Abstract
Background
Hymenoptera venom allergy (HVA) is a potentially life‐threatening condition and the second most common cause of severe allergic reactions in children after food allergy. The risk of recurrence of systemic reaction is approximately 32% in untreated children; therefore, these patients need to undergo diagnostic tests and, if indicated, venom immunotherapy (VIT). However real‐life data on VIT in children remain limited.
Methods
We conducted an observational study in a cohort of children and adolescents (n = 40) with HVA and treated with VIT in an Italian tertiary allergy center between 1999 and 2023. Data included demographic features, index reaction, pre‐existing risk factors, timeline of VIT, adverse reactions to VIT, re‐sting outcomes and serological exams were analyzed.
Results
The cohort was predominantly male (87.5%). Adverse reactions to VIT were infrequent, occurred mainly as local reactions, and showed low rates per injection. Among patients who completed ≥3 or ≥5 years of VIT, no severe systemic reactions were observed during treatment and epinephrine was never required. Re‐stings during VIT were common, occurring up to 75.0%, mainly during the maintenance phase. Reactions were mild and limited to cutaneous symptoms. Among patients re‐stung after completion of VIT (9/27 patients, 33%), no systemic reactions were observed and no epinephrine was required. Venom‐specific IgE levels significantly decreased after completion of VIT (p = .004).
Conclusions
The EAACI guidelines provide general recommendations for children, but many are based on limited pediatric evidence. This study provides additional data about the favorable safety profile and efficacy of VIT in children and adolescents with HVA.
Keywords: adolescents, children, duration, efficacy, hymenoptera venom allergy, immunotherapy, safety, venom
Key message.
This real‐life study confirms that venom immunotherapy is safe and effective in children and adolescents with Hymenoptera venom allergy. Adverse reactions were infrequent, predominantly local, and no severe systemic reactions or epinephrine use occurred, even in patients completing long‐term treatment. Re‐stings during and after venom immunotherapy were common but were associated with mild or no reactions, supporting sustained protection after treatment completion. These findings provide pediatric‐specific evidence supporting current guideline‐based use of venom immunotherapy in children.
1. INTRODUCTION
Hymenoptera venom allergy (HVA) is a potentially life‐threatening allergic reaction following a sting from insects of the Apidae or Vespidae families and represents the second most common cause of anaphylaxis in children after food allergy. 1
Despite being a relatively rare condition when compared to other pediatric allergic diseases, HVA considerably affects the quality of life of children and their caregivers. 2
Hymenoptera stings naturally occur during childhood, with re‐sting rates ranging from 43% to 56%, and males more likely to be stung. 3 , 4
Children are more likely to be re‐stung than adults, due to greater outdoor exposure, especially at younger ages, 5 , 6 and they more often experience mild cutaneous reactions, while cardiovascular involvement is uncommon. 3 , 6
Evidence regarding risk factors for severe SRs in children remains limited and sometimes inconsistent. Current evidence does not support atopy as a risk factor for venom allergy, while asthma may be associated with increased severity of SRs rather than disease onset. 7 , 8 The number of stings has also been proposed as a potential risk factor for reaction severity. 9
A diagnostic workup should be performed in patients with a history of systemic reactions beyond generalized skin symptoms or in case of skin reactions if specific risk factors are present, following a Hymenoptera sting. Accurate clinical history is essential, particularly for insect identification, which may be supported by entomological charts. 10
Diagnostic evaluation includes skin tests and laboratory analyses including venom‐specific IgE, and component‐resolved diagnostics. 11 In selected cases, additional tests such as CAP inhibition or basophil activation tests may be required when available, in specialized centers. 12 , 13
VIT is the only disease‐modifying treatment of HVA, and it provides effective protection against reactions following re‐stings.
In untreated children who have experienced a previous moderate‐to‐severe reaction (grade II‐III according to the Mueller classification), the risk of SR upon re‐sting has been reported to be approximately 30%, although estimates vary among pediatric studies. 14 , 15
Current European Academy of Allergy and Clinical Immunology (EAACI) guidelines recommend performing VIT in patients with SR beyond generalized skin symptoms with a documented sensitization to the venom of the culprit insect. In selected cases, VIT may be considered even in children with cutaneous/mucosal systemic reactions or large local reactions when additional factors are present, such as high risk of exposure, significant impairment of quality of life, in those with a clonal mast cell disorder or difficult access to emergency care. 16
There is currently no consensus regarding the most appropriate protocol in the pediatric population. Different protocols can be used for the induction phase, but a conventional protocol (16 weekly subcutaneous injections) appears to be most frequently chosen. 17 The specific regimen used in our center is described in the Methods section.
Despite the above data, evidence on the natural history of HVA and on the safety and efficacy of VIT in children remains limited compared with adults, although recent long‐term real‐life pediatric studies have started to address this gap. 18
Our study aims to further expand current knowledge on pediatric HVA by providing additional real‐life data on the safety and efficacy of VIT in children and adolescents from a European tertiary allergy center.
2. METHODS
2.1. Study design and study cohort
This is a non‐interventional, observational, monocentric study, with no commercial purposes, conducted at the Allergy Department of the Integrated University Hospital of Verona in Italy.
The study included children and adolescents who were advised to start VIT at our center between 1999 and 2023, following a systemic allergic reaction to Hymenoptera sting. The hospital serves both rural and urban populations. Demographic data and clinical information were collected for each patient, including characteristics of the initial reaction, diagnostic findings, VIT course, adverse reactions, and outcomes after re‐stings. Diagnostic testing and VIT were performed using standardized commercially available venom extracts available in routine clinical practice at our center during the study period.
All procedures were part of routine clinical practice and conducted in accordance with current EAACI recommendations. 16 Written informed consent for diagnostic procedures and treatment was obtained from all patients' parents or legal guardians.
2.2. Diagnosis
The diagnosis of HVA was established according to current EAACI guidelines. 16 All patients underwent a comprehensive diagnostic work‐up including detailed clinical history, skin testing, and laboratory investigations.
A structured clinical history was collected for each patient, including detailed information on the index reaction. Attention was paid to the identification of the culprit insect; when needed, an entomological chart was used to facilitate recognition. Reaction severity was graded according to the Mueller classification. Information on previous reactions or subsequent re‐stings was also collected.
Additional contextual factors were systematically recorded, including place of residence (e.g. rural areas, distance from emergency departments) and the presence of comorbidities.
Skin tests were performed in accordance with EAACI recommendations using commercially available venom extracts (Anallergo, Italy). Skin prick tests were performed at a concentration of 100 μg/mL, then intradermal tests at concentrations of 0.1 and 1 μg/mL for the following venoms: Apis mellifera, Vespula spp., Polistes dominula, and Vespa crabro. A wheal diameter at least 3 mm was considered positive.
Laboratory investigations included basal tryptase, total serum IgE, venom specific IgE and component‐resolved diagnostics, performed using ImmunoCAP (Thermo Fisher Scientific, Uppsala, Sweden). Venom‐specific IgE was considered positive at values ≥0.35 kUA/L. Total serum IgE was measured as part of the routine allergy work‐up performed in all patients, although it was not used as a diagnostic criterion for Hymenoptera venom allergy. The following allergenic components were tested: rApi m 1, rApi m 2, rApi m 3, rApi m 5 and rApi m 10 for Apis mellifera; rVes v 1 and rVes v 5 for Vespula spp.; rPol d 5 for Polistes dominula; and venom specific IgE for Vespa crabro Sensitization to cross‐reactive carbohydrate determinants (CCD) was assessed using MUXF3 (bromelain). In patients showing double positivity of venom specific IgE to Vespula and Polistes, component‐resolved diagnostics were used to support interpretation of sensitization patterns. Predominant sensitization to rVes v 1 and/or rVes v 5 was considered suggestive of primary sensitization to Vespula spp., whereas sensitization to rPol d 5 was evaluated in conjunction with the overall molecular profile and clinical history, in accordance with current literature and EAACI recommendations. 16 In selected cases, when clinical history and routine diagnostic tests were inconclusive in identifying the culprit insect, CAP inhibition was performed.
2.3. VIT protocol
All patients underwent subcutaneous VIT using a 7‐week build‐up cluster protocol. During the build‐up phase, increasing doses of venom were administered weekly starting from 0.01 μg and reaching 100 μg, with intermediate cumulative doses of 5, 10, 20, 40, and 70 μg, in line with the manufacturer's induction scheme (Table S1).
During the maintenance phase, injections of 100 μg were administered every 4 weeks during the first year of treatment, every 5–6 weeks during subsequent years and progressively extended up to every 8 weeks by the fifth year of therapy, according to clinical tolerance and routine practice.
All patients were kept under medical observation for at least 30 min after each VIT administration to monitor for potential adverse reactions.
Throughout the study period, venom immunotherapy was performed using commercially available venom extracts routinely adopted in our center, in line with contemporary clinical practice and EAACI recommendations. The following commercially available venom extracts were used: purified aqueous extracts for Apis mellifera (Stallergenes Greer, Antony, France) and Vespula spp. (Allergy Therapeutics, Worthing, United Kingdom), and a depot L‐tyrosine‐adsorbed allergoid extract for Polistes dominula (Anallergo, Florence, Italy).
2.4. Adverse reactions
Adverse reactions (ARs) occurring during venom immunotherapy were systematically evaluated and classified according to their clinical presentation. Local reactions (LRs) were defined as erythema and swelling confined to the injection site, whereas large local reactions (LLRs) were defined as swelling exceeding 10 cm in diameter and lasting more than 24 h. Systemic reactions (SRs) were defined as the occurrence of symptoms beyond the injection site involving one or more organ systems.
For each adverse reaction, the following variables were recorded: clinical symptoms, treatment required, phase of the protocol, injection number at which the reaction occurred, and the venom extract administered.
The severity of both systemic reactions to index stings and systemic reactions occurring during VIT was graded according to the Mueller classification. 19
2.5. Statistical analysis
Descriptive statistics were used to summarize demographic and clinical characteristics of the study population. Categorical variables were reported as absolute numbers and percentages, while continuous variables were expressed as median and range. Comparisons between paired continuous variables were performed using the Wilcoxon signed‐rank test, whereas comparisons between independent continuous variables were conducted using the Mann–Whitney U test. Associations between categorical variables were evaluated using Fisher's exact test, which was chosen in preference to the chi‐square test due to small sample sizes. All statistical tests were two‐sided, and a p‐value <0.05 was considered statistically significant. All analyses were conducted using Stata version 18 (StatCorp, College Station, TX, USA) and Python (SciPy, statsmodels, scikit‐learn).
3. RESULTS
3.1. Patients characteristics
A total of 40 children and adolescents were enrolled, most of them male (n = 35, 87.5%).
Six of them (15.8%) presented with a history of atopy, mainly allergic asthma and rhino‐conjunctivitis.
The median baseline serum tryptase level was 4.5 μg/L (range 2–14 μg/L, normal value <11.40 μg/L). Only one child had hypertryptasemia (13.9 μg/L), with mastocytosis and hereditary alpha tryptasemia excluded by bone marrow biopsy and genetic testing, respectively.
The median value of total IgE was 368 kU/L (range 37–2689 kU/L).
Severity of initial reactions was assessed using Mueller scale (grade 1–4): grade 1 was observed in 7 children (17.5%), grade 2 in 5 (12.5%), grade 3 in 23 children (57.5%), and grade 4 in 4 (10%).
One patient was treated for LLR because he lived in a rural area far from the nearest emergency department, which contributed to the clinical decision to start VIT. Among patients with Mueller grade I reactions, the decision to initiate VIT was based on individualized specialist assessment, considering factors such as residence in remote mountainous areas with limited access to emergency care and increased risk of exposure to hymenoptera.
Six patients (16.2%) required epinephrine to manage the index reaction; all were classified as grade 3 or 4, and three children experienced loss of consciousness (grade 4).
No association was observed between baseline serum tryptase levels and reaction severity (Mueller grade 1–2 vs. 3–4; p = .17). Similarly, atopy was not associated with reaction severity (Fisher's exact test, p = 1.00).
When patients were stratified according to the duration of venom immunotherapy, 27 children (67.5%) completed at least 5 years of VIT, 8 (20.0%) received VIT for 3–4 years, and 5 (12.5%) discontinued treatment before 3 years. None of these patients discontinued VIT because of treatment‐related adverse reactions. Reasons for discontinuation included transfer to another allergy center and other non‐medical causes. The proportion of male patients was high across all groups, particularly among those completing ≥5 years of VIT (92.6%). Median age at VIT initiation progressively increased with longer treatment duration (8 years in patients treated <3 years vs. 11 years in those treated ≥5 years). A high proportion of patients in all groups had experienced severe initial systemic reactions (Mueller grade III–IV), with no substantial differences across duration categories.
Figure 1 details the distribution of venom extracts used for immunotherapy across treatment‐duration groups, together with the main demographic characteristics and index reaction severity.
FIGURE 1.
Baseline characteristics of study population stratified by venom immunotherapy (VIT) duration. Patient distribution, sex, median age at VIT initiation, frequency of severe index reactions (Mueller grades III–IV), and venom prescribed for immunotherapy are shown for each treatment‐duration group. Created with BioRender.com.
3.2. Safety of VIT
The occurrence of adverse reactions was evaluated in all 40 patients who initiated VIT. Eleven patients (27,5%) experienced adverse reactions during treatment, all occurring during the build‐up phase. No patient discontinued VIT because of adverse reactions. None of the five patients who discontinued VIT before completing 3 years experienced adverse reactions during treatment or reported re‐stings during treatment. Additional subgroup analyses were subsequently performed according to treatment duration (≥3 years and ≥5 years). When the analysis was restricted to patients who completed at least 3 years of venom immunotherapy, adverse reactions were reported in 3 of 8 patients (37.5%) in the ≥3‐year group and in 8 of 27 patients (29.6%) among those completing ≥5 years of treatment.
Among patients experiencing adverse reactions, local reactions were reported in 33.3% of patients in the ≥3‐year group and in 50.0% of those completing ≥5 years of VIT, while the remaining reactions consisted of large local reactions or mild systemic symptoms.
A total of 377 injections were administered in patients treated for ≥3 years and 1783 injections in those completing ≥5 years of VIT. The rate of local reactions per injection was 7.96% and 11.0%, respectively. No severe systemic reactions were observed, and epinephrine was never required.
All these reactions were well managed through premedication with oral antihistamine and/or topical corticosteroids. None of these patients needed pre‐treatment with omalizumab to increase VIT tolerance nor a modification of the induction scheme.
The final dose of 100 μg of venom was successfully reached in all patients.
In an exploratory analysis restricted to patients who completed at least 5 years of venom immunotherapy, no statistically significant differences were observed between patients with and without adverse reactions in terms of baseline serum tryptase levels (p = .073), history of atopy (p = .28), severity of the index sting reaction, age at VIT initiation, or type of venom extract used (all p > .05).
Data on adverse reactions to VIT are shown in Table 1.
TABLE 1.
Adverse reactions to VIT.
| VIT 3–4 years (n = 8) | VIT ≥5 years (n = 27) | |
|---|---|---|
| Patients with ≥1 AR, n (%) | 3 (37.5%) | 8 (29.6%) |
| Patients with LR, n (%) | 1/3 (33.3%) | 4/8 (50.0%) |
| VIT performed | 1 Apis M. |
2 Apis M. 2 Polistes D. |
| Total injections, n | 377 | 1783 |
| Total LR, n | 30 | 196 |
| LR per injection, % | 7.96% | 11.0% |
| Patients with large local reactions (LLR), n (%) | 1/3 (33.3%) | 1/8 (12.5%) |
| VIT performed | 1 Polistes D. | 1 Apis M. |
| Patients with systemic reactions, n (%) | 1/3 (33.3%) | 3/8 (37.5%) |
| Transient and mild hypotension | 0 | 1 (Polistes D.) |
| Headache | 1 (Polistes D.) | 0 |
| Weakness | 0 | 1 (Vespula spp.) |
| Flushing | 0 | 1 (Apis M.) |
3.3. Effectiveness of VIT
3.3.1. Re‐stings during VIT
Among patients who completed at least 3 years of venom immunotherapy, 6/8 (75.0%) experienced at least one re‐sting during treatment, compared with 18/27 (66.7%) among those completing at least 5 years. The median time from VIT initiation to re‐sting was 12 months (range 5–24) in the ≥3‐year group and 24 months (range 6–60) in the ≥5‐year group.
Re‐stings occurred during the build‐up phase in 2/6 patients (33.3%) in the ≥3‐year group and in 2/18 patients (11.1%) in the ≥5‐year group, whereas most re‐stings occurred during maintenance (66.7% and 88.9%, respectively).
All re‐stings were concordant with the venom used for VIT in the ≥3‐year group (6/6, 100%), while concordance was observed in 16/18 (88.9%) of re‐stings in the ≥5‐year group; two re‐stings (11.1%) were discordant.
Clinical reactions upon re‐sting were infrequent and mild. Two patients in the ≥3‐year group (2/6, 33.3%) and one patient in the ≥5‐year group (1/18, 5.6%) reported a reaction, all classified as Mueller grade I and managed with oral antihistamines and oral corticosteroids. No moderate‐to‐severe systemic reactions were recorded and no epinephrine was required.
Furthermore, in two asymptomatic children, an adrenaline autoinjector was administered by school staff as a precautionary measure.
Data about re‐sting during VIT are summarized in Table 2.
TABLE 2.
Re‐stings during venom immunotherapy according to treatment duration.
| VIT 3–4 years (n = 8) | VIT ≥5 years (n = 27) | |
|---|---|---|
| Patients with ≥1 re‐sting during VIT, n (%) | 6 (75.0%) | 18 (66.7%) |
| Time from VIT initiation to re‐sting, median (range), months | 12 (5–24) months | 24 (6–60) months |
| VIT phase at re‐sting, n/N (%) | ||
| Build‐up phase | 2/6 (33.3%) | 2/18 (11.1%) |
| Maintenance phase | 4/6 (66.7%) | 16/18 (88.9%) |
| Re‐sting concordance with VIT venom, n/N (%) | ||
| Concordant | 6/6 (100%) | 16/18 (88.9%) |
| Discordant | 0/6 (0%) | 2/18 (11.1%) |
| Patients with a reaction upon re‐sting, n/N (%) | 2/6 (33.3%) | 1/18 (5.6%) |
| VIT phase |
|
|
| Mueller grade (I–IV) | Grade I | Grade I |
| Treatment | Oral antihistamines and oral corticosteroids | Oral antihistamines and oral corticosteroids |
3.3.2. Re‐stings after completion of venom immunotherapy
Among patients who completed at least 5 years of venom immunotherapy, 9 out of 27 (33.3%) experienced at least one re‐sting after VIT discontinuation. Re‐stings were concordant with the venom used for immunotherapy in 6/9 cases (66.7%), while 3/9 re‐stings (33.3%) were discordant. Notably, none of the patients experienced clinical reactions upon re‐sting after VIT completion (0/9), demonstrating that a good protection profile was achieved. Data about re‐sting after completion VIT are summarized in Table 3.
TABLE 3.
Re‐stings after completion of venom immunotherapy.
| VIT ≥5 years (n = 27) | |
|---|---|
| Patients with ≥1 re‐sting after VIT, n (%) | 9 (33.3%) |
| Re‐sting concordance with VIT venom, n/N (%) | |
| Concordant | 6/9 (66.7%) |
| Discordant | 3/9 (33.3%) |
| Patients with a reaction upon re‐sting, n/N (%) | 0/9 (0%) |
3.3.3. Venom‐specific IgE
Venom‐specific IgE levels directed against the culprit venom were evaluated before and after completion of venom immunotherapy. When analyses were restricted to patients with paired pre‐ and post‐treatment measurements, a significant reduction in venom‐specific IgE levels was observed after VIT completion (Wilcoxon signed‐rank test, p = .004). Consistent trends toward IgE reduction were observed across individual venom types; however, analyses stratified by venom were underpowered and did not consistently reach statistical significance. In an exploratory analysis including all available venom‐specific IgE values analyzed as independent samples, post‐treatment IgE levels were significantly lower than baseline values (Mann–Whitney U test, p = .0098), further supporting a global decrease in IgE levels following VIT. Overall, median venom‐specific IgE levels decreased from 15.4 kUA/L (range 0.35–100) before VIT to 1.73 kUA/L (range 0.34–27.2) after treatment. Similar reductions were observed in the individual venom groups, with median values decreasing from 25.0 to 5.56 kUA/L for Apis mellifera, from 24.6 to 7.2 kUA/L for Vespula spp., and from 12.5 to 1.17 kUA/L for Polistes dominula. The distribution of venom‐specific IgE levels before and after VIT completion is shown in Figure 2.
FIGURE 2.
Distribution of venom‐specific IgE levels before and after completion of venom immunotherapy. Boxplots show venom‐specific IgE levels measured before initiation of venom immunotherapy (PRE‐VIT) and after treatment completion (POST‐VIT). The central line represents the median, boxes indicate the interquartile range, and circles represent outliers. A significant reduction in venom‐specific IgE levels was observed after completion of venom immunotherapy.
4. DISCUSSION
This real‐life study provides additional evidence supporting the safety and effectiveness of venom immunotherapy in children and adolescents with Hymenoptera venom allergy treated in a tertiary allergy center. Data available about these aspects are still scarce, and most of them come from certain geographical areas.
Our study cohort showed a marked male predominance, consistent with previous pediatric studies on Hymenoptera venom allergy. 20 This epidemiological finding is likely related to greater outdoor exposure, and consequently increased sting risk among boys. 21
In the adult population a male predominance is almost invariably observed in cohorts of patients with HVA, and male sex was identified as a predictor of more severe reactions in different studies. 8
Atopy was observed in a minority of patients, mainly in the form of allergic asthma and rhino‐conjunctivitis.
Current evidence suggests that atopy is not a risk factor for the development of Hymenoptera venom allergy, although asthma may be associated with increased severity of systemic reactions rather than with disease onset. 5 , 22 In our cohort, no significant association between atopy and either the occurrence or the severity of systemic reactions was observed.
Baseline serum tryptase has been proposed as a potential risk factor for severe reactions in children with HVA. Previous pediatric studies reported increased risk of systemic reactions in children with higher baseline tryptase levels, even within normal ranges. 7 , 23
However, in our cohort, no significant association between baseline tryptase levels and severity of SRs was found.
Our results support the favorable safety profile of VIT in children and adolescents.
Adverse reactions were uncommon and consisted mainly of local reactions, whereas systemic reactions were mild and successfully managed with oral antihistamines and/or corticosteroids. No patient required omalizumab pre‐treatment, modification of the induction protocol, or epinephrine administration during VIT. Importantly, the 7‐week cluster build‐up protocol was well tolerated, supporting its feasibility in the pediatric population when performed in a specialized center.
These findings are consistent with previous pediatric studies reporting low rates of systemic reactions during VIT, which were more frequent during the build‐up phase with bee venom, and localized reactions such as redness, swelling, itching, and tenderness around the injection site, expected in approximately one‐third of pediatric patients. 24 , 25 , 26
No significant associations were observed between adverse reactions to VIT and baseline clinical and laboratory characteristics, although the study may have been underpowered to detect weaker associations given the relatively small sample size.
The effectiveness data were also encouraging. Re‐stings during VIT were relatively common, reflecting real‐life exposure in children and adolescents, but reactions were infrequent and exclusively mild.
Only one patient in the ≥5‐year group experienced a Mueller grade I reaction when re‐stung during VIT, and no moderate‐to‐severe systemic reactions occurred. Among patients re‐stung after completion of VIT, no systemic reactions were observed, suggesting sustained long‐term protection after treatment discontinuation.
Two children, despite the absence of symptoms, were administered an adrenaline auto injector as a precautionary measure by their caregivers, highlighting the significant psychological burden associated with Hymenoptera venom allergy in children and their caregivers. Fear of severe reactions may persist even during or after successful VIT and can influence post‐sting management behaviors. This observation underlines the importance of structured patient education, individualized emergency action plans, and continuous reassurance during follow‐up.
Studies currently available show similar results. 27
The decision to discontinue VIT in children remains challenging, particularly in countries where sting challenge testing is not admitted, such as Italy.
Notably, 33.3% of the study cohort (9/27) experienced a re‐sting after completing VIT, 66.7% of these re‐stings were concordant with the venom used for immunotherapy, and no systemic reactions or epinephrine use were recorded. To support this observation, specific IgE levels were reassessed at the end of VIT, showing a clear reduction in sIgE values for the culprit Hymenoptera.
Another important aspect of pediatric VIT concerns the duration of long‐term protection after treatment discontinuation. Data addressing this issue in children remain limited.
At our center patients and caregivers are routinely encouraged to report subsequent re‐stings after the discontinuation of VIT for the subsequent years, with the aim to continue long‐term regular monitoring. For the purposes of this study, additional follow‐up information was also collected by contacting patients who had completed VIT several years earlier on an exceptional basis. This study has several limitations, including its retrospective design, the inclusion of some parent‐reported events, potential recall bias, and the relatively small sample size. In addition, because the study spans more than two decades, changes in product availability, diagnostic platforms, and routine clinical practice over time cannot be completely excluded and should be considered when interpreting the findings.
Nevertheless, this study contributes to the limited real‐life data on the natural history of HVA and VIT in childhood. Larger prospective multicenter studies are needed to better define risk factors, long‐term protection, and optimal treatment strategies in this population and support the development of specific pediatric guidelines.
5. CONCLUSION
There is a lack of real‐life data in literature regarding management of HVA in children. Although fatalities mainly occur in adults, the potential risk of death due to HVA is also present in children. Understanding the natural history and epidemiology of HVA is essential for improving preventive and therapeutic strategies.
The present study confirmed safety of VIT in pediatric patients, with a low rate of adverse reactions happening mostly during the build‐up phase.
Indeed, VIT is confirmed as the only treatment able to modify the natural history of HVA, protecting patients with IgE‐mediated allergies from systemic reactions after subsequent stings and improving patients' quality of life.
AUTHOR CONTRIBUTIONS
Francesca Norelli: Conceptualization; writing – original draft; writing – review and editing; investigation. Bianca Olivieri: Writing – review and editing; supervision; methodology; formal analysis; data curation; visualization. Valentina Gueli: Conceptualization; writing – review and editing; writing – original draft; investigation; visualization. Patrizia Bonadonna: Writing – review and editing; supervision; conceptualization; project administration; validation; resources. Francesco Taus: Methodology; formal analysis; data curation. Giovanna Sfriso: Writing – review and editing. Francesca Nalin: Writing – review and editing. Giorgia Marta: Writing – review and editing. Elisa Olivieri: Resources; writing – review and editing.
FUNDING INFORMATION
The authors have nothing to report.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Supporting information
Table S1. Induction schedule for subcutaneous Hymenoptera venom immunotherapy used in our center. The table details vial concentrations, administered doses, cumulative venom doses, and timing of injections during the build‐up phase, according to our routine clinical practice, until achievement of the maintenance dose of 100 μg.
Gueli V, Norelli F, Taus F, et al. Venom immunotherapy in children and adolescents: Efficacy and safety in an Italian tertiary allergy center. Pediatr Allergy Immunol. 2026;37:e70466. doi: 10.1111/pai.70466
Editor: Marina Atanaskovic‐Markovic
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Induction schedule for subcutaneous Hymenoptera venom immunotherapy used in our center. The table details vial concentrations, administered doses, cumulative venom doses, and timing of injections during the build‐up phase, according to our routine clinical practice, until achievement of the maintenance dose of 100 μg.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.