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Stinging Insects: Allergy Implications
Stinging Insects: Allergy Implications ~mYER
B. MARKS, M.D.
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A pediatric colleague from San Salvador related this story concerning his wife: When she was about 5 years of age, while clasping the trunk of a tree, she was stung by a puss caterpillar. Shortly thereafter she developed marked iocal itching and intense edema of her right forearm. The itching and swelling subsided after a few hours with the use of cold compresses. Several years later, at the age of 12 years, she was stung on the top of her head by a honeybee. She reacted with marked pain, itching, and local swelling of her entire scalp. The swelling extended into her forehead and the nape of her neck. Marked periorbital edema was present; her palpebral apertures were mere slits. Cold compresses and antihistamines brought about complete resolution after about 4 days. There were no untoward sequelae. The doctor, newly graduated, was assigned to practice in a primitive country district in El Salvador as part of his medical training program. He had recently married and had taken his wife, about 20 years of age, to reside in an adobe farmhouse. One evening she was bitten on the lip by a cone-nosed bug, Triatoma megista. (This insect is often called the "kissing bug" because of its propensity for biting in or near the mucocutaneous junction or vermilion border.) Within minutes the young woman developed flushing and generalized itching, angioedema of the lips, periorbital areas, and ears, generalized urticaria, laryngospasm, and constriction of the chest, lapsing into syncope and shock. Her systolic pressure was under 80 mm. Her husband gave her repeated injections of epinephrine, intravenous diphenhydramine (Benadryl), and intramuscular corticosteroids. This therapeutic regimen saved her, he believed, from certain death. The Triatome bug, which is one of the main vectors of American trypanosomiasis (Chagas' disease), abounds in the cracks of rural mud dwellings in his country, hiding away in the daytime and coming out at night to bite and feed. It is possible that the doctor's wife had been previously bitten by Triatoma megista without being aware of it; or some common antigenic determinant from the previous insect stings had sensitized her. Later studies failed to show any evidence of trypanosomiasis infection.
The foregoing account is not typical, in that the majority of severe reactions to stinging insects in adult life may be traced to initial and subsequent stings of the Hymenoptera order (bees, wasps, yellowjackets, and hornets) in childhood. In fact, 65 per cent of persons once sensitized " Clinical Associate Professor of Pediatrics, University of Miami School of Medicine, Miami; Director, Pediatric Allergy Clinic, Jackson Memorial Hospital, Miami; and Consulting Pediatric Allergist, Mount Sinai Hospital, Miami Beach, Florida.
Pediatric Clinics of North America-Vol. 16, No.1, February, 1969
177
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Table 1.
*
CLASS ARACHNIDA
ORDER
ORDER
ORDER
ORDER
ORDER
ORDER
HYMENOPTERA
lEPIDOPTERA
DIPTERA
SIPHONAPTERA
HEMIPTERA
ARANEIDA
I I
I
WASP
I I I
I
'STINGING CATERPillARS
MOSQUITO
Puss
SAND flY
Soddlebod
VEllOW JACKET
I
I
TRIATOME or KISSING BUG" (Conenosel
FLEA
I
10 Moth Hog Moth
MARKS
Phylum Arthropoda
CLASS INSECT A
BE,
B.
I
I
SP1DER
ORDER
ORDER
SCORPIONIDA 1 ACARINA
I
SCORPION
Block Widow Brown Recluse
I I
MITE
TICK
I
ASSASSIN BUG
DEERFLY
\ BfDBUG
HORNET
fiRE ANT
to these insect stings, when re-stung, develop increasingly marked reactions. 26 The phylum Arthropoda includes more species than all of the other phyla of the animal kingdom together. Table 1 depicts several
*
Honeybee (A pis mellifera)
Wasp (Polistesl
A. Or,ly Hymenopterous insect losing stinger.
A. Slender,spindie-shaped body with elongated waist.
B. Me,s! common stinging insect.
B. Habitat: Found under eaves of roof in sheltered places or behind shutters. Circulor,honeycolTlb-type nest of paper cells.
C. FrEquents clover(in lawns and meadows), D. Hobitat: Hollows of dead trees;man-made hives.
Yellow Jacket (Vespula vulgaris)
Hornet (Vespula maculata or Vespa crabo germano)
A. Next most common stinging insect.
A. Narrow waist with squat,compact body (some body contour
B. Smaller than honeybee. C. Has narrow waist with blunt,truncated body. D. Habitat: Usually in ground under old lumber and logs and rocks. Nests are round and paper-like, often containing several hundred insects.
as yellow jacket only larger). B. Habitat: Large,round paper-like,pear-shaped hives in trees or bushes.
Figure 1.
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orders in this phylum capable of causing serious local and constitutional reactions in man. The familiar hymenoptera, the largest and most specialized order of insects, produce the greatest morbidity and mortality. Most stings are caused by the social and not by the solitary species. The principal offenders are the honeybee, paper wasp, yellowjacket, and hornet (Fig. 1). They are the only insect group for which an effective control, that of hyposensitization, is available. Some degree of success has been attained with hyposensitization for mosquito, flea, and deerfly allergy. Hymenopterous insects killed 229 persons during a 10-year period ending in 1959. 45 Bees were responsible for most of the deaths in this study, numbering 124; wasps were next with 69; yellowjackets followed with 22; hornets with 10; and fire ants with 4 deaths. The interval between sting and death recorded in 208 of the 229 fatalities was less than an hourI These catastrophes have occurred in a wide variety of age groups, although the highest incidence was noted in both sexes after the age of 25 years. 3 , 27
PEDIATRIC AGE INCIDENCE
According to a recent cooperative study on stinging insect allergy,27 15 per cent of 2606 persons tabulated with severe reactions were in the age group ranging from 1 to 20 years. Barr5 reported on 82 patients who had suffered hymenoptera stings; the median age was 11 Y2 years, and there were 54 male and 28 female patients. Frazier,24 reviewing his 78 pediatric patients, found that 37 per cent were children 5 to 8 years of age. He also found that insect stings occurred in boys about twice as frequently as in girls. The peak incidence of insect stings occurs during the summer months, usually during July and August. In tropical and subtropical climates, persons may receive insect stings the year round. In children, stings are more frequent on the extremities, but may occur anywhere on the exposed body.
SYMPTOM COMPLEXES
Allergic manifestations to stings vary in children as they do in adults. In most children stung by hymenoptera, the immediate local reaction is severe swelling at the site of the sting, which may last for hours to several days. Repeated stings may cause a diminution of the response from naturally acquired immunity, or, on the other hand, increasing sensitization. It is difficult to predict how patients will react to subsequent stings once an allergic state has been induced.
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Some children have a serum sickness, delayed type of reaction following an insect sting, consisting of swelling at the site of the sting for 24 hours or more with generalized urticaria, angioedema, and, at times, arthralgia. Of the immediate systemic reactions seen in children, the moderate, general type is the rule. 41 These manifestations consist of generalized Hushing, itching, and urticaria; angioedema of the eyelids, lips, cheeks, ears, hands, and feet; allergic edema of the tongue, larynx, trachea, and bronchial tree; and with mild chest constriction and respiratory difficulty. Fortunately, severe, general anaphylactic reactions with hypotension, tachycardia, profuse sweating, nausea, vomiting, vertigo, and shock are seen infrequently in childhood. Since children and their parents may fail to associate current symptoms with a delayed type of insect reaction, it is important to ascertain whether a sting occurred several days before. Barnard4 stated that delayed allergic reactions to insect stings may be serious and even fatal. Fogel19 and associates cited the development of a fatal connective tissue disease which may have occurred after a wasp sting on the foot of a 12-year-old boy 19 days before admission to the hospital. Burke and Jellinek14 reported the onset of a nearly fatal case of SchonleinHenoch syndrome in a 4-year-old girl after a sting on the ankle by either a deerHy or a wasp 7 days previously. Siegel and colleagues55 detailed severe anaphylactoid purpura of the nonthrombocytopenic Schonlein-Henoch type in a child 3 years of age who developed, in addition, urticarial and visceral manifestations from repeated mosquito bites 2 weeks before being hospitalized. Feingold and BenjaminP8 disclosed that patients developed delayed local reactions to Hea bites even without preceding wheal formation where sensitization previously existed. Bowenl l related the death of a 3-year-old boy from several fire ant stings; he had previously been stung and perhaps sensitized by them. Serious constitutional allergic reactions were reported from fire ant stings by Caro et aP5 These workers stated that reactions to the stings of the fire ant are both local and systemic. The local changes suggest that a powerful necrotizing toxin of unknown nature is responsible, but this is unlikely to be formic acid. In this connection, Blum and associates8. 9 disclosed that the venom of the fire ant is the only hymenopterous venom known to be nonproteinaceous. Thus sensitization to fire ant venom may result even in the absence of proteinaceous substrates. They stated that the venom of the fire ant is necrotic, hemolytic, antibiotic, and fungicidal as well as insecticidal. The necrotic pustule forming at the sting site is characteristic of no other hymenopterous venom. The disfiguring scars which often result from fire ant stings become discolored and persist for years. Blum10 knew of two authenticated cases of anaphylactic reactions to fire ant stings. Barnard,3 in a later report on 50 hymenopterous insect sting fatalities,
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stated that the most common lesion in 35 subjects (70 per cent) was that of angioedema with respiratory obstruction. Thirty of these patients died within 6 hours of their stings, but others had delayed reactions with fatalities several days later. Fifteen of the 50 patients died from anaphylactic, vascular, and cerebral reactions. Immediate, fatal reactions were caused mainly from wasp stings, followed by bees, and then by yellowjackets. The last caused the slowest reactions with the fewest fatalities. Stings on the neck may have been responsible for more fatal reactions in the first 30 minutes than stings elsewhere on the body. Of the 50 fatal subjects cited, five were in the age group of 1 to 25 years.
IMMUNOLOGIC CONSIDERATIONS
Rabbits were immunized by Foubert and Stier20 to the pulped bodies of hymenoptera and demonstrated high precipitin titers. Gel diffusion studies showed that honeybee, wasp (Polistes), yellowjacket, and hornet contained common antigens which were probably immunologically identical. They also found that each insect had several antigens specific to its own genus. Barr5 showed that a rabbit hypersensitized to the four hymenoptera gave both Ouchterlony precipitin bands and positive passive cutaneous anaphylactic reactions to honeybee, wasp, and hornet, with some precipitin bands common to more than one insect. He was, however, unable to show either a positive precipitin band or PCA test for yellowjacket antigen. McCormick37 first found precipitins in the postmortem serum of a person who had died shortly after being stung by a Polistes wasp. Brown13 and colleagues demonstrated precipitin bands to various hymenoptera in a number of human sera by the Ouchterlony technique. Loveless 33 , 35 believed that immunization should be carried out with a course of venom extracts only. She reported greatly reduced reactions to deliberate as well as accidental stings. In contrast to the administration of whole-body extracts, reactions to the venom preparations were nil or trivial. However, studies by many workers 1, 2, 31,32,43 revealed that some antigens may be common to the body, to the sting sac, and to the venom itself. Many investigators5, 20,34, 59 have found some antigens specific to one type of insect and others common to several types. Thus the sting of a single insect may sensitize an individual to the entire hymenoptera group.26, 29, 57 At present the use of venom extracts is experimental, and only whole-body insect allergens are available commercially. They are made up as individual or polyvalent mixtures of the four common hymenoptera insects. Barr5 noted that 69 out of 82 previously stung patients tested intradermally reacted to two or more insect antigens. In only nine of the patients did the skin test correlate with the description of the stinging
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insect. One, a boy, had a constitutional reaction to skin testing. This youngster, when initially stung, exhibited only a large local reaction.
DIFFERENTIAL DIAGNOSIS
Most children, and their parents if present, are often unable to identify the stinging insect. Brock12 stated that most hymenopterous insects cannot be distinguished by their size or color, but only by their shape or habitat. Mueller39 emphasized that actual identification is unreliable and that treatment should be directed against all four types of stinging insects. Many commercial laboratories will supply the physician with charts depicting the hymenoptera group in their natural colors, which will often help in the identification of the offending insect. Additional colored photographs or drawings of troublesome nonhymenopterous insects indigenous to certain geographic areas should also be displayed. In the honeybee, when the barbed stinger is embedded in the flesh, the contractions of the venom sac not only cause deeper penetration of the stinger, but a greater outpouring of venom. 22 The bee, in escaping, loses its stinging apparatus and dies. The wasp stinger, however, is not barbed; the insect can return to sting the patient again and again, particularly when it is agitated. Following a hymenoptera sting, the initial pain radiating along the nerves from the site is usually a toxic, nonallergic reaction from the injected venom. 30 , 52, 60 Since the venom contains antigenic components, immediate or delayed hypersensitivity responses may ensue, depending upon the sensitized state of the individual. Swelling of an extremity after an insect sting extending beyond two nonadjacent limb joints indicates allergy and the need for specific treatment. 5 Houser and Caplin26 stated that it is often impossible to differentiate between toxic and allergic reactions to insect venom. When local or generalized urticaria, angioedema, dizziness, headache, fever, muscle spasms, and sometimes seizures occur, one may be dealing with a toxic reaction, particularly when multiple stings have occurred. Giddiness, hyperventilation, gastrointestinal symptoms, and syncope from fright may occur. One must agree with their conclusions that, when in doubt, one should treat the patient immediately as if an allergic reaction had occurred, with subsequent management to prevent future catastrophic, constitutional effects. The stings of mosquitoes and fleas in certain persons may produce an allergic response with local swelling and mild, constitutional symptoms; but severe, general reactions are unusual. In some children, flea bites may cause papular urticaria associated with a delayed type of immune response. 1S Intense itching with excoriation and secondary in-
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fection may occur. Contact with pets infested with fleas is the usual predisposing factor. Urticaria from food allergy should be excluded by history and by configuration and location of the individual or grouped lesions. Bedbug bites must also be considered. Although members of the class Arachnida causing bites or stings are often considered true insects, such is not the case. They rarely produce hypersensitivity reactions, but cause severe, local necrosis and neurotoxic, constitutional effects. This is true of the black widow and brown recluse spiders and scorpions. Sensitivity to avian mites occurs with papular lesions in some persons in close contact with pet birds.
DISCUSSION
In an earlier questionnaire study27 under the auspices of the Insect Allergy Committee of the American Academy of Allergy, it was shown that only about 27 per cent of persons hypersensitive to insect stings had an atopic history. Thus severe and even fatal reactions may occur in nonatopic persons. Barnard,3 however, in his study of fatal responses to hymenoptera stings, revealed an incidence of 72 per cent with positive histories of allergy. The possibility that moderate or severe general reactions to insect stings in persons who have never been stung before might be due to previous, repeated sensitization by inhalation of insect dust has been suggested. 36 ,46 Much has been written on insects as inhalant allergens. 6, 16, 17, 50, 64 The fact that about 50 per cent of 630 persons who suffered severe, systemic reactions to hymenoptera stings recalled no earlier sting, or at most, only a minor, local reaction,27 may reflect this inhalant sensitization concept. Unpubished studies of the Insect Allergy Committee of the American Academy of Allergy for 1967 and 196828 reveal that approximately 90 per cent of hyposensitized patients still under treatment showed less reaction following subsequent hymenoptera stings; slightly over 80 per cent of hyposensitized patients who had discontinued treatment reacted less severely; and, surprisingly, 68.8 per cent (in 1968) of nonhyposensitized patients were not as reactive as previously. This latter, untreated group is of interest because, since 1964, when improvement in reactivity to stings was as low as 39 per cent, there has been a rising trend of improvement annually to the present level. This may be attributed to the use of symptomatic medication, particularly epinephrine, immediately after an insect sting, with decrease in the sensitivity of these patients. It was at first thought that there might be diminution of the clinical sensitivity in this group as the time interval between stings increased, but close scrutiny of the available data did not support this view. In both 1967 and 1968, most patients enjoyed long-lasting protection
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after hyposensitization was stopped. The data indicated that immunity continued for 5 years. Patients who were stung within a year of hyposensitization therapy did poorer than those who were stung after a year. Eleven patients reported that because of the increased severity of reaction to stings, they had again started hyposensitization therapy. Of these eleven, two were re-stung and claimed less severe reactions. Five of 38 patients who reported worse reactions had been on emulsion therapy. Although immunity to stinging insects is marked following the recommended hyposensitization program, most members of the Subcommittee on Prolonged Therapy concluded that, for the present, patients should receive booster doses on an average of every 3 or 4 months until more information becomes available. This should offer protection to the small group of persons who lose their immunity shortly after discontinuance of supposedly adequate hyposensitization. There have been reports of fatalities from insect stings after cessation of hyposensitization. H , 58 Prince 49 stated that severe, persistent, local reactions from stings in patients undergoing hyposensitization could represent a serum sickness type of delayed response. This type of reaction, he believed, would not respond to any prophylactic injection program.
SKIN TESTING
Although most commercial laboratories that process intradermal testing kits composed of individual or polyvalent mixtures of whole-body extracts containing the four common hymenoptera recommend skin testing beginning with a 1:1 million dilution, this dose may invite severe general reactions in some highly sensitive persons. 60 ,61 Mueller3 9 ,41 discussed two children who had severe constitutional reactions with this dilution and mentioned a child who had a mild systemic reaction with itching and urticaria with a dilution of 1: 100 million I I have found it expedient to begin intradermal skin 'testing with a 1:100 million dilution of the whole-body polyvalent extract. I have never encountered untoward reactions to this dilution. Serial intracutaneous testing is then carried out to determine the dilution necessary to begin treatment, so that unnecessary injections may be eliminated in attaining the maintenance dose. 42 Rarely, however, is treatment started under a dilution of 1: 100,000. Schwartz's experience51 with serial intracutaneous skin testing in an insect sting-sensitive group was somewhat different, revealing positive tests in much lower dilutions. Even persons with histories of life-threatening sting experiences reacted only to dilutions no greater than 1:10,000. No more than 0.02 ml. is injected intradermally to raise a wheal. All tests are then read in 20 minutes. Skin testing by the scratch technique is also done, but with a 1:10 dilution, using individual extracts of honeybee, wasp (Polistes), hornet, and yellowjacket, prior to intracu-
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taneous testing. This is performed for two reasons: (1) to attempt to correlate the individual stinging insect with the clinical history; and (2) to determine the reactivity of the patient. A refractory period may occur after an insect sting; it is therefore best to wait at least 2 weeks after the sting to commence skin testing. 53 Saline dilutions of the intracutaneous skin testing materials should be made fresh at least every 12 weeks and kept refrigerated; they may lose their potency after this period. Schwartz51 concurred with Bernton and colleagues 7 that it was not uncommon to find positive skin tests in patients without clinical sensitivity to insect stings. It may be that nonspecific irritants or histaminereleasing substances present in the whole-body insect extracts produce the positive skin tests. The clinical history remains the all-important factor in the diagnosis of stinging insect allergy.
TREATMENT
Emergency Procedures Since it is unlikely that a physician will be available to the patient during the first few minutes after the sting occurs, it is during this period that the child, if old enough, or the parents, should use methods taught by their physician to prevent the onset of life-threatening, generalized reactions. After these measures have been carried out, prompt medical attention should be sought at the nearest hospital or physician's office. The sensitized person should always carry with him an insect sting first aid kitll> containing a preloaded, sterile syringe of epinephrine hydrochloride 1: 1000, an ephedrine sulfate tablet, an antihistamine, and a tourniquet. The syringe containing the epinephrine must be examined frequently to determine whether the solution has turned brown, which is an indication that the epinephrine has become oxidized and useless. Extra, individually packaged, prefilled, disposable syringes of epinephrine hydrochloride 1:1000 are available and should be kept in the refrigerator at all times for replacement purposes in the kit when necessary. A Medihaler-Epi (Riker) should always be carried by the person who is sting-sensitive. It affords additional protection and may be used alone for mild reactions and in combination with the injection of epinephrine when a severe constitutional reaction ensues. A tourniquet should be applied proximal to the site of the sting if on an extremity and the epinephrine injected deep subcutaneously above the tourniquet or into another limb. The application of the tourniquet serves to slow down the absorptive rate of the venom. It should be loosened from time to time so as to prevent permanent or serious circulatory changes in the distal extremities. The tourniquet should be used as long as even mild constitutional symptoms are evident. II>
Center Laboratories, Port Washington, New York.
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The content of the emergency kit must be used promptly in re-stung patients exhibiting constitutional reactions who, although under hyposensitization, have not had a full year of treatment. Patients under hyposensitization for over 1 year, when re-stung, need receive no emergency measures, unless, for psychological reasons, one wishes the patient to take ephedrine or antihistamine tablets. Beta-adrenergic receptor agents, like sublingual isoproterenol tablets or isoproterenol aerosols, do not combat shock effectively. Reliance should be placed strictly on the use of epinephrine. After a sting by a honeybee, the stinger must be removed immediately by a quick flick of the fingernail, tweezer, or knife blade, care being used not to compress the venom sac to prevent more venom from entering the circulation. If only a local reaction with marked swelling results, early use of an ice pack and elevation of the limb are helpful. Spraying with dexamethasone topical aerosol (Decadron) relieves the pain and pruritus. Oral antihistamines, as well as analgesics, are indicated. The patient with a generalized reaction, who shows signs of anaphylaxis, impending or absolute, should promptly be given an injection of epinephrine hydrochloride 1: lOOO by the physician. Depending upon the age of the child, 0.2 to 0.5 ml. is injected deep subcutaneously and massaged vigorously into the tissues. In desperate situations, intravenous or intracardiac epinephrine may need to be administered. A 1:10,000 dilution is used to prevent cerebral vascular accidents or myocardial necrosis. An antihistamine is then injected intramuscularly or intravenously. Chlorpheniramine maleate (Chlor-Trimeton), 100 mg. per ml., 0.1 to 0.25 ml.; diphenhydramine hydrochloride (Benadryl), 50 mg. per ml., 0.5 to 1.0 ml.; and tripelennamine hydrochloride (Pyribenzamine), 25 mg. per ml., 0.5 to 1.0 ml., are all valuable antihistaminic adjuncts. For the prevention and treatment of delayed reactions, intramuscular corticosteroids should be used, but only as a third line of defense. Dexamethasone phosphate (Decadron), 4 to 8 mg., or betamethasone acetate (Celestone Soluspan), 6 to 12 mg., may be injected into the vastus lateralis or gluteus muscles. For unconsciousness and shock, an intravenous "cocktail" of 500 ml. 5 per cent dextrose in water, containing 100 mg. hydrocortisone (SoluCortef), aminophylline (for bronchospasm), 12 mg. per kg. per day, and an antihistamine, should be promptly administered. If a vasopressor is also indicated, levarterenol bitartrate (Levophed), 0.2 per cent, 2 ml., may be used; although I have found that epinephrine hydrochloride 1:lO00 exerts an excellent pressor effect as well as combatting shock when 0.5 ml. is added to the entire contents of the intravenous "cocktail." Oxygen and IPPB respirators, using racemic epinephrine (Vaponefrin), prevent hypoxemia and possible vascular and cerebral complications. Laryngeal obstruction may call for immediate tracheostomy, as fatalities have been known to occur from laryngospasm. 44 , 64
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An emergency identification tag should be carried at all times by a person sensitized to insect stings. Preventive Procedures Sting-sensitive persons should learn the haunts and habits of hymenoptera, thus minimizing their chances of being re-stung. They should avoid commercial beekeeping establishments, orchards, flowers, blooming trees, and shrubs. Insects are attracted to decorative, dark-colored, and rough-textured clothing. Sensitized children should wear garments of smooth-finished fabrics having neutral colors. Colors like white, green, tan, and khaki do not, as a rule, attract insects. 36 When playing out of doors, these children should wear clothes with long sleeves, long trousers, a cap or hat, and shoes. Frazier3 reported that of 24 children stung on the bare feet, 16 developed generalized reactions. Scented hair sprays, tonics or pomades, colognes, perfumes, and odoriferous lotions or powders may attract all forms of stinging insects. Precautionary measures like adequate screening of windows and doors, cleanliness about garbage receptacles, and avoidance of picnic areas, should be exercised. A sting-sensitive child must be relieved of gardening chores, particularly hedge-clipping. He should be cautioned against taking short cuts through hedges. Regular inspection of the premises is important. Hives and nests about the home should be destroyed. It might be well to employ a professional pest exterminator, since the danger of removing nests of the hymenoptera order by inexperienced persons may be great. Repellents for stinging insects have not proved efficacious.21 . 38, 48 However, the United States Department of Agriculture found the best all-purpose repellent yet developed to be N,N-diethyl-m-toluamide ("deet").56 The "deet" preparations are known commercially as Off!, McKesson Mosquitotone, and others. They can be purchased as liquids, foams, pressurized sprays, sticks, creams, and wipe-on tissues. An aerosol insecticide spray should always be present in the glove compartment of the automobile to be used in case of. entry of a stinging insect.s6 . 62 Oral thiamine hydrochloride was reported by Shannon54 as an effective repellent against most mosquitoes in 1943. Careful studies by Wilson and co-workers 63 a year later disproved this assertion. Perlman,48 however, stated that thiamine hydrochloride in doses of 50 mg., three times daily, prevented flea bites. Mueller4° found that 70 per cent of 100 insect-sensitive patients were seldom or never annoyed when a daily dose of 75 to 150 mg. of thiamine hydrochloride was taken. My own experience with the use of oral thiamine hydrochloride in the control of insect sensitivity to mosquitoes and sand flies has been equally good. Over 50 per cent of children displaying severe local responses to insect bites showed improvement with doses of 25 mg. three times daily. Perhaps a larger percentage of children would have responded if the dose
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of this innocuous vitamin preparation had been increased two or even threefold. Thiamine hydrochloride most likely acts to combine with the sensible and insensible perspiration of the host to repel insects by its odor. It would be of interest to explore a double-blind study with oral thiamine hydrochloride on sting-sensitive patients to note the incidence of hymenoptera re-stings in patients currently on hyposensitization, patients who have discontinued hyposensitization, and those who have never had any hyposensitization. Hyposensitization As stated earlier, the latest survey of the Insect Allergy Committee of the American Academy of Allergy showed that 90 per cent of stingsensitive patients, when placed on hyposensitization, described marked improvement in their reaction when re-stung.28 Houser and Caplin,26 in their review of the literature, were unable to find any reports of fatalities in re-stung patients while undergoing hyposensitization. If a child has responded with a generalized reaction to a hymenoptera sting, whether mild or severe, hyposensitization is mandatory. A history of repeated stings with progressively larger local reactions emphatically invites a program of hyposensitization. Severe local, delayed reactions, particularly with angioedema and generalized urticaria, place the patient in the same category. Polyvalent extracts of whole bodies of mixed bees, wasps, yellowjackets, and hornets are used. They are available from most commercial allergen laboratories. The starting dose is usually 0.05 m!. of a 1:1 million dilution, although in very sensitive persons the initial dose may be 0.05 m!. of a 1: 10 million or even a 1: 100 million dilution. Injections are increased by 0.05 m!. weekly until a volume and concentration of 0.50 m!. of 1:100 is reached, which becomes the maintenance dose. (Mueller39 computed this dose to be equivalent in antigenic activity to the venom of one to two stings.) Injections are then spaced at intervals of every 2 'weeks, every 3 weeks, and finally every 4 weeks. In the il1ithor's experience, this maintenance dose has offered patients excellent protection whenever re-stings occurred. Hyposensitization should be continued for a minimum of 3 years, with booster doses administered every 3 or 4 months thereafter. Though protection may persist for years in some persons following cessation of hyposensitization, contrariwise, it may be lost in less than a year in others; hence the necessity for long-term management. Friedman and Mascia 25 have reported on a 3-year study of 48 sting-sensitive children with generalized reactions who received Allpyral whole-body insect extracts containing the four common hymenoptera. They stated that 22 patients, or 46 per cent of their treated group, when re-stung, gave evidence of excellent protection. Future studies may assess the value of this therapeutic modality.
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Occasionally, severe local and constitutional reactions may be produced by hyposensitization. The injection schedule should then be carefully monitored by the physician and the next dose reduced by half or more, depending on the severity of the reaction. If no further reaction ensues, 0.02 ml. increments are used to rebuild the dosage level. Injections are never given in the buttocks. If a reaction occurs from accidental intravascular injection, a tourniquet is applied above the site of the injection and 0.20 to 0.30 ml. epinephrine hydrochloride 1: 1000 is injected into the other arm promptly and repeated if necessary. Sus-Phrine (Cooper), 0.10 to 0.15 ml., which has immediate and long-acting effects, is efficacious for reactions of this type.
SUMMARY Every physician should be acquainted with stinging insect hypersensitivity involving particularly the hymenoptera order, which includes bee, wasp, yellowjacket, and hornet. Stings from these insects are capable of inducing not qnly severe local and constitutional reactions, but, at times, even death. Hymenoptera rank highest in incidence of serious insect sting reactions in man. Stinging insect allergy in children is discussed as to etiology, occurrence, symptom complexes, differential diagnosis, immunologic considerations, and treatment involving emergent, preventive, and hyposensitization procedures. Emphasis is placed on the immediate management of sensitized persons following insect stings. Epinephrine and antihistaminic preparations should be used promptly in severe local and in all types of constitutional reactions. Since corticosteroids act slowly, they are administered last in the emergency therapeutic program. They are especially useful in delayed reactions, in sting-sensitive persons. A history of untoward reactions to stinging insects is of far greater importance than dependence on the results of skin tests. The immediate and subsequent management of the insect~sensitive patient should be based primarily on the history.
REFERENCES 1. Arbesman, C. E., Langlois, C., Bronson, P., and Shulman, S.: The allergic response
to stinging insects. VII. Fractionation of whole body and venom sac extracts of yellow jacket. J. Allergy, 38:1, 1966. 2. Arbesman, C. E., Langlois, C., and Shulman, S.: The allergic response to stinging insects. IV. Cross-reactions between bee, wasp, and yellow jacket. J. Allergy, 36:147, 1965. 3. Barnard, J. H.: Allergic and patholOgic findings in 50 insect-sting fatalities. J. Allergy, 40:107, 1967. 4. Barnard, J. H.: Severe, hidden, delayed reactions from insect stings. N.Y. State J. Med., 66: 1206, 1966.
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5. Barr, S. K: Allergy to insect stings: Clinical and laboratory studies. Med. Ann. D.C., 36:395, 1967. 6. Benson, R L., and Semenov, H.: Allergy in its relation to bee sting. J. Allergy, 1:105, 1930. 7. Bernton, H. S., and Brown, H.: Studies on the Hymenoptera: Skin reactions of normal persons to honeybee. J. Allergy, 36:315, 1965. 8. Blum, M. S., and Callahan, P. S.: Chemical and biological properties of the venom of the imported fire ant (Solenopsis saevissima var. richteri Forel) and the isolation of the insecticidal component. Proc. 11th Int. Congr. Ent., 3:290, 1960. 9. Blum, M. S., Walker, J. R, Callahan, P. S., and Novak, A. F.: Chemical, insecticidal and antibiotic properties of fire ant venom. Science, 128:306, 1958. 10. Blum, M. S., personal communication. 11. Bowen, R: Insects and allergic problems. South. Med. J., 44:836, 1951. 12. Brock, T.: Resume of insect allergy. Ann. Allergy, 19:288, 1961. 13. Brown, H., Bernton, H. S., and Stauch, J. K: Allergy to the Hymenoptera: Precipitins in human sera and their relation to "desensitization." Presented at the Fifth International Congress of Allergology in Madrid, Spain, October 1964. 14. Burke, D. M., and Jellinek, H. L.: Nearly fatal case of Schoenlein-Henoch syndrome follOwing insect bite. Amer. J. Dis. Child., 88:772, 1954. 15. Caro, M. R, Derbes, V. J., and Jung, R: Skin responses to the sting of the imported fire ant (Solenopsis saevissima). Arch. Derm., 75:475, 1957. 16. Ellis, R. V., and Ahrens, H. F.: Hypersensitiveness to airborne bee allergen. J. Allergy, 3:247, 1932. 17. Feinberg, A. R, Feinberg, S. M., and Benaim-Pinto, C.: Asthma and rhiniti~ from insect allergens. I. Clinical importance. J. Allergy, 27:437, 1956. 18. Feingold, B. F., and Benjamini, K: Allergy to flea bites. Clinical and experi mental observations. Ann. Allergy, 19: 1275, 1961. 19. Fogel, B. J., Weinberg, T., and Markowitz, M.: A fatal connective tissue disease following a wasp sting. Amer. J. Dis. Child., 114:325, 1967. 20. Foubert, K L., and Stier, R A.: Antigenic relationships between honeybees, wasps, yellow hornets, black hornets, and yellow jackets. J. Allergy, 29:13,1958. 21. Frazier, C. A.: Allergic reactions to stings of insects. In Conn, H. F., ed.: Current Therapy, Philadelphia, W. B. Saunders Co., 1966, pp. 465-468. 22. Frazier, C. A.: Insect sting allergy and its management. W. Virginia Med. J., 62:99, 1966. 23. Frazier, C. A.: Insect sting reactions in children. Ann. Allergy, 23:37, 1965. 24. Frazier, C. A.: Insect sting reactions in children-character, recognition, therapy. CIin. Pediat., 15:463, 1966. . 25. Friedman, K A., Jr., and Mascia, A. V.: The treatment of insect sting in children with Allpyral. Ann. Allergy, 26:430, 1968. 26. Houser, D. D., and Caplin, I.: Insect sting allergy. A clinical review. Amer. J. Dis. Child., 113:498, 1967. 27. Insect Allergy Committee of the American Academy of Allergy: Insect-sting allergy. Questionnaire study of 2606 cases. J.A.M.A., 193:115, 1965. 28. Insect Allergy Committee of the American Academy of Allergy: Unpublished studies for 1967 and 1968. Permission granted by P. J. Torsney, M. D., committee chairman, for use of this material. 29. Johnson, R. B., and Halpern, S. R: Reactions to insect bites. Cutis, 2:311, 1966. 30. Kennedy, C. B.: Insect stings and bites: Diagnosis, treatment, and prevention. Postgrad. Med., 37:193, 1965. 31. LanglOis, C., Shulman, S., and Arbesman, C. K: The allergic response to stinging insects. II. Immunological studies of human sera from allergic individuals. J. Allergy, 36: 12, 1965. 32. Langlois, C., Shulman, S., and Arbesman, C. K: The allergic response to stinging insects. III. The specificity of venom sac antigens. J. Allergy, 36:109, 1965. 33. Loveless, M. H.: Immunization with native, incriminated wasp venom in sting allergy: Twelve-year study of safety and effectiveness of a single visit, yearly course. Fed. Proc., 27:368, 1968 (abstract). 34. Loveless, M. H., and Fackler, W. R: Wasp venom allergy and immunity. Ann. Allergy, 14:347, 1956.
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35. Loveless, M. H., and NaIl, T. M.: Use of Polistes venom in petrolatum: Arlacel repositories to immunize against yellow jacket wasp-sting allergy. J. Immun., 94:785, 1965. 36. Mayer, L. D.: Allergic reactions to insect stings. J. Kentucky Med. Assn., 65:668, 1967. 37. McCormick, W. F.: Fatal anaphylactic reactions to wasp stings. A review, with immunologic studies of a fatal case. Amer. J. Clin. Path., 39:485, 1963. 38. Morse, R. A., and Ghent, R. L.: Protective measures against stinging insects. New York J. Med., 59:1546, 1951. 39. Mueller, H. L.: Diagnosis and treatment of insect sensitivity. J. Asthma Res., 3: 331, 1966. 40. Mueller, H. L., in M. Samter, et al.: Immunological Diseases. Boston, Little, Brown & Co., 1965, p. 682. 41. Mueller, H. L.: Insect allergy. PEDIAT. CLIN. N. AMER., 6:917, 1959. 42. Mueller, H. L.: Serial intracutaneous testing for bee and wasp sensitivity. J. Allergy, 30:123, 1959. 43. O'Connor, R., and Erickson, R.: Hymenoptera antigens: An immunological comparison of venoms, venom sac extracts, and whole insect extracts. Ann. Allergy, 23: 151, 1965. 44. O'Connor, R., Stier, R. A., Rosenbrook, W., Jr., and Erickson, R. W.: Death from "wasp" sting. Ann. Allergy, 22:385, 1964. 45. Parrish, H. M.: Analysis of 460 fatalities from venomous animals in the United States. Amer. J. Med. Sci., 245:129, 1963. 46. Peck, G. A.: Insect sting anaphylaxis. Calif. Med., 99:166, 1963. 47. Perlman, F.: Insects as inhalant allergens. l Allergy, 29:302, 1958. 48. Perlman, F.: Treatment for severe reactions to bites and stings of arthropods. Med. Times, 90:813, 1962. 49. Prince, H. E.: Desensitization with emulsified insect allergens. Texas Med., 64: 38, 1968. 50. Randolph, H.: Allergic response to dust of insect origin. J.A.M.A., 103:560, 1934. 51. Schwartz, H. J.: Skin sensitivity in insect allergy. J.A.M.A., 194:703, 1965. 52. Shaffer, J. H.: Hyposensitization with insect extracts (answer to query in Questions and Answers). J.A.M.A., 187:968, 1964. 53. Shaffer, J. H.: Stinging insects-a threat to life. lA.M.A., 177:473, 1961. 54. Shannon, W. R.: Thiamin chloride-an aid in the solution of the mosquito problem. Minn. Med., 26:799, 1943. 55. Siegel, J. M., Brown, H. E., and DiLeo, L. W.: Purpura as a result of insect allergy: Treatment with cortisone. Postgrad. M.J., 15:46, 1954. 56. Smith, C. N. et al.: U.S. Department of Agriculture, Pub. ARS-33-26, 1960. 57. Swinny, B.: Allergy to insect stings. In Speer, F., ed.: The Allergic Child. New York, Hoeber Medical Division, Harper & Row, 1963. 58. Swinny, B.: Severe reactions from insect stings. Texas State M.J., 46:639, 1950. 59. Terr, A. I., and McLean, J. A.: Studies on insect sting hypersensitivity: I. Precipitin-in-gel tests and passive cutaneous anaphylaxis. J. Allergy, 35:127, 1964. 60. Thomas, J. W.: Allergic reactions following insect bites and stings and their management. W. Virginia Med. J., 55:115, 1959. 61. Thomas, J. W.: Insect allergy prophylaxis and emergency treatment. New Physician, 12:270, 1963. 62. Vanselow, N. A.: Hypersensitivity to Hymenoptera insects. l Arkansas Med. Soc., 63:428, 1967. 63. Wilson, C. S., Mathieson, D. R., and Jackowski, L. A.: Ingested thiamin chloride as a mosquito repellent. Science, 100:147, 1944. 64. Wiseman, R. D., Woodin, W. G., Miller, H. C., and Myers, M. A.: Insect allergy as a possible cause of inhalant sensitivity. J. Allergy, 30:191, 1959. Department of Pediatrics University of Miami School of Medicine P.O. Box 875 Miami, Florida 33152
B. MARKS, M.D.
<)
A pediatric colleague from San Salvador related this story concerning his wife: When she was about 5 years of age, while clasping the trunk of a tree, she was stung by a puss caterpillar. Shortly thereafter she developed marked iocal itching and intense edema of her right forearm. The itching and swelling subsided after a few hours with the use of cold compresses. Several years later, at the age of 12 years, she was stung on the top of her head by a honeybee. She reacted with marked pain, itching, and local swelling of her entire scalp. The swelling extended into her forehead and the nape of her neck. Marked periorbital edema was present; her palpebral apertures were mere slits. Cold compresses and antihistamines brought about complete resolution after about 4 days. There were no untoward sequelae. The doctor, newly graduated, was assigned to practice in a primitive country district in El Salvador as part of his medical training program. He had recently married and had taken his wife, about 20 years of age, to reside in an adobe farmhouse. One evening she was bitten on the lip by a cone-nosed bug, Triatoma megista. (This insect is often called the "kissing bug" because of its propensity for biting in or near the mucocutaneous junction or vermilion border.) Within minutes the young woman developed flushing and generalized itching, angioedema of the lips, periorbital areas, and ears, generalized urticaria, laryngospasm, and constriction of the chest, lapsing into syncope and shock. Her systolic pressure was under 80 mm. Her husband gave her repeated injections of epinephrine, intravenous diphenhydramine (Benadryl), and intramuscular corticosteroids. This therapeutic regimen saved her, he believed, from certain death. The Triatome bug, which is one of the main vectors of American trypanosomiasis (Chagas' disease), abounds in the cracks of rural mud dwellings in his country, hiding away in the daytime and coming out at night to bite and feed. It is possible that the doctor's wife had been previously bitten by Triatoma megista without being aware of it; or some common antigenic determinant from the previous insect stings had sensitized her. Later studies failed to show any evidence of trypanosomiasis infection.
The foregoing account is not typical, in that the majority of severe reactions to stinging insects in adult life may be traced to initial and subsequent stings of the Hymenoptera order (bees, wasps, yellowjackets, and hornets) in childhood. In fact, 65 per cent of persons once sensitized " Clinical Associate Professor of Pediatrics, University of Miami School of Medicine, Miami; Director, Pediatric Allergy Clinic, Jackson Memorial Hospital, Miami; and Consulting Pediatric Allergist, Mount Sinai Hospital, Miami Beach, Florida.
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Table 1.
*
CLASS ARACHNIDA
ORDER
ORDER
ORDER
ORDER
ORDER
ORDER
HYMENOPTERA
lEPIDOPTERA
DIPTERA
SIPHONAPTERA
HEMIPTERA
ARANEIDA
I I
I
WASP
I I I
I
'STINGING CATERPillARS
MOSQUITO
Puss
SAND flY
Soddlebod
VEllOW JACKET
I
I
TRIATOME or KISSING BUG" (Conenosel
FLEA
I
10 Moth Hog Moth
MARKS
Phylum Arthropoda
CLASS INSECT A
BE,
B.
I
I
SP1DER
ORDER
ORDER
SCORPIONIDA 1 ACARINA
I
SCORPION
Block Widow Brown Recluse
I I
MITE
TICK
I
ASSASSIN BUG
DEERFLY
\ BfDBUG
HORNET
fiRE ANT
to these insect stings, when re-stung, develop increasingly marked reactions. 26 The phylum Arthropoda includes more species than all of the other phyla of the animal kingdom together. Table 1 depicts several
*
Honeybee (A pis mellifera)
Wasp (Polistesl
A. Or,ly Hymenopterous insect losing stinger.
A. Slender,spindie-shaped body with elongated waist.
B. Me,s! common stinging insect.
B. Habitat: Found under eaves of roof in sheltered places or behind shutters. Circulor,honeycolTlb-type nest of paper cells.
C. FrEquents clover(in lawns and meadows), D. Hobitat: Hollows of dead trees;man-made hives.
Yellow Jacket (Vespula vulgaris)
Hornet (Vespula maculata or Vespa crabo germano)
A. Next most common stinging insect.
A. Narrow waist with squat,compact body (some body contour
B. Smaller than honeybee. C. Has narrow waist with blunt,truncated body. D. Habitat: Usually in ground under old lumber and logs and rocks. Nests are round and paper-like, often containing several hundred insects.
as yellow jacket only larger). B. Habitat: Large,round paper-like,pear-shaped hives in trees or bushes.
Figure 1.
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orders in this phylum capable of causing serious local and constitutional reactions in man. The familiar hymenoptera, the largest and most specialized order of insects, produce the greatest morbidity and mortality. Most stings are caused by the social and not by the solitary species. The principal offenders are the honeybee, paper wasp, yellowjacket, and hornet (Fig. 1). They are the only insect group for which an effective control, that of hyposensitization, is available. Some degree of success has been attained with hyposensitization for mosquito, flea, and deerfly allergy. Hymenopterous insects killed 229 persons during a 10-year period ending in 1959. 45 Bees were responsible for most of the deaths in this study, numbering 124; wasps were next with 69; yellowjackets followed with 22; hornets with 10; and fire ants with 4 deaths. The interval between sting and death recorded in 208 of the 229 fatalities was less than an hourI These catastrophes have occurred in a wide variety of age groups, although the highest incidence was noted in both sexes after the age of 25 years. 3 , 27
PEDIATRIC AGE INCIDENCE
According to a recent cooperative study on stinging insect allergy,27 15 per cent of 2606 persons tabulated with severe reactions were in the age group ranging from 1 to 20 years. Barr5 reported on 82 patients who had suffered hymenoptera stings; the median age was 11 Y2 years, and there were 54 male and 28 female patients. Frazier,24 reviewing his 78 pediatric patients, found that 37 per cent were children 5 to 8 years of age. He also found that insect stings occurred in boys about twice as frequently as in girls. The peak incidence of insect stings occurs during the summer months, usually during July and August. In tropical and subtropical climates, persons may receive insect stings the year round. In children, stings are more frequent on the extremities, but may occur anywhere on the exposed body.
SYMPTOM COMPLEXES
Allergic manifestations to stings vary in children as they do in adults. In most children stung by hymenoptera, the immediate local reaction is severe swelling at the site of the sting, which may last for hours to several days. Repeated stings may cause a diminution of the response from naturally acquired immunity, or, on the other hand, increasing sensitization. It is difficult to predict how patients will react to subsequent stings once an allergic state has been induced.
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Some children have a serum sickness, delayed type of reaction following an insect sting, consisting of swelling at the site of the sting for 24 hours or more with generalized urticaria, angioedema, and, at times, arthralgia. Of the immediate systemic reactions seen in children, the moderate, general type is the rule. 41 These manifestations consist of generalized Hushing, itching, and urticaria; angioedema of the eyelids, lips, cheeks, ears, hands, and feet; allergic edema of the tongue, larynx, trachea, and bronchial tree; and with mild chest constriction and respiratory difficulty. Fortunately, severe, general anaphylactic reactions with hypotension, tachycardia, profuse sweating, nausea, vomiting, vertigo, and shock are seen infrequently in childhood. Since children and their parents may fail to associate current symptoms with a delayed type of insect reaction, it is important to ascertain whether a sting occurred several days before. Barnard4 stated that delayed allergic reactions to insect stings may be serious and even fatal. Fogel19 and associates cited the development of a fatal connective tissue disease which may have occurred after a wasp sting on the foot of a 12-year-old boy 19 days before admission to the hospital. Burke and Jellinek14 reported the onset of a nearly fatal case of SchonleinHenoch syndrome in a 4-year-old girl after a sting on the ankle by either a deerHy or a wasp 7 days previously. Siegel and colleagues55 detailed severe anaphylactoid purpura of the nonthrombocytopenic Schonlein-Henoch type in a child 3 years of age who developed, in addition, urticarial and visceral manifestations from repeated mosquito bites 2 weeks before being hospitalized. Feingold and BenjaminP8 disclosed that patients developed delayed local reactions to Hea bites even without preceding wheal formation where sensitization previously existed. Bowenl l related the death of a 3-year-old boy from several fire ant stings; he had previously been stung and perhaps sensitized by them. Serious constitutional allergic reactions were reported from fire ant stings by Caro et aP5 These workers stated that reactions to the stings of the fire ant are both local and systemic. The local changes suggest that a powerful necrotizing toxin of unknown nature is responsible, but this is unlikely to be formic acid. In this connection, Blum and associates8. 9 disclosed that the venom of the fire ant is the only hymenopterous venom known to be nonproteinaceous. Thus sensitization to fire ant venom may result even in the absence of proteinaceous substrates. They stated that the venom of the fire ant is necrotic, hemolytic, antibiotic, and fungicidal as well as insecticidal. The necrotic pustule forming at the sting site is characteristic of no other hymenopterous venom. The disfiguring scars which often result from fire ant stings become discolored and persist for years. Blum10 knew of two authenticated cases of anaphylactic reactions to fire ant stings. Barnard,3 in a later report on 50 hymenopterous insect sting fatalities,
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stated that the most common lesion in 35 subjects (70 per cent) was that of angioedema with respiratory obstruction. Thirty of these patients died within 6 hours of their stings, but others had delayed reactions with fatalities several days later. Fifteen of the 50 patients died from anaphylactic, vascular, and cerebral reactions. Immediate, fatal reactions were caused mainly from wasp stings, followed by bees, and then by yellowjackets. The last caused the slowest reactions with the fewest fatalities. Stings on the neck may have been responsible for more fatal reactions in the first 30 minutes than stings elsewhere on the body. Of the 50 fatal subjects cited, five were in the age group of 1 to 25 years.
IMMUNOLOGIC CONSIDERATIONS
Rabbits were immunized by Foubert and Stier20 to the pulped bodies of hymenoptera and demonstrated high precipitin titers. Gel diffusion studies showed that honeybee, wasp (Polistes), yellowjacket, and hornet contained common antigens which were probably immunologically identical. They also found that each insect had several antigens specific to its own genus. Barr5 showed that a rabbit hypersensitized to the four hymenoptera gave both Ouchterlony precipitin bands and positive passive cutaneous anaphylactic reactions to honeybee, wasp, and hornet, with some precipitin bands common to more than one insect. He was, however, unable to show either a positive precipitin band or PCA test for yellowjacket antigen. McCormick37 first found precipitins in the postmortem serum of a person who had died shortly after being stung by a Polistes wasp. Brown13 and colleagues demonstrated precipitin bands to various hymenoptera in a number of human sera by the Ouchterlony technique. Loveless 33 , 35 believed that immunization should be carried out with a course of venom extracts only. She reported greatly reduced reactions to deliberate as well as accidental stings. In contrast to the administration of whole-body extracts, reactions to the venom preparations were nil or trivial. However, studies by many workers 1, 2, 31,32,43 revealed that some antigens may be common to the body, to the sting sac, and to the venom itself. Many investigators5, 20,34, 59 have found some antigens specific to one type of insect and others common to several types. Thus the sting of a single insect may sensitize an individual to the entire hymenoptera group.26, 29, 57 At present the use of venom extracts is experimental, and only whole-body insect allergens are available commercially. They are made up as individual or polyvalent mixtures of the four common hymenoptera insects. Barr5 noted that 69 out of 82 previously stung patients tested intradermally reacted to two or more insect antigens. In only nine of the patients did the skin test correlate with the description of the stinging
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insect. One, a boy, had a constitutional reaction to skin testing. This youngster, when initially stung, exhibited only a large local reaction.
DIFFERENTIAL DIAGNOSIS
Most children, and their parents if present, are often unable to identify the stinging insect. Brock12 stated that most hymenopterous insects cannot be distinguished by their size or color, but only by their shape or habitat. Mueller39 emphasized that actual identification is unreliable and that treatment should be directed against all four types of stinging insects. Many commercial laboratories will supply the physician with charts depicting the hymenoptera group in their natural colors, which will often help in the identification of the offending insect. Additional colored photographs or drawings of troublesome nonhymenopterous insects indigenous to certain geographic areas should also be displayed. In the honeybee, when the barbed stinger is embedded in the flesh, the contractions of the venom sac not only cause deeper penetration of the stinger, but a greater outpouring of venom. 22 The bee, in escaping, loses its stinging apparatus and dies. The wasp stinger, however, is not barbed; the insect can return to sting the patient again and again, particularly when it is agitated. Following a hymenoptera sting, the initial pain radiating along the nerves from the site is usually a toxic, nonallergic reaction from the injected venom. 30 , 52, 60 Since the venom contains antigenic components, immediate or delayed hypersensitivity responses may ensue, depending upon the sensitized state of the individual. Swelling of an extremity after an insect sting extending beyond two nonadjacent limb joints indicates allergy and the need for specific treatment. 5 Houser and Caplin26 stated that it is often impossible to differentiate between toxic and allergic reactions to insect venom. When local or generalized urticaria, angioedema, dizziness, headache, fever, muscle spasms, and sometimes seizures occur, one may be dealing with a toxic reaction, particularly when multiple stings have occurred. Giddiness, hyperventilation, gastrointestinal symptoms, and syncope from fright may occur. One must agree with their conclusions that, when in doubt, one should treat the patient immediately as if an allergic reaction had occurred, with subsequent management to prevent future catastrophic, constitutional effects. The stings of mosquitoes and fleas in certain persons may produce an allergic response with local swelling and mild, constitutional symptoms; but severe, general reactions are unusual. In some children, flea bites may cause papular urticaria associated with a delayed type of immune response. 1S Intense itching with excoriation and secondary in-
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fection may occur. Contact with pets infested with fleas is the usual predisposing factor. Urticaria from food allergy should be excluded by history and by configuration and location of the individual or grouped lesions. Bedbug bites must also be considered. Although members of the class Arachnida causing bites or stings are often considered true insects, such is not the case. They rarely produce hypersensitivity reactions, but cause severe, local necrosis and neurotoxic, constitutional effects. This is true of the black widow and brown recluse spiders and scorpions. Sensitivity to avian mites occurs with papular lesions in some persons in close contact with pet birds.
DISCUSSION
In an earlier questionnaire study27 under the auspices of the Insect Allergy Committee of the American Academy of Allergy, it was shown that only about 27 per cent of persons hypersensitive to insect stings had an atopic history. Thus severe and even fatal reactions may occur in nonatopic persons. Barnard,3 however, in his study of fatal responses to hymenoptera stings, revealed an incidence of 72 per cent with positive histories of allergy. The possibility that moderate or severe general reactions to insect stings in persons who have never been stung before might be due to previous, repeated sensitization by inhalation of insect dust has been suggested. 36 ,46 Much has been written on insects as inhalant allergens. 6, 16, 17, 50, 64 The fact that about 50 per cent of 630 persons who suffered severe, systemic reactions to hymenoptera stings recalled no earlier sting, or at most, only a minor, local reaction,27 may reflect this inhalant sensitization concept. Unpubished studies of the Insect Allergy Committee of the American Academy of Allergy for 1967 and 196828 reveal that approximately 90 per cent of hyposensitized patients still under treatment showed less reaction following subsequent hymenoptera stings; slightly over 80 per cent of hyposensitized patients who had discontinued treatment reacted less severely; and, surprisingly, 68.8 per cent (in 1968) of nonhyposensitized patients were not as reactive as previously. This latter, untreated group is of interest because, since 1964, when improvement in reactivity to stings was as low as 39 per cent, there has been a rising trend of improvement annually to the present level. This may be attributed to the use of symptomatic medication, particularly epinephrine, immediately after an insect sting, with decrease in the sensitivity of these patients. It was at first thought that there might be diminution of the clinical sensitivity in this group as the time interval between stings increased, but close scrutiny of the available data did not support this view. In both 1967 and 1968, most patients enjoyed long-lasting protection
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after hyposensitization was stopped. The data indicated that immunity continued for 5 years. Patients who were stung within a year of hyposensitization therapy did poorer than those who were stung after a year. Eleven patients reported that because of the increased severity of reaction to stings, they had again started hyposensitization therapy. Of these eleven, two were re-stung and claimed less severe reactions. Five of 38 patients who reported worse reactions had been on emulsion therapy. Although immunity to stinging insects is marked following the recommended hyposensitization program, most members of the Subcommittee on Prolonged Therapy concluded that, for the present, patients should receive booster doses on an average of every 3 or 4 months until more information becomes available. This should offer protection to the small group of persons who lose their immunity shortly after discontinuance of supposedly adequate hyposensitization. There have been reports of fatalities from insect stings after cessation of hyposensitization. H , 58 Prince 49 stated that severe, persistent, local reactions from stings in patients undergoing hyposensitization could represent a serum sickness type of delayed response. This type of reaction, he believed, would not respond to any prophylactic injection program.
SKIN TESTING
Although most commercial laboratories that process intradermal testing kits composed of individual or polyvalent mixtures of whole-body extracts containing the four common hymenoptera recommend skin testing beginning with a 1:1 million dilution, this dose may invite severe general reactions in some highly sensitive persons. 60 ,61 Mueller3 9 ,41 discussed two children who had severe constitutional reactions with this dilution and mentioned a child who had a mild systemic reaction with itching and urticaria with a dilution of 1: 100 million I I have found it expedient to begin intradermal skin 'testing with a 1:100 million dilution of the whole-body polyvalent extract. I have never encountered untoward reactions to this dilution. Serial intracutaneous testing is then carried out to determine the dilution necessary to begin treatment, so that unnecessary injections may be eliminated in attaining the maintenance dose. 42 Rarely, however, is treatment started under a dilution of 1: 100,000. Schwartz's experience51 with serial intracutaneous skin testing in an insect sting-sensitive group was somewhat different, revealing positive tests in much lower dilutions. Even persons with histories of life-threatening sting experiences reacted only to dilutions no greater than 1:10,000. No more than 0.02 ml. is injected intradermally to raise a wheal. All tests are then read in 20 minutes. Skin testing by the scratch technique is also done, but with a 1:10 dilution, using individual extracts of honeybee, wasp (Polistes), hornet, and yellowjacket, prior to intracu-
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taneous testing. This is performed for two reasons: (1) to attempt to correlate the individual stinging insect with the clinical history; and (2) to determine the reactivity of the patient. A refractory period may occur after an insect sting; it is therefore best to wait at least 2 weeks after the sting to commence skin testing. 53 Saline dilutions of the intracutaneous skin testing materials should be made fresh at least every 12 weeks and kept refrigerated; they may lose their potency after this period. Schwartz51 concurred with Bernton and colleagues 7 that it was not uncommon to find positive skin tests in patients without clinical sensitivity to insect stings. It may be that nonspecific irritants or histaminereleasing substances present in the whole-body insect extracts produce the positive skin tests. The clinical history remains the all-important factor in the diagnosis of stinging insect allergy.
TREATMENT
Emergency Procedures Since it is unlikely that a physician will be available to the patient during the first few minutes after the sting occurs, it is during this period that the child, if old enough, or the parents, should use methods taught by their physician to prevent the onset of life-threatening, generalized reactions. After these measures have been carried out, prompt medical attention should be sought at the nearest hospital or physician's office. The sensitized person should always carry with him an insect sting first aid kitll> containing a preloaded, sterile syringe of epinephrine hydrochloride 1: 1000, an ephedrine sulfate tablet, an antihistamine, and a tourniquet. The syringe containing the epinephrine must be examined frequently to determine whether the solution has turned brown, which is an indication that the epinephrine has become oxidized and useless. Extra, individually packaged, prefilled, disposable syringes of epinephrine hydrochloride 1:1000 are available and should be kept in the refrigerator at all times for replacement purposes in the kit when necessary. A Medihaler-Epi (Riker) should always be carried by the person who is sting-sensitive. It affords additional protection and may be used alone for mild reactions and in combination with the injection of epinephrine when a severe constitutional reaction ensues. A tourniquet should be applied proximal to the site of the sting if on an extremity and the epinephrine injected deep subcutaneously above the tourniquet or into another limb. The application of the tourniquet serves to slow down the absorptive rate of the venom. It should be loosened from time to time so as to prevent permanent or serious circulatory changes in the distal extremities. The tourniquet should be used as long as even mild constitutional symptoms are evident. II>
Center Laboratories, Port Washington, New York.
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The content of the emergency kit must be used promptly in re-stung patients exhibiting constitutional reactions who, although under hyposensitization, have not had a full year of treatment. Patients under hyposensitization for over 1 year, when re-stung, need receive no emergency measures, unless, for psychological reasons, one wishes the patient to take ephedrine or antihistamine tablets. Beta-adrenergic receptor agents, like sublingual isoproterenol tablets or isoproterenol aerosols, do not combat shock effectively. Reliance should be placed strictly on the use of epinephrine. After a sting by a honeybee, the stinger must be removed immediately by a quick flick of the fingernail, tweezer, or knife blade, care being used not to compress the venom sac to prevent more venom from entering the circulation. If only a local reaction with marked swelling results, early use of an ice pack and elevation of the limb are helpful. Spraying with dexamethasone topical aerosol (Decadron) relieves the pain and pruritus. Oral antihistamines, as well as analgesics, are indicated. The patient with a generalized reaction, who shows signs of anaphylaxis, impending or absolute, should promptly be given an injection of epinephrine hydrochloride 1: lOOO by the physician. Depending upon the age of the child, 0.2 to 0.5 ml. is injected deep subcutaneously and massaged vigorously into the tissues. In desperate situations, intravenous or intracardiac epinephrine may need to be administered. A 1:10,000 dilution is used to prevent cerebral vascular accidents or myocardial necrosis. An antihistamine is then injected intramuscularly or intravenously. Chlorpheniramine maleate (Chlor-Trimeton), 100 mg. per ml., 0.1 to 0.25 ml.; diphenhydramine hydrochloride (Benadryl), 50 mg. per ml., 0.5 to 1.0 ml.; and tripelennamine hydrochloride (Pyribenzamine), 25 mg. per ml., 0.5 to 1.0 ml., are all valuable antihistaminic adjuncts. For the prevention and treatment of delayed reactions, intramuscular corticosteroids should be used, but only as a third line of defense. Dexamethasone phosphate (Decadron), 4 to 8 mg., or betamethasone acetate (Celestone Soluspan), 6 to 12 mg., may be injected into the vastus lateralis or gluteus muscles. For unconsciousness and shock, an intravenous "cocktail" of 500 ml. 5 per cent dextrose in water, containing 100 mg. hydrocortisone (SoluCortef), aminophylline (for bronchospasm), 12 mg. per kg. per day, and an antihistamine, should be promptly administered. If a vasopressor is also indicated, levarterenol bitartrate (Levophed), 0.2 per cent, 2 ml., may be used; although I have found that epinephrine hydrochloride 1:lO00 exerts an excellent pressor effect as well as combatting shock when 0.5 ml. is added to the entire contents of the intravenous "cocktail." Oxygen and IPPB respirators, using racemic epinephrine (Vaponefrin), prevent hypoxemia and possible vascular and cerebral complications. Laryngeal obstruction may call for immediate tracheostomy, as fatalities have been known to occur from laryngospasm. 44 , 64
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An emergency identification tag should be carried at all times by a person sensitized to insect stings. Preventive Procedures Sting-sensitive persons should learn the haunts and habits of hymenoptera, thus minimizing their chances of being re-stung. They should avoid commercial beekeeping establishments, orchards, flowers, blooming trees, and shrubs. Insects are attracted to decorative, dark-colored, and rough-textured clothing. Sensitized children should wear garments of smooth-finished fabrics having neutral colors. Colors like white, green, tan, and khaki do not, as a rule, attract insects. 36 When playing out of doors, these children should wear clothes with long sleeves, long trousers, a cap or hat, and shoes. Frazier3 reported that of 24 children stung on the bare feet, 16 developed generalized reactions. Scented hair sprays, tonics or pomades, colognes, perfumes, and odoriferous lotions or powders may attract all forms of stinging insects. Precautionary measures like adequate screening of windows and doors, cleanliness about garbage receptacles, and avoidance of picnic areas, should be exercised. A sting-sensitive child must be relieved of gardening chores, particularly hedge-clipping. He should be cautioned against taking short cuts through hedges. Regular inspection of the premises is important. Hives and nests about the home should be destroyed. It might be well to employ a professional pest exterminator, since the danger of removing nests of the hymenoptera order by inexperienced persons may be great. Repellents for stinging insects have not proved efficacious.21 . 38, 48 However, the United States Department of Agriculture found the best all-purpose repellent yet developed to be N,N-diethyl-m-toluamide ("deet").56 The "deet" preparations are known commercially as Off!, McKesson Mosquitotone, and others. They can be purchased as liquids, foams, pressurized sprays, sticks, creams, and wipe-on tissues. An aerosol insecticide spray should always be present in the glove compartment of the automobile to be used in case of. entry of a stinging insect.s6 . 62 Oral thiamine hydrochloride was reported by Shannon54 as an effective repellent against most mosquitoes in 1943. Careful studies by Wilson and co-workers 63 a year later disproved this assertion. Perlman,48 however, stated that thiamine hydrochloride in doses of 50 mg., three times daily, prevented flea bites. Mueller4° found that 70 per cent of 100 insect-sensitive patients were seldom or never annoyed when a daily dose of 75 to 150 mg. of thiamine hydrochloride was taken. My own experience with the use of oral thiamine hydrochloride in the control of insect sensitivity to mosquitoes and sand flies has been equally good. Over 50 per cent of children displaying severe local responses to insect bites showed improvement with doses of 25 mg. three times daily. Perhaps a larger percentage of children would have responded if the dose
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of this innocuous vitamin preparation had been increased two or even threefold. Thiamine hydrochloride most likely acts to combine with the sensible and insensible perspiration of the host to repel insects by its odor. It would be of interest to explore a double-blind study with oral thiamine hydrochloride on sting-sensitive patients to note the incidence of hymenoptera re-stings in patients currently on hyposensitization, patients who have discontinued hyposensitization, and those who have never had any hyposensitization. Hyposensitization As stated earlier, the latest survey of the Insect Allergy Committee of the American Academy of Allergy showed that 90 per cent of stingsensitive patients, when placed on hyposensitization, described marked improvement in their reaction when re-stung.28 Houser and Caplin,26 in their review of the literature, were unable to find any reports of fatalities in re-stung patients while undergoing hyposensitization. If a child has responded with a generalized reaction to a hymenoptera sting, whether mild or severe, hyposensitization is mandatory. A history of repeated stings with progressively larger local reactions emphatically invites a program of hyposensitization. Severe local, delayed reactions, particularly with angioedema and generalized urticaria, place the patient in the same category. Polyvalent extracts of whole bodies of mixed bees, wasps, yellowjackets, and hornets are used. They are available from most commercial allergen laboratories. The starting dose is usually 0.05 m!. of a 1:1 million dilution, although in very sensitive persons the initial dose may be 0.05 m!. of a 1: 10 million or even a 1: 100 million dilution. Injections are increased by 0.05 m!. weekly until a volume and concentration of 0.50 m!. of 1:100 is reached, which becomes the maintenance dose. (Mueller39 computed this dose to be equivalent in antigenic activity to the venom of one to two stings.) Injections are then spaced at intervals of every 2 'weeks, every 3 weeks, and finally every 4 weeks. In the il1ithor's experience, this maintenance dose has offered patients excellent protection whenever re-stings occurred. Hyposensitization should be continued for a minimum of 3 years, with booster doses administered every 3 or 4 months thereafter. Though protection may persist for years in some persons following cessation of hyposensitization, contrariwise, it may be lost in less than a year in others; hence the necessity for long-term management. Friedman and Mascia 25 have reported on a 3-year study of 48 sting-sensitive children with generalized reactions who received Allpyral whole-body insect extracts containing the four common hymenoptera. They stated that 22 patients, or 46 per cent of their treated group, when re-stung, gave evidence of excellent protection. Future studies may assess the value of this therapeutic modality.
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Occasionally, severe local and constitutional reactions may be produced by hyposensitization. The injection schedule should then be carefully monitored by the physician and the next dose reduced by half or more, depending on the severity of the reaction. If no further reaction ensues, 0.02 ml. increments are used to rebuild the dosage level. Injections are never given in the buttocks. If a reaction occurs from accidental intravascular injection, a tourniquet is applied above the site of the injection and 0.20 to 0.30 ml. epinephrine hydrochloride 1: 1000 is injected into the other arm promptly and repeated if necessary. Sus-Phrine (Cooper), 0.10 to 0.15 ml., which has immediate and long-acting effects, is efficacious for reactions of this type.
SUMMARY Every physician should be acquainted with stinging insect hypersensitivity involving particularly the hymenoptera order, which includes bee, wasp, yellowjacket, and hornet. Stings from these insects are capable of inducing not qnly severe local and constitutional reactions, but, at times, even death. Hymenoptera rank highest in incidence of serious insect sting reactions in man. Stinging insect allergy in children is discussed as to etiology, occurrence, symptom complexes, differential diagnosis, immunologic considerations, and treatment involving emergent, preventive, and hyposensitization procedures. Emphasis is placed on the immediate management of sensitized persons following insect stings. Epinephrine and antihistaminic preparations should be used promptly in severe local and in all types of constitutional reactions. Since corticosteroids act slowly, they are administered last in the emergency therapeutic program. They are especially useful in delayed reactions, in sting-sensitive persons. A history of untoward reactions to stinging insects is of far greater importance than dependence on the results of skin tests. The immediate and subsequent management of the insect~sensitive patient should be based primarily on the history.
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to stinging insects. VII. Fractionation of whole body and venom sac extracts of yellow jacket. J. Allergy, 38:1, 1966. 2. Arbesman, C. E., Langlois, C., and Shulman, S.: The allergic response to stinging insects. IV. Cross-reactions between bee, wasp, and yellow jacket. J. Allergy, 36:147, 1965. 3. Barnard, J. H.: Allergic and patholOgic findings in 50 insect-sting fatalities. J. Allergy, 40:107, 1967. 4. Barnard, J. H.: Severe, hidden, delayed reactions from insect stings. N.Y. State J. Med., 66: 1206, 1966.
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5. Barr, S. K: Allergy to insect stings: Clinical and laboratory studies. Med. Ann. D.C., 36:395, 1967. 6. Benson, R L., and Semenov, H.: Allergy in its relation to bee sting. J. Allergy, 1:105, 1930. 7. Bernton, H. S., and Brown, H.: Studies on the Hymenoptera: Skin reactions of normal persons to honeybee. J. Allergy, 36:315, 1965. 8. Blum, M. S., and Callahan, P. S.: Chemical and biological properties of the venom of the imported fire ant (Solenopsis saevissima var. richteri Forel) and the isolation of the insecticidal component. Proc. 11th Int. Congr. Ent., 3:290, 1960. 9. Blum, M. S., Walker, J. R, Callahan, P. S., and Novak, A. F.: Chemical, insecticidal and antibiotic properties of fire ant venom. Science, 128:306, 1958. 10. Blum, M. S., personal communication. 11. Bowen, R: Insects and allergic problems. South. Med. J., 44:836, 1951. 12. Brock, T.: Resume of insect allergy. Ann. Allergy, 19:288, 1961. 13. Brown, H., Bernton, H. S., and Stauch, J. K: Allergy to the Hymenoptera: Precipitins in human sera and their relation to "desensitization." Presented at the Fifth International Congress of Allergology in Madrid, Spain, October 1964. 14. Burke, D. M., and Jellinek, H. L.: Nearly fatal case of Schoenlein-Henoch syndrome follOwing insect bite. Amer. J. Dis. Child., 88:772, 1954. 15. Caro, M. R, Derbes, V. J., and Jung, R: Skin responses to the sting of the imported fire ant (Solenopsis saevissima). Arch. Derm., 75:475, 1957. 16. Ellis, R. V., and Ahrens, H. F.: Hypersensitiveness to airborne bee allergen. J. Allergy, 3:247, 1932. 17. Feinberg, A. R, Feinberg, S. M., and Benaim-Pinto, C.: Asthma and rhiniti~ from insect allergens. I. Clinical importance. J. Allergy, 27:437, 1956. 18. Feingold, B. F., and Benjamini, K: Allergy to flea bites. Clinical and experi mental observations. Ann. Allergy, 19: 1275, 1961. 19. Fogel, B. J., Weinberg, T., and Markowitz, M.: A fatal connective tissue disease following a wasp sting. Amer. J. Dis. Child., 114:325, 1967. 20. Foubert, K L., and Stier, R A.: Antigenic relationships between honeybees, wasps, yellow hornets, black hornets, and yellow jackets. J. Allergy, 29:13,1958. 21. Frazier, C. A.: Allergic reactions to stings of insects. In Conn, H. F., ed.: Current Therapy, Philadelphia, W. B. Saunders Co., 1966, pp. 465-468. 22. Frazier, C. A.: Insect sting allergy and its management. W. Virginia Med. J., 62:99, 1966. 23. Frazier, C. A.: Insect sting reactions in children. Ann. Allergy, 23:37, 1965. 24. Frazier, C. A.: Insect sting reactions in children-character, recognition, therapy. CIin. Pediat., 15:463, 1966. . 25. Friedman, K A., Jr., and Mascia, A. V.: The treatment of insect sting in children with Allpyral. Ann. Allergy, 26:430, 1968. 26. Houser, D. D., and Caplin, I.: Insect sting allergy. A clinical review. Amer. J. Dis. Child., 113:498, 1967. 27. Insect Allergy Committee of the American Academy of Allergy: Insect-sting allergy. Questionnaire study of 2606 cases. J.A.M.A., 193:115, 1965. 28. Insect Allergy Committee of the American Academy of Allergy: Unpublished studies for 1967 and 1968. Permission granted by P. J. Torsney, M. D., committee chairman, for use of this material. 29. Johnson, R. B., and Halpern, S. R: Reactions to insect bites. Cutis, 2:311, 1966. 30. Kennedy, C. B.: Insect stings and bites: Diagnosis, treatment, and prevention. Postgrad. Med., 37:193, 1965. 31. LanglOis, C., Shulman, S., and Arbesman, C. K: The allergic response to stinging insects. II. Immunological studies of human sera from allergic individuals. J. Allergy, 36: 12, 1965. 32. Langlois, C., Shulman, S., and Arbesman, C. K: The allergic response to stinging insects. III. The specificity of venom sac antigens. J. Allergy, 36:109, 1965. 33. Loveless, M. H.: Immunization with native, incriminated wasp venom in sting allergy: Twelve-year study of safety and effectiveness of a single visit, yearly course. Fed. Proc., 27:368, 1968 (abstract). 34. Loveless, M. H., and Fackler, W. R: Wasp venom allergy and immunity. Ann. Allergy, 14:347, 1956.
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35. Loveless, M. H., and NaIl, T. M.: Use of Polistes venom in petrolatum: Arlacel repositories to immunize against yellow jacket wasp-sting allergy. J. Immun., 94:785, 1965. 36. Mayer, L. D.: Allergic reactions to insect stings. J. Kentucky Med. Assn., 65:668, 1967. 37. McCormick, W. F.: Fatal anaphylactic reactions to wasp stings. A review, with immunologic studies of a fatal case. Amer. J. Clin. Path., 39:485, 1963. 38. Morse, R. A., and Ghent, R. L.: Protective measures against stinging insects. New York J. Med., 59:1546, 1951. 39. Mueller, H. L.: Diagnosis and treatment of insect sensitivity. J. Asthma Res., 3: 331, 1966. 40. Mueller, H. L., in M. Samter, et al.: Immunological Diseases. Boston, Little, Brown & Co., 1965, p. 682. 41. Mueller, H. L.: Insect allergy. PEDIAT. CLIN. N. AMER., 6:917, 1959. 42. Mueller, H. L.: Serial intracutaneous testing for bee and wasp sensitivity. J. Allergy, 30:123, 1959. 43. O'Connor, R., and Erickson, R.: Hymenoptera antigens: An immunological comparison of venoms, venom sac extracts, and whole insect extracts. Ann. Allergy, 23: 151, 1965. 44. O'Connor, R., Stier, R. A., Rosenbrook, W., Jr., and Erickson, R. W.: Death from "wasp" sting. Ann. Allergy, 22:385, 1964. 45. Parrish, H. M.: Analysis of 460 fatalities from venomous animals in the United States. Amer. J. Med. Sci., 245:129, 1963. 46. Peck, G. A.: Insect sting anaphylaxis. Calif. Med., 99:166, 1963. 47. Perlman, F.: Insects as inhalant allergens. l Allergy, 29:302, 1958. 48. Perlman, F.: Treatment for severe reactions to bites and stings of arthropods. Med. Times, 90:813, 1962. 49. Prince, H. E.: Desensitization with emulsified insect allergens. Texas Med., 64: 38, 1968. 50. Randolph, H.: Allergic response to dust of insect origin. J.A.M.A., 103:560, 1934. 51. Schwartz, H. J.: Skin sensitivity in insect allergy. J.A.M.A., 194:703, 1965. 52. Shaffer, J. H.: Hyposensitization with insect extracts (answer to query in Questions and Answers). J.A.M.A., 187:968, 1964. 53. Shaffer, J. H.: Stinging insects-a threat to life. lA.M.A., 177:473, 1961. 54. Shannon, W. R.: Thiamin chloride-an aid in the solution of the mosquito problem. Minn. Med., 26:799, 1943. 55. Siegel, J. M., Brown, H. E., and DiLeo, L. W.: Purpura as a result of insect allergy: Treatment with cortisone. Postgrad. M.J., 15:46, 1954. 56. Smith, C. N. et al.: U.S. Department of Agriculture, Pub. ARS-33-26, 1960. 57. Swinny, B.: Allergy to insect stings. In Speer, F., ed.: The Allergic Child. New York, Hoeber Medical Division, Harper & Row, 1963. 58. Swinny, B.: Severe reactions from insect stings. Texas State M.J., 46:639, 1950. 59. Terr, A. I., and McLean, J. A.: Studies on insect sting hypersensitivity: I. Precipitin-in-gel tests and passive cutaneous anaphylaxis. J. Allergy, 35:127, 1964. 60. Thomas, J. W.: Allergic reactions following insect bites and stings and their management. W. Virginia Med. J., 55:115, 1959. 61. Thomas, J. W.: Insect allergy prophylaxis and emergency treatment. New Physician, 12:270, 1963. 62. Vanselow, N. A.: Hypersensitivity to Hymenoptera insects. l Arkansas Med. Soc., 63:428, 1967. 63. Wilson, C. S., Mathieson, D. R., and Jackowski, L. A.: Ingested thiamin chloride as a mosquito repellent. Science, 100:147, 1944. 64. Wiseman, R. D., Woodin, W. G., Miller, H. C., and Myers, M. A.: Insect allergy as a possible cause of inhalant sensitivity. J. Allergy, 30:191, 1959. Department of Pediatrics University of Miami School of Medicine P.O. Box 875 Miami, Florida 33152