Front. Pediatr. Frontiers in Pediatrics Front. Pediatr. 2296-2360 Frontiers Media S.A. 10.3389/fped.2023.1192081 Pediatrics Opinion Venom immunotherapy protocols in the pediatric population: how to choose? SarettaFrancesca 1 † GiovanniniMattia 2 3 † PessinaBenedetta 2 * ‡ BarniSimona 3 LiccioliGiulia 3 SartiLucrezia 3 TomeiLeonardo 2 FaziCamilla 2 PegoraroFrancesco 2 VallerianiClaudia 4 RicciSilvia 2 5 AzzariChiara 2 5 NovembreElio 2 MoriFrancesca 3 Pediatric Department, Latisana-Palmanova Hospital, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy Department of Health Sciences, University of Florence, Florence, Italy Allergy Unit, Meyer Children's Hospital IRCCS, Florence, Italy Immunology Laboratory, Meyer Children's Hospital IRCCS, Florence, Italy Immunology Unit, Meyer Children's Hospital IRCCS, Florence, Italy

Edited by: Marzia Duse, Sapienza University of Rome, Italy

Reviewed by: Jernej Zavrsnik, Health Center dr Adolf Drolc, Slovenia Linda Cox, Consultant, United States

 Correspondence: Benedetta Pessina benedetta.pessina@unifi.it

These authors share first authorship

ORCID Benedetta Pessina orcid.org/0000-0002-1387-3463

 07092023 2023 111192081 22032023 05062023 © 2023 Saretta, Giovannini, Pessina, Barni, Liccioli, Sarti, Tomei, Fazi, Pegoraro, Valleriani, Ricci, Azzari, Novembre and Mori. 2023Saretta, Giovannini, Pessina, Barni, Liccioli, Sarti, Tomei, Fazi, Pegoraro, Valleriani, Ricci, Azzari, Novembre and Mori

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 precision medicine hymenoptera venom allergy protocols pediatrics venom immunotherapy section-at-acceptancePediatric Immunology 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 (1–3).

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 four-year-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 (26–28).

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.

Summary of pediatric studies reporting VIT protocols.

Study Population Protocol Reaction as per Notes
patient injection
Conventional protocols
Albuhairi et al. (34)Ann Allergy Asthma Immunol 2018ONLYCHILDREN 78 children (5–18 y/o)M: 60—F: 188 y/o at sting9 y/o at VIT10.4% mild cutaneous5.3% LLR (≥5 cm)72.7% moderate SR11.6% severe SR75.3% treated with mixed venom extracts Build-up: weekly increases starting from 0.1 mcg (8–10 weeks)Maintenance: 100 mcg (every 4–6 weeks) 9% SR (7/78)- 5/7 grade 1- 2/7 grade 26/7 immediate (≤30 min)1/7 delayed4/7 during build-up 3/7 during maintenance 0.2% SR/injection (3564 doses)5/7 required therapyNo adrenalineNone had history of severe SR at sting Risk factor: male sex (for moderate/severe field SR) (p = 0.008)No risk factors for VIT-SR (atopy, age, sex, asthma, venom)21 (27%) re-stung during VIT (one in build-up):- 1 (5%) moderate SR (hives and cough)- 12 (57%) local reactions- 8 (38%) no reactions
Gür Çetinkaya et al. (35)Ann Allergy Asthma Immunol2018ONLYCHILDREN 107 childrenM: 77—F: 30median age 10 y/oAt least 1 systemic reaction after sting75.7% wasp23.3% honeybee0.9% both venoms17 did not complete VIT Build-up: weekly increases starting from 3 to 8 mcg (6 months)Maintenance: 100 mcg (every 4–6 weeks for 5 years) 52/107 had AR37.4% local reactions4.7% LLR (2 during build-up, 2 at maintenance, 1 not specified)6.5% SR (7/107)- 4/7 grade 1–2- 2/7 grade 3- 1/7 grade 43/7 during build-up4/7 during maintenance 0.17% SR/injection (5671 doses)Local 1.6%LLR 0.14% Risk factor: asthma in multivariate analysis (p = 0.016)Wasp = more local reactions; honeybee = more severe systemic reactions.SR during honeybee VIT 16%; SR during wasp VIT 3.7% (p = 0.031).33/68 contacted (48.5%) were re-stung averagely in a 34-month interval from VIT starting date:- 4 (12%) SR (mild, grade 1–2)- 1 (3%) LLR- 19 (58%) local- 9 (27%) no reactions
Chipps et al. (11)J Pediatr1980ONLYCHILDREN 44 children (4–14 y/o)mean age 9.6 y/o98% at least cutaneous48% at least respiratory9% hypotension27% life threatening SR50% vespid venom11.3% honeybee venom38.6% > 1 (vespid +/− honeybee Build-up: weekly increases starting from 0.1 to 1 mcg on day 1 (6 weeks)Maintenance: 100 mcg (every 1–4 weeks) 6.8% SR (3/44)27% LLR (12/44) 0.3% SR/injectionLLR 2.5%1 required adrenaline Only 1 reaction at hospital sting challenge (20 children), in a child with low venom-specific IgG titers
Clustered and semi-rush protocols
Konstantinou et al. (28)Pediatr Allergy Immunol 2011ONLYCHILDREN 54 childrenM: 29—F: 25mean age 9.5 y/o77.8% grade 313% grade 3/49.2% grade 41 lost to follow-up Modified-cluster build-up: cumulative dose on day 1 = 0.6111 mcg to 50 mcg in 31 daysMaintenance: 50 mcgevery 4 weeks for 1° yearevery 5 weeks for 2°–3°every 6 weeks for 4°–5° 3.8% SR (2/53): maintenance dose was increased to 100 mcg51/53 who completed VIT showed no side effects apart from mild reactions at injection site75.5% needed antihistamine therapy, more often during build-upIn the 2 with SR:both allergic to honeybee;-1 boy with generalized urticaria during build-up-1 girl with rhinitis, wheezing, dyspnea, hypotension and asthenia 53 completed 5 years (1 lost to follow-up without reported reactions)At re-sting (21/51 with 50 mcg maintenance): no SR- 10/21 during VIT- 11/21 after VIT was completed
Carballada Gonzales et al. (36)Allergol Immunopathol2009ONLYCHILDREN 21 children (4–16 y/o)M: 13—F: 8mean age 11.8 y/o9.5% grade 128.6% grade 257.1% grade 34.8% grade 480.9% honeybee19.1% hornet85.7% completed VIT Semi-rush build-up: 1–2 weekly injection of 9 increasing dosesMaintenance: 100 mcgVIT for 5 years or until negative test 5 adverse reactionsall for honeybee venom3 local2 SR (9.5%)no LLR1 adrenaline1 antihistamines and BDVIT resumed with previous tolerated dose 7 (33.3%) re-stung (5 during maintenance):- 4/7 no reactions- 3/7 mild local reactions
Rush and ultra-rush protocols
Glaeser et al. (37)Clin Mol Allergy2022ONLY CHILDREN 19 childrenmedian age 9 y/oAll with history of honeybee anaphylaxis16% grade 142% grade 242% grade 30% grade 4 Rush build-up: 1 mcg to 100 mcg in 3 days SR 15.8% (n = 3)-1 grade 1-2 grade 2Local reactions 58.8%All reactions on day 2(1 at 40 mcg and 2 at 80 mcg) All reached maintenance dose (100 mcg) and entered maintenance phase, no further reactions in 2 years
Stoevesandt et al. (38)Allergy Asthma Clin Immunol2017CHILDRENvs.ADULTS 71 children (7–17 y/o)M: 45—F: 26median 14 y/o981 adult controlsSR 9.9% children vs.SR 26.5% adults (p = 0.001)Honeybee allergy:32.4% children vs. 14.7% adults(p < 0.001)Lower baseline tryptase levels in children (p = 0.014) Rush build-up: 0.1 mcg to 100 mcg in 3 or 5 daysMaintenance: 100 mcg SR 6.9% children vs. 2.5% adults(p = 0.046)Children anaphylaxis (n = 5):- 2 honeybee: grade 1 and grade 2- 3 wasp: all grade 1No adrenaline needed, all reached 100 mcg doseLRR children 9.7% vs. 6.8% adults(p = ns) 72 cycles in children (1 child only received double VIT for both honeybee and wasp)1029 cycles in adults728 injections among children10217 injections among adults Regression modelVIT honeybee (OR 2.25, p = 0.039) and build-up in 5 days vs. 3 days build-up (OR 2.64, p = 0.011) associated with increased risk for VIT-SRHigher rate of VIT anaphylaxis in children due to higher prevalence of honeybee venom allergy in children
Nittner-Marszalska et al. (39)J Investig Allergol Clin Immunol 2016CHILDRENvs.ADULTS 134 children 4-17 y/oM: 94—F: 40mean age 12.6 y/o207 adult controls9.0% grade 117.9% grade 247.8% grade 325.3% grade 448.5% wasp(M: 66.2%)51.5% honeybee (M: 73.9%) Ultra-rush build-up: 0.1 mcg to 101.1 mcg in 3.5 hMaintenance: not described SR 3.7% children (n = 5) vs.7.7% adults(p = ns)SR to honeybee venom:7.2% children vs. 21.4% adults(p = 0.034)All 5 children were allergic to honeybee:- 4/5 had grade 4 first SR- 4/5 had grade 3 VIT-SRAll during build-up Children:- total and specific IgE higher than adults (p < 0.001)- lower median tryptase than adults (p = 0.009)Increased VIT-SR risk if first reaction was grade 4 compared to grade 3 (p = 0.016); grade 1–2 field reactions did not show any VIT-SRIncreased VIT-SR risk in children allergic to honeybee compared to wasp allergy (p = 0.058).No difference adults/children who experienced VIT-SR with respect to asthma, atopy, severity previous reaction, skin tests or sIgE
Steiss et al. (40)J Aller Ther2013ONLYCHILDREN 90 children (4–17 y/o)M: 56—F: 34mean age 9.3 y/o7.8% grade 118.9% grade 264.4% grade 38.9% grade 457.8% wasp42.2% honeybee Modified ultra-rush build-up:day 1: 7 doses up to 80 mcgday 2: 100 mcgMaintenance: 100 mcg booster at week 1, week 3, then every 4–6 weeks 2.2% SR (n = 2), both honeybee1 mild dyspnea1 urticaria16.7% local maximum 15 cm22.2% LLR maximum 20 cmMedian: 40–80 mcgno difference honeybee/wasp 0.002% SR (720 injections)No adrenalineIV antihistamines or corticosteroid +/− inhaled BD
Kohli-Wiesner et al. (41)J Allergy2012ONLYCHILDREN 94 children (4–15 y/o)M: 70—F: 24mean age 10.4 y/oAll grade 2–465% honeybee35% wasp8.5% both venoms102 ultra-rush (double allergy counted twice)15 group A 4–8 y/o60 group B 8–12 y/o27 group C 12–15 y/o Ultra-rush build-up: 0.1 mcg to 110 mcg cumulative dose in 210 min in at least 6 injectionsBooster on day 7:two 50 mcg doses with a 30-min intervalWeek 3 and 7: 100 mcg 16% SR (n = 16)- 6/16 (37.5%) grade 1- 2/16 (12.5%) grade 2- 5/16 (31%) grade 3- 3/16 (19%) unclassifiableNo SR in group A18% SR in group B19% SR in group CSR F 29% vs. M 12%(p = 0.034)More SR reaction at 50 mcgNo adrenalineNo antihistamine premedication SR honeybee 20% vs. 8% wasp(p = ns)
Steiss et al. (42)Allergy Asthma Proc2006ONLYCHILDREN 43 children- 16 honeybee 7 M—9 F- 27 wasp 19 M—8 Fmean age 9.5 y/ograde 1: 1 honeybee, 0 waspgrade 2: 12 honeybee, 15 waspgrade 3: 3 honeybee, 12 waspgrade 4: 0 honeybee, 0 wasp 11.6% (n = 5) ultra-rush build-up:day 1: 9 doses up to 100 mcg in 24 hday 2: 100 mcgvs.88.4% (n = 38) modified ultra-rush build-up:day 1: 7 doses up to 80 mcg in 3 hday 2: 100 mcgMaintenance: 100 mcg booster at week 1, week 3, then every 4–6 weeks No SR58.1% no reaction16.2% local maximum 15 cm25.6% LLR maximum 20 cmmedian 40–80 mcgno difference honeybee/wasp 38 children with 304 injections (8 each)No therapy neededReduction dose needed
Birnbaum et al. (43)Clin Exp Allergy 2003CHILDRENvs.ADULTS 51 childrenmean age 9.2 y/o- 33.3% honeybee- 74.5% yellow jacket- 19.6% wasp207 adultsage 40.62 y/o195 single VIT59 double VIT4 triple VIT Ultra-rush build-up: in 3.5 hday 1: 6 doses, 0.1–40 mcgday 15: 2 doses, 50 mcgday 45: 1 dose, 100 mcgCumulative dose 101.1 mcgMaintenance: 100 mcg monthly 13.9% SR (n = 36, 33 on day 1, 2 on day 15, 1 on day 45)SR: 10.8% children vs. 11.2% adults(p = ns)Association between field severity and VIT severitychildren (p = 0.025)adult (p = 0.016)Most reactions at 10–40 mcg2 required adrenaline No late reactionsNo severe cardiovascular reactions in childrenHoneybee venom and prior sting grade 3–4 increased risk of VIT-SRNo relation between IgE and risk of VIT-SRAge and sex not a risk factor for VIT-SRMore positive skin test risk factor for VIT-SR
Comparison between different protocols
Johnston et al. (44)J Paediatr Child Health2022ONLY CHILDREN 14 children6 URVIT (median age 7.3 y/o, M: 5)8 CVIT (median age8 y/o, M: 6)All with history of honeybee anaphylaxis URVIT build-up: in 3.5 hday 1: 6 doses, 0.1–40 mcgday 15: 2 doses, 50 mcgday 45: 1 dose, 100 mcgCumulative dose 101.1 mcgCVIT build-up: from 0.1 mcg to 100 mcg, weekly increases for 14 weeks SR: URVIT 16.6% vs. CVIT 25%11/14 none or local reaction only 149 injections1 required adrenaline (CVIT group) URVIT completed updosing protocol in shorter time (6 vs. 14 weeks), had fewer hospital visits (3 vs. 12) and fewer injections (9 vs. 12).Cumulative distance savings for the URVIT group
Confino-Cohen et al. (45)J Allergy Clin Immunol Pract 2017ONLY CHILDREN 127 children (2–18 y/o)M: 97—F: 30mean age 10.56 y/o66% rush34% conventional3.1% grade 189.8% grade 27.1% grade 3RVIT honeybee 83.3%CVIT honeybee 69.7%(p = 0.015) Rush build-up: 0.05 mcg to 100 mcg in 3 daysConventional build-up: 0.05 mcg to 100 mcg in 17 weeksMaintenance: 100 mcg SR during build-up:RVIT 19.0% vs. CVIT 23.2% (p = ns)- grade 1: RVIT 81.3% vs. CVIT 85%- grade 2: RVIT 18.7% vs. CVIT 20%Adrenaline use: RVIT 4.7% vs. CVIT 9.3% (p = ns)SR at maintenance:RVIT 9.3% vs. CVIT 14.8% (p = ns)-grade 1: RVIT 100% vs. CVIT 50%-grade 2: RVIT 0 vs. CVIT 50%No grade 3 reactions FU available for 102/127 children (some did only build-up phase then FU by family physician)75 RVIT and 27 CVITMaintenance dose reached in 90.7% CVIT vs. 98.8% RVIT(p = 0.04)Less SR for honeybee-rush vs. honeybee-conventional (RVIT 18% vs. 30% CVIT, p = ns)Age group 2–6 years:13 RVIT (all honeybee)8 CVIT (6 honeybee, 2 also wasp/yellow jacket)Mostly grade 2 reactions at field sting and mostly grade 1 during VIT (reduction of severity)No adrenaline neededMaintenance dose reached in 92.3% RVIT vs. 100% CVIT
Martínez-Cañavate et al. (33)Allergol Immunopathol 2010ONLY CHILDREN 175 children (2–17 y/o)M: 135—F: 40mean age 9.9 y/o17% beekeeper son 68.9% previous sting83.9% local reaction8% anaphylaxisCompared VIT vs. prevention vs. clinical manifestations 135/175 VIT for average duration of 3.5 yearsCVIT 92/135RVIT 25/135cluster 16/135URVIT 2/13545 honeybee45 Polistes39 wasp2 wasp + Polistes 0.4% SR (n = 6)- wasp 2/6 grade 3- Polistes 1/6 grade 3- honeybee 3/6 grade 1–32/92 conventional1/25 rush1/16 cluster2 not specified25% local reactions (n = 35)- wasp 7/35- Polistes 14/35- honeybee 14/35 Most of VIT are prescribed for local reactions
Treated vs. untreated
Golden et al. (5)N Engl J Med 2004ONLY CHILDREN 1033 children(356 VIT, mean duration 3.5 years)226 LLR (no VIT)462 mild skin (110 VIT)345 moderate-severe (246 VIT)512 (50%) children (mean age 8 y/o) answered survey:VIT: 46%no VIT: 53% SR:VIT: 3% (2/64)no VIT: 17% (19/111)(p = 0.007)Untreated at re-sting:LLR: 7% SRMild: 13% SRModerate-severe: 32% SR Similar rate of sting between VIT and no VIT (p = 0.22)History of moderate-severe reactions has a higher rate of reaction if not treated (32% vs. 5%, p = 0.007)Frequency of SR decreases over the 20-year observation period(p = ns)SR rate in untreated with mild skin reactions is lower than the rate in untreated with moderate-severe reactions(p = 0.05)Long protection of VIT even 10 to 20 years after therapy is suspended
Omalizumab pretreatment
Droitcourt et al. (46)Allergol Int2019ONLY CHILDREN 3 teenagers with severe anaphylaxis15 y/o M honeybee12 y/o M wasp14 y/o M honeybee rush VIT with omalizumab pretreatment Dyspnea and generalized urticariaAnaphylaxisDyspnea, stridor and generalized urticaria All toleratedThe same department had treated 90 children with 5.6% of SR during rush build-up phase

AR, allergic reactions; BD, bronchodilators; CVIT, conventional venom immunotherapy; F, female; FU, follow-up; IM, intramuscular; LLR, large local reactions; M, male; ns, not significant; RVIT, rush venom immunotherapy; SR, systemic reactions; URVIT, ultra-rush venom immunotherapy; VIT, venom immunotherapy; vs.: versus; y/o, years old.

 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 significant risk factor for SR prediction has been identified (e.g., age, atopy, gender, asthma, or type of venom).

A similar result was obtained in another study by Gür Çetinkaya et al. (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. Pre-existing 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 semi-rush 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 3- or 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.

Kohli-Weisner et al. (41) also used an ultra-rush protocol in 94 children, mostly with an allergy to honeybees (65%). Among 102 desensitization procedures, 16 (16%) showed adverse effects. Most of these reactions were, however, grades 1–2 (50%), and none required adrenaline administration. Interestingly, younger children (4–8 years) had no SR, compared to older children and adolescents, who reported 18% and 19% SR, respectively.

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.

 Author contributions

MG and EN: conceptualized the work. FS, MG, BP and EN: collected the data and drafted the manuscript. FS, MG, BP, SB, GL, LS, LT, CF, FP, CV, SR, CA, EN and FM: analyzed the data. FS, MG, BP, SB, GL, LS, LT, CF, FP, CV, SR, CA, EN and FM: critically revised the manuscript. All authors contributed to the article and approved the submitted version.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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