no equal test assay systems for serum sIgE, which makes for a difficult comparison between studies and techniques. Several studies have tried to describe the predictive values of IgE levels for clinical reactivity [8], but the differences are quite significant mainly due to various selection criteria, age of the patient or different criteria for analyzing the clinical reactivity [9,11,12]. ...
Aim:
The present study analyzed clinical and biological factors that might predict achievement of tolerance in patients with IgE-mediated cow milk allergy (CMA).
Method:
Seventy patients with IgE-mediated CMA (44.24 ± 24.16 months) were included in the study. The patients were evaluated clinically through skin prick test and sIgE to whole milk, casein, beta-lactoglobulin and alpha-lactalbumin. An eviction diet of 6 months was established, followed by oral food challenge test (OFC) and oral immunotherapy (OIT) with baked milk for 6 months. The tolerance was assessed after 2 years follow up.
Results:
Thirty percent of patients presented anaphylaxis of different degrees of severity as first manifestation of CMA. Sixty-two patients followed OIT or an accelerated reintroduction of milk. Ten patients (14.28%) did not obtain tolerance to milk within 2 years. A larger wheal in SPT and higher sIgE to milk, casein and betalactoglobulin were noted in patients with positive OFC. A basal level of <2.5 kU/l for sIgE to milk and <11.73 kU/l for sIgE to caseins predicted the occurrence of tolerance in patients with all types of clinical manifestations, including anaphylaxis.
Conclusion:
Basal levels of sIgE to milk and casein may help to identify patients that could become tolerant to milk.
... Quantitative determination of egg white (EW)-specific IgE enables prediction of allergic reactions in oral food challenge (OFC) testing as well as monitoring of oral immunotherapy. Probability curves providing the likelihood of a positive outcome of an OFC or of manifest symptoms to egg have been established, based on levels of specific IgE to both EW and Gal d 1 (ovomucoid) [10][11][12]. ...
Background
Measurements of allergen-specific IgE antibodies with different manufacturers’ assays show modest or poor agreement. This study compares analytical performance of specific IgE tests for whole allergen extracts and individual allergen components of two assay systems, IMMULITE and ImmunoCAP, using human sera as well as monoclonal antibodies.
Methods
Comparisons were performed for specific IgE to house dust mite (HDM, n = 44), egg white (EW, n = 36) and the allergen components rDer p 1, rDer p 2, nGal d 1, nGal d 2 and nGal d 4 in human sera and with monoclonal mouse/human chimeric IgE antibodies specific for the same allergen components. Competitive interference with IgE measurement was investigated using allergen-specific monoclonal IgG and IgG4 antibodies.
Results
Measurements of IgE to HDM and EW in serial dilutions of human sera revealed weaker dilution linearity with IMMULITE than with ImmunoCAP. Analysis of five different monoclonal IgE antibodies with total and specific IgE assays, expected to return similar levels, gave an average specific/total IgE ratio of 0.96 (range 0.71–1.14) with ImmunoCAP and 1.89 (range 0.76–2.85) with IMMULITE, indicating overestimation of specific IgE by IMMULITE. With the EW IgE tests of both assay systems, measurements of a chimeric anti-Gal d 2 IgE antibody were unaffected by a competing mouse IgG antibody. While the same was true for measurement of a chimeric anti-Der p 1 IgE antibody using the HDM test in ImmunoCAP, a suppression of measured concentrations by up to 42% was observed in IMMULITE. Similarly, measurement of HDM-specific IgE in human sera by ImmunoCAP was unaffected by a competing monoclonal anti-Der p 2 IgG4 antibody while IMMULITE displayed a reduction of HDM-specific IgE values by up to 30%.
Conclusions
In this evaluation of analytical performance of two widely used assay systems, ImmunoCAP showed higher accuracy in quantitation of specific IgE and greater resistance against competing allergen-specific non-IgE antibodies which may arise through natural or dietary exposure, or as a result of allergen immunotherapy treatment.
... De kans op allergische symptomen bij sensibilisatie blijkt afhankelijk van de leeftijd [Garcia-Ara 2004;Komata 2007;Van der Gugten 2008]. Er werd geen samenhang gevonden tussen de sIgE-concentratie en de ernst van de symptomen. ...
... Numerous papers have analyzed the possibility of establishing a cutoff for sIgEs and SPTs for CM and its proteins that could predict whether a patient would react to an OFC [24]. Actually, several studies showed that cutoffs can vary with age [25], and many researchers are attempting to recommend diagnostic cutoffs for children [26,27]. However, cutoffs may change among different studies because of the type of allergen used to perform SPTs (commercial extract vs raw milk) or because of the degree of cooking [24]. ...
Cow's milk allergy (CMA) is one of the most common food allergies in infants, and its prevalence has increased over recent years. In the present paper, we focus on CMA as a model of food allergies in children. Understanding the diagnostic features of CMA is essential in order to manage patients with this disorder, guide the use of an elimination diet, and find the best moment to start an oral food challenge (OFC) and liberalize the diet. To date, no shared tolerance markers for the diagnosis of food allergy have been identified, and OFC remains the gold standard. Recently, oral immunotherapy (OIT) has emerged as a new therapeutic strategy and has changed the natural history of CMA. Before this, patients had to strictly avoid the food allergen, resulting in a decline in quality of life and subsequent nutritional, social, and psychological impairments. Thanks to the introduction of OIT, the passive approach involving rigid exclusion has changed to a proactive one. Both the heterogeneity in the diagnostic process among the studies and the variability of OIT data limit the comprehension of the real epidemiology of CMA, and, consequentially, its natural history. Therefore, well-planned randomized controlled trials are needed to standardize CMA diagnosis, prevention, and treatment strategies.
... In recent years, allergen-specific IgE antibody measurements have taken on new meaning in their ability to predict whether an individual with a suspected food allergy to potent allergenic foods, such as chicken egg, cow's milk, peanut, and fish, will fail a double-blind placebo-controlled food challenge with a 95% probability. [14][15][16][17][18][19] To date, however, the reported IgE anti-food values leading to the generation of predictive cutpoints have been exclusively measured by using 1 of 3 clinically available IgE antibody assays, namely, the ImmunoCAP. Past studies that have examined IgE assay performance have continued to show that despite the fact that various assays report results in the same IgE antibody units (kU A /L), they measure different populations of IgE antibody. ...
Context.—The diagnostic algorithm for human allergic disease involves confirmation of sensitization by detection of allergen-specific immunoglobulin E (IgE) antibody in individuals suspected of having allergic disease because of a history of allergic symptoms after known allergen exposure. Previous studies showed wide disparity among clinically reported allergen-specific IgE levels from different serologic assays.
Objective.—To validate the relative analytic performance (sensitivity, interassay reproducibility, linearity/parallelism, intermethod agreement) of clinically used total and allergen-specific IgE assays by using College of American Pathologists' Diagnostic Allergy “SE” Proficiency Survey data.
Design.—Data from 2 SE survey cycles were used to assess relative analytic performance of the ImmunoCAP (Phadia), Immulite (Siemens Healthcare-Diagnostics), and HYTEC 288 (HYCOR-Agilent Technologies) total and allergen-specific IgE assays. In each cycle, 2 recalcified plasma pools from atopic donors were diluted twice with IgE-negative serum and evaluated in approximately 200 federally certified clinical laboratories for total IgE and IgE antibody to 5 allergen specificities. Statistical analysis evaluated analytic sensitivity, linearity, reproducibility, and intermethod agreement.
Results.—Interlaboratory intramethod, intermethod, and interdilution agreement of all 6 clinically used total serum IgE assays were excellent, with coefficients of variation (CVs) below 15%. Interlaboratory intramethod, and interdilution agreement of 3 clinically used allergen-specific IgE assays were also excellent with CVs below 15%. However, intermethod CVs identified between-assay disagreement greater than 20% in 80% of allergen-specific IgE measurements. Allergen reagents and patients' immune response heterogeneity are suggested probable causes.
Conclusions.—Clinical total and allergen-specific IgE assays display excellent analytic sensitivity, precision, reproducibility, and linearity. Marked variability in quantitative estimates of allergen-specific IgE from clinically used automated immunoassays is a concern that may be ameliorated with component allergen use.
... In other words, the diagnostic performance of both assay methods is better when testing is conducted at an older age for milk allergy and at a younger age for wheat allergy. Our results for milk allergen are in line with those reported by Komata et al.,15 who demonstrated better performance of the ImmunoCAP assay for egg and milk sIgE in patients older than 2 years. In the wheat assay, however, we assume that younger patients tend to react more strongly to the water-insoluble components of the wheat allergens (gliadins and glutenins), leading to better performance. ...
Purpose:
ImmunoCAP® (ImmunoCAP) and IMMULITE® 2000 3gAllergy™ (3gAllergy) systems are major quantitative allergen-specific immunoglobulin E (sIgE) assay methods. Due to the heterogeneous nature of allergenic extracts and differences in the assay format, quantitation of allergen-sIgEs is not expected to correlate well between different methods. However, we have recently reported good agreement between the methods in the diagnosis of egg allergy. This study aimed to determine and correlate the predictive values of sIgE by the two systems in the diagnosis of milk and wheat allergies.
Methods:
Children who had undergone oral food challenge (OFC) for the diagnosis of milk and wheat allergies were enrolled. The OFCs were performed to diagnose either true allergy in the 1-year-old group (A) or tolerance in the 2- to 6-year-old group (B). Milk, casein and β-lactoglobulin, and wheat and ω-5 gliadin sIgE values were measured using the 2 systems. The predictive accuracy of each sIgE for the OFC outcome was assessed using receiver operating characteristic (ROC) curves. The probability of a positive OFC outcome was estimated by logistic regression analysis.
Results:
A total of 395 patients were recruited from 7 primary care clinics and 19 hospitals in Japan. Milk and wheat OFCs were performed for 87 and 102 group A patients, and 124 and 82 group B patients, respectively. ROC analysis yielded similar areas under the curve for the 2 assays (0.7-0.9). The log-transformed sIgE data showed a strong linear correlation with the estimated probabilities (R > 0.9).
Conclusions:
The 2 systems may be interchangeable for diagnosis of milk and wheat allergies in young children.
... In this study, we repeated the nested CV a total of 10 times in separate splits and averaged the result to avoid sampling bias and data overfitting. Additionally, to assess the relative usefulness of the ML models, we compared their predictive performance with that determined using previously proposed cutoff levels for EW-sIgE and OM-sIGE, which were reported by Komata et al, 8 Ando et al, 9 and Haneda et al 10 Table 1. Table 2, AUCs for the LR and linear SVM models exceeded 0.80. ...
Serum levels of allergen‐specific IgE (sIgE) are among the tools used to diagnose hen’s egg allergy. However, sIgE levels may lead to false‐positive results and reliable diagnostic cutoff levels are currently unclear.(1) Recently, machine learning (ML) techniques have been applied to predict clinical diagnoses and prognoses in many fields of medicine.(2),(3) To the best of our knowledge, there are no published studies that have applied ML methods to issues related to outcomes from heated egg oral food challenge (OFC). We hypothesized that an ML approach may help clinicians to make clinical decisions regarding the need for and conduct of OFC in the clinical setting. We aim to construct a ML method that will reliably predict the outcome of heated egg OFC using routinely available laboratory data.
... Komata et al compared sIgE levels for egg and cow's milk in children <1 year old, 1 year old and 2 years old or greater and found that younger children react on low levels of sIgE compared to older children. 13 Children with a history of reaction to a food were more likely to have a positive OFC result. Inoue et al reported in a study on cashew allergy in children, and all PPVs calculated were higher if the child had a previous clinical history of reaction to cashew compared to those that had no previous reaction. ...
Food allergy is increasing in prevalence, affecting up to 10% of children in developed countries. Food allergy can significantly affect the quality of life and well‐being of patients and their families; therefore, an accurate diagnosis is of extreme importance. Some food allergies can spontaneously resolve in 50%‐60% of cow’s milk and egg‐allergic, 20% of peanut‐allergic and 9% of tree nut‐allergic children by school age. For that reason, food‐allergic status should be monitored over time to determine when to reintroduce the food back into the child’s diet. The gold‐standard to confirm the diagnosis and the resolution of food allergy is an oral food challenge; however, this involves the risk of causing an acute‐allergic reaction and requires clinical experience and resources to treat allergic reactions of any degree of severity. In the clinical setting, biomarkers have been used and validated to enable an accurate diagnosis when combined with the clinical history, deferring the oral food challenge, whenever possible. In this review, we cover the tools available to support the diagnosis of food allergies and to predict food allergy resolution over time. We review the latest evidence on different testing modalities and how effective they are in guiding clinical decision making in practice. We also evaluate predictive test cut‐offs for the more common food allergens to try and provide guidance on when challenges might be most successful in determining oral tolerance in children.
... More recent work demonstrating that in vitro quantification of IgE specific to allergen extracts correlated with the likelihood of allergic reactions [17][18][19][20] , fueled the development of new diagnostic assays and the search for the ideal biomarker. The ability to refine proteins that drive IgE responses, e.g. ...
Identification of allergenic IgE epitopes is instrumental for the development of novel diagnostic and prognostic methods in food allergy. In this work, we present the quantification and validation of a Bead-Based Epitope Assay (BBEA) that through multiplexing of epitopes and multiple sample processing enables completion of large experiments in a short period of time, using minimal quantities of patients’ blood. Peptides that are uniquely coupled to beads are incubated with serum or plasma samples, and after a secondary fluorophore-labeled antibody is added, the level of fluorescence is quantified with a Luminex reader. The signal is then normalized and converted to epitope-specific antibody binding values. We show that the effect of technical artifacts, i.e. well position or reading order, is minimal; and batch effects - different individual microplate runs - can be easily estimated and eliminated from the data. Epitope-specific antibody binding quantified with BBEA is highly reliable, reproducible and has greater sensitivity of epitope detection compared to peptide microarrays. IgE directed at allergenic epitopes is a sensitive biomarker of food allergy and can be used to predict allergy severity and phenotypes; and quantification of the relationship between epitope-specific IgE and IgG4 can further improve our understanding of the immune mechanisms behind allergic sensitization.
... Cor a 14-sIgE at the threshold of 0.35 kU A /L would correctly diagnose 80.4% of children, striking the best balance between false-negative and false-positive results. However, as very low levels of sIgE to primary allergens can also be relevant, 43 especially in young children, 44 it may be important to quantify sIgE levels to the limit of detection (0.1 kU A /L), 45 and to carefully review the clinical history of each patient. Therefore, these tests (Cor a 9 and Cor a 14) should be used in association with limit the risk of misclassifying patients. ...
Background
Hazelnut‐specific IgE antibodies (sIgEs) in serum support the diagnosis of hazelnut allergy, but extract‐based tests have low diagnostic specificity, commonly leading to over‐diagnosis. Measuring sensitization to individual allergen components may enhance the diagnosis of hazelnut allergy. We systematically examined data on diagnostic accuracy of sIgE to commercially available hazelnut components to compare their individual contributions in diagnosing hazelnut allergy.
Methods
Seven databases were searched for diagnostic studies on patients suspected of having hazelnut allergy. Studies employing component‐specific IgE testing on patients whose final diagnosis was determined by oral food challenges were included in the meta‐analysis. Study quality was assessed as recommended by Cochrane.
Results
Seven cross‐sectional studies and one case‐control study were identified, seven presenting data on children (N = 635), and one on a mixed age population. Overall, the diagnostic accuracies of sIgE to both Cor a 9 and Cor a 14 were significantly higher than for Cor a 1‐sIgE (P < .05). In children, the specificity of Cor a 14‐sIgE at 0.35 kUA/L cutoff was 81.7% (95% CI 77.1, 85.6), and 67.3% (60.3, 73.6) for Cor a 9‐sIgE. The specificities for Cor a 1‐sIgE and hazelnut‐sIgE were 22.5% (7.4, 51.2) and 10.8% (3.4, 29.8), respectively. The sensitivity of Cor a 1‐sIgE (60.2% [46.9, 72.2]) was lower than for hazelnut extract‐sIgE (95.7% [88.7, 98.5]), while their specificities did not differ significantly.
Conclusion
sIgE to Cor a 14 and Cor a 9 hazelnut storage proteins increases diagnostic specificity in assessing hazelnut allergy in children. The combined use of hazelnut extract and hazelnut storage proteins may improve diagnostic value.
... Low levels of sensitization have been associated with clinical food allergy amongst young children. 2,28,29 We therefore report if sensitization to any one of the EAT study food allergens breached thresholds at ≥0.10 kU/L or ≥ 0.35 kU/L at 3 months, and SPT ≥1 mm, ≥3 mm or ≥0.35 kU/lat 12 and 36 months. Unless otherwise stated, sensitization levels reported in the manuscript text refer to the ≥3 mm or ≥0.35 kU/L cutoff values. ...
Background
The prevention of food allergy is a key priority for reducing the burden of allergic disease. Environmental exposures modulate the risk of developing food allergy and some of this may be mediated by the infants’ developing microbiome. However, the role of potentially protective environmental exposures, such as pet ownership, is largely uninvestigated with respect to food allergy.
Methods
We performed a secondary cohort analysis in the Enquiring About Tolerance (EAT) study, which enrolled 1303 three‐month infants onto a randomized trial to prevent food allergy. A survey elicited domestic animal ownership and participants were examined for atopic dermatitis (AD) at enrolment. Sensitization to foods and aeroallergens were elicited by skin and serum testing at 3, 12 and 36 months. Food allergy status was determined by double‐blind placebo‐controlled food challenges between 1 and 3 years.
Results
Food allergy was diagnosed amongst 6.1% (68/1124) of participants with complete data. No significant relationships were demonstrated between food allergy and caesarean delivery, infections or antibiotic exposure in early life. After adjusting for familial atopic disease, maternal dog/cat sensitization and participant AD, living with dogs was associated with a 90% reduction in the odds of infants developing food allergy (adjusted odds ratio (aOR) 0.10 (confidence interval (CI) 0.01‐0.71), P = 0.02). None of the 49 infants living with at least two dogs developed food allergy, suggesting a dose‐response relationship (each dog owned aOR 0.12 (CI 0.02‐0.81), P = 0.03). No relationship was demonstrated between owning dogs or cats and the development of AD.
Conclusion
Dog ownership in infancy may prevent food allergy.
... However, food and inhalant allergens cosensitized subgroups had significantly low body mass index (BMI) (AR subgroup p Z 0.02, Asthma subgroup p Z 0.019) than the other subgroups ( Table 1). 39 of 87 (44.83%) allergic rhinitis children were assigned to the food and inhalant allergens cosensitized subgroup (AR food group) and 48 (55.17%) to the inhalant allergen sensitized subgroup (AR inhalant group). The AR food group had significantly higher total IgE levels (p Z 0.02) and lower nPEFR values (p Z 0.04) compared with the AR inhalant group (Fig. 1) (Fig. 2). ...
Background:
Sensitization to allergen has long been known to be relate to childhood allergic diseases. Polysensitised children have more severe atopic diseases, whereas allergic rhinitis or asthma children with cosensitized to food and inhalant allergens were under-researched.
Objective:
To realize the association between sensitization to food allergens and pediatric allergic rhinitis and asthma in Taiwan.
Methods:
We included 138 participants with sensitized to allergen as assessed by serum-specific IgE. 87 of 138 participants had allergic rhinitis and 51 participants had asthma. All participants underwent a physical examination and measurement of serum total and specific IgE values. Besides, nasal peak expiratory flow rate (nPEFR) that was performed by the participants with allergic rhinitis and were requested to complete the Pediatric Rhinoconjunctivitis Quality of Life Questionnaires (PRQLQ). Lung function test and asthma control test (ACT)/child asthma control test (C-ACT) were performed by the participants with asthma.
Results:
39 of 87 allergic rhinitis participants with sensitized to food and inhalant allergens (AR food group), 48 of 87 allergic rhinitis participants with sensitized to inhalant allergen alone (AR inhalant group). The AR food group had significantly lower nPEFR values and higher total IgE values (p < 0.05) compared with the AR inhalant group. The AR food group had higher PRQLQ scores than the AR inhalant group. 24 of 51 asthma participants with sensitized to food and inhalant allergens (Asthma food group), 27 of 51 asthma participants with sensitized to inhalant allergen alone (Asthma inhalant group). The Asthma food group had significantly higher total IgE values (p < 0.05) compared with the Asthma inhalant group. The Asthma food group had lower lung function test values and asthma control test (ACT) scores than the other group.
Conclusions:
Children with cosensitized to food and inhalant allergens have more severe clinical symptoms and abnormal laboratory findings. Sensitization to food allergen was more related to pediatric allergic rhinitis than asthma. We may need larger, longer and extended studies to confirm these findings.
... The inclusion criteria for individuals with a high level of specific IgE were selected based on the results of a previous trial reporting that individuals fulfilling these conditions have a 95% probability of having CMA. 12 Children with a current diagnosis of severe persistent asthma were excluded from the study. When paediatricians at Fujita Health University encountered children at the paediatric allergy clinics who satisfied the study criteria, they explained the study to the families and asked them to participate. ...
Background and objectives:
The safety and tolerability of hydrolysed cow's milk protein-based formulas, particularly partially hydrolysed formulas (pHFs), in children with cow's milk allergy (CMA) remain poorly understood. We evaluated the tolerability of hydrolysed cow's milk-based formulas in children with CMA.
Methods and study design:
A three-period double-blind crossover evaluation compared the allergic tolerance against three dietary cow's milk-based formulas: extensively hydrolysed cow's milk formula (eHF), pHF, and regular cow's milk formula (rCMF). The primary outcome was the rate of tolerance against a maximum of 20.0 mL of formula.
Results:
Controlled food challenges were performed in 25 children (18 boys; 7 girls) with a median age of 4.25 years (range: 1-9 years) diagnosed with CMA. The median cow's milk-specific immunoglobulin E level was 31.9 UA/mL (range: 1.16-735 UA/mL). The tolerance rate ratios for rCMF were lower than those for pHF (2 vs 16; p<0.01) and eHF (2 vs 22; p<0.01). The allergic symptom scores induced by intake of pHF and eHF were significantly lower than those of rCMF (p=0.01 and p<0.01, respectively), and the pHF and eHF scores were not significantly different.
Conclusions:
Compared to rCMF, the partially and extensively hydrolysed whey and casein formulas evaluated in this study were better tolerated and therefore safer for children with CMA. Although further confirmation from additional centres is needed, our findings suggest the use of pHF in patients with mild CMA. Some children with CMA react to hydrolysed formulas; therefore, food challenge tests in these children should be undertaken with caution.
... In Japan, a paper was published in 2007 that reported the cutoff value of sIgE of cow's milk allergy at 5.8 in cases of infants under one, 38.6 in cases of one-year-olds, and 58.3 kU A /L in cases of those over two. 25 There was one paper published in Korea that examined DDP of cow's milk sIgE in Korean children. However, the subject was limited to pediatric atopic dermatitis patients. ...
Background
Anaphylaxis is increasing in young children. The aim of the present study was to analyze the clinical characteristics of anaphylaxis in Korean infants, with a focus on food triggers.
Methods
The study analyzed the medical records of infants aged 0 to 2 years old who had been diagnosed with anaphylaxis in 23 secondary or tertiary hospitals in Korea.
Results
We identified 363 cases of infantile anaphylaxis (66.9% male). Cutaneous symptoms were most prevalent (98.6%), followed by respiratory (83.2%), gastrointestinal (29.8%), and neurologic (11.6%) symptoms. Cardiovascular symptoms were noted in 7.7% of the cases. Most of the cases of anaphylaxis (338; 93.1%) were induced by foods. The most common trigger food was cow's milk and cow's milk products (43.8%), followed by hen's eggs (21.9%), walnuts (8.3%), wheat (7.7%), peanuts (4.8%), other nuts (3.0%), and fish (2.1%). In cow's milk-induced anaphylaxis cases, more than half the cases had cow's milk specific immunoglobulin E (sIgE) levels that were lower than the diagnostic decision points (DDPs), which is 5 kUA/L for those under the age of 1 and 15 kUA/L for those over the age of 1. In anaphylaxis induced by hen's egg, most of the cases (91.8%) had hen's egg sIgE levels that were higher than the DDP, which is 2 kUA/L for those under the age of 2 and 7 kUA/L for those over the age of 2. Of the infantile anaphylaxis cases, 46.8% had been treated with epinephrine, and 25.1% had been prescribed an epinephrine auto-injector.
Conclusion
Cow's milk is the most frequent trigger food of anaphylaxis in Korean infants. However, we found no significant correlation between the sIgE level and clinical severity. Education is required regarding the importance of epinephrine as the first line therapy for anaphylaxis and on properly prescribing epinephrine for infants with a history of anaphylaxis.
... Two factors were involved in the onset of anaphylaxis after skin exposure in the present case. The first was the high concentration of specific IgE to the wheat allergen before age 3 months and the higher clinical relevance of lower levels of specific IgE at lower ages [8]. The other is that the wheat was raw (cooking can reduce its allergenicity) [9]. ...
... Although, previous literature has found asthma to be a significant predictor of severe reactions (51,62), our data did not find asthma to be a significant factor associated with positive challenge outcome. Some studies have shown that age can affect IgE and SPT cutoff levels (22,63,64), with lower cutoffs typically used in children <2 years of age (65,66), however our analysis did not reveal strong associations with age, SPT/sIgE/sIgEr cutoff levels and challenge outcomes. This is likely due to the limited number of participants aged <2 years who were challenged in our cohort. ...
Background: Double-blind placebo-controlled food challenges (DBPCFCs) remain the gold standard for the diagnosis of food allergy; however, challenges require significant time and resources and place the patient at an increased risk for severe allergic adverse events. There have been continued efforts to identify alternative diagnostic methods to replace or minimize the need for oral food challenges (OFCs) in the diagnosis of food allergy.
Methods: Data was extracted for all IRB-approved, Stanford-initiated clinical protocols involving standardized screening OFCs to a cumulative dose of 500 mg protein to any of 11 food allergens in participants with elevated skin prick test (SPT) and/or specific IgE (sIgE) values to the challenged food across 7 sites. Baseline population characteristics, biomarkers, and challenge outcomes were analyzed to develop diagnostic criteria predictive of positive OFCs across multiple allergens in our multi-allergic cohorts.
Results: A total of 1247 OFCs completed by 427 participants were analyzed in this cohort. Eighty-five percent of all OFCs had positive challenges. A history of atopic dermatitis and multiple food allergies were significantly associated with a higher risk of positive OFCs. The majority of food-specific SPT, sIgE, and sIgE/total IgE (tIgE) thresholds calculated from cumulative tolerated dose (CTD)-dependent receiver operator curves (ROC) had high discrimination of OFC outcome (area under the curves > 0.75). Participants with values above the thresholds were more likely to have positive challenges.
Conclusions: This is the first study, to our knowledge, to not only adjust for tolerated allergen dose in predicting OFC outcome, but to also use this method to establish biomarker thresholds. The presented findings suggest that readily obtainable biomarker values and patient demographics may be of use in the prediction of OFC outcome and food allergy. In the subset of patients with SPT or sIgE values above the thresholds, values appear highly predictive of a positive OFC and true food allergy. While these values are relatively high, they may serve as an appropriate substitute for food challenges in clinical and research settings.
... Inclusion criteria were as follows: an age of between 1 and 20 years at the start of the trial, and a known history of systemic symptoms induced by ingesting small amounts of milk allergens or high cow's milk-specific IgE values, with a 95% probability of CMPA (according to a previous trial [11]). Participants with a current diagnosis of severe persistent asthma were excluded from the trial. ...
Background:
Partially hydrolyzed cow's milk protein-based formula (pHF) possesses low allergenicity. Here, we investigate the safety and efficacy of oral immunotherapy using pHF for children with cow's milk protein allergy (CMPA).
Objectives:
A randomized, double-blind, controlled single-center trial was conducted to evaluate the efficacy and safety of pHF oral immunotherapy in children with CMPA.
Methods:
Participants were randomized into double-blind pHF-pHF and extensively hydrolyzed cow's milk protein-based formula (eHF)-pHF groups. During this phase, the pHF-pHF group received pHF and the eHF-pHF group received eHF. During the open phase, all participants received pHF. The primary end point was a change in thresholds between baseline and the end of the first phase. Secondary end points were changes in thresholds between baseline and the end of the second phase, and casein-specific immunoglobulin (Ig)E, IgG4, and basophil activation.
Results:
Twenty-five children, aged 1-9 years, were randomized into pHF-pHF and eHF-pHF groups. The threshold between baseline and the end of the first phase was significantly elevated in the pHF-pHF group (p = 0.048), but not in the eHF-pHF group. The threshold between other phases did not change significantly in either group. There were significant decreases in casein-specific IgE antibody levels between baseline and the second phase in the eHF-pHF group (p = 0.014). No participants suffered systemic allergic reactions requiring adrenaline or systemic corticosteroids after receiving the formulas.
Conclusions:
The results of this trial suggest that, in children with CMPA, tolerance to cow's milk might be safely enhanced by intake of pHF, relative to that of eHF.
Purpose of review
Food allergy is a growing health problem that affects both patients and society in multiple ways. Despite the emergence of novel diagnostic tools, such as component-resolved diagnostics (CRD) and basophil activation tests (BAT), oral food challenge (OFC) still plays an indispensable role in the management of food allergies. This review aimed to highlight the indications and safety concerns of conducting an OFC and to provide insights into post-OFC management based on recent findings.
Recent findings
Standardized OFC protocols have regional diversification, especially in Japan and Western countries. Recent studies suggested that the interval between doses should be at least more than an hour. Furthermore, applying a stepwise method tailored to the patient's specific immunoglobulin E level and history of anaphylaxis seems to mitigate these risks. Recent surveys have shown that, following a positive OFC, options other than strict avoidance are also selected.
Summary
OFC serves diverse purposes, yet the risks it carries warrant caution. The stepwise protocol appears promising for its safety. Subthreshold consumption following OFC shows potential; however, further research on its efficacy and safety is required. Management following OFC should be tailored and well discussed between clinicians and patients.
The European Academy of Allergy and Clinical Immunology (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta‐analyses to assess the accuracy of diagnostic tests for IgE‐mediated food allergy. We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 October 2012 and 30 June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full texts and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta‐analyses were undertaken for food‐test combinations for which three or more studies were available. A total of 149 studies comprising 24,489 patients met the inclusion criteria and they were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% were undertaken in Europe, ≥95% were conducted in a specialized paediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% double‐blind placebo‐controlled food challenges. Skin prick test (SPT) with fresh cow's milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE (sIgE) to individual components had high specificity: Ara h 2‐sIgE had 92%, Cor a 14‐sIgE 95%, Ana o 3‐sIgE 94%, casein‐sIgE 93%, ovomucoid‐sIgE 92/91% for the diagnosis of peanut, hazelnut, cashew, cow's milk and raw/cooked egg allergies, respectively. The basophil activation test (BAT) was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. In conclusion, SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies.
Food allergens are a major concern for individuals who are susceptible to food allergies and may experience various health issues due to allergens in their food. Most allergenic foods are subjected to heat treatment before being consumed. However, thermal processing and prolonged storage can cause glycation reactions to occur in food. The glycation reaction is a common processing method requiring no special chemicals or equipment. It may affect the allergenicity of proteins by altering the structure of the epitope, revealing hidden epitopes, concealing linear epitopes, or creating new ones. Changes in food allergenicity following glycation processing depend on several factors, including the allergen's characteristics, processing parameters, and matrix, and are therefore hard to predict. This review examines how glycation reactions affect the allergenicity of different allergen groups in allergenic foods.
Allergy is defined clinically, by symptoms upon allergen exposure. A patient is considered sensitized when allergen-specific IgE antibody can be detected in serum or plasma or a skin test is positive, even if no clinical reaction has been experienced. Sensitization should be regarded as a requisite and risk factor for allergy but is not synonymous with an allergy diagnosis. To provide a correct allergy diagnosis, test results regarding allergen-specific IgE must always be considered in view of the patient's case history and clinical observations. Correct assessment of a patient's sensitization to specific allergens relies on the use of accurate and quantitative methods for detection of specific IgE (sIgE) antibodies. The evolution of sIgE immunoassays towards higher analytical performance and the use of different cut-off levels in the interpretation of test results sometimes causes confusion. Earlier versions of sIgE assays offered a Limit of Quantitation of 0.35 kilounits of sIgE per liter (kUA/L), which also became an established cut-off level for a positive test result in the clinic use of the assays. Current sIgE assays are capable of reliably measuring sIgE levels as low as 0.1 kUA/L and can thereby demonstrate sensitization in cases where previous assays could not. When the outcome of sIgE test results is evaluated, it is critically important to distinguish between the analytical data as such and the clinical interpretation of them. Even though sIgE may be present in the absence of symptoms of allergy, available information suggests that sIgE concentrations between 0.1 kUA/L and 0.35 kUA/L may be clinically relevant in some individuals, not least among children, although this needs to be further evaluated. Moreover, it is becoming widely adopted that non-dichotomous interpretation of sIgE levels may offer a diagnostic benefit compared to using a pre-defined cut-off level.
Background:
Oral food challenges (OFC) are required to diagnose food allergies but are resource-intensive.
Objective:
To reduce the need for OFCs, we sought to determine serum specific immunoglobulin E (sIgE) cutoff levels for cow's milk and its major allergens predicting oral milk challenge outcomes in children with suspected cow's milk allergy.
Methods:
A total of 135 Finnish children (median age, 1.8 years [range, 1.0-14.1 years]) with suspected cow's milk allergyunderwent open OFC with unheated cow's milk. The sIgE levels to milk (f2), casein (Bos d 8), alpha-lactalbumin (Bos d 4),beta-lactoglobulin (Bos d 5), and bovine serum albumin (BSA) (Bos d 6) were measured and compared with the challenge outcomes.
Results:
Of the 135 OFCs, 5 were excluded from the study due to purely subjective symptoms. Of the 130 remaining OFCs, 98 results (75%) were positive. In a receiver operating characteristic analysis with 1-2-year-old children, no individual allergen sIgE had a better area under the curve than milk sIgE (0.824). A milk sIgE level > 6.30 kU/L gave 94% specificity and 33% sensitivity for positive OFCs. In 3-14-year-old children, a cutoff value >13.9 kU/L predicted a positive OFC result with 93% specificity and 25% sensitivity. Children with moderate-to-severe reactions had higher sIgE levels to milk, alphalactalbumin, and BSA than did children with mild reactions.
Conclusion:
Molecular allergy diagnostics did not improve the predictive performance compared with milk sIgE. The milk sIgE value that exceeds the cutoff for 95% specificity in combination with the clinical history may help to reduce the need for OFCs. The severity of an allergic reaction cannot reliably be predicted from sIgE measurements.
In vitro allergy testing is a useful tool in the diagnosis of immunoglobulin E (IgE)-mediated allergies. While it does not have the same sensitivity as in vivo testing, there are certain circumstances under which in vitro testing is indicated or may be the method of choice. In vitro testing primarily consists of measuring specific IgE antibody to an allergen through the use of immunoassays. Allergen-specific IgE binds to allergen, and the amount of allergen bound IgE is then measured using labeled antihuman IgE antibodies. ImmunoCAP, which uses an enzyme immunoassay, is currently the “reference standard” for in vitro IgE testing. Specific IgE testing can be performed using singleplex or multiplex systems, and there are differing opinions regarding the preferred testing system. Specific IgE testing is available for environmental allergens, foods, venoms, latex, drugs, and occupational allergens. However, the sensitivity and utility of specific IgE values for these allergens vary. For example, the specific IgE assay for a standardized allergen such as cat has a higher sensitivity than the assay for a nonstandardized allergen such as dog. Difficulties in interpreting specific IgE results can also arise due to the presence of cross-reactive IgE antibodies, although component-resolved diagnostics has proven helpful in distinguishing responsible allergens from cross-reactive components. Other in vitro tests include total IgE and tryptase levels, which are commonly used in evaluation of allergic disease as well as basophil activation tests, which have been used in the evaluation of hypersensitivity reactions on a research basis but not yet in clinical practice.
Chapter 8 of "Japanese Guidelines for Food Allergy 2021" covers diagnostics and examinations for food allergy, excluding oral food challenges. Significant updates include an updated flowchart for food allergy diagnosis that is simpler and easier to understand, detailed interview points by age group, detailed description of how to interpret specific IgE antibody tests, including probability curves and ROC curves, and other tests. The other tests are also described in detail and their diagnostic significance. Since the diagnosis of allergy to each allergen is discussed in a separate chapter of the guideline, the content of this chapter is limited to a general discussion. A deep understanding of these tests allows for more accurate diagnosis and management options.
Background
Food allergy diagnosis and management causes a number of social and emotional challenges for individuals with food allergies and their caregivers. This has led to increased interest in developing approaches to accurately predict food allergy diagnosis, severity of food allergic reactions, and treatment outcomes. However, the utility of these approaches is somewhat conflicting.
Objective
We sought to develop and utilize a murine model that mimics the disease course of food allergy diagnosis and treatment in humans and to identify biomarkers that predict reactivity during food challenge (FC) and responsiveness during oral immunotherapy (OIT) and how these outcomes are modified by genetics.
Methods
Skin-sensitized intestinal IL-9 transgenic (IL9Tg) and IL9Tg mice backcrossed onto the IL-4RαY709F background received a single intragastric exposure of egg antigen (ovalbumin), underwent oral FC and OIT; food allergy severity, mast cell activation, and ovalbumin-specific IgE levels were examined to determine the predictability of these outcomes in determining reactivity and treatment outcomes.
Results
Subcutaneous sensitization and a single intragastric allergen challenge of egg antigen to BALB/c IL9Tg mice and Il4raY709F IL9Tg induced a food allergic reaction. Enhanced IL-4Rα signaling altered the symptoms induced by the first oral exposure, decreased the cumulative antigen dose, increased the severity of reaction during oral FC, and altered the frequency of adverse events and OIT outcomes. Biomarkers after first oral exposure indicated that only the severity of the initial reaction significantly correlated with cumulative dose of oral FC.
Conclusion
Collectively, these data indicate that single nucleotide polymorphisms in IL-4Rα can alter clinical symptoms of food allergic reactions, severity, and reactive dose during FC and OIT, and that severity of first reaction can predict the likelihood of reaction during FC in mice with IL-4Rα gain of function.
Immunoglobulin-E (IgE) -dependent food allergy is diagnosed by "allergic reactions induced by foods" and "presence of antigen-specific IgE antibodies". If the causative food cannot be identified, the diagnosis of food allergy is confirmed by an oral food challenge (OFC). It is necessary to select the medical institution and OFC method to improve the safety of OFC. If it is difficult to perform OFC at the respective facility, the physician needs to refer the patient to a medical institution that can perform OFC immediately.
However, there are still cases in which patients are instructed to avoid food without a correct diagnosis. In cases of infantile atopic dermatitis, we experienced cases in which the patients were instructed to avoid multiple foods due to positive antigen-specific IgE testing only without treatment of eczema. There have also been cases of people who were diagnosed with food allergies in infancy and continued to avoid the causative food without undergoing OFC until adolescence. We have also experienced cases in which patients were instructed to avoid foods on which they have incorrect knowledge of cross-reactivities, such as peanuts, tree nuts, and crustaceans. In this article, we aimed to describe the correct diagnosis and evaluation of food allergy in childhood and contribute to the improvement of the quality of food allergy treatment.
The oral food challenge (OFC) is the gold standard for diagnosing an immediate-type food allergy.; however, other tests can be used in combination to reduce the risk of OFC.
Although probability curves predicting the probability of symptom induction based on specific IgE antibody titers have been reported, they are affected by the target population's age and the OFC method. Recently, allergen component-specific IgE antibody tests have become available for clinical practice, and cutoff values for ovomucoid in hen's egg, ω-5 gliadin in wheat, 2S albumin in seed nuts, Ara h 2 in peanut, Jug r 1 in walnut, and Ana o 3 in cashew nut have been reported.
A positive skin prick test (SPT) would lead to diagnosis in infants even if the specific IgE antibody test is negative. Additionally, SPT of buckwheat is more useful than the specific IgE antibody test for diagnosis.
Although advances in immunological testing have improved the diagnostic accuracy of immediate-type food allergy, it cannot be used as a definitive diagnosis at present-the importance of assessing the risk before OFC is increasing. The development of applications to facilitate stratified diagnosis is needed.
Food allergy is an immune-mediated disease and must be differentiated from other adverse effects related to food that are non-immune mediated. Symptoms of immunoglobulin (Ig) E-mediated allergy can range from mild to severe, and life-threatening anaphylaxis may occur. Current recommended strategies for diagnosis include the use of skin prick tests, allergen-specific serum IgE, and/or oral food challenges. Management entails allergen avoidance and appropriate treatment of allergic reactions should accidental ingestions occur. Treatment approaches under investigation include immunotherapy as well as biologics and novel vaccines. Attention has also recently focused on implementing strategies for prevention of food allergy.
The practice of food allergy (FA) for clinicians has boomed, with a dramatic rise in the number of patients and families seeking care and with many advances on several fronts. The practice itself sometimes is evidence-based science and sometimes an art of pattern and phenotype recognition. This article examines the tools for diagnosis and management and therapy options available to physicians providing care for patients with FA. The article touches on pressing needs of clinicians and highlights the rapid and important movements in national and international support and advances that will have a positive impact on the field of FA.
The management of food allergy is complicated by the lack of highly predictive biomarkers for diagnosis and prediction of disease course. The measurement of food-specific IgE is a useful tool together with clinical history but is an imprecise predictor of clinical reactivity. The gold standard for diagnosis and clinical research is a double-blind placebo-controlled food challenge. Improvement in our understanding of immune mechanisms of disease, development of high-throughput technologies, and advances in bioinformatics have yielded a number of promising new biomarkers of food allergy. In this review, we will discuss advances in immunoglobulin measurements, the utility of the basophil activation test, T-cell profiling, and the use of -omic technologies (transcriptome, epigenome, microbiome, and metabolome) as biomarker tools in food allergy.
The diagnosis of food allergy in clinical practice has not been standardized, and food allergy is overdiagnosed in patients with atopic dermatitis (AD). This overdiagnosis of food allergy leads to unnecessary elimination diets that may exert potential adverse effects on the health of children with AD. Unlike classic IgE-mediated food allergy, food allergy in patients with AD may manifest as non-eczematous reactions, isolated eczematous reactions, or a combination of these reactions. The diagnosis of food allergy in children with AD should be made based on a thorough clinical history (detailed allergic history and feeding history), clinical manifestations, and laboratory workup including skin prick testing, serum specific IgE measurement, atopy patch testing, and oral food challenges. Once an underlying food allergy is confirmed in a patient with AD, comprehensive management is generally recommended. Avoidance of the food allergen is the main treatment approach, but there is a need for regular clinical follow-up, including evaluation of the nutritional status and supervision of growth and development. Multidisciplinary cooperation between dermatologists, nutritionists, and pediatricians is required.
Egg allergy is one of the most frequent food allergies in children and the diagnosis of egg allergy is based on the history, IgE tests as well as standardized food challenges [1]. Measurement of egg specific IgE can also be useful in predicting allergic reactions in oral food challenge (OFC) tests and in monitoring oral immunotherapy. Probability curves providing the likelihood of a positive outcome of an OFC/positive symptoms with the help of specific IgE measurements have been established for both egg and ovomucoid [2‐4].
Food allergy is an immune-mediated disease and must be differentiated from other adverse effects related to food that are non-immune mediated. Symptoms of immunoglobulin (Ig) E-mediated allergy can range from mild to severe, and life-threatening anaphylaxis may occur. Current recommended strategies for diagnosis include the use of skin prick tests, allergen-specific serum IgE, and/or oral food challenges. Management entails allergen avoidance and appropriate treatment of allergic reactions should accidental ingestions occur. Treatment approaches under investigation include immunotherapy as well as biologics and novel vaccines. Attention has also recently focused on implementing strategies for prevention of food allergy.
La alergia a la proteína de leche de vaca (APLV) es la alergia alimentaria más frecuente en niños menores de 3 años, con una incidencia estimada entre 2-7.5%. Comprende reacciones mediadas IgE, no mediadas por IgE y mixtas. La APLV involucra tres sistemas: respiratorio, gastrointestinal y piel. Su diagnóstico es clínico y se conforma o excluye con la eliminación del alérgeno. Si el lactante es alimentado con leche materna la madre debe continuar con su administración, evitando alimentos que contengan proteína de leche de vaca y ella deberá recibir suplementos de calcio 1000 mg al día. Si recibe fórmula artificial, ésta debe ser eliminada e iniciar una fórmula extensamente hidrolizada. Dado que cada día la APLV está incrementando a edades mayores y observamos un aumento en la severidad, decidimos realizar la presente revisión y dar a conocer los factores de riesgo involucrados, para hacer un diagnóstico precoz y evitar así el compromiso sobre el estado nutricional, ya que por desconocer estos, la mayoría de los niños son sometidos a cambios frecuentes de fórmulas y eliminaciones dietéticas innecesarias. Palabras clave Hipersensibilidad a los alimentos, hipersensibilidad a la leche, lactancia materna
The double-blind, placebo-controlled food challenge (DBPCFC) is the "gold standard" for diagnosis of food hypersensitivity. Skin prick tests and RASTs are sensitive indicators of food-specific IgE antibodies but poor predictors of clinical reactivity. Previous studies suggested that high concentrations of food-specific IgE antibody were predictive of food-induced clinical symptoms. Because the CAP System FEIA (Pharmacia Diagnostics, Uppsala, Sweden) provides a quantitative assessment of allergen-specific IgE antibody, this study was undertaken to determine the potential utility of the CAP System FEIA in diagnosis of IgE-mediated food hypersensitivity.
Sera from 196 patients with food allergy were analyzed for specific IgE antibodies to egg, milk, peanut, soy, wheat, and fish by CAP System FEIA. Sera were randomly selected from 300 stored samples of children and adolescents who had been evaluated by history, skin prick tests, and DBPCFCs. The study population was highly atopic; all patients had atopic dermatitis, and approximately 50% had asthma and allergic rhinitis at the time of initial evaluation. The performance characteristics of the CAP System FEIA were compared with those of skin prick tests and the outcome of DBPCFCs or "convincing" histories of anaphylactic reactions.
The prevalence of specific food allergies in the study population varied from 22% for wheat to 73% for egg. Allergy to egg, milk, peanut, and soy accounted for 87% of confirmed reactions. The performance characteristics of skin prick tests and CAP System FEIA (egg, milk, peanut, fish) were comparable, with excellent sensitivity and negative predictive accuracy but poor specificity and positive predictive accuracy. The performance characteristics of the CAP System FEIA for soy and wheat were poor. For egg, milk, peanut, and fish allergy, diagnostic levels of IgE, which could predict clinical reactivity in this population with greater than 95% certainty, were identified: egg, 6 kilounits of allergen-specific IgE per liter (kU[A]/L); milk, 32 kU(A)/L; peanut, 15 kU(A)/L; and fish, 20 kU(A)/L.
When compared with the outcome of DBPCFCs, results of CAP System FEIA are generally comparable to those of skin prick tests in predicting symptomatic food hypersensitivity. Furthermore, by measuring the concentrations of food-specific IgE antibodies with the CAP System FEIA, it is possible to identify a subset of patients who are highly likely (>95%) to experience clinical reactions to egg, milk, peanut, or fish. This could eliminate the need to perform DBPCFCs in a significant number of patients suspected of having IgE-mediated food allergy.
Typical manifestations of Behcet's disease (BD) and a positive pathergy reaction were observed in a few patients with chronic myeloid leukaemia (CML) on interferon alpha (IFN-alpha) therapy and the significance of this observation was assessed in a prospective study. The skin pathergy test was applied to 15 patients with CML prior to IFN-alpha therapy, 29 patients with CML following IFN-alpha therapy and 30 patients with BD. Twenty-five patients with inflammatory arthropathies (IA), 20 patients with recurrent oral ulcers (ROU), 23 patients treated with IFN-alpha for various disorders and 20 normal individuals were also studied as control groups. The pathergy reaction was positive in nearly a quarter of IFN-alpha-treated CML cases (24%) as well as one-half of the patients with BD (50%). All CML patients prior to IFN-alpha treatment and all patients using IFN-alpha for other diseases were negative for the pathergy reaction. These results may indicate a similarly altered neutrophil function in both BD and IFN-alpha-treated CML patients.
Pathergy is the development of a papulopustular lesion around a puncture site on the skin, 24-48 hours after the injection of a sterile substance1. The pathergy test is used in some parts of the world as a diagnostic criterion for Behcet's disease2.
A prospective study of the incidence and characteristics of spontaneously occurring delayed skin test reactions has been carried out. A total of 292 subjects were studied, 200 atopic by history; they received 2,700 intradermal skin tests to 12 common inhalant antigens. Thirteen per cent of the total group of skin tests manifested a positive immediate reaction; 6 per cent of the tests exhibited a delayed reaction with induration of 5 mm. or greater at 48 hours. There was a significantly higher incidence of immediate reactions in the atopic group for the majority of antigens studied (p < 0.01 for 7 of 12 antigens). However, the atopic individuals exhibited no greater incidence of delayed reactions than the nonatopic individuals (p > 0.05 for 10 of 12 antigens). Skin biopsies performed 48 hours after the application of the skin tests demonstrated four distinct classes of response: (1) Negative immediate-negative delayed responses were characterized by minor perivascular round cell infiltration which was indistinguishable from that seen in control injection sites. (2) Positive immediate-negative delayed sites demonstrated a similarly mild perivascular reaction, but many eosinophils were seen. (3) Negative immediate-positive delayed responses to inhalant antigens were histologically indistinguishable from tuberculin reactions, with dense perivascular and interstitial round cell infiltrations. (4) Positive immediate-positive delayed responses contained a similarly dense perivascular and interstitial infiltrate, but eosinophils were prominent.
Immune regulatory dysfunction, circulating immune complexes (CIC), and polymorphonuclear (PMN) cell migration were investigated in patients with Behçet's syndrome. Six patients meeting rigorous clinical criteria were evaluated. Only one patient showed evidence of immune regulatory dysfunction (increased T4/T8 ratio). Although C1q binding and Raji cell assays for CIC yielded positive results in only one of five patients, all five patients had in vivo "histamine trap test" evidence of CIC (all controls had normal results). Sera from all Behçet's syndrome patients increased migration of neutrophils to zymosan-activated serum. Colchicine therapy abolished the enhancing effect of the patient's sera on movement of PMN cells from patients and controls. An immune complex-mediated injury that is followed by an excessive accumulation of PMN cells may lead to the cutaneous lesions and other lesions in Behçet's syndrome. Further evaluation of colchicine therapy is warranted on the basis of these studies.
Occasionally parents report a reaction developing at the site of an allergen skin test several hours after application of the test, despite there having been no immediate reaction. The medical literature contains little information regarding isolated late reactions (ILRs) to allergen skin testing.
The goal of this project was to determine the incidence of ILRs in children undergoing allergen skin testing.
Prick and intradermal (ID) skin testing was performed for routine clinical indications in an allergy clinic. Children with a positive histamine control, and at least one negative immediate reaction to allergen skin testing were enrolled in the study. The parents were given detailed instructions to examine the skin test sites 6 hours later, and to record the size of any erythematous indurated sites. Circles of various diameters were included on the report form to assist the parents' size estimates.
Fifty-seven children enrolled in the study and 50 returned the forms. No patients reported ILRs to prick skin tests. Eighteen of the 50 respondents reported 40 ILRs to ID tests, of > or = 5 mm diameter; 7 of these were > or = 10 mm. The most common allergen causing ILR was cockroach, accounting for 20% of the ILRs. Each of the other allergens also caused ILRs. The clinical history did not show a definite correlation of symptoms with exposure to the allergens causing ILRs, although all 14 patients with ILRs to indoor allergens had year-round symptoms. There was no correlation between the incidence of ILRs and age, gender, or diagnosis of asthma.
ILRs to allergen skin testing occurred in 36% of pediatric allergy clinic patients. The clinical significance of such reactions is unknown.
Dermographism is the appearance of whealing and erythema within minutes in a site where skin has been exposed to pressure or mechanical irritation. In our clinical observations, dermographism seems to be frequent in patients with Behçet's disease. Since the prevalence of allergic responses is reportedly increased in vasculitic syndromes, we aimed to assess dermographism and atopy in a group of Behçet's patients. The study group comprised 30 consecutive patients with Behçet's disease. The study was carried out in two parts: elicited dermographism and atopy tests. In the first part, dermographism was investigated in the study group (Behçet's patients) and 230 healthy controls. In the second part, the study group, 30 healthy controls and 17 patients with allergic bronchial asthma were evaluated for specific and nonspecific atopy. Dermographism was found to be increased in patients with Behçet's disease. Peripheral blood eosinophil count, serum total IgE and nasal eosinophil scores were similar in patients with Behçet's disease and healthy controls. Although blood eosinophil count and serum total IgE levels were higher in allergic bronchial asthma patients than in Behçet's patients, the difference was significant only in the former. Skin prick test was positive in three of the patients with Behçet's disease and in six healthy controls. The difference was statistically insignificant (p > 0.05). None of the Behçet's disease patients had pathergy or a pathergy-like reaction at the site of the skin prick test after 48 h. In conclusion, our results confirm the general impression that dermographism is common in patients suffering from Behçet's disease.
The double-blind, placebo-controlled food challenge is considered the gold standard for diagnosing food allergy. However, in a retrospective analysis of children and adolescents with atopic dermatitis and food allergy, discrete food-specific IgE concentrations were established that could predict clinical reactivity to egg, milk, peanut, and fish with greater than 95% certainty.
The purpose of this investigation was to determine the utility of these 95% predictive decision points in a prospective evaluation of food allergy.
Sera from 100 consecutive children and adolescents referred for evaluation of food allergy were analyzed for specific IgE antibodies to egg, milk, peanut, soy, wheat, and fish by using the Pharmacia CAP System FEIA. Food-specific IgE values were compared with history and the results of skin prick tests and food challenges to determine the efficacy of previously established 95% predictive decision points in identifying patients with increased probability of reacting during a specific food challenge.
One hundred children (62% male; median age, 3.8 years; range, 0.4-14.3 years) were evaluated for food allergy. The diagnosis of food allergy was established by means of history or oral food challenge. On the basis of the previously established 95% predictive decision points for egg, milk, peanut, and fish allergy, greater than 95% of food allergies diagnosed in this prospective study were correctly identified by quantifying serum food-specific IgE concentrations.
In a prospective study of children and adolescents referred for evaluation of food allergy, previously established 95% predictive decision points of food-specific IgE antibody concentrations for 4 major food allergens were effective in predicting clinical reactivity. Quantification of food-specific IgE is a useful test for diagnosing symptomatic allergy to egg, milk, peanut, and fish in the pediatric population and could eliminate the need to perform double-blind, placebo-controlled food challenges in a significant number of children.
The demonstration of specific IgE antibodies to egg supports the existence of allergy to this food, but a correct diagnosis can only be obtained after a challenge test. Several studies have assessed different cut-off points in the level of these antibodies as predictors of clinical reactivity.
Validation of the specific IgE antibodies measured by the CAP System Fluorescence enzyme immunoassay (FEIA) technique in the diagnosis of egg allergy in children under 2 years of age.
A prospective study of 81 children with suspected egg allergy was performed. Specific IgE antibodies was quantified for egg white, egg yolk, ovoalbumin and ovomucoid. The diagnostic challenge test was carried out following the previously established criteria. The validity of the specific IgE antibodies was analysed using children with a negative diagnostic challenge test as control group.
The prevalence of egg allergy in the group studied was 79% and egg white was the allergen that showed the greatest diagnostic efficacy. The sensitivity and positive predictive value of the prick test and of the CAP to egg white were excellent and the specificity and the negative predictive value had lower values. A level of > or = 0.35 KU(A)/L for specific IgE antibodies to egg white predicted the existence of reaction in 94% of the cases.
Quantification of the specific IgE antibodies to egg white is useful in the diagnosis of egg allergy. In children under 2 years of age with a background of immediate hypersensitivity after egg ingestion and presence of specific IgE antibodies to egg white of > or = 0.35 KU(A)/L, diagnostic challenge test is not necessary to establish the diagnosis of allergy to this food.
Previously published articles described a relationship between food-specific IgE and the outcome of food challenge in children with egg allergy. These investigations defined different levels of predictive values in different study populations and thus pointed toward the possibility of a certain level of specific IgE to egg white predicting a positive outcome in food challenge.
The purpose of this study was to determine the utility of specific IgE in estimating threshold level to predict a positive outcome in food challenge.
Fifty-six children were evaluated for egg allergy by titrated oral challenges. Sera were analyzed for specific IgE to egg white in 56 patients by using the Magic Lite test and 32 of 56 patients also by the CAP test. Values of specific IgE to egg white were compared to the outcome of challenges and the threshold level.
The diagnostic level of specific IgE predicting clinical reactivity in this population with greater than 95% certainty was identified as 10.8 standardized units/mL (Magic Lite) and 1.5 kilounits of allergen-specific IgE/L (CAP), respectively. We found no significant relationship between the specific IgE concentration (egg white) and the challenge threshold level.
Although the specific IgE concentration correlated to a positive outcome in food challenge, there was no significant relationship between the quantification of specific IgE and the challenge threshold level. Therefore the standardized food challenge still remains the gold standard in the diagnosis of food allergy.
While ulcerative lichen planus is a common diagnosis when involving the mucosa, it is uncommonly found on the cutaneous surface. Cutaneous ulcerative lichen planus is usually found on the palmar or plantar surfaces and has only rarely been described elsewhere. We describe a case of cutaneous ulcerative lichen planus involving the pretibia and exhibiting pathergy, which to our knowledge has not been previously reported. We also describe successful treatment with oral acitretin in conjunction with topical and intralesional corticosteroids.
IgE-mediated cow's milk proteins (CMPs) allergy shows a tendency to disappear with age. The sooner tolerance is detected, the earlier the substitute diets can be suspended and the quicker family emotional hardship is alleviated.
To analyse the specific IgE levels to cow's milk and its proteins, which help to separate tolerant from no tolerant children in the follow-up of infants with allergy to cow's milk.
Sixty-six infants diagnosed with IgE-mediated allergy to CMPs were included in this prospective follow-up study. Periodic reassessments were carried out every 6 months until they were 2-years old and then, annually, until tolerance arose or until the last reassessment in which tolerance had not been achieved. Non-tolerant infants were followed, at least, for a period of 3 years. In each visit, the same skin tests and determination of specific IgE (CAP System FEIA) for milk and its proteins were carried out. The open challenge test was repeated unless a clear transgression to milk, which came to be positive, had taken place within the previous 3 months in each of the follow-up visits. Specific IgE levels to milk and its proteins, in different moments of the follow-up were analysed by means of the receiver-operating characteristic curve to predict clinical reactivity.
Throughout the follow-up 45 (68%) infants became tolerant. The follow-up mean for tolerant infants was 21.2 months whereas for non-tolerant infants it was 58 months. The specific IgE levels which were predictors of the clinical reactivity (positive predictive value (PPV)> or =90%), grew as the age of the infants increased: 1.5, 6 and 14 kU(A)/L for milk in the age range 13-18 and 19-24 months and in the third year, respectively. Specific IgE levels to casein: 0.6, 3 and 5 kU(A)/L, respectively, predicted clinical reactivity (PPV> or =90%) in the different analysed moments of the follow-up. The cut-off points: 2.7, 9 and 24 kU(A)/L for milk and 2, 4.2 and 9 kU(A)/L for casein, respectively, predicted clinical reactivity with an accuracy > or =95% corresponding to a specificity of 90%.
Monitorization of specific IgE concentration for milk and casein by means of the CAP system in allergic children to CMPs allows us to predict, to a high degree of probability, clinical reactivity. Age factor must be taken into account to evaluate the specific IgE levels which are predictors of tolerance or clinical reactivity.
Specific serum IgE is considered as one of the important diagnostic measures in the diagnostic work-up of food allergy.
To evaluate the role of specific serum IgE in predicting the outcome of oral food challenges, and to determine threshold concentrations of specific serum IgE that could render double-blind, placebo-controlled food challenges unnecessary.
In 501 children (median age 13 months), 992 controlled oral challenges were performed with cow's milk (CM), hen's egg (HE), wheat and soy. 440/501 (88%) children suffered from atopic dermatitis. For all children, specific IgE concentrations in serum were determined. Sensitivity, specificity, positive and negative predictive values, receiver operator characteristics-curves as well as predictive decision points were calculated.
Four hundred and forty-five out of 992 oral food challenges with allergens were assessed as positive. Sensitivity of specific serum IgE was 97% for HE, 83% for CM, 69% for soy, and 79% for wheat. Specificity was 51% for HE, 53% for CM, 50% for soy, and 38% for wheat. Calculating 90%, 95% and 99% predicted probabilities using logistic regression revealed predictive decision points of 6.3, 12.6, and 59.2 kU/L for HE, respectively. Subdividing our children in those of below or above 1 year of age resulted in a markedly different predicted probability for HE. For CM, only the 90% predicted probability (88.8 kU/L) could be calculated. No decision points could be determined for CM, wheat and soy.
In general, specific serum IgE levels showed a correlation with the outcome of positive oral food challenges for CM and HE. Meaningful predictive decision points can be calculated for HE, which may help to avoid oral food challenges in some cases. However, data need to be ascertained for each allergen separately. Furthermore, the age of the patient population under investigation must also be taken into account.
A 15‐year‐old, unmarried female presented to our dermatology department for an intensely pruritic skin rash that had appeared abruptly 3 days earlier. She had a remarkable medical history for a case of allergic rhinitis and several attacks of asthma in her early childhood. The condition waxed and waned initially but had improved in recent years. Physical examination revealed several erythematous plaques, papules studded with scattered pustules having diameters less than 0.3 mm. Conspicuous scratch marks had caused erythematous wheal‐like indurations also studded with pustules in a linear distribution across the waist, forearms ( Fig. 1 ), and back ( Fig. 2 ). Discrete papulopustules were present on the face, nape and neck. The patient was otherwise healthy. There were no other symptoms such as fever, malaise, weakness, or lymphadenopathy
Papulopustulosis with adjacent linear Koebner form distribution over the flexor aspect of the forearm
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The pathergy phenomenon observed on the right upper back
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Laboratory results were normal for hepatic and renal functions, serum electrolytes, glucose, protein, erythrocyte sedimentation rate (8 mm/h), and C‐reactive protein (0.355 mg/l). A human immunodeficiency virus (HIV) antibody screen test was negative. Serum was positive for herpes simplex virus (HSV)‐1 and HSV‐2 IgG (in low titers), but negative for HSV‐1 and HSV‐2 IgM. White blood cell count revealed leukocytosis (11.2 × 10 ³ /l), with a differential count of 68% neutrophils, 27% lymphocytes, and 8% eosinophils. Serum IgA, IgG, and IgM were within normal limits, but the IgE level was elevated (677 mg/dl). Cultures from peripheral blood and pustules were negative. A Tzank smear performed on the pustules showed no multinucleated giant cells. Fungal testing of skin scrapings from the initial lesion site gave negative results. Routine stool tests, including common pathogen and parasite screens, were negative, and urinalysis results were unremarkable.
A biopsy specimen obtained from a skin pustule showed subcorneal eosinophilic and neutrophilic pustules in the follicular infundibulum with marked spongiosis of the follicular epithelium. ( Fig. 3 ). There was a moderately dense superficial and deep perivascular mixed inflammatory cell infiltrate comprising eosinophils, neutrophils and lymphocytes. Migration of eosinophils and neutrophils through the vessel wall with variable luminal intramural fibrin deposition, histologically indicative of vasculopathy, was seen. There was concomitant slight perivascular dermal necrosis. ( Fig. 4 )
There is a striking inflammatory reaction involving the follicle characterized by migration of eosinophils, lymphocytes and neutrophils into the outer root sheath epithelium of the follicle (there are perifollicular vasculopathic changes, including those occurring in the context of red cell extravasation)
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The perifollicular microvasculature demonstrates endothelial cell hyperplasia with striking proplastic alterations of the endothelium leading to luminal attenuation (⋆). The perivascular connective tissue exhibits incipient necrobiotic change, fulfilling morphologic criteria warranting the designation of pathergy (→)
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Based on the clinical presentation and light microscopic findings on biopsy, a diagnosis of eosinophilic pustular folliculitis with pathergy was made. Systemic prednisolone 30 mg in divided doses was given. After 1 week of systemic corticosteroid therapy, the patient's condition was significantly improved and the patient was subsequently discharged. Two months later she had a relapse, upon which corticosteroid therapy was commenced leading to lesional resolution. The foci of eosinophilic folliculitis healed with areas of hyperpigmentation with variable scarring.
The severity of allergic reactions to food appears to be affected by many interacting factors. It is uncertain whether challenge-based reactions reflect the severity of past reactions or can predict future risk.
To explore the relationship of a subject's clinical history of past reactions to the severity of reaction elicited by a low-dose, double-blind, placebo-controlled food challenge (DBPCFC) with peanut.
Cross-sectional questionnaire assessment of community-based allergic reactions and low-dose DBPCFC in self-selected peanut-allergic subjects. Reaction severity was assessed using a novel scoring system, taking account of the dose of allergen ingested.
Forty subjects (15 males, 23 children, 23 asthmatics by history) were studied. Only the most recent community reaction predicted the severity of reaction in the DBPCFC, but even this association was weak (r=0.37, P=0.03). Peanut-specific IgE (PsIgE) and skin prick test (SPT) weal size were not associated with community score but PsIgE level correlated well with the challenge score (r=0.6, P=0.001). Asthma did not affect the eliciting dose or challenge score directly but the association of PsIgE and challenge score was stronger in those without asthma (r=0.72, P=0.001) than in those with asthma (r=0.48, P=0.02).
The scoring system developed appears to improve the sensitivity of assessment of reactions induced by DBPCFC. This is the first prospective study showing an association between PsIgE levels and clinical reactivity in DBPCFC, an effect that is more pronounced in non-asthmatics. This finding has important implications for the clinical care of subjects with food allergy. There is a poor correlation between the severity of reported reactions in the community and the severity of reaction elicited during low-dose DBPCFC with peanut.
Once food elimination is introduced, it is important to know for doctors when patients generally develop oral tolerance against eliminated food. To clarify the point, following study was conducted.
We analyzed 304 patient profiles with food allergy in our division between 1994 and 2001. The diagnosis of oral tolerance was determined by the results of food challenges or the accidental episodes of ingestion.
By the age of 3 years old, 78% of food allergy patients with soybean, 63% of those with wheat, 60% of those with cow's milk, 51% of those with egg yolk, and 31% of those with egg white developed oral tolerance, respectively. IgE CAP RAST scores against cow's milk, egg yolk, and egg white in the patients without tolerance were significantly higher than those in the patients with tolerance.
Patients developed oral tolerance firstly against soybean followed by wheat, cow's milk, egg yolk and egg white during the first 3 years of life. The specific IgE antibody levels against egg and cow's milk are important for the diagnosis of tolerance.
Available online March 15
Available online March 15, 2007.
doi:10.1016/j.jaci.2007.01.033