Danijela Bokanovic

Detection of IgE to recombinant Api m 1 and rVes v 5 is valuable but not sufficient to distinguish bee from wasp venom allergy

To the Editor: Hofmann et al tackle an important problem in Hymenoptera venom allergy: the frequently observed (asymptomatic) double sensitization to bee andwasp venom, and the problemof identifying the relevant venom for immunotherapy. Component-resolved diagnosis is undoubtedly a major advancement in the diagnosis of Hymenoptera venom allergy. Nevertheless, the following aspects should be noted: Hofmann et al aswell asM€uller et al enrolled patients on the basis of a positive skin test response. However, some patients with a venom allergy have negative skin tests. Golden et al frequently observed negative skin tests in patients with allergy toHymenoptera venom, and a considerable number of these patients reacted to sting challenges. Particularly, a low total IgE level is linked to negative skin tests and nondetectable specific IgE (sIgE) but is associated with more severe reactions. Therefore, patients at high risk could bemissed. Second, the low frequency of sensitization to recombinant (r) Api m 1 compared with the bee venom extract is a cause for concern. Initially, a prevalence of sIgE to rApi m 1 of 97% with the ADVIA system (Siemens, Tarrytown, NY) was reported, but Hofmann et al registered a frequency of only 79% for the ImmunoCAP assay (Phadia, Uppsala, Sweden). We rechecked the sensitivity of sIgE to bee venom extract and rApi m1 in the same system. The data fromHofmann et al could be confirmed at 2Austrian centers,where positive skin testswereused as inclusion criterion. However, an even lower frequency of sensitization to rApi m 1 was registered at 1 Austrian center when all patients with systemic sting reactions in the past were included (Table I). Furthermore, regional differences in sensitization patterns have to be taken into account. In Europe, approximately two thirds of patients with allergy to Hymenoptera venom react towasp stings and only one third to bee stings. By contrast, IgE determination reveals double-positive results in up to 59%of patients. Thus, a diagnostic tool is urgently needed to exclude cross-reactivity via cross-reactive carbohydrate determinants. Because wasp venom allergies are more frequent, and bee venom bears more cross-reactive carbohydrate determinants, typically nonspecific cross-reactions to bee venom must be excluded. Is it adequate merely to determine Api m 1 for this purpose? In the worst case, 38 of 100 patients with bee venom allergy will not be diagnosed by sIgE to rApi m 1, as shown in Table I. Why is this so? Given the limited availability of the substances, we randomly analyzed 40 sera from the low-sensitivity group regarding sIgE to bee venom hyaluronidase (rApi m 2) andmelittin (native [n]Apim 4)with research prototype ImmunoCAPassays.All but 1 patient had detectable sIgE to beevenomextract, whereas 13 patients (32.5%) could not be diagnosed with rApi m 1 alone. After the use of rApi m 2 and nApi m 4, 6 additional patients could be diagnosed, and only 7 (17.5%) remained negative. In detail, 5 patients had detectable sIgE to rApi m 2 and 1 putatively to nApi m 4 only. Generally, 65.0% of patients were sensitized to rApi m 1, 52.2% to rApi m 2, and 42.5% to nApi m 4. From these data, it can be assumed that sensitization to multiple allergens might be common. Furthermore, we could again confirm the clinical relevance of Api m 2 beyond its carbohydrate epitopes. Therefore, these preliminary results indicate that a genuine bee venom sensitization can most likely be excluded in cases of negative sIgE test results to at least Api m 1 and 2.Nevertheless, addition of beevenomallergens likeApim3, 4, 5, 6, and 10would further increase diagnostic accuracy.A similar approach might be valid to exclude genuine wasp venom sensitization: because up to 13% of patients with wasp venom allergy could be missed, the combined determination of sIgE to Ves v 1 and 5 is essential. Taken together, the data indicate that the suggested approach of using rApi m 1 and rVes v 5 is insufficient and even fraught with risk for some patients because genuine sensitization to other major allergens might be missed. Gunter J. Sturm, MD Wolfgang Hemmer, PhD Thomas Hawranek, MD Roland Lang, PhD Markus Ollert, MD Edzard Spillner, PhD Simon Blank, PhD Danijela Bokanovic, MD Werner Aberer, MD

Ves v 5 can establish the diagnosis in patients without detectable specific IgE to wasp venom and a possible north-south difference in Api m 1 sensitization in Europe

To the Editor: We read with great interest the publication of Koro sec et al. Although Ves v 5 is by far the most important allergen of wasp venom, some patients are solely sensitized to Ves v 1. We were able to confirm that recombinant Ves v 1 (rVes v 1) is a useful supplement to rVes v 5 by using the CAP system: 13 of 163 patients with an unambiguous diagnosis of wasp venom allergy were negative for rVes v 5. Six of these had specific IgE (sIgE) to rVes v 1. Therefore, 95.7% of the patients (156 of 163) could be diagnosed with the combination of rVes v 1 and rVes v 5. However, we would like to emphasize an interesting aspect of rVes v 5. Koro sec et al included only those patients who had a detectable sIgE to wasp venom for further analysis. Although the sensitivity of the wasp venom extract is high, in a small number of patients sIgE cannot be verified. We investigated 26 wasp venom–allergic patients without detectable sIgE to wasp venom. Interestingly, 17 of the 26 (65.4%) could be diagnosed with rVes v 5 but not with rVes v 1 in the CAP system. Paradoxically, diagnosis could be established with the major allergen component but not with the wasp venom extract. The reasons for this discrepancy are a matter of speculation. The likeliest explanation is that wasp venom extract is a mix of different Vespula species and Ves v 5 is likely to be underrepresented in the venom mix. Therefore, it is important to consider determining rVes v 5 in patients with a clear history of wasp venom allergy and negative sIgE to wasp venom, which could enhance the general sensitivity of this test. In contrast, the situation is different in bee venom allergy. A low sensitivity of Api m 1 has been recently described by our group and was confirmed by another group. Although 12 bee venom allergens have been identified so far and sensitization to multiple allergens might be common, only rApi m 1 is commercially available for testing. However, some report a higher frequency of Api m 1 sensitization and we also observed differences between our study centers. Hofmann et al suggested that sensitivity might depend on the inclusion criteria of patients and that patients without detectable sIgE to bee venom and negative skin test results are more likely to be negative for Api m 1. We hypothesize that geographic differences rather than inclusion criteria may play a role. In 2 Italian centers, all patients had sIgE to bee venom, but only 13 of 30 (57.9%) in Verona (Northern Italy) and 16 of 38 (56.7%) in Ancona (Central Italy) were sensitized to rApi m 1, respectively. This confirms our recently observed low sensitivity of 61.8% and suggests a possible north-south difference in Api m 1 sensitization in Europe (Fig 1). From this data it is obvious that sensitization to Api m1 decreases from north to south Europe. One could speculate that the venom composition might vary and therefore cause these discrepancies. Therefore, despite considerable progress by the introduction of recombinant allergens, larger studies to determine individual sensitization patterns of patients from different regions with the whole panel of venom components (when available) are needed. Gunter J. Sturm, MD Maria Beatrice Bil o, MD Patrizia Bonadonna, MD Wolfgang Hemmer, PhD Beatrice Caruso, PhD Danijela Bokanovic, MD Werner Aberer, MD

Allergen immunotherapy for insect venom allergy: a systematic review and meta-analysis.

The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines on Allergen Immunotherapy (AIT) for the management of insect venom allergy. To inform this process, we sought to assess the effectiveness, cost‐effectiveness and safety of AIT in the management of insect venom allergy.

Simultaneous intradermal testing with hymenoptera venoms is safe and more efficient than sequential testing.

According to current guidelines, skin testing for hymenoptera venom allergy should be performed in a stepwise manner, maintaining 15‐ to 20‐min intervals between the injections of venom. Given the long‐winded procedure of sequential skin testing, we retrospectively explored the safety of simultaneous intradermal testing.

Determination of sIgE to rPhl p 1 is sufficient to diagnose grass pollen allergy

New diagnostic tools such as the basophil activation test (BAT) and component‐resolved diagnosis (CRD) are promising for hymenoptera venom or food allergy. A clear benefit for inhalant allergens has not yet been shown. Our aim was to compare new and established tests for grass pollen allergy.

Prevalence of hymenoptera venom allergy and poor adherence to immunotherapy in Austria.

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Allergen immunotherapy for insect venom allergy: protocol for a systematic review

AbstractBackground The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for the Management of Insect Venom Allergy. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in the management of insect venom allergy. MethodsWe will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised. Discussion The findings from this review will be used to inform the development of recomendations for EAACI’s Guidelines on AIT.

Questionable diagnostic benefit of the commercially available panel of bee venom components

For many years, only the major allergen rApi m 1 has been available on the ImmunoCAP system for routine diagnosis of bee venom (BV) allergy. Now, there are five components available, and we aimed to detect the sensitivity and specificity of rApi m 1, 2, 3, 5, and 10 in BV‐allergic patients. We further evaluated the sensitivity of rApi m 1 and 2 of an alternative platform and investigated possible differences in the sensitization profile between monosensitization and clinically relevant double sensitization. Analysis of the whole panel of BV allergens of the CAP system still resulted in a lower sensitivity than analysis of the combination of rApi m 1 and 2 of the Immulite (71.6% vs 85.8%). Sensitization rate of rApi m 5 was more than doubled in double‐sensitized patients, while there was no difference for rApi m 2. The benefit of the commercially available panel of BV components is questionable, due to the insufficient sensitivity and still unavailable important cross‐reacting allergens.

Immunological differences between insect venom-allergic patients with and without immunotherapy and asymptomatically sensitized subjects

Currently available tests are unable to distinguish between asymptomatic sensitization and clinically relevant Hymenoptera venom allergy. A reliable serological marker to monitor venom immunotherapy (VIT) does also not exist. Our aim was to find reliable serological markers to predict tolerance to bee and vespid stings.

Erratum to: Allergen immunotherapy for insect venom allergy: protocol for a systematic review

Unfortunately this article [1] was published with an error in the Funding section. The BM4SIT project is not acknowledged. This section should be corrected to the below: Funding EAACI and the BM4SIT project (Grant Number 601763) in the European Union’s Seventh Framework Programme FP7.