Abstract
Introduction
The first-line treatment for patients with Hymenoptera venom allergy, a potentially life-threatening condition, is venom immunotherapy (VIT). However, for reasons still unclear, honeybee VIT (HBV-IT) is less effective than yellow jacket VIT (YJV-IT).
Methods
This retrospective monocentric study aimed to investigate the safety and efficacy of naturally composed Hymenoptera venom (NC-HV) in a rush protocol involving a high total venom dose and to compare the results with those previously obtained using size-excluded Hymenoptera venom (SE-HV). Data regarding the number of build-up cycles and maintenance of VIT with NC-HV were retrieved from institutional records. The VIT protection rate was determined by the results of the sting challenge test (SCT).
Results
We evaluated 648 individuals treated with NC-HV and compared their results with data from 1,258 individuals treated with SE-HV. The frequency of systemic reactions (SRs) with NC-HV in HBV-IT was 25.6%, and that with YJV-IT was 10.1%. Compared with previous experience with SE-HV, the use of NC-HV was associated with an increased frequency of SRs (SR rates of HBV-IT 10.4 and YJV-IT 6.3%). The protection rate in HBV-IT, as determined by SCT, was 100% with NC-HV, which is notably higher than the 95.4% previously reported with SE-HV. The efficacy of YJV-IT was equivalent to 99.0% for NC-HV and 99.6% for SE-HV.
Conclusion
Nearly complete protection was achieved with the NC-HV. The efficacy gap between HBV-IT and YJV-IT, which has limited VIT for decades, can be overcome with NC-HV in combination with a high total venom dose rush protocol.
Keywords: Venom immunotherapy, Rush protocol, Hymenoptera venom allergy, Efficacy, Safety
Introduction
Sting from yellow jacket wasps and honeybees can cause IgE-mediated allergic systemic reactions (SRs), which can become potentially life-threatening medical conditions, in cases of anaphylaxis [1, 2]. Therefore, the diagnosis and treatment of Hymenoptera venom allergy (HVA) is a key task in clinical allergology. Venom immunotherapy (VIT), a prime example of allergen immunotherapy that involves the subcutaneous administration of Hymenoptera venom preparations, modifies the immune system and induces tolerance to Hymenoptera venom [3]. As a consequence of historical peculiarities in the regulatory framework for allergy treatment in Europe, VIT remains a heterogeneous therapeutic procedure [4]. A common element of these treatment procedures is a stepwise increase in the venom dose to 100 µg as the targeted dose during the build-up cycle, followed by a maintenance period of 3–5 years [5]. All Hymenoptera venom preparations authorized under pharmaceutical law for VIT undergo rigorous purification and standardization procedures during the manufacturing of crude venom [4, 5]. The final products can be divided into three groups based on the different manufacturing strategies. A product that undergoes less stringent size exclusion steps during purification is more similar to the original crude venom and can be termed “naturally composed Hymenoptera venom” (NC-HV) [6, 7]. Stringent size exclusion steps during the purification process, which removes physiologically active substances with low molecular weights of up to 5,000 Da, result in a product termed “size-excluded Hymenoptera venom” (SE-HV) [6, 7]. For delayed release, venom extracts can be adsorbed to aluminum hydroxide and termed “aluminum-adsorbed Hymenoptera venom” [5]. In this way, the maintenance dose can be reached within hours or weeks to months, depending on whether an ultra-rush, rush, cluster, or conventional schedule is used in the build-up cycle [8]. A recent multiomics study revealed that very early molecular switches are especially important for achieving favorable long-term VIT outcomes in the initiation phase of therapy [9]. The requirements for VIT are a favorable safety profile, defined as a manageable SR rate, and high efficacy, defined ideally as a (near) complete protection rate against SRs following subsequent bee or wasp stings. There is substantial evidence indicating that VIT is a safe and effective treatment for individuals with HVAs [10]. However, notable differences exist between the various protocols currently employed in clinical practice [11–19]. The most pronounced differences in terms of the safety profiles and efficacy of VIT are observed between honeybee venom (HBV) and yellow jacket venom (YJV). The implementation of HBV-IT (HBV-IT) is associated with an increased risk of SRs, with an expected incidence of 14–20% among treated patients [8, 15]. A further limitation of HBV-IT is that, according to the literature, the efficacy of the protection is assumed to be only 77–84%, in contrast to the 91–99% reported for VIT with yellow jacket (YJV-IT) [8]. Compared with YJV, HBV is more complex and contains more allergenic venom components [20]; this results in more heterogeneous sensitization profiles among individuals with HBV allergies [20]. Some venom components, such as icarapin (Api m10), are present only in small amounts in HBV [6]. Therefore, standardizing these components in the pharmaceutical manufacturing process is challenging, which can result in differences in allergen content between different approved HBV preparations [6]. Attempts have been made to overcome the limitations of HBV-IT by replacing native bee extracts with hypoallergenic preparations [8]. However, HBV allergoids cannot be manufactured in a reproducible manner, and recombinant HBV derivatives exhibit reduced immunogenicity [8]. Therefore, allergen preparations derived from native HBV extracts remain the gold standard in VIT [8]. Retrospective monocenter studies or open observational multicentric studies performed as investigator-initiated trials can help optimize the safety and efficacy of VIT. In this study, we investigated an established in-house-standard rush protocol using an NC-HV preparation that was newly introduced to our clinic.
Patients and Methods
Treatment Concept for HVA
Since 2004, the diagnosis and treatment of HVA at the Department of Dermatology at the University of Tübingen have followed a standardized procedure, which routinely includes administering a sting challenge test (SCT) to verify the efficacy of VIT [12]. Starting in 2017, the SE-HV (ALK-SQ insect venom, ALK-Abelló Arzneimittel GmbH, Hamburg, Germany) utilized for VIT unexpectedly became unavailable in Germany for an extended period. For compensation, patients were switched to an NC-HV preparation (Venomil insect venom, Bencard Allergie GmbH Deutschland, Munich, Germany) and treated over the recommended period of 3 to 5 years. An established in-house-standard rush protocol developed by Brehler et al. [21] for VIT build-up for use with SE-NV was applied with the newly introduced NC-HV (shown in online suppl. E1; for all online suppl. material, see https://doi.org/10.1159/000547194). The protocol used is identical to the two-day rush protocol recommended in the product’s Summary of Product Characteristics for the first eight doses (total venom dose 251.11 µg), although here, it was extended over three inpatient days [22]. A unique aspect of the Brehler regime is that the intended maintenance dose of 100 µg is administered twice within one day (as an additional 9th injection), verifying the tolerance of a cumulative 200 µg of venom on the final day of build-up (total venom dose 351.11 µg). Therefore, the applied regime is a modified VIT schedule. Importantly, contrary to common practices in Europe, we did not premedicate patients with antihistamines during the build-up cycle, as we strongly believe it is important not to mask early signs of SRs [23].
Study Concept
All patients who underwent VIT between February 22, 2017, and December 31, 2022, were included in this retrospective study, and follow-up observation was considered until March 31, 2023. The objective of this study was to compare the safety and efficacy of VIT with NC-HV with those of VIT with SE-HV preparations. Of particular interest was the identification of similarities and differences in the application of these preparations in routine clinical practice. The results from our previous cohort study involving treatment with SE-HV preparations [12] served as a reference for comparison with the results of this study. The methodology employed for identifying treated patients and the collection of clinical data are consistent with that described in a previous publication [12].
Statistical Analysis
The data were processed in an SPSS-derived database and analyzed with SPSS Statistics (version 29; IBM, Armonk, USA). Qualitative variables are reported as proportions, and intergroup comparisons were made with the chi-square test or Fisher’s exact test. Continuous variables are represented as medians, minimum and maximum values, or as the means with standard deviations. Z-differences were calculated as described by Kuss [24]. P values <0.05 were regarded as indicating statistical significance.
Results
Description of the Cohort Treated with NC-HV
The data of 648 patients with HVA who underwent VIT with the NC-HV were retrospectively evaluated in this study. All eligible patients were included. The patient cohort was composed of 52.8% (n = 342) males, and the overall median age was 48.6 years (minimum 6.6 years/maximum 78.9 years). Within our patient cohort, 8.2% (n = 47/648) were children or adolescents (<18 years), and 12.5% (n = 81/648) were elderly adults (>65 years). On the basis of medical history and allergy testing results, VIT with either HBV or YJV was recommended for 98.15% of the patients (n = 636/648). A minority of patients, 1.85% (n = 12/648), underwent dual VIT with both HBV and YJV.
Experience during Build-Up with the NC-HV
In this retrospective study, we evaluated the data corresponding to 660 inpatient VIT build-up cycles with NC-HV preparations following (shown in Table 1) the described rush protocol, including 156 treatments with HBV and 504 treatments with YJV. An extended large local reaction at the injection site led to discontinuation of the build-up cycle in 1 patient who received YJV-IT. SRs were documented as adverse events during the build-up phase in 25.6% (n = 40/156) of the patients receiving HBV-IT and 10.1% (n = 51/504) of those receiving YJV-IT (shown in Fig. 1). Compared with the cohort treated with SE-HV (SRs during the build-up phase: HBV-IT 10.4% [n = 35/335] and YJV-IT 6.3% [n = 62/982]) [11], the risk for SRs among those treated with NC-HV was greater for both, with an odds ratio of 3.06 (95% CI 1.85–5.04, p < 0.001), and for YJV, with an odds ratio of 1.67 (95% CI 1.13–2.46, p = 0.009). The grading severity of SRs during the build-up cycle according to Ring and Messmer is shown in Figure 2. The distribution of the SRs according to the interval from injection is shown in online supplement E2, and the therapeutic response to the SRs is shown in online supplement E3. Regardless of the use of NC-HV or SE-HV or the species of origin of the venom, the risk of requiring epinephrine in response to the development of SRs manifesting as anaphylaxis was highest within a dose range of 0.01 µg to 20 µg of HV (odds ratio 7.33, CI 2.20–24.39, p < 0.001) for this build-up schedule.
Table 1.
Comparison of the key parameters (age, sex, specific IgE, total IgE, and tryptase) of the cohorts treated with NC-HV and SE-HV for honeybee and yellow jacket allergies
| | HBV-IT | YJV-IT | ||||
|---|---|---|---|---|---|---|
| NC-HV (n = 156) | SE-HV (n = 335) | z-difference (p value) | NC-HV (n = 504) | SE-HV (n = 982) | z-difference (p value) | |
| Age (mean+SD) | 42.1 yrs (SD 16.8 yrs) | 43.4 yrs (SD 17.4 yrs) | z = −0.789 (p = 0.43, n.s.) | 47.1 yrs (SD 16.4 yrs) | 46.7 yrs (SD 16.4 yrs) | z = 0.445 (p = 0.66, n.s.) |
| Sex (men) (proportion) | 59.6% | 58.5% | z = −0.2306 (p = 0.81, n.s.) | 50.6% | 51.1% | z = 0.1825 (p = 0.90, n.s.) |
| Bee or wasp sIgE (mean+SD) | 21.1 kU/L (SD 25.9 kU/L) | 18.5 kU/L (SD 26.4 kU/L) | z = 1.029 (p = 0.32, n.s.) | 15.7 kU/L (SD 22.3 kU/L) | 11.5 kU/L (SD 20.1 kU/L) | z = 3.55 (p = 0.0003) |
| Total IgE level (mean+SD) | 172 kU/L (SD 236 kU/L) | 156 kU/L (SD 210 kU/L) | z = 0.723 (p = 0.47) | 159 kU/L (SD 320 kU/L) | 163 kU/L (SD 300 kU/L) | z = 0.233 (p = 0.81, n.s.) |
| Elevated tryptase (>11.4 µg/L) (proportion) | 9.6% | 9.6% | z = 0 (p = 1.0, n.s.) | 9.7% | 7.9% | z = 1.177 (p = 0.24, n.s.) |
| Tryptase level (mean+SD) | 6.51 µg/L (SD 9.12 µg/L) | 6.49 µg/L (SD 8.94 µg/L) | z = −0.1393 (p = 0.89, n.s.) | 6.37 µg/L (SD 8.63 µg/L) | 5.91 µg/L (SD 5.51 µg/L) | z = 1.088 (p = 0.28, n.s.) |
Fig. 1.
Frequency of SRs as adverse events for each injection of NC-HV in the rush protocol separately for HBV (a) and YJV (b) and comparison with previously published data involving SE-HV [12].
Fig. 2.
Distribution of the severity of system reactions during build-up with NC-HV (graded from Ring and Messmer) separately for HBV (a) and YJV (b) and comparison with previously published data regarding SE-HV [12].
Among 92 patients who experienced adverse events (SRs or large local reactions) during the build-up cycle, 77.2% (71 patients) were switched to maintenance therapy with a reduced dose on an outpatient basis after only one week. The last tolerated venom dose in the build-up schedule was selected as the provisional maintenance dose for at least 12 weeks. When the VIT build-up was repeated starting on day 2 of the schedule, 68 patients (95.8%) reached the full maintenance dose of 100 µg without experiencing further complications and did not require additional anti-allergic medication. Among the 3 patients who also experienced SRs during the second build-up phase, 2 patients reached the regular maintenance dose within a third build-up phase after a further increase in the temporary maintenance dose. In the third patient, we initiated anti-IgE mAb (omalizumab) therapy before the next attempt at a build-up cycle.
In our presented cohort of patients, we implemented omalizumab therapy as an adjuvant medication for only 7 patients. To this end, 300 mg of omalizumab was administered at 4-week intervals for 12 weeks prior to VIT and discontinued 12 weeks after the intended maintenance dose was reached. Three patients were able to successfully complete VIT build-up. In another patient, treatment was discontinued owing to the development of myocardial infarction as an unrelated comorbidity. In 3 other patients, VIT was discontinued, as we were unable to induce stable immunological tolerance to the venom. In one of these patients, this was due to recurrent anaphylaxis in the repeated build-up phase, and in the other 2 patients, it was due to anaphylaxis in the maintenance phase after omalizumab was discontinued.
On a case-by-case basis, we increased the venom maintenance dose in 28 patients with systemic mastocytosis and/or elevated basal serum tryptase-level-related anaphylaxis risk. These patients underwent a second build-up cycle after at least 3 months of tolerance to the regular maintenance dose. Updosing to a maintenance dose of 200 µg of HBV was attempted in 8 patients (2 patients with omalizumab). In 2 patients, VIT elicited anaphylaxis III°, which resulted in the permanent discontinuation of VIT. Among patients with an allergy to YJV, 18 patients reached a maintenance dose of 150 µg, and 2 patients reached a maintenance dose of 200 µg upon a second build-up phase without any complications.
Owing to SR recurrence during the build-up cycle, 10 patients decided to discontinue VIT. VIT was permanently discontinued in 7 patients due to anaphylaxis during the build-up cycle, who were then switched to maintenance or maintenance therapy after termination of comedication with omalizumab, and in 1 patient due to noncompliance during the switch to the maintenance phase of VIT; this resulted in a discontinuation rate of 2.8% (n = 18/648 individuals) in the early phase of VIT.
Efficacy of VIT with NC-HV
Patients were contacted to participate in an SCT as an inpatient procedure. During the course of telephone contact, another 29 individuals were identified as having discontinued their VIT in the maintenance phase, resulting in a discontinuation rate for NC-HV of 7.3% (n = 47/648 individuals). The course and reasons for nonparticipation in the SCT program are illustrated in a flowchart (shown in online suppl. E4). A total of 273 SCTs involving living bees or wasps were performed under allergological and anesthesiological emergency standards. In the HBV-IT cohort, SCTs were performed after a median of 17.2 months (minimum 10.3 months/maximum 57.0 months) following the initiation of treatment. In the wasp VIT cohort, the median duration until SCT was performed was 28.0 months (minimum 16.3 months/maximum 53.2 months) following the initiation of treatment due to a limited capacity for inpatient appointments for SCTs. In the SCTs involving honeybees, all 76 patients tolerated the stings without experiencing SRs, indicating 100% efficacy of the HBV-IT. Among the yellow jacket SCTs, 195 out of the 197 YJV-allergic patients tolerated wasp stings without experiencing SRs, indicating an efficacy of YJV-IT of 99%. The 2 patients with YJV allergy for whom VIT failed presented with abnormal tryptase levels (1 patient with mastocytosis and a VIT maintenance dose of 200 µg and 1 patient with suspected hereditary alpha tryptasemia). On the basis of the SCT results, we compared the efficacy of NC-HV with the previously determined efficacy of VIT with that of SE-HV, which demonstrated protection rates of 95.4% for HBV and 99.6% for YJV. A comparison of the two cohorts revealed a slight but measurable superiority in the protection rate of the NC-HV honeybee product (odds ratio of 0.95, 95% CI 0.93–0.98, p = 0.046) over the purified formulation. However, no difference was observed for YJV-IT between the two products. A subanalysis involving 110 VIT patients with tryptase levels >11.4 µg/L from both cohorts revealed no reaction to the SCT among the 32 patients without VIT dose escalation and only a single patient who experienced an SR to the SCT among the 78 patients with VIT dose escalation.
Discussion
The 2017 EAACI guidelines on allergen immunotherapy, HVA, highlight evidence gaps for VIT [1]. One of the identified evidence gaps with a need for studies was stated as follows: “comparison of purified and nonpurified HBV preparations with respect to safety and efficacy verified by sting challenges.” [1] The data presented in this study are not based on a direct head-head comparison in a randomized clinical trial but rather on a retrospective evaluation of regular treatment cases. Owing to the high standardization of the local VIT program and the high similarity of the two cohorts, a direct comparison of the different Hymenoptera venom preparations used is possible. Therefore, this study may contribute to the understanding of the influence of SE-HV and NC-HV preparations of Hymenoptera venom on the safety and efficacy of VIT.
When assessing the safety of the build-up cycle, it is essential to differentiate between schema-, Hymenoptera species-, and product-related influences. In a rush schema, the administration of a series of injections results in the accumulation of venom. When the cumulative daily dose of venom in the Brehler regime exceeds 100 µg, with No. 7 (80 µg, 150 µg/day) or No. 9 (100 µg, 200 µg/day) injections, SRs occur most frequently. These SRs were predominantly skin related (anaphylaxis grade I) and did not require extensive therapeutic management. The critical dose range of the schema is between injection No. 3 (1 µg) and No. 5 (20 µg). SRs within this dose range are rare, but most frequently, they require the therapeutic use of adrenaline owing to its life-threatening clinical manifestations. To the more complex composition of HBV, the frequency of SRs in HBV-IT is higher than that in YJV-IT [6]. In an effort to enhance tolerability, low-molecular-weight physiologically active substances, with a molecular weight of up to 5,000 Da, are filtered out during the manufacturing process of SE-HV [7]. Compared with SE-HV, NC-HV was associated with an increased risk of SRs during the build-up cycle, particularly for HBV-IT, and was less pronounced for YJV-IT. In a comparison of the distribution of SRs within the schema and the grade of severity of the SRs, both products exhibited very similar patterns. As no premedication with antihistamines was administered according to in-house standards, it is not possible to determine whether antihistamines might also have an effect on the frequency of SRs.
According to the prevailing professional consensus, YJV-IT and HBV-IT exhibit divergent efficacy profiles [8, 15]. No difference in efficacy was observed for YJV-IT between the SE-HV (99.6%) and the NC-HV (99.0%) in the cohort observations in this study. These findings are consistent with the literature, which reports high protection rates for YJV-IT of 91–99% [8]. The common literature indicates a significantly lower protection rate of 77–84% for HBV-IT [8]. The reference for an efficacy of 84% is a retrospective monocentric study by Rueff et al. [25] from 2014 and is based on the evaluation of SCTs. In addition, a prospective, observational, multicenter study by the EACCI Interest Group from 2013 estimated a protection rate of 89% on the basis of self-reported sting experiences [26]. Our findings, which were based on the evaluation of SCTs, revealed a protection rate of 95.4% for SE-HV and 100% for NC-HV for HBV-IT. A statistical comparison revealed that the risk of VIT failure was slightly lower for the NC-HV. In a retrospective multicenter study examining the sensitization profiles of individuals with a history of single or multiple VIT failures and HBV allergies, the results demonstrated a clear dominance of sensitizations to Api m10 [27]. It is thus postulated that HBV-IT with NC-HV may be advantageous for those suffering from HBV allergies with sensitization to venom components that may only be present at low concentrations in native HBV [6]. A more salient issue is the fact that both products for HBV-IT are within the range of efficacy of YJV-IT. This finding is clinically relevant and differs from the data presented in the literature.
This raises the questions of what center-specific factors may have contributed to this higher efficacy of HBV-IT and what mechanistic insights this provides. A unique feature of the Brehler protocol is that the target maintenance dose of 100 µg is injected twice [21]. This last injection is not intended to be used for conversion to aluminum-adsorbed Hymenoptera venom [21]. This injection sequence is a familiar element of updosing protocols for a 200-µg maintenance dose [1, 2]. According to the safety analysis, this final injection is the second most frequent time point for the SR and identifies individuals who are not sufficiently tolerant to the HV. Compared with conventional, other rush or ultra-rush protocols, this protocol not only requires tolerance to a higher dose of venom at the end of the build-up cycle but also uses a higher total cumulative venom dose of 351 µg venom for the build-up cycle in general. Therefore, this protocol can be classified as a high-dose protocol. Early in the development of rush protocols, Birnbaum et al. [28] described a correlation between total venom dose and the risk of SR during build-up. The data from this study support the hypothesis that there may also be a correlation between the total venom dose and the efficacy of VIT. In this case, the safety and efficacy of a VIT would be areas of interdependence that cannot be optimized separately. This hypothesis is supported by a case study by Ruëff et al. [29], who reported that immunological tolerance can be achieved in the case of VIT failure by updosing. As a retrospectively derived result from a monocentric cohort, there may be further factors that influence the effectiveness as a limitation for generalization. One such factor is the prophylactic updosing of patients with elevated basal tryptase levels to maintenance doses of 150 or 200 µg, which was regularly carried out in both cohorts. According to a common clinical assumption, immunologic tolerance develops mainly during maintenance treatment over a period of several months and is positively influenced by the total duration of VIT [25]. Consistent with this concept, a recently published analysis of the safety and efficacy of VIT from a large, prospective, multicenter observational study concluded that all venom preparations and regimens used in the study were comparable in terms of the safety and efficacy of VIT [23, 30]. Current translational research on VIT based on a multiomics approach challenges this established concept. This observational study revealed measurable very early molecular and cellular switches in tolerance-mediating pathways within only hours. [8]. These findings suggest that the build-up phase plays a greater role in the development of tolerance than previously thought [9]. There have also been observations suggesting that the immune system is activated differently by rush and conventional build-up regimens [9]. These observations bring new scientific interest to the regimens used for VIT build-up and necessitate reevaluating the various strategies regarding the efficacy of therapy. It is hypothetically conceivable that the efficacy of HBV-IT may be more influenced by the chosen build-up strategy than by the selection of a SE-HV or NC-HV product.
In conclusion, when a high cumulative total dose rush protocol and an NC-HV extract are used, it is possible to treat individuals with HBV allergy as effectively as individuals with YJV allergy. The results of this study show that data obtained from routine clinical practice can help stimulate new approaches to research. Future clinical and translational studies should evaluate the impact of VIT build-up protocols, especially on the efficacy of HBV-IT.
Acknowledgments
The authors thank Selma Cetinkaya, Jutta Schatz, Catrin Walker, Elisabeth Merkle, Bettina Keller, Uta Hamacher, and Cornelia Grimmel for their excellent technical assistance.
Statement of Ethics
This study was performed in accordance with the Declaration of Helsinki. This human study was approved by the Ethics Committee of the University Medical Faculty Tübingen (No. 065/2019/BO2, Amendment 1). This study is a retrospective analysis of the safety and efficacy of an approved standard therapy. Data processing for scientific and statistical purposes is based on “patient data donation” by means of broad consent and in accordance with the applicable data protection laws of the state of Baden-Wuerttemberg. Therefore, no study-specific consent is required from adult participants, parents, legal guardians, or next of kin.
Conflict of Interest Statement
J. Fischer reports speaker fees from ALK-Abelló, Bencard, Bristol Myers Squibb, Novartis, Janssen Cilag, Sanofi-Aventis, Ärzteverband Deutscher Allergologen e.V. (AeDA), and Gesellschaft für Experimentelle und Klinische Atemwegsforschung mbH (GEKA); consulting fees from Bencard and Sanofi-Aventis; and travel support from Pierre Fabre Oncology, outside the submitted work. He is a member of the AeDA and Deutsche Gesellschaft für Allergologie und klinische Immunologie e.V. (DGAKI) and serves as the deputy spokesperson for the Insect Venom Allergy Working Group (DGAKI), in addition to holding a position on the German Guideline Commission on Hymenoptera Allergy. M. Kneilling reports travel support from Lilly, Takeda, and the World Molecular Imaging Society (WMIC) without relation to the submitted work. S. Volc has received consulting fees from AbbVie, Almirall Hermal, Amgen, LEO Pharma, Novartis, and Pfizer as well as support for attending meetings and/or travel from AbbVie, Amgen, Almirall Hermal, and Pfizer. He has received payment or honoraria for lectures and presentations from Almirall Hermal, LEO Pharma, Novartis, and Pfizer. The other authors have no conflicts of interest to declare.
Funding Sources
Bencard Allergie GmbH, Munich, Germany, provided a publication grant. The funder had no role in the design, data collection, data analysis, and reporting of this study.
Author Contributions
J. Fischer conceived, designed, and supervised the study, and wrote the paper in close collaboration with all coauthors. L. Löffelad collected and analyzed the data with NC-HV as part of her doctoral thesis. P. Kranert collected and analyzed the data with SE-HV as part of her doctoral thesis. J. Fischer, S. Volc, and M. Kneilling examined the patients in the Allergy Unit.
Funding Statement
Bencard Allergie GmbH, Munich, Germany, provided a publication grant. The funder had no role in the design, data collection, data analysis, and reporting of this study.
Data Availability Statement
All the data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All the data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding author.
