Venom immunotherapy protocols in the pediatric population: how to choose?

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Introduction
Anaphylaxis from insect stings is one of the main causes of anaphylaxis in adults (1) and in children (2).Venom immunotherapy (VIT) is, to date, the only available long-term, natural history-modifying treatment for Hymenoptera venom allergy (HVA), and it is currently recommended mostly for sensitized patients with a history of systemic reactions (SR) after insect stings (1)(2)(3).
This recommendation is also indicated in the pediatric age (4), in which the risk of future reactions following a previous moderate-to-severe field sting is approximately 32% in untreated children (p = 0.007) (5).As for adults, in some specific pediatric cases, VIT can be suggested even more in the presence of risk factors (e.g., increased risk of a sting as in beekeepers' children, impaired quality of life, such as in the case of anxiety, remoteness from the emergency department) (4).In children with reported large local reactions (LLR, a swelling >10 cm and lasting >24 h), VIT is generally not recommended (5,6).
Over the decades, VIT has proved to be safe and effective for all ages and for different HVA, providing 77%-84% effectiveness in the case of honeybee allergy and up to 91%-96% in vespid allergy (3).
In 1925, Braun et al. (7) described the first attempt of VIT with honeybee venom obtained from the insect's whole body.This type of therapy was used until the 1970s, when the first report with whole venom (8) and the first randomized controlled study (9) were published by Busse et al. and Hunt and al., respectively.In 1974, Lichtenstein et al. (10) performed the first desensitization with honeybee venom in pediatrics, in a fouryear-old boy who was previously treated with whole-body extract without efficacy.In a period of two months, after showing repeated SR, the child reached the maintenance dose of 100 mcg, and he showed no SR at an in-hospital sting challenge.
One of the first studies on pediatric ages was conducted by Chipps et al. (11) on a group of 44 children (4-14 years) with a conventional protocol.The maintenance dose of 100 mcg was reached in six weeks, with a "modified-rush" build-up on day one (from 0.01 to 1 mcg).In this cohort, three (6.8%)children presented a SR, and only one was severe enough to require adrenaline treatment.An in-hospital sting challenge was conducted 15 weeks after starting VIT, showing only one reaction in a child with low IgG titers, demonstrating the efficacy and safety of this procedure in children.
In 2017, an extensive systematic review and meta-analysis was published on VIT by Dhami et al. (12).The authors concluded that VIT reduced the risk of SR (odds ratio, OR = 0.08, 95% confidence interval, CI 0.03-0.26)and improved quality of life (risk difference = 1.41, 95% CI 1.04-1.79).Adverse effects were reported in both the build-up and maintenance phases, but most of them were mild, and no fatalities were recorded.Among these studies, there were only three specifically evaluating VIT in childhood (5, 13, 14) and they were all considered with a low-moderate quality assessment.
Similar results were observed in a Cochrane review published by Boyle et al. in 2012 (15).VIT improved quality of life (mean difference in favor of VIT 1.21 points on a 7-point scale, 95% CI 0.75-1.67)and prevented both LLR (relative risk, RR = 0.41, 95% CI 0.24-0.69)and SR (RR = 0.10, 95% CI 0.03-0.28).VIT was generally well tolerated, with a risk of SR of 9.3% in treated patients vs. 0.7% in the placebo group, higher for honeybee venom (14.2%) than for wasp venom (2.8%).
In clinical practice, tests becoming negative happens only for a small percentage of patients (16).Studies recommend performing VIT for at least 3-5 years and maintaining a follow-up after suspending it (17).In specific cases, it may be suggested to continue VIT for more than 5 years, such as in the presence of specific risk factors like SR from field sting during VIT (4).
Venom immunotherapy (VIT) is, to date, the only available long-term treatment for HVA.Recommendations provided by scientific societies may also be applied to childhood, though no international pediatric-specific documents have been published for the management of HVA.In the last years, despite the huge amount of literature on VIT being produced, most of the studies evaluate only adult populations.Some of these also include children, but often, pediatric data are not separately analyzed.In the most recent years, some scientific groups have specifically studied the indications, safety, and efficacy of VIT in childhood.Nonetheless, it is still difficult to compare those studies since they analyze different VIT regimens in heterogeneous populations.In this review, we aim to dissert and evaluate relevant articles with specific data on VIT in pediatric ages.

Materials and methods
We performed a literature search in Medline through PubMed using default keywords related to pediatric Hymenoptera Venom Allergy and Allergen Immunotherapy.Original studies and review articles, with a focus on meta-analyses and randomized controlled trials in English, were identified up to February 1st, 2023.

Results
VIT can be carried out with different protocols, all of which have already been proven safe and effective in pediatric ages.VIT involves a build-up phase with progressively increasing doses (starting from 0.001 mcg to 0.1 mcg) of the chosen venom until the maintenance dose is reached, which is usually 100 mcg (18,19).A starting dose of 1 mcg may be considered safe as well (20).
As underlined by Golden (21), there is no consensus on the actual duration of the build-up phase, according to existing literature, but the main build-up phase protocols are usually defined (1) conventional: months, (2) clustered or semi-rush: weeks, (3) rush or ultra-rush: days.
During maintenance, the achieved dose should be injected every four weeks in the first year and then every six to eight weeks in the following years, although some authors considered 12-week or even longer intervals between doses safe (22-24).A higher maintenance dose at 150-200 mcg may be prescribed in high-risk patients, e.g., if a patient had a SR at re-sting while on VIT (3,25), whereas a lower dose (50 mcg) has been suggested sufficient for children (26)(27)(28).
Especially in some countries, as highlighted in an editorial by Golden (29), the protocol choice may rely more on healthcare system organization than on scientific or clinical reasons.Rush/ ultra-rush protocols are usually preferred to concentrate evaluations and therapies in a few days, in countries where healthcare is provided in specialized centers, and upon the patient's request or need (e.g., rapid achievement of maintenance dose, low compliance with conventional protocol).Even though literature has already proven the safety and efficacy of rush and ultra-rush protocols (30), conventional and clustered protocols seem to be generally preferred in clinical practice.In a survey conducted in the United States (29, 31), most allergists preferred conventional (64%) compared to eight-week (31%) and rush protocols (5%).In the United Kingdom, allergists prefer conventional protocols (92%) while only 25% of respondents have ever used clustered or rush/ultra-rush protocols (32).In another survey, Martínez-Cañavate et al. (33) analyzed one of the largest groups of children treated with VIT in Spain.In most cases, a conventional protocol was chosen (68.2%), followed by rush (18.5%), clustered (11.8%), and ultra-rush (1.5%).
A summary of pediatric studies reporting VIT protocols is shown in Table 1, and some examples are discussed below.

Conventional protocols
In a group of 78 children with a history of SR (mild 10.4%, moderate 72.7%, severe 11.6%) studied by Albuhairi et al., treatment with a conventional protocol resulted in 9% of SR during VIT (34).None of those were severe, with a 0.2% SR rate per injection.Twenty-one children were re-stung during VIT, and 12 (57%) showed a local reaction, one (5%) showed a SR, and eight (38%) showed no reactions at all.No statistically  35) which analyzed 107 children with at least one SR after a Hymenoptera sting, treated with a conventional protocol.Overall, 52 (48.5%) children showed an allergic reaction during VIT: 40 (37.4%)local reactions, seven (6.5%) SR, and five (4.7%)LLR.Most local reactions occurred during the build-up phase (p < 0.001) and were more frequently observed with wasp VIT (p = 0.047).Regarding SR, these were mostly mild-moderate (grades 1-3 according to Mueller classification) and occurred more frequently for honeybee VIT (p = 0.031).Of the 68 children whose parents completed a follow-up survey, a re-sting during or after VIT occurred in 33 (48.5%) subjects, and 24 (72.7%)showed reactions that were more frequently local.Preexisting asthma was the only risk factor for LLR and SR in a multivariate analysis (p = 0.016).

Clustered and semi-rush protocols
In a study by Konstantinou et al., 54 children with at least one anaphylactic reaction to Hymenoptera venom were treated with a modified clustered protocol, consisting of a build-up phase lasting roughly 5 weeks and reaching a maintenance dose of 50 mcg (28).The maintenance dose was given every 4 weeks for the first year, then every 5 weeks for the second and third years, and every 6 weeks for the last two years.One child was lost to follow-up.Almost all remaining children (52/53) tolerated the protocol without side effects except for mild injection site reactions.Two children (3.8%) showed SR during VIT, and in these cases, the maintenance dose was increased to 100 mcg.Twenty-one (41.2%) of the 51 children who completed the modified-clustered protocol have been re-stung at least once with no SR reported, thus demonstrating the safety of clustered protocol and the efficacy even with a lower maintenance dose.
In another study by Carballada González et al., 21 children who were mostly allergic to honeybees (80.9%) and treated with a semirush protocol with one or two weekly injections of nine increasing doses of venom, an SR rate of 9.5% was reported (2/21 children) (36).Seven of 21 patients (33%) were re-stung after VIT, and none showed an SR, confirming the efficacy of the intervention.

Rush and ultra-rush protocols
In a small study by Glaeser et al., three of the included 19 patients (15.8%) showed an anaphylactic reaction to rush honeybee venom immunotherapy (37).Nonetheless, all children could continue VIT with a modified up-dosing protocol and did not experience further side effects, but no conclusions can be drawn due to the small sample size of the study.
Another study by Stoevesandt et al. analyzed the safety of a 3or 5-days rush protocol in a cohort of 71 children/adolescents and 981 adult controls (38).In this work, 5-day build-up protocols (p = 0.011; OR 2.64; CI 1.25-5.57)and honeybee VIT (p = 0.039; OR 2.25; CI 1.04-4.87)were associated with an increased risk of SR during VIT.While children usually may show a lower rate of SR than adults, in this study, SR were reported in 6.9% of children compared to 2.5% of adults (p = 0.046).However, all pediatric SR cases were mild/moderate (grades 1-2), and this discrepancy was attributed by the authors to the higher frequency of honeybee allergy in children (32.4%) than in adults (14.7%) (p < 0.001).
Two studies on different populations used the same ultra-rush protocol.Birnbaum et al. (43) showed a 10.8% rate of SR in 51 children (74.5% with yellow jacket allergy), while Nittner-Marszalska et al. (39) reported a 3.7% rate in 134 children (51.5% with honeybee allergy).In both studies, the risk of severe SR during VIT significantly increased with the severity of the first reaction.Besides honeybee allergy, no other risk factors were found to be statistically significant.
In another modified ultra-rush protocol study in a cohort of 38 children by Steiss et al. (42) no SR was reported, and most children (58.1%) showed no reactions at all.In a more recent retrospective study by the same group, performed on a larger cohort, the same modified ultra-rush protocol was demonstrated to be safe as well, despite a 2.2% rate of mild SR (40).
Analyzing the various published studies, it can be seen that some defined ultra-rush protocols are really similar compared to others labeled as rush.

Comparison between different protocols
In a study by Johnston et al., ultra-rush and conventional protocols were compared in a small cohort of 14 pediatric honeybee-allergic children.Six received ultra-rush honeybee VIT and showed a lower rate of SR (16%) compared with the conventional group (25%) while requiring fewer injections, hospital visits, and saving travel distance (44).
Similarly, in a study by Confino-Cohen et al., rush and conventional protocols were compared in children (45).Eighty-four out of 127 children were treated with rush VIT and compared to those treated with conventional VIT.Slightly more SR (23.2% vs. 19.0%)were reported during the build-up phase in the conventional group, but this difference was not statistically significant.No severe SR was reported, and the need for adrenaline was more frequent in the conventional group (9.3% vs. 4.7%, not statistically significant).Nonetheless, a significantly higher proportion of children in the rush group reached the maintenance dose compared to the conventional protocol (98.8% vs. 90.7%).Authors conclude that rush protocols are safe in childhood and more efficient than conventional protocols in terms of compliance, despite being less frequently prescribed in the United States.

Omalizumab pretreatment
Droitcourt et al. (46) have pretreated three male teenagers undergoing VIT with omalizumab.All had severe anaphylaxis with the Hymenoptera sting (two by honeybee and one by wasp) and reported SR during the build-up phase of a rush VIT protocol.Pretreatment with omalizumab 2 and 4 weeks before VIT onset allowed to complete build-up and reach the maintenance dose without SR.

Conclusion
In children, the occurrence of SR with conventional VIT may be similar to other protocols, although conventional VIT appears to be more frequently chosen in clinical practice than other protocols.However, greater severity of reported allergic reactions may not be excluded with faster protocols.It is also important to underline the difficulty in comparing published studies on different regimens, where there seems to be high variability among different experiences.
To date, it is still difficult to recommend one VIT protocol over another in children.The choice of protocol must always be discussed with caregivers, even though sometimes, they may be dependent on local expertise.Future extensive data coming from high-quality studies, including, e.g., the potential role of component-resolved diagnostics, of the molecular identification of allergens in the extracts used for VIT or of specific biomarkers may help tailor the choice of protocol on patients in a precision medicine perspective.

TABLE 1
Summary of pediatric studies reporting VIT protocols.