Future Sting Research Articles

Shared Decision-Making in Insect Sting Allergy: To Bee or Not to Bee?

Evaluation and management of insect sting allergy are often not straightforward when there is uncertainty about the history of reaction, the significance of test results, and the risk of severe reaction to future stings. Patients encounter misinformation about the chance of reaction and may have strong beliefs about the need for treatment. Shared decision-making encourages the clinician to listen to the patients' concerns and beliefs, share relevant information and evidence, and partner with patients to incorporate their values and preferences. This review discusses some major decision points in diagnosis and treatment of insect-allergic patients, with attention to the potential burdens or harms that are important to patients and factors that relate to patients' values and preferences concerning the choices they must make. This is especially true in patients with no history of moderate to severe sting anaphylaxis in whom the risk may be overestimated, but it can also be important in patients who underestimate the risk associated with severe sting anaphylaxis. Clinicians should become more knowledgeable about patient-important beliefs and outcomes and engage in shared decision-making to help patients understand and be comfortable with the choices they must make.

High burden of clonal mast cell disorders and hereditary α-tryptasemia in patients who need Hymenoptera venom immunotherapy.

In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT. 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms. 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01). By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.

Venom Anaphylaxis: Decision Points for a More Aggressive Workup.

Diagnostic testing of patients who present for evaluation of insect venom allergy can involve many levels of investigation. A detailed initial history is critical for diagnosis and prognosis. The severity of previous sting reactions and the presence or absence of urticaria or hypotension predict severe future sting reactions and underlying mast cell disorders. Venom skin tests and specific IgE measurement can confirm the diagnosis but have limited positive predictive value for the frequency and severity of future sting reactions. Testing for serum IgE to recombinant venom component allergens can distinguish true allergy from cross-reactivity to honey bee and yellowjacket venoms. Basophil activation tests can improve the detection of venom allergy and predict the severity of reactions and the efficacy of venom immunotherapy but are limited in availability. An elevated basal serum tryptase level is an important marker for severe sting anaphylaxis and underlying mast cell disorders (eg, hereditary α-tryptasemia and clonal mast cell disease). When there is high suspicion (eg, using the Red Espanola de Mastocytosis score), bone marrow biopsy is the definitive tool to characterize mast cell disorders that are associated with the most severe outcomes in patients with insect sting allergy.

Summer Buzz: All You Need to Know about Insect Sting Allergies.

Insect stings can generate a range of immune and clinical reactions. Most reactions are local and self-limiting. Allergic reactions to insect stings can occur at all ages, with or without previous stings. Individuals with a history of anaphylaxis carry a significant risk of life-threatening anaphylaxis with future stings. Health-care providers are often unaware of the tremendous clinical benefits of venom immunotherapy for these select patients. Scientific knowledge about the natural history, risk factors, and optimal therapy for insect sting allergies has improved considerably in recent years.

Large local reactions to insect envenomation.

Insect stings often induce large local reactions (LLRs) that result in morbidity. These reactions do have an immunologic basis; however, patients presenting with LLRs should be managed differently than those with systemic allergic reactions, as described in this review. Morbidity results from the inflammation itself along with the iatrogenic consequences of treatment. The prescription of antihistamine medications and the use of antibiotics are generally not indicated for patients with LLRs because of the risks/side-effects of these medications and the low probability of benefit. Some patients are also concerned over the possibility that a future sting will evolve into a life-threatening reaction. Although these reactions do involve IgE, patients are not at sufficient risk to warrant prescription of autoinjectable epinephrine. Venom-specific immunotherapy can be considered when LLRs are frequent and associated with significant impairment. Clinicians can reduce morbidity from LLRs by reassuring the patients, avoiding medications that result in side-effects when they are not indicated, and referring to an allergist when there are additional concerns, such as frequent impairment.

Stinging insect allergy and venom immunotherapy.

The Hymenoptera order is divided into three families: Apidae, Vespidae, and Formicidae. Apidae include the honeybee, bumblebee, and sweat bee, which are all docile and tend to sting mostly on provocation. The Africanized killer bee, a product of interbreeding between the domestic and African honeybee, is very aggressive and is mostly found in Mexico, Central America, Arizona, and California. The yellow jacket, yellow hornet, white (bald) faced hornet, and paper wasp all belong to the Vespidae family. The Formicidae family includes the harvester ant and the fire ant. When a "bee" sting results in a large local reaction, defined as >10 cm induration and lasting > 24 hours, the likelihood of anaphylaxis from a future sting is approximately 5%. For comparison, when there is a history of anaphylaxis from a previous Hymenoptera sting and the patient has positive skin test results to venom, at least 60% of adults and 20-32% of children will develop anaphylaxis with a future sting. Both patient groups should be instructed about avoidance measures and about carrying and knowing when to self-inject epinephrine, but immunotherapy with Hymenoptera venom is indicated for those patients with a history of anaphylaxis from the index sting and not for patients who have experienced a large local reaction. Immunotherapy is highly effective in that, by 4 years of injections, the incidence of subsequent sting-induced reactions is 3%. This incidence may increase modestly after discontinuation of injections but has not been reported to be > 10% in follow up.

Large Local Reactions to Insect Stings

Large local reactions (LLRs) are IgE-mediated late-phase inflammatory reactions that can cause great morbidity but are associated with a relatively low risk of future anaphylaxis. Patients with LLR may benefit from consultation with an allergist to help clarify the relative risk, to plan the best treatment for future stings, and to determine whether or not to pursue testing or venom immunotherapy (VIT). The chance of anaphylaxis to future stings is <5%, so VIT is not generally recommended to people who have had LLR. Whether to prescribe an epinephrine injector is often determined by the frequency of exposure, the proximity to medical care, and the impact on quality of life. For people who have unavoidable exposure and need treatment almost every year for LLR, VIT can be recommended with confidence that it will significantly and safely reduce the severity of LLR to stings.

A Pitfall to Avoid When Using an Allergen Microarray: The Incidental Detection of IgE to Unexpected Allergens

The introduction of new laboratory techniques to detect specific IgE antibodies against single allergen molecules rather than whole extracts represents a significant advance in allergy diagnostics. The advantages of such component-resolved diagnosis can be summarized as follows: (1) the ability to identify the truly responsible allergens in polysensitized patients, whether they be genuine (causing specific sensitization to their corresponding allergen source) or primary (the original sensitizing molecule); (2) distinguishing these allergens from simply cross-reactive components; (3) improving the appropriateness of the prescribed specific immunotherapy; and (4) identifying a risk profile for food allergens. Component-resolved diagnosis is performed using either a singleplex (1 assay per sample) platform or a multiplex (multiple assays per sample) platform. Using an immuno solid-phase allergen chip microarray that falls into the latter category--it currently tests sensitivity to 112 allergens--may lead to a pitfall: detecting IgE to unexpected allergens, such as Hymenoptera venom. In fact, testing insect venom sensitivity in individuals with no history of reactions to stings is contrary to current guidelines and presents the physician with the dilemma of how to manage this information; moreover, this may become a legal issue. Based on what is currently known about venom allergy, it remains likely that a positive sensitization test result will have no clinical significance, but the possibility of reacting to a future sting cannot be completely ruled out. Because this problem has not been previously encountered using the more common allergy tests, no indications are currently available on how to effectively manage these cases.

Unusual reactions to hymenoptera stings: what should we keep in mind?

This review includes a variety of extremely rare and unusual hymenoptera sting (HS) circumstances with regard to sting localization, geographic region, massivity of multiple stings, and particularly related to clinical symptoms. Such reactions occur in a temporal relationship to HS (s), differ from typical allergic symptomatology, and sometimes need follow-up during many months. With respect to pathogenesis, the major mechanisms involved are toxic, autoimmune, and other delayed immunological ones. While delayed inflammatory symptoms of the nervous system are considered as delayed hypersensitization or autoimmune entities, generalized rhabdomyolysis and consecutive acute kidney injury is considered a toxic reaction, mostly induced by massive envenomation to wasps or "Africanized" bees. Hemorrhagic episodes of targeted organ (s) could be additional potential risk for acute kidney injury, while the bee venom-induced hemorrhage is proposed to be a nonimmune-mediated anaphylactic symptom. The hemodynamic involvement of vital organs and systems with hypoxia and hypovolemia together with simultaneous immunoglobulin E (IgE) sensitization are considered potential indications for venom immunotherapy. In contrast, patients who have experienced various complications with unknown or nonallergic mechanisms should be informed about the importance of epinephrine's use and additional measures on future sting avoidance. In conclusion, although unusual reactions are extremely rare, it is important to keep them in mind.

Sensitization to Hymenoptera venoms is common, but systemic sting reactions are rare

Sensitization to Hymenoptera venom without systemic sting reactions (SSRs) is commonly observed in the general population. Clinical relevance for a future sting has not yet been investigated. We aimed to evaluate the effect of these debatable sensitizations with deliberate sting challenges and to monitor serologic changes for up to 2 years. One hundred thirty-one challenges with bees and wasps were performed in 94 subjects with a hitherto irrelevant sensitization. The clinical outcome was recorded, and results of specific IgE (sIgE) determinations, skin tests, and basophil activation tests were correlated to the sting reaction. sIgE levels were monitored in reactors and nonreactors after 3 hours, 1 week, 4 weeks, and 1 year. Only 5 (5.3%) patients had SSRs, but 41 (43.6%) had large local reactions (LLRs) after the sting. Compared with the general population, there was a 9.5-fold higher risk for LLRs but not for SSRs. Three hours after the sting, sIgE levels slightly decreased, but none of the 94 subjects' results turned negative. After 1 week, sIgE levels already increased, increasing up to 3.5-fold (range, 0.2- to 34.0-fold) baseline levels after 4 weeks. To assess the clinical relevance of this increase, we randomly selected 18 patients for a re-sting. Again, 50% had an LLR, but none had an SSR. Although sensitization to Hymenoptera venoms was common, the risk of SSRs in sensitized subjects was low in our study. The sIgE level increase after the sting was not an indicator for conversion into symptomatic sensitization. Currently available tests were not able to distinguish between asymptomatic sensitization, LLRs, and SSRs.

An update on venom allergy

Allergic reactions to stinging insects may be unexpected, frightening, and severe. A clear understanding of recent advances in the field facilitates appropriate care of children who experience severe reactions to hymenoptera stings. Recent investigations have underscored the importance of appropriate patient selection for potentially life-saving venom immunotherapy. Venom immunotherapy is effective in preventing future anaphylaxis from hymenoptera stings. Immunotherapy is indicated for patients with a history of anaphylaxis. Children who develop large local swelling or strictly cutaneous systemic reactions generally do not require immunotherapy. Component resolved diagnostic testing has been investigated to clarify the possibility of multiple venom allergies in patients with sensitization to multiple venoms. Rapid recognition and treatment of anaphylaxis are critical. Subsequent education about avoiding future stings and attention to emergency preparedness with appropriate prescription of self-injectable epinephrine is important. Referral of patients who have experienced venom-associated anaphylaxis for possible venom immunotherapy can prevent future severe episodes of anaphylaxis resulting from stings.

Management of Insect Sting Hypersensitivity: An Update

Reactions to Hymenoptera insect stings are common. While most are self-limited, some induce systemic allergic reactions or anaphylaxis. Prompt recognition, diagnosis, and treatment of these reactions are important for improving quality-of-life and reducing the risk of future sting reactions. This review summarizes the current recommendations to diagnose and treat Hymenoptera sting induced allergic reactions and highlights considerations for various populations throughout the world.

Chapter 4: Stinging insect allergy and venom immunotherapy

The Hymenoptera order is divided into three families: Apids, Vespidae, and Formicidae. Apids include the honeybee, bumblebee, and sweat bee, which are all docile and tend to sting mostly on provocation. The Africanized killer bee, a product of interbreeding between the domestic and African honeybee, is very aggressive and is found mostly in Mexico, Central America, Arizona, and California. The yellow jacket, yellow hornet, white (bald)-faced hornet, and paper wasp all belong to the Vespidae family. The Formicidae family includes the harvester ant and the fire ant. When a "bee" sting results in a large local reaction, defined as >5 in. and lasting >24 hours, the likelihood of anaphylaxis from a future sting is ∼5%. For comparison, when there is a history of anaphylaxis from a previous Hymenoptera sting and the patient has positive skin tests to venom, at least 60% of adults and 20-32% of children will develop anaphylaxis with a future sting. Both patient groups should be instructed about avoidance measures and carrying and knowing when to self-inject epinephrine, but immunotherapy (IT) with Hymenoptera venom is indicated for those patients with a history of anaphylaxis from the index sting and not for patients who have experienced a large local reaction. IT is highly effective in that by 4 years of injections, the incidence of subsequent sting-induced anaphylactic reactions is 3%. This incidence may increase modestly after discontinuation of injections but has not been reported >10% in follow-up.

Insect Allergy

Anaphylaxis is a life-threatening allergic condition. The 3 most common triggers for anaphylaxis are food, medications, and insects. All of these triggers are the sources of considerable morbidity and mortality, but of the 3, only insect allergy is treatable through means other than trigger avoidance. Because ≥ 40 deaths per year are attributed to insect stings, it is critical that healthcare providers and the public understand the proper diagnosis as well as the long-term treatment of this potentially life-threatening allergy. Unlike food and medication allergy, which are managed primarily by allergen avoidance, Hymenoptera allergy is managed prospectively using venom immunotherapy; this results in a protective level of up to 98%. Insects of the order Hymenoptera include bees, wasps, hornets, yellowjackets, and ants. They are responsible for the majority of the fatal and near-fatal sting events. Understanding the biology and habitat of the various Hymenoptera species is helpful in recommending insect-avoidance strategies. The diagnosis of insect allergy relies on a history of a systemic allergic reaction with appropriate testing for venom-specific immunoglobulin E. If the history of a systemic reaction to an insect sting and the presence of venom specific immunoglobulin E is confirmed, venom immunotherapy is indicated. The proper and primary means of treating acute anaphylaxis is immediate epinephrine-and studies suggest that it is underutilized in the acute setting. However, it is venom immunotherapy, a disease-modifying therapy, that provides the affected individual with the most effective protection against future sting reactions. Long-term management of insect allergy and anaphylaxis includes appropriate referral to an allergist familiar with insect allergy and, if indicated, venom immunotherapy.

Allergen immunotherapy

Specific immunotherapy (SIT) involves the administration of allergen extracts to achieve clinical tolerance of those allergens that cause symptoms in patients with allergic conditions. Immunotherapy is effective in patients with mild forms of allergic disease and also in those who do not respond well to standard drug therapy. Most SIT is given by means of injection, but there is increasing interest in performing SIT through the sublingual route. SIT remains the treatment of choice for patients with systemic allergic reactions to wasp and bee stings and should be considered as an option in patients with allergic rhinitis, asthma, or both. SIT can modify the course of allergic disease by reducing the risk of new allergic sensitizations and inhibiting the development of clinical asthma in children treated for allergic rhinitis. The precise mechanisms responsible for the beneficial effects of SIT remain a matter of research and debate. An effect on regulatory T cells seems most probable and is associated with switching of allergen-specific B cells toward IgG4 production. Few direct comparisons of SIT and drug therapy have been made. Existing data suggest that the effects of SIT take longer to develop, but once established, SIT achieves long-lasting relief of allergic symptoms, whereas the benefits of drugs only last as long as they are continued.

Self-injectable Epinephrine for First-Aid Management of Anaphylaxis

To the Editor.—Sicherer et al are to be commended for a fine, comprehensive article on the role of self-injectable epinephrine in the management of anaphylaxis.1 However, there is one misstatement that I feel should be corrected. In describing when self-injectable epinephrine should be prescribed, the authors stated that it should be prescribed to a child who has experienced generalized acute urticaria after an insect sting, “because the risk of a more severe reaction from a future sting is approximately 10%.” However, the reference they give (a practice parameter update2) actually states that “patients 16 years of age and younger who have experienced cutaneous systemic reactions without other allergic manifestations have approximately a 10% chance of having a systemic reaction if re-stung. If a systemic reaction does occur, it is likely to be limited to the skin.”This is clarified even further in the original reference on which the above-mentioned statement was based,3 which stated that “196 stings in 86 untreated children resulted in 18 systemic reactions… . Sixteen of these 18 reactions were judged to be milder than the patient's reaction to the first sting, 2 were similar in severity, and none were more severe.” Therefore, although it is certainly not unreasonable to prescribe self-injectable epinephrine for children with cutaneous-only reactions to insect stings, we can also be quite reassuring to patients and caregivers that the chances of a more severe reaction are, in fact, very small.

Clinical and entomological factors influence the outcome of sting challenge studies

The reported frequency of systemic reactions to challenge sting varies greatly. To evaluate the interaction of clinical and entomological factors that determine the outcome of a challenge sting. Patients allergic to yellow jacket were stung and monitored for systemic reaction. The frequency and severity of sting reactions were analyzed in relation to the species of insect used and patient characteristics. Objective systemic reactions occurred in 21 of 69 patients (30%) stung with Vespula maculifrons and in 8 of 71 patients (11%) with Vespula germanica (P=.005). Systemic reactions were more frequent in patients with a severe history (9/30; 30%) than in those with a mild or moderate history (21/145; 14%; P=.04). In only 1 of 111 patients (0.9%) was the reaction to sting challenge more severe than previous reactions. The reaction rate was higher when venom skin tests were positive at <1.0 microg/mL (17/75=23%) than when sensitivity was milder (9/100=9%; P=.012). We compared sting outcome and venom-induced histamine release in relation to insects collected in July or in October, and found no difference. Allergic reactions to sting challenge are determined by the species of yellow jacket used, the severity of previous sting reactions, and the degree of skin test sensitivity, but not by the time of year. These factors are important to clinicians when they evaluate the chance of reaction to a future sting and to researchers when they design and report sting challenge studies.

Insect Stings

Insect Stings

Insect sting allergy. A study from 1980 to 2003 of patients who started treatment with venom immunotherapy between 1980 and 1998

BackgroundPreviously we treated patients with insect sting allergy with venom immunotherapy (IT) using whole body insect extracts. From 1980 we changed to insect venoms. The purpose of this study was to analyse data from the patients in order to improve our treatment.MethodsThis is an open, single centre study on patients treated with venom IT 14 years or older with a history of a systemic allergic reaction to an insect sting, a positive skin prick test (SPT) or a positive RAST and willingness to comply with five years of IT. Clinical and laboratory data were registered prospectively at the start of IT and after five years of treatment until 2003 on patients who started IT between 1980 and 1998. Questionnaires were answered in 1989, 1993 and 2003. Statistical analysis was done with Pearson's chi square, Fisher's exact or the t-test.ResultsOf 315 patients treated, 44 were given bee, 248 common wasp and 23 both venoms. Of the common wasp sting incidents 5.5 % resulted in a severe allergic reaction (SAR) during adequate IT and 22% after cessation. Seventy-one per cent of the patients carried epinephrine. Precautionary steps were taken by 77% of the patients during or after inadequate IT. On or after adequate IT 83% felt completely or substantially safe. Surprisingly 29 % of those inadequately treated felt safer and 50% were satisfied with having had the opportunity to be treated. The SPT became negative in 68% of the wasp allergic patients after five years of adequate IT. Increased risk of experiencing SAR to a future sting in wasp allergic patients after cessation of adequate IT was significantly associated with a SAR due to IT during the rush regimen. SAR due to IT occurred very rarely during maintenance dosing.ConclusionAdequate venom IT is very effective while ongoing but somewhat less effective after cessation, while inadequate treatment gives poor results. More of our patients should complete five years of IT and some should continue IT. The type of reaction to IT during incremental dosing may be of help in deciding who should continue beyond five years. Maintenance IT may be taken over by the general physician.

Allergic reactions to insect stings and bites.

Insect stings are an important cause of anaphylaxis. Anaphylaxis can also occur from insect bites but is less common. Insect venoms contain several well-characterized allergens that can trigger anaphylactic reactions. Effective methods to diagnose insect sting allergy and assess risk of future sting reactions have been developed. Management strategies using insect avoidance measures, self-injectable epinephrine, and allergen immunotherapy are very effective in reducing insect-allergic patients' risk of reaction from future stings. Diagnostic and management strategies for patients allergic to insect bites are less developed.