Subspecialty Clinics: Allergic Diseases Management of Insect Sting Hypersensitivity
JAMES T. C. LI, M.D., Ph.D., Division ofAllergic Diseases and Internal Medicine; JOHN W. YUNGINGER, M.D., Section of General Pediatrics and Pediatric Allergy and Immunology
Approximately 1 to 3 % of the general population has had a systemic reaction to insect stings. Adults whose reactions include urticaria, obstruction ofthe upper or lower airway, or hypotension and children whose reactions include obstruction of the upper or lower airway or hypotension have an increased risk offuture systemic reactions to stings. Allergy skin tests to Hymenoptera venoms can help to identify the offending insect and to classify the reactions as allergic; however, because 15 % ofthe general population may have positive results to such tests, persons who have not experienced a systemic reaction to insect stings should not be tested. Venom immunotherapy is highly effective and confers 98 to 99% protection in patients who have experienced previous systemic reactions to insect stings. Reaction rates to venom skin tests or venom immunotherapy are low and are similar to those in allergy testing and immunotherapy for hay fever. Generally, patients who have had systemic reactions to stings should be assessed by an allergist to determine whether they are candidates for immunotherapy with Hymenoptera venom. The decision to institute venom immunotherapy should be based on the disposition of the patient, the severity ofthe reaction, and the risk ofsubsequent stings. Deliberate sting challenges are clinically useful for guiding immunotherapy.
Virtually all physicians and most laypersons are aware that stings from bees, yellow jackets, hornets, and wasps can cause severe allergic reactions. Although most clinicians know that allergy tests and immunotherapy are available, some are unsure about who should be referred for assessment. Herein we offer guidelines to help clinicians decide which patients need allergy testing and which should be considered for immunotherapy.: We also review recent studies that suggest that immunotherapy for insect sting hypersensitivity need not continue for a lifetime in all patients. Finally, we describe a role for deliberate sting challenge in a research and clinical setting.
Address reprint requests to Dr. J. T. C. Li, Division of Allergic Diseases, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:188-194,1992
REPORT OF CASE A 48-year-old man came to the Mayo Allergy Clinic in 1977 because of a history of three allergic reactions to insect stings. The first reaction occurred when he was 37 years old. He was stung on the hand by an insect, which was later identified as a wasp or hornet. Within 2 minutes, he experienced flushing, shortness of breath, and weakness. His wife drove him 2 miles to a local hospital, where he was unable to get out of the car unassisted because of wooziness. Emergency treatment including epinephrine resulted in improvement of his condition within minutes and complete recovery in a few hours. The second sting reaction occurred when the patient was 40 years old and was working for the Department of Natural Resources. While using a bulldozer to move topsoil, he inadvertently disturbed a yellow jacket nest and was stung once. Although working with a crew, the patient was alone at 188
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the time. Flushing, dizziness, and weakness developed. He tried to drive the bulldozer to find help, but he was unable to control it and hit a tree. He was crawling on his hands and knees when he lost consciousness. Fortunately, a fellow crew member returned and took the patient to the nearest hospital. After administration of epinephrine and intravenous fluids, the patient recovered. He was instructed to have an epinephrine kit with him at all times. Furthermore, he was told not to work outdoors alone. In 1977, the patient had another reaction while camping in the woods with a group of teenagers. (They had assured the patient that they were capable of driving him to the hospital if he were stung.) While cutting down a tree, he was stung bya hornet. Although he immediately experienced dizziness and weakness, he was able to administer one dose of epinephrine from a multiple-dose preloaded syringe. The reaction, however, progressed rapidly, and he was unable to administer a second dose. The teenagers could not operate the manual transmission of the available vehicle, but they were able to summon help. Although the patient had lost consciousness, his condition improved after administration of epinephrine, and he recovered completely in a hospital. Because of a history of insect sting hypersensitivity, the patient was advised to consider a career change to an indoor occupation, but he chose to continue to work outdoors.
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classification of the reaction, severity of the reaction, identification of the offending insect, and general patient characteristics (such as occupation or coexisting diseases) should be determined because all these factors affect the therapeutic options. Diagnosis.-Usually, a sting reaction results in a small area of edema, erythema, and pruritus at the sting site. This self-limited reaction necessitates no specific treatment. A large local reaction is similar except that the edema and erythema are much more pronounced and may persist for several days. A typical example is a sting on the hand that causes local swelling that extends to the elbow. Although some patients who experience large local reactions may have increased levels of venom-specific IgE antibodies," thorough follow-up studies suggest that such persons are not at an increased risk of future systemic reactions." Because venom constituents contain various vasoactive amines, peptides, and enzymes,'? a nonallergic toxic reaction can develop in a person who sustains multiple stings. Clinically, such reactions can mimic anaphylaxis. Urticarial reactions, which are the most common, can be considered mild and systemic and are almost always accompanied by pruritus. Severe systemic reactions can include bronchoconstriction, hypotension, and typical symptoms and signs of anaphylaxis from any cause. Usually, symptoms of anaphylaxis develop within 10 minutes after a sting, although delayed reactions have been described. II Persons who DISCUSSION The Hymenoptera order of insects consists of two superfami- have had anaphylactic reactions to an insect sting have an lies-the apids (honeybees and bumblebees) and the vespids increased risk for anaphylaxis from subsequent stings. In (yellow jackets, hornets, and wasps) (Fig. 1). The major these sensitive persons, anaphylaxis will occur 35 to 60% of allergenic constituents ofhoneybee venom are phospholipase the time after subsequent stings by an identical insect.P:" Clinical assessment of the severity of anaphylaxis as well as ~' hyaluronidase, and acid phosphatase. I The major allergens in vespid venom are similar, including phospholipase, the response to therapy is important because patients who hyaluronidase, and an unusual protein identified as antigen 5. 2 have experienced severe reactions are also likely to have The cross-reaction between yellow jacket and hornet venoms severe reactions after subsequent stings." Furthermore, seis strong; the cross-reaction between these species and bees or vere anaphylactic reactions may not respond to a single wasps is limited. injection of epinephrine.F:" Some systemic reactions may be Typically, 25 to 40 deaths yearly in the United States are followed by a "late-phase" anaphylactic episode 4 to 12 hours attributed to insect sting anaphylaxis;' although the actual after the immediate reaction." The mechanism of this late incidence of fatal allergic reactions to these insects is un- phase is poorly understood and apparently is not prevented by known. Determinations of IgE antibody to Hymenoptera systemically administered glucocorticoid drugs." Patients venom in serum of persons who died unexpectedly imply that who experience severe reactions should be observed for 8 to some of these deaths may have been caused by anaphylaxis to 12 hours after the sting. By only elicitation of the history, it can be difficult to an insect sting." Studies have shown that 1.2 to 3% of the general adult population report that they have a history of a distinguish anaphylaxis without urticaria and cutaneous angiosystemic reaction.v This finding contrasts with the observa- edema from a hysterical, vasovagal, or hyperventilation retions that 2 to 7% of asymptomatic persons have increased sponse to an insect sting. Vasovagal reactions are often serum IgE antibodies to venom? and that approximately 15% preceded by nausea and typically involve bradycardia. Alof asymptomatic persons have positive results of skin tests to lergy tests can be helpful in such instances. venom." Sometimes patients are able to provide clues that can help Elicitation of History.-A detailed history is crucial for clinicians identify the offending insect. Beekeeping is a. proper management of insect sting hypersensitivity. The popular hobby, and the location of a beehive close to the
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Fig. 1. Hymenoptera insects. A, Bumblebee (Bombus). B, Honeybee (Apis mellifera). C, White-faced hornet (Vespula maculata). D, Yellow hornet (Vespula arenaria). E, Paper wasp (Polistes). F, Yellow jacket (Vespula favopilosas, (From Parker CW [ed]: Systemic anaphylaxis. In Clinical Immunology. Philadelphia, WB Saunders Company, 1980, pp 1208-1218. By permission.)
patient's residence or work site is often informative. Furthermore, the honeybee is the only stinging insect that usually leaves a stinger and attached venom sac at the sting site; therefore, a retained stinger implies a honeybee." Yellow jackets build nests in the ground and are sometimes referred to as "ground wasps." Hornets build large nests in trees or under branches. The nests of wasps have a paper-honeycomb appearance and are located under eaves and roofs. Allergy Skin Tests.-Allergy skin tests for insect sting hypersensitivity involve pricking the skin and intraderrnally injecting venom. A wheal and flare reaction that occurs 15 minutes after application of the reagent signifies a positive response. Skin tests to Hymenoptera venoms are safe. The Hymenoptera venom study of the American Academy of Allergy and Immunology showed that a severe hypersensitiv-
ity reaction to venom skin tests developed in only 8 of 3,236 sting-sensitive patients (0.25%).20 Skin tests to Hymenoptera venoms can be helpful in classifying the sting reaction. Hyperventilation and vasovagal and toxic reactions are much more likely to yield negative results than are IgE-mediated reactions that involve urticaria, bronchospasm, or hypotension. Of note; results of skin tests in true allergic patients can be falsely negative if the tests are conducted within 4 weeks after the most recent sting reaction." The mechanism for this result is unknown. Therefore, patients tested earlier than 4 weeks after a sting reaction should be retested later if the initial results are negative. The major role of allergy tests for insect stings is in assessing a patient for possible immunotherapy. In general, patients who have experienced a systemic sting reaction and
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whose test results are positive to Hymenoptera venom are suitable candidates for venom immunotherapy. An exception is children in whom only urticarial reactions develop (not hypotension or obstruction of the upper or lower airway). A follow-up study of such children showed that they are not at an increased risk of having more severe systemic reactions after repeated stings;" therefore, immunotherapy (and hence skin tests) is unnecessary for all such children. Immunotherapy, however, is effective for preventing the urticarial reactions that can occur after subsequent stings and can be offered to selected patients. Because patients with local or large local reactions do not have an increased risk of future severe reactions, neither tests nor immunotherapy is necessary. In a few patients who have systemic reactions to insect stings, test results will be negative." The pathophysiologic mechanism of this type of reaction is unclear but is being investigated. Such patients, however, should not receive immunotherapy. Because approximately 15% of persons who do not report any sting reaction have positive results of skin tests to Hymenoptera venom, testing persons who are curious about their risk of allergy to insect stings is not useful. Furthermore, the frequency of clinically unimportant positive results in such patients is high. IgE antibodies to Hymenoptera venoms can be measured in vitro by using the radioallergosorbent test. This test, however, is not as sensitive as skin tests, which are the preferred method.e'-" Management.-Clinicians have the responsibility of offering sound, rational management options to patients with insect sting hypersensitivity. Therefore, clinicians should be familiar with the occupation and hobbies of such patients. Although venom immunotherapy is highly effective in preventing sting reactions (see subsequent discussion), not all sting-sensitive patients choose to undergo immunotherapy. Sensitive persons who are outdoors for a substantial amount of time, either for employment or during leisure time, have the highest risk for repeated stings. Persons who are anxious about or preoccupied with their hypersensitivity or who are uncomfortable with self-administration of epinephrine also may be candidates for immunotherapy, such as children who are unable to administer epinephrine to themselves. Furthermore, day-care employees may be uncomfortable providing care for a child at risk for sting anaphylaxis. Persons who decline immunotherapy often spend most of their time indoors, accept the risk of anaphylaxis with equanimity, and are comfortable with self-administration of epinephrine to minimize future reactions. Immunotherapy may be difficult for persons who live far from a physician's office or who cannot afford it. Preventive Measures.-Patients who have experienced anaphylaxis to insect stings should know that the possibility of
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occurrence of anaphylaxis on repeated stings is 35 to 60%. Thus, whenever possible, they should take measures to avoid repeated stings. Such patients should carry an epinephrine kit and be familiar with its operation. The number of stingsensitive patients who comply with these instructions is unknown. Furthermore, severe sting reactions do not always resolve after treatment with a single dose of epinephrine. Sting-sensitive patients should wear a bracelet that identifies them as allergic to insect stings. Monoamine oxidase inhibitors and l3-adrenergicblocking agents can interfere with the treatment of anaphylaxis with use of sympathomimetic agents." Sting-sensitive patients should be warned of these drug interactions; in fact, these medications are contraindicated for patients undergoing venom immunotherapy. Venom Immunotherapy.-Many well-controlled clinical studies have clearly shown that venom immunotherapy is 98 to 99% effective in preventing systemic reactions in stingsensitive patients." As a subgroup, sensitive beekeepers can expect 84% protection from bee venom immunotherapy." The schedules for immunotherapy vary. The usual maintenance dosage is 100 ug of venom every 4 to 6 weeks. This amount is approximately twice the venom in a live honeybee sting and 20 times that in a vespid sting. The ability to tolerate 100 ug of venom by injection, however, is not an absolute guarantee that a person can tolerate an insect sting without a reaction." The final maintenance dose and dosing interval are individualized on the basis of reactions to injections of immunotherapy and the level of protection. The buildup phase involves administering increasing doses of venom until the maintenance dose is reached. A typical protocol consists of weekly injections for 17 weeks; eventually, the interval would be increased to every 6 weeks. Occasionally, patients may receive three injections daily; thus, the maintenance dose is reached in 9 weeks. The risk of systemic reaction to injections of venom immunotherapy is minimal but real. The Hymenoptera venom study showed that 171 of 1,41opatients (12%) who underwent venom immunotherapy had 327 systemic treatment reactions." Ofthese 327 reactions, 28 (9%) were severe. These rates are similar to those from immunotherapy for aeroallergens. Most physicians require their patients who receive immunotherapy to remain in an observation area for 30 minutes after injection of the venom. Patients should not be allowed to administer immunotherapy at home because selfadministration is hazardous. Currently, determining the optimal duration of venom immunotherapy is of considerable interest. A long-term follow-up study of patients who have discontinued venom immunotherapy and who subsequently receive periodic deliberate live sting challenges would be the best approach. Keating and co-workers'? studied 51 patients with sting sensitivity
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who were protected by immunotherapy, as demonstrated by 80 60 an uneventful deliberate sting. All patients discontinued immunotherapy and were deliberately stung 1 year later. Of :r E the 51 patients, 2 (4%) sustained a generalized reaction on iii' OJ liJ c: subsequent sting. When Golden and colleagues" followed up 3 ri 40 30 S' sting-sensitive patients for 3 to 7 years after injections of ~ ~ venom immunotherapy (5 years oftreatment), they also found 1C a systemic reaction rate of4%. Ofinterest, three patients who ~ ~ had systemic reactions exhibited weak or negative results to venom skin tests when the immunotherapy was discontinued. 0 2 3 4 These and other studies suggest that venom immunotherapy Hours after sting can be discontinued in some patients after 3 to 5 years, although a small risk of anaphylaxis remains. How venom immunotherapy protects sting-sensitive pa- Fig. 2. Plasma tryptase (e) and histamine (0) levels after a bee sting tients is unknown; however, it stimulates venom-specific IgG challenge. (From Schwartz and associates." By permission of the antibodies to levels 2 to 3 times baseline level. 32 These high American Society for Clinical Investigation, Inc.) levels of antibodies decline when immunotherapy is discontinued. In general, venom immunotherapy initially increases levels of venom-specific IgE antibodies, which subsequently despite a history of severe reactions to honeybee stings. decrease with continued treatment. No defined level of IgG Usually, immunotherapy with honeybee venom is approxiantibody exists, however, that can be considered protective; mately 84% effective." Therefore, some persons will remain likewise, no level of IgE antibody signifies a nonallergic at risk for anaphylaxis and will face a high degree of exposure. status. 13 For such patients, a series of deliberate stings without reaction Treatment of Reactions.-Smalllocal reactions are self- ensures protection. In research, deliberate stings to sensitive patients have limited and do not need specific treatment. Large local reactions can be managed with cold compresses-and antihis- clearly shown involvement of the mast cell in sting anaphytamines. A brief course of orally administered corticosteroids laxis. Plasma histamine reaches'a peak in 5 to 10 minutes after is effective for treating large local reactions and can be a bee sting challenge and decreases to baseline levels in 30 to 40 minutes (Fig. 2).35 Serum tryptase (a neutral protease prescribed for selected patients. For most patients, immediate treatment of systemic reac- found only in mast cells) reaches peak levels 1 to 2 hours after tions to insect stings is identical to that of anaphylaxis of any challenge and remains detectable 4 hours later. These studies cause and should include epinephrine. In patients who have show that sting anaphylaxis is caused by IgE-mediated desevere or protracted reactions, multiple doses of epinephrine granulation of mast cells. may be necessary in addition to the usual supportive measures (protection of airway, intravenously administered fluids, FOLLOW-UP OF CASE vasopressors, and oxygen). Patients who have severe reac- Our patient had three sting reactions, all of which were severe tions should be observed for 8 to 12 hours to ensure complete and almost certainly represented pronounced anaphylaxis. recovery, and prompt treatment should be provided if a late- Venom-specific IgE antibodies, which were measured a few phase reaction occurs. Patients taking ~-adrenergic blocking days after the third sting, were normal. When the patient agents in whom severe anaphylaxis develops may benefit returned for venom skin tests at a later time, results were positive to the venom of the yellow jacket, wasp, and whitefrom intravenously administered glucagon." No Treatment-A review of the natural history of sting faced hornet. After we thoroughly discussed the associated sensitivity shows that sting-sensitive persons tend to lose their risks and benefits, the patient underwent immunotherapy to sensitivity in time. One follow-up study revealed that the the venom of the offending insects. Eventually, a maintereaction rate in unselected untreated patients after 7 years was nance program of 100 ug of each venom every 4 weeks was only 12%.34 reached. Because the patient had had severe reactions yet continued Role ofDeliberate Stings.-Deliberate insect sting challenges are and will remain a research (nonroutine) procedure. to work outdoors, the patient, the physician, and the patient's In individual cases, the patient and the physician may need to employer all considered it important to determine whether the determine with certainty whether venom immunotherapy is patient was protected from future sting reactions. For at least effective in preventing anaphylaxis. For example, sting- one of the past sting reactions, a single dose of epinephrine sensitive beekeepers will often refuse to quit their hobby was ineffective. The patient's employer had considered
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prohibiting him from performing duties in the field, a restriction that was opposed by the patient. Therefore, as part of a research protocol, the patient has returned to the Mayo Clinic annually for deliberate stings from the yellow jacket, white-faced hornet, and wasp (depending on insect availability)-the insects to which he was originally sensitive. All these challenges have been well tolerated. After 7 years of injections of immunotherapy administered every 4 weeks, the regimen was changed in 1985 to every 6 weeks (for patient convenience). Subsequent deliberate (and several field) stings were welltolerated. Venom skin tests were repeated after 10 years of venom immunotherapy. Although the results of these tests were negative, the venom immunotherapy was continued because a small risk of anaphylaxis from a field sting remained" and because the patient wished to retain the peace of mind obtained from years of successful immunotherapy. At age 61 years, the patient continues full-time employment with the Department of Natural Resources.
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Franklin R, Baer H: Comparison of honeybee venoms and their components from various sources. J Allergy Clin Immuno1 55:285-298, 1975 2. King TP, Sobotka AK, A1agonA, Kochoumian L, Lichtenstein LM: Protein allergens of white-faced hornet, yellow hornet, and yellow jacket venoms. Biochemistry 17:5165-5174, 1978 3. Barnard JH: Studies of 400 Hymenoptera sting deaths in the United States. J Allergy Clin Immuno1 52:259-264, 1973 4. Schwartz HJ, Sutheimer C, Gauerke MB, Yunginger JW: Hymenoptera venom-specific IgE antibodies, post-mortem sera from victims of sudden, unexpected death. C1in Allergy 18:461-468,1988 5. Charpin D, Vervloet D, Haddi E, Segalen C, Tafforeau M, Birnbaum J, Lanteaume A, Charpin J: Prevalence ofallergy to Hymenoptera stings. Allergy Proc 11:29-32, 1990 6. Golden DBK, Marsh DG, Kagey-Sobotka A, Freidhoff L, Szklo M, Valentine MD, Lichtenstein LM: Epidemiology of insect venom sensitivity. JAMA 262:240-244,1989 7. Zora JA, Swanson MC, Yunginger JW: A study of the' prevalence and clinical significance of venom-specific IgE. J Allergy Clin Immuno1 81:77-82,1988 8. Green AW, Reisman RE, Arbesman CE: Clinical and immunologic studies of patients with large local reactions following insect stings. J Allergy Clin Immuno1 66:186-189, 1980 9. Mauriello PM, Barde SH, Georgitis JW, Reisman RE: Natural history oflarge local reactions from stinging insects. J Allergy Clin Immunol 74:494-498,1984 10. Habermann E: Bee and wasp venoms. Science 177:314-322, 1972 11. Lockey RF, Turkeltaub PC, Baird-Warren lA, Olive CA, Olive ES, Peppe BC, Bukantz SC: The Hymenoptera venom study I, 1979-1982: demographics and history-sting data. J Allergy Clin Immunol 82:370-381, 1988
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Hunt KJ, Valentine MD, Sobotka AK, Benton AW, Amodio FJ, Lichtenstein LM: A controlled trial of immunotherapy in insect hypersensitivity. N Eng1 J Med 299:157-161,1978 Parker JL, Santrach PJ, DahlbergMJE, Yunginger JW: Evaluation of Hymenoptera-sting sensitivity with deliberate sting challenges: inadequacy of present diagnostic methods. J Allergy Clin Immuno1 69:200-207, 1982 Blaauw PJ, Smithuis LOMJ: The evaluation of the common diagnostic methods of hypersensitivity for bee and yellow jacket venom by means ofan in-hospital insect sting. J Allergy Clin Immuno1 75:556-562, 1985 Reisman RE, Dvorin OJ, Randolph CC, Georgitis JW: Stinging insect allergy: natural history and modification with venom immunotherapy. J Allergy Clin Immunol 75 :735-740, 1985 Reisman RE: Natural history of insect sting allergy: relationship of severity of symptoms of initial sting anaphylaxis to resting reactions (abstract). J Allergy Clin Immuno1 87:238, 1991 Smith PL, Kagey-Sobotka A, Bleecker ER, Traystman R, Kaplan AP, Gra1nick H, Valentine MD, Permutt S, Lichtenstein LM: Physiologic manifestations of human anaphylaxis. J C1in Invest 66:1072 J1080, 1980 Stark BJ, Sullivan TJ: Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 78:76-83,1986 Mulfinger L, Yunginger J, Styer W, Guralnick M, Lintner T: Sting morphology and frequency of sting autotomy among medically important vespids (Vespidae) and the honey bee (Apis mallifera). J Med Entomo1 (in press) LockeyRF, TurkeltaubPC, Olive CA, Baird-Warren lA, Olive ES, Bukantz SC: The Hymenoptera venom study II: skin test results and safety of venom skin testing. J Allergy Clin Immuno1 84:967-974, 1989 Yunginger JW: Diagnosis of insect allergy. In Monograph on Insect Allergy. Edited by MI Levine, RF Lockey. Pittsburgh, American Academy of Allergy Committee on Insects, 1981, pp 37-41 Valentine MD, Schuberth KC, Kagey-Sobotka A, Graft DF, Kwiterovich KA, Szklo M, Lichtenstein LM: The value of immunotherapy with venom in children with allergy to insect stings. N EnglJ Med 323:1601-1603, 1990 Clayton WF, Georgitis JW, Reisman RE: Insect sting anaphylaxis in patients without detectable serum venom-specific IgE. Clin Allergy 15:329-333, 1985 Hunt KJ, Valentine MD, Sobotka AK, Lichtenstein LM: Diagnosis of allergy to stinging insects by skin testing with Hymenoptera venoms. Ann Intern Med 85:56-59,1976 Sobotka AK, Adkinson NF Jr, Valentine MD, Lichtenstein LM: Allergy to insect stings. IV. Diagnosis by radioal1ergosorbent test (R.A.S.T.). J Immunol 121:2477-2484, 1978 Jacobs RL, Rake GW Jr, Fournier DC, Chi1tonRJ, Cu1verWG, Beckmann CH: Potentiated anaphylaxis in patients with druginduced beta-adrenergic blockade. J Allergy Clin Immunol 68:125-127,1981 Valentine MD, Lichtenstein LM: Anaphylaxis and stinging insect hypersensitivity. JAMA 258:2881-2885, 1987 Yunginger JW, Paull BR, Jones RT, Santrach PJ: Rush venom immunotherapy program for honeybee sting sensitivity. J Allergy Clin Immuno1 63:340-347,1979 Lockey RF, Turke1taub PC, Olive ES, Hubbard JM, BairdWarren lA, Bukantz SC: The Hymenoptera venom study III:
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safety of venom immunotherapy. J Allergy Clin Immunol 86:775-780,1990 Keating MU, Kagey-Sobotka A, Hamilton RG, Yunginger JW: Clinical and immunologic follow-up ofpatients who stop venom immunotherapy. J Allergy Clin Immunol 88:339- 348, 1991 Golden DBK, Kwiterovich KA, Valentine MD, Kagey-Sobotka A, Lichtenstein LM: Risk and benefit of discontinuing venom immunotherapy (VIT) after 5 years (abstract). J Allergy Clin Immuno1 87:237,1991 Golden DBK, Meyers DA, Kagey-Sobotka A, Valentine MD, Lichtenstein LM: Clinical relevance of the venom-specific
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immunoglobulin G antibody level during immunotherapy. J Allergy C1in Immunol 69:489-493,1982 Farah AE: Glucagon and the circulation. Pharmaco1 Rev 35:181-217,1983 Sav1iwa1aNM, Reisman RE: Studies of the natural history of stinging-insect allergy: long-term follow-up of patients without immunotherapy. J AllergyClin Immunol 80:741-745, 1987 Schwartz LB, Yunginger JW, Miller J, Bokhari R, Dull D: Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis. J Clin Invest 83:1551-1555,1989
JAMES T. C. LI, M.D., Ph.D., Division ofAllergic Diseases and Internal Medicine; JOHN W. YUNGINGER, M.D., Section of General Pediatrics and Pediatric Allergy and Immunology
Approximately 1 to 3 % of the general population has had a systemic reaction to insect stings. Adults whose reactions include urticaria, obstruction ofthe upper or lower airway, or hypotension and children whose reactions include obstruction of the upper or lower airway or hypotension have an increased risk offuture systemic reactions to stings. Allergy skin tests to Hymenoptera venoms can help to identify the offending insect and to classify the reactions as allergic; however, because 15 % ofthe general population may have positive results to such tests, persons who have not experienced a systemic reaction to insect stings should not be tested. Venom immunotherapy is highly effective and confers 98 to 99% protection in patients who have experienced previous systemic reactions to insect stings. Reaction rates to venom skin tests or venom immunotherapy are low and are similar to those in allergy testing and immunotherapy for hay fever. Generally, patients who have had systemic reactions to stings should be assessed by an allergist to determine whether they are candidates for immunotherapy with Hymenoptera venom. The decision to institute venom immunotherapy should be based on the disposition of the patient, the severity ofthe reaction, and the risk ofsubsequent stings. Deliberate sting challenges are clinically useful for guiding immunotherapy.
Virtually all physicians and most laypersons are aware that stings from bees, yellow jackets, hornets, and wasps can cause severe allergic reactions. Although most clinicians know that allergy tests and immunotherapy are available, some are unsure about who should be referred for assessment. Herein we offer guidelines to help clinicians decide which patients need allergy testing and which should be considered for immunotherapy.: We also review recent studies that suggest that immunotherapy for insect sting hypersensitivity need not continue for a lifetime in all patients. Finally, we describe a role for deliberate sting challenge in a research and clinical setting.
Address reprint requests to Dr. J. T. C. Li, Division of Allergic Diseases, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:188-194,1992
REPORT OF CASE A 48-year-old man came to the Mayo Allergy Clinic in 1977 because of a history of three allergic reactions to insect stings. The first reaction occurred when he was 37 years old. He was stung on the hand by an insect, which was later identified as a wasp or hornet. Within 2 minutes, he experienced flushing, shortness of breath, and weakness. His wife drove him 2 miles to a local hospital, where he was unable to get out of the car unassisted because of wooziness. Emergency treatment including epinephrine resulted in improvement of his condition within minutes and complete recovery in a few hours. The second sting reaction occurred when the patient was 40 years old and was working for the Department of Natural Resources. While using a bulldozer to move topsoil, he inadvertently disturbed a yellow jacket nest and was stung once. Although working with a crew, the patient was alone at 188
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the time. Flushing, dizziness, and weakness developed. He tried to drive the bulldozer to find help, but he was unable to control it and hit a tree. He was crawling on his hands and knees when he lost consciousness. Fortunately, a fellow crew member returned and took the patient to the nearest hospital. After administration of epinephrine and intravenous fluids, the patient recovered. He was instructed to have an epinephrine kit with him at all times. Furthermore, he was told not to work outdoors alone. In 1977, the patient had another reaction while camping in the woods with a group of teenagers. (They had assured the patient that they were capable of driving him to the hospital if he were stung.) While cutting down a tree, he was stung bya hornet. Although he immediately experienced dizziness and weakness, he was able to administer one dose of epinephrine from a multiple-dose preloaded syringe. The reaction, however, progressed rapidly, and he was unable to administer a second dose. The teenagers could not operate the manual transmission of the available vehicle, but they were able to summon help. Although the patient had lost consciousness, his condition improved after administration of epinephrine, and he recovered completely in a hospital. Because of a history of insect sting hypersensitivity, the patient was advised to consider a career change to an indoor occupation, but he chose to continue to work outdoors.
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classification of the reaction, severity of the reaction, identification of the offending insect, and general patient characteristics (such as occupation or coexisting diseases) should be determined because all these factors affect the therapeutic options. Diagnosis.-Usually, a sting reaction results in a small area of edema, erythema, and pruritus at the sting site. This self-limited reaction necessitates no specific treatment. A large local reaction is similar except that the edema and erythema are much more pronounced and may persist for several days. A typical example is a sting on the hand that causes local swelling that extends to the elbow. Although some patients who experience large local reactions may have increased levels of venom-specific IgE antibodies," thorough follow-up studies suggest that such persons are not at an increased risk of future systemic reactions." Because venom constituents contain various vasoactive amines, peptides, and enzymes,'? a nonallergic toxic reaction can develop in a person who sustains multiple stings. Clinically, such reactions can mimic anaphylaxis. Urticarial reactions, which are the most common, can be considered mild and systemic and are almost always accompanied by pruritus. Severe systemic reactions can include bronchoconstriction, hypotension, and typical symptoms and signs of anaphylaxis from any cause. Usually, symptoms of anaphylaxis develop within 10 minutes after a sting, although delayed reactions have been described. II Persons who DISCUSSION The Hymenoptera order of insects consists of two superfami- have had anaphylactic reactions to an insect sting have an lies-the apids (honeybees and bumblebees) and the vespids increased risk for anaphylaxis from subsequent stings. In (yellow jackets, hornets, and wasps) (Fig. 1). The major these sensitive persons, anaphylaxis will occur 35 to 60% of allergenic constituents ofhoneybee venom are phospholipase the time after subsequent stings by an identical insect.P:" Clinical assessment of the severity of anaphylaxis as well as ~' hyaluronidase, and acid phosphatase. I The major allergens in vespid venom are similar, including phospholipase, the response to therapy is important because patients who hyaluronidase, and an unusual protein identified as antigen 5. 2 have experienced severe reactions are also likely to have The cross-reaction between yellow jacket and hornet venoms severe reactions after subsequent stings." Furthermore, seis strong; the cross-reaction between these species and bees or vere anaphylactic reactions may not respond to a single wasps is limited. injection of epinephrine.F:" Some systemic reactions may be Typically, 25 to 40 deaths yearly in the United States are followed by a "late-phase" anaphylactic episode 4 to 12 hours attributed to insect sting anaphylaxis;' although the actual after the immediate reaction." The mechanism of this late incidence of fatal allergic reactions to these insects is un- phase is poorly understood and apparently is not prevented by known. Determinations of IgE antibody to Hymenoptera systemically administered glucocorticoid drugs." Patients venom in serum of persons who died unexpectedly imply that who experience severe reactions should be observed for 8 to some of these deaths may have been caused by anaphylaxis to 12 hours after the sting. By only elicitation of the history, it can be difficult to an insect sting." Studies have shown that 1.2 to 3% of the general adult population report that they have a history of a distinguish anaphylaxis without urticaria and cutaneous angiosystemic reaction.v This finding contrasts with the observa- edema from a hysterical, vasovagal, or hyperventilation retions that 2 to 7% of asymptomatic persons have increased sponse to an insect sting. Vasovagal reactions are often serum IgE antibodies to venom? and that approximately 15% preceded by nausea and typically involve bradycardia. Alof asymptomatic persons have positive results of skin tests to lergy tests can be helpful in such instances. venom." Sometimes patients are able to provide clues that can help Elicitation of History.-A detailed history is crucial for clinicians identify the offending insect. Beekeeping is a. proper management of insect sting hypersensitivity. The popular hobby, and the location of a beehive close to the
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Fig. 1. Hymenoptera insects. A, Bumblebee (Bombus). B, Honeybee (Apis mellifera). C, White-faced hornet (Vespula maculata). D, Yellow hornet (Vespula arenaria). E, Paper wasp (Polistes). F, Yellow jacket (Vespula favopilosas, (From Parker CW [ed]: Systemic anaphylaxis. In Clinical Immunology. Philadelphia, WB Saunders Company, 1980, pp 1208-1218. By permission.)
patient's residence or work site is often informative. Furthermore, the honeybee is the only stinging insect that usually leaves a stinger and attached venom sac at the sting site; therefore, a retained stinger implies a honeybee." Yellow jackets build nests in the ground and are sometimes referred to as "ground wasps." Hornets build large nests in trees or under branches. The nests of wasps have a paper-honeycomb appearance and are located under eaves and roofs. Allergy Skin Tests.-Allergy skin tests for insect sting hypersensitivity involve pricking the skin and intraderrnally injecting venom. A wheal and flare reaction that occurs 15 minutes after application of the reagent signifies a positive response. Skin tests to Hymenoptera venoms are safe. The Hymenoptera venom study of the American Academy of Allergy and Immunology showed that a severe hypersensitiv-
ity reaction to venom skin tests developed in only 8 of 3,236 sting-sensitive patients (0.25%).20 Skin tests to Hymenoptera venoms can be helpful in classifying the sting reaction. Hyperventilation and vasovagal and toxic reactions are much more likely to yield negative results than are IgE-mediated reactions that involve urticaria, bronchospasm, or hypotension. Of note; results of skin tests in true allergic patients can be falsely negative if the tests are conducted within 4 weeks after the most recent sting reaction." The mechanism for this result is unknown. Therefore, patients tested earlier than 4 weeks after a sting reaction should be retested later if the initial results are negative. The major role of allergy tests for insect stings is in assessing a patient for possible immunotherapy. In general, patients who have experienced a systemic sting reaction and
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whose test results are positive to Hymenoptera venom are suitable candidates for venom immunotherapy. An exception is children in whom only urticarial reactions develop (not hypotension or obstruction of the upper or lower airway). A follow-up study of such children showed that they are not at an increased risk of having more severe systemic reactions after repeated stings;" therefore, immunotherapy (and hence skin tests) is unnecessary for all such children. Immunotherapy, however, is effective for preventing the urticarial reactions that can occur after subsequent stings and can be offered to selected patients. Because patients with local or large local reactions do not have an increased risk of future severe reactions, neither tests nor immunotherapy is necessary. In a few patients who have systemic reactions to insect stings, test results will be negative." The pathophysiologic mechanism of this type of reaction is unclear but is being investigated. Such patients, however, should not receive immunotherapy. Because approximately 15% of persons who do not report any sting reaction have positive results of skin tests to Hymenoptera venom, testing persons who are curious about their risk of allergy to insect stings is not useful. Furthermore, the frequency of clinically unimportant positive results in such patients is high. IgE antibodies to Hymenoptera venoms can be measured in vitro by using the radioallergosorbent test. This test, however, is not as sensitive as skin tests, which are the preferred method.e'-" Management.-Clinicians have the responsibility of offering sound, rational management options to patients with insect sting hypersensitivity. Therefore, clinicians should be familiar with the occupation and hobbies of such patients. Although venom immunotherapy is highly effective in preventing sting reactions (see subsequent discussion), not all sting-sensitive patients choose to undergo immunotherapy. Sensitive persons who are outdoors for a substantial amount of time, either for employment or during leisure time, have the highest risk for repeated stings. Persons who are anxious about or preoccupied with their hypersensitivity or who are uncomfortable with self-administration of epinephrine also may be candidates for immunotherapy, such as children who are unable to administer epinephrine to themselves. Furthermore, day-care employees may be uncomfortable providing care for a child at risk for sting anaphylaxis. Persons who decline immunotherapy often spend most of their time indoors, accept the risk of anaphylaxis with equanimity, and are comfortable with self-administration of epinephrine to minimize future reactions. Immunotherapy may be difficult for persons who live far from a physician's office or who cannot afford it. Preventive Measures.-Patients who have experienced anaphylaxis to insect stings should know that the possibility of
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occurrence of anaphylaxis on repeated stings is 35 to 60%. Thus, whenever possible, they should take measures to avoid repeated stings. Such patients should carry an epinephrine kit and be familiar with its operation. The number of stingsensitive patients who comply with these instructions is unknown. Furthermore, severe sting reactions do not always resolve after treatment with a single dose of epinephrine. Sting-sensitive patients should wear a bracelet that identifies them as allergic to insect stings. Monoamine oxidase inhibitors and l3-adrenergicblocking agents can interfere with the treatment of anaphylaxis with use of sympathomimetic agents." Sting-sensitive patients should be warned of these drug interactions; in fact, these medications are contraindicated for patients undergoing venom immunotherapy. Venom Immunotherapy.-Many well-controlled clinical studies have clearly shown that venom immunotherapy is 98 to 99% effective in preventing systemic reactions in stingsensitive patients." As a subgroup, sensitive beekeepers can expect 84% protection from bee venom immunotherapy." The schedules for immunotherapy vary. The usual maintenance dosage is 100 ug of venom every 4 to 6 weeks. This amount is approximately twice the venom in a live honeybee sting and 20 times that in a vespid sting. The ability to tolerate 100 ug of venom by injection, however, is not an absolute guarantee that a person can tolerate an insect sting without a reaction." The final maintenance dose and dosing interval are individualized on the basis of reactions to injections of immunotherapy and the level of protection. The buildup phase involves administering increasing doses of venom until the maintenance dose is reached. A typical protocol consists of weekly injections for 17 weeks; eventually, the interval would be increased to every 6 weeks. Occasionally, patients may receive three injections daily; thus, the maintenance dose is reached in 9 weeks. The risk of systemic reaction to injections of venom immunotherapy is minimal but real. The Hymenoptera venom study showed that 171 of 1,41opatients (12%) who underwent venom immunotherapy had 327 systemic treatment reactions." Ofthese 327 reactions, 28 (9%) were severe. These rates are similar to those from immunotherapy for aeroallergens. Most physicians require their patients who receive immunotherapy to remain in an observation area for 30 minutes after injection of the venom. Patients should not be allowed to administer immunotherapy at home because selfadministration is hazardous. Currently, determining the optimal duration of venom immunotherapy is of considerable interest. A long-term follow-up study of patients who have discontinued venom immunotherapy and who subsequently receive periodic deliberate live sting challenges would be the best approach. Keating and co-workers'? studied 51 patients with sting sensitivity
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who were protected by immunotherapy, as demonstrated by 80 60 an uneventful deliberate sting. All patients discontinued immunotherapy and were deliberately stung 1 year later. Of :r E the 51 patients, 2 (4%) sustained a generalized reaction on iii' OJ liJ c: subsequent sting. When Golden and colleagues" followed up 3 ri 40 30 S' sting-sensitive patients for 3 to 7 years after injections of ~ ~ venom immunotherapy (5 years oftreatment), they also found 1C a systemic reaction rate of4%. Ofinterest, three patients who ~ ~ had systemic reactions exhibited weak or negative results to venom skin tests when the immunotherapy was discontinued. 0 2 3 4 These and other studies suggest that venom immunotherapy Hours after sting can be discontinued in some patients after 3 to 5 years, although a small risk of anaphylaxis remains. How venom immunotherapy protects sting-sensitive pa- Fig. 2. Plasma tryptase (e) and histamine (0) levels after a bee sting tients is unknown; however, it stimulates venom-specific IgG challenge. (From Schwartz and associates." By permission of the antibodies to levels 2 to 3 times baseline level. 32 These high American Society for Clinical Investigation, Inc.) levels of antibodies decline when immunotherapy is discontinued. In general, venom immunotherapy initially increases levels of venom-specific IgE antibodies, which subsequently despite a history of severe reactions to honeybee stings. decrease with continued treatment. No defined level of IgG Usually, immunotherapy with honeybee venom is approxiantibody exists, however, that can be considered protective; mately 84% effective." Therefore, some persons will remain likewise, no level of IgE antibody signifies a nonallergic at risk for anaphylaxis and will face a high degree of exposure. status. 13 For such patients, a series of deliberate stings without reaction Treatment of Reactions.-Smalllocal reactions are self- ensures protection. In research, deliberate stings to sensitive patients have limited and do not need specific treatment. Large local reactions can be managed with cold compresses-and antihis- clearly shown involvement of the mast cell in sting anaphytamines. A brief course of orally administered corticosteroids laxis. Plasma histamine reaches'a peak in 5 to 10 minutes after is effective for treating large local reactions and can be a bee sting challenge and decreases to baseline levels in 30 to 40 minutes (Fig. 2).35 Serum tryptase (a neutral protease prescribed for selected patients. For most patients, immediate treatment of systemic reac- found only in mast cells) reaches peak levels 1 to 2 hours after tions to insect stings is identical to that of anaphylaxis of any challenge and remains detectable 4 hours later. These studies cause and should include epinephrine. In patients who have show that sting anaphylaxis is caused by IgE-mediated desevere or protracted reactions, multiple doses of epinephrine granulation of mast cells. may be necessary in addition to the usual supportive measures (protection of airway, intravenously administered fluids, FOLLOW-UP OF CASE vasopressors, and oxygen). Patients who have severe reac- Our patient had three sting reactions, all of which were severe tions should be observed for 8 to 12 hours to ensure complete and almost certainly represented pronounced anaphylaxis. recovery, and prompt treatment should be provided if a late- Venom-specific IgE antibodies, which were measured a few phase reaction occurs. Patients taking ~-adrenergic blocking days after the third sting, were normal. When the patient agents in whom severe anaphylaxis develops may benefit returned for venom skin tests at a later time, results were positive to the venom of the yellow jacket, wasp, and whitefrom intravenously administered glucagon." No Treatment-A review of the natural history of sting faced hornet. After we thoroughly discussed the associated sensitivity shows that sting-sensitive persons tend to lose their risks and benefits, the patient underwent immunotherapy to sensitivity in time. One follow-up study revealed that the the venom of the offending insects. Eventually, a maintereaction rate in unselected untreated patients after 7 years was nance program of 100 ug of each venom every 4 weeks was only 12%.34 reached. Because the patient had had severe reactions yet continued Role ofDeliberate Stings.-Deliberate insect sting challenges are and will remain a research (nonroutine) procedure. to work outdoors, the patient, the physician, and the patient's In individual cases, the patient and the physician may need to employer all considered it important to determine whether the determine with certainty whether venom immunotherapy is patient was protected from future sting reactions. For at least effective in preventing anaphylaxis. For example, sting- one of the past sting reactions, a single dose of epinephrine sensitive beekeepers will often refuse to quit their hobby was ineffective. The patient's employer had considered
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prohibiting him from performing duties in the field, a restriction that was opposed by the patient. Therefore, as part of a research protocol, the patient has returned to the Mayo Clinic annually for deliberate stings from the yellow jacket, white-faced hornet, and wasp (depending on insect availability)-the insects to which he was originally sensitive. All these challenges have been well tolerated. After 7 years of injections of immunotherapy administered every 4 weeks, the regimen was changed in 1985 to every 6 weeks (for patient convenience). Subsequent deliberate (and several field) stings were welltolerated. Venom skin tests were repeated after 10 years of venom immunotherapy. Although the results of these tests were negative, the venom immunotherapy was continued because a small risk of anaphylaxis from a field sting remained" and because the patient wished to retain the peace of mind obtained from years of successful immunotherapy. At age 61 years, the patient continues full-time employment with the Department of Natural Resources.
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