L. J. Masthoff

Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults

BACKGROUND Component-resolved diagnosis has been shown to improve the diagnosis of food allergy. OBJECTIVE We sought to evaluate whether component-resolved diagnosis might help to identify patients at risk of objective allergic reactions to hazelnut. METHOD A total of 161 hazelnut-sensitized patients were included: 40 children and 15 adults with objective symptoms on double-blind, placebo-controlled food challenges (DBPCFCs) and 24 adults with a convincing objective history were compared with 41 children and 41 adults with no or subjective symptoms on DBPCFCs (grouped together). IgE levels to hazelnut extract and single components were analyzed with ImmunoCAP. RESULTS IgE levels to hazelnut extract were significantly higher in children with objective than with no or subjective symptoms. In 13% of children and 49% of adults with hazelnut allergy with objective symptoms, only sensitization to rCor a 1.04 was observed and not to other water-soluble allergens. Sensitization to rCor a 8 was rare, which is in contrast to rCor a 1. Sensitization to nCor a 9, rCor a 14, or both was strongly associated with hazelnut allergy with objective symptoms. By using adapted cutoff levels, a diagnostic discrimination between severity groups was obtained. IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 5 kUA/L or greater (children) and IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 1 kUA/L or greater (adults) had a specificity of greater than 90% and accounted for 83% of children and 44% of adults with hazelnut allergy with objective symptoms. CONCLUSION Sensitization to Cor a 9 and Cor a 14 is highly specific for patients with objective symptoms in DBPCFCs as a marker for a more severe hazelnut allergic phenotype.

Diagnostic value of hazelnut allergy tests including rCor a 1 spiking in double-blind challenged children

The diagnostic value of hazelnut allergy tests in double‐blind challenged children is largely unknown. The aim of this study was to analyze the performance of current diagnostic tests for hazelnut allergy in children and the effect of spiking.

Peanut allergy is common among hazelnut-sensitized subjects but is not primarily the result of IgE cross-reactivity.

Hazelnut and peanut are botanically unrelated foods, but patients are often sensitized and allergic to both, for reasons that are not well understood.

Objective eliciting doses of peanut‐allergic adults and children can be combined for risk assessment purposes

To improve food labelling strategies, information regarding eliciting doses (EDs) and the effect of patient characteristics on these EDs is necessary.

Hazelnut allergy differs between children and adults in frequency of severity, aetiology and relevance of diagnostic parameters

Hazelnut allergy in adults is often birch pollen related, whereas in children, non‐pollen‐related hazelnut allergy is more frequent.

Major hazelnut and peanut allergens are potent in basophil activation and cross-react at T-cell level

To the Editor, Sensitization to hazelnut and peanut has already been shown early in life, before introduction of hazelnut and peanut into the diet. Cross-reactions between structurally related proteins in hazelnut and peanut may play a role in this pattern of concomitant sensitization. Cross-reactions may be induced at IgE and T-cell level. A previous paper by our group showed limited cross-reactivity between seed storage proteins in hazelnut and peanut at IgE level. The aim of this study was to assess the potency of the response to hazelnut and peanut allergens in basophil activation and at T-cell level in a hazelnut allergic population with or without additional peanut allergy and to evaluate potential T-cell cross-reactivity between hazelnut and peanut. Nineteen patients (12 children and 7 adults) with objective symptoms to hazelnut in DBPCFC or by history were selected from a cohort of 161 patients with a sensitization to hazelnut extract (Tables S1,S2 and Data S1). The basophil activation test was performed with passively sensitized basophils in a subset of 11 patients with high levels of sensitization to the different hazelnut allergens (Data S1). Five of these patients also had a peanut allergy with objective symptoms (Table S1). In the 11 patients, IgE to hazelnut extract was significantly higher than to different purified hazelnut and peanut allergens, peanut, and birch pollen extract and rBet v 1. IgE to rCor a 14 was significantly higher than IgE to nCor a 9 (P < .01), while IgE to rCor a 1 was not significantly different from IgE to nCor a 9 or rCor a 14 (Table S2). Basophil activation (CD-sens: Figure 1) showed that the 2S albumin rCor a 14 was the most potent hazelnut allergen, followed by the PR-10 protein rCor a 1 (P = .08) and the 11S globulin nCor a 9 (P = .02). In two patients with higher IgE levels to Cor a 9 than to Cor a 14 (HN011C and HN135C), Cor a 14 was still more potent in basophil activation (data not shown), suggesting that Cor a 14 is intrinsically more potent in basophil activation. This pattern was equivalent to that of peanut allergens, for which the 2S albumins in peanut Ara h 2 and Ara h 6 were the most potent. The strong potency of 2S albumins in basophil activation further confirms the relevance of IgE to Cor a 14 or Ara h 2 in the diagnostic workup of hazelnut and peanut allergy. The basophil response to hazelnut and peanut extract and their purified allergens in individuals with an objective allergy to both hazelnut and peanut was comparable (data not shown). The potency of allergens in basophil activation correlated positively with the IgE levels (data not shown). In contrast to IgE responses, T-cell responses are more difficult to study. As only a small fraction of the CD4+ T-cell pool is allergen-specific, T-cell responses were studied in allergen-specific T-cell lines (TCLs). Sixteen hazelnutand 9 peanut-specific TCLs were generated from PBMCs from 16 patients with a hazelnut allergy with objective symptoms (Table S1). TCLs with a proliferative response to hazelnut extract with an SI ≥ 2.0 were selected. The majority of hazelnutand peanut-specific TCLs showed a significant proliferation to both hazelnut and peanut extract, as well as their major allergens (Figure 2A,B). Upon stimulation, hazelnutand peanut-specific TCLs produced mainly IL-13 and IFN-c, and limited amounts of IL-10 (Figure 2C). The TCLs were specific, as evidenced by their unresponsiveness to casein, an unrelated cow’s milk allergen (data not shown). The magnitude of the response to purified hazelnut and peanut allergens was significantly lower than to hazelnut and peanut extract (Figure 2A,B). Cross-reactivity at T-cell level between hazelnut and peanut has been described previously in five patients, partially driven by Ara h 1 or Ara h 2. We performed an additional characterization of the component in hazelnut extract causing strong T-cell proliferation. To identify the component causing the strong T-cell proliferation in hazelnut extract, individual major allergens were tested. Cor a 1, Cor a 9 and Cor a 14 could be excluded based on

Sensitization to Cor a 9 and Cor a 14 is highly specific for a severe hazelnut allergy in Dutch children and adults

Background Component-resolved diagnosis has been shown to improve diagnosis of food allergy. The aim of this study was to evaluate whether component-resolved diagnosis may help to identify patients at risk of severe allergic reactions to hazelnut. Methods A total of 161 hazelnut-sensitized patients were included: 40 children and 15 adults with objective symptoms in DBPCFC and 24 adults with a convincing severe history were compared to 41 children and 41 adults with no or subjective symptoms in DBPCFC (grouped together). IgE levels to hazelnut extract and single components were analyzed with ImmunoCAP.

The level of specific IgE is a moderate predictor for the outcome of a double-blind placebo-controlled food challenge for hazelnut in children

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.