Update in stinging insect hypersensitivity

Abstract

Background:

The ACAAI//AAAAI Joint Task Force on Practice Parameters periodically develops updated guidance based on all available evidence.

Methods:

This review summarizes advances in diagnosis and management of insect sting allergy from published practice parameters, and developments under review for the 2026 update.

Results:

Changes in the species and distribution of stinging insects in the US may be due to migration and invasion. Overall prevalence has not changed, but fatalities from insect sting allergy increased 50% in 30 years. Diagnostic evaluation includes both skin and serum immunoglobulinE testing although positive predictive value is dependent on the history. Evaluation may include venom component testing. Mastocytosis and hereditary alpha tryptasemia must be considered in many cases; testing for baseline serum tryptase is now routine. Testing for c-KIT gene mutation in peripheral blood and tryptase genotype are important supplemental tests. The risk of beta blockers and angiotensin converting enzyme inhibitors is relatively low in most cases, and they are not contraindicated during venom immunotherapy (VIT). VIT is indicated in high-risk patients (30–70% risk of anaphylaxis), but is not required in those with cutaneous reactions (3–10% risk of anaphylaxis). VIT can be safely initiated with rush regimens. Recurrent systemic reactions are rare, and may require omalizumab treatment (off-label). VIT can be discontinued after 5 years in most patients, but extended or indefinite VIT (often at 12-week intervals) is recommended in patients with known high-risk factors or where stopping would cause markedly impaired quality of life.

Conclusion:

Continued research has refined our clinical approach to patients with concerns about stinging insect hypersensitivity.

UPDATE IN STINGING INSECT HYPERSENSITIVITY

Allergic reactions to insect stings remain a common problem, although recurrent reactions can be prevented with targeted testing and venom immunotherapy (VIT). There is a need for improved public and professional education to increase awareness and implementation of this management approach. Continued research has refined our clinical approach to patients with concerns about stinging insect hypersensitivity. The Joint Task Force on Practice Parameters (JTFPP) of the American Academy of Allergy Asthma and Immunology (AAAAI) and the American College of Allergy Asthma and Immunology (ACAAI) periodically develops updated guidance based on all available evidence. This review focuses on advances and updates in a number of areas, including epidemiology, insect species, diagnosis, tryptase, mast cell disorders, use of β-blockers (BB) and angiotensin converting enzyme inhibitors (ACEi), treatment choices, and VIT.

Methods

This narrative review focuses on selected topics from the Stinging Insect Hypersensitivity Practice Parameter Update 2016¹ as well as updates from the upcoming 2026 Update (in development). A more complete review can be found in the published Practice Parameters and recent review articles and chapters.^1,2

Insects and Epidemiology

The order Hymenoptera includes three main families of stinging insects: the bees, the vespid wasps, and the ants. There is minimal cross-reactivity between honey bee and bumble bee venoms. There is a test for bumble bee immunoglobulin E (IgE), but no venom is available for skin testing or VIT. The vespids include the yellowjackets (YJs) (Vespula), which have >95% cross-reactivity with the Dolichovespula (yellow hornet and white-faced hornet). The true hornets (Vespa) are also very closely related to the Vespula. The European hornet (Vespa crabro) is common in the United States. The Polistes “paper” wasps are also vespids but have only 50% cross-reactivity with other vespids, so some patients can be specifically allergic to both. The primary stinging ants in the United States are the imported fire ants (IFA) (Solenopsis). Other groups of stinging ants around the world and in the United States have no minimal cross-reactivity with IFA venom.

The distribution of many insects has been changing due to climate change (e.g., YJs in Alaska) or invasion (see Table 1). For example, IFA invaded Alabama 100 years ago, and Africanized (“killer”) honey bees invaded Texas 35 years ago. The Mediterranean wasp (Polistes dominulus) invaded eastern North America ∼45 years ago and has since spread across the United States. The most recent threat comes from an Asian hornet (Vespa velutina) that is not only expanding its territory in Asia but has invaded western Europe, becoming the most common cause of sting anaphylaxis in parts of Spain and France.³ There are now reports of established nests^4,5 in Georgia and South Carolina as of 2024. There is concern that VIT with Vespula (YJ) venom may not reliably protect against anaphylaxis to V. velutina.

Table 1.

Stinging insect invasion and migration in the United States

IFA = Imported fire ant; YJ = yellow jacket; VIT = venom immunotherapy.

The prevalence of insect sting allergy is not, as believed by some clinicians, decreasing. In fact, a surprising report from Morbidity and Mortality Weekly Report in 2023 suggests that mortality is increasing.⁶ The number of deaths from insect stings in the United States was reported to be 40 per year in the 1960s⁷ and was unchanged in the 1990s.⁸ However, National Vital Statistics for 2011–2021 show a mean of >60 deaths per year and increasing over time.⁶

Diagnostic Evaluation

To identify the risk of a systemic reaction (or anaphylaxis) to a subsequent sting, the clinician begins with the history, venom skin tests, and serum IgE to venom. The severity of the history predicts not only the chance of a systemic reaction but also the severity. The more severe the previous sting reaction, the more likely it is to occur again, and the more likely to be severe.⁹ Interestingly, that study also found that, when it comes to YJ stings, the severity of the reaction also depends on the species of YJ. Thus, a patient who had a severe YJ sting reaction in the past but no reaction to a more recent YJ sting cannot be certain that he or she would not react, or would react more severely, to a future YJ sting.

Both venom skin tests and serum IgE tests can confirm the presence of venom sensitization. The stronger the results of these tests, the greater the likelihood of a systemic reaction to a sting. However, the strength of the test is not a reliable indicator of the severity of a future reaction. Some patients have very strong sensitivity but little or no reaction to a sting, and others have barely detectable venom sensitivity but get life-threatening anaphylaxis to a sting.¹

There are important caveats with regard to venom allergy testing. Asymptomatic sensitization is present in >20% of adults and in up to 40% of those who were stung in recent months. Thus, a positive test result can confirm a clear history of allergic sting reaction but cannot be diagnostic by itself. Also, the clinical significance of venom IgE levels of 0.1–0.34 kU/L is unknown. All the published data¹ on the diagnostic significance are based on the threshold of 0.35 kU/L. Lower levels of sensitization have not been validated for the predictive value. In such cases, the burden of diagnosis falls on the history. When skin testing, using only a single concentration of 1.0 μg/mL without preliminary skin prick test (SPT) or serum IgE may be considered. Although counterintuitive and not safe with aeroallergens, testing with only 1.0 μg/mL is safe with venoms (but not yet demonstrated with IFA whole-body extract). This is most appropriate and useful in young children and others with fear of needles; however, which is better: venom skin tests or serum IgE tests? Actually, neither is perfect, and they are often complementary. They both have good sensitivity and limited specificity (because of the frequency of asymptomatic sensitization). They both have a potential refractory (anergic) period of a few weeks after a sting reaction. During this period either skin test or serum IgE can be negative, although at least one of the tests is positive even after 1 week in almost 80% of patients.¹⁰

A new and very useful option for supplemental evaluation is component-resolved diagnosis (CRD) by using venom component allergens.¹¹ Although this does not usually increase the diagnostic sensitivity of serum IgE testing, it does increase specificity by differentiating cross-reactivity from a specific allergy. Almost half of patients tested have positive IgE results for both HB and YJ venoms, even though many have had a reaction to only one insect. When using venom CRD tests, if the patient has an IgE value to unique HB allergens (Api m 1, 3, 4, or 10), then he or she is HB allergic, and, if positive to unique YJ allergens (Ves v 1 or 5) he or she is YJ allergic, and requires VIT with that venom (or both of indicated); however, if the only positive component for a particular venom is cross-reactive (Api m 2, 5, or 12 for HB; Ves v 2, 3, or 6 for YJ), then the patient may not require VIT for that venom. Not all of these components are yet available for clinical use.

Ideally, diagnostic evaluation would predict the risk of future sting anaphylaxis so the most appropriate patients could be identified to receive VIT. There is no test that is fully accurate for this purpose. Even when the history and diagnostic test results are both positive, the reported frequency of systemic reaction to a subsequent sting ranges from 30% to 65%. There are many reasons for this variation. Some studies included patients at low risk (e.g., children, or patients with large local or cutaneous systemic reactions), and some reported field stings, whereas others used supervised sting challenge. The late Bob Reisman showed that the risk was almost twice as high in adults as in children (73% versus 40%).¹² He also found that the risk did not decline over a 10-year period (contrary to previous beliefs) but varied from sting to sting, observations that have been confirmed in other studies.¹³ Even sting challenge has a 20% false-negative rate. In studies in which there was no reaction to sting challenge, when the patients returned for repeated challenge, 20% had a reaction.¹⁴ The variability in reaction to a sting may be more pronounced with Vespula than with honey bees, in part due to the greater variability in the amount of venom delivered per sting. The goal of risk stratification of patients with insect allergy is to distinguish those at greatest risk for severe anaphylaxis. There are many risk factors, cofactors, and augmentation factors for anaphylactic reactions of all causes. For sting anaphylaxis, in addition to age and cardiovascular (C-V) disease, the most important factors are a history of very severe reaction, absence of urticaria, and elevated basal serum tryptase (bST).¹⁵

Tryptase and Mast Cell Disorders

The bST level is now an essential test in evaluation of patients who are candidates for VIT (see Table 2). Bonadona et al.¹⁶ reported in 2009 that, of 379 patients with sting anaphylaxis, 11.6% had a bST level >11.4 ng/mL. In patients with hypotensive reactions, 25% had elevated bST levels.¹⁶ Only 4 of the 379 patients had no detectable venom-specific IgE, and all 4 had elevated bST values.¹⁶ Also in 2009, a multicenter European study showed a linear correlation between the bST level and the relative risk for severe anaphylaxis.¹⁷ The practice parameters recommend measuring the bST level in patients with severe sting reactions (especially those with hypotension and lack of urticaria), and those with a history of sting anaphylaxis but negative diagnostic tests, but also more broadly for all patients who are candidates for VIT.^1,15

Table 2.

Evaluation for mast cell disorders in insect sting anaphylaxis

bST = Basal serum tryptase; c-KIT = c-KIT D816V gene mutation; BM = bone marrow biopsy; REMA = Spanish Mastocytosis Network scoring system; HαT = hereditary α tryptasemia.

^*Adapted from Ref. 23.

Measuring the bST level is only one aspect of investigating the special connection between insect sting anaphylaxis and mast cell disorders. These conditions may otherwise be silent but increase the risk of severe anaphylaxis. Clonal mast cell disorders (CMD) (primarily systemic mastocytosis) may be present in >10% of patients with sting anaphylaxis and possibly >25% of those with hypotensive reactions.^18–20 Anaphylaxis (almost always severe) has occurred in ∼40% of patients with known CMD, and insect stings are the most common cause.²¹ Measuring the bST level is the first step in this investigation but should be accompanied by testing for the c-KIT D816V gene mutation by using a high-sensitivity polymerase chain reaction (PCR) assay. The subtypes of CMD that are particularly common in patients with sting anaphylaxis are more difficult to detect, so, unless the blood c-KIT mutation test result is positive, a bone marrow biopsy is required to reveal the presence of CMD.²² The need for a bone marrow biopsy can be determined by scoring systems such as the Red Española de Mastocytosis (REMA) score.²³ Measuring the bST level also aims to identify hereditary α-tryptasemia (HαT), which occurs in patients with sting anaphylaxis at two to three times the frequency in the general population, and is known to predispose to more severe anaphylaxis.¹⁸ Any patient with sting anaphylaxis in whom the bST level is >8 ng/mL should be tested for HαT. An elevated bST level with a negative HαT in patients with sting anaphylaxis strongly suggests mastocytosis.^22,24

BBs and ACEi

Another concern in patients at risk for anaphylaxis is the use of BBs or ACEi. These medications have long been contraindicated in such patients, including subcutaneous immunotherapy, although, for VIT, this is a relative contraindication that is judged less important than the potentially life-saving nature of VIT. New evidence in the past 5 years led to moderation of this concern as expressed in the most recent update of the Anaphylaxis Practice Parameters.¹⁵ The first and only systematic review and meta-analysis²⁵ of the risk of anaphylaxis of any cause in patients taking BB or ACEi reported that both were associated with increased severity but not an increased incidence of anaphylaxis. Results of the meta-analysis showed²⁵ the odds ratio for severe anaphylaxis was three to five times higher for the underlying C-V disease than for the BB or ACEi, respectively. Thus, the risk is related primarily to the C-V disease more than to the medications. In an evaluation of the risk of BB or ACEi in patients with insect sting anaphylaxis, there was no increased frequency of severe anaphylaxis in those taking the medications before VIT (retrospectively), and BB or ACEi were not associated with more systemic reactions to VIT injections or to stings during VIT (prospectively).²⁶ The recommendation of the updated Practice Parameters are shown in Table 3.

Table 3.

Recommendations in anaphylaxis: 2023 Practice Parameter Update^* with regard to the use of BB or ACEi in patients with insect sting anaphylaxis

BB = β-Blockers; ACEi = angiotensin converting enzyme inhibitor; VIT = venom immunotherapy.

^*Adapted from Ref. 15.

#These recommendations are conditional; special circumstances may modify the recommendations; shared decision-making is encouraged (Ref. 15).

Treatment

So who needs VIT? Clearly, it is indicated for those at greatest risk for sting anaphylaxis and not so much for those likely to have cutaneous (mild) systemic reaction (cutSR), large local reaction (LLR), or no reaction to a sting. The most important question in most cases is “will a future sting reaction be severe?” Overall, the chance of a future reaction being more severe than previous reactions is very small for insect sting allergy, but it is important to recognize the factors associated with increased risk. The greatest risk is in patients who previously had severe sting reactions; they have a 50–75% chance of a systemic reaction to a sting, about half of which will be severe.¹ For those who had moderate (non–life-threatening) anaphylaxis, there is an ∼30–50% chance of a systemic reaction but much fewer will be severe. This is still a clear indication for VIT.¹

The situation is different for patients with a previous cutSR. This is the most common history in children, and it was shown >35 years ago that they rarely progress to more severe reactions and do not require VIT.²⁷ Sting challenge studies¹ that included adults with cutSR reported that 5–15% had the same reaction again, but <3% had a more severe reaction, similar to the reported outcome in children. In a sting challenge study, only 2 of 81 adults with previous cutSR developed a moderate systemic reaction after sting challenge, and none were severe.⁹ These reports support the new recommendation to suggest that VIT is not required for adults with cutSR, although it remains an option for those with frequent exposure or markedly impaired quality of life despite the favorable prognosis.¹

Patients with a previous LLR have not been carefully studied, and there are few actual sting challenge data. Limited observations from decades ago showed a relatively low risk (4–10%) of a subsequent systemic reaction, with about half of those being just cutSR. Anaphylaxis to sting challenge was observed in 1 of 41 patients with LLR (2.4%).²⁸ Based on these reports, VIT is not required for those with LLR, but, as in patients with cutSR, it remains an option for those with frequent exposure or markedly impaired quality of life. However, there can be considerable morbidity from LLR and patients often require a brief course of corticosteroid medication. Those with frequent unavoidable exposure may consider VIT simply to reduce the morbidity and avoid steroid treatment. VIT has been shown to reduce the size and duration of the LLR by 50–70%.²⁸

VIT

When VIT is initiated, the starting dose and buildup regimen must be considered. One of several counterintuitive features of insect allergy is that there is no need to begin with extremely low doses. The starting dose can be 1 μg (0.1 mL of 10 μg/mL) without increasing the very small risk of a systemic reaction to the first dose. This alone can help shorten the buildup phase by many weeks. Another counter-intuitive feature of VIT is that it is actually safer to use a rush (e.g., 3 days) or semirush (weekly for 6–8 weeks) regimen than the conventional regimen that is in the product package insert of current venom extracts.^29,30 For decades before 2017 another venom product was available in the United States with an U.S. Food and Drug Administration approved an 8-week modified rush regimen. Ultrarush regimens, achieving the full 100-μg dose in hours, may have a greater risk of systemic reactions. Premedication with second-generation H1 antihistamines is always recommended during the buildup stage.

Systemic reactions during maintenance VIT are very unusual and may raise suspicion of an underlying mast cell condition. After a systemic reaction during buildup or maintenance VIT, the standard measure is to reduce the next scheduled dose by 50% and then build it up again. If systemic reactions recur while using a conventional regimen, then the counterintuitive recommendation is to restart treatment by using a rush regimen and premedication, including prednisone.³¹ This commonly solves the problem, but, if systemic reactions recur, then omalizumab is recommended to facilitate treatment to the maintenance dose. Although this is an off-label recommendation, it is supported by a great deal of published evidence.² However, reports to date describe a variety of approaches to the dose, duration, and timing of omalizumab when administered concomitantly with VIT. Thus, no specific recommendations are available.

The duration of VIT was somewhat controversial until the late 1990s when studies in the United States and Europe demonstrated that 5 years is better than 3 years for induction of sustained unresponsiveness and suppression of venom IgE.^32,33 Those studies and others¹ also identified high-risk factors that predispose to relapse (i.e., systemic sting reaction) after stopping VIT. Patients who are candidates for extended or indefinite VIT include those with a history of very severe sting anaphylaxis, elevated baseline serum tryptase or CMD, systemic reaction during VIT (to venom injection or sting), honey bee anaphylaxis (e.g., beekeepers), or frequent exposure.¹ Other considerations include C-V disease, use of BB or ACEi, or simply impaired quality of life that impacts their ability to engage in normal activities. Extended studies of discontinuing immunotherapy with up to 13 years of observation, found a 10% chance of a reaction to any sting and a cumulative 17% risk of systemic reaction (because some patients had two or more sting events, did not react to the first but reacting to a later sting).³⁴ Thus, more frequent stings carry a greater chance of reacting to at least one of the stings. Based on our experience at Johns Hopkins, about two-thirds of patients on VIT have none of these risk factors, and have <3% risk of anaphylaxis to future stings after stopping VIT. The other third, with one or more risk factors, has an estimated 45% risk of anaphylaxis to a future sting if they stop VIT.