David B. K. Golden MD, FACP1
1Associate Professor of Medicine, Johns Hopkins University School of Medicine
The author is a consultant and participates in the speakers' bureaus for ALK Laboratories and Dey Laboratories and has received research support from ALK Laboratories.
Allergic reactions to insect venom primarily occur as a result of stings by insects of the order Hymenoptera. Biting insects can cause allergic swelling at the site of the bite, but only rarely does anaphylaxis result. Nonallergic reactions to insect venom have also been reported; these include nephropathy and renal failure, central and peripheral neurologic syndromes, idiopathic thrombocytopenic purpura, and rhabdomyolysis. These are toxic reactions and are not IgE mediated. Allergic reactions to stings manifest themselves as either late-phase local inflammation (i.e., severe prolonged swelling) or systemic responses (e.g., anaphylaxis).
Allergic reactions to Hymenoptera stings have been reported in persons of all ages. The reactions may be preceded by a number of uneventful stings. Systemic allergic reactions are reported in up to 1% of children and 3% of adults, although allergic antibodies to Hymenoptera venoms can be detected in 17% to 26% of adults.1 The frequency of large local allergic reactions is uncertain but is estimated to be about 10% in adults. Fatal allergic reactions to insect stings may occur at any age but are most common in adults older than 45 years.2 Half of those persons in whom a fatal reaction occurred had no previous history of allergy to insect stings; the other half had previous reactions but failed to take adequate preventive measures. In the United States, at least 40 deaths occur each year as the result of insect stings; other sting fatalities may go unrecognized. In many cases of unexplained sudden death, postmortem blood samples show the presence of both Hymenoptera venom-specific IgE antibodies and elevated serum tryptase levels, indicating the true cause of the fatal reactions.3
For 50 years, whole body extracts were used as standard immunotherapy treatment; such use was based on a lack of knowledge of the natural history of insect sting allergy.4 We now recognize that the risk of an anaphylactic reaction to a sting varies in accordance with the history of previous stings and is correlated with the results of venom skin testing or radioallergosorbent testing (RAST). In patients at highest risk, the risk of reaction is 50% to 70%; other persons with a history of insect-sting allergy can have a much lower risk. Most affected children have only cutaneous systemic reactions, with no respiratory or vascular symptoms, and have less than a 10% to 15% risk of a systemic reaction to a subsequent sting.5 The risk of a systemic reaction is less than 10% in adults or children who have experienced only large local reactions to stings. Insect sting allergy is self-limited in many cases, and the risk of an allergic reaction declines gradually with time after the initial sting reaction [see Table 1]. The risk of reaction falls from 50% initially to 33% after 3 to 5 years; the risk of a new reaction is 20% to 25% if more than 10 years have passed since the last reaction.6 However, in some individuals, the risk of anaphylaxis persists for decades, even with no intervening stings.
Table 1 Risk of Systemic Reactions and Clinical Recommendations Based on Reaction to Previous Stings and Results of the Venom Skin Test or RAST
Hymenoptera allergy is directed against the allergenic proteins in the venoms of the stinging insects. Three families of Hymenoptera are important causes of allergy. The bees (i.e., honeybees and bumblebees) and vespids (i.e., yellow jackets, hornets, and wasps) are the best known [see Figures 1 and 2]. Imported fire ants (Solenopsis species) are a rapidly increasing public health hazard in the Southeast and South Central United States, especially on the Gulf Coast [see Figure 3].7 Honeybee stings are more common in agricultural areas. Yellow jackets are the most frequent culprits in the northern areas of North America and Europe, whereas paper wasps (Polistes species) are more commonly implicated along the Gulf Coast in the United States and the Mediterranean Coast in Europe. Stinging ants of various species have become an increasing cause of anaphylaxis in Australia and Asia.8
Figure 1. The honeybee (Apis mellifera).
Figure 2. The European hornet (Vespa crabro germana) was introduced into the United States in the mid-19th century. In the United States, its habitat includes most of the eastern United States, Louisiana, and the Dakotas. Although it is a woodland species, its nests can be found in barns, attics, hollow walls, birdhouses, and abandoned beehives.
Figure 3. Red imported fire ant (Solenopsis invicta).
Knowledge of the behavior of these insects can be helpful in evaluating the history of affected patients. Honeybees are relatively docile and rarely sting or swarm unless provoked. Stings usually occur as a result of garden exposures or from going barefoot outdoors. The barbed stinger of the honeybee remains in the skin, causing the death of the honeybee. Africanized honeybees (killer bees) are more aggressive and are now present in the southern United States.9 Although an Africanized honeybee is no different from a domestic honeybee with regard to anatomy or venom, Africanized honeybees have a tendency to swarm with little provocation and to sting in large numbers. A large number of stings can cause massive envenomation; the resulting toxic reactions have been fatal to livestock and humans. Bumblebees sting infrequently, but they are a cause of occupational anaphylaxis in European greenhouse agriculture.10
Yellow jackets usually nest underground or in the cracks of buildings or wooden ties or logs used in residential landscaping, whereas hornets generally build their nests in shrubs and trees. Paper wasps build an open nest with visible cells; nests are often found on the eaves or windowsills of a home or in the railings of decks or fences. Yellow jackets are scavengers; they are commonly found around food at picnics and in orchards, trashcans, and dumpsters. They are highly aggressive and will sting quite readily. Wasps are less aggressive but will sting readily when disturbed. The vespid stinger usually has finer barbs than the stinger of the bee and does not as commonly remain in the skin.
Fire ants have stingers, and it is the sting rather than the bite that causes the allergic reaction. Fire ants are widespread in the southeastern United States; in many areas, stings are very frequent, with up to 50% of the population being stung each year. Fire ants build nests in the shape of large mounds; these nests are common in residential and coastal areas. In most cases of fire-ant stings, multiple ants each administer multiple stings, which cause minimal pain. The unique lesions form sterile pustules that can become infected if excoriated [see Figure 4].
Figure 4. Appearance of a pustule resulting from the sting of a fire ant. This photograph was taken 24 hours after the patient was stung.
The allergic sensitivity is directed against proteins in the venoms (but not in the saliva or bodies) of the stinging insects.11 Honeybee venom contains unique allergens, whereas the vespid venoms cross-react extensively with one another and contain essentially the same allergens. The venom of Polistes wasps is less cross-reactive than that of the other vespids. Only 50% of patients who are allergic to yellow-jacket venom experience reactions to wasp venom. Some of the allergenic proteins in fire-ant venom are unique, with relatively little cross-reactivity with the venom of Asian stinging ants.
The pathogenesis of Hymenoptera allergy is the same as that of other forms of anaphylaxis. An initial encounter with a sting in genetically susceptible individuals causes the production of IgE antibodies to the venom allergens. The IgE antibodies become affixed to tissue mast cells and circulating basophils, which thus become armed for response to a later encounter with the same allergen. A subsequent sting can cause cross-linking of these allergic antibodies, leading to the release of mediators (e.g., histamine, leukotrienes, and cytokines) that cause the clinical manifestations of the allergic reaction. There is an association between conditions involving abnormal mast cell number or function and insect-sting anaphylaxis. The allergic reactions to stings are more severe in patients with elevated baseline serum tryptase levels or mastocytosis, and there is a higher incidence of treatment failures and relapse after treatment in these patients.12,13,14 Whole body extracts of imported fire ants are used for diagnostic testing and are effective for immunotherapy, whereas whole body extracts of the other Hymenoptera insects have proved not to contain venom allergens. Venom extracts of Australian jack jumper ants have proved effective for diagnosis and treatment.
Allergic reactions to insect stings may cause local allergic inflammation or the full spectrum of manifestations of anaphylaxis. Large local reactions are late-phase allergic reactions. Progressive swelling begins 6 to 12 hours after the sting, reaching peak size in 24 to 48 hours and resolving in 5 to 10 days. Large local reactions may be defined as being greater than 6 in. in diameter; they can be massive in size and cause considerable pain. On the extremities, inflammatory lymphangitic streaks can occur toward the axillary or inguinal nodes and may be mistaken for signs of infection. Systemic reactions most commonly cause cutaneous signs and symptoms, including generalized flushing, pruritus, urticaria, and angioedema. Other typical manifestations are respiratory (e.g., throat or chest tightness, dyspnea, wheezing) or circulatory (e.g., light-headedness, hypotension, or unconsciousness). Less common signs of anaphylaxis include gastrointestinal or uterine cramps, cardiac arrhythmias (e.g., tachycardia or, occasionally, bradycardia), and coronary vasospasm.15
In children younger than 17 years, systemic reactions to stings usually cause only cutaneous symptoms (e.g., urticaria or angioedema). Respiratory symptoms are less common, and circulatory manifestations are infrequent. Systemic reactions usually follow a predictable and individual pattern in each patient, with worsening of the reaction occurring in less than 10% of cases.16 Affected individuals commonly do not seek medical attention and usually fail to report having sting reactions unless they are asked.
The diagnosis of insect-sting allergy rests on a history of allergic reactivity, because venom-specific IgE antibodies can be detected in many normal individuals. The positive venom skin test provides confirmation of the allergic nature of the sting reaction and helps define allergenic specificity. The history is most important and should be reviewed in detail with respect to the nature, number, and timing of stings in the past; the time course of the reaction; and all associated symptoms and treatments. The family history, atopic history, and general medical history are also of interest. In addition, it is helpful to know of any medications the patient took before the reaction occurred, as well as any medications the patient is currently using.
It is most important to measure the vital signs, including airflow when there is dyspnea, and to document cutaneous signs. Some patients have symptoms, such as dizziness and dyspnea, that do not correspond to the objective signs (e.g., blood pressure, peak expiratory flow rate) and may be the result of anxiety, panic, and hyperventilation. Any history suggestive of systemic allergic reaction must be taken seriously.
The diagnosis of insect-venom allergy can be confirmed by skin tests or serologic tests using Hymenoptera venoms. Both methods are useful, and they are often complementary in the diagnostic evaluation of affected patients. Interpretation of both methods requires specific experience and training to prevent false conclusions. Diagnostic tests are not usually performed in the absence of a history of a systemic allergic reaction. This is because a positive test occurs in 20% to 30% of adults and is associated with a relatively low chance (17%) of a systemic reaction to a future sting.1
Intradermal skin tests using serial dilutions of the five Hymenoptera venom protein extracts is the recommended procedure. In the case of fire-ant sensitivity, whole body extracts of imported fire ants give reasonable diagnostic sensitivity and specificity. For Hymenoptera venom testing, intradermal tests are performed with venom concentrations ranging from 0.001 to 1 µg/ml to find the minimum concentration that yields a positive result, as compared with a negative diluent control (e.g., human serum albumin saline) and a positive histamine control. Puncture tests with a venom concentration of 1 µg/ml may be used initially for patients with a history of very severe reactions.
The diagnosis of insect-sting allergy by detection of allergen-specific IgE antibodies in the serum (typically by RAST) is a method of high potential but variable performance.17 In patients with a history of allergic reaction to a sting, a clear elevation in the level of venom-specific IgE is certainly diagnostic; but the standardization and reproducibility of the test are sometimes unreliable, and the test yields negative results in 15% to 20% of patients whose skin test results are positive. In the majority of patients who have a definite history of insect-sting reactions, skin-test results are clearly positive; however, in many others, the results are clearly negative. Negative skin-test results in a patient with a history of insect-sting reactions may represent the loss of sensitivity, but it is important to test for venom-specific IgE antibodies in the serum (e.g., by use of RAST).18 Venom skin tests can be negative in 50% of allergic patients in the first weeks after a sting reaction,19 and it has recently been shown that the results of venom skin tests can vary over a period of weeks.20 If necessary, the venom skin test may be repeated after several months. Alternate diagnostic methods such as basophil activation tests may be useful in difficult cases, but the diagnostic accuracy of these tests is no better than that of existing methods.21 In addition, increased basophil activation may be associated with a higher risk of adverse reactions to venom immunotherapy.22
A few cases of sting anaphylaxis are non-IgE mediated and may be related to subclinical mastocytosis or simply toxic mast cell hyperreleasability.14 It is important to note that the degree of sensitivity as detected by skin testing or RAST does not correlate reliably with the degree of sting reaction. The strongest sensitivity to skin tests often occurs in patients who have had only large local reactions, and some patients who have had near-fatal anaphylactic shock show only weak sensitivity on skin testing or RAST. Because of cross-reactivity, skin tests are positive to all three of the common vespid venoms (i.e., yellow jacket, yellow hornet, and white-faced hornet) in 95% of patients allergic to yellow-jacket venom. More than half of patients sensitive to yellow-jacket venom also have positive reactions to testing for sensitivity to Polistes wasp venom. It is possible to determine whether the patient has a specific or a cross-reactive sensitivity to wasp venom using a RAST-inhibition test in specialized laboratories.23
Although the diagnosis of insect-sting allergy is relatively straightforward, the history and diagnostic tests can be misleading in some cases. Local swelling may be the result of nonallergic inflammation, but infection is very uncommon and would likely occur many days after the sting. Local cutaneous signs should not be mistaken for a systemic eruption. Symptoms of dyspnea, chest discomfort, and dizziness can be the result of hyperventilation associated with anxiety. Patients with asthma who receive a sting may have asthmatic symptoms that are difficult to distinguish from an allergic reaction. More than 1% of patients with a history of allergic reactions to insect stings have an underlying abnormality in the release of mediators by mast cells or basophils, as demonstrated by elevated baseline serum tryptase levels. Some of these patients have a form of mastocytosis.12,14,24
The treatment of the acute systemic allergic reaction to insect stings is the same as that of other causes of anaphylaxis. The treatment of choice is epinephrine by intramuscular injection.25,26 The recommended dose is 0.3 to 0.5 mg (0.3 to 0.5 ml of a solution of 1:1,000 weight in volume [w/v]) for adults and 0.01 mg/kg for children. Delay in the use of epinephrine has contributed to fatal reactions. Some persons in anaphylactic shock are resistant to epinephrine. Patients taking beta-blocker medications can also be resistant to the effects of epinephrine. In some cases, anaphylaxis is prolonged or recurrent (biphasic) for 6 to 24 hours and may require intensive medical care.27 All patients with anaphylaxis should receive full emergency medical attention and remain under observation for 6 hours or longer. Corticosteroids have no role in the treatment of acute anaphylaxis; they are administered to prevent late-phase reactions, but there is no evidence that steroids prevent biphasic anaphylaxis.
Large local reactions may require a burst of corticosteroid, which is most effective if started within 2 hours of the sting. After an initial dose of 40 to 60 mg, the dose is tapered over 3 to 5 days.
Patients who are discharged from emergency care after suffering anaphylaxis must receive information on the risk of future reactions. They should also be advised to receive allergy consultation, and they should be given information about prevention. When outdoors, the affected person should avoid bushes and gardens, as well as food and drink that are most likely to attract insects. Drinks, especially in cans, bottles, and straws, can be an unsuspected source of a sting to the tongue or throat. Prescription of an epinephrine autoinjector (e.g., EpiPen and EpiPen Jr., Dey, Napa, California; TwinJect 0.15 mg and TwinJect 0.3 mg, Verus, San Diego, California) should be considered for any patient who has experienced a systemic allergic reaction. Some patients may need to use epinephrine immediately after receiving a sting (until they can be immunized); however, most patients can wait for the signs of a developing reaction before using epinephrine. Brief delay in treatment is reasonable because the majority of persons with a history of mild to moderate systemic reactions do not react to a challenge sting, and reactions that occur are generally not more severe than previous reactions. The age at which a patient should be prescribed an adult-strength autoinjector, rather than a pediatric autoinjector, is uncertain; use of the adult-strength injector may be considered when the child attains a weight of 25 kg.28 All patients should understand that use of an epinephrine kit is not a substitute for emergency medical attention.
Current indications for venom immunotherapy are a history of previous systemic allergic reaction to a sting and a positive venom skin test.29,30,31 The patients at highest risk are those with a recent history of anaphylaxis and positive skin-test results; in such patients, the risk of a systemic reaction to a subsequent sting is approximately 50%. Children and adults with a history of large local reactions are at low risk for a systemic reaction (i.e., < 10%),32,33 as are children whose systemic reactions are limited to cutaneous signs and symptoms.5 In these low-risk persons, venom immunotherapy is not required, but some patients will still request treatment for reasons related to fear of reaction or frequent exposure. Children with moderate or severe systemic reactions have a relatively high risk of recurrence of systemic allergic reactions even 10 to 20 years after an allergic reaction to an insect sting.32 There are some cases of progressively worsening allergic reactions in adults, so all adults with systemic reactions are advised to undergo venom immunotherapy. There is no test that accurately predicts which patients will progress to more severe reactions and which will not. Patients with a history of anaphylaxis from a sting may have no reaction to a subsequent sting and still have a severe reaction to a later sting. The variability of the occurrence of the reaction may be the result of intrinsic biologic variables; in some cases, variability has been associated with differences in the species of insect.34
The rationale for treatment to prevent impairment of the health-related quality of life has been clinically validated.35 It is generally not sufficient to recommend avoidance measures and carrying an epinephrine kit. If the kit is needed, then a potentially dangerous reaction is already occurring, whereas venom immunotherapy completely prevents the reaction. In fact, most patients do not find it reassuring to have an epinephrine injector,36 and the great majority of patients suffering a repeat episode of anaphylaxis do not use the prescribed injector for a variety of reasons.
The selection of venoms for immunotherapy should include all venoms that gave a positive result on diagnostic tests. Fire ant immunotherapy utilizes whole body extracts, which seem to be effective.37 Venom immunotherapy for anaphylaxis from the sting of the jack jumper ant was proven effective in a double-blind placebo-controlled trial.38 Initial venom immunotherapy can be completed with a regimen of eight weekly injections or a traditional regimen lasting for 4 to 6 months. Rush immunotherapy, typically administered over a period of 2 to 3 days, has been reported to be as safe and effective as the usual regimens.39,40 The recommended maintenance dose is 100 µg of each of the venoms for which a positive result was seen on skin testing. Standard therapy is 85% to 98% effective in completely preventing systemic allergic reactions, but some patients require higher doses for full protection.41 The same dose has been recommended for children 3 years of age and older, even though their immune response to venom immunotherapy is twice that of adults.
Venom immunotherapy causes reactions no more frequently than inhalant allergen immunotherapy.42 Systemic symptoms occur in 10% to 15% of patients during the initial weeks of treatment, regardless of the regimen used. Most reactions are mild, and fewer than half of the reactions require epinephrine. In unusual cases, there can be repeated problems with systemic reactions to injections. Large local reactions are common but are not predictive of systemic reactions to subsequent injections. All patients must achieve a dose of at least 100 µg to have optimal clinical protection.
Maintenance and monitoring
After the full dose has been reached, the same dose is repeated at 4-week intervals for at least 1 year. The dosing interval may then be increased to once every 6 to 8 weeks over several years of treatment. Therapeutic efficacy can be confirmed serologically, but use of only some assays for venom-specific IgG antibodies has correlated strongly with clinical protection.43 Venom skin testing or RAST is repeated periodically—usually every 2 to 3 years—to determine whether there has been a significant decline in venom-specific IgE.44 The results of skin testing generally remain unchanged during the first 2 to 3 years but show a significant decline after 4 to 6 years.6 Fewer than 20% of patients have negative skin-test results after 5 years, but 50% to 60% have negative results after 7 to 10 years.45 The mechanism of venom immunotherapy may be different during the initial stages (associated with increased production of IL-10) than during the later stages of tolerance (for which osteopontin may be a marker).46,47
The package inserts for the commercial venom immunotherapy products available in the United States recommend indefinite immunotherapy. However, the published practice parameters reflect more recent experience and recommendations.31,44 In most patients, skin-test results and RAST results remain positive after 5 to 10 years of treatment. Studies of several hundred adults and children show that even when skin tests remain positive, venom immunotherapy can usually be stopped after 5 years.44 Observation of patients for 5 to 10 years after completing a 5- to 8-year course of venom treatment has shown a 5% to 10% risk of systemic symptoms after any sting but only a 2% risk of a reaction requiring epinephrine treatment.45,48 Patients who have a higher frequency of relapse include those receiving honeybee-venom therapy, those with a history of very severe pretreatment sting reactions, and those who have had a systemic reaction to a sting, or to an injection, during the period of venom immunotherapy.29,49 Several studies have shown that 5 years of therapy is superior to 3 years for suppression of the IgE response and for longer-lasting remission.50,51 Some patients prefer to continue venom treatment for their continued sense of security. Children who have had a 3- to 5-year course of venom immunotherapy show persistent tolerance even 10 to 20 years after discontinuing treatment.32
The photographs in Figures 1 and 2 are by Stephen B. Bambara; the photographs in Figures 3 and 4 are by James Baker, Ph.D. All photographs are courtesy of the North Carolina State University Department of Entomology.
Editors: Dale, David C.; Federman, Daniel D.