Venom Immunotherapy In Patients Research Articles

COVID-19 vaccination in the setting of mastocytosis—Pfizer-BioNTech mRNA vaccine is safe and well tolerated

COVID-19 vaccination in the setting of mastocytosis—Pfizer-BioNTech mRNA vaccine is safe and well tolerated

The Asian wasp Vespa velutina nigrithorax: Entomological and allergological characteristics.

The yellow-legged or Asian wasp (Vespa velutina nigrithorax) has spread rapidly across Europe since its first introduction in France, in 2004. Originally from South-East Asia, it is considered an invasive species outside its native region. Apart from the ecological and economic implications of its presence, it may cause health problems to humans due to the toxic and allergenic components of its venom. Vespa velutina nigrithorax has become the most prevalent cause of anaphylaxis due to Hymenoptera venom in some regions of Spain. Although sIgE against both antigen 5 (Vesp v 5) and A1-phospholipase (Vesp v 1) has been detected in these patients, only Vesp v 5 may be considered a dominant allergen. Interestingly, Vesp v 1 appears to be a glycosylated allergen different from A1-phospholipases from other species. Inhibition studies suggest that Vespula spp venom could behave as primary sensitizer. Besides, changes in sIgE and sIgG4 during Vespula venom immunotherapy in patients with anaphylaxis due to V.velutina support the use of Vespula venom extracts to treat these patients. The purpose of this review is to explore the biological behaviour of V.velutina and to summarize the current knowledge of the allergic reactions provoked by this wasp.

Prevalence of mastocytosis and Hymenoptera venom allergy in the United States

Mastocytosis is a risk factor for Hymenoptera venom anaphylaxis (HVA). Current guidelines recommend measuring tryptase in patients with HVA and that those with mastocytosis pursue lifelong venom immunotherapy (VIT). Available data on HVA and mastocytosis largely derive from European single-center studies, and the prevalence of HVA with and without mastocytosis in the United States is unknown. We sought to determine the prevalence of HVA and mastocytosis in the United States using an insurance claims database and evaluate the impact of mastocytosis on VIT in patients with HVA in a US cohort. The IBM Watson Database, consisting of insurance claims from approximately 27 million US patients in 2018, was queried to identify patients with HVA and/or mastocytosis. Furthermore, a retrospective study of 161 patients undergoing VIT between 2015 and 2018 at the University of Michigan was conducted. In the IBM Watson Database, the prevalence of HVA was 167 per 100,000 (0.167%) and the prevalence of mastocytosis 10 per 100,000 (0.010%) overall and 97 per 100,000 (0.097%) among those with HVA. Mastocytosis showed a 9.7-fold increase among patients with HVA versus the general population. In the U-M cohort, 2.6% of patients with VIT had mastocytosis. Tryptase level did not correlate with venom reaction severity but was higher in patients with systemic VIT reactions. We observed a lower US HVA prevalence than previously reported. Mastocytosis was more common in US patients with HVA, though at lower rates than previously reported. In patients with VIT there was no correlation between tryptase level and reaction severity.

Safety and Adherence to Venom Immunotherapy During COVID-19 Pandemic

BackgroundAccording to expert consensus, the time interval between Hymenoptera venom immunotherapy (VIT) injections can be extended up to 12 weeks, without significant impact on efficacy and safety. However, the coronavirus disease 2019 pandemic caused longer delays, and no recommendations are available to manage this huge extension.ObjectivesTo provide advice on how to resume VIT safely after a long delay from the last injection considering the potential risk factors for side effects, without starting again with the induction phase.MethodsAll the patients who delayed VIT because of the pandemic were consecutively enrolled in this single-center study. The time extension was decided according to their risk profile (eg, long prepandemic time interval, severe pre-VIT reaction, older age, multitreatments), and correlation analyses were performed to find potential risk factors of side effects.ResultsThe mean delay from the pre- (7 weeks) to the postpandemic VIT interval (15.5 weeks) was 8.5 weeks. The total amount of the prepandemic VIT maintenance dose was safely administered in 1 day in 78% of patients, whereas only 3, of 87, experienced side effects, and their potential risk factors were identified in bee venom allergy and recent VIT initiation.ConclusionsIn a real-world setting, long VIT delays may be safe and well tolerated, but more caution should be paid in resuming VIT in patients with long prepandemic maintenance interval, severe pre-VIT reaction, recent VIT initiation, older age, multidrug treatments, and bee venom allergy. This is useful in any case of long, unplanned, and unavoidable VIT delay.

Venom immunotherapy in patients with mastocytosis

Venom immunotherapy in patients with mastocytosis

Venom immunotherapy in patients with mastocytosis

Background: A clear relationship has been demonstrated between hymenoptera venom anaphylaxis (HVA) and primary mast cell activation syndromes (MCAS). Methods: This review describes the clinical and biological characteristics of patients with primary MCAS who present with HVA, the diagnostic tests that have demonstrated to be useful, and the safety and effectiveness of venom immunotherapy (VIT) in these individuals. Results: Patients presenting with dizziness or hypotension and without skin involvement after an insect sting are at an increased risk of presenting clonal mast cells (MCs). They usually have low MC burden and highly sensitive techniques are mandatory to reach a final assessment. Skin testing and determinations of specific IgE are useful in detecting patients who are candidates for VIT, which has proved to be safe and effective. Conclusions: Patients with primary MCAS and IgE-mediated HVA are candidates to receive VIT. Their management does not differ much from general population with the exception of VIT duration.

Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection.

Patients with clonal mast cell disorders (cMCD), systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS), represent an increased risk for Hymenoptera venom anaphylaxis (HVA). Lifelong venom immunotherapy (VIT) is recommended; however, its efficacy and safety are controversial. Hence, we sought to evaluate the efficacy and safety of VIT in HVA patients with cMCD. A retrospective study was conducted among 46 patients with Vespula venom allergy who had experienced severe HVA, 32 cMCD (22 with SM and 10 with MMAS) and 14 controls. There were no differences between cMCD patients and controls in age (58 vs 66) and duration of VIT (47 vs 48months), respectively. During VIT, 11 (34%) cMCD patients experienced adverse reactions (ARs) (7% in controls), including 1 anaphylaxis. There were 23 re-stings in 17 (53%) patients during VIT. Of episodes, four (17%) presented with anaphylaxis, 14 (60%) presented with local reaction, and five (23%) were asymptomatic. In 11 episodes (48%), the patient did not take epinephrine, of these 8 (73%) presented with local reaction, and 3 (27%) were asymptomatic. Patient-based protection from anaphylaxis was 76% (4/17) in cMCD vs. 100% in controls during VIT. The venom-specific IgG4 concentrations increased during VIT (P<.001) although tryptase and IgE were unaltered. Both safety and efficacy of VIT in cMCD patients were slightly reduced than controls. Severe ARs were rare. The elevated IgG4 levels may be a biomarker for efficacy of VIT in cMCD patients, as it correlates with protection from re-stings.

Exclusive Bee Venom Allergy: Risk Factors and Outcome of Immunotherapy

Introduction: Venom immunotherapy (VIT) is considered to be the gold-standard treatment for patients with Hymenoptera venom allergy. Data regarding VIT in bee venom (BV) allergic patients are scarce. Aim: The aim of this study was to evaluate the outcome of VIT in patients with exclusive BV allergy and to try to define risk factors for VIT-induced systemic reactions (VIT-ISR) and VIT failure. Methods: This is a retrospective study including data from all BV allergic patients that were treated by VIT in the Allergy Unit at the Meir Medical Center in the years 1995–2018. Results: Two hundred and forty-seven patients with exclusive BV allergy were included; 206 (83.4%) preferred to undergo rush buildup. Sixty-nine patients (27.9%) had at least 1 reaction during buildup, with the c-kit mutation being the only significant risk factor (100 vs. 28.9%, p = 0.02). Female gender (25.4 vs. 13.3%, p = 0.04), conventional buildup schedule (26.8 vs. 14.1%, p = 0.04), and c-kit mutation (100 vs. 16.8%, p < 0.01) but not tryptase level were found to be significantly more frequent in recurrent reactors. Females (20.3 vs. 9%, p = 0.03), patients with severe systemic reaction to the index sting (24.3 vs. 9.5%, p = 0.004), and c-kit mutation (66 vs. 12%, p = 0.05) but not tryptase level were found to be risk factors for severe systemic reactions. Conclusion: Despite the considerably high rate of VIT-ISR in patients with exclusive BV allergy, VIT can be performed safely and efficiently. C-kit mutation, and not basal serum tryptase level, seems to be a preferable biomarker for VIT-ISR in these patients.

An institutional review of flying Hymenoptera venom immunotherapy in patients with cutaneous systemic reactions only

An institutional review of flying Hymenoptera venom immunotherapy in patients with cutaneous systemic reactions only

Triple IgE-positivity to hornet, wasp and bee venom in the patient with anaphylaxis: Diagnostic and therapeutic approach

Introduction. Triple-positivity (TP) or double-positivity (DP) for serum-specific immunoglobulin E (sIgE) antibodies against hornet venom (HV), wasp venom (WV) and/or honeybee venom (BV) causes significant problem in a selection of appropriate venom immunotherapy. However, DP/TP can be caused by cross-reactions resulting either from partial sequence identity of protein allergens in the venoms, or may be related to cross-reacting carbohydrate determinants (CCDs). Case report. A 60-year-old man was stung by a wasp and two days later by hornet. In both cases, within 15 minutes he developed hypotension and generalized urticaria and he was successfully treated with epinephrine, corticosteroids and fluids. After eight weeks, the examination revealed the negative skin prick test for all three venoms, but the sIgE-determination (ELISA, Biopharm) showed triple sensitization to native BV (0.55 IU/mL), WV (3.35 IU/mL) and HV (0.37 IU/mL). He was receiving the venom immunotherapy with venom mixtures for one year. In order to distinguish true multiple sensitization from cross-reactivity, the molecular-allergy testing by ImmunCAP with the CCD-free recombinant major allergens was performed. A high sensitization to Antigen 5-rVes v5 of WV (31.4 kU/L) was demonstrated while sIgE to phospholipase A2-rApi m1 of BV (0.15 kU/L) was negative; sIgE to CCDMUXF3- bromelain (0.75 kU/L) explained the sIgE-positivity for native BV. After these findings, a venom immunotherapy only with WV was initiated. Conclusion. In our patient, triple-IgE-positivity to native venoms detected by the ELISA was caused by cross-reactivity to CCDs. We recommend the molecular-allergy testing with the nonglycosylated recombinant allergens before starting the venom immunotherapy in patients with multiple-sIgE-positivity to native Hymenoptera venoms.

Specific Immunotherapy in Hymenoptera Venom Allergy and Concomitant Malignancy: A Retrospective Follow-up Focusing on Effectiveness and Safety.

Malignancies are often considered a contraindication for allergen-specific immunotherapy. Consequently, patients with severe Hymenoptera venom allergy and cancer require specific care. The aim of this retrospective study was to assess patients with Hymenoptera venom allergy and cancer undergoing venom immunotherapy (VIT). The study population comprised all patients referred for evaluation of Hymenoptera venom allergy or for a routine check-up during VIT from January 1, 2004 to December 31, 2008. Of the patients assessed, 2% (51 of 2594) had a documented Hymenoptera venom allergy and cancer (25 female, 26 male; mean age 58 years). Of these, 42 patients received VIT (82%): 25 patients had a previously diagnosed malignancy, 16 were diagnosed with malignancy during VIT, and 1 patient was diagnosed with cancer after completion of VIT. The most frequent type of tumor was breast cancer in female patients (60%) and prostate cancer in male patients (39%). Systemic allergic reactions during VIT were recorded in 7% of patients. A total of 19 patients experienced a field sting or underwent a sting challenge test during VIT: 95% tolerated the sting well. VIT was halted definitively in 9 patients (new diagnosis of cancer in 7 patients, reactivation of cancer in 1, and progressive polyneuropathy in 1). The effectiveness and adverse effects of VIT in patients with Hymenoptera venom allergy and cancer in remission are comparable to those of patients without malignancy. Our findings show that patients with Hymenoptera venom allergy and cancer are eligible for VIT.

Venom Immunotherapy in High-Risk Patients: The Advantage of the Rush Build-Up Protocol

Background: Venom immunotherapy (VIT) is considered to be the gold standard treatment for patients with hymenoptera venom allergy. This treatment induces systemic reactions (SR) in a significant number of patients. Objective: To evaluate the outcome of VIT in patients with known risk factors for VIT-induced SR and to compare rush VIT (RVIT) and conventional VIT (CVIT). Methods: All of the patients who received VIT and had at least one of the following risk factors were included: current cardiovascular disease, uncontrolled asthma, high basal serum tryptase, current treatment with β-blockers or angiotensin-converting enzyme inhibitors, and age >70 or <5 years. Results: Sixty-four patients were included, and most of them (52; 81.5%) were allergic exclusively to bee venom. Thirty-five (54.7%) patients underwent RVIT and 29 CVIT. The incidence of patients who developed SR during the build-up phase was similar for RVIT and CVIT (25.7 and 27.5%, respectively; p = 1). However, the incidence of SR per injection was significantly higher in CVIT than in RVIT (5.6 and 2.75%, respectively; p = 0.01). Most reactions (79.1%) were mild, limited to the skin. Most of the patients (92.1%) reached the full maintenance dose of 100 μg. This dose was reached by a significantly larger number of patients receiving RVIT compared to CVIT (100 and 82.7%, respectively; p = 0.01). None of the patients experienced exacerbation of their concurrent chronic disease during VIT. Conclusion: VIT can be performed safely and efficiently in patients with risk factors for immunotherapy. In these patients RVIT appears to be safer and more efficient than CVIT.

Venom Immunotherapy in Patients with Clonal Mast Cell Disorders: Efficacy, Safety, and Practical Considerations

A preferential association between systemic mastocytosis (SM) and hymenoptera allergy (HVA) has been observed. Patients with both diseases are at risk for more severe reactions, and venom immunotherapy (VIT) may represent a life-saving treatment, but the use of VIT in such patients raised concerns about its safety. We evaluated a large population of patients with SM and HVA who received VIT. This prospective study was performed in Italy and Spain. A diagnosis of SM and HVA and a VIT prescription were made according to international recommendations. The patients were carefully followed up during VIT, with special attention to field stings. A total of 84 patients (70 men, 14 women; mean age 52.1 years) were included, 81% with grade IV reaction, 91% with indolent SM. No difference was seen between the Italian and Spanish patients. There were 10 adverse reactions during the induction phase: 3 with the conventional induction and 7 with the rush-modified induction, none resulted in epinephrine administration and/or hospitalization. Fifty patients had one or more field re-sting (95 episodes), none during induction. The time elapsed from starting VIT and first re-sting was 2 months to 7 years, and the number of re-stings per patient was 1-6. Of the 50 patients who were re-stung, 43 (86%) resulted in being fully protected. Seven patients had reactions, and the maintenance dose was safely increased to 200 mcg. The maintenance dose interval was not different between patients with and those without reactions at re-stings. VIT is well tolerated, safe, and effective in patients with SM.

Venom Immunotherapy in Patients with Clonal Mast CELL Disorders: Efficacy, Safety and Practical Considerations

A preferential association between systemic mastocytosis (SM) and hymenoptera allergy (HVA) has been observed. Patients with both diseases are at risk for more severe reactions and venom immunotherapy (VIT) represents a life-saving treatment. Immunotherapy in patients with mastocytosis raised concerns about safety. We evaluated a large population of patients with SM and HVA receiving VIT. This study was carried out in Italy and Spain. Diagnosis of SM and HVA and VIT prescription were made according to international recommendations. Patients’ were fully characterized and followed-up during VIT, expecially for field stings. 84 patients (70 male, mean age 52.1), were included, 81% with grade IV reaction, 91% with indolent SM. No relevant difference was seen between Italian and Spanish patients. VIT was well tolerated. There were 10 adverse reactions during the induction: 3 with conventional induction and 7 with rush-modified regimen, none in epinephrine administration or hospitalization. Fifty patients had one or more field resting, for a total of 95 episodes, none during the build-up. Time elapsed from starting of VIT and first resting was 2 months to 7 years, and number of restings per patient ranged from 1 to 6. Of the 50 restung patients 43 (86%) resulted to be fully protected. Seven patients had reactions (4 maintenance dose was increased to 200 mcg). The maintenance dose interval was not significantly different between patients with and without reactions at restings. VIT is well tolerated, safe and effective in patients with SM. Slow induction protocols would be preferred.

Venom Immunotherapy in Patients with Mastocytosis and Hymenoptera Venom Anaphylaxis

Systemic mastocytosis (SM) is typically suspected in patients with cutaneous mastocytosis (CM). In recent years, the presence of clonal mast cells (MCs) in a subset of patients with systemic symptoms associated with MC activation in the absence of CM has been reported and termed monoclonal MC activation syndromes or clonal systemic MC activation syndromes. In these cases, bone marrow (BM) MC numbers are usually lower than in SM with CM, there are no detectable BM MC aggregates, and serum baseline tryptase is often <20 µg/l; thus, diagnosis of SM in these patients should be based on careful evaluation of other minor WHO criteria for SM in reference centers, where highly sensitive techniques for immunophenotypic analysis and investigation of KIT mutations on fluorescence-activated cell sorter-purified BM MCs are routinely performed. The prevalence of hymenoptera venom anaphylaxis (HVA) among SM patients is higher than among the normal population and it has been reported to be approximately 5%. In SM patients with IgE-mediated HVA, venom immunotherapy is safe and effective and it should be prescribed lifelong. Severe adverse reactions to hymenoptera stings or venom immunotherapy have been associated with increased serum baseline tryptase; however, presence of clonal MC has not been ruled out in most reports and thus both SM and clonal MC activation syndrome might be underdiagnosed in such patients. In fact, clonal 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. The Spanish Network on Mastocytosis has developed a scoring system based on patient gender, the clinical symptoms observed during anaphylaxis and serum baseline tryptase to predict for the presence of both MC clonality and SM among individuals who suffer from anaphylaxis.

Evaluation of basophil activation in mastocytosis with Hymenoptera venom anaphylaxis

Basophil activation tests (BATs) have been demonstrated to be useful in detecting IgE-mediated sensitization by measuring basophil activation surface markers (CD63 and CD203c). Hymenoptera venom is one of the best known mediators-release trigger in patients with systemic mastocytosis (SM). The aim of this study was to investigate the use of BATs as an additional diagnostic tool in patients with mastocytosis suffering from hymenoptera venom anaphylaxis (HVA). A total of 22 patients with history of HVA and SM, together with a group of 11 patients with HVA in whom SM was ruled out after a complete bone marrow study, were analyzed. Among 11 SM patients who had specific serum IgE (sIgE) against hymenoptera venom and an evaluable BAT, a positive BAT was found in nine. Additionally, a positive BAT was detected in three of seven patients who had no sIgE. These three patients had low levels of total IgE compared with control population (mean of 20 vs. 78 IU/mL); one had discontinued immunotherapy after 5 years, when sIgE levels had turned negative, and, in the other two patients, BAT identified the culprit insect. BAT is a useful complementary diagnostic tool to sIgE in mastocytosis patients with HVA, and it may contribute to predict or confirm these nearly fatal reactions, especially before discontinuing venom immunotherapy in patients who are negative for skin tests or sIgE or display low total IgE levels; in such cases, it also provides evidence on the culprit insect prompting HVA.

Practice of venom immunotherapy in the United Kingdom: a national audit and review of literature

Venom immunotherapy (VIT) is the only effective treatment for prevention of serious allergic reactions to bee and wasp stings in sensitized individuals. However, controversies exist relating to diagnosis, indications for treatment and treatment schedules. We audited current practice of VIT in the United Kingdom to evaluate adherence to international guidelines. An online questionnaire was sent to all clinicians practising immunotherapy identified on the British Society of Allergy and Clinical Immunology website. Eighty-six questionnaires were sent and 53 responses (61.6%) were received. Of these, 48 (85%) carried out VIT at their centre. Skin prick tests (SPT) and serum venom-specific IgE (SSIgE) were equally preferred as first-line investigation. Fifty percent of the respondents perform intradermal tests if both SPT and SSIgE are negative. While 8% of respondents commence VIT in patients with negative SSIgE and a history of severe reaction, 57% prefer to repeat the tests in 6-12 months if serum tryptase is elevated. If the insect responsible is uncertain and SSIgE is detected against bee and wasp venoms, 22% of the respondents will desensitize to both while 32% initiate treatment against the venom with the higher SSIgE. A protocol of weekly up-dosing for 12 weeks is preferred for induction and only 25% of respondents have ever used rush or ultra-rush protocols. Three years is thought to be optimum duration of VIT by most (56%). Eleven percent perform sting challenges at the end of treatment. Although 47% measure SSIgE at the end of treatment, only 3% use these results as a basis for discontinuing VIT. Currently there is considerable variation in the diagnosis and management of hymenoptera venom allergy in the United Kingdom. This audit has demonstrated that the current international guidelines for the diagnosis and management of hymenoptera venom allergy are not being followed by UK allergy practitioners.

Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis

Anaphylaxis after Hymenoptera sting has been described in patients with mastocytosis. Venom immunotherapy (VIT) is a safe and effective way to treat patients with Hymenoptera anaphylaxis, but few studies have addressed its usefulness in patients with systemic mastocytosis. To study the effectiveness and safety of VIT in patients with systemic mastocytosis having anaphylaxis after Hymenoptera sting. A total of 21 mastocytosis patients-4 women (19%) and 17 men (81%) with a median age of 50 years (range, 29-74 years)-with Hymenoptera sting anaphylaxis who were treated with VIT and followed for a median of 52 months (range, 2-250 months) were studied. In 18 of 21 patients-16 of them lacking skin involvement-anaphylaxis was the presenting symptom. Six patients (29%) experienced adverse reactions during VIT, 3 during initiation and 3 during maintenance. Twelve patients (57%) were resting while undergoing VIT; 9 (75%) presented local reactions and 3 (25%) systemic reactions, 1 of which required intubation. The Hymenoptera specific IgE decreased from 4.15 kU/L (range, 0.44-100 kU/L) before immunotherapy to 1.2 kU/L (range, 0.34-69.4 kU/L) after 4 years (P < .003). Venom immunotherapy is effective to treat IgE-mediated Hymenoptera anaphylaxis in patients with mastocytosis. Its use is recommended despite a relatively high risk of adverse reactions during the build-up phase because it provides protection from anaphylaxis in around 3/4 of the patients.

Safety of Venom Immunotherapy in Patients Pretreated with Antihistamines—A Retrospective Study

Immunotherapy is the only effective method of treatment of allergy to Hymenoptera venom. Pretreatment with antihistamines diminishes the incidence of adverse reactions (AR) such as large local and mild systemic reactions but it is suggested that it may mask a development of serious allergic reactions. The aim of the study was a retrospective evaluation of the incidence and nature of AR during venom immunotherapy in patients receiving pretreatment with antihistamines in the Department of Pneumonology and Allergy of the Medical University of Lodz. 50 patients started "ultra-rush" immunotherapy in our center, 8 were taken in our care after the initiation phase had been conducted elsewhere. During the dose increase phase 10 systemic adverse reactions were observed. 50% of them were only subjective and the rest mild objective reactions. During the maintenance phase 10 systemic reactions were noted, among them 2 cases of the anaphylactic shock. The incidence of systemic adverse reactions was 1 per 86 injections. Late as well as unusual reactions appeared twice. Venom immunotherapy combined with pretreatment with antihistamines is safe. A vast majority of systemic adverse reactions is of subjective and mild objective nature and appropriate treatment leads to containment of severe reactions.

Indications de la désensibilisation en fonction des données épidémiologiques récentes

In most cases, hymenoptera venom allergy is caused by bees or wasps, but also occasionally by hornets, bumblebees or other members of the Vespidae family. The prevalence of sensitisation to venom in adults who have not had an allergic reaction following an insect sting but who have a positive skin test and/or specific IgE is estimated to be between 9.3% and 28.7%. The prevalence of systemic reactions in the general population reported in the literature ranges from 0.15% to 3.3%. The risk of having another systemic reaction following a subsequent sting depends on a number of factors: (1) the severity of the preceding reaction, (2) age, (3) the responsible insect, (4) occupation, (5) interval since the previous reaction. The risk of having a particularly severe reaction also depends on several other factors: the presence of cardiovascular disease, treatment with a beta-blocker, an elevated serum tryptase, and the presence of mastocytosis. The indications for venom immunotherapy in patients with positive skin and/or blood tests must take include consideration of the risk factors for a severe reaction with a new sting.