The lecture below can be accessed on the Disease Management section of the Cleveland Clinic, under Allergy and Immunology (to go to this link and see others in the series, please click here)

Hymenoptera Venom Allergy

Velma L. Paschall

Contents

Definition

Hymenoptera venom allergy is an immunoglobulin E (IgE)- mediated hypersensitivity to the venom of insects in the insect order Hymenoptera. This allergic reaction may be caused by stings from a number of species in this insect order, occurring only in epersons who have previously been sensitized to Hymenoptera venom.

Epidemiology

Insect sting allergy can develop at any age and usually manifests after several uneventful stings. The incidence of systemic reactions to Hymenoptera venom is approximately 3% in adults. Although children are stung more often than adults, systemic reactions occur in only about 1% of children younger than 17 years, and many of these reactions are relatively mild. Large local reactions to Hymenoptera stings are more common in children, with an estimated incidence of 20% and 10%, respectively, for children and adults. The prevalence of insect sting allergy is twice as high in male as in female patients and may be a result of increased exposure rather than inherent susceptibility. There is no clear association with other allergies, and only 30% of patients with venom allergy are atopic. In addition, insect sting allergy is statistically not more likely to occur in persons with a family history of sting reactions.

At least 50 deaths per year occur in the United States from insect sting reactions, and many other sting fatalities may be unrecognized. Approximately one half of deaths occur in victims with no history of a prior sting reaction. Most fatalities (80%) occur in adults older than 40 years, and only 2% occur in persons younger than 20 years.

Hymenoptera Stinging Insects

All the stinging insects belong to the insect order Hymenoptera, of which there are 16,000 species in North America. Less than 1% are responsible for human stings (Fig. 1). All the species that are medically important belong to three families: Apidae, Vespidae, and Formicidae. Only the females of each species have stingers, which are ovipositors that have lost their egg-laying function and have been modified for stinging and envenomization. Most species sting in defense of themselves and their nests, although some species also sting as a means of capturing their prey.

Figure 1: Click to Enlarge

Apidae Family

Honeybees are found throughout the United States and live in colonies of up to 65,000 bees. Feral honeybees are less common than domestic honeybees and build their nests inside hollow trees or logs. Domestic honeybees live in human-made hives and are commercially managed for honey production and pollination. They are relatively docile insects and usually sting only when provoked. When a honeybee stings, it leaves a barbed stinger with an attached venom sac in the victim’s skin, resulting in evisceration of the bee and its subsequent death. Most honeybee stings, other than in beekeepers, occur in people walking barefoot on lawns or handling flowering plants. Africanized honeybees, commonly referred to as “killer bees,” migrated into the United States in 1990 from Mexico and have become a major stinging threat in southern Texas. These bees were brought to Brazil from Africa in 1956 in an attempt to replace the European honeybee with a more productive tropical-climate honeybee. Africanized bees look like domestic honeybees and deliver the same venom, but they mount an aggressive response when they perceive a threat to their hive. The tendency to swarm and then sting in very large numbers has resulted in deaths in cattle and humans because of toxic reactions.

Vespidae Family

Yellow jackets, hornets, and wasps are the stinging insects in the Vespidae family that are of medical importance in the United States. Vespids make nests of masticated wood containing layers of combs with many individual cells. The comb layers are arranged vertically and, except for wasp nests, are encased in an outer layer of paper. Unlike honeybees, vespids have relatively smooth stingers and can sting repeatedly. Some species of yellow jackets occasionally leave their stingers in the skin, however.

Yellow jackets account for most stings overall in the United States. They are especially prevalent in the Northeast and Midwest. They prefer to build their nests underground or in human-made structures low to the ground. They are notorious scavengers and often seek food in picnic areas and around trash containers. They are the most aggressive of all the vespids and sting with little or no provocation during the late summer and early fall, when their colony numbers are largest and food supplies are somewhat limited.

New World hornets are closely related to yellow jackets; they are slightly larger but have similar coloring. Yellow hornets and white-faced (or bald-faced) hornets are actually aerial yellow jackets. They build large nests in trees or shrubs. Like yellow jackets, they are aggressive insects, particularly in the vicinity of their nests. Old World hornets, also known as European hornets, were accidentally introduced into the Eastern United States in the mid-1800s. These hornets usually build their nests in hollow trees and, unlike the other members of the Vespidae family, they typically fly at night and are attracted to bright lights. Although they are much larger and more fearsome in appearance than the New World hornets, they are less aggressive. The population of these insects is gradually increasing, but they are still minor stinging threats.

Paper wasps can be found throughout the United States, most commonly in the southern states. Wasp colonies are relatively small, and wasps are less aggressive than yellow jackets and hornets. Wasps tend to build their nests near human habitation (e.g., under the eaves of houses, on porches, and below deck railings), and stinging encounters with these insects are, therefore, common.

Formicidae Family

Fire ants are the medically important members of the Formicidae family, and several species of both native and imported fire ants exist in the United States. Both can cause severe allergic reactions, but imported fire ants are much more aggressive and prolific and inflict the most stings. Imported fire ants were introduced in 1940 through the port of Mobile, Alabama, by cargo ships from South America. They have spread through the surrounding states and Gulf coast. Imported fire ants build large nests (mounds) in the soil, and when their nests are disturbed, the ants attack in mass and sting their victims repeatedly. A characteristic sterile pustule typically forms at the site of each sting after 24 hours.

Hymenoptera Venoms

Venoms of the flying Hymenoptera are largely aqueous solutions containing proteins, peptides, and vasoactive amines. The toxic properties of the venom are caused by these components collectively, and several of the venom proteins are allergenic. Immunologic cross-reactivity exists among the Hymenoptera venoms and is extensive between yellow jackets and hornets, moderate between wasps and other vespids, and minimal between honeybees and vespids. Imported fire ant venom is distinctly different from the other venoms and consists of a mixture of piperidine alkaloids and a small aqueous component containing allergenic proteins. One of these proteins is similar to one of the vespid allergens, and cross-reactivity between fire ants and vespids occasionally occurs.

Pathophysiology

Both systemic and large local reactions to stinging insects are usually caused by IgE-mediated reactions to Hymenoptera venom. At least one prior sting is required to sensitize a person to venom, and sensitization is more likely to occur following multiple simultaneous stings or subsequent stings occurring over a relatively short period of time. Once sensitization has occurred, a sting can cause mast cell and basophil degranulation, resulting in release of the histamine and other inflammatory mediators responsible for the signs and symptoms of anaphylactic and some large local reactions. See the article “Anaphylaxis,” for further information on the pathophysiology of anaphylaxis.

Signs and Symptoms

Most Hymenoptera stings cause small local reactions of no significant medical consequence. These normal sting reactions are characterized by pain, itching, redness, and swelling at the sting site that resolve within several hours and are caused by the pharmacologic properties of the venom. Some large local reactions are caused by a late-phase IgE-dependent reaction that is mild initially but progresses after 12 to 24 hours to a diameter of more than 5 cm; these usually peak in intensity at 48 to 72 hours. These reactions are contiguous with the sting site and occasionally involve an entire extremity. In rare cases, massive swelling causes local anatomic compression. Large local sting reactions typically resolve gradually over 5 to 10 days. Virtually all patients with large local reactions continue to have similar reactions with subsequent stings. This tendency is not modified with venom immunotherapy; therefore, patients with large local reactions are not candidates for further diagnostic evaluation (see later).

Systemic reactions cause signs and symptoms in one or more organ systems and are almost always IgE-mediated. Systemic reactions cause a spectrum of manifestations, ranging from cutaneous signs (pruritus, flushing, urticaria, angioedema) to respiratory involvement (cough, throat and/or chest tightness, dyspnea, wheezing) and cardiovascular compromise (dizziness, hypotension, unconsciousness), depending on the severity of the reaction. Gastrointestinal manifestations (nausea, vomiting, diarrhea) and uterine cramping also occur occasionally. Cardiac anaphylaxis with manifestations of coronary vasospasm, arrhythmias, or bradycardia can also occur following stings, even in persons with no underlying cardiac disease. Systemic reactions usually cause signs and symptoms starting within minutes following a sting. In general, the sooner the symptoms occur, the more severe the reaction. Cutaneous signs and symptoms occur in 80% of adults and 95% of children with systemic reactions, but they are the sole manifestation of the reaction in only 15% of adults. Isolated cutaneous reactions occur in 60% of children, however, who tend to have a more benign course than adults. Although symptoms involving the upper and lower airways occur with approximately the same frequency in children and adults, children have a much lower incidence of cardiovascular manifestations (Table 1).

Table 1 Symptoms and Signs of Insect Sting Anaphylaxis in Adults and Children

	Frequency (%)

Symptom or Sign	Adults	Children
Cutaneous only	15	60
Urticaria/angioedema	80	95
Dizziness/hypotension	60	10
Dyspnea/wheezing	50	40
Throat tightness/hoarseness	40	40
Loss of consciousness	30	5

From Golden DBK, Lichtenstein LM. Insect sting allergy. In Kaplan AP (ed): Allergy. New York, Churchill Livingstone, 1985, pp 507-524.

Systemic reactions also occur occasionally as a result of the toxic properties of Hymenoptera venom. They are most often associated with multiple simultaneous stings or underlying mastocytosis. These reactions may be indistinguishable from acute, systemic IgE- mediated reactions. Large numbers of stings can cause other serious reactions including rhabdomyolysis with renal failure, hemolysis, acute respiratory distress syndrome, and diffuse intravascular coagulation. Delayed reactions of unknown mechanism that rarely occur following stings include serum-sickness–like reactions, neuropathies, Guillain-Barré syndrome, myocarditis, and glomerulonephritis.

Diagnosis

History

The diagnosis of Hymenoptera venom allergy is based primarily on a convincing history, inasmuch as positive skin test results occur in 15% to 20% of persons who are clinically nonreactive. Physicians should ask about serious sting reactions when obtaining a medical history, because many affected persons fail to mention them during a routine history and examination. Details of the history that might help distinguish the type of reaction (toxic or allergic, local or systemic) include the number of stings and their locations on the body, the nature and timing of prior stings, the time course of the reaction, and the symptoms and treatment.

Skin Testing

Positive skin tests to Hymenoptera venom extracts confirm IgE-mediated hypersensitivity in the context of a positive sting reaction history and help identify specific insects to which a patient is allergic. Venom protein extracts are used for diagnostic testing because whole-body extracts do not contain sufficient venom to distinguish allergic from nonallergic persons. Whole-body extracts are currently still being used for the diagnosis of fire ant allergy, because commercial fire ant venom extracts are not yet available. Fire ant whole-body extracts, unlike those of the flying Hymenoptera insects, have sufficient sensitivity and specificity to be useful diagnostically, although fire ant venom extracts, which are still under development, appear to be superior. Hymenoptera venom testing is usually performed with each of the five commercial venom extracts available in the United States, because patients are often inaccurate with regard to identification of the sting culprit.

Venom testing is usually performed initially with prick tests. If results are negative, intradermal skin tests are performed beginning with a venom concentration around 0.001 μg/mL. If the skin tests at this concentration are still negative, the venom concentration is increased by 10-fold increments until a positive skin test occurs, up to a maximum concentration of 1.0 μg/mL. Skin testing with higher concentrations is not performed because they are more likely to cause false-positive reactions caused by the irritant properties of the venom. Because of the known cross-reactivities among the vespid venoms, skin tests are often positive to several venoms even when there has been a reaction to only a single insect sting.

Although most patients with convincing histories of sting reactions have positive skin test results, some skin tests are negative. Skin test findings may be negative during the first 6 weeks after a sting because of a refractory period or anergy, and skin testing in these patients should be repeated after 1 or 2 months. Negative skin tests can also occur in patients with a positive history who had remote sting reactions and have lost their sensitivity and in persons who had systemic non–IgE-mediated reactions as a result of toxic effects of the venom or underlying mastocytosis. Some patients with a positive history and a negative skin test do have venom-specific IgE antibodies in the serum that can be detected by serologic testing using a radioallergosorbent test (RAST). Venom skin tests do not correlate perfectly with serologic venom-specific IgE assays, which are negative in approximately 20% of patients with positive skin tests. On the other hand, venom skin tests are negative in approximately 10% of subjects with detectable venom-specific IgE antibodies.

Venom skin tests and RAST should be considered complementary because neither test alone detects all patients with insect sting allergy. In a 2003 rostrum paper, the Insect Committee of the American Academy of Allergy, Asthma, and Immunology recommended that the published 1999 practice parameter for stinging insect allergy revise the diagnostic algorithm for insect sting allergy to include IgE antivenom serologic testing in patients with positive histories and negative skin tests. The updated 2004 practice parameter for stinging insect hypersensitivity recommends that for patients who have had a severe systemic reaction to an insect sting and who have negative venom skin test, repeat skin testing or in vitro testing for venom-specific IgE antibodies should be performed before concluding that venom immunotherapy is not necessary.

The level of sensitivity of venom skin testing or serologic testing does not accurately predict the severity of subsequent sting reactions. Low sensitivity on skin tests or RAST may be present in some persons who have had near-fatal anaphylactic reactions, and the strongest reactions on skin tests are often in patients who have had only large local reactions to stings.

In most cases, skin testing is not necessary in patients with histories of only large local reactions or in children who have had only mild systemic reactions limited to the skin (flushing, urticaria, angioedema) because their risk of having a more serious reaction subsequently is relatively low (Table 2).

Table 2 Indications for Insect Venom Skin Testing

Patient	Local Reaction	Cutaneous Systemic Reaction	Anaphylaxis
Child	No	No	Yes
Adult	No	Yes	Yes

Treatment

Treatment of Acute Reactions

Local reactions to insect stings are usually treated with cold packs, oral antihistamines, analgesics, and topical corticosteroids, all of which can help alleviate the associated itching and the local pain and swelling. A short course of an oral corticosteroid may be given for very large local reactions and is most effective within the first few hours after a sting. Occasionally, large local reactions are mistaken for cellulitis, and lymphangitic streaks can occur on the extremities as a result of drainage of inflammatory mediators. When these reactions occur in the 24 to 48 hours after a sting, infection is extremely unlikely, and treatment should include cold packs and an oral corticosteroid given for 4 to 5 days.

Treatment of Systemic Reactions

Mild systemic reactions manifested only by cutaneous symptoms may respond to antihistamines alone. Most systemic reactions, however, require treatment with epinephrine. Patients with any signs or symptoms of upper or lower airway obstruction or hypotension should immediately receive aqueous epinephrine intramuscularly, emergency medical attention and treatment, and close observation for 4 hours or longer depending on the reaction severity. Some patients require additional doses of epinephrine and/or other treatment for severe anaphylactic reactions. The recommended dose of epinephrine is 0.3 to 0.5 mg (0.3-0.5 mL of 1 : 1000 weight/ volume solution) for adults, and 0.01 mg/kg (maximum 0.3 mg) or 0.01 mL/kg of 1 : 1000 weight/volume solution (maximum 0.3 mL) for children. Delay in the use of epinephrine has contributed to fatalities, and some patients with anaphylactic shock are resistant to epinephrine. Patients who are taking beta blockers can also be resistant to epinephrine and can require large amounts of intravenous fluids and glucagon to reverse anaphylaxis. See the article “Anaphylaxis,” for additional information on the treatment of anaphylaxis.

Future Sting Reactions

Prevention

After acute care of a sting reaction, patients should be given a prescription for an epinephrine autoinjector, referral to an allergist or immunologist, and instructions on preventing insect stings. Epinephrine autoinjectors are available in only two strengths (EpiPen 0.3 mg and EpiPen Jr. 0.15 mg). The EpiPen Jr. is usually preferred in children weighing less than 25 kg. Patients and their caregivers should be given instructions on the correct technique for use of the device and reminded to replace it at expiration. Patients should be advised to minimize high-risk exposure to stinging insects that can occur through lawn and garden work, working near trash bins, and eating and drinking outdoors. Stings to the mouth and tongue can occur from ingesting food or flavored drinks that are being scavenged by yellow jackets. Additional information on avoidance and on identification of insects is available at www.aaaai.org/patients/publicedmat/tips/stinginginsect.stm.

Natural History

The risk that a future sting will cause an allergic reaction depends on the history and on the person’s immunologic status. For adults who have had a severe systemic reaction and who have positive skin tests or RAST, the risk of a subsequent systemic reaction is approximately 60%, but it is significantly less, approximately 20%, if the prior reaction caused only cutaneous symptoms (flushing, urticaria, angioedema). The outcomes of subsequent stings can vary within an individual patient because of variations in the insect species, the amount of allergen delivered, and fluctuation in the patient’s immunologic and physiologic status. The risk of a recurrent systemic sting reaction is higher in patients with honeybee allergy than in those allergic to vespids. Patients who have had severe reactions have a higher risk of recurrent sting reactions than do those who have sustained milder reactions, and adults have a higher risk of recurrent systemic reactions than children.

In general, individuals have a stereotypical response to stings that does not vary greatly from one sting to another; despite popular opinion, it is unusual for patients to have increasingly severe reactions with each subsequent sting. Children who have had mild systemic reactions limited to the skin have only a 10% risk of subsequent systemic reaction, and less than 1% risk of having a reaction more severe than the prior one. The risk of recurrence of a severe systemic reaction in a child is significantly higher, approximately 40%, although it is still lower than for a comparable reaction in an adult.

Adults and children who have had only large local reactions have a relatively low risk (5%-10%) of having a systemic reaction with a subsequent sting, although most of them will continue to have large local reactions.

Venom Immunotherapy

Indications

Venom immunotherapy is the treatment of choice for preventing allergic sting reactions in patients who have a significant risk of a serious reaction to a future sting. Children who have had systemic reactions limited to the skin do not require immunotherapy because they have a very low risk of anaphylaxis from future stings. Adults who have had only mild systemic sting reactions and who have positive skin tests and/or positive RAST results are usually advised to undergo immunotherapy, however, because of their increased risk (compared with children) of having systemic reactions that progress from isolated cutaneous symptoms to anaphylaxis. Immunotherapy is indicated for children and adults who have had severe systemic reactions and have positive skin tests and/or RAST results. Fig. 2 illustrates a clinical algorithm of evaluation and management of insect sting anaphylaxis. Venom immunotherapy is not required for either adults or children who have had only large local reactions because of their low risk of anaphylaxis with subsequent stings.

Figure 2: Click to Enlarge

Selection of Venoms and Dosing

The selection of venom extracts used for immunotherapy is based on the results of the skin tests to the individual venoms. Therapy usually includes all venoms that are positive on skin testing, and mixed vespid venom (containing equal parts of yellow jacket, yellow hornet, and white-faced hornet venoms) is most often used in patients with vespid allergy. Although yellow jacket venom may protect against reactions to hornet stings because of their extensive cross-reactivity, the clinical protection is less reliable with single vespid venom than with mixed vespid venom therapy. Separate injections of honeybee venom and wasp venom extracts are given if skin tests are positive to either or both of these venoms. Immunotherapy with whole-body extracts of fire ants is available for patients with histories of systemic IgE-mediated reactions to fire ant stings.

Venom immunotherapy is initiated at a very small dose of venom that is increased to the full maintenance dose according to a schedule recommended by the laboratory that prepared the venom extract and/or by the prescribing physician. Adverse reactions are usually no more common with rapid dosage regimens that can achieve maintenance doses in days or weeks than with traditional regimens that take 4 to 6 months. The standard recommended maintenance dose is 100 μg for each venom to which the patient has a positive skin test. This dose was originally selected because it was approximately twice the amount of venom in a single honeybee sting (50 μg). The amount of venom injected by a vespid varies significantly, with estimates ranging from 2 to 20 μg per sting.

Maintenance venom immunotherapy is usually administered at 4-week intervals for at least 1 year. Several studies have shown that the maintenance interval may be extended to 6 to 8 weeks over several years in most patients. Some physicians elect to repeat skin tests every 2 to 3 years while patients are receiving maintenance therapy, although only 50% to 60% of patients have a negative skin test even after 7 to 10 years of therapy.

Efficacy

Venom immunotherapy is extremely efficacious in preventing subsequent systemic reactions in patients with stinging insect allergy. Efficacy is highest with mixed vespid venom; it is 98% effective in preventing subsequent systemic reactions with a maintenance dose of 300 μg (100 μg per venom). For therapy with individual venoms (i.e., honeybee, yellow jacket, or wasp) at a dose of 100 μg per venom, immunotherapy is 75% to 95% effective in preventing systemic reactions to future stings. Those few patients who continue to have systemic reactions usually have milder reactions than before beginning treatment. Increasing the maintenance dose of immunotherapy to 200 μg provides full protection for most patients who have had systemic reactions while receiving treatment with single venoms at a dose of 100 μg.

Safety

Adverse reactions to venom immunotherapy are no more frequent than reactions to immunotherapy for inhalant allergens (i.e., pollen, mold, dust mites). Systemic reactions occur in 5% to 15% of patients, most commonly during the first few weeks of treatment and while receiving maintenance doses, and are more likely to occur in patients receiving honeybee venom than in those being treated with yellow jacket venom. Most systemic reactions to venom immunotherapy are mild and do not require epinephrine. Large local reactions occur in up to 50% of patients receiving venom immunotherapy and are not predictive of systemic reactions to subsequent injections. Pretreatment with antihistamines given before injections decreases both local and systemic reactions and does not interfere with the efficacy of immunotherapy.

Patients who are taking beta blockers are at increased risk for more serious anaphylaxis if they have a systemic reaction during venom immunotherapy in part because they are more likely to be refractory to treatment with epinephrine. An effort should be made to substitute alternative medication (e.g., diuretic or calcium channel blocker for treatment of hypertension) before initiating immunotherapy in these patients. As with inhalant immunotherapy, maintenance venom immunotherapy can be continued during pregnancy, although it is not recommended that it be initiated during pregnancy. Venom immunotherapy should be performed only in an office or clinic that is prepared to give immediate treatment of anaphylaxis, and patients must remain in the office for at least 30 minutes before going home after an injection.

Duration and Outcomes

Since 1979, when the U.S. Food and Drug Administration approved Hymenoptera venom extracts for venom immunotherapy, the product package inserts have recommended that therapy be continued indefinitely. Some experts have suggested that venom immunotherapy can be stopped if venom skin test or venom-specific IgE antibody levels become negative on retesting. However, most patients continue to have positive skin tests and/or venom-specific IgE antibodies after 5 years of therapy. More recent studies have shown that venom immunotherapy can be discontinued after 5 years of therapy in most patients. Although there is usually no reaction to a sting during the first 2 years after stopping treatment, the risk of relapse increases during the third year and does not disappear even up to 15 years after discontinuation. Golden and colleagues reported that after stopping immunotherapy, the chance of a systemic reaction is approximately 10% with each future sting for 10 or more years after treatment is discontinued, even if venom skin tests become negative. Most reactions that occur are less severe than those occurring before venom immunotherapy, although some patients who have had life-threatening reactions before treatment can have very severe reactions after stopping treatment. Patients with honeybee allergy and those who had a systemic reaction while receiving immunotherapy, from either an injection or a field sting, also appear to have higher frequencies of anaphylaxis after discontinuing venom immunotherapy. These patients, as well as those who had very severe reactions before starting therapy, appear to have a higher risk of relapse and should, therefore, probably receive venom immunotherapy indefinitely (Box 1). Extension of immunotherapy beyond 5 years’ duration may be considered in other patients who are unwilling to accept the 10% risk of systemic reaction with each future sting.

Box 1 Duration of Venom Immunotherapy
In most patients venom immunotherapy can be stopped after 5 years of treatment.
Patients with higher frequencies of anaphylaxis recurrence after immunotherapy is stopped include:
● Those with honeybee allergy
● Those who had a systemic reaction during treatment (sting or venom injection)
● Those who received treatment for less than 5 years
● Those who had severe (nearly fatal) sting reactions before treatment
Patients with any of these high-risk characteristics should probably receive venom immunotherapy indefinitely.

Summary

Hymenoptera venom allergy is an IgE-mediated hypersensitivity to the venom of stinging insects in the insect order Hymenoptera.
Large local reactions from insect stings tend to recur after subsequent stings, with relatively low risk (5% to 10%) of developing anaphylaxis.
Adults who have had a severe systemic reaction to an insect sting and who have positive skin tests have approximately a 60% risk of anaphylaxis with each subsequent sting.
The diagnosis of Hymenoptera allergy is based on a convincing history and positive skin tests and/or radioallergosorbent test (RAST).
People at risk of insect sting anaphylaxis should be educated regarding measures to avoid insect stings, have an epinephrine autoinjector immediately available, and be advised to receive venom immunotherapy.

Cleveland Clinic Lecture: Hymenoptera Venom Allergy