Stinging insect allergy

Transcription

1 Journal of Wilderness Medicine 1, (1990) Stinging insect allergy l.r. WARPINSKP and R.K. BUSH2* 1Department ofmedicine, University of Wisconsin Medical School, Madison, Wisconsin 2Allergy Section, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, Wisconsin 53705, USA Insect stings occur commonly, with clinical responses ranging from mild local reactions to lifethreatening anaphylaxis. Stings from Hymenoptera (yellow jackets, hornets, wasps, honey bees, and imported fire ants) account for the majority of severe allergic reactions to insects. Patients who present with a systemic reaction should receive emergency therapy and be provided with selfinjectable epinephrine (Epi-Pen ) until definitive treatment can be provided. Anaphylactic symptoms and hypotension may be prominent in persons taking beta adrenergic blockers and may necessitate vigorous treatment. The diagnosis of Hymenoptera hypersensitivity can be established by venom skin testing. In more than 95% of cases, immunotherapy with specific venom is effective in preventing subsequent systemic reactions to Hymenoptera stings. Key words: Hymenoptera, allergy, immunotherapy, fire ant, beta adrenergic blockers Introduction Allergic reactions to insects of the-order Hymenoptera have been noted for many years. While minor reactions to insect stings are most common, severe, life-threatening reactions also occur, and an estimated deaths per year in the United States are due to stinging insect allergy. The management of a systemic reaction to a stinging insect involves use of epinephrine, and assessment and treatment of signs of life-threatening anaphylaxis. Symptoms of hypotension and anaphylaxis may be profound and especially refractory to treatment in persons receiving beta-blocker therapy. Two to four weeks after the systemic reaction, the patient should receive an allergy evaluation. With present venom skin testing, Hymenoptera sensitivity can be effectively diagnosed and treated in susceptible persons. All persons at risk for a subsequent systemic reaction should carry epinephrine for self-treatment. Clinical aspects Initial estimates indicated that % of the population was at risk for an allergic sting reaction [1]. Recent studies, however, indicate that Hymenoptera sensitivity may be even more common. In a population-based study by Golden etal. [2],4% of persons surveyed reported a history of a systemic sting reaction and more than 20% demonstrated Hymenoptera sensitivity by skin test or RAST testing. Similarly, Herbert and Salkie demonstrated venom-specific 19B by RAST in 12% of a group of 86 office workers [3]. The prevalence of venom-specific 19B varies seasonally, from 0.9% of blood donors *To whom correspondence should be addressed /90 $ Chapman and Hall Ltd.

2 250 Warpinski and Bush tested in April and May to 7% of those tested in October and November [4]. The clinical significance of venom-specific IgE has been of great concern. Zora et al. [4] attempted to assess the significance of venom-specific IgE by skin test or RAST in persons with no history of systemic reaction to a Hymenoptera sting. Nine sting challenges were tolerated without systemic reaction in eight such persons. Schwartz et al. [5] looked for venom-specific antibodies in persons who experienced sudden unexpected death. Venom-specific IgE was elevated in 23% of these persons, compared to 6% of controls. Recently observed antigenic cross-reactivity between white faced hornet venom and leaf protein of tobacco and tomato [6] may explain venom-specific IgE and anaphylaxis in some persons after the first Hymenoptera sting. Although many persons may exhibit asymptomatic Hymenoptera sensitization that is clinically irrelevant, the finding of an increased rate of venom-specific IgE in sudden-death patients raises the concern that some of these deaths may be due to Hymenoptera hypersensitivity. For perspective, Hymenoptera-related deaths are more common than all other venom-related fatalities. Of 460 deaths attributed to venomous animals in the United States, Parrish found that 50% were due to Hymenoptera, 30% to poisonous snakes, and 14% to poisonous spiders [7]. In addition to the winged Hymenoptera, allergic reactions have been seen with members of the family Formicidae, which includes fire ants and harvester ants. Of these, the imported fire ant is a major clinical problem. Imported fire ants comprise two species, Solenopsis richteri Forel (black fire ant) and Solenopsis invicta Buren (red fire ant). They are noted for their aggressive behavior, violent stings, and toxic venoms. Both species were imported from South America into the United States through Mobile, Alabama, around 1920 [8]. The black fire ant is now found largely along the Mississippi-Alabama border, extending into northwestern Alabama. In contrast, the red fire ant infests over 200 million acres in 13 southern states and continues to spread to several million additional acres per year. Imported fire ants are chiefly agricultural pests, but more than 30 million people live in infested areas. Another member of the family Formicidae, the harvester ant, has also been associated with anaphylactic reactions. Its range includes most of the western and southern United States. Antigens appear to be genus-specific and do not extensively cross-react with those of the imported fire ant [9]. Taxonomy of Hymenoptera The insect order Hymenoptera comprises three families: Apidae (honeybees and bumblebees), Vespidae (hornets, yellow jackets and wasps), and Formicidae (fire ants and harvester ants) (Fig. 1). Antigenically, the Hymenoptera may be divided into four major groups: honeybees, hornets and yellow jackets, wasps, and fire ants. Crossreactivity exists between venom proteins from different winged Hymenoptera, but there is sufficient antigenic variability among species to merit testing and treatment with individual venoms. In general, while there is some cross-reactivity between bees and vespids, the greatest antigenic similarities are between hornets and yellow jackets, whereas wasp and bee allergens appear to be more distinct. Fire ant allergens do not appear to cross-react with those of other Hymenoptera.

3 Stinging insect allergy 251 Hymenoptera I Apidae honeybees bumblebees Fig. 1. Taxonomy of Hymenoptera Vespl I'dae hornets yellow jackets wasps I Formicidae fire ants harvester ants Clinical featnres Stinging insect allergy affects persons of all ages and occurs without regard to a personal history of atopy. Although most reactions are seen in persons under 20 years of age, most fatalities are in adults. There is a 2: 1 male-to-female ratio ofstinging insect allergy, which is generally attributed to higher male exposure. The seasonal variation in stinging insect allergic reactions corresponds to seasonal changes in prevalence of elevated venomspecific 19B. Hymenoptera-related deaths begin to increase in April. They peak in July and August, then drop off after October [7]. Identification of the offending insect is difficult at the time of the sting. Honeybees are unlikely to sting unless provoked, whereas yellow jackets are aggressive and will sting without provocation. Occasionally, a person will be stung after disrupting a ground nest of hornets or will identify a typical wasp nest at the time of the sting. However, positive identification ofthe offending insect is usually not possible on clinical grounds. While the stinger is typically left in place by the honeybee, vespids also leave a stinger in some instances. Greene et al. [10] found a retained stinger in 43 of 44 honey bee stings; but notably, they also found a retained stinger in 51 of 79 stings from one species of yellow jacket and 5 of 64 stings from another yellow jacket species. Imported fire ants are very aggressive. To initiate a sting, the ant first bites with its jaws, securing itself to its victim. It then proceeds to pivot about the head, stinging up to 20 times with its abdominal stinger. The sting is characterized by almost immediate pain, itching, and burning. Within 4-8 h, clear vesicles develop with surrounding erythema. Typically, a sterile pustule is seen by 24 h. This finding is of diagnostic significance because this is almost the only insect in the United States that produces such a sterile pustule. Clinical reports of fire ant allergy have become increasingly common over the last 30 years [11-13]. Although the characteristic skin findings first attracted attention, it is the potential for systemic reactions that has generated the most concern. Most commonly, systemic reactions include urticaria and angioedema in addition to respiratory and cardiovascular symptoms. Rhoades et al. [14] reported 83 fatalities and two near fatalities secondary to imported fire ant stings. The majority of deaths were caused by fewer than five stings. The victims ranged in age from newborn to 65 years old. Half of the fatal stings occurred in field settings and were occupationally related. The remaining deaths occurred around the victims' home. Nonfatal cases of multiple ant stings have been reported. One 18-month-old child sustained 220 stings without apparent adverse effect, and an inebriated man reportedly received 5000 stings without any toxic side effects [15].

4 252 Warpinski and Bush Types ofreactions Reactions to stinging insects range from mild local irritation to fatal anaphylaxis. In addition to IgE-mediated allergic reactions, there are idiosyncratic and toxic reactions to the venom constituents. Insect stings are painful owing to the injection of a complex mixture of small peptides, vasoactive amines, and proteins. Major venom constituents include phospholipase, hyaluronidase, and other enzymatic proteins that may contribute to the tissue damage associated with insect stings. In addition, honeybee venom contains a large amount ofmellitin, a relatively small peptide that is highly toxic and destructive to cells [16]. Fire ant venom is unique among the Hymenoptera venoms in its composition (primarily alkaloids) and its very low protein content (approximately 1%). In contrast, venoms from honeybees, yellow jackets, hornets, and wasps contain about 50% protein by dry weight. Fire ant venom has bactericidal, hemolytic, cytotoxic and insecticidal properties [17]. Characterization of fire ant antigens has revealed allergens ranging in molecular weight from to 42000, a range similar to that of important aeroallergens [18]. Local reactions are characteristic of Hymenoptera stings. For most persons, these involve a circumscribed area of pain, warmth, and induration. In some, however, a large local reaction develops, characterized by extensive swelling at the sting site. These reactions peak at h and may last for up to one week. In persons who experience large local reactions, subsequent stings tend to result in repeated local reactions, regardless of venom immunotherapy. Repeated studies have shown that the presence of a large local reaction does not predict subsequent occurrence of a systemic reaction [19]. Systemic reactions range from diffuse urticaria and mild asthma to anaphylaxis. The unpredictable nature of systemic reactions makes prevention difficult in the general population. Most persons who experience a systemic reaction to a Hymenoptera sting have no prior history of a systemic reaction. In a study of 400 fatalities from Hymenoptera stings, Barnard found that only 59 had known Hymenoptera sensitivity [20]. The pathologic features of Hymenoptera fatalities are indistinguishable from fatal anaphylaxis from other causes. Respiratory tract obstruction is the major cause of death in more than two-thirds of cases. Cardiovascular collapse (anaphylactic shock, coronary occlusion) and neurologic reactions are responsible for the remaining fatalities [20]. Myocardial infarction may also complicate anaphylaxis to Hymenoptera. Freye and Ehrlich [21] describe two patients who suffered acute myocardial infarction following vespid stings. One person was stung on the back of the neck and the other received stings. Neither had a history of cardiac disease nor Hymenoptera sensitivity. Muller et al. [22] reviewed the case histories of 1463 patients with anaphylaxis to Hymenoptera. Thirty-two developed symptoms of chest pain, documented myocardial infarction, or arrhythmias. Of these 32, eight had pre-existing coronary artery disease and five had hypertension. Two of three patients receiving beta-blocker therapy suffered asystole, which was fatal in one instance. Although most systemic reactions occur in children and adolescents, mortality is most common in adults - particularly those with pre-existing cardiac disease and those receiving beta-blocker therapy [23]. Underscoring the role of beta-blocker therapy in potentiating severe systemic reactions to Hymenoptera stings, Lantner and Reisman [24] evaluated 158 cases of potentially fatal anaphylaxis to Hymenoptera. The 45 patients

5 Stinging insect allergy 253 who lost consciousness had an increased incidence of pre-existing cardiac disease and beta-blocker therapy. Prompt treatment of systemic reactions is mandated because most fatal reactions occur within minutes of the sting. Barnard [20] found that 87% of those experiencing nonfatal systemic reactions sought treatment within 1 h of the sting. In contrast, only 12% of the fatalities were treated within 1 h of their sting and 66% sought no treatment at all. These findings emphasize the value of self-treatment with epinephrine before emergency care is obtained at a medical facility. Though most anaphylactic reactions to Hymenoptera are IgE-mediated, some severe systemic reactions appear to involve other mechanisms. Lomnitzer et al. [25] described a subgroup of patients developing anaphylaxis after honeybee sting who had low honeybee-specific IgE, IgG, and lymphocyte reactivity. It is unclear whether these persons should receive venom immunotherapy. Toxic reactions are caused by multiple stings or direct systemic absorption of venom and frequently result in sensitization of the person. Symptoms are similar to those with anaphylaxis. Idiosyncratic reactions to Hymenoptera stings include neurologic conditions such as Guillian-Barre syndrome and vascular disorders such as nephritis and serum sickness. These reactions are generally thought not to be IgE-mediated, though some persons manifest late-onset urticaria and serum sickness on the basis of IgE-mediated hypersensitivity [26]. Diagnosis The diagnosis of stinging insect hypersensitivity is based upon the clinical history and demonstration of venom-specific IgE, either by skin testing or RAST. It is critical to document the circumstances surrounding the sting, concurrent medical problems and therapy, and signs of anaphylaxis such as hypotension, laryngeal edema, urticaria, and bronchospasm. Persons who experience a severe systemic reaction to a Hymenoptera sting should undergo venom skin testing after an interval of at least 2-4 weeks. Venom skin testing is not indicated in instances of large local reactions or non-ige-mediated reactions. Venom skin testing is more sensitive than RAST and the results are available immediately. While venom skin testing is preferred, in vitro testing may be indicated in patients with a history of severe systemic reactions but negative skin tests. Engler et al. [27] identified two persons who had repeated severe systemic reactions to bee stings in the face of negative venom skin tests. One of these had a negative skin test at flgml-1 but repeatedly experienced anaphylaxis during skin testing. Although both of the patients had detectable venom-specific IgE by RAST, these cases could represent anaphylaxis due to non-ige-mediated mechanisms. Diagnosis of fire ant allergy is based on a history of a painful ant sting in an endemic area and demonstration of IgE-mediated hypersensitivity by skin testing or RAST. Development of a sterile pustule is a helpful confirmatory finding. When the diagnosis is unclear, examination of the scene of the sting may be useful, as fire ants inhabit a characteristic dome-shaped colony. Currently, skin testing is usually performed with whole-body extract, whereas in other Hymenoptera, only purified venom can be reliably used for diagnosis and treatment. Treatment Acute local reactions to Hymenoptera stings are treated with first aid measures such as

6 254 Warpinski and Bush cold compresses and, at times, antihistamines. For minor sting reactions, this will be sufficient. Large local reactions are generally managed with antihistamines, nonsteroidal anti-inflammatory agents, and occasionally systemic corticosteroids. On the other hand, systemic reactions demand prompt, aggressive medical attention. The emergency management of anaphylaxis includes epinephrine, airway management, volume expansion, and blood pressure support. Corticosteroids may be given acutely primarily to prevent the late allergic response to the sting. Concomitant beta-blocker therapy may necessitate particularly vigorous therapy. Hymenoptera sting-related anaphylaxis may be profound and prolonged, especially in persons taking concomitant beta-blocker therapy, and may be refractory to customary therapy. In a study of three unimmunized or whole body extract-treated persons, deliberate sting challenges produced almost immediate hypotension. Two of the three subjects required vigorous therapy, including 5 I of saline, 7 mg of epinephrine, and 1 g of hydrocortisone acetate for one person whose anaphylactic reaction persisted for 2 h [28]. The potential for severe systemic reactions to Hymenoptera should not be underestimated. Since most fatalities from Hymenoptera stings occur within 60 min of the sting, all persons at risk of repeated systemic reaction to a Hymenoptera sting should be instructed in self-treatment with injectable epinephrine (Epi-Pen and Epi-Pen Jr., Center Laboratories, Port Washington, NY; Ana-kit, Hollister-Stier, Spokane, WA) before discharge from the emergency room or doctor's office. We prefer Epi-Pen because of its better acceptance by patients. If an Ana-kit is prescribed, the patient should be required to demonstrate proper self-injection technique. Of course, for emergency self-treatment to be effective, patients must carry the epinephrine whenever at risk of a Hymenoptera sting. Self-treatment with epinephrine should be administered at the first sign of a severe systemic reaction such as throat swelling or respiratory difficulty. Medical evaluation and treatment should then be promptly obtained, in view of the potential for prolonged anaphylaxis. At least two to four weeks after the initial systemic reaction, the patient should be evaluated for IgE-mediated hypersensitivity. Prophylactic treatment of stinging insect allergy involves avoidance and venomspecific immunotherapy. Measures designed to minimize the likelihood of Hymenoptera stings include avoidance of perfumes and brightly colored clothing, and exercising caution when outdoors during summer and fall. Use of insect repellants may also be beneficial. Over the past years, venom-specific immunotherapy has been shown to be both safe and effective in preventing severe systemic reactions to stinging insects. Untreated persons are at about a 60% risk of repeated systemic reaction to a subsequent Hymenoptera sting. After initiation of venom-specific maintenance immunotherapy, that risk is reduced to less than 5% [29]. Compared with adults, children who experience only generalized cutaneous reactions are at much less risk of a subsequent severe systemic reaction and are therefore not candidates for venom immunotherapy. Customary regimens of venom immunotherapy involve weekly or twice-weekly injections of increasing amounts of venom for 6-14 weeks, followed by maintenance therapy every 3-4 weeks. Selection of the appropriate venom for immunotherapy is based on the clinical history and results of venom skin testing. Highly sensitive persons who have severe systemic reactions during the warm months could be at immediate risk if they are re-stung in the 8-12 weeks needed for initiation of immunotherapy. In these persons, a modified form of 'rush' immunotherapy may be administered over 1-3 days,

7 Stinging insect allergy 255 Table 1. Guidelines for Venom Immunotherapy [31] 1. Purified venom should be used for diagnosis and treatment of Hymenoptera hypersensitivity. 2. Only persons with a history of a severe systemic reaction to Hymenoptera and demonstrated venom-specific IgE should be treated with venom immunotherapy. 3. Children who experience only cutaneous sting reactions are not candidates for venom immunotherapy. 4. Venom immunotherapy is not indicated for the treatment of large local reactions or non-ige-mediated reactions. followed by maintenance injections. Rush immunotherapy may also be indicated for persons who are unwilling or unable to receive weekly injections until maintenance doses are attained. Traditionally, venom immunotherapy has been continued indefinitely, but recent evidence suggests that five years may be sufficient [30]. Guidelines for venom immunotherapy are summarized in Table 1. Immunotherapy for persons at risk of severe systemic reactions to fire ants can be performed with either whole body extract or purified venom, as both appear to confer excellent protection against a subsequent systemic reaction upon re-sting. Currently, however, only whole body extract is commercially available. In some areas of southeastern United States, fire ant immunotherapy accounts for up to half of all immunotherapy for Hymenoptera allergy [32], underscoring the regional importance of fire ant allergy. Natural history ofstinging insect allergy Many features of Hymenoptera hypersensitivity indicate it is largely a self-limited condition. At an average interval of 4.5 years after the last sting, the reaction rate to subsequent stings was 35% per sting. However, after a mean of 7.3 years, the reaction rate dropped to 12% per sting [33]. These data suggest that the longer the time interval since the previous sting, the lower the subsequent reaction rate. The nature of the initial sting reaction also influences the nature of later reactions. Large local reactions are typically followed by large local reactions. Severe systemic reactions place a person at risk for further severe reactions upon re-sting. Summary Insect stings usually cause minor, self-limited reactions, but occasionally result in fatal events. Persons who experience a severe systemic reaction to an insect sting require timely and aggressive therapy. The early use of epinephrine, including self-treatment at the onset of systemic symptoms, may prove life-saving. In persons on beta-blocker therapy, management may be particularly difficult and aggressive measures may be required. With venom skin testing, persons at risk of a subsequent systemic reaction can be identified and effectively treated with immunotherapy. References 1. Settipane, G.A. and Boyd, G.K. Prevalence of bee sting allergy in 4992 Boy Scouts. Acta Allerg (Kobenhavn) 1970; 25,

8 256 Warpinski and Bush 2. Golden, D.B.K., Valentine, M.D., Kagey-Sobotka, A and Lichtenstein, L.M. Prevalence of Hymenoptera venom allergy. J Allergy Clin Immunol1982; 69, Herbert, F.A and Salkie, M.L. Sensitivity to Hymenoptera in adult males. Ann Allergy 1982; 48, Zora, J.A, Swanson, M.e. and Yunginger, J.W. A study of the prevalence and clinical significance of venom-specific IgE. J Allergy Clin Immunol1988; 81, Schwartz, H.J., Sutheimer, e., Gauerke, M.G. and Yunginger, J.W. Hymenoptera venomspecific IgE antibodies in post-mortem sera from victims of sudden, unexpected death. Clin Allergy 1988; 18, King, T.P. Human antibody response to hornet venom allergen Dol m VB and tobacco leaf protein PR-1b. J Allergy Clin Immunol1989; 83, Parrish, H.M. Analysis of 460 fatalities from venomous animals in the United States. Am J Med 1963; 245, Paull, B.R Imported fire ant allergy. Postgrad Med 1984; 76, Pinnas, J.L., Strunk, RC., Wang, T.M. and Thompson, H.e. Harvester ant sensitivity: in vitro and in vivo studies using whole body extracts and venom. J Allergy Clin ImmunoI1977; 59, Greene, A, Breisch, N.L., Golden, D.B.K., et al. The sting that stays: autotomy in two common yellowjacket species. J Allergy Clin Immunol1989; 83, Triplett, RF. Sensitivity to the imported fire ant: successful treatment with immunotherapy. South Med J 1973; 66, Lockey, RE Systemic reactions to stinging ants. J Allergy Clin Immunol1974; 54, Rhoades, R.B., Schafer, W.L., Schmid, W.H., et al. Hypersensitivity to the imported fire ant. J Allergy Clin Immunol1975; 56, Rhoades, RB., Stafford, e.t., James, F.K., Bunker-Soler, A and Impson, L.K. Survey of fatal anaphylactic reactions to imported fire ant stings. J Allergy Clin Immunol1988; 81, Smith, J.D. and Smith, E.B. Multiple fire ant stings. A complication of alcoholism. Arch DermatoI1971; 103, Reisman, RE. Insect allergy. In: Middleton, E., Reed, e.e., Ellis, E.F., Adkinson, N.F., Yunginger, J.W. eds, Allergy principles and practice, 3rd Ed. St. Louis: e.v. Mosby, 1988: James, EK., Pence, H.L., Driggers, D.P., Jacobs, R.L. and Horton, D.E. Imported fire ant hypersensitivity. J Allergy Clin Immunol1976; 58, Nordvall, S.L., Johansson, S.G.O., Ledford, D.K. and Lockey, RF. Allergens of the imported fire ant. J Allergy Clin Immunol1988; 82, Mauriello, P.M., Barde, S.H., Georgitis, J.W. and Reisman, RE. Natural history of large local reactions from stinging insects. J Allergy Clin Immunol1984; 74, Barnard, J.H. Studies of 400 Hymenoptera sting deaths in the United States. J Allergy Clin Immunol1973; 52, Freye, H.B. and Ehrlich, B. Acute myocardial infarction following Hymenoptera envenomation. NER Allergy Proc 1989; 10, Miiller, u., Stettler, R and Hottinger, S. Cardiac symptoms (CS) during anaphylaxis to Hymenoptera stings (HA). J Allergy Clin Immunol1989; 83, Toogood, J.H. Risk of anaphylaxis in patients receiving beta-blocker drugs. (Editorial.) J Allergy Clin Immunol1988; 81, Lantner, R and Reisman, RE., Clinical and immunologic features and subsequent course of patients with severe insect sting anaphylaxis. J Allergy Clin Immunol1989; 83, Lomnitzer, R, Lanner, A and Rabson,AR Low specific IgE, IgG and lymphocyte reactivity in a group of patients developing anaphylaxis following a honey-bee sting. Clin Allergy 1988; 18,39-44.

9 Stinging insect allergy Livingston, A. and Reisman, RE. Late-onset allergic reactions, including serum sickness, following insect stings. J Allergy Clin Immunology 1989; 83, Engler, RJ.M., Yang, E., Salata, K. and Carpenter, G. Recurrent systemic reactions (SR) with bee stings (BST) despite negative (NEG) skin test (SKT) with Hymenoptera venoms. J Allergy Clin Immunol1989; 83, Smith, P.L., Kagey-Sobotka, A., Bleecker, E.R, et al. Physiologic manifestations of human anaphylaxis. J Clin Invest 1980; 66, Hunt, K.J., Valentine, M.D., Sobotka, A.K., Benton, A.W., Amodio, F.J. and Lichtenstein, L.M. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978; 299, Golden, D.B.K., Kwiterovich, K.A., Kagey-Sobotka, A., Valentine, M.D. and Lichtenstein, L.M. Discontinuing venom immunotherapy (VIT): determinants of clinical reactivity. J Allergy Clin Immunol1989; 83, Golden, D.B.K. and Schwartz, H.J. Guidelines for venom immunotherapy. J Allergy Clin Immunol1986; 77, Stafford, C.T., Rhoades, RB., Bunker-Soler, A.L., Thompson, W.O. and Impson, L.K. Survey of whole body-extract immunotherapy for imported fire ant- and other Hymenoptera-sting allergy. J Allergy Clin Immunol1989; 83, Reisman, RE. Studies of the natural history of insect sting allergy. NER Allergy Proc 1989; 10,