Curr Allergy Asthma Rep (2014) 14:449 DOI 10.1007/s11882-014-0449-1
IMMUNOTHERAPY AND IMMUNOMODULATORS (L COX, SECTION EDITOR)
Venom Immunotherapy: an Updated Review Darío Antolín-Amérigo & Carmen Moreno Aguilar & Arantza Vega & Melchor Alvarez-Mon
# Springer Science+Business Media New York 2014
Abstract Venom immunotherapy (VIT) is the most effective form of specific immunotherapy to date. Hitherto, several relevant queries remain unanswered, namely optimal doses, duration, and means of assessment. Important progress has been lately made in terms of diagnosis by means of component-resolved diagnosis. Moreover, basophil activation test results in patients with negative serum immunoglobulin E (IgE) and skin prick test confer this technique a promising future, although these outcomes shall be considered with caution. This review aims to unravel the important advances made on diagnosis, management, and prognosis and also focuses on several undetermined aspects of VIT.
effective form of specific immunotherapy to date. However, several relevant queries remain unanswered, namely optimal doses, duration, and means of assessment [1••, 2•, 3]. VIT has been a model for the efficacy and reliability of allergen immunotherapy using standardized extracts and treatment regimens [4, 5••, 6•, 7••, 8], achieving an improvement in healthrelated quality of life (HRQL) [9, 10]. This review aims to unravel the important advances made on diagnosis, management, and prognosis and also focuses on several undetermined aspects of VIT.
Keywords Hymenoptera . Immunotherapy . Venom immunotherapy . Diagnosis . Hypersensitivity . Intradermal tests . Tryptase . Mastocytosis . Sensitization . Allergen
Accuracy in the identification of the disease-eliciting allergen is a condition for precise prescription of any successful tailormade treatment, as specific immunotherapy [11••, 12, 13]. In general terms, diagnosis of hymenoptera venom allergy (HVA) is established by a history of anaphylactic sting reactions, positive skin test responses, and/or detection of specific immunoglobulin E (IgE) to a specific venom [14]. Notwithstanding, significant progression has been achieved in the assessment of venom allergic patients, mainly due to component-resolved diagnosis, which helps to distinguish between true double venom allergy and cross-reactivity, in order to assess the appropriateness of the election of a specific venom. In consonance with current guidelines, skin testing for hymenoptera venom allergy should be performed in a stepwise manner, allowing 15- to 20-min intervals between the intradermal tests (IDT) of venom [15, 16•]. Despite the fact that the former recommended scheme has been unquestioned for years, a recent study aimed to assess the safety of simultaneous IDT; consequently, 478 consecutive patients received all venom concentrations (0.02 ml of 0.001, 0.01, 0.1, and 1.0 μg/ml of honey bee and wasp venom), administered simultaneously to the skin. Four hundred and seventy-two
Introduction Insect hypersensitivity affects up to 5–7.5 % of the population. Interestingly, venom immunotherapy (VIT) is the most This article is part of the Topical Collection on Immunotherapy and Immunomodulators D. Antolín-Amérigo (*) : M. Alvarez-Mon Servicio de Enfermedades del Sistema Inmune-Alergia, Hospital Universitario Príncipe de Asturias, Departamento de Medicina, Universidad de Alcalá, Carretera Alcalá-Meco S/N, 28805 Alcalá de Henares, Madrid, Spain e-mail: [email protected] C. Moreno Aguilar Sección Alergia, Hospital Universitario Reina Sofía, Córdoba, Spain A. Vega Sección de Alergología, Gerencia de Atención Integrada de Guadalajara, Guadalajara, Spain
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(98.7 %) patients tolerated the simultaneous IDT with two venoms without any side effects, warranting prompt results along with excellent safety [16•]. The analysis of gene expression and subsequent prediction models are a promising tool aimed to enrich VIT assessment, regarding effectiveness and duration of VIT, but also could be useful to circumvent sting challenges [17, 18]; however, it is not commonly performed in clinical practice and remains in most cases for investigational purposes. Component-resolved analysis with recombinant speciesspecific major allergens (rSSMA) may help to distinguish true double sensitization from cross-reactivity [19••], which may be crucial especially when the stinging insect was not identified and when skin tests and specific IgE to the native allergens are unsuccessful for the identification of the culprit insect. The main species-specific major allergens for hymenoptera venom allergy (HVA) are Api m 1 (phospholipase A2) for honeybee, Pol d 1 and Pol d 5 for Polistes, Ves v 1 (phospholipase A1), and Ves v 5 (antigen 5) for Vespula [19••, 20•, 21•, 22] (Table 1), which are produced in a form free of crossreacting carbohydrate determinants (CCDs). Their assessment improves the differential diagnosis among true double sensitization and cross-reactivity [19••]. Recently, rVes v 5-spiked, a yellow jacket venom (YJV) ImmunoCAP enhanced by spiking with rVes v5, demonstrated a more reliable detection of yellow jacket venom (YJV) sensitization in patients with insect venom allergy, improving the sensitivity to 96.8 % [23]. Previously, it was observed that IgE reactivity was higher to the major YJV allergen Ves v 5 than to YJV extract, and sometimes, IgE reactivity was only detectable by Ves v 5 ImmunoCAP. In a study comprising 59 allergic individuals of a Mediterranean region, the determination of specific IgE against phospholipases and antigen 5s seems to be sufficient to discriminate the source of sensitization in vespid-allergic individuals, although regional phenotypes may arise. Interestingly, in this group of Mediterranean patients, very low levels of antigen 5s were seen in about 48 % of patients (12/25 cases) [20•]. However, recombinant Api m 1 has shown extensively variable activity and has limited clinical utility that may be determined by several factors, including the source of the protein [24]. It also seems that, at least in Europe, there may be a north-south decrease in the rate of sensitization to Api m 1, the reason still to be determined. Another issue regarding Api m 1 is the low sensitivity (61.8 %), which has to be improved after further investigation [25•], but maybe these results arose because Api m 1 was recombinant instead of native, which would have elicited enhanced results. On the contrary, Api m 10, albeit a potential relevant allergen, which may be present in 50 % of HBV patients, may be underrepresented in therapeutical extracts [26•]. Recent findings have brought insight into component-resolved diagnosis along with a more precise analysis which will improve the understanding of the underlying
Curr Allergy Asthma Rep (2014) 14:449
mechanisms of venom allergy. One of those advances is Api m 6 (serin protease inhibitor), despite the fact that it is underrepresented and consequently may be considered a minor allergen, could be relevant in some phenotypes of HVA [27]. Furthermore, Api m 3, Api m 10, or both have been detected in 68 % of HBV patients and, interestingly, represented the only HBV allergen-specific IgE in 5 % of the patients. Limited inhibition of IgE binding by therapeutic HBV along with limited induction of Api m 3- and Api m 10-specific IgG4 in patients obtaining immunotherapy strengthens latest reports on the potential underrepresentation of these allergens in therapeutic HBV extracts [28]. In general terms, individuals who have not suffered systemic reactions do not undergo additional testing to discard venom allergy (Table 2) [14, 29••]. It has been stated that different risk factors may predispose an individual suffering from HVA to developing severe systemic reactions (SSR), namely serum basal tryptase concentration >5 ng/L, male sex, previous less severe systemic reactions to hymenoptera stings, and ACEinhibitor intake [30]. It remains elusive whether the pattern of sensitization to specific venom allergen components is predictive of the potential benefit of VIT or even of the clinical outcome from a sting [31]. Latest findings suggest that there may be regional differences among sensitized patients [25•]. Basophil activation test (BAT), an in vitro method which identifies and quantifies the potential modifications of specific activation markers on the surface membrane or inside the basophils by flow cytometry, has been proposed for diagnosis of many hypersensitivity reactions. These changes are measured by means of monoclonal antibodies coupled to specific fluorochromes [32]. Basophils are identified by specific markers, namely CCR3+/CD3−, CD123+/HLA-DR−, and IgE+/CD203c+. In a second step, the upregulation of specific activation markers is determined. CD63 and CD 203 are the most commonly used cell markers. It is commercially available for practitioners although it requires a flow cytometer, which is available only in selected centers. BAT is a promising option, evidencing to be more sensitive (80 %) than IDT (50 %), in patients with negative serum IgE and skin prick test results, and also predicting the risk of systemic reactions to VIT [1••, 33–35]. The former is endorsed by a study in which 35 out of 47 patients with a positive history of sting allergy demonstrated a positive basophil CD63 response after stimulation with bee and/or wasp venom. Intradermal venom skin tests resulted positive in 17 (46 %) out of 37 patients who underwent this diagnostic method. Out of 20 patients who showed negative IDR test results, 12 patients showed a positive CD63 response (60 %). Contrarily, out of nine patients who showed a negative CD63 response, only one was detected by IDR testing (11 %) [33, 34].
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Table 1 Component resolved diagnosis and Hymenoptera venom allergy Antigen
Group 1 PLA
Apis mellifera Vespula vulgaris
Api m 2 Api m 1, PLA 2 Sensitivity, 60 %a Ves v 2 Ves v 1, PLA 1 Sensitivity (combined with Ves v 5), 92–96 %a
Polistes Pol d 1, PLA 1 dominula
Group 2 Group 3 Group 4 hyaluronidase acid melittin phosphatase Api m 3
Group 5
Api m 4
Group 10 icarapin
Carbohydrates Vitellogenin
Api m 10
MUXF3
Api m 12
MUXF3
Ves v 6
Ves v 5 Sensitivity, 83.4 %a Sensitivity (combined with Ves v 1), 92–96 %a Ves v 5-spiked Sensitivity, 96.8 %a Pol d 5
Pol d 2
Api m 3 and Api m 10 may represent the only HBV allergen specific IgE in up to 5% of the patients. Moreover: 68% of patients show IgE reactivity to Api m 3, Api m 10 or both Köhler et al. [28] a
Data from Vos et al. [23] and Korošec et al. [24•]
However, in a study performed over 52 patients diagnosed from mastocytosis who had suffered from previous hymenoptera stings, after performing usual tests (namely skin tests and serum specific Immunoglobulin E (sIgE) against hymenoptera venoms), seven resulted negative to diagnostic tests. In six of seven of those patients, BAT was negative with all venoms. Therefore, BAT could be useful to confirm previous tests [35, 36•, 37]. The utility of BAT has been shown in 14 patients who still reacted to bee or wasp sting, where basophil response at a venom concentration of 0.1 μg/mL was significantly higher than in patients who tolerated field re-stings (p=0.03; t test), so it may be used to assess VIT efficiency [38]. Moreover, after 2– 4 years of VIT, a marked CD63 decrease was evident in 85 % of 31 children who underwent honeybee (HB) immunotherapy. In addition, elevated basophil sensitivity measured in this group of children before VIT was associated with the appearance of side effects observed during the buildup phase [39] and was predictive of HB sensitivity after VIT (clinical relapse). Though promising, BAT remains to be standardized in terms of methodology and interpretation; consequently, these results shall be considered with caution [1••, 3].
Table 2 Decision regarding VIT based on diagnostic tests (adults/ children)
Efficacy of VIT and Its Assessment In a recent meta-analysis comprising six randomized controlled studies and one quasi-randomized controlled study [40••], VIT proved to be effective for preventing systemic allergic reactions to an insect sting, either accidentally or by means of in-hospital controlled sting challenge. In the trials, 3/113 (2.7 %) participants treated with VIT experienced a subsequent systemic allergic reaction to a sting, compared with 37/93 (39.8 %) untreated participants (risk ratio [RR] 0.10, 95 % confidence interval [CI] 0.03 to 0.28). Moreover, VIT displayed effectiveness in preventing large local reactions to a sting (RR 0.41, 95 % CI 0.24 to 0.69) and for improving quality of life (mean difference [MD] in favor of VIT 1.21 points on a 7-point scale, 95 % CI 0.75 to 1.67) [9, 10]. The honey bee (HB) sting challenge is considered until now a reliable and irreplaceable approach to evaluate the efficacy of VIT [15, 54•, 41], but it has the hurdle of requiring live insects and inducing severe and potentially life-threatening anaphylaxis. Hence, a potential new means of assessing VIT efficacy using a microsyringe has been developed, comparing its feasibility and reliability with stan-
Type reaction
Diagnostic tests ST and/ or IgE
Decision regarding venom immunotherapy
Respiratory and cardiovascular symptoms
Positive Negative Positive
Yes No Yes
Negative Positive* Negative Positive Negative
No Yes* No No No
Urticaria if risk factors or quality of life impairment present Large local* *If life-threatening and/or quality of life impairment + high exposure + positive diagnostic tests, VIT shall be considered
Unusual
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dard sting challenge. Patients on bee VIT and without systemic reactions at field sting were enrolled [42]. Nineteen patients underwent a sting challenge with live bee, and large local reactions (LLR) were assessed up to 48 h. Those patients displaying systemic reactions at the sting challenge were excluded from the syringe challenge, for ethical reasons. The syringe challenge was fulfilled in 15 patients, by injecting 0.5 μL fresh unfiltered bee venom at 2-mm depth (the length of the sting left by a bee). The same follow-up as at the first challenge was performed. Bee-specific immunoglobulin E (IgE) and tryptase were measured after each challenge. Nineteen patients underwent the sting challenge with live bees. Four had immediate systemic reactions (urticaria or asthma) and were excluded from the second challenge. The remaining 15 patients with LLR underwent the syringe challenge. No significant difference was seen in the maximum area of the LLR between the challenge with live bees and the syringe challenge. Also, no change was seen in tryptase and specific antibodies. In patients with a history of systemic reactions to stings, the frequency of systemic reactions to subsequent stings is correlated with the severity of the previous reactions. In a study using challenge stings, systemic reactions occurred in more than 40 % of those with previous severe reactions but only 23 % in those with previous moderate systemic reactions and 17 % in those with mild (cutaneous) systemic reactions [43]. A surprising proportion (up to 30 % in several large studies) of people with a history of systemic reaction to a sting has negative venom skin test results. However, many of these individuals have positive serum IgE test results, leaving approximately 15 % of history-positive patients with no detectable venom-specific IgE. In sting challenge studies, only approximately 6 % of such individuals have a systemic reaction to a challenge sting [43, 54•]. There are many potential reasons for venom skin test results to be negative despite a convincing history. The test results can be negative in 20 to 50 % of patients during the refractory period soon after a sting reaction but are positive 4 to 6 weeks after the sting. Another possible problem is the inherent variability of venom skin tests, which can reveal a 10fold increase or decrease in the concentration for a positive result when performed weeks or months apart. The clinical implication is the potential to omit a particular venom in treatment when a subsequent test could have a positive result. Skin tests and sIgE against the culprit venom once a year have been used as means of assessment of the efficacy, showing improvement and even negativization of the former after completing VIT [44]. Venom skin test and serum IgE usually decline in a linear fashion (on a logarithmic scale) after stopping treatment [45]. This decline tends to continue despite sting challenge every 2–4 years, although there is a transient increase in serum IgE (but not skin tests) after each sting. Concerning novel data in relation to immune system modification, elevated VIT initiation doses and rush or ultrarush
Curr Allergy Asthma Rep (2014) 14:449
protocols have demonstrated efficacy [46] and even elicited immunological changes after 24 h of use, such as a significant decrease of sCTLA-4 [47•]. Furthermore, basophil threshold sensitivity to antihigh-affinity IgE receptor (FceRI) stimulation and FceRI gene and cell-surface expression at the beginning and just before the first maintenance dose in ultrarush and/or semi-rush VIT have been investigated, evincing marked desensitization of FceRI-activated basophils, after short-term VIT [48]. Other proposed early markers of immunotherapy with protective effects comprise the following: increased tryptophan degradation and IL-10 levels, production of IL-10 cells, and in the same line, the upregulation of histamine receptor 2 [49–51]. Additional studies have shown attenuated histamine, sulfidoleukotriene, and cytokine release even 1 week after the initiation of VIT [52]. Therefore, efficacy can be assessed and demonstrated, at least both theoretically and experimentally, during the early course of VIT. Although there is poor correlation between the amount of serum specific IgG (sIgG) and clinical protection, sIgG correlates with the dose of allergen that has been given, yet in most studies, the changes in serum levels showed no relationship with clinical response [53]. Schemes and Dosage Up-dosing schedules are diverse and difficult to compare, due to the heterogeneity in patient conditions, comorbidities, extracts used, and protocols among different hospitals, even in a specific country. Hence, this question remains unsolved and probably the best initiation schedule would be the one that suited an individual with its own clinical characteristics in a particular clinical setting, always aiming to optimize safety, efficacy, time, and convenience. Despite the fact that VIT is notably effective, there are enclosed adverse reactions [54•] (Tables 3, 4, 5, 6, and 7). Notwithstanding that their comparison is challenging, due to the heterogeneity of the variables and methods recorded in the former, in general, protocols for VIT may be divided into slow protocols, in which the time required to fulfill the maintenance dose (generally of 100 mcg) is several weeks (weekly intervals), with a rush protocol is several days (4–7 days), with an ultrarapid or ultrarush is few hours or 1–2 days, or cluster (a modified rush approach schedule, which involves administering several injections at 15–30-min intervals during the first visits and reaches a maintenance dose in about 6 weeks). It is strongly suggested to weigh the pros and cons of an ultrarush therapy and providing particular surveillance to those patients actually receiving that type of buildup. Nevertheless, rush and ultrarush protocols are cost-effective, making them suitable and desirable for both patients and physicians [55, 56]. In Europe, purified and nonpurified aqueous venom extracts are commercially available for the rush, ultrarush, and clustered and maintenance phases, and aluminum hydroxide
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Table 3 Ultrarush buildup protocols and percentage of systemic adverse reactions (SAR) First author
Year
Number of samples
Type of study
Bee/wasp
Cumulative dose
Time (min)
SAR (%)
Schiavino
2004
57
Prosp.
9:48
101
150
Patella Birnbaum Birnbaum
2012 1993 2003
27 217 258 (children, adults)
Prosp. Retrosp. Retrosp.
9:18 Bee, wasp 90:235
111 101 101
180 210 210
Köhli-Wiesner Roll
2012 2003
94 (children) 67
Retrosp. Retrosp.
65:37 (8 both) 20:47 (13 both)
111 111
210 240
Bee 11 Wasp 6 0 6.9 Bee 30 Wasp 3.2–6.1 16 17.5
adsorbed (depot) preparations for the conventional buildup and maintenance phases [57]. In Europe, where the recommended maintenance dose is 100 μg on a monthly basis, both for children and adults, the proven rate of protection in terms of honeybee immunotherapy is 77–94 %, while vespid VIT accomplished 91–100 % [2•, 14]. However, 200 μg may be suitable for those patients who have experienced systemic reactions after a sting in spite of following VIT with 100 μg or in exposed populations, such as beekeepers [58]. Likewise, American extracts for vespid venom allergy, which may contain up to 300 μg provide considerable efficacy rates of 98 % [2•]. Despite current European guidelines recommend 100 μg monthly for children as maintenance dose, there is evidence that 50 μg/month during 5 years proved to be safe and effective enough to induce tolerance in children with hymenoptera venom hypersensitivity [59]. Until present, no placebocontrolled prospective studies have been devised in terms of VIT, due to the potentially life-threatening condition that a Table 4 Rush buildup protocols and percentage of systemic adverse reactions (SAR)
NPA nonpurified aqueous, PA purified aqueous
sting may suppose for those patients who would be allocated in the placebo group. One study showed a significant dosedependent increase in serum venom-specific immunoglobulin G (IgG) and greater clinical efficacy in patients receiving 100-μg monthly venom maintenance dose instead of a 50-μg monthly maintenance dose [11••, 58]. With regard to the interval of VIT administration during maintenance phase, current guidelines favor 4- to 6-week intervals [14]. Nonetheless, several studies promote extended maintenance doses (EMD), ranging from 2 to 4 months [60–62, 63•], showing comparable efficacy and increasing convenience of both the patients and the physicians. Seventy-six patients (60 male; mean age 48 years) receiving the EMD (3- or 4-month interval) were re-stung on 247 occasions by the insect for which they were receiving immunotherapy. The group receiving conventional maintenance dose (CMD) included 110 patients (82 male; mean age 44 years) certainly re-stung on 167 occasions by the specific insect. The percentage of re-sting without reaction was 93.5 % in the EMD group and 81.5 % in the CMD group,
First author
Year
Number of samples
Type of study
Bee/ wasp
Cumulative dose
Time (days)
SAR (%)
Brehler Goldberg
2000 2011
403 179
Retrosp. Retrosp.
57:346 93:47a
350 264
2 3
Sturm Birnbaum Patella Wenzel Brehler Sánchez-Morillas
2002 1993 2012 2003 2000 2005
101 46 25 178 335 44
Retrosp. Retrosp. Prosp. Retrosp. Retrosp. Retrosp.
52:49 Bee, wasp 9:16 24:154b 32:303 7:32c
339 530 223 556 415 325.5
4 4 5 7 3–6 3
Bilò
2012
80
Prosp.
Bee
223.11
5
Bilò
2009
94
Prosp.
38:56
–
Bee 7 Wasp 2
10.7 Bee 31.1 Wasp 16.3 6.9 28.2 9 17.9 13.7 Bee 14.3 Wasp 3.1 NPA 27.5 PA 2.5 NPA 27.5
Yunginger Quercia
1979 2006
20 35
Retrosp. Retrosp.
Bee Bee
200 –
3 –
a
1 4 p a t i e n t s Ve s p u l a + Dolichovespula VIT
b
2 patients bee and wasp VIT
c
8 patients various wasp venoms
PA 2.5 85 20
449, Page 6 of 12 Table 5 Semi-rush buildup protocols and percentage of side effects
n.a. not available a
Two patients wasp+bee VIT
Curr Allergy Asthma Rep (2014) 14:449
First author
Year
Number of samples
Type of study
Bee/ wasp
Cumulative dose
Time (days)
SAR (%)
Ruëff
1997
144
Retrosp.
560
5–7
16.7
555
7
17.8
430 n.a.
7–9 n.a.
22.4 39
Wenzel
2003
178
Retrosp.
Bee, wasp 26:152a
Brehler Przybilla
2000 1987
317 282
Retrosp. Retrosp.
33:284 n.a.
with a significant difference in favor of the former (p=0.001); therefore, the EMD regimen was comparable both in efficacy and safety to the conventional maintenance dose schedule [63•]. Currently, the common accepted policy for stopping immunotherapy is 3–5 years; however, longer-term treatment shall be considered in those patients with a higher risk of severe systemic reactions (SSR) (e.g., older age, history of previous SSR, elevated basal serum tryptase, mast cell activation syndrome, or use of beta-blockers) [2•]. Prolonged VIT seems to reduce the risk of a relapse. Thus in one study, SR to re-sting discontinuing VIT was reported on only 4.8 % of 82 patients with a VIT duration of ≥50 months as opposed to 17.8 % of 118 with a VIT duration of 33–49 months [14, 64, 65]. Safety of VIT On the other hand, the observational prospective multicenter study performed over 680 patients by the Insect Venom Allergy Interest Group of the EAACI [30] aimed to identify independent predictors for a higher complication rate during VIT. According to the results of the study, risk factors for an emergency intervention during immunotherapy were the following: honeybee VIT using rush or ultrarush protocols; younger age; the type of dose increase (ultrarush, rush) during therapy; a long interval between the most recent sting reaction and VIT; an accompanying antihypertensive therapy; basal tryptase concentration (BTC) for vespid allergic patients (odds ratio 2.337; 95 % CI 1.279–4.260; pvespid venom Buildup phase>maintenance phase Elderly age Dose increase schedule Short time interval between sting and initiation of VIT Treatment with beta blockers/ACE inhibitors Clonal mast cell activation syndrome Elevated serum basal tryptase (surrogate marker for anaphylaxis)
Hymenoptera Venom Allergy and Mast Cell Activation Syndrome Most studies do not screen for both SM and clonal mast cell (MC) activation syndrome, limiting the patients included to the ones suffering from urticaria pigmentosa (UP); therefore, MC activation syndrome might be underdiagnosed in such patients. In fact, clonal bone marrow (BM) MC appears to be a relevant risk factor for both HVA and severe reactions to venom immunotherapy, while the increase in serum baseline tryptase by itself should be considered as a powerful surrogate marker for anaphylaxis [71•] (Fig. 1).
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Fig. 1 REMA score and VIT. (Reprinted from González-deOlano et al. [71•]. Copyright 2011; with permission from Future Medicine Ltd.)
The authors have validated a simple and efficient model which is suitable to predict systemic mastocytosis (SM), namely the REMA score. Efficiency of the REMA score for predicting MC clonality and SM was assessed by receiver operating characteristic (ROC) curve analyses and compared to those obtained by means of sBt levels alone. ROC curve analyses confirmed the greater sensitivity and a similar specificity of the REMA score versus sBt levels (84 vs. 59 % and 74 vs. 70 % for MC clonality and 87 vs. 62 % and 73 vs. 71 % for SM, respectively). There is a higher prevalence of indolent systemic mastocytosis (ISM) without skin lesions (ISMs−) in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to BM mast cells (MCs) than ISM with skin lesions (ISMs+). Intriguingly, in almost one half of ISMs− patients, MC-mediator release episodes may be triggered exclusively by insects. In a study which comprised a total of 335 patients presenting with MC activation syndrome, including 143 insect ISMs−, 72 ISMs− triggered by other factors (other ISMs−), 56 ISMs+, and 64 nonclonal MC activation syndrome. Compared with other ISMs− and ISMs+ patients, insect ISMs− cases showed marked male predominance (78 vs 53 and 46 %; p
IMMUNOTHERAPY AND IMMUNOMODULATORS (L COX, SECTION EDITOR)
Venom Immunotherapy: an Updated Review Darío Antolín-Amérigo & Carmen Moreno Aguilar & Arantza Vega & Melchor Alvarez-Mon
# Springer Science+Business Media New York 2014
Abstract Venom immunotherapy (VIT) is the most effective form of specific immunotherapy to date. Hitherto, several relevant queries remain unanswered, namely optimal doses, duration, and means of assessment. Important progress has been lately made in terms of diagnosis by means of component-resolved diagnosis. Moreover, basophil activation test results in patients with negative serum immunoglobulin E (IgE) and skin prick test confer this technique a promising future, although these outcomes shall be considered with caution. This review aims to unravel the important advances made on diagnosis, management, and prognosis and also focuses on several undetermined aspects of VIT.
effective form of specific immunotherapy to date. However, several relevant queries remain unanswered, namely optimal doses, duration, and means of assessment [1••, 2•, 3]. VIT has been a model for the efficacy and reliability of allergen immunotherapy using standardized extracts and treatment regimens [4, 5••, 6•, 7••, 8], achieving an improvement in healthrelated quality of life (HRQL) [9, 10]. This review aims to unravel the important advances made on diagnosis, management, and prognosis and also focuses on several undetermined aspects of VIT.
Keywords Hymenoptera . Immunotherapy . Venom immunotherapy . Diagnosis . Hypersensitivity . Intradermal tests . Tryptase . Mastocytosis . Sensitization . Allergen
Accuracy in the identification of the disease-eliciting allergen is a condition for precise prescription of any successful tailormade treatment, as specific immunotherapy [11••, 12, 13]. In general terms, diagnosis of hymenoptera venom allergy (HVA) is established by a history of anaphylactic sting reactions, positive skin test responses, and/or detection of specific immunoglobulin E (IgE) to a specific venom [14]. Notwithstanding, significant progression has been achieved in the assessment of venom allergic patients, mainly due to component-resolved diagnosis, which helps to distinguish between true double venom allergy and cross-reactivity, in order to assess the appropriateness of the election of a specific venom. In consonance with current guidelines, skin testing for hymenoptera venom allergy should be performed in a stepwise manner, allowing 15- to 20-min intervals between the intradermal tests (IDT) of venom [15, 16•]. Despite the fact that the former recommended scheme has been unquestioned for years, a recent study aimed to assess the safety of simultaneous IDT; consequently, 478 consecutive patients received all venom concentrations (0.02 ml of 0.001, 0.01, 0.1, and 1.0 μg/ml of honey bee and wasp venom), administered simultaneously to the skin. Four hundred and seventy-two
Introduction Insect hypersensitivity affects up to 5–7.5 % of the population. Interestingly, venom immunotherapy (VIT) is the most This article is part of the Topical Collection on Immunotherapy and Immunomodulators D. Antolín-Amérigo (*) : M. Alvarez-Mon Servicio de Enfermedades del Sistema Inmune-Alergia, Hospital Universitario Príncipe de Asturias, Departamento de Medicina, Universidad de Alcalá, Carretera Alcalá-Meco S/N, 28805 Alcalá de Henares, Madrid, Spain e-mail: [email protected] C. Moreno Aguilar Sección Alergia, Hospital Universitario Reina Sofía, Córdoba, Spain A. Vega Sección de Alergología, Gerencia de Atención Integrada de Guadalajara, Guadalajara, Spain
Advances in Diagnosis
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(98.7 %) patients tolerated the simultaneous IDT with two venoms without any side effects, warranting prompt results along with excellent safety [16•]. The analysis of gene expression and subsequent prediction models are a promising tool aimed to enrich VIT assessment, regarding effectiveness and duration of VIT, but also could be useful to circumvent sting challenges [17, 18]; however, it is not commonly performed in clinical practice and remains in most cases for investigational purposes. Component-resolved analysis with recombinant speciesspecific major allergens (rSSMA) may help to distinguish true double sensitization from cross-reactivity [19••], which may be crucial especially when the stinging insect was not identified and when skin tests and specific IgE to the native allergens are unsuccessful for the identification of the culprit insect. The main species-specific major allergens for hymenoptera venom allergy (HVA) are Api m 1 (phospholipase A2) for honeybee, Pol d 1 and Pol d 5 for Polistes, Ves v 1 (phospholipase A1), and Ves v 5 (antigen 5) for Vespula [19••, 20•, 21•, 22] (Table 1), which are produced in a form free of crossreacting carbohydrate determinants (CCDs). Their assessment improves the differential diagnosis among true double sensitization and cross-reactivity [19••]. Recently, rVes v 5-spiked, a yellow jacket venom (YJV) ImmunoCAP enhanced by spiking with rVes v5, demonstrated a more reliable detection of yellow jacket venom (YJV) sensitization in patients with insect venom allergy, improving the sensitivity to 96.8 % [23]. Previously, it was observed that IgE reactivity was higher to the major YJV allergen Ves v 5 than to YJV extract, and sometimes, IgE reactivity was only detectable by Ves v 5 ImmunoCAP. In a study comprising 59 allergic individuals of a Mediterranean region, the determination of specific IgE against phospholipases and antigen 5s seems to be sufficient to discriminate the source of sensitization in vespid-allergic individuals, although regional phenotypes may arise. Interestingly, in this group of Mediterranean patients, very low levels of antigen 5s were seen in about 48 % of patients (12/25 cases) [20•]. However, recombinant Api m 1 has shown extensively variable activity and has limited clinical utility that may be determined by several factors, including the source of the protein [24]. It also seems that, at least in Europe, there may be a north-south decrease in the rate of sensitization to Api m 1, the reason still to be determined. Another issue regarding Api m 1 is the low sensitivity (61.8 %), which has to be improved after further investigation [25•], but maybe these results arose because Api m 1 was recombinant instead of native, which would have elicited enhanced results. On the contrary, Api m 10, albeit a potential relevant allergen, which may be present in 50 % of HBV patients, may be underrepresented in therapeutical extracts [26•]. Recent findings have brought insight into component-resolved diagnosis along with a more precise analysis which will improve the understanding of the underlying
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mechanisms of venom allergy. One of those advances is Api m 6 (serin protease inhibitor), despite the fact that it is underrepresented and consequently may be considered a minor allergen, could be relevant in some phenotypes of HVA [27]. Furthermore, Api m 3, Api m 10, or both have been detected in 68 % of HBV patients and, interestingly, represented the only HBV allergen-specific IgE in 5 % of the patients. Limited inhibition of IgE binding by therapeutic HBV along with limited induction of Api m 3- and Api m 10-specific IgG4 in patients obtaining immunotherapy strengthens latest reports on the potential underrepresentation of these allergens in therapeutic HBV extracts [28]. In general terms, individuals who have not suffered systemic reactions do not undergo additional testing to discard venom allergy (Table 2) [14, 29••]. It has been stated that different risk factors may predispose an individual suffering from HVA to developing severe systemic reactions (SSR), namely serum basal tryptase concentration >5 ng/L, male sex, previous less severe systemic reactions to hymenoptera stings, and ACEinhibitor intake [30]. It remains elusive whether the pattern of sensitization to specific venom allergen components is predictive of the potential benefit of VIT or even of the clinical outcome from a sting [31]. Latest findings suggest that there may be regional differences among sensitized patients [25•]. Basophil activation test (BAT), an in vitro method which identifies and quantifies the potential modifications of specific activation markers on the surface membrane or inside the basophils by flow cytometry, has been proposed for diagnosis of many hypersensitivity reactions. These changes are measured by means of monoclonal antibodies coupled to specific fluorochromes [32]. Basophils are identified by specific markers, namely CCR3+/CD3−, CD123+/HLA-DR−, and IgE+/CD203c+. In a second step, the upregulation of specific activation markers is determined. CD63 and CD 203 are the most commonly used cell markers. It is commercially available for practitioners although it requires a flow cytometer, which is available only in selected centers. BAT is a promising option, evidencing to be more sensitive (80 %) than IDT (50 %), in patients with negative serum IgE and skin prick test results, and also predicting the risk of systemic reactions to VIT [1••, 33–35]. The former is endorsed by a study in which 35 out of 47 patients with a positive history of sting allergy demonstrated a positive basophil CD63 response after stimulation with bee and/or wasp venom. Intradermal venom skin tests resulted positive in 17 (46 %) out of 37 patients who underwent this diagnostic method. Out of 20 patients who showed negative IDR test results, 12 patients showed a positive CD63 response (60 %). Contrarily, out of nine patients who showed a negative CD63 response, only one was detected by IDR testing (11 %) [33, 34].
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Table 1 Component resolved diagnosis and Hymenoptera venom allergy Antigen
Group 1 PLA
Apis mellifera Vespula vulgaris
Api m 2 Api m 1, PLA 2 Sensitivity, 60 %a Ves v 2 Ves v 1, PLA 1 Sensitivity (combined with Ves v 5), 92–96 %a
Polistes Pol d 1, PLA 1 dominula
Group 2 Group 3 Group 4 hyaluronidase acid melittin phosphatase Api m 3
Group 5
Api m 4
Group 10 icarapin
Carbohydrates Vitellogenin
Api m 10
MUXF3
Api m 12
MUXF3
Ves v 6
Ves v 5 Sensitivity, 83.4 %a Sensitivity (combined with Ves v 1), 92–96 %a Ves v 5-spiked Sensitivity, 96.8 %a Pol d 5
Pol d 2
Api m 3 and Api m 10 may represent the only HBV allergen specific IgE in up to 5% of the patients. Moreover: 68% of patients show IgE reactivity to Api m 3, Api m 10 or both Köhler et al. [28] a
Data from Vos et al. [23] and Korošec et al. [24•]
However, in a study performed over 52 patients diagnosed from mastocytosis who had suffered from previous hymenoptera stings, after performing usual tests (namely skin tests and serum specific Immunoglobulin E (sIgE) against hymenoptera venoms), seven resulted negative to diagnostic tests. In six of seven of those patients, BAT was negative with all venoms. Therefore, BAT could be useful to confirm previous tests [35, 36•, 37]. The utility of BAT has been shown in 14 patients who still reacted to bee or wasp sting, where basophil response at a venom concentration of 0.1 μg/mL was significantly higher than in patients who tolerated field re-stings (p=0.03; t test), so it may be used to assess VIT efficiency [38]. Moreover, after 2– 4 years of VIT, a marked CD63 decrease was evident in 85 % of 31 children who underwent honeybee (HB) immunotherapy. In addition, elevated basophil sensitivity measured in this group of children before VIT was associated with the appearance of side effects observed during the buildup phase [39] and was predictive of HB sensitivity after VIT (clinical relapse). Though promising, BAT remains to be standardized in terms of methodology and interpretation; consequently, these results shall be considered with caution [1••, 3].
Table 2 Decision regarding VIT based on diagnostic tests (adults/ children)
Efficacy of VIT and Its Assessment In a recent meta-analysis comprising six randomized controlled studies and one quasi-randomized controlled study [40••], VIT proved to be effective for preventing systemic allergic reactions to an insect sting, either accidentally or by means of in-hospital controlled sting challenge. In the trials, 3/113 (2.7 %) participants treated with VIT experienced a subsequent systemic allergic reaction to a sting, compared with 37/93 (39.8 %) untreated participants (risk ratio [RR] 0.10, 95 % confidence interval [CI] 0.03 to 0.28). Moreover, VIT displayed effectiveness in preventing large local reactions to a sting (RR 0.41, 95 % CI 0.24 to 0.69) and for improving quality of life (mean difference [MD] in favor of VIT 1.21 points on a 7-point scale, 95 % CI 0.75 to 1.67) [9, 10]. The honey bee (HB) sting challenge is considered until now a reliable and irreplaceable approach to evaluate the efficacy of VIT [15, 54•, 41], but it has the hurdle of requiring live insects and inducing severe and potentially life-threatening anaphylaxis. Hence, a potential new means of assessing VIT efficacy using a microsyringe has been developed, comparing its feasibility and reliability with stan-
Type reaction
Diagnostic tests ST and/ or IgE
Decision regarding venom immunotherapy
Respiratory and cardiovascular symptoms
Positive Negative Positive
Yes No Yes
Negative Positive* Negative Positive Negative
No Yes* No No No
Urticaria if risk factors or quality of life impairment present Large local* *If life-threatening and/or quality of life impairment + high exposure + positive diagnostic tests, VIT shall be considered
Unusual
449, Page 4 of 12
dard sting challenge. Patients on bee VIT and without systemic reactions at field sting were enrolled [42]. Nineteen patients underwent a sting challenge with live bee, and large local reactions (LLR) were assessed up to 48 h. Those patients displaying systemic reactions at the sting challenge were excluded from the syringe challenge, for ethical reasons. The syringe challenge was fulfilled in 15 patients, by injecting 0.5 μL fresh unfiltered bee venom at 2-mm depth (the length of the sting left by a bee). The same follow-up as at the first challenge was performed. Bee-specific immunoglobulin E (IgE) and tryptase were measured after each challenge. Nineteen patients underwent the sting challenge with live bees. Four had immediate systemic reactions (urticaria or asthma) and were excluded from the second challenge. The remaining 15 patients with LLR underwent the syringe challenge. No significant difference was seen in the maximum area of the LLR between the challenge with live bees and the syringe challenge. Also, no change was seen in tryptase and specific antibodies. In patients with a history of systemic reactions to stings, the frequency of systemic reactions to subsequent stings is correlated with the severity of the previous reactions. In a study using challenge stings, systemic reactions occurred in more than 40 % of those with previous severe reactions but only 23 % in those with previous moderate systemic reactions and 17 % in those with mild (cutaneous) systemic reactions [43]. A surprising proportion (up to 30 % in several large studies) of people with a history of systemic reaction to a sting has negative venom skin test results. However, many of these individuals have positive serum IgE test results, leaving approximately 15 % of history-positive patients with no detectable venom-specific IgE. In sting challenge studies, only approximately 6 % of such individuals have a systemic reaction to a challenge sting [43, 54•]. There are many potential reasons for venom skin test results to be negative despite a convincing history. The test results can be negative in 20 to 50 % of patients during the refractory period soon after a sting reaction but are positive 4 to 6 weeks after the sting. Another possible problem is the inherent variability of venom skin tests, which can reveal a 10fold increase or decrease in the concentration for a positive result when performed weeks or months apart. The clinical implication is the potential to omit a particular venom in treatment when a subsequent test could have a positive result. Skin tests and sIgE against the culprit venom once a year have been used as means of assessment of the efficacy, showing improvement and even negativization of the former after completing VIT [44]. Venom skin test and serum IgE usually decline in a linear fashion (on a logarithmic scale) after stopping treatment [45]. This decline tends to continue despite sting challenge every 2–4 years, although there is a transient increase in serum IgE (but not skin tests) after each sting. Concerning novel data in relation to immune system modification, elevated VIT initiation doses and rush or ultrarush
Curr Allergy Asthma Rep (2014) 14:449
protocols have demonstrated efficacy [46] and even elicited immunological changes after 24 h of use, such as a significant decrease of sCTLA-4 [47•]. Furthermore, basophil threshold sensitivity to antihigh-affinity IgE receptor (FceRI) stimulation and FceRI gene and cell-surface expression at the beginning and just before the first maintenance dose in ultrarush and/or semi-rush VIT have been investigated, evincing marked desensitization of FceRI-activated basophils, after short-term VIT [48]. Other proposed early markers of immunotherapy with protective effects comprise the following: increased tryptophan degradation and IL-10 levels, production of IL-10 cells, and in the same line, the upregulation of histamine receptor 2 [49–51]. Additional studies have shown attenuated histamine, sulfidoleukotriene, and cytokine release even 1 week after the initiation of VIT [52]. Therefore, efficacy can be assessed and demonstrated, at least both theoretically and experimentally, during the early course of VIT. Although there is poor correlation between the amount of serum specific IgG (sIgG) and clinical protection, sIgG correlates with the dose of allergen that has been given, yet in most studies, the changes in serum levels showed no relationship with clinical response [53]. Schemes and Dosage Up-dosing schedules are diverse and difficult to compare, due to the heterogeneity in patient conditions, comorbidities, extracts used, and protocols among different hospitals, even in a specific country. Hence, this question remains unsolved and probably the best initiation schedule would be the one that suited an individual with its own clinical characteristics in a particular clinical setting, always aiming to optimize safety, efficacy, time, and convenience. Despite the fact that VIT is notably effective, there are enclosed adverse reactions [54•] (Tables 3, 4, 5, 6, and 7). Notwithstanding that their comparison is challenging, due to the heterogeneity of the variables and methods recorded in the former, in general, protocols for VIT may be divided into slow protocols, in which the time required to fulfill the maintenance dose (generally of 100 mcg) is several weeks (weekly intervals), with a rush protocol is several days (4–7 days), with an ultrarapid or ultrarush is few hours or 1–2 days, or cluster (a modified rush approach schedule, which involves administering several injections at 15–30-min intervals during the first visits and reaches a maintenance dose in about 6 weeks). It is strongly suggested to weigh the pros and cons of an ultrarush therapy and providing particular surveillance to those patients actually receiving that type of buildup. Nevertheless, rush and ultrarush protocols are cost-effective, making them suitable and desirable for both patients and physicians [55, 56]. In Europe, purified and nonpurified aqueous venom extracts are commercially available for the rush, ultrarush, and clustered and maintenance phases, and aluminum hydroxide
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Table 3 Ultrarush buildup protocols and percentage of systemic adverse reactions (SAR) First author
Year
Number of samples
Type of study
Bee/wasp
Cumulative dose
Time (min)
SAR (%)
Schiavino
2004
57
Prosp.
9:48
101
150
Patella Birnbaum Birnbaum
2012 1993 2003
27 217 258 (children, adults)
Prosp. Retrosp. Retrosp.
9:18 Bee, wasp 90:235
111 101 101
180 210 210
Köhli-Wiesner Roll
2012 2003
94 (children) 67
Retrosp. Retrosp.
65:37 (8 both) 20:47 (13 both)
111 111
210 240
Bee 11 Wasp 6 0 6.9 Bee 30 Wasp 3.2–6.1 16 17.5
adsorbed (depot) preparations for the conventional buildup and maintenance phases [57]. In Europe, where the recommended maintenance dose is 100 μg on a monthly basis, both for children and adults, the proven rate of protection in terms of honeybee immunotherapy is 77–94 %, while vespid VIT accomplished 91–100 % [2•, 14]. However, 200 μg may be suitable for those patients who have experienced systemic reactions after a sting in spite of following VIT with 100 μg or in exposed populations, such as beekeepers [58]. Likewise, American extracts for vespid venom allergy, which may contain up to 300 μg provide considerable efficacy rates of 98 % [2•]. Despite current European guidelines recommend 100 μg monthly for children as maintenance dose, there is evidence that 50 μg/month during 5 years proved to be safe and effective enough to induce tolerance in children with hymenoptera venom hypersensitivity [59]. Until present, no placebocontrolled prospective studies have been devised in terms of VIT, due to the potentially life-threatening condition that a Table 4 Rush buildup protocols and percentage of systemic adverse reactions (SAR)
NPA nonpurified aqueous, PA purified aqueous
sting may suppose for those patients who would be allocated in the placebo group. One study showed a significant dosedependent increase in serum venom-specific immunoglobulin G (IgG) and greater clinical efficacy in patients receiving 100-μg monthly venom maintenance dose instead of a 50-μg monthly maintenance dose [11••, 58]. With regard to the interval of VIT administration during maintenance phase, current guidelines favor 4- to 6-week intervals [14]. Nonetheless, several studies promote extended maintenance doses (EMD), ranging from 2 to 4 months [60–62, 63•], showing comparable efficacy and increasing convenience of both the patients and the physicians. Seventy-six patients (60 male; mean age 48 years) receiving the EMD (3- or 4-month interval) were re-stung on 247 occasions by the insect for which they were receiving immunotherapy. The group receiving conventional maintenance dose (CMD) included 110 patients (82 male; mean age 44 years) certainly re-stung on 167 occasions by the specific insect. The percentage of re-sting without reaction was 93.5 % in the EMD group and 81.5 % in the CMD group,
First author
Year
Number of samples
Type of study
Bee/ wasp
Cumulative dose
Time (days)
SAR (%)
Brehler Goldberg
2000 2011
403 179
Retrosp. Retrosp.
57:346 93:47a
350 264
2 3
Sturm Birnbaum Patella Wenzel Brehler Sánchez-Morillas
2002 1993 2012 2003 2000 2005
101 46 25 178 335 44
Retrosp. Retrosp. Prosp. Retrosp. Retrosp. Retrosp.
52:49 Bee, wasp 9:16 24:154b 32:303 7:32c
339 530 223 556 415 325.5
4 4 5 7 3–6 3
Bilò
2012
80
Prosp.
Bee
223.11
5
Bilò
2009
94
Prosp.
38:56
–
Bee 7 Wasp 2
10.7 Bee 31.1 Wasp 16.3 6.9 28.2 9 17.9 13.7 Bee 14.3 Wasp 3.1 NPA 27.5 PA 2.5 NPA 27.5
Yunginger Quercia
1979 2006
20 35
Retrosp. Retrosp.
Bee Bee
200 –
3 –
a
1 4 p a t i e n t s Ve s p u l a + Dolichovespula VIT
b
2 patients bee and wasp VIT
c
8 patients various wasp venoms
PA 2.5 85 20
449, Page 6 of 12 Table 5 Semi-rush buildup protocols and percentage of side effects
n.a. not available a
Two patients wasp+bee VIT
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First author
Year
Number of samples
Type of study
Bee/ wasp
Cumulative dose
Time (days)
SAR (%)
Ruëff
1997
144
Retrosp.
560
5–7
16.7
555
7
17.8
430 n.a.
7–9 n.a.
22.4 39
Wenzel
2003
178
Retrosp.
Bee, wasp 26:152a
Brehler Przybilla
2000 1987
317 282
Retrosp. Retrosp.
33:284 n.a.
with a significant difference in favor of the former (p=0.001); therefore, the EMD regimen was comparable both in efficacy and safety to the conventional maintenance dose schedule [63•]. Currently, the common accepted policy for stopping immunotherapy is 3–5 years; however, longer-term treatment shall be considered in those patients with a higher risk of severe systemic reactions (SSR) (e.g., older age, history of previous SSR, elevated basal serum tryptase, mast cell activation syndrome, or use of beta-blockers) [2•]. Prolonged VIT seems to reduce the risk of a relapse. Thus in one study, SR to re-sting discontinuing VIT was reported on only 4.8 % of 82 patients with a VIT duration of ≥50 months as opposed to 17.8 % of 118 with a VIT duration of 33–49 months [14, 64, 65]. Safety of VIT On the other hand, the observational prospective multicenter study performed over 680 patients by the Insect Venom Allergy Interest Group of the EAACI [30] aimed to identify independent predictors for a higher complication rate during VIT. According to the results of the study, risk factors for an emergency intervention during immunotherapy were the following: honeybee VIT using rush or ultrarush protocols; younger age; the type of dose increase (ultrarush, rush) during therapy; a long interval between the most recent sting reaction and VIT; an accompanying antihypertensive therapy; basal tryptase concentration (BTC) for vespid allergic patients (odds ratio 2.337; 95 % CI 1.279–4.260; pvespid venom Buildup phase>maintenance phase Elderly age Dose increase schedule Short time interval between sting and initiation of VIT Treatment with beta blockers/ACE inhibitors Clonal mast cell activation syndrome Elevated serum basal tryptase (surrogate marker for anaphylaxis)
Hymenoptera Venom Allergy and Mast Cell Activation Syndrome Most studies do not screen for both SM and clonal mast cell (MC) activation syndrome, limiting the patients included to the ones suffering from urticaria pigmentosa (UP); therefore, MC activation syndrome might be underdiagnosed in such patients. In fact, clonal bone marrow (BM) MC appears to be a relevant risk factor for both HVA and severe reactions to venom immunotherapy, while the increase in serum baseline tryptase by itself should be considered as a powerful surrogate marker for anaphylaxis [71•] (Fig. 1).
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Fig. 1 REMA score and VIT. (Reprinted from González-deOlano et al. [71•]. Copyright 2011; with permission from Future Medicine Ltd.)
The authors have validated a simple and efficient model which is suitable to predict systemic mastocytosis (SM), namely the REMA score. Efficiency of the REMA score for predicting MC clonality and SM was assessed by receiver operating characteristic (ROC) curve analyses and compared to those obtained by means of sBt levels alone. ROC curve analyses confirmed the greater sensitivity and a similar specificity of the REMA score versus sBt levels (84 vs. 59 % and 74 vs. 70 % for MC clonality and 87 vs. 62 % and 73 vs. 71 % for SM, respectively). There is a higher prevalence of indolent systemic mastocytosis (ISM) without skin lesions (ISMs−) in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to BM mast cells (MCs) than ISM with skin lesions (ISMs+). Intriguingly, in almost one half of ISMs− patients, MC-mediator release episodes may be triggered exclusively by insects. In a study which comprised a total of 335 patients presenting with MC activation syndrome, including 143 insect ISMs−, 72 ISMs− triggered by other factors (other ISMs−), 56 ISMs+, and 64 nonclonal MC activation syndrome. Compared with other ISMs− and ISMs+ patients, insect ISMs− cases showed marked male predominance (78 vs 53 and 46 %; p
