Hypersensitivity to Hymenoptera Stings
http://www.100md.com
《新英格兰医药杂志》
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.
A 29-year-old man reported that he was stung by a flying hymenopteran — he does not know what type — outside his door, where he had previously noted a nest. Skin itching, diffuse hives, swelling of his arms and legs, tightness in his throat, dizziness, and difficulty talking developed immediately, and he was taken to a local clinic where he received epinephrine and antihistamines. He was observed for two hours, and all symptoms resolved. How should his case be managed subsequently?
The Clinical Problem
Insects of the order Hymenoptera, which includes ants, bees, hornets, wasps, and yellow jackets, have a stinging apparatus at the tail end of their abdominal segment and are capable of delivering between 100 ng (fire ants)1 and 50 μg (bees)2 of venom (Table 1 and Figure 1). Although the venoms have various peptide and protein components, some of which are capable of inducing toxic or vasoactive responses, it has been estimated that about 1500 stings would be required to deliver a lethal dose of hymenoptera venom for a nonallergic adult who weighs 70 kg.5 Despite this estimate, about 40 deaths a year are attributed to hymenoptera stings6; these deaths are ascribed to anaphylaxis occurring in persons with a history of prior stings in whom specific IgE antibodies developed to various venom components. Due to the vasoactive components of the venoms, most people experience a local reaction to hymenoptera stings consisting of redness, swelling, tenderness, and pain at the site of the sting. This reaction is self-limited and will resolve within hours. If the sting occurs near or within the oral cavity, there is a potential for respiratory compromise.
Table 1. Characteristics of Hymenoptera.
Figure 1. Species of Hymenoptera and Their Geographical Distribution.
Fire-ant venom is composed primarily of a transpiperidine alkaloid that causes tissue necrosis. Most fire-ant stings produce a blister within 24 hours, which often fills with necrotic material, giving the appearance of a pustule (Figure 2). Despite their appearance, these blisters are not infected and should be left intact.
Figure 2. Stings from a Fire Ant on an Ankle, Showing the Pseudopustule.
The clustering of the stings (white arrow) contrasts with the single sting (black arrow) in the photograph, which was taken 24 hours after the event. This pattern is typical of fire-ant stings, as one ant will often inflict multiple stings in a semicircular arc if given time to do so. Also, the pseudopustule is typical of fire-ant stings; it is not a pustule. The stings occurred just above the level of the ankle sock the patient was wearing on the day of the event.
Occasionally, persons will have swelling from a hymenoptera sting that may involve a large area and persist for up to a week. These large local reactions are not life threatening unless they involve the airway. They may result in considerable morbidity because of a temporary loss of function, such as occurs when the sting involves a foot or hand or is near an eye. Secondary infections can frequently complicate fire-ant stings when the pseudopustule is opened, and they can sometimes complicate other hymenoptera stings. Although it may be difficult in some cases to distinguish a secondary infection from a large local reaction, in the latter event the swelling usually peaks within 48 hours, whereas progression of swelling for more than two days, accompanied by fever or lymphadenitis, suggests secondary infection.
The reactions that lead to anaphylaxis, however, are of more concern than secondary infections. Some anaphylactic events are restricted to cutaneous findings (pruritus, urticaria, and angioedema). Others have a broader effect, with systemic symptoms that may involve the gastrointestinal tract (metallic taste, nausea, vomiting, diarrhea, and abdominal cramping), genitourinary tract (uterine cramps), or nervous system (sense of impending doom, light-headedness, and dizziness). Reactions that involve the cardiopulmonary system (breathing difficulties, bronchospasm, hypotension, and arrhythmia) pose the greatest risk. Initial subjective symptoms may progress rapidly (in seconds to minutes) to life-threatening cardiopulmonary collapse. The risk of anaphylaxis with any event is dependent on the nature of the most severe previous reaction experienced by a patient (Table 2). Neuropathic and vasculitic responses and reactions that resemble serum sickness have in rare cases been reported after insect stings.15,16
Table 2. Risk of Anaphylactic Reactions to Hymenoptera Stings after an Initial Event.
Strategies and Evidence
Immediate Therapy
The optimal choice of immediate therapy for insect stings depends on the type of reaction. Strategies are based on anecdotal evidence. Local reactions are best treated symptomatically with nonsteroidal antiinflammatory agents, antihistamines, and cold compresses. Topical antihistamines and corticosteroids may also be used. When large local reactions occur, oral steroids are often added to the therapeutic mix.
The definitive therapy for anaphylaxis is epinephrine by injection (0.01 mg per kilogram of body weight; maximum, 0.3 and 0.5 mg per dose, for children and adults, respectively), and this should be administered to any patient who has more than a cutaneous reaction. Antihistamines are often added to treat cutaneous signs and symptoms. Supplemental oxygen, beta-agonists for bronchospasm, and intravenous fluids for hypotension are sometimes indicated. Occasionally, for a reaction that does not respond to the initial dose of epinephrine, steroids (oral or intravenous) are added, although definitive support for their addition is lacking.
There is a distressing tendency by both patients and physicians to treat anaphylaxis without using epinephrine,17,18 perhaps because of concern about adverse effects of epinephrine on the heart. However, anaphylaxis itself has been associated with coronary vasospasm.19,20,21,22 The fact that available data suggest that a failure or delay in administering epinephrine increases the chance of a fatal outcome in anaphylaxis23 underscores the prevailing opinion that epinephrine must be considered the definitive therapy for anaphylaxis.
Epinephrine auto-injectors should be prescribed for any patient who has had an anaphylactic reaction to a hymenoptera sting. The instructions for use are printed on the side of each injector, but these should be reviewed with the patient when prescribing the medication. Patients should be educated to use epinephrine if signs or symptoms beyond a cutaneous reaction develop after a hymenoptera sting, and always to seek additional medical care after using an injector.
Long-Term Therapy
Avoidance
The long-term goal is to prevent future systemic anaphylactic events. The optimal approach to prevent IgE-mediated disease is avoidance of the antigen, but this may not be feasible in practice. Current recommendations for avoidance are summarized in Table 1. The proximity of the habitats of wasps and fire ants to those of humans makes these insects the most likely members of the order to cause anaphylaxis.24
Immunotherapy
If avoidance of hymenoptera cannot be ensured, the next step is to minimize the potential for anaphylaxis if a sting should occur. Immunotherapy with hymenoptera venom has been shown to reduce the potential risk of anaphylaxis with subsequent stings significantly13,14 (Table 2). Although the administration of whole-body extracts is no more effective than placebo therapy for treating the stings of flying hymenoptera,13 whole-body extracts of fire ants appear to be as useful in preventing future reactions as is venom immunotherapy for flying hymenoptera,25 perhaps because whole-body extracts of fire ants (in contrast to those of flying hymenoptera) contain adequate amounts of venom.26 Whole-body extract therapy for fire ants has not been compared directly with fire-ant venom immunotherapy.
Evaluation
The evaluation of patients for whom immunotherapy is considered begins with a review of the history of stings and reactions. The circumstances of the sting may suggest a particular agent (Table 1). The presence of a stinger or a venom sac at the site of a sting suggests, but is not definitive of, a honeybee sting, as occasionally other hymenoptera may leave a stinger in place. Fire ants are usually easy to identify since they do not fly away and will grasp victims with their mandibles and inflict multiple stings if allowed (Figure 2).
The clinical course is also reviewed to verify the diagnosis of anaphylaxis. It is sometimes difficult to separate anxiety symptoms from true anaphylaxis in the setting of a sting. This is especially true if there are no documented objective findings, such as urticaria, hypotension, or air-flow reduction. However, when patients are concerned enough to seek an evaluation even with an unclear or remote history, it is appropriate to test them for specific IgE antibodies. If the results of these tests are negative, patients can be reassured; if they are positive, immunotherapy should be offered. Age is also important. Studies have shown that in children under the age of 16 years who have cutaneous anaphylaxis (urticaria, angioedema, or both), the risk of systemic (in addition to cutaneous) anaphylaxis in response to future stings is only slightly greater than the risk in the general population6 (Table 2). It is uncertain whether the same is true in adults.
Subsequent evaluation involves testing for the presence of specific IgE antibodies.27,28 Initial testing is usually delayed for four to six weeks after the sting event to eliminate the possibility of a false negative result caused by a depletion of mediators in the setting of anaphylaxis. If the particular agent is known, then testing includes only that insect. It is often unclear which insect was the perpetrator, in which case testing of sensitivity to each of the flying hymenoptera is warranted.
Typically, testing involves in vivo skin testing for specific IgE antibodies; this is more sensitive than in vitro methods, which are an alternative. The prick method (a needle pricks the skin through a drop of the antigen) is used as the first step (a dilution of 1:1000 weight/volume for fire-ant venom; 1 μg per milliliter for venom from other hymenoptera). If the result of this test is negative, testing proceeds with an intradermal method (antigen is injected into the dermis), usually using about 0.001 μg per milliliter (1:1,000,000 wt/vol for fire-ant venom) and increases sequentially by 10 times the previous amount to 1.0 μg per milliliter (1:1000 wt/vol for fire-ant venom); above these concentrations, false positive test results may occur. Testing is stopped when the skin test is positive (the reaction is equivalent to or greater than a histamine control). If the maximal intradermal dose is reached without a positive response, the test result is considered negative. If a false negative result is suspected (on the basis of a history suggestive of anaphylaxis), or for patients who cannot be skin-tested (those who have severe dermatitis or who are receiving medications that suppress the histamine response), in vitro methods are reasonable alternatives. Immunotherapy is then offered to anyone who has both a history consistent with anaphylaxis after a sting and specific IgE antibodies to the potential agent, as demonstrated by positive results on skin testing or in vitro testing.
Whereas there may be extensive cross-reactivity between some venom components, such as antigen 5 (one of the more potent vespid antigens), there are enough highly specific components of the venoms (including differences between molecules common to all the venoms, such as phospholipases)29 to support the recommendation that all venoms for which skin testing yields positive results should be used in treatment. Treatment with more than one venom can be administered concurrently, but this generally requires multiple injections per visit; an exception is the commercial preparation that is a mixture of venoms from the yellow jacket, white-faced hornet, and yellow hornet (maximal dose, 100 μg of each species' venom).
Therapy
Immunotherapy starts at 0.1 μg per milliliter for most hymenoptera venoms (1:100,000 wt/vol for fire-ant venom). Each subsequent dose increases the amount of venom delivered to the patient, generally until a dose of 100 μg per milliliter for the venom of flying hymenoptera (0.5 ml of 1:100 wt/vol for fire-ant venom) is reached; 100 μg is twice the dose to which a patient would be exposed in a routine sting, and it is the dose used in initial studies showing the effectiveness of venom immunotherapy. Usually the doses are delivered once a week. This means there is a three-to-six-month period required to reach the maintenance dose. So-called rush protocols have been published,30,31,32 in which a shorter dosing interval is used to reach maintenance doses in weeks or even days, and they appear to provide good protection from sting challenges. These are particularly useful when the risk of exposure is high and ongoing, as may occur with patients who must work or play outdoors.33 These protocols have not been compared directly with standard immunotherapy protocols in randomized controlled trials, but they have been found to give reasonably equivalent protection against direct sting challenges.
When a maintenance level is reached, the interval between injections is often expanded to one month. Some observational data suggest that the interval may be expanded to 8 or even 12 weeks without losing protection.34,35 The maintenance dose and interval may be adjusted on the basis of clinical criteria. For instance, if a patient receives a sting that results in symptoms while receiving maintenance immunotherapy, the dose interval may be shortened or the dose increased to more than 100 μg.36
Protection after a course of immunotherapy appears to last a long time. In a recent report involving a follow-up evaluation of children 10 to 20 years after they had received immunotherapy, only 5 percent of the children with a history of a moderate-to-severe sting reactions who reported a subsequent sting had had a recurrent systemic reaction, as compared with 32 percent of untreated children with a similar history.37
The risks associated with hymenoptera immunotherapy are the same as for other allergen immunotherapy. The risk of anaphylaxis after an immunotherapy injection is low (fewer than 1.6 reactions per 100 injections).13 The majority (88 percent) of patients complete an immunotherapy course without reactions, and most reactions that occur are mild.38 Rarely, more severe reactions occur, including death (about 1 in 5 million injections for all types of immunotherapy).39 Therefore, immunotherapy should be administered only in a medical setting by trained personnel capable of recognizing and treating anaphylaxis.
Areas of Uncertainty
An important unanswered question relates to the optimal duration of maintenance immunotherapy. The package insert that comes with the venom immunotherapy recommends indefinite use, whereas current clinical guidelines recommend discontinuing immunotherapy after three to five years of the maintenance-level dose,40,41 especially if the patient no longer has specific IgE antibodies (as evaluated by repeated skin testing).42,43 However, data from patients who have not received immunotherapy indicate that the loss of these antibodies is no guarantee that anaphylaxis will not occur. In one report, 98 patients (including patients with and patients without a history of anaphylaxis) who had positive tests for specific IgE antibodies at baseline slowly lost their positive responses over time. However, the risk of anaphylaxis was not eliminated; at a mean of four years after initial evaluation, approximately 17 percent of patients (11 of 65) who had subsequent stings had anaphylactic reactions, despite the presumed loss of specific IgE antibodies.44 Other reports have documented reactions to hymenoptera stings after discontinuing immunotherapy.37,45 Given these data, some allergists extend venom immunotherapy longer than the suggested three to five years. Consideration of an extended course may be warranted particularly for patients who have had a severe reaction (for such patients, some allergists might continue immunotherapy indefinitely).
Another area that requires additional research is the treatment of patients who have a history of a reaction suggestive of anaphylaxis but in whom testing for specific IgE antibodies yields negative results. One potential explanation is that the earlier reaction was not to hymenoptera; the stings or bites of other insects (mosquitoes, biting flies, and reduvids) and arthropods (spiders, scorpions, and ticks) may also result in anaphylaxis. In rare cases, people with mastocytosis may have an anaphylactoid response to hymenoptera stings without actually having specific IgE antibodies.46 A more common explanation is the imperfect sensitivity of tests for specific IgE antibodies.10,47,48 Twenty percent of patients with negative in vitro tests will have positive results on skin testing, and 10 percent of patients whose skin test is negative will have positive results on in vitro testing.49 In cases in which the suspicion of hymenoptera hypersensitivity is high, and initial tests are negative, it has been recommended that repeated testing be undertaken with both in vivo and in vitro methods.50,51
Guidelines
Under the joint auspices of the American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma and Immunology, the Journal of Allergy and Clinical Immunology will publish the newest set of guidelines for insect hypersensitivity this year.52 In general, the recommendations presented here are consistent with these guidelines.
Summary and Conclusions
For patients with a clear history of anaphylaxis, such as the one described in the vignette, information should be provided on avoidance and on the use of emergency treatment with epinephrine auto-injectors. Patients should be advised to carry an auto-injector and to wear a medical alert bracelet. Referral to an allergist is warranted, and skin testing should be performed for sensitivity to honeybees, wasps, white-faced hornets, yellow hornets, and yellow jackets. Venom immunotherapy should be administered for all venoms for which testing results are positive. The protective benefit is expected from the immunotherapy by the time maintenance dose is reached, usually by three to six months with standard protocols. A rush protocol would be recommended if the patient's risk of being stung again before standard immunotherapy could work were considered high. Although immunotherapy is often administered by allergists, it may be delivered by any practitioner who is willing to observe the patient and to treat anaphylaxis if it should occur.
Source Information
From the Department of Allergy and Immunology, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, TX.
Address reprint requests to Dr. Freeman at the Department of Allergy and Immunology, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, TX, 78023, or at tfree95900@aol.com.
References
Hoffman DR, Dove DE, Jacobson RS. Allergens in Hymenoptera venom. XX. Isolation of four allergens from imported fire ant (Solenopsis invicta) venom. J Allergy Clin Immunol 1988;82:818-827.
Hoffman DR, Jacobson RS. Allergens in Hymenoptera venom. XII. How much protein in a sting? Ann Allergy 1984;52:276-278.
Guralnick MW, Benton AW. Entomological aspects of insect sting allergy. In: Levin MI, Lockey RF, eds. Monograph on insect allergy. 4th ed. Milwaukee: American Academy of Allergy, Asthma and Immunology, 2003:11-26.
McKenna WR. Africanized honeybees. In: Levin MI, Lockey RF, eds. Monograph on insect allergy. 4th ed. Milwaukee: American Academy of Allergy, Asthma and Immunology, 2003:27-36.
Goddard J. Physician's guide to arthropods of medical importance. 4th ed. Boca Raton, Fla.: CRC Press, 2003:4.
Barnard JH. Studies of 400 Hymenoptera sting deaths in the United States. J Allergy Clin Immunol 1973;52:259-264.
Golden DBK. Epidemiology of allergy to insect venoms and stings. Allergy Proc 1989;10:103-107.
Settipane GA, Boyd GK. Prevalence of bee sting allergy in 4,992 Boy Scouts. Acta Allergol 1970;25:286-291.
Chaffee F. The prevalence of bee sting allergy in an allergic population. Acta Allergol 1970;25:292-293.
Golden DBK, Marsh DG, Kagey-Sobotka A, et al. Epidemiology of insect venom sensitivity. JAMA 1989;262:240-244.
Graft DF, Schuberth KC, Kagey-Sobotka A, et al. A prospective study of the natural history of large local reactions after Hymenoptera stings in children. J Pediatr 1984;104:664-668.
Schuberth KC, Lichtenstein LM, Kagey-Sobotka A, Szklo M, Kwiterovich KA, Valentine MD. Epidemiologic study of insect allergy in children. II. Effect of accidental stings in allergic children. J Pediatr 1983;102:361-365.
Hunt KJ, Valentine MD, Sobotka AK, Benton AW, Amodio FJ, Lichtenstein LM. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:157-161.
Golden DBK, Valentine MD, Kagey-Sobotka A, Lichtenstein LM. Regimens of Hymenoptera venom immunotherapy. Ann Intern Med 1980;92:620-624.
Light WC, Reisman RE, Shimizu M, Arbesman CE. Unusual reactions following insect stings: clinical features and immunologic analysis. J Allergy Clin Immunol 1977;59:391-397.
Reisman RE, Livingston A. Late-onset allergic reactions, including serum sickness, after insect stings. J Allergy Clin Immunol 1989;84:331-337.
Clark S, Bock SA, Gaeta TJ, Brenner BE, Cydulka RK, Camargo CA. Multicenter study of emergency department visits for food allergies. J Allergy Clin Immunol 2004;113:347-352.
Simons FE. First-aid treatment of anaphylaxis to food: focus on epinephrine. J Allergy Clin Immunol 2004;113:837-844.
Fujita Y, Chikamitsu M, Kimura M, Toriumi T, Endoh S, Sari A. An anaphylactic reaction possibly associated with an intraoperative coronary artery spasm during general anesthesia. J Clin Anesth 2001;13:221-226.
Matucci RO, Cecchi L, Vultaggio A, et al. Coronary vasospasm during an acute allergic reaction. Allergy 2002;57:867-868.
Conraads VM, Jorens PG, Ebo DG, Claeys MJ, Bosmans JM, Vrints CJ. Coronary artery spasm complicating anaphylaxis secondary to skin disinfectant. Chest 1998;113:1417-1419.
Machiels JP, Jacques JM, de Meester A. Coronary artery spasm during anaphylaxis. Ann Emerg Med 1996;27:674-675.
Bock SA, Mu?oz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 2001;107:191-193.
Freeman TM. Hymenoptera hypersensitivity in an imported fire ant endemic area. Ann Allergy Asthma Immunol 1997;78:369-372.
Freeman TM, Hylander RD, Ortiz AA, Martin MF. Imported fire ant immunotherapy: effectiveness of whole body extracts. J Allergy Clin Immunol 1992;90:210-215.
Hoffman DR, Jacobson RS, Schmidt M, Smith AM. Allergens in Hymenoptera venoms. XXIII. The venom content of imported fire ant whole body extracts. Ann Allergy 1991;66:29-31.
Hunt KJ, Valentine MD, Sobotka AK, Lichtenstein LM. Diagnosis of allergy to stinging insects by skin testing with Hymenoptera venoms. Ann Intern Med 1976;85:56-59.
Georgitis J, Reisman RE. Venom skin tests in insect-allergic and insect-nonallergic populations. J Allergy Clin Immunol 1985;76:803-807.
Hoffman DR. Hymenoptera venoms: composition, standardization, stability. In: Levin MI, Lockey RF, eds. Monograph on insect allergy. 4th ed. Milwaukee: American Academy of Allergy, Asthma and Immunology, 2003:37-54.
Yunginger JW, Paull BR, Jones RT, Santrach PJ. Rush venom immunotherapy program for honeybee sting sensitivity. J Allergy Clin Immunol 1979;63:340-347.
Bernstein JA, Kagen SL, Bernstein DI, Bernstein IL. Rapid venom immunotherapy is safe for routine use in the treatment of patients with Hymenoptera anaphylaxis. Ann Allergy 1994;73:423-428.
Tankersley MS, Walker RL, Butler WK, Hagan LL, Napoli DC, Freeman TM. Safety and efficacy of an imported fire ant rush immunotherapy protocol with and without prophylactic treatment. J Allergy Clin Immunol 2002;109:556-562.
Duplantier JE, Freeman TM, Bahna SL, Good RA, Sher MR. Successful rush immunotherapy for anaphylaxis to imported fire ants. J Allergy Clin Immunol 1998;101:855-856.
Golden DB, Kagey-Sobotka A, Valentine MD, Lichtenstein LM. Prolonged maintenance interval in Hymenoptera venom immunotherapy. J Allergy Clin Immunol 1981;67:482-484.
Goldberg A, Confino-Cohen R. Maintenance venom immunotherapy administered at 3-month intervals is both safe and efficacious. J Allergy Clin Immunol 2001;107:902-906.
Rueff F, Wenderoth A, Przybilla B. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses. J Allergy Clin Immunol 2001;108:1027-1032.
Golden DBK, Kagey-Sobotka A, Norman PS, Hamilton RG, Lichtenstein LM. Outcomes of allergy to insect stings in children, with and without venom immunotherapy. N Engl J Med 2004;351:668-674.
Lockey RF, Turkeltaub PC, Olive ES, Hubbard JM, Baird-Warren IA, Bukantz SC. The Hymenoptera venom study. III. Safety of venom immunotherapy. J Allergy Clin Immunol 1990;86:775-780.
Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 1987;79:660-677.
Golden D, Kwiterovich K, Kagey-Sobotka A, Valentine MD, Lichtenstein LM. Discontinuing venom immunotherapy: outcome after five years. J Allergy Clin Immunol 1996;97:579-587.
Haugaard L, Norregaard O, Dahl R. In-hospital sting challenge in insect venom-allergic patients after stopping venom immunotherapy. J Allergy Clin Immunol 1991;87:699-702.
Reisman RE. Duration of venom immunotherapy: relationship to the severity of symptoms of initial insect sting anaphylaxis. J Allergy Clin Immunol 1993;92:831-836.
Lerch E, Müller UR. Long-term protection after stopping venom immunotherapy: results of re-stings in 200 patients. J Allergy Clin Immunol 1998;101:606-612.
Golden DB, Marsh DG, Freidhoff LR, et al. Natural history of Hymenoptera venom sensitivity in adults. J Allergy Clin Immunol 1997;100:760-766.
Golden DBK, Kwiterovich KA, Kagey-Sobotka A, Lichtenstein LM. Discontinuing venom immunotherapy: extended observations. J Allergy Clin Immunol 1998;101:298-305.
Kontou-Fili K. Patients with negative skin tests. Curr Opin Allergy Clin Immunol 2002;2:353-357.
Parker JL, Santrach PJ, Dahlberg MJE, Yunginger JW. Evaluation of Hymenoptera-sting sensitivity with deliberate sting challenges: inadequacy of present diagnostic methods. J Allergy Clin Immunol 1982;69:200-207.
Sobotka AK, Adkinson NF Jr, Valentine MD, Lichtenstein LM. Allergy to insect stings. IV. Diagnosis by radioallergosorbent tests (RAST). J Immunol 1978;121:2477-2484.
Golden DBK. Diagnostic methods in insect allergy. In Levin MI, Lockey RF, eds. Monograph on insect allergy. 4th ed. Milwaukee: American Academy of Allergy, Asthma and Immunology, 2003:63-74.
Reisman RE. Insect sting allergy: the dilemma of the negative skin test reactor. J Allergy Clin Immunol 2001;107:781-782.
Golden DB, Tracy JM, Freeman TM, Hoffman DR. Negative venom skin test results in patients with histories of systemic reaction to a sting. J Allergy Clin Immunol 2003;112:495-498.
Moffitt JE, Golden DBK, Reisman RE, et al. Stinging insect hypersensitivity: a practice parameter update. J Allergy Clin Immunol 2004;114:869-886.(Theodore M. Freeman, M.D.)
A 29-year-old man reported that he was stung by a flying hymenopteran — he does not know what type — outside his door, where he had previously noted a nest. Skin itching, diffuse hives, swelling of his arms and legs, tightness in his throat, dizziness, and difficulty talking developed immediately, and he was taken to a local clinic where he received epinephrine and antihistamines. He was observed for two hours, and all symptoms resolved. How should his case be managed subsequently?
The Clinical Problem
Insects of the order Hymenoptera, which includes ants, bees, hornets, wasps, and yellow jackets, have a stinging apparatus at the tail end of their abdominal segment and are capable of delivering between 100 ng (fire ants)1 and 50 μg (bees)2 of venom (Table 1 and Figure 1). Although the venoms have various peptide and protein components, some of which are capable of inducing toxic or vasoactive responses, it has been estimated that about 1500 stings would be required to deliver a lethal dose of hymenoptera venom for a nonallergic adult who weighs 70 kg.5 Despite this estimate, about 40 deaths a year are attributed to hymenoptera stings6; these deaths are ascribed to anaphylaxis occurring in persons with a history of prior stings in whom specific IgE antibodies developed to various venom components. Due to the vasoactive components of the venoms, most people experience a local reaction to hymenoptera stings consisting of redness, swelling, tenderness, and pain at the site of the sting. This reaction is self-limited and will resolve within hours. If the sting occurs near or within the oral cavity, there is a potential for respiratory compromise.
Table 1. Characteristics of Hymenoptera.
Figure 1. Species of Hymenoptera and Their Geographical Distribution.
Fire-ant venom is composed primarily of a transpiperidine alkaloid that causes tissue necrosis. Most fire-ant stings produce a blister within 24 hours, which often fills with necrotic material, giving the appearance of a pustule (Figure 2). Despite their appearance, these blisters are not infected and should be left intact.
Figure 2. Stings from a Fire Ant on an Ankle, Showing the Pseudopustule.
The clustering of the stings (white arrow) contrasts with the single sting (black arrow) in the photograph, which was taken 24 hours after the event. This pattern is typical of fire-ant stings, as one ant will often inflict multiple stings in a semicircular arc if given time to do so. Also, the pseudopustule is typical of fire-ant stings; it is not a pustule. The stings occurred just above the level of the ankle sock the patient was wearing on the day of the event.
Occasionally, persons will have swelling from a hymenoptera sting that may involve a large area and persist for up to a week. These large local reactions are not life threatening unless they involve the airway. They may result in considerable morbidity because of a temporary loss of function, such as occurs when the sting involves a foot or hand or is near an eye. Secondary infections can frequently complicate fire-ant stings when the pseudopustule is opened, and they can sometimes complicate other hymenoptera stings. Although it may be difficult in some cases to distinguish a secondary infection from a large local reaction, in the latter event the swelling usually peaks within 48 hours, whereas progression of swelling for more than two days, accompanied by fever or lymphadenitis, suggests secondary infection.
The reactions that lead to anaphylaxis, however, are of more concern than secondary infections. Some anaphylactic events are restricted to cutaneous findings (pruritus, urticaria, and angioedema). Others have a broader effect, with systemic symptoms that may involve the gastrointestinal tract (metallic taste, nausea, vomiting, diarrhea, and abdominal cramping), genitourinary tract (uterine cramps), or nervous system (sense of impending doom, light-headedness, and dizziness). Reactions that involve the cardiopulmonary system (breathing difficulties, bronchospasm, hypotension, and arrhythmia) pose the greatest risk. Initial subjective symptoms may progress rapidly (in seconds to minutes) to life-threatening cardiopulmonary collapse. The risk of anaphylaxis with any event is dependent on the nature of the most severe previous reaction experienced by a patient (Table 2). Neuropathic and vasculitic responses and reactions that resemble serum sickness have in rare cases been reported after insect stings.15,16
Table 2. Risk of Anaphylactic Reactions to Hymenoptera Stings after an Initial Event.
Strategies and Evidence
Immediate Therapy
The optimal choice of immediate therapy for insect stings depends on the type of reaction. Strategies are based on anecdotal evidence. Local reactions are best treated symptomatically with nonsteroidal antiinflammatory agents, antihistamines, and cold compresses. Topical antihistamines and corticosteroids may also be used. When large local reactions occur, oral steroids are often added to the therapeutic mix.
The definitive therapy for anaphylaxis is epinephrine by injection (0.01 mg per kilogram of body weight; maximum, 0.3 and 0.5 mg per dose, for children and adults, respectively), and this should be administered to any patient who has more than a cutaneous reaction. Antihistamines are often added to treat cutaneous signs and symptoms. Supplemental oxygen, beta-agonists for bronchospasm, and intravenous fluids for hypotension are sometimes indicated. Occasionally, for a reaction that does not respond to the initial dose of epinephrine, steroids (oral or intravenous) are added, although definitive support for their addition is lacking.
There is a distressing tendency by both patients and physicians to treat anaphylaxis without using epinephrine,17,18 perhaps because of concern about adverse effects of epinephrine on the heart. However, anaphylaxis itself has been associated with coronary vasospasm.19,20,21,22 The fact that available data suggest that a failure or delay in administering epinephrine increases the chance of a fatal outcome in anaphylaxis23 underscores the prevailing opinion that epinephrine must be considered the definitive therapy for anaphylaxis.
Epinephrine auto-injectors should be prescribed for any patient who has had an anaphylactic reaction to a hymenoptera sting. The instructions for use are printed on the side of each injector, but these should be reviewed with the patient when prescribing the medication. Patients should be educated to use epinephrine if signs or symptoms beyond a cutaneous reaction develop after a hymenoptera sting, and always to seek additional medical care after using an injector.
Long-Term Therapy
Avoidance
The long-term goal is to prevent future systemic anaphylactic events. The optimal approach to prevent IgE-mediated disease is avoidance of the antigen, but this may not be feasible in practice. Current recommendations for avoidance are summarized in Table 1. The proximity of the habitats of wasps and fire ants to those of humans makes these insects the most likely members of the order to cause anaphylaxis.24
Immunotherapy
If avoidance of hymenoptera cannot be ensured, the next step is to minimize the potential for anaphylaxis if a sting should occur. Immunotherapy with hymenoptera venom has been shown to reduce the potential risk of anaphylaxis with subsequent stings significantly13,14 (Table 2). Although the administration of whole-body extracts is no more effective than placebo therapy for treating the stings of flying hymenoptera,13 whole-body extracts of fire ants appear to be as useful in preventing future reactions as is venom immunotherapy for flying hymenoptera,25 perhaps because whole-body extracts of fire ants (in contrast to those of flying hymenoptera) contain adequate amounts of venom.26 Whole-body extract therapy for fire ants has not been compared directly with fire-ant venom immunotherapy.
Evaluation
The evaluation of patients for whom immunotherapy is considered begins with a review of the history of stings and reactions. The circumstances of the sting may suggest a particular agent (Table 1). The presence of a stinger or a venom sac at the site of a sting suggests, but is not definitive of, a honeybee sting, as occasionally other hymenoptera may leave a stinger in place. Fire ants are usually easy to identify since they do not fly away and will grasp victims with their mandibles and inflict multiple stings if allowed (Figure 2).
The clinical course is also reviewed to verify the diagnosis of anaphylaxis. It is sometimes difficult to separate anxiety symptoms from true anaphylaxis in the setting of a sting. This is especially true if there are no documented objective findings, such as urticaria, hypotension, or air-flow reduction. However, when patients are concerned enough to seek an evaluation even with an unclear or remote history, it is appropriate to test them for specific IgE antibodies. If the results of these tests are negative, patients can be reassured; if they are positive, immunotherapy should be offered. Age is also important. Studies have shown that in children under the age of 16 years who have cutaneous anaphylaxis (urticaria, angioedema, or both), the risk of systemic (in addition to cutaneous) anaphylaxis in response to future stings is only slightly greater than the risk in the general population6 (Table 2). It is uncertain whether the same is true in adults.
Subsequent evaluation involves testing for the presence of specific IgE antibodies.27,28 Initial testing is usually delayed for four to six weeks after the sting event to eliminate the possibility of a false negative result caused by a depletion of mediators in the setting of anaphylaxis. If the particular agent is known, then testing includes only that insect. It is often unclear which insect was the perpetrator, in which case testing of sensitivity to each of the flying hymenoptera is warranted.
Typically, testing involves in vivo skin testing for specific IgE antibodies; this is more sensitive than in vitro methods, which are an alternative. The prick method (a needle pricks the skin through a drop of the antigen) is used as the first step (a dilution of 1:1000 weight/volume for fire-ant venom; 1 μg per milliliter for venom from other hymenoptera). If the result of this test is negative, testing proceeds with an intradermal method (antigen is injected into the dermis), usually using about 0.001 μg per milliliter (1:1,000,000 wt/vol for fire-ant venom) and increases sequentially by 10 times the previous amount to 1.0 μg per milliliter (1:1000 wt/vol for fire-ant venom); above these concentrations, false positive test results may occur. Testing is stopped when the skin test is positive (the reaction is equivalent to or greater than a histamine control). If the maximal intradermal dose is reached without a positive response, the test result is considered negative. If a false negative result is suspected (on the basis of a history suggestive of anaphylaxis), or for patients who cannot be skin-tested (those who have severe dermatitis or who are receiving medications that suppress the histamine response), in vitro methods are reasonable alternatives. Immunotherapy is then offered to anyone who has both a history consistent with anaphylaxis after a sting and specific IgE antibodies to the potential agent, as demonstrated by positive results on skin testing or in vitro testing.
Whereas there may be extensive cross-reactivity between some venom components, such as antigen 5 (one of the more potent vespid antigens), there are enough highly specific components of the venoms (including differences between molecules common to all the venoms, such as phospholipases)29 to support the recommendation that all venoms for which skin testing yields positive results should be used in treatment. Treatment with more than one venom can be administered concurrently, but this generally requires multiple injections per visit; an exception is the commercial preparation that is a mixture of venoms from the yellow jacket, white-faced hornet, and yellow hornet (maximal dose, 100 μg of each species' venom).
Therapy
Immunotherapy starts at 0.1 μg per milliliter for most hymenoptera venoms (1:100,000 wt/vol for fire-ant venom). Each subsequent dose increases the amount of venom delivered to the patient, generally until a dose of 100 μg per milliliter for the venom of flying hymenoptera (0.5 ml of 1:100 wt/vol for fire-ant venom) is reached; 100 μg is twice the dose to which a patient would be exposed in a routine sting, and it is the dose used in initial studies showing the effectiveness of venom immunotherapy. Usually the doses are delivered once a week. This means there is a three-to-six-month period required to reach the maintenance dose. So-called rush protocols have been published,30,31,32 in which a shorter dosing interval is used to reach maintenance doses in weeks or even days, and they appear to provide good protection from sting challenges. These are particularly useful when the risk of exposure is high and ongoing, as may occur with patients who must work or play outdoors.33 These protocols have not been compared directly with standard immunotherapy protocols in randomized controlled trials, but they have been found to give reasonably equivalent protection against direct sting challenges.
When a maintenance level is reached, the interval between injections is often expanded to one month. Some observational data suggest that the interval may be expanded to 8 or even 12 weeks without losing protection.34,35 The maintenance dose and interval may be adjusted on the basis of clinical criteria. For instance, if a patient receives a sting that results in symptoms while receiving maintenance immunotherapy, the dose interval may be shortened or the dose increased to more than 100 μg.36
Protection after a course of immunotherapy appears to last a long time. In a recent report involving a follow-up evaluation of children 10 to 20 years after they had received immunotherapy, only 5 percent of the children with a history of a moderate-to-severe sting reactions who reported a subsequent sting had had a recurrent systemic reaction, as compared with 32 percent of untreated children with a similar history.37
The risks associated with hymenoptera immunotherapy are the same as for other allergen immunotherapy. The risk of anaphylaxis after an immunotherapy injection is low (fewer than 1.6 reactions per 100 injections).13 The majority (88 percent) of patients complete an immunotherapy course without reactions, and most reactions that occur are mild.38 Rarely, more severe reactions occur, including death (about 1 in 5 million injections for all types of immunotherapy).39 Therefore, immunotherapy should be administered only in a medical setting by trained personnel capable of recognizing and treating anaphylaxis.
Areas of Uncertainty
An important unanswered question relates to the optimal duration of maintenance immunotherapy. The package insert that comes with the venom immunotherapy recommends indefinite use, whereas current clinical guidelines recommend discontinuing immunotherapy after three to five years of the maintenance-level dose,40,41 especially if the patient no longer has specific IgE antibodies (as evaluated by repeated skin testing).42,43 However, data from patients who have not received immunotherapy indicate that the loss of these antibodies is no guarantee that anaphylaxis will not occur. In one report, 98 patients (including patients with and patients without a history of anaphylaxis) who had positive tests for specific IgE antibodies at baseline slowly lost their positive responses over time. However, the risk of anaphylaxis was not eliminated; at a mean of four years after initial evaluation, approximately 17 percent of patients (11 of 65) who had subsequent stings had anaphylactic reactions, despite the presumed loss of specific IgE antibodies.44 Other reports have documented reactions to hymenoptera stings after discontinuing immunotherapy.37,45 Given these data, some allergists extend venom immunotherapy longer than the suggested three to five years. Consideration of an extended course may be warranted particularly for patients who have had a severe reaction (for such patients, some allergists might continue immunotherapy indefinitely).
Another area that requires additional research is the treatment of patients who have a history of a reaction suggestive of anaphylaxis but in whom testing for specific IgE antibodies yields negative results. One potential explanation is that the earlier reaction was not to hymenoptera; the stings or bites of other insects (mosquitoes, biting flies, and reduvids) and arthropods (spiders, scorpions, and ticks) may also result in anaphylaxis. In rare cases, people with mastocytosis may have an anaphylactoid response to hymenoptera stings without actually having specific IgE antibodies.46 A more common explanation is the imperfect sensitivity of tests for specific IgE antibodies.10,47,48 Twenty percent of patients with negative in vitro tests will have positive results on skin testing, and 10 percent of patients whose skin test is negative will have positive results on in vitro testing.49 In cases in which the suspicion of hymenoptera hypersensitivity is high, and initial tests are negative, it has been recommended that repeated testing be undertaken with both in vivo and in vitro methods.50,51
Guidelines
Under the joint auspices of the American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma and Immunology, the Journal of Allergy and Clinical Immunology will publish the newest set of guidelines for insect hypersensitivity this year.52 In general, the recommendations presented here are consistent with these guidelines.
Summary and Conclusions
For patients with a clear history of anaphylaxis, such as the one described in the vignette, information should be provided on avoidance and on the use of emergency treatment with epinephrine auto-injectors. Patients should be advised to carry an auto-injector and to wear a medical alert bracelet. Referral to an allergist is warranted, and skin testing should be performed for sensitivity to honeybees, wasps, white-faced hornets, yellow hornets, and yellow jackets. Venom immunotherapy should be administered for all venoms for which testing results are positive. The protective benefit is expected from the immunotherapy by the time maintenance dose is reached, usually by three to six months with standard protocols. A rush protocol would be recommended if the patient's risk of being stung again before standard immunotherapy could work were considered high. Although immunotherapy is often administered by allergists, it may be delivered by any practitioner who is willing to observe the patient and to treat anaphylaxis if it should occur.
Source Information
From the Department of Allergy and Immunology, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, TX.
Address reprint requests to Dr. Freeman at the Department of Allergy and Immunology, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, TX, 78023, or at tfree95900@aol.com.
References
Hoffman DR, Dove DE, Jacobson RS. Allergens in Hymenoptera venom. XX. Isolation of four allergens from imported fire ant (Solenopsis invicta) venom. J Allergy Clin Immunol 1988;82:818-827.
Hoffman DR, Jacobson RS. Allergens in Hymenoptera venom. XII. How much protein in a sting? Ann Allergy 1984;52:276-278.
Guralnick MW, Benton AW. Entomological aspects of insect sting allergy. In: Levin MI, Lockey RF, eds. Monograph on insect allergy. 4th ed. Milwaukee: American Academy of Allergy, Asthma and Immunology, 2003:11-26.
McKenna WR. Africanized honeybees. In: Levin MI, Lockey RF, eds. Monograph on insect allergy. 4th ed. Milwaukee: American Academy of Allergy, Asthma and Immunology, 2003:27-36.
Goddard J. Physician's guide to arthropods of medical importance. 4th ed. Boca Raton, Fla.: CRC Press, 2003:4.
Barnard JH. Studies of 400 Hymenoptera sting deaths in the United States. J Allergy Clin Immunol 1973;52:259-264.
Golden DBK. Epidemiology of allergy to insect venoms and stings. Allergy Proc 1989;10:103-107.
Settipane GA, Boyd GK. Prevalence of bee sting allergy in 4,992 Boy Scouts. Acta Allergol 1970;25:286-291.
Chaffee F. The prevalence of bee sting allergy in an allergic population. Acta Allergol 1970;25:292-293.
Golden DBK, Marsh DG, Kagey-Sobotka A, et al. Epidemiology of insect venom sensitivity. JAMA 1989;262:240-244.
Graft DF, Schuberth KC, Kagey-Sobotka A, et al. A prospective study of the natural history of large local reactions after Hymenoptera stings in children. J Pediatr 1984;104:664-668.
Schuberth KC, Lichtenstein LM, Kagey-Sobotka A, Szklo M, Kwiterovich KA, Valentine MD. Epidemiologic study of insect allergy in children. II. Effect of accidental stings in allergic children. J Pediatr 1983;102:361-365.
Hunt KJ, Valentine MD, Sobotka AK, Benton AW, Amodio FJ, Lichtenstein LM. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:157-161.
Golden DBK, Valentine MD, Kagey-Sobotka A, Lichtenstein LM. Regimens of Hymenoptera venom immunotherapy. Ann Intern Med 1980;92:620-624.
Light WC, Reisman RE, Shimizu M, Arbesman CE. Unusual reactions following insect stings: clinical features and immunologic analysis. J Allergy Clin Immunol 1977;59:391-397.
Reisman RE, Livingston A. Late-onset allergic reactions, including serum sickness, after insect stings. J Allergy Clin Immunol 1989;84:331-337.
Clark S, Bock SA, Gaeta TJ, Brenner BE, Cydulka RK, Camargo CA. Multicenter study of emergency department visits for food allergies. J Allergy Clin Immunol 2004;113:347-352.
Simons FE. First-aid treatment of anaphylaxis to food: focus on epinephrine. J Allergy Clin Immunol 2004;113:837-844.
Fujita Y, Chikamitsu M, Kimura M, Toriumi T, Endoh S, Sari A. An anaphylactic reaction possibly associated with an intraoperative coronary artery spasm during general anesthesia. J Clin Anesth 2001;13:221-226.
Matucci RO, Cecchi L, Vultaggio A, et al. Coronary vasospasm during an acute allergic reaction. Allergy 2002;57:867-868.
Conraads VM, Jorens PG, Ebo DG, Claeys MJ, Bosmans JM, Vrints CJ. Coronary artery spasm complicating anaphylaxis secondary to skin disinfectant. Chest 1998;113:1417-1419.
Machiels JP, Jacques JM, de Meester A. Coronary artery spasm during anaphylaxis. Ann Emerg Med 1996;27:674-675.
Bock SA, Mu?oz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 2001;107:191-193.
Freeman TM. Hymenoptera hypersensitivity in an imported fire ant endemic area. Ann Allergy Asthma Immunol 1997;78:369-372.
Freeman TM, Hylander RD, Ortiz AA, Martin MF. Imported fire ant immunotherapy: effectiveness of whole body extracts. J Allergy Clin Immunol 1992;90:210-215.
Hoffman DR, Jacobson RS, Schmidt M, Smith AM. Allergens in Hymenoptera venoms. XXIII. The venom content of imported fire ant whole body extracts. Ann Allergy 1991;66:29-31.
Hunt KJ, Valentine MD, Sobotka AK, Lichtenstein LM. Diagnosis of allergy to stinging insects by skin testing with Hymenoptera venoms. Ann Intern Med 1976;85:56-59.
Georgitis J, Reisman RE. Venom skin tests in insect-allergic and insect-nonallergic populations. J Allergy Clin Immunol 1985;76:803-807.
Hoffman DR. Hymenoptera venoms: composition, standardization, stability. In: Levin MI, Lockey RF, eds. Monograph on insect allergy. 4th ed. Milwaukee: American Academy of Allergy, Asthma and Immunology, 2003:37-54.
Yunginger JW, Paull BR, Jones RT, Santrach PJ. Rush venom immunotherapy program for honeybee sting sensitivity. J Allergy Clin Immunol 1979;63:340-347.
Bernstein JA, Kagen SL, Bernstein DI, Bernstein IL. Rapid venom immunotherapy is safe for routine use in the treatment of patients with Hymenoptera anaphylaxis. Ann Allergy 1994;73:423-428.
Tankersley MS, Walker RL, Butler WK, Hagan LL, Napoli DC, Freeman TM. Safety and efficacy of an imported fire ant rush immunotherapy protocol with and without prophylactic treatment. J Allergy Clin Immunol 2002;109:556-562.
Duplantier JE, Freeman TM, Bahna SL, Good RA, Sher MR. Successful rush immunotherapy for anaphylaxis to imported fire ants. J Allergy Clin Immunol 1998;101:855-856.
Golden DB, Kagey-Sobotka A, Valentine MD, Lichtenstein LM. Prolonged maintenance interval in Hymenoptera venom immunotherapy. J Allergy Clin Immunol 1981;67:482-484.
Goldberg A, Confino-Cohen R. Maintenance venom immunotherapy administered at 3-month intervals is both safe and efficacious. J Allergy Clin Immunol 2001;107:902-906.
Rueff F, Wenderoth A, Przybilla B. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses. J Allergy Clin Immunol 2001;108:1027-1032.
Golden DBK, Kagey-Sobotka A, Norman PS, Hamilton RG, Lichtenstein LM. Outcomes of allergy to insect stings in children, with and without venom immunotherapy. N Engl J Med 2004;351:668-674.
Lockey RF, Turkeltaub PC, Olive ES, Hubbard JM, Baird-Warren IA, Bukantz SC. The Hymenoptera venom study. III. Safety of venom immunotherapy. J Allergy Clin Immunol 1990;86:775-780.
Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 1987;79:660-677.
Golden D, Kwiterovich K, Kagey-Sobotka A, Valentine MD, Lichtenstein LM. Discontinuing venom immunotherapy: outcome after five years. J Allergy Clin Immunol 1996;97:579-587.
Haugaard L, Norregaard O, Dahl R. In-hospital sting challenge in insect venom-allergic patients after stopping venom immunotherapy. J Allergy Clin Immunol 1991;87:699-702.
Reisman RE. Duration of venom immunotherapy: relationship to the severity of symptoms of initial insect sting anaphylaxis. J Allergy Clin Immunol 1993;92:831-836.
Lerch E, Müller UR. Long-term protection after stopping venom immunotherapy: results of re-stings in 200 patients. J Allergy Clin Immunol 1998;101:606-612.
Golden DB, Marsh DG, Freidhoff LR, et al. Natural history of Hymenoptera venom sensitivity in adults. J Allergy Clin Immunol 1997;100:760-766.
Golden DBK, Kwiterovich KA, Kagey-Sobotka A, Lichtenstein LM. Discontinuing venom immunotherapy: extended observations. J Allergy Clin Immunol 1998;101:298-305.
Kontou-Fili K. Patients with negative skin tests. Curr Opin Allergy Clin Immunol 2002;2:353-357.
Parker JL, Santrach PJ, Dahlberg MJE, Yunginger JW. Evaluation of Hymenoptera-sting sensitivity with deliberate sting challenges: inadequacy of present diagnostic methods. J Allergy Clin Immunol 1982;69:200-207.
Sobotka AK, Adkinson NF Jr, Valentine MD, Lichtenstein LM. Allergy to insect stings. IV. Diagnosis by radioallergosorbent tests (RAST). J Immunol 1978;121:2477-2484.
Golden DBK. Diagnostic methods in insect allergy. In Levin MI, Lockey RF, eds. Monograph on insect allergy. 4th ed. Milwaukee: American Academy of Allergy, Asthma and Immunology, 2003:63-74.
Reisman RE. Insect sting allergy: the dilemma of the negative skin test reactor. J Allergy Clin Immunol 2001;107:781-782.
Golden DB, Tracy JM, Freeman TM, Hoffman DR. Negative venom skin test results in patients with histories of systemic reaction to a sting. J Allergy Clin Immunol 2003;112:495-498.
Moffitt JE, Golden DBK, Reisman RE, et al. Stinging insect hypersensitivity: a practice parameter update. J Allergy Clin Immunol 2004;114:869-886.(Theodore M. Freeman, M.D.)