Diagnosis and treatment of Hymenoptera venom allergy: S2k Guideline of the German Society of Allergology and Clinical Immunology (DGAKI) in collaboration with the Arbeitsgemeinschaft für Berufs- und Umweltdermatologie e.V. (ABD), the Medical Association of German Allergologists (AeDA), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNOKC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Allergy and Environmental Medicine (GPA), German Respiratory Society (DGP), and the Austrian Society for Allergy and Immunology (ÖGAI).

Hymenoptera venom (HV) is injected into the skin during a sting by Hymenoptera such as bees or wasps. Some components of HV are potential allergens and can cause large local and/or systemic allergic reactions (SAR) in sensitized individuals. During their lifetime, ~ 3% of the general population will develop SAR following a Hymenoptera sting. This guideline presents the diagnostic and therapeutic approach to SAR following Hymenoptera stings. Symptomatic therapy is usually required after a severe local reaction, but specific diagnosis or allergen immunotherapy (AIT) with HV (VIT) is not necessary. When taking a patient's medical history after SAR, clinicians should discuss possible risk factors for more frequent stings and more severe anaphylactic reactions. The most important risk factors for more severe SAR are mast cell disease and, especially in children, uncontrolled asthma. Therefore, if the SAR extends beyond the skin (according to the Ring and Messmer classification: grade > I), the baseline serum tryptase concentration shall be measured and the skin shall be examined for possible mastocytosis. The medical history should also include questions specific to asthma symptoms. To demonstrate sensitization to HV, allergists shall determine concentrations of specific IgE antibodies (sIgE) to bee and/or vespid venoms, their constituents and other venoms as appropriate. If the results are negative less than 2 weeks after the sting, the tests shall be repeated (at least 4 - 6 weeks after the sting). If only sIgE to the total venom extracts have been determined, if there is double sensitization, or if the results are implausible, allergists shall determine sIgE to the different venom components. Skin testing may be omitted if in-vitro methods have provided a definitive diagnosis. If neither laboratory diagnosis nor skin testing has led to conclusive results, additional cellular testing can be performed. Therapy for HV allergy includes prophylaxis of reexposure, patient self treatment measures (including use of rescue medication) in the event of re-stings, and VIT. Following a grade I SAR and in the absence of other risk factors for repeated sting exposure or more severe anaphylaxis, it is not necessary to prescribe an adrenaline auto-injector (AAI) or to administer VIT. Under certain conditions, VIT can be administered even in the presence of previous grade I anaphylaxis, e.g., if there are additional risk factors or if quality of life would be reduced without VIT. Physicians should be aware of the contraindications to VIT, although they can be overridden in justified individual cases after weighing benefits and risks. The use of ß-blockers and ACE inhibitors is not a contraindication to VIT. Patients should be informed about possible interactions. For VIT, the venom extract shall be used that, according to the patient's history and the results of the allergy diagnostics, was the trigger of the disease. If, in the case of double sensitization and an unclear history regarding the trigger, it is not possible to determine the culprit venom even with additional diagnostic procedures, VIT shall be performed with both venom extracts. The standard maintenance dose of VIT is 100 µg HV. In adult patients with bee venom allergy and an increased risk of sting exposure or particularly severe anaphylaxis, a maintenance dose of 200 µg can be considered from the start of VIT. Administration of a non-sedating H1-blocking antihistamine can be considered to reduce side effects. The maintenance dose should be given at 4-weekly intervals during the first year and, following the manufacturer's instructions, every 5 - 6 weeks from the second year, depending on the preparation used; if a depot preparation is used, the interval can be extended to 8 weeks from the third year onwards. If significant recurrent systemic reactions occur during VIT, clinicians shall identify and as possible eliminate co-factors that promote these reactions. If this is not possible or if there are no such co-factors, if prophylactic administration of an H1-blocking antihistamine is not effective, and if a higher dose of VIT has not led to tolerability of VIT, physicians should should consider additional treatment with an anti IgE antibody such as omalizumab as off lable use. For practical reasons, only a small number of patients are able to undergo sting challenge tests to check the success of the therapy, which requires in-hospital monitoring and emergency standby. To perform such a provocation test, patients must have tolerated VIT at the planned maintenance dose. In the event of treatment failure while on treatment with an ACE inhibitor, physicians should consider discontinuing the ACE inhibitor. In the absence of tolerance induction, physicians shall increase the maintenance dose (200 µg to a maximum of 400 µg in adults, maximum of 200 µg HV in children). If increasing the maintenance dose does not provide adequate protection and there are risk factors for a severe anaphylactic reaction, physicians should consider a co-medication based on an anti-IgE antibody (omalizumab; off-label use) during the insect flight season. In patients without specific risk factors, VIT can be discontinued after 3 - 5 years if maintenance therapy has been tolerated without recurrent anaphylactic events. Prolonged or permanent VIT can be considered in patients with mastocytosis, a history of cardiovascular or respiratory arrest due to Hymenoptera sting (severity grade IV), or other specific constellations associated with an increased individual risk of recurrent and/or severe SAR (e.g., hereditary α-tryptasemia). In cases of strongly increased, unavoidable insect exposure, adults may receive VIT until the end of intense contact. The prescription of an AAI can be omitted in patients with a history of SAR grade I and II when the maintenance dose of VIT has been reached and tolerated, provided that there are no additional risk factors. The same holds true once the VIT has been terminated after the regular treatment period. Patients with a history of SAR grade ≥ III reaction, or grade II reaction combined with additional factors that increase the risk of non response or repeated severe sting reactions, should carry an emergency kit, including an AAI, during VIT and after regular termination of the VIT.

FPIES: Data for Germany in international comparison.

Food protein-induced enterocolitis syndrome (FPIES) is a rare, non-IgE-mediated food allergy. The triggering foods differ significantly from the typical triggers of an IgE-mediated food allergy. Until recently, there were no data on triggers of FPIES in Germany. In order to create an advisory basis for the care of German patients, a large multicenter study was initiated and published at the end of 2021. This revealed clear differences in international comparisons. The most frequent triggers for FPIES in Germany are cow's milk, fish, vegetables, and meat. Most children (84%) react to only one food. The prognosis is usually good, depending on the trigger. Regional data should be used for counseling patients with FPIES. Specific recommendations for this are given in this article.

Organ-specific symptom patterns during oral food challenge in children with peanut and tree nut allergy.

BACKGROUND: Peanut and tree nut allergies are common in childhood and often severe in nature. The clinical picture shows a wide variety of symptoms. OBJECTIVE: To analyze the distribution of clinical symptoms and severity during oral food challenges (OFC) in children. METHODS: Analysis of 1.013 prospectively recorded, positive OFCs with peanut (n = 607), hazelnut (n = 266), walnut (n = 97), and cashew (n = 43). Symptoms were categorized as immediate-type skin, gastrointestinal, upper and lower respiratory, cardiovascular symptoms, and eczema exacerbation. Symptom severity and treatment were recorded. RESULTS: Skin symptoms presented in 78%, followed by gastrointestinal (47%), upper (42%), and lower respiratory symptoms (32%). Cardiovascular symptoms presented in 6%. In three-quarter of the reactions, more than one organ was involved. Importantly, severe reactions occurred at every dose level. Peanut- and cashew-allergic patients had a higher relative risk of gastrointestinal symptoms compared with hazelnut- and walnut-allergic patients. Patients without vomiting had a 1.7 times higher risk developing immediate-type skin and/or lower respiratory symptoms. Three-quarter of the patients ever had eczema but worsening presented in only 10.5% of the OFCs. In patients with multiple food allergies, organs involved, eliciting dose and severity differed between allergens. CONCLUSION: Although comparisons between allergen groups with different clinical history, severity, comorbidities and laboratory data are difficult and might contain bias, our data confirm the high allergenic potential of peanut and tree nuts. The rare occurrence of eczema worsening emphasizes that avoidance diets of peanuts and tree nuts to cure eczema seem to be unnecessary and may hamper tolerance maintenance.

Different Patterns of Foods Triggering FPIES in Germany.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food allergy mainly affecting infants and young children. Allergic FPIES reactions differ from IgE-mediated food allergies, for example, regarding elicitors and clinical course. OBJECTIVE: The aim of our study was to describe causative agents and development of tolerance in German children with FPIES. METHODS: We conducted a retrospective survey on children with FPIES from 14 centers in Germany assessing a 6-year period. RESULTS: We analyzed 142 patients with 190 FPIES reactions, 130 of which met acute FPIES criteria and 60 were defined as chronic FPIES. The most frequent eliciting food for acute FPIES was cow's milk, followed by fish, vegetables (eg, potato, pumpkin), meats (eg, beef), and grains. A total of 119 children reacted to 1 food only, 16 children to 2 or 3 foods, and 7 children to ≥4 foods. In chronic FPIES, all but 4 exclusively breastfed infants reacted to cow's milk feeding. IgE sensitization to the triggering food was found in 21 of 152 (14%) cases. Two children developed additional IgE-mediated symptoms upon a food challenge. Time to proof of tolerance was shortest in cow's milk-induced FPIES, and it was shorter in chronic than in acute FPIES. CONCLUSION: In our national survey, we identified triggers for acute FPIES that partially differ from those reported internationally. Mainly foods introduced early in infant nutrition triggered acute reactions. Time to proven tolerance was shown to be contingent on FPIES symptomatology and on the triggering food. These data should be considered regarding nutritional advice for infants with FPIES.

[Pitfalls in the diagnostics of food allergies in children and adolescents]. / Fallstricke in der Diagnostik von Nahrungsmittelallergien bei Kindern und Jugendlichen.

For the diagnostics of food allergies several points need to be considered. Firstly, it is important to recognize the various clinical pictures that can be caused by a food allergy. The assignment to a disease decides which further examinations are necessary and reasonable. In immunoglobulin (Ig) E­mediated allergies, the detection of sensitization by determining the specific IgE or the prick test in addition to the medical history is an important mainstay of the diagnostics. Crucial is the fact that the detection of a sensitization against an extract from an allergen source only rarely implies an actual allergy. The majority of positive findings are not clinically relevant. The modern procedure of component-resolved allergy diagnostics improves the significance. Nevertheless, the diagnosis can often only be achieved by oral provocation tests. This article points out possible difficulties with the interpretation of the findings.

Allergen Recognition Patterns in Walnut Allergy Are Age Dependent and Correlate with the Severity of Allergic Reactions.

BACKGROUND: Walnut is an important elicitor of food allergy in children and adults with a high rate of severe reactions. Multicenter studies using a common clinical protocol and a comprehensive allergen are lacking. OBJECTIVE: To investigate potential correlations between molecular sensitization patterns and clinical characteristics of walnut-allergic patients. METHODS: A total of 91 walnut-allergic subjects and 24 tolerant controls from Switzerland, Germany, and Spain were included. Walnut allergy was established by food challenge in all but anaphylactic subjects. Specific IgE (sIgE) to walnut extract, rJug r 1 (2S albumin), rJug r 3 (nonspecific lipid transfer protein 1), nJug r 4 (11S globulin), rJug r 5 (PR-10 protein), 2 vicilin fractions, profiling, and cross-reactive carbohydrate determinant was determined by ImmunoCAP. A threshold of 0.10 kUA/L was used for positivity. RESULTS: Sensitivity of sIgE to walnut extract was 87% and increased to 96% for the sum of all walnut components. sIgE to walnut extract and all walnut components, except rJug r 5, was significantly higher in patients younger than 14 years at inclusion. Stratification by age at onset of walnut allergy led to similar results. All patients younger than 14 years had severe reactions, whereas 38% of patients 14 years or older were mild reactors. Severe reactors (n = 70) had higher sIgE levels than did mild reactors (n = 21) to walnut extract (P < .0001), rJug r 1 (P < .0001), nJug r 4 (P = .0003), and both vicilin fractions (P < .0001), but not to Jug r 3 and Jug r 5. CONCLUSIONS: Sensitization to walnut storage proteins is acquired in childhood and correlates with severe reactions. sIgE levels to storage proteins Jug r 1 and Jug r 4 and vicilin fractions, but not to nonspecific lipid transfer protein and PR-10 proteins, correlate with systemic reactions to walnut.

Sensitivity encoding for diffusion-weighted MR imaging at 3.0 T: intraindividual comparative study.

PURPOSE: To prospectively evaluate whether diffusion-weighted (DW) magnetic resonance (MR) imaging with sensitivity encoding (SENSE) at 3.0 T can help to improve image quality and confidence in and accuracy of diagnosis of ischemic lesions, compared with DW MR imaging with conventional phase encoding, in patients. MATERIALS AND METHODS: Patients provided informed consent after the study had been explained, and the institutional review board approved the study protocol. Eighty-five patients (46 male and 39 female patients; age range, 13-86 years; mean age, 52 years) underwent single-shot spin-echo echo-planar DW MR imaging at 3.0 T twice, in a randomized order: once with conventional phase encoding (repetition time msec/echo time msec, 4283/79) and once with SENSE (3141/69, with a reduction factor of three). With both, 128 x 128 matrix, 24 4-mm-thick sections, and two b values of 0 and 1000 sec/mm(2) were used. An eight-element SENSE-compatible receive-only surface coil was used; the built-in body coil served for radiofrequency transmission and generation of the coil sensitivity profile. SENSE and conventional phase encoding were compared for image quality, signal-to-noise ratio, relative signal intensity (SI), and lesion contrast. Two neuroradiologists read images. Diagnostic accuracy of and confidence in detection of apparent diffusion coefficient (ADC) lesions with conventional phase encoding and SENSE at MR imaging were compared; matched-pairs Wilcoxon signed rank test was used to test statistical significance. RESULTS: No major SENSE-related artifacts were seen. At MR imaging with SENSE, consistently and significantly (P < .001) higher image quality scores were achieved because of substantial reduction of image distortions and blurring. Lesion contrast was equivalent with both techniques. Diagnostic confidence for demonstration and exclusion of lesions was significantly (P < .001) higher at MR imaging with SENSE. In three patients, small microembolic lesions were only prospectively diagnosed at MR imaging with SENSE, whereas they were masked by adjacent susceptibility effects and therefore overlooked at MR imaging with conventional phase encoding. CONCLUSION: Parallel MR imaging with SENSE is feasible at 3.0 T. It significantly improves image quality, particularly by reducing or even preventing susceptibility-induced SI changes and image blurring. There was a significantly improved diagnostic confidence with which ADC changes were identified or excluded.

Acute and subacute ischemic stroke at high-field-strength (3.0-T) diffusion-weighted MR imaging: intraindividual comparative study.

PURPOSE: To compare signal-to-noise ratios (SNRs), contrast-to-noise ratios (CNRs), image quality, and confidence in diagnosis between 1.5- and 3.0-T diffusion-weighted (DW) magnetic resonance (MR) imaging of ischemic stroke lesions. MATERIALS AND METHODS: The study design was approved by the institutional review board, and all patients gave informed consent. In a prospective intraindividual study, 25 patients who had clinical symptoms consistent with ischemic stroke underwent DW MR imaging at both 1.5 T and 3.0 T. The 3.0- or 1.5-T examination was performed immediately one after the other, in random order. Two readers in consensus recorded the presence and number of ischemic lesions and rated image quality and lesion conspicuity. The image SNR and the CNR of the ischemic lesions were quantified. Paired Student t and Wilcoxon matched-pairs signed rank tests were used to test for statistical significance. RESULTS: Image quality at 3.0-T DW MR imaging was consistently lower than that at 1.5-T DW MR imaging owing to greater image distortions (P < .05). Yet, overall SNR and lesion CNR at 3.0 T increased significantly; mean increases were 48.8% (P < .001) and 96.3% (P < .01), respectively. The higher overall SNR and lesion CNR translated into a significantly higher sensitivity in the detection of ischemic lesions at 3.0 T than at 1.5 T. Of the total of 48 lesions that were identified in 19 of the 25 patients, 47 (98%) were diagnosed at 3.0 T and 36 (75%) were diagnosed at 1.5 T. In addition, the conspicuity of the lesions that were visible with both systems was significantly higher at 3.0 T (P < .001). CONCLUSION: Although 3.0-T DW MR imaging generates greater image distortions, it yields increased SNR and CNR compared with DW MR imaging at 1.5 T. The increased CNR at 3.0 T translates into a significantly improved diagnostic confidence in the detection of focal apparent diffusion coefficient changes in the setting of subacute and acute ischemic stroke.