Literature about the value of diagnostic tests for hazelnut allergy in children is scarce. For peanut allergy cutoff levels of specific IgE with a 95% positive predictive value (PPV) were published. To evaluate current diagnostics for hazelnut allergy in children, data of 151 children, who underwent a double-blind placebo-controlled food challenge (DBPCFC) for hazelnut were analyzed. The PPV or negative predictive value (NPV) of the level of specific IgE (CAP) for hazelnut and the size of the skin prick test (SPT) for hazelnut was determined. The influence of spiking of the CAP for hazelnut with rCor a 1 was analyzed. The level of specific IgE for hazelnut was a moderate predictor for a positive DBPCFC for hazelnut. No cutoff levels of specific IgE for hazelnut with a 95% PPV could be determined. Before Cor a 1 spiking the maximum reached PPV was 73% for a cutoff level of 26 kUA/L, after spiking the maximum reached PPV was 64% for a cutoff level of 31 kUA/L. The spiking increased the NPV from 91% to 100% for a cutoff level of 0.35 kUA/L. SPT was a better predictor for a positive DBPCFC compared to the level of specific IgE. When the SPT >16 mm, the PPV was 100%. By combining both tests, the PPV reached 100% when the level of specific IgE for hazelnut was >5 kUA/L and the level of SPT was >12mm. However, the PPV of 100% for SPT alone and the combination of CAP and SPT accounted for only 11% respectively 13% of the children undergoing a DBPCFC for hazelnut. So, the level of specific IgE and reactivity of SPT are moderate predictors for the outcome of a DBPCFC for hazelnut in children. New diagnostic tools are needed to replace the DBPCFC which is burdensome, expensive and limited available.

Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. To the Editor: Public awareness regarding peanut allergy is growing.1Sampson H.A. Utility of food-specific IgE concentrations in predicting symptomatic food allergy.J Allergy Clin Immunol. 2001; 107: 891-896Abstract Full Text Full Text PDF PubMed Scopus (1210) Google Scholar Double-blind, placebo-controlled food challenges (DBPCFCs) are the gold standard for diagnosing food allergy.2Sicherer S.H. Food allergy: when and how to perform oral food challenges.Pediatr Allergy Immunol. 1999; 10: 226-234Crossref PubMed Scopus (159) Google Scholar Although DBPCFCs are important to determine the clinical relevance of sensitization to allergens, this method is expensive and time-consuming and requires dedicated hospital facilities. Several studies have investigated the association between peanut-specific IgE levels and the outcome of DBPCFCs.1Sampson H.A. Utility of food-specific IgE concentrations in predicting symptomatic food allergy.J Allergy Clin Immunol. 2001; 107: 891-896Abstract Full Text Full Text PDF PubMed Scopus (1210) Google Scholar, 3Maloney J.M. Rudengren M. Ahlstedt S. Bock S.A. Sampson H.A. The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.J Allergy Clin Immunol. 2008; 122: 145-151Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 4Perry T.T. Matsui E.C. Kay Conover-Walker M. Wood R.A. The relationship of allergen-specific IgE levels and oral food challenge outcome.J Allergy Clin Immunol. 2004; 114: 144-149Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 5Rance F. Abbal M. Lauwers-Cances V. Improved screening for peanut allergy by the combined use of skin prick tests and specific IgE assays.J Allergy Clin Immunol. 2002; 109: 1027-1033Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 6Roberts G. Lack G. Diagnosing peanut allergy with skin prick and specific IgE testing.J Allergy Clin Immunol. 2005; 115: 1291-1296Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 7Sampson H.A. Ho D.G. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents.J Allergy Clin Immunol. 1997; 100: 444-451Abstract Full Text Full Text PDF PubMed Scopus (1004) Google Scholar Cutoff levels were formulated and have differed significantly, ranging from 5 to 57 KU/L to produce a 100% positive predictive value.5Rance F. Abbal M. Lauwers-Cances V. Improved screening for peanut allergy by the combined use of skin prick tests and specific IgE assays.J Allergy Clin Immunol. 2002; 109: 1027-1033Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar These studies were not consistent with respect to the study population, nature of the provocation test (open or double blind), provocation protocol, and focus on early, late, or both types of reactions. In most studies DBPCFCs were not performed in case of a history of anaphylaxis.1Sampson H.A. Utility of food-specific IgE concentrations in predicting symptomatic food allergy.J Allergy Clin Immunol. 2001; 107: 891-896Abstract Full Text Full Text PDF PubMed Scopus (1210) Google Scholar, 3Maloney J.M. Rudengren M. Ahlstedt S. Bock S.A. Sampson H.A. The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.J Allergy Clin Immunol. 2008; 122: 145-151Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 6Roberts G. Lack G. Diagnosing peanut allergy with skin prick and specific IgE testing.J Allergy Clin Immunol. 2005; 115: 1291-1296Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 7Sampson H.A. Ho D.G. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents.J Allergy Clin Immunol. 1997; 100: 444-451Abstract Full Text Full Text PDF PubMed Scopus (1004) Google Scholar Frequently, confirmation of a food allergy was solely based on a positive skin test response, increased food-specific IgE levels, or an open provocation.1Sampson H.A. Utility of food-specific IgE concentrations in predicting symptomatic food allergy.J Allergy Clin Immunol. 2001; 107: 891-896Abstract Full Text Full Text PDF PubMed Scopus (1210) Google Scholar, 3Maloney J.M. Rudengren M. Ahlstedt S. Bock S.A. Sampson H.A. The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.J Allergy Clin Immunol. 2008; 122: 145-151Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 4Perry T.T. Matsui E.C. Kay Conover-Walker M. Wood R.A. The relationship of allergen-specific IgE levels and oral food challenge outcome.J Allergy Clin Immunol. 2004; 114: 144-149Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar We conducted a study in which the peanut-specific IgE level was determined in all children suspected of having peanut allergy within 6 months before the challenge, and a DBPCFC was performed independently of a possible history of anaphylaxis. The purpose of this study was to determine the utility of peanut-specific IgE levels in a large, unselected pediatric population using the DBPCFC as a gold standard. We studied 103 Dutch children referred to our tertiary hospital and suspected of peanut allergy (70 boys and 33 girls). The median age was 6.7 years (5.0-10.3 years). The study population was highly atopic, with 88.3% having atopic dermatitis, 57.3% having asthma, and 35.0% having allergic rhinitis. All participants underwent a DBPCFC between January 2004 and July 2008. DBPCFCs were performed as described previously.8Flinterman A.E. Pasmans S.G. Hoekstra M.O. Meijer Y. van H.E. Knol E.F. et al.Determination of no-observed-adverse-effect levels and eliciting doses in a representative group of peanut-sensitized children.J Allergy Clin Immunol. 2006; 117: 448-454Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar The DBPCFCs were performed in the day care unit. Every child remained under observation after the final dose for at least 2 hours depending on severity of the symptoms to minimize the risk associated with these challenges. DBPCFC results were considered positive after the occurrence of objective symptoms (urticaria, angioedema, vomiting, stridor, and hypotension) or after the occurrence of 3 subjective symptoms (nausea, oral allergy, and abdominal pain). Serum samples were obtained and analyzed for peanut-specific IgE by using the CAP system FEIA (Pharmacia Diagnostic, Uppsala, Sweden). Receiver operator characteristic curves were calculated. Two-by-two tables were used to estimate sensitivity, specificity, and positive and negative predictive value. Logistic regression analysis was used to determine the utility of specific IgE to predict the outcome of the DBPCFC (predicted probability). Peanut allergy was confirmed in 56 (54.4%) of 103 patients. The receiver operator characteristic curve revealed an area under the curve of 0.91. This means that peanut-specific IgE levels are a useful tool in predicting the outcome of a DBPCFC. Table I shows the peanut-specific cutoff levels calculated by using 2 × 2 tables. Use of 2 × 2 tables revealed 90%, 95%, and 100% positive predictive values of 10.4, 24.8, and 26.5 KU/L, respectively. It should be noted that these cutoff levels have poor sensitivity. Therefore physicians cannot assume that a patient with a peanut-specific IgE level of less than these levels will not have an allergic reaction. Logistic regression analysis led to a predicted probability of 90% and 95% at peanut-specific IgE cutoff levels of 24.8 and 43.8 KU/L, respectively. The association between specific IgE levels and the outcome of the food challenge (logistic regression model) is presented in Fig 1. The higher the concentration of peanut-specific IgE levels, the higher the predicted probability of a positive DBPCFC result.Table ICutoff levels of peanut-specific IgECutoff level (kU/L)SensitivitySpecificityNegative predictive valuePositive predictive value∗Probability of allergy among those who had specific IgE levels of greater than the cutoff level (the denominator is the number of subjects with levels greater than the cutoff value). using 2 × 2 table 9010.466%92%68% 9524.148%98%61% 10026.548%100%62%Predicted probability†Model-predicted probability of allergy at different levels of specific IgE (denominator is total sample size). using logistic regression (ln IgE) 502.79 9021.8 9543.8 9771.3 99‡Specific IgE level greater than 100 KU/L, clinically not relevant.∗ Probability of allergy among those who had specific IgE levels of greater than the cutoff level (the denominator is the number of subjects with levels greater than the cutoff value).† Model-predicted probability of allergy at different levels of specific IgE (denominator is total sample size).‡ Specific IgE level greater than 100 KU/L, clinically not relevant. Open table in a new tab Our results are in the range of those described by Roberts and Lack6Roberts G. Lack G. Diagnosing peanut allergy with skin prick and specific IgE testing.J Allergy Clin Immunol. 2005; 115: 1291-1296Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar and Rance et al.5Rance F. Abbal M. Lauwers-Cances V. Improved screening for peanut allergy by the combined use of skin prick tests and specific IgE assays.J Allergy Clin Immunol. 2002; 109: 1027-1033Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar Rance et al5Rance F. Abbal M. Lauwers-Cances V. Improved screening for peanut allergy by the combined use of skin prick tests and specific IgE assays.J Allergy Clin Immunol. 2002; 109: 1027-1033Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar found relatively high cutoff levels. They found a positive predictive value of 100% using a cutoff value of 57 KU/L. This is higher than our cutoff level of 26.5 KU/L and could probably be explained by a single child in their study having a negative provocation result with a peanut-specific IgE level of 57 KU/L, thereby increasing the 100% cutoff value. The area under the curve was 0.87 compared with 0.91 according to our data. The area under the curve classifies the accuracy of a diagnostic test. An area of 1 represents a perfect test, and an area of 0.5 represents a worthless test. A strength of the study5Rance F. Abbal M. Lauwers-Cances V. Improved screening for peanut allergy by the combined use of skin prick tests and specific IgE assays.J Allergy Clin Immunol. 2002; 109: 1027-1033Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar is that all children underwent a DBPCFC independent of the anaphylactic history, as in our study. A number of studies found significantly lower specific IgE cutoff levels.1Sampson H.A. Utility of food-specific IgE concentrations in predicting symptomatic food allergy.J Allergy Clin Immunol. 2001; 107: 891-896Abstract Full Text Full Text PDF PubMed Scopus (1210) Google Scholar, 3Maloney J.M. Rudengren M. Ahlstedt S. Bock S.A. Sampson H.A. The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.J Allergy Clin Immunol. 2008; 122: 145-151Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 4Perry T.T. Matsui E.C. Kay Conover-Walker M. Wood R.A. The relationship of allergen-specific IgE levels and oral food challenge outcome.J Allergy Clin Immunol. 2004; 114: 144-149Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 7Sampson H.A. Ho D.G. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents.J Allergy Clin Immunol. 1997; 100: 444-451Abstract Full Text Full Text PDF PubMed Scopus (1004) Google Scholar Sampson et al1Sampson H.A. Utility of food-specific IgE concentrations in predicting symptomatic food allergy.J Allergy Clin Immunol. 2001; 107: 891-896Abstract Full Text Full Text PDF PubMed Scopus (1210) Google Scholar, 7Sampson H.A. Ho D.G. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents.J Allergy Clin Immunol. 1997; 100: 444-451Abstract Full Text Full Text PDF PubMed Scopus (1004) Google Scholar found a 95% cutoff level of 15 KU/L. One explanation could be the difference in study populations. Another more important explanation could be that a substantial number of children (43%) were given diagnoses of peanut allergy by means of history without undergoing a DBPCFC. Our data clearly demonstrate that peanut allergy cannot be diagnosed solely on the basis of a history of a suspected allergic reaction to peanut. Sixteen of 34 children with a history of an anaphylactic reaction had a negative food challenge result. Eight of these children were able to eat peanuts without an allergic reaction: 1 child only eats traces of peanut, 2 children still have allergic reactions, and data on the remaining 5 children could not be discovered. We emphasize that a history of an anaphylactic reaction does not automatically indicate a diagnosis of peanut allergy. Bock and Atkins9Bock S.A. Atkins F.M. Patterns of food hypersensitivity during sixteen years of double-blind, placebo-controlled food challenges.J Pediatr. 1990; 117: 561-567Abstract Full Text PDF PubMed Scopus (459) Google Scholar previously concluded that a history of anaphylaxis was validated by a DBPCFC in less than 50% of the subjects. Another factor that usually draws little attention is the influence of the statistical method used. We used 2 × 2 tables to describe our data and logistic regression analysis to generate probability curves that predict the likelihood of patients with a particular peanut-specific IgE level reacting during a food challenge. In conclusion, our study has several strengths compared with the studies previously mentioned. We performed DBPCFCs in all children suspected of peanut allergy independent of a history of anaphylaxis to peanut. Another strength of our study was the relatively large group of children analyzed and that the analysis was performed with specific IgE levels determined within 6 months before the challenge. A weakness of our study is the fact that the clinician supervising the DBPCFCs was not blind to the peanut-specific IgE level and the retrospective nature of this study. However, all children underwent a standardized DBPCFC. We do not expect that blinding of the clinician or a prospective study would lead to a different outcome. The clinical relevance of the present study is the ability to predict the outcome of a DBPCFC at every specific IgE level. As many as 54% of DBPCFC results were positive. By using the logistic regression curve, a physician will be able to estimate the probability of a certain patient reacting to peanut during the DBPCFC. The previously formulated cutoff levels can be used by physicians in case of a similarity in patient characteristics to decide whether a DBPCFC is indicated. By using the (90%, 95%, and 100% positive predictive value) specific IgE cutoff levels, DBPCFCs would be superfluous in at least some of the children who were planning to undergo a DBPCFC. However, DBPCFCs still remain important to determine the severity of the allergic reaction and the amount of peanut that will lead to an allergic reaction.

Zijlstra WT, Flinterman AE, Soeters L, Knulst AC, Sinnema G, L’Hoir MP, Pasmans SG. Parental anxiety before and after food challenges in children with suspected peanut and hazelnut allergy. Pediatr Allergy Immunol 2010: 21: e439–e445. © 2009 John Wiley & Sons A/SAs ingestion of peanut and hazelnut by allergic children is potentially life threatening, parents of these children need to be vigilant about their child’s dietary intake. This may cause high levels of anxiety. To assess parental anxiety about food‐allergic reaction in their child (state anxiety) and their personal disposition to anxiety (trait anxiety). Parental anxiety was investigated again after food challenges. Fifty‐seven children (3–16 yr, mean age 7.2) with suspected peanut or hazelnut allergy (mean specific IgE 20.9) were evaluated by double‐blind, placebo‐controlled food challenge (DBPCFC). Thirty‐two children (56%) developed an allergic reaction. All parents completed the Spielberger State‐Trait Anxiety Inventory (STAI) prior to DBPCFC and 2 wk, 3 months and 1 yr thereafter. The mean anxiety scores on these moments were compared with each other and with general Dutch norms. The STAI was also investigated in a group that refused DBPCFC. Prior to DBPCFC, parents had high levels of state anxiety in contrast to a lower trait anxiety compared to the norm group. After DBPCFC, the state anxiety was significantly lower, regardless of a positive or negative outcome (p ≤ 0.05). The state anxiety was still significant lower after 1 yr (p ≤ 0.03). The trait anxiety remained unchanged in mothers and slightly decreased in fathers. The state anxiety in the group that refused DBPCFC was comparable to the challenge group, but the trait anxiety was significantly higher (p = 0.038). Parents of children with suspected peanut or hazelnut allergy show high levels of anxiety about a food‐allergic reaction. After DBPCFC, the anxiety was significantly lower, even in the group with a positive outcome.

Background: Hazelnut allergy in birch pollen-exposed areas is usually due to cross-reactivity (Cor a 1 and 2) and is usually mild in nature (oral allergy). In areas without birches, severe reactions are more prevalent and linked to sensitization to the lipid transfer protein (LTP) Cor a 8.Objective: We sought to investigate whether sensitization to LTP plays a role in more severe (objective) hazelnut-induced symptoms in children from a birch-endemic area.Methods: Sensitization to Cor a 8, Cor a 2, Cor a 1, and Bet v 1 was determined by means of RASTs and immunoblotting in hazelnut-sensitized children with (n = 8) and without (n = 18) objective reactions during double-blind, placebo-controlled food challenges. Additionally, samples from 191 hazelnut-sensitized nonchallenged children were analyzed.Results: Children with objective reactions during double-blind, placebo-controlled food challenge had higher IgE titers to hazelnut (P < .001) and recognized more allergens on immunoblotting (P = .001) than those without such reactions. All children with objective symptoms were sensitized to Cor a 8 (0.51-23.3 IU/rnL) compared with only 1 child without objective reactions (0.90 IU/mL). In a multivariate analysis only IgE against Cor a 8 remained as an independent risk factor (undefined odds ratio; P < .0001). In the group of nonchallenged children (n = 191), the prevalence of LTP sensitization was greater than 30%. Unexpectedly, sensitization to Cor a I was observed in children not sensitized to Bet v 1.Conclusion: Sensitization to hazelnut LTP is a risk factor for objective symptoms in children from a birch-endemic area.

PURPOSE OF REVIEW:Hazelnut allergy can vary between mild oral symptoms and potentially dangerous anaphylaxis. There is a need to predict which subjects are at risk for severe reactions. In this study, possibilities for 'component-resolved diagnosis', based on sensitization to different allergens in hazelnut, are discussed.RECENT FINDINGS:One type of hazelnut allergy can be associated with sensitization to homologues of pollen allergens, predominantly birch, in hazelnut: Cor a 1 (Bet v 1) and Cor a 2 (profilin). These allergens account for relatively mild symptoms. However, subjects can also be sensitized to several other allergens in hazelnut that are related to more severe symptoms. These allergens are homologues of allergens in other nuts and peanut: Cor a 8 (lipid transfer protein) and Cor a 9 (11S globulin) and perhaps Cor a 11 (7S globulin). The clinical relevance of these and other potential hazelnut allergens has to be further defined. The diagnosis of hazelnut has to be confirmed by oral double-blind placebo-controlled food challenge.SUMMARY:Sensitization to hazelnut can either be associated with mild oral symptoms, depending on sensitization to pollen, or with more serious allergic symptoms, related to sensitization to homologues of nut and peanut allergens.

To the Editor: In areas where birch trees are endemic, hazelnut allergy is often the result of primary sensitization to cross-reactive birch pollen allergen Bet v 1, usually resulting in mild oral allergy syndrome (OAS) in both adults and children.1Hirschwehr R. Valenta R. Ebner C. Ferreira F. Sperr W.R. Valent P. et al.Identification of common allergenic structures in hazel pollen and hazelnuts: a possible explanation for sensitivity to hazelnuts in patients allergic to tree pollen.J Allergy Clin Immunol. 1992; 90: 927-936Abstract Full Text PDF PubMed Scopus (262) Google Scholar, 2Cudowska B. Kaczmarski M. Diagnostic value of birch recombinant allergens (rBet v 1, profilin rBet v 2) in children with pollen-related food allergy.Rocz Akad Med Bialymst. 2004; 49: 111-115PubMed Google Scholar On the other hand, sensitization to hazelnut in early childhood has been related to sensitization to other tree nuts and peanut,3Pumphrey R.S. Wilson P.B. Faragher E.B. Edwards S.R. Specific immunoglobulin E to peanut, hazelnut and Brazil nut in 731 patients: similar patterns found at all ages.Clin Exp Allergy. 1999; 29: 1256-1259Crossref PubMed Scopus (45) Google Scholar, 4Clark A.T. Ewan P.W. The development and progression of allergy to multiple nuts at different ages.Pediatr Allergy Immunol. 2005; 16: 507-511Crossref PubMed Scopus (93) Google Scholar which can all cause serious reactions.5Sicherer S.H. Furlong T.J. Munoz-Furlong A. Burks A.W. Sampson H.A. A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants.J Allergy Clin Immunol. 2001; 108: 128-132Abstract Full Text PDF PubMed Scopus (316) Google Scholar Children can be sensitized to hazelnut at an early age.3Pumphrey R.S. Wilson P.B. Faragher E.B. Edwards S.R. Specific immunoglobulin E to peanut, hazelnut and Brazil nut in 731 patients: similar patterns found at all ages.Clin Exp Allergy. 1999; 29: 1256-1259Crossref PubMed Scopus (45) Google Scholar Remarkably, a large proportion has never to their knowledge ingested hazelnut, and most allergic reactions to nuts in childhood occur after the first known exposure.6Sicherer S.H. Burks A.W. Sampson H.A. Clinical features of acute allergic reactions to peanut and tree nuts in children.Pediatrics. 1998; 102: e6Crossref PubMed Scopus (376) Google Scholar This is the first study to determine the clinical relevance of hazelnut sensitization and eliciting doses (EDs) in childhood by double-blind placebo-controlled food challenge (DBPCFC). Furthermore, we investigated the relation between hazelnut allergy and sensitization to birch pollen and other species of nut and peanut. Twenty-eight sensitized children (8 female, 20 male; age 4-16 years) with suspected allergy to hazelnut were recruited. All children were atopic, with atopic dermatitis the most frequently reported condition (86%). Sixteen children (57%) had seasonal rhinoconjunctivitis. Asthma-related symptoms were reported by 13 children (47%). Sensitization was re-evaluated before DBPCFC by a skin prick test (SPT) with commercial hazelnut extract (ALK-Abelló, Nieuwegein, The Netherlands) and specific IgE levels using the CAP system FEIA (Pharmacia Diagnostics, Uppsala, Sweden) to hazelnut, birch pollen, almond, pecan, walnut, Brazil nut, pistachio, cashew, and peanut. Double-blind placebo-controlled food challenges were performed as described previously,7Flinterman A.E. Pasmans S.G. Hoekstra M.O. Meijer Y. van Hoffen E. Knol E.F. et al.Determination of no-observed-adverse-effect levels and eliciting doses in a representative group of peanut-sensitized children.J Allergy Clin Immunol. 2006; 117: 448-454Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar but not in the tree pollen season between mid-February and mid-June. Briefly, the challenge was composed of 9 portions of defatted hazelnut flour in series: 10 μg, 100 μg, 500 μg, 1 mg, 10 mg, 100 mg, 300 mg, 1 g, and 3 g (protein content, 15.5%; kindly provided by the Food Allergy Research and Resource Program, University of Nebraska). Four placebos were randomly interspersed by the pharmacist to complete the procedure in 1 day. The last dose was unblind and consisted of 10 hazelnuts (5 g; approximately 635 mg protein), because this amount could not be masked in edible portions for children. The challenge was only discontinued after the occurrence of an objective reaction. Sixteen children (57%) did not show any reaction on hazelnut ingestion during the challenge procedure. In 12 children (43%), hazelnut allergy was confirmed by challenge. Doses as large as 1 mg (0.16 mg protein) were tolerated by all children (Table I). Four children (4/12; 33%) reported only OAS without developing objective symptoms at doses starting from 10 mg. One child (#17) refused further portions after aggravating symptoms of OAS at 3 subsequent doses. These children with only OAS were all sensitized to birch pollen. The interval between ingestion and OAS was always less than 10 minutes.Table ISensitization to hazelnut, pollen, and other species of nut, and the results of DBPCFC per individual (n = 28)HazelnutPollen∗Specific IgE in kUA/L; 0: <0.35; 100: >100.Other species of nut and peanut∗Specific IgE in kUA/L; 0: <0.35; 100: >100.DBPCFC HazelnutNo.Age (y)IgE∗Specific IgE in kUA/L; 0: <0.35; 100: >100.SPT†SPT diameter in millimeters.GrassBirchAlmondPecanWalnutBrazilPistachioCashewPeanutSymptoms‡Symptoms: ap, abdominal pain; bro, bronchoconstriction; dia, diarrhea; rc, rhinoconjunctivitis; urt, urticaria; vom, vomiting.ED OAS (mg)ED objective (mg)189410010011114210None——292649760000004None——31417100561000101None——48441001000—0—1015None——516141000010087None——6142621839191022020100None——77150270000339None——8408000—0——40None——9412215301106312None——10603000000441None——1174§Individual with allergic reaction to hazelnut by history.571001111638None——12511258100764810010048None——134126800001122None——147122420001333None——156451001000101101None——1640400.40000003None——17128§Individual with allergic reaction to hazelnut by history.8751136263654OAS100—1842626273332527OAS>3000—19101455800001412725OAS10—20517230000000OAS>3000—2141611329321710840OAS, ap, vom>3000>30002264§Individual with allergic reaction to hazelnut by history.7335122140212866OAS, urt100>300023845126010011322310565952OAS, rc, ap, vom3000>3000241320103462974—1815100OAS, urt, ap100>300025438§Individual with allergic reaction to hazelnut by history.1710222223663OAS, ap, vom100300268481771007131218272750OAS, ap, vom100300027627700.5017410162OAS, urt, rc, bro>3000>300028655100012313710010066OAS, ap, dia>3000>3000∗ Specific IgE in kUA/L; 0: <0.35; 100: >100.† SPT diameter in millimeters.‡ Symptoms: ap, abdominal pain; bro, bronchoconstriction; dia, diarrhea; rc, rhinoconjunctivitis; urt, urticaria; vom, vomiting.§ Individual with allergic reaction to hazelnut by history. Open table in a new tab Eight children (8/12; 67%) developed an objective reaction to hazelnut, such as systemic urticaria, rhinoconjunctivitis, vomiting, and dyspnea. ED for objective reactions ranged from 300 mg to 10 hazelnuts. In 5 children, the objective reactions were preceded by OAS on previous doses (100 mg to 3 g). In 3 children, OAS and objective symptoms developed on the same dose. Late reactions (as long as 24 hours after DBPCFC) were not reported. Three of the children with an objective reaction had low or undetectable birch pollen–specific IgE (<0.35-0.5 international kilounits allergen-specific IgE per liter [kUA/L]), as well as grass pollen-specific IgE (<0.35-1.0 kUA/L). Skin prick test reactivity was significantly different between children without hazelnut allergy, children with only OAS, and children with objective symptoms; the latter group had the highest SPT reactivity. Specific IgE to hazelnut, but also to other species of nut, was significantly higher in children with objective reactions compared with children without objective reaction (children with only OAS or children without any reaction; P < .05 for all nuts, except for peanut, P = .205). Children with objective reactions were sensitized to more species of nuts (median, 6; range, 5-6) than children with only OAS (median, 4.5; range, 0-6) or no reaction (median, 2.5; range, 0-6). IgE reactivity to cross-reactive carbohydrate determinants of glycoproteins was determined in all children using RAST.8Van de Veen M.J. van Ree R. Aalberse R.C. Akkerdaas J. Koppelman S.J. Jansen H.M. et al.Poor biologic activity of cross-reactive IgE directed to carbohydrate determinants of glycoproteins.J Allergy Clin Immunol. 1997; 100: 327-334Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar This was negative in all but 1 patient (#23; data not shown) and was not associated with the type of reaction. Challenges are an important tool in diagnosing food allergy.9Bindslev-Jensen C. Ballmer-Weber B.K. Bengtsson U. Blanco C. Ebner C. Hourihane J. et al.Standardization of food challenges in patients with immediate reactions to foods: position paper from the European Academy of Allergology and Clinical Immunology.Allergy. 2004; 59: 690-697Crossref PubMed Scopus (576) Google Scholar In this study, fewer than half of the children with sensitization to hazelnut appeared to be allergic to hazelnut. Moreover, challenges with increasing doses of hazelnut are the only way to determine ED. Doses as large as 1 mg hazelnut flour were tolerated by all children. The ED for OAS (≥10 mg; 1.6 mg protein) and for objective symptoms (≥300 mg; 46.5 mg protein) were in line with previous studies on hazelnut allergy in adults.10Wensing M. Penninks A.H. Hefle S.L. Akkerdaas J.H. van Ree R. Koppelman S.J. et al.The range of minimum provoking doses in hazelnut-allergic patients as determined by double-blind, placebo-controlled food challenges.Clin Exp Allergy. 2002; 32: 1757-1762Crossref PubMed Scopus (93) Google Scholar, 11Ortolani C. Ballmer-Weber B.K. Hansen K.S. Ispano M. Wuthrich B. Bindslev-Jensen C. et al.Hazelnut allergy: a double-blind, placebo-controlled food challenge multicenter study.J Allergy Clin Immunol. 2000; 105: 577-581Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 12Enrique E. Pineda F. Malek T. Bartra J. Basagana M. Tella R. et al.Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract.J Allergy Clin Immunol. 2005; 116: 1073-1079Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar Similar EDs for objective symptoms to peanut were described in a comparable study in peanut-sensitized children: 100 mg peanut flour (50 mg protein).7Flinterman A.E. Pasmans S.G. Hoekstra M.O. Meijer Y. van Hoffen E. Knol E.F. et al.Determination of no-observed-adverse-effect levels and eliciting doses in a representative group of peanut-sensitized children.J Allergy Clin Immunol. 2006; 117: 448-454Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Although ED for hazelnut appeared to be the same in children and adults, children experienced more objective reactions than adults from our hospital (8/12, 67%, vs 2/29, 6.9%).10Wensing M. Penninks A.H. Hefle S.L. Akkerdaas J.H. van Ree R. Koppelman S.J. et al.The range of minimum provoking doses in hazelnut-allergic patients as determined by double-blind, placebo-controlled food challenges.Clin Exp Allergy. 2002; 32: 1757-1762Crossref PubMed Scopus (93) Google Scholar It is unlikely that this is the result of a selection bias because the referral area is similar. In our study, children with only OAS were all sensitized to birch pollen. In contrast, 3 of the children with additional objective symptoms to hazelnut had low or even undetectable birch pollen–specific IgE. This suggests a nonpollen-related route of sensitization to hazelnut in at least some of the children from areas where birch trees are endemic. In particular, children with objective reactions to hazelnut had high levels of specific IgE to other nuts. The differences in sensitization to nuts between children with and without objective reactions to hazelnut did not appear to be explained by cross-reactive carbohydrate determinant reactivity. Atopic parameters such as total IgE levels and the scoring of atopic dermatitis were similar (data not shown); hence, this does not explain the differences in sensitization either. Although we did not investigate the clinical relevance of all nuts and the history did not provide information on previous exposure to most nuts, avoidance of all nuts may still be advisable in children with objective reactions to hazelnut. For future preventive and therapeutic strategies, it would be interesting to investigate which major allergens are responsible for the primary sensitization in children with objective reactions to hazelnut.13Pastorello E.A. Vieths S. Pravettoni V. Farioli L. Trambaioli C. Fortunato D. et al.Identification of hazelnut major allergens in sensitive patients with positive double-blind, placebo-controlled food challenge results.J Allergy Clin Immunol. 2002; 109: 563-570Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar Our data indicate that sensitization to hazelnut is not clinically relevant in about half of the children. OAS was reported by all children with a reaction to hazelnut, at doses starting from 10 mg. Additional objective symptoms were observed in at least 67% of the reactions. These objective reactions to hazelnut were not always accompanied by sensitization to birch pollen, but always by sensitization to other nuts and peanut. This suggests that the route of clinically relevant sensitization to hazelnut in children, in an area where birch trees are endemic, can be nonpollen-related.

Objective: To monitor the pattern of cerebral oxygen saturation (rSat), by use of NIRS, in term infants before, during and after the arterial switch operation and to evaluate its relation to neurodevelopmental outcome. Methods: In 20 neonates without pre-existing brain damage hemodynamics and arterial oxygen saturation (AO(2)-Sat) were monitored simultaneously with rSat and amplitude-integrated EEG (aEEG) from 4 h to 12 h before up to 36 h after cardiopulmonary bypass (CPB) and short duration of cardiac arrest during deep hypothermia (DHCA). The Bayleys developmental scale was performed at 30 months. Results: Before surgery rSat was < 50% in 16 patients. During CPB rSat increased to normal values, with a sharp decrease during brief CA (median 6.5 min). Post-CPB rSat showed a transient decrease (30-45%) despite normal PaO2 with sustained normalization after 6-26 h. Recovery time of the rSat seemed longer when pre-operative rSat was below 35%, and for lower minimum nasopharyngeal temperature and longer duration of CPB and of DHCA. Recovery time of the aEEG varied and did not correlate with normalization of rSat. Neurodevelopmental outcome was normal in all but two patients. Patients with lower pre-operative rSat (< 35%) tended to have lower DQ (developmental quotient) scores at 30-36 months. (median: mental 102 and motor 101 (range 58-125) compared with mental 100 and motor 110 (range 83-125)) Conclusion: Despite prompt normalization of circulation and oxygenation after surgery, recovery of rSat of the brain took 6-26 h, probably because of higher energy demand after CPB. Pre-operative cerebral oxygenation may be underestimated as a possible cause of adverse post-operative outcome.